Pediatric Endocrinology, Fourth Edition (Clinical Pediatrics, 9)

Citation preview

Pediatric Endocrinology FOURTH EDITION REVISED AND EXPANDED

EDITED BY

Fima Lifshitz Miami Children's Hospital, University of Miami School of Medicine State University of New York Health Science Center at Brooklyn Pediatric Sunshine Academics and Sansum Medical Research Institute

u MARCEL

MARCEL DEKKER, INC.

NEW YORK • BASEL

Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-0816-4 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright 䉷 2003 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

Clinical Pediatrics Series Editor

Fima Lifshitz Miami Children's Hospital University of Miami School of Medicine State University of New York Health Science Center at Brooklyn Pediatnc Sunshine Academics and Sansum Medical Research Institute

1. Common Pediatric Disorders: Metabolism, Heart Disease, Allergies, Substance Abuse, and Trauma, edited by Fima Lifshitz 2. Congenital Metabolic Diseases: Diagnosis and Treatment, edited by Raul A. Wapnir 3. Pediatric Endocrinology: A Clinical Guide, edited by Fima Lifshitz 4. Antimicrobial Therapy in Infants and Children, edited by Gideon Koren, Charles G. Prober, and Ronald Gold 5. Food Allergy: A Practical Approach to Diagnosis and Management, edited by Lawrence T. Chiaramonte, Arlene T. Schneider, and Fima Lifshitz 6. Metabolic Bone Disease in Children, edited by Salvador Castells and Laurence Finberg 7. Pediatric Endocrinology: A Clinical Guide, Second Edition, Revised and Expanded, edited by Fima Lifshitz 8. Pediatric Endocrinology: A Clinical Guide, Third Edition, Revised and Expanded, edited by Fima Lifshitz 9. Pediatric Endocrinology: Fourth Edition, Revised and Expanded, edited by Fima Lifshitz

Additional Volumes in Preparation

To the cycle of life, the new generation To my grandchildren, Jonah and Rebecca

About the Series

‘‘Clinical Pediatrics’’ is a series of books designed to continually update the knowledge of the practicing pediatrician in diverse areas of the specialty. Each volume in the series addresses rapidly developing topics that are changing the attitudes and treatment approaches of the clinician. The chapters comprising the volumes represent the state of the art on the various subjects from the vantage point of recognized experts in the field. The books already published in this series are Common Pediatric Disorders, Congenital Metabolic Diseases, Antimicrobial Therapy in Infants and Children, Food Allergy, Metabolic Bone Disease, and Pediatric Endocrinology. The first edition of the last book was published in 1985, the second edition in 1990, and the third edition in 1996. This book has become the most sought-after reference book in the field, making necessary an updated fourth edition. This fourth edition of Pediatric Endocrinology is the ninth book in the Clinical Pediatrics series. It is an updated, improved, and greatly expanded version, which covers the field in a comprehensive manner to update clinicians on the numerous recent advances in pediatric endocrinology. The most frequent encounters by pediatricians are covered and reviewed in a practical, patient-oriented, yet scientific style, making it an invaluable resource for pediatricians and specialists alike. These books serve as the foundation for the volumes that will follow, each complementing the others. Together, they will constitute a comprehensive review of the most recent developments in pediatrics. Fima Lifshitz

iv

Foreword

The fourth edition of Pediatric Endocrinology is designed according to the same concept as that of the first three, but it far exceeds the very significant accomplishments of the previous editions. The first three editions, each of which was more complete and broadly informative than the last, were written for a diversified audience of general pediatricians, pediatric endocrinologists, geneticists, and others. Each of these texts became the most used and sought-after in the field in the United States and throughout the world. Pediatric Endocrinology became established as the most respected book on the subject, dating back to the publication of the first edition in 1985. A review of the content of this, the fourth edition, reveals an even more improved text. Each chapter is written by highly respected clinicians who are also investigators in the topics covered. The book has a very practical clinical approach, yet it provides comprehensive coverage of all the major endocrine glands and diseases. The content of each of the various chapters is fully inclusive, which augments the value of the presentation of each subject. The balance between the clinical material and the physiology, physiopathophysiology, and treatment information is ideal. The review of each topic is as updated as is feasible in constructing a book of this magnitude. Readers and users of this text will be pleased and appreciative of the effort and successful accomplishment of Dr. Lifshitz and his colleagues who edited and authored this fourth edition. Dr. Lifshitz has again demonstrated his insight and capability as an accomplished educator for students at all levels. Congratulations on this contribution, a legacy to pediatric endocrinology! Robert M. Blizzard, M.D. Professor and Chairman Emeritus The University of Virginia School of Medicine Charlottesville, Virginia, U.S.A.

As the number of pediatric endocrinologists continues to grow worldwide, so does the scope of the field. The spectrum of pediatric endocrinology has expanded to encompass genetics, nutrition, immunology, biochemistry, and psychology. In addition, the explosive increase in numbers of patients seen in today’s pediatric endocrine clinics reflects the heightened awareness of the role of hormones in health and disease in children. Molecular genetic studies completed since the last edition of the book have further elucidated the etiology of many endocrine and metabolic disorders. These new studies have been incorporated into the chapters of the fourth edition, edited by our friend and colleague, Dr. Fima Lifshitz. New chapters have been added to this edition, while existing chapters have been updated, creating a thorough yet succinct book. I would like to congratulate Dr. Lifshitz who, again, has assembled the foremost specialists in all areas of pediatric endocrinology to create this book, which has become indispensable to pediatric clinicians and researchers alike. Maria I. New, M.D. Weill Medical College of Cornell University New York Presbyterian Hospital New York, New York, U.S.A.

v

Preface The more you practice what you know, the more you know what to practice. W. Jenkins

The fourth edition of Pediatric Endocrinology is a comprehensive book in the field designed to meet the needs of the practicing physician, yet it is written at a level suitable for the subspecialist. The 43 chapters of this book are completely updated and the information contained provides state-of-the-art knowledge in all areas of the specialty. There have been multiple changes in the field since 1985 when the first edition was published. The most important advances were incorporated into the previous editions and were brought to the clinicians in didactic, practical chapters. Each contained comprehensive discussions addressing all clinical situations encountered in the practice of this subspecialty. The fourth edition of Pediatric Endocrinology constitutes the culmination of the experience and accomplishments reflected in previous editions. It is a mature, seasoned book that reflects the continuous growth and accumulated wisdom of the 63 contributors. Their knowledge is eloquently transmitted in each chapter. As in previous editions, the book is divided into seven parts, each dealing with a major area of childhood endocrinology: ‘‘Growth and Growth Disorders,’’ ‘‘Adrenal Disorders and Sexual Development Abnormalities,’’ ‘‘Thyroid Disorders,’’ ‘‘Disorders of Calcium and Phosphorus Metabolism,’’ ‘‘Hypoglycemia and Diabetes Mellitus’’ and ‘‘Miscellaneous Disorders.’’ The final part includes an updated chapter on dynamic tests used by pediatric endocrinologists, as well as one with a more complete collection of newer and updated reference charts and tables utilized to assess patients with growth disorders and endocrine alterations. Additionally, there are two new chapters of current interest; one on reimbursement issues with a coding supplement, and another on using the Web to obtain information on genetic and hormone disorders. These should make it easier for the busy practitioner to care for children with pediatric endocrine disorders. Also included are new conceptual chapters on major topics in the field not covered in previous editions, i.e., worrisome growth, multiple endocrine neoplasia syndromes, hyperlipoproteinemias, hypertension, and supplements to enhance athletic performance. Each of the 43 chapters of this book contains sufficient material to cover the topic in its entirety and impart new information to enhance the knowledge of the practitioner and the subspecialist. It provides the reader with the most updated and pertinent information to address questions asked in the care of patients with endocrine and endocrine-related disorders. From pathophysiology to treatment, there is a succinct and clear description of the subject in each chapter. The book fully encompasses the daily problems seen in pediatric endocrine practices. The field of pediatric endocrinology has rapidly advanced and changed very significantly in many aspects, not only in medical knowledge and the scientific basis of endocrinology. The practice of the specialty has also evolved and changed radically, together with changes brought about by ‘‘managed health care.’’ It has changed the way we care for our patients and the way we practice our specialty, as well as many other aspects of our practice. Not all of these changes have been positive. One of the most significant casualties has been the transmission of the knowledge accumulated by prominent academic pediatric endocrinologists. As the editor of this book I experienced first-hand this sad state of affairs. Since the last edition was published in 1996, the support for teaching endeavors in many institutions has virtually vanished, and the academic pediatric endocrinologist is now an endangered species. Many of our colleagues have moved to other areas and away from clinical academic practices, and those who stayed work on a battlefront and have no time to invest in teaching endeavors. Those who contributed to this book did so on their own time, often against the implicit wishes and mandates of administration. The current constraints of the health care system have also taken a toll in academic programs. It praises productivity in other areas, not in teaching, nor in writing and transmitting knowledge through a chapter in a book. Even secretarial support was often not available to some contributors for this activity. Thus, I am particularly and evermore grateful to my colleagues who revised and updated their chapters, and to those who provided new sections for this book. They all made very significant contributions, which continue to make this book a most valuable and necessary tool for pediatricians and pediatric endocrinologists alike. I believe this edition was brought forth with much more effort

vii

viii

Preface

and commitment than previous ones, and I profusely thank all the contributors; without their dedication and talent there would not be a fourth edition. Hopefully the cycle of healthcare will continue to evolve and to move forward positively. I wish that in the future the academic pediatric endocrinologist will be given the recognition and support that are deserved. This will allow us to devote energy to enhancing our knowledge and passing it on to practicing physicians for the health of our children. Fima Lifshitz, M.D.

Contents

About the Series Foreword Robert M. Blizzard Foreword Maria I. New Preface Contributors Online References Cited in Text

iv v v vii xxi xxv

I. GROWTH AND GROWTH DISORDERS 1.

Worrisome Growth Fima Lifshitz and Diego Botero I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII.

2.

1

The General Problem The Medical Problem Diagnosis of Short Stature Growth Patterns Constitutional Growth Delay Familial Short Stature Pathological Short Stature Intrauterine Growth Retardation Failure to Thrive Nutritional Growth Retardation Laboratory Aids in Differentiating Short Stature Final Considerations References

Hypopituitarism and Other Disorders of the Growth Hormone and Insulin-Like Growth Factor Axis Arlan L. Rosenbloom and Ellen Lancon Connor I. II. III. IV. V. VI. VII. VIII. IX. X.

Introduction Pituitary Gland, Growth Hormone, and IGF-I Classification of Disorders Involving the GH/IGF-I Axis Congenital GH Deficiency Acquired GH Deficiency Congenital GH Insensitivity Acquired GH Insensitivity Primary IGF-I Deficiency and IGF-I Resistance Diagnostic Evaluation Treatment References ix

1 2 3 4 10 13 14 15 20 25 34 35 35 47 47 47 54 54 58 64 67 67 68 74 78

x

Contents 3.

Growth Hormone Treatment David B. Allen I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV. XVI.

4.

Skeletal Dysplasias Mordechai Shohat and David L. Rimoin I. II. III. IV. V. VI. VII. VIII. IX.

5.

Introduction Growth Hormone Physiology Growth Hormone Effects Growth Hormone Deficiency Idiopathic Short Stature and Constitutional Growth Delay Turner Syndrome and Noonan Syndrome Intrauterine Growth Retardation Chronic Renal Failure and Hypophosphatemic Rickets Skeletal Dysplasias Glucocorticoid-Treated Children Prader-Willi Syndrome Other Syndromes and Defects Associated with Short Stature Adults with GH Deficiency and the Elderly Catabolic States Adverse Effects of GH Treatment Ethical Issues in GH Treatment References

Introduction Differentiation International Classification and Nomenclature Diagnosis and Assessment Prenatal Diagnosis Management Extended Limb Lengthening Growth Hormone Therapy in Achondroplasia Collection of Skeletal Tissues References

Tall Stature and Excessive Growth Syndromes S. Douglas Frasier I. II. III. IV. V. VI. VII. VIII. IX. X.

Definition and Classification of Overgrowth Syndromes Growth Hormone Excess Cerebral Gigantism (Sotos Syndrome) Klinefelter Syndrome XYY Syndrome Marfan Syndrome Homocystinuria Beckwith-Wiedemann Syndrome Hemihypertrophy Constitutional Tall Stature References

87 87 88 89 90 95 97 98 99 99 100 101 102 102 103 103 105 106 113 113 113 114 114 129 129 129 130 130 131 133 133 133 135 137 138 138 139 140 141 141 143

II. ADRENAL DISORDERS AND SEXUAL DEVELOPMENT ABNORMALITIES 6.

Adrenal Cortex: Hypo- and Hyperfunction Claude J. Migeon and Roberto L. Lanes I. Introduction II. Physiology III. Hypoadrenocorticism

147 147 147 154

Contents

xi IV. V. VI. VII. VIII. IX. X. XI. XII. XIII.

7.

Congenital Adrenal Hyperplasia Maria I. New and Lucia Ghizzoni I. II. III. IV. V. VI. VII. VIII. IX. X.

8.

The Catecholamines Pheochromocytoma Multiple Endocrine Neoplasia Syndromes Neuroblastoma Ganglioneuroma Neural Tumors and Chronic Diarrhea References

Puberty and Its Disorders Peter A. Lee I. II. III. IV. V. VI.

10.

Introduction Pathophysiology Clinical Features Clinical Forms of Adrenal Hyperplasia Caused by 21-Hydroxylase Deficiency Pubertal Maturation in Classical Congenital Adrenal Hyperplasia Genetics Epidemiology Diagnosis Treatment Conclusion References

Disorders of the Adrenal Medulla: Catecholamine-Producing Tumors in Childhood Karel Pacak, Martina Weise, Graeme Eisenhofer, Frederieke M. Brouwers, and Christian A. Koch I. II. III. IV. V. VI.

9.

Hypoadrenocorticism: Primary Adrenocortical Insufficiency Addison’s Disease (Chronic Hypoadrenocorticism) Hypoadrenocorticism Secondary to Deficient CRH and/or ACTH Secretion Hypoadrenocorticism Secondary to End-Organ Unresponsiveness Treatment of Hypoadrenocorticism Hyperadrenocorticism Hypercortisolism Adrenogenital Syndrome Feminizing Adrenal Tumors Hyperaldosteronism References

Normal Puberty Precocious Puberty Therapy Partial Pubertal Development: Variants of Normal Inappropriate Sex-Steroid-Stimulated Changes for Sex Delayed Puberty and Hypogonadism Presenting During Adolescence References

Turner Syndrome E. Kirk Neely and Ron G. Rosenfeld I. II. III. IV.

Introduction Features of Turner Syndrome The Genetic Basis of TS Medical Therapies References

154 159 160 162 163 163 164 166 167 168 170 175

175 175 178 178 181 183 183 183 187 187 187 193

193 194 197 199 203 203 203 211

211 214 223 225 226 227 235 239

239 239 247 249 252

xii

Contents 11.

Nonendocrine Vaginal Bleeding Albert Altchek I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII.

12.

Hirsutism, Polycystic Ovary Syndrome, and Menstrual Disorders Songya Pang I. II. III. IV. V. VI. VII.

13.

Introduction Causes of Local Nonendocrine Bleeding Severe Vaginal Infections as a Cause of Local Nonendocrine Bleeding Trauma as a Cause of Local Nonendocrine Bleeding Foreign Bodies in the Vagina as a Cause of Local Nonendocrine Bleeding Vulvar Lesions as a Cause of Local Nonendocrine Bleeding Prolapse of the Urethra as a Cause of Local Nonendocrine Bleeding Anal Lesions as a Cause of Local Nonendocrine Bleeding Polyps of the Hymen as a Cause of Local Nonendocrine Bleeding Malignant and Benign Tumors of the Vagina, Uterus, and Ovaries Coagulation Defects as a Cause of Local Nonhormonal Bleeding Evaluation Conclusion References

Introduction Physiology of Androgen Metabolism Physiology of Hair Growth, Proposed Intradermal Immunoregulation, and Skin Androgen Metabolism Pathophysiology and Causes of Hirsutism and Polycystic Ovary Syndrome Diagnostic Approach and Differential Diagnosis Treatment of Hirsutism and Polycystic Ovary Syndrome Menstrual Disorders in Adolescents References

Disorders of Sexual Differentiation Adriana A. Carrillo, Marco Danon, and Gary D. Berkovitz I. II. III. IV. V. VI. VII. VIII. IX.

Gonadal Differentiation Anatomical Sex Differentiation of the Reproductive Tract Hormonal Control of Sex Differentiation Ambiguous Genitalia Diagnostic Evaluation for Ambiguous Genitalia Management of Intersex Micropenis Hypospadias Cryptorchidism References

257 257 258 259 260 261 261 265 265 266 266 268 270 272 273 277 277 277 282 284 294 298 301 309 319 319 320 323 325 334 336 339 339 340 342

III. THYROID DISORDERS 14.

Thyroid Disorders in Infancy Guy Van Vliet I. II. III. IV. V. VI. VII. VIII.

Introduction Changes in Thyroid Hormone Economy from Conception to 3 Years of Age Congenital Hypothyroidism Hypothyroxinemia of the Newborn Congenital Hyperthyroidism Acquired Hypo- and Hyperthyroidism in Infancy Structural Thyroid Problems Conclusion References

347 347 347 348 353 354 355 355 356 356

Contents 15.

xiii Hypothyroidism John S. Dallas and Thomas P. Foley, Jr. I. II. III. IV. V. VI.

16.

Hyperthyroidism John S. Dallas and Thomas P. Foley, Jr. I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII.

17.

Pathogenesis and Etiology Graves’ Disease Autonomous Thyroid Nodule Familial Nonautoimmune Hyperthyroidism TSH-Induced Hyperthyroidism Subacute and Hashimoto’s Thyroiditis Exogenous Thyroid Hormone Euthyroid Hyperthyroxinemia T3 and T4 Toxicosis Graves’ Ophthalmopathy Laboratory Evaluation Prognosis and Treatment References

Thyromegaly John S. Dallas and Thomas P. Foley, Jr. I. II. III. IV. V. VI. VII. VIII. IX. X.

18.

Historical Background Classification and Causes Pathophysiology Clinical Presentation Diagnostic Evaluation Clinical Course and Management References

Introduction Pathogenesis Autoimmune Thyroid Disease: Thyroiditis Acute and Subacute Thyroiditis Iodine Deficiency Goitrogens Familial Thyroid Dyshormonogenesis Idiopathic Goiter Nodular Thyromegaly Evaluation of Patients with Thyromegaly References

Thyroid Tumors in Children Donald Zimmerman I. II. III. IV. V.

Epidemiology Pathology Pathogenesis Diagnosis Treatment References

359 359 360 362 362 364 366 368 371 371 371 375 376 377 378 378 379 381 382 383 384 388 393 393 393 394 399 400 400 400 401 402 403 404 407 407 408 411 414 414 417

IV. DISORDERS OF CALCIUM AND PHOSPHORUS METABOLISM 19.

Hypoparathyroidism and Mineral Homeostasis Jaakko Perheentupa

421

xiv

Contents I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV. XVI. XVII.

20.

Introduction The Parathyroid Glands Parathyroid Hormone and Regulation of Its Secretion Assays for Parathyroid Hormone PTH/PtHrP Receptors Mechanism of Parathyroid Hormone Action Pathogenesis of Hyperparathyroidism Differential Diagnosis Recognition and Diagnosis Primary Hyperparathyroidism Secondary and Tertiary Hyperparathyroidism Complications of Hyperparathyroidism and Hypercalcemia Treatment of Hyperparathyroidism and Hypercalcemia Management After Parathyroidectomy Summary References

Neonatal Calcium and Phosphorus Disorders Winston W. K. Koo I. II. III. IV. V. VI. VII. VIII. IX.

22.

421 421 423 425 428 429 429 430 432 432 433 437 442 444 444 449 453 457

Hyperparathyroidism in Children Scott A. Rivkees and Thomas O. Carpenter I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV.

21.

Introduction Physiological Background: The Parathyroid Glands and Hormones Calcitriol (1,25-Dihydroxycalciferol) The Kidneys The Skeleton The Intestine Calcium, Phosphate, and Magnesium in Plasma Manifestations of Deficient Parathyroid Hormone Action Causes of Hypoparathyroidism Familial Isolated Hypoparathyroidism Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy (APECED) (MIM 240300) Hypoparathyroidism of Dysmorphic Syndromes Transient Hyperparathyroidism Other Acquired Hypoparathyroidism Pseudohypoparathyroidism Diagnosis Therapy References

Introduction Maintenance of Calcium and Phosphorus Homeostasis Hormonal Control of Calcium and P Homeostasis via PTH, CT, and 1,25(OH)2D Nonclassic Control of Calcium and P Homeostasis Hypocalcemia Hypercalcemia Hypophosphatemia Hyperphosphatemia Skeletal Manifestations of Disturbed Mineral Homeostasis References

Metabolic Bone Disease Joseph M. Gertner I. II. III. IV.

Introduction Rickets Disorders of Vitamin D Metabolism Disorders of Phosphate Homeostasis

469 469 469 470 470 470 471 471 472 472 473 473 474 474 475 475 476 481 481 481 483 490 491 497 500 502 503 505 517 517 517 520 521

Contents

xv V. VI. VII. VIII.

Ricketslike Conditions Metabolic and Genetic Disorders Intrinsic to the Skeleton Skeletal Dysplasia Treatment of Skeletal Disorders References

525 526 531 534 536

V. HYPOGLYCEMIA AND DIABETES MELLITUS 23.

24.

Hypoglycemia in the Newborn, Including the Infant of a Diabetic Mother Hussien M. Farrag and Richard M. Cowett

541

I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV. XVI. XVII. XVIII.

541 541 547 553 555 555 557 557 557 558 560 560 561 562 563 563 563 564 568

Hypoglycemia in Children Joseph I. Wolfsdorf and David A. Weinstein I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV. XVI.

25.

Introduction Neonatal Euglycemia and Hypoglycemia Glucose Metabolism Clinical Assessment Preterm Appropriate for Gestational Age Neonates Small for Gestational Age Infants Congenital Heart Disease/Congestive Heart Failure Perinatal Stress/Hypoxia Cold Injury and Sepsis Hyperinsulinism: The Infant of the Diabetic Mother Rh Incompatability and Hypoglycemia Exchange Transfusion and Umbilical Catheter Persistent Hyperinsulinemic Hypoglycemia Hypoglycemia Following Maternal Ethanol Consumption and Miscellaneous Causes Beckwith-Wiedemann Syndrome Defective Gluconeogenesis/Glycogenolysis Evaluation Treatment References

Introduction Definition of Hypoglycemia Overview of Fuel Metabolism Regulation of Insulin Secretion Clinical Manifestations of Hypoglycemia Causes of Hypoglycemia in Infants and Children Hyperinsulinism Hormone Deficiency Disorders of Glycogen Synthesis and Glycogen Degradation Disorders of Gluconeogenesis Disorders of Amino Acid Metabolism Miscellaneous Causes of Hypoglycemia Disorders of Carnitine Metabolism, Fatty Acid ␤-Oxidation, and Ketone Synthesis Determining the Cause of Hypoglycemia Treatment Hypoglycemia and Diabetes Mellitus References

Diabetes in the Child and Adolescent Arlan L. Rosenbloom and Janet H. Silverstein I. II. III. IV.

Introduction Diagnosis and Classification Type 1 Diabetes Type 2 Diabetes

575 575 575 576 579 580 581 583 585 586 589 590 591 592 596 598 598 603 611 611 611 614 627

xvi

Contents V. Other Types of Diabetes References 26.

Management of the Child with Diabetes Oscar Escobar, Dorothy J. Becker, and Allan L. Drash I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII.

27.

Introduction Metabolic Disturbances as a Consequence of Insulin Deficiency Management Insulin Therapy Intensive Diabetes Therapy Somogyi Effect and Dawn Phenomenon Dietary Management Exercise as a Therapeutic Modality Education and Emotional Support The Therapeutic Team Therapeutic Objectives and Monitoring Requirements Consultations and Referrals Clinical Assessment and Therapeutic Decision-Making References

Diabetic Ketoacidosis Dorothy J. Becker, Allan L. Drash, and Oscar Escobar I. II. III. IV. V. VI. VII. VIII. IX.

Introduction Presentation and Clinical Features Pathogenesis Causes of Diabetic Ketoacidosis Differential Diagnosis Clinical Assessment Therapy Complications of DKA Preventive Therapy References

639 641 653 653 653 654 654 656 657 658 659 659 660 661 664 665 666 669 669 669 670 673 674 674 675 679 680 680

VI. MISCELLANEOUS DISORDERS 28.

Autoimmune Endocrinopathies William E. Winter I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII.

29.

Autoimmunity and Autoimmune Diseases Classification and Recognition of Autoimmune Diseases Autoimmunity to the Pancreatic Islets, Insulin Receptors, and Insulin Autoimmune Thyroid Disease Autoimmune Addison’s Disease Acquired Primary Gonadal Failure Idiopathic Hypoparathyroidism Hypophysitis and Autoimmune Disease of the Pituitary Autoimmune Diabetes Insipidus Associated Nonendocrine Autoimmune Diseases Autoimmune Disease Associations Clinical Approach to the Autoimmune Endocrinopathies and Related Diseases Summary References

Multiple Endocrine Neoplasia Syndromes Giulia Costi and Noel K. Maclaren

683 683 689 691 697 702 703 703 704 704 704 705 707 708 708 721

Contents

xvii I. II. III. IV. V. VI. VII.

30.

Introduction MEN-1 MEN-2 Adrenal Adenoma Thyroid Adenomas Pituitary Adenomas Pancreatic Adenomas References

721 721 723 724 726 727 730 730

Endocrine Tumors in Children Muhammad A. Jabbar

735

I. II. III. IV.

31.

Nontraditional Inheritance of Endocrine Disorders Judith G. Hall I. II. III. IV. V. VI. VII.

32.

749 749 749 750 751 751 752 752 752

Disorders of Water Homeostasis Joseph A. Majzoub and Louis J. Muglia

755

Introduction Regulation of Thirst and Fluid Balance Central Diabetes Insipidus Nephrogenic Diabetes Insipidus Hyponatremia and the Syndrome of Inappropriate Secretion of Vasopressin Concluding Remarks References

Emergencies of Inborn Metabolic Diseases Jose E. Abdenur I. II. III. IV. V. VI.

34.

735 735 737 740 745

Introduction Uniparental Disomy Mosaicism Germline Mosaicism Genomic Imprinting Cytoplasmic Inheritance Summary References

I. II. III. IV. V. VI.

33.

Introduction Adrenal Tumors Gonadal Tumors Tumors of Endocrine Pancreas References

Introduction Urea Cycle Defects Organic Acidemias Fatty Acid Oxidation Defects Primary Lactic Acidemias Maple Syrup Urine Disease References

Obesity in Children Ramin Alemzadeh, Russell Rising, Maribel Cedillo, and Fima Lifshitz I. II. III. IV. V.

Prevalence Morbidity Social Obesity Growth Assessment Who Is at Risk?

755 755 761 767 769 775 776 787 787 787 792 798 805 811 812 823 823 824 826 827 831

xviii

Contents VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV. XVI. XVII. XVIII. XIX.

35.

Hyperlipoproteinemias in Children and Adolescents Kurt Widhalm I. II. III. IV. V. VI. VII.

36.

Introduction Growth Puberty Growth Hormone Secretion Thyroid Gonadal and Reproductive Function Other Endocrine Complications Follow-Up and Management References

Endocrine Alterations in Human Immunodeficiency Virus Infections Robert Rapaport and Daphne Sack-Rivers I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII.

38.

Introduction Lipoprotein Background and Basics Definition of Hyperlipoproteinemia/Dyslipoproteinemia Familial Hypercholesterolemia Treatment Familial Combined Hyperlipidemia Hypertriglyceridemia/Chylomicronemia Syndrome References

Endocrine Disorders After Cancer Therapy Raphae¨l Rappaport and Elisabeth Thibaud I. II. III. IV. V. VI. VII. VIII.

37.

Genetics Energy Balance Physical Activity Hyperinsulinism Hormonal Alterations Hypothalamus Treatment Modalities Diets Exercise Family Involvement Other Therapies Yo-Yo Weight Cycling Prevention Final Considerations References

Introduction Growth Adrenal Function Thyroid Gonads Pancreas Parathyroid Prolactin Hypothalamus and Pituitary Endocrine Alterations Secondary to Treatment Future Hormonal Therapy in HIV Infections Conclusion References

Hypertension in Children: Endocrine Considerations Julie R. Ingelfinger

832 836 836 837 838 840 840 841 844 844 845 847 847 848 848 859 859 859 860 861 861 863 863 863 865 865 865 867 867 868 868 870 870 871 875 875 876 880 882 883 884 885 885 885 886 886 887 887 895

Contents

xix I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV. XVI.

Introduction Normal Blood Pressure and Its Definition Causes of Hypertension Complications of Hypertension: Patterns and Diagnosis Steroidogenic Enzyme Defects Primary Aldosteronism: Aldosterone-Producing Adenoma and Bilateral Adrenal Hyperplasia Glucocorticoid-Responsive Aldosteronism: Dexamethasone-Suppressible Hyperaldosteronism (OMIM 103900) Apparent Mineralocorticoid Excess (OMIM 218030) Mutations in Renal Transporters Causing Low-Renin Hypertension Cushing Syndrome and Hypertension Hypertension in Pheochromocytoma and Neural Crest Tumors Hypertension in Thyroid Disease Hyperparathyroidism and Hypertension Prevention of Hypertension and Endocrine Systems Primary Hypertension: How Often Endocrine? Treatment References

895 895 895 895 902 903 905 906 906 907 907 908 909 909 909 909 912

VII. ADDITIONAL INFORMATION AND RESOURCES 39.

Dietary Supplements to Enhance Athletic Performance Alan D. Rogol I. II. III. IV. V. VI. VII. VIII. IX. X.

40.

Using the Web to Obtain Information on Genetic and Hormone Disorders John A. Phillips III I. II. III. IV. V. VI.

41.

Introduction Using the Web to Obtain Information for Dysmorphic Patients How to Generate a Differential Diagnosis for a Family Having Unusual Endocrine Problems How to Obtain Information on a Case of Endocrine Neoplasia Selected Web Sites on Growth and Hormone Disorders Conclusions References

Hormone Measurements and Dynamic Tests in Pediatric Endocrinology Adriana A. Carrillo and Fred Chasalow I. II. III. IV.

42.

Introduction Dietary Supplements: Herbal Products Ephedra Ginseng Creatine Anabolic Steroids Dehydroepiandrosterone Androstenedione Growth Hormone and Insulin-Like Growth Factor 1 Conclusions References

Introduction Role of the Laboratory Practical Considerations Practical Protocols for Dynamic Testing in Children References

Reimbursement Issues in Endocrinology: A Coding Supplement Bridget F. Recker

917 917 917 918 918 918 919 920 920 921 921 921 923 923 924 925 929 931 933 933 935 935 935 937 938 955 959

xx

Contents I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII.

43.

Reimbursement CPT Coding ICD-9 (ICD-10 Coming) Linking CPT and ICD Coding Collections Denial and Appeal Contracting Chart Reviews Stimulation Testing Diabetic Education Clinical Trials What Is Needed? Frequently Used Diagnosed Codes for the Pediatric Endocrine Practice References

Reference Charts Used Frequently by Endocrinologists in Assessing the Growth and Development of Youth Adriana A. Carillo and Bridget F. Recker I. Standards of Growth and Development II. Miscellaneous Standards III. Standard Growth Charts for Children with Genetic or Pathological Conditions

Index

959 959 960 960 961 961 962 962 962 963 963 966 967 967 969 971 998 1011 1041

Contributors

Jose E. Abdenur, M.D. Associate Scientific Director, Foundation for the Study of Neurometabolic Diseases, and Associate Professor of Biochemistry, University of Buenos Aires School of Dentistry, Buenos Aires, Argentina Ramin Alemzadeh, M.D., FAAP Associate Professor, Section of Pediatric Endocrinology & Diabetes, and Director, Children’s Diabetes Program, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A. David B. Allen, M.D. Professor and Director of Endocrinology and Residency Training, Department of Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin, U.S.A. Albert Altchek, M.D. Clinical Professor with Tenure of Obstetrics, Gynecology, and Reproductive Science, and Chief of Pediatric and Adolescent Gynecology, Mount Sinai School of Medicine and Hospital, New York, New York, U.S.A. Dorothy J. Becker, M.D. Professor of Pediatrics and Director, Division of Endocrinology, Diabetes & Metabolism, University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Gary D. Berkovitz, M.D. Professor of Pediatrics and Chief, Pediatric Endocrinology, Mailman Center for Child Development, University of Miami School of Medicine, Miami, Florida, U.S.A. Diego Botero, M.D. Attending in Endocrinology, Children’s Hospital, and Instructor in Pediatrics, Harvard Medical School, Boston, Massachusetts, U.S.A. Frederieke M. Brouwers, M.D. Research Fellow, Unit on Clinical Neuroendocrinology, Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, U.S.A. Thomas O. Carpenter, M.D. Professor, Department of Pediatrics, Yale University School of Medicine, and Attending Physician, Yale–New Haven Hospital, New Haven, Connecticut, U.S.A. Adriana A. Carrillo, M.D. Fellow in Pediatric Endocrinology, Jackson Memorial Hospital, University of Miami School of Medicine, Miami, Florida, U.S.A. Maribel Cedillo, B.S.

Research Nutritionist, EMTAC, Inc., Miami, Florida, U.S.A.

Fred Chasalow, Ph.D. Former Chief of Pediatric Endocrine Research and Former Director of Pediatric Endocrine Laboratory, Maimonides Medical Center, Brooklyn, New York, U.S.A. Ellen Lancon Connor, M.D. Assistant Professor, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, U.S.A. xxi

xxii

Contributors

Giulia Costi, M.D. Endocrine Fellow, Juvenile Diabetes Program, Department of Pediatrics, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, New York, U.S.A. Richard M. Cowett, M.D. Former Chief, Division of Neonatology, Children’s Hospital, Youngstown, and Professor, Department of Pediatrics, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio, U.S.A. John S. Dallas, M.D. Associate Professor and Director, Division of Pediatric Endocrinology, Department of Pediatrics, University of Texas Medical Branch–Galveston, Galveston, Texas, U.S.A. Marco Danon, M.D. Staff Attending, Department of Medical Education, Miami Children’s Hospital, Miami, Florida, and Associate Professor, Department of Pediatrics, State University of New York, Brooklyn, New York, U.S.A. Allan L. Drash, M.D. Professor Emeritus of Pediatrics, University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Graeme Eisenhofer, Ph.D. Staff Scientist, Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, U.S.A. Oscar Escobar, M.D. Assistant Professor, Division of Endocrinology, Department of Pediatrics, University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Hussien M. Farrag, M.D. Assistant Professor of Pediatrics, Tufts University School of Medicine, and Division of Newborn Medicine, Department of Pediatrics, Baystate Medical Center, Springfield, Massachusetts, U.S.A. Thomas P. Foley, Jr., M.D. Professor, Department of Pediatrics, School of Medicine, and Professor of Epidemiology, Graduate School of Public Health, University of Pittsburgh and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. S. Douglas Frasier, M.D. Emeritus Professor, Division of Endocrinology, Department of Pediatrics, UCLA School of Medicine, Los Angeles, California, U.S.A. Joseph M. Gertner, M.B., M.R.C.P. Vice President, Clinical Research, Serono Inc., Rockland, and Division of Endocrinology, Department of Medicine, Children’s Hospital, Boston, Massachusetts, U.S.A. Lucia Ghizzoni, M.D., Ph.D.

Assistant Professor, Department of Pediatrics, University of Parma, Parma, Italy

Judith G. Hall, O.C., M.D., F.R.C.P.(C.), F.A.A.P., F.C.C.M.G., F.A.B.M.G. Professor of Pediatrics and Medical Genetics, Department of Pediatrics, University of British Columbia, and British Columbia Children’s Hospital, Vancouver, British Columbia, Canada Julie R. Ingelfinger, M.D. Professor of Pediatrics, Harvard Medical School; Senior Consultant in Nephrology, Massachusetts General Hospital for Children, Massachusetts General Hospital; and Deputy Editor, New England Journal of Medicine, Boston, Massachusetts, U.S.A. Muhammad A. Jabbar, M.D. Associate Professor, Department of Pediatrics, Hurley Medical Center, Michigan State University School of Medicine, Flint, Michigan, U.S.A. Christian A. Koch, M.D., F.A.C.E. Investigator and Attending Physician, Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, U.S.A. Winston W. K. Koo, M.B., F.R.A.C.P. Professor of Pediatrics, Obstetrics and Gynecology, Department of Pediatrics, Hutzel Hospital and Children’s Hospital of Michigan, Wayne State University, Detroit, Michigan, U.S.A. Roberto L. Lanes, M.D. Coordinator, Pediatric Endocrine Unit, Hospital de Clinicas Caracas, and Professor, Post Graduate Courses in Pediatrics and Endocrinology, Hospital Central ‘‘Dr. Carlos Arvelo,’’ Universidad Central de Venezuela, Caracas, Venezuela Peter A. Lee, M.D., Ph.D. Professor of Pediatrics, Pennsylania State College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania, U.S.A. Fima Lifshitz, M.D. Former Chief-of-Staff and Chair of Nutrition Sciences, Miami Children’s Hospital, Professor of Pediatrics, University of Miami School of Medicine, Miami, Florida; State University of New York Health Science Center at Brooklyn, Brooklyn,

Contributors

xxiii

New York; President, Pediatric Sunshine Academics; and Senior Nutrition Scientist and Director of Pediatrics, Sansum Medical Research Institute, Santa Barbara, California, U.S.A. Noel K. Maclaren, M.D. Professor, Department of Pediatrics, and Director, Juvenile Diabetes Center, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, New York, U.S.A. Joseph A. Majzoub, M.D. Chief, Division of Endocrinology, Children’s Hospital, and Professor of Pediatrics, Harvard Medical School, Boston, Massachusetts, U.S.A. Claude J. Migeon, M.D. Professor of Pediatrics, Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, and Children’s Medical and Surgical Center, Johns Hopkins Hospital, Baltimore, Maryland, U.S.A. Louis J. Muglia, M.D., Ph.D. Division of Pediatric Endocrinology and Metabolism, St. Louis Children’s Hospital, and Associate Professor of Pediatrics, Molecular Biology and Pharmacology, and Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, U.S.A. E. Kirk Neely, M.D. Clinical Associate Professor, Division of Pediatric Endocrinology, Stanford University Medical Center, Stanford Medical School, Stanford, California, U.S.A. Maria I. New, M.D. Professor and Chairman, Department of Pediatrics, and Chief, Pediatric Endocrinology, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, New York, U.S.A. Karel Pacak, M.D., Ph.D., D.Sc. Chief, Unit on Clinical Neuroendocrinology, Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, U.S.A. Songya Pang, M.D. Professor of Pediatrics and Chief of Pediatric Endocrinology, Department of Pediatrics, University of Illinois at Chicago College of Medicine, Chicago, Illinois, U.S.A. Jaakko Perheentupa, M.D., Ph.D. Professor (Emeritus) of Pediatrics and Former Director, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland John A. Phillips III, M.D. Director, Division of Medical Genetics, David T. Karzon Professor of Pediatrics, and Professor of Medicine and Biochemistry, Vanderbilt University School of Medicine, and Adjunct Professor of Microbiology, Meharry Medical College, Nashville, Tennessee, U.S.A. Robert Rapaport, M.D. Emma Elizabeth Sullivan Professor and Director, Division of Pediatric Endocrinology and Diabetes, Mount Sinai School of Medicine, New York, New York, U.S.A. Raphae¨l Rappaport, M.D. Malades, Paris, France

Professor Emeritus, Departments of Pediatrics and Developmental Biology, Hoˆpital Necker–Enfants

Bridget F. Recker, R.N., Ed.M., C.C.R.C. Research Coordinator, University Physicians Group–Endocrine Division, Staten Island University Hospital, Staten Island, New York, U.S.A. David L. Rimoin, M.D., Ph.D. Steven Spielberg Chair of Pediatrics and Director, Medical Genetics–Birth Defects Center, Cedars– Sinai Medical Center, and Professor of Pediatrics and Medicine, UCLA School of Medicine, Los Angeles, California, U.S.A. Russell Rising, M.S., Ph.D.

Senior Research Scientist, EMTAC, Inc., Miami, Florida, U.S.A.

Scott A. Rivkees, M.D. Associate Professor of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, U.S.A. Alan D. Rogol, M.D., Ph.D. Professor of Clinical Pediatrics, University of Virginia, Charlottesville, and Clinical Professor of Internal Medicine, Medical College of Virginia, Richmond, Virginia, U.S.A. Arlan L. Rosenbloom, M.D. Distinguished Professor Emeritus, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, U.S.A.

xxiv

Contributors

Ron G. Rosenfeld, M.D. Oregon Credit Union Endowment Professor and Chair, Department of Pediatrics, and Professor, Department of Cell and Developmental Biology, Oregon Health and Science University, and Physician-in-Chief, Doernbecher Children’s Hospital, Portland, Oregon, U.S.A. Daphne Sack-Rivers York, U.S.A.

Research Assistant, Division of Pediatric Endocrinology and Diabetes, Mount Sinai Hospital, New York, New

Mordechai Shohat, M.D. Professor of Pediatrics and Genetics, and Director, Department of Medical Genetics, Rabin Medical Center —Beilinson Campus, Petah Tikva, Israel Janet H. Silverstein, M.D. Professor and Chief, Division of Pediatric Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, U.S.A. Elisabeth Thibaud, M.D. Gynecologist, Pediatric Endocrinology and Gynecology Unit, Department of Pediatrics, Hoˆpital Necker– Enfants Malades, Paris, France Guy Van Vliet, M.D. Professor, Department of Pediatrics, University of Montreal, and Chief, Endocrinology Service, Sainte-Justine Hospital, Montreal, Quebec, Canada David A. Weinstein, M.D., M.M.Sc. Assistant in Endocrinology, Children’s Hospital, and Instructor in Pediatrics, Division of Endocrinology, Harvard Medical School, Boston, Massachusetts, U.S.A. Martina Weise, M.D. Head, Endocrinology and Diabetes Section, Institute for Drugs and Medical Devices, Bonn, Germany Kurt Widhalm, M.D. Professor of Pediatrics and Clinical Chemistry, Division of Neonatology, Intensive Care and Congenital Disorders, Department of Pediatrics, University of Vienna, Vienna, Austria William E. Winter, M.D. Professor, Department of Pathology, Immunology and Laboratory Medicine; Medical Director, Department of Pediatrics and Department of Molecular Genetics and Microbiology; Section Chief, Clinical Chemistry; and Director, Pathology Residency Training Program, University of Florida College of Medicine, Gainesville, Florida, U.S.A. Joseph I. Wolfsdorf, M.B., B.Ch. Senior Associate in Medicine, Attending Physician in Endocrinology, and Director, Diabetes Program, Children’s Hospital; and Associate Professor of Pediatrics, Harvard Medical School, Boston, Massachusetts, U.S.A. Donald Zimmerman, M.D. Professor of Pediatrics, Mayo Medical School, and Consultant in Pediatric Endocrinology and Metabolism, Mayo Medical Clinic, Rochester, Minnesota, U.S.A.

Online References Cited in Text

American Diabetes Association (http://www.diabetes.org), 931 Chromosomal Variation in Man (http://www.wiley.com/products/subject/life/borgaonkar/access.html), 931 Cytogenic resources (http://www.kumc.edu/gec/geneinfo.html), 931 Dysmorphic Human–Mouse Homology database (DHMHD) (http://www.hgmp.mrc.ac.uk/DHMHD/dysmorph.html), 931 Endocrine Society (http://www.endo-society.org), 931 Eurogrowth study group, (www.eurogrowth.org), 3 Gene Test Database http://www.genetests.org/servlet/access, 925 GeneMap’99 (http://www.ncbi.nlm.nih.gov/genemap), 932 GeneTests (http://www.genetests.org/servlet/access), 932 Genetic Alliance (http://www.geneticalliance.org), 932 Genetic Conditions/Rare Conditions Support Groups and Information Page (http://www.kumc.edu/gec/support), 932 Genetics Education Center (http://www.kumc.edu/gev/geneinfo.html), 932 Glossary of Genetic Terms (http://www.kumc.edu/gec/glossary.html), 932 Growth Charts www.cdc.gov/growthcharts, 2 Head Circumference for Age http://www.cdc.gov/growthcharts, 978 Human Growth Foundation (http://www.hgfound.org), 35, 932 Information for Genetic Professionals (http://www.kumc.edu/gec/geneinfo.html), 932 International Skeletal Dysplasia Registry, http://www.csmc.edu/genetics/skeldys, 130 International Society for Pediatric and Adolescent Diabetes (http://www.ispad.org), 932 Lawson Wilkins Pediatric Endocrine Society (http://www.lwpes.org), 932 Length and Weight for Age http://www.cdc.gov/growthcharts, 977 Magic Foundation (http://www.magicfoundation.org), 932 March of Dimes (http://www.modimes.org), 932 MEDLINE PubMed (http://www.cnbi.nlm.nih.gov), 932 National Association for Rare Disorders (NORD) (http://www.NORD-rdb.com/⬃orphan), 932 National Human Genome Research Institute (NHGRI) (http://www.nhgri.nih.gov), 932 NCBI Education (http://www.ncbi.nlm.nih.gov/education/index.html), 932 NCBI Site Map (http://www.ncbi.nlm.nih.gov/Sitemap/index.html), 932 Neurofibromatosis Homepage (http://www.ng.org), 932 OMIM (http://www.ncbi.nlm.nih.gov/OMIM), 932 Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/omim, 905, 923–924, 932 Policy Statements from the American Academy of Pediatrics (http://www.aap.org/policy/pprgtoc.html), 932 Policy Statements from the American College of Human Genetics (http://www.faseb.org/genetics/acmg/pol-menu.htm), 932 Primer on Molecular Genetics (http://www.ornl.gov/hgmis/publicat/primer/intro.html), 932 Quackwatch (http://www.quackwatch.com), 932 Rare Genetic Diseases in Children (http://www.mcrcr2.med.nyu.edu/murphp01/lysosome/lysosome.htm), 932 RETgermline mutation screening http://endocrine.mdacc.tmc.edu, 197 Simulated Genetic Counseling Session (http://www.kumc.edu/gec/gcsim.html), 933 Skeletal Dysplasias www.csmc.edu/genetics/skeldys, 114, 129 Skeletal dysplasias, Nomenclature of Constitutional Disorders of Bone, www.csme.edu/genetics/skeldys/nomenclature, 125 Stature for Age http://www.cdc.gov/growthcharts, 979 Vasopressin Gene www.medcon.mcgill.ca/nephros/avp㛭npii.html, 761

xxv

1 Worrisome Growth Fima Lifshitz Miami Children’s Hospital and University of Miami School of Medicine, Miami, Florida; State University of New York Health Science Center at Brooklyn, Brooklyn, New York; Pediatric Sunshine Academics; and Sansum Medical Research Institute, Santa Barbara, California, U.S.A.

Diego Botero Children’s Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.

I.

prejudice, like sexism or racism, is well established in this country and may be prevalent throughout the world. It has been called heightism. (The reader is referred to the book The Height of Your Life, by Ralph Keyes, for a very comprehensive and interesting review of this problem.) This book approaches heightism in a wry and humorous fashion. It highlights facts regarding height so basic to our relationships with others that we have ceased to think about them. It is from this book that the following comments have been extracted. So pervasive is the bias against short people that no one notices it—no one, that is, except the short person. The English language illustrates this bias clearly. Feisty is the classic example, a word normally used in tandem with ‘‘little.’’ Distinguished, by contrast, may not be synonymous with ‘‘tall’’ but rarely is used to refer to short persons. Other very important phrases remind us regularly of the importance of height: compare ‘‘looks up to’’ and ‘‘looks down upon.’’ The question is always; how tall are you, instead of the neutral, what is your height? The song ‘‘Short People’’ by Randy Newman describes those below-average in height who have ‘‘grubby little fingers’’ and ‘‘dirty little minds’’ with ‘‘no reason to live.’’ This song is a spoof of bigotry with a catchy tune, yet it made the hit parade. The composer meant it as a joke; of course, he is 5 feet 11 inches! Height is one of the most important traits both parties try to match when it comes to selecting a personal relationship. In romantic matters, little men are ‘‘cut down to size.’’ An ideal lover is never short, and at present both genders seem to feel that in relationships the male should be taller than the female. Even Sandy Allen, who at 7 feet 71/2 inches is certified by The Guinness Book of World Records as the tallest woman in the world, was quoted as

THE GENERAL PROBLEM

One of the primary concerns of pediatricians is the appropriate growth of their patients. Parents and children also worry about ‘‘growth’’ as evidence of good health. Several conditions, as discussed later, may alter the height, weight, and growth progression of a patient; these must be diagnosed and treated. However, there are other problems in being short, even when the body size is only mildly affected. Indeed, any person who is below average height (in the United States 5 feet 9 inches for men and 5 feet 5 inches for women) may also experience a number of psychosocial difficulties. Dwarfs have these problems to a greater degree, with various amounts of tolerance and rejection according to the different customs and beliefs of the locality in which they live. Recent medical research on the subject questioned whether short stature is a handicap (1) or whether this is a problem that requires growth hormone therapy (2). Also there are issues concerning the quality of life and the potential benefits that may be attained by increasing adult height (3). There are additional questions about the reasons for internalizing behavior problems and/or poor social skills of short stature individuals. All these concerns challenge the justification for extraordinary means of treating a short-stature child. It has been postulated that growth hormone treatment in short children is an issue beyond medicine, involving many aspects best resolved at present by a research approach (4, 5). However, there is ample evidence of prejudice in our society towards the short person. The psychosocial prejudice toward the short person transcends age, gender, race, creed, and financial status: all short people may be victims of discrimination. This seldom mentioned form of 1

2

saying, ‘‘I’ve got this old-fashioned idea, I will never marry anyone smaller than I am.’’ She never married. Thus, the tall man seems to have all of womankind to choose from, whereas the short man appears to be limited to short women. Indeed, there may be more interreligious and interracial marriages than there are couples in which the man is shorter than the woman. The former Secretary of State Henry Kissinger was acknowledged as a truly unusual phenomenon because he married a taller woman. Rewards for being tall in our society include money. Business, it seems, is interested in short men mostly as customers for elevator shoes. The president of the Mutual Life Insurance Company surveyed its policyholders and found a nearly perfect correlation between body height and policy value. Several studies have pointed out that taller persons earn higher salaries. Corporate recruiters also tend to choose the taller of two equally qualified applicants. Even when he succeeds, despite the odds against him, the short person is often accused of being a ‘‘Little Napoleon.’’ Height is more than a mere statistic: for men it is a measure of manhood. Height brings acknowledgment, deference, and power. Big and strong are, from childhood, considered nearly the same word. The dominant figures in advertisements and legendary figures in the movies are usually represented by tall people. Height is equated with power to such a degree that it plays a very important role in politics. Most US presidents have not been short; the shortest was James Madison at 5 feet 4 inches. Only six other presidents were slightly below the present average height. Americans have usually favored the taller political candidate. As a matter of fact, the taller of the two major presidential candidates is usually sent to the White House. There have been only four exceptions. In 1924, Calvin Coolidge (5 feet 10 inches) defeated John Davis (5 feet 11 inches); in 1972, Richard Nixon (6 feet) defeated George McGovern (6 feet 1 inch), in 1976 Jimmy Carter (5 feet 6 inches) defeated Gerald Ford (6 feet 1 inch). In the 2000 election, both candidates were over 6 feet tall, but George W. Bush, who is slightly shorter than Al Gore, won the election only by a Supreme Court decision, while the popular vote went to the taller Mr. Gore by a substantial margin. In this, as in most presidential elections, the American public voted by the inch. However, this form of prejudice may also transcend the United States. For the first time in the history of Mexico, the very tall opposition candidate Mr. Vicente Fox defeated the official shorter presidential candidate of the PRI Party in the 2000 election. This was a very unusual accomplishment since the PRI party had held power consecutively for over 75 years. Although human esthetics and social tastes clearly favor tallness, nature shows no such preference. Anthropologists estimate that, for most of history, natural selection kept adult male heights within a range below our current averages. Supporting the natural selection process, infants’ skeletons, which are abundant in old graveyards, are

Lifshitz and Botero

rather tall; in fact their length is comparable to our present norms. Some experts think that these two phenomena are related. It seems that environmental problems were more detrimental to youngsters destined to be large, and only those destined to be small survived the rigors of malnutrition and disease. Ashley Montagu, in Human Evolution, wrote: ‘‘At least in part the recent increase in overall size visible in the modern adult population is due to the fact that improved standards of food and medical care have allowed genetic combinations to survive which would have been selected against in ages past.’’

II.

THE MEDICAL PROBLEM

Pediatricians are often consulted by parents worried about short stature in their children. This term needs definition. ‘‘Short stature’’ has been defined as height below the third percentile; therefore, 3% of normal children would be classified as being short. ‘‘Dwarfism,’’ the severe form of short stature, is defined as height below 3 standard deviations (SD) from the mean. The population selected for reference is important when judgments are made about the shortness of an individual. A number of different reference charts have been used in this country in recent decades, each varying somewhat from others because of the representative population from whom the data were derived (e.g., predominantly rural children from Iowa vs. Boston city children). A revision of the 1977 National Child Health Survey growth percentile was recently completed and was published in May 2000 by the Center for Disease Control and Prevention (CDC) (www.cdc.gov/ growthcharts). These growth charts are included in the chapter of Reference Charts in this book (Chapter 43). These new charts are recommended for use as an enhanced instrument to evaluate the size and growth of children (6). These charts are based on more up-to-date improved data gathered from the National Health Examination Surveys (NHANES I, II, and III) with five supplementary data sources. They feature several noteworthy items including the inclusion of 3rd and 97th percentiles. In addition, these charts contain data extending to 20 years of age, and they better represent the current growth patterns of the population. One other important contribution is that there is better continuity between 2–3 years and the >2 years growth in the charts. The new 2000 CDC percentiles have been adjusted slightly to account for the fact that recumbent length should be greater than the stated differences of 0.8 cm in the national surveys. Another significant consequence of updating the data is that the new percentiles of the CDC tend to be a bit higher for weight from 0 to 2 years. The 2000 growth charts also include body mass index (BMI) values of years 2 and older. Although these growth charts constitute an important advancement over the previous charts used (1977 NCHS percentiles), they are not ideal for use in all infants and children. In particular they may misdiagnose the normalcy

Worrisome Growth

of growth in some young children as discussed below, including constitutional short stature or breastfed babies. These growth charts show average growth patterns of height and weight gain during specific periods in life (i.e., adolescent growth spurt). These percentile charts were based on cross-sectional data that effectively average growth across different periods. In individual patients the developmental stage of puberty will therefore make the pattern of growth vary in accordance with it, and that is not shown in the charts. In theory, useful supplementary growth charts for the pubertal periods are available, but these data were derived from nonrepresentative samples recorded a long time ago. Another concern with the CDC 2000 graphs is that it is hard to visualize the metric numbers in the axis, and the grids are not easy to follow. Therefore in this book we have published an improved version of those graphs. (See Chapter 43 for Reference Charts). A program for monitoring the growth of children has been prepared by the Eurogrowth Study Group (www. eurogrowth.org). This is excellent for individually tracking the physical growth of children from birth to 36 months of age (7). It allows the monitoring and the plotting of individual growth data, calculates growth velocity, provides body mass index centiles, measures influences of breastfeeding on growth, modifies growth by midparental height, corrects growth for gestational age of premature infants, calculates Z scores, and offers multilingual access (8–11). It is a highly recommended tool to assess growth in children up to 36 months of age. Pediatricians know that most children with mild short stature eventually become average-sized adults; however, some children have serious growth disturbances that may prevent them from reaching normal adult size. The Newcastle study in England (12) supported the need for an explanation of the cause of short stature in all children whose height falls below the third percentile. Almost half of the 5000 infants born in Newcastle in 1960 were measured for height at age 10. The height of 111 children fell below the third percentile: 16 were found to have a previously unsuspected organic disease as a cause of short stature. These findings demonstrate that it is unusual for a ‘‘normal’’ child to have a height below the third percentile, although most of these children may be healthy. However, it may also be inferred that in 10–15% of children who are short, a pathological condition may be found to account for the short stature. Therefore, the cause of short stature should always be investigated in all children whose height is below the 3rd percentile and more importantly in those who fail to grow at appropriate growth rates. Growth-related disorders are also the most frequent problems encountered by pediatric endocrinologists. Pediatricians often seek consultation to help in the diagnosis and management of children with growth disturbances and these children are referred to pediatric endocrinologists. Even in a pediatric endocrine referral center, a large pro-

3

portion of patients with short stature are usually healthy children. At times children are referred for short stature although they are of normal height. This may be because of either poor, inaccurate measurements, or because of the need of a pediatric endocrinologist to reassure a patient or family when a child is growing in the lower end of the normal range. A pathological condition accounted for poor growth and/or short stature in about one-third of the shortstature patients seen in a tertiary referral center (13).

Ill.

DIAGNOSIS OF SHORT STATURE

In most instances of short stature a diagnosis is usually made, although in some patients the cause of short stature may defy the differential diagnosis of numerous experts. The different causes of short stature in children are listed in Table 1. This classification differentiates most forms of short stature into two main categories: short patients who are normal and short patients who have an abnormality that produces the short stature and poor growth. These basic concepts should be considered in the diagnosis of all short patients. That is, one must differentiate between the short child who is healthy and growing normally from those who are sick and not growing well. This is most important, since a clinician must determine if a short child is subject to a pathological cause, which must be diagnosed to provide adequate treatment, from one who may only need reassurance without a major work-up. Each of these two possible categories of short stature denotes not only the cause but also the pathophysiological process involved and the prognosis for final adult height. The specific applicable situation should be recognized by the physician before subjecting the patient to expensive and complicated investigations. Other classifications to determine the different categories of short patients have been used by pediatric endocrinologists. For example, familial or genetic short stature was referred to as ‘‘intrinsic shortness.’’ Constitutional growth delay was called ‘‘delayed growth,’’ and all other disorders resulting in poor growth were called ‘‘attenuated growth’’ and/or ‘‘normal variance short stature’’ (14). Other authors have used the term ‘‘idiopathic short stature’’ to describe short individuals who are growing poorly, who have no demonstrable functional abnormality in growth hormone secretion, and whose parents are normal in height (15). Idiopathic short stature often implies a continuum of growth hormone insufficiency, not clearly demonstrable by the classic biochemical criteria (Chapters 2, 3 and 41). However, these terms to classify short patients are unnecessary because the two categories proposed above are inclusive and sufficient to understand and clarify growth problems. A specific diagnosis can usually be made to define the patient’s condition by appropriate observations. These include accurate measurements over time and specific comprehensive testing when the usual laboratory data do not define the diagnosis.

4 Table 1

Lifshitz and Botero Causes of Short Stature

Normal Constitutional growth delay Genetic-familial short stature Constitutional growth delay and familial short stature Pathological Nutritional Hypocaloric Chronic inflammatory bowel disease Malabsorption Celiac disease Zinc deficiency Endocrine Hypothyroidism Isolated growth hormone deficiency Hypopituitarism Excess cortisol Precocious puberty Chromosome defects Turner syndrome Down syndrome Low birth weight short stature (intrauterine growth retardation) Sporadic Characteristic appearance Russell-Silver syndrome De Lange syndrome Seckel bird-headed dwarfism Dubowitz syndrome Bloom syndrome Johanson-Blizzard syndrome Bone development disorders Achondroplasia Chondrodystrophies Other skeletal disorders Metabolic Mucopolysaccharidosis Other storage disorders Chronic disease Chronic renal disease Chronic liver disease Congenital heart disease Pulmonary (cystic fibrosis, bronchial asthma) Poorly controlled diabetes mellitus Chronic infections (including human immunodeficiency virus infection) Associated with birth defects or mental retardation Specific syndromes Nonspecific defects Psychosocial Chronic drug intake Glucocorticoids High-dosage estrogens High-dosage androgens Methyphenidate Dextroamphetamine

Pediatric endocrinologists believe that short stature by itself may not be of concern for the individual, if he or she is healthy. However, there is ample evidence that height may play a role in the risk for adult-onset disease. For example, in large population studies it was found that short stature raises the risk for coronary heart disease. The Physician Health Study (16), the Framingham Study (17), and the Royal Canadian Health Force Study (18) showed that the size of the individual was important as a risk factor for myocardial infarction in adults. Although the mechanisms for the increased risk were not elucidated, they may be related to the size of the coronary arteries, which would be expected to be smaller in shorter individuals. Thus, they would be more prone to be blocked by atherosclerotic plaque than in taller adults who would have larger arteries.

IV. A.

GROWTH PATTERNS Growth Progression

The most important tool to assess growth problems in a short child is to evaluate the pattern of growth. Growth is a continuous process that starts at conception and ends with fusion of the epiphysis after pubertal development is completed. At any time during this process there may be variations or alterations in growth progression. These can only be identified with accurate measurements over time. Unfortunately, the most frequent method of measuring height, using a flip-up horizontal bar on a weighing scale, is subject to great errors caused by the child’s slumping posture and considerable variation in the angle of the horizontal bar. Children should be measured standing upright and fully extended against a wall or firm vertical structure to which a properly mounted, accurate measuring device is attached. A steel tape measure, properly affixed to the wall, serves this purpose well and economically. The child stands shoeless, heels down, as erect as possible, and with the head directly forward. The back of the head, chest, gluteal area, and heels should touch the vertical surface. A firm object (e.g., a carpenter’s angle) is then placed at a right angle over the top of the head and against the wall above the head. A Harpenden stadiometer (Holtain Limited, Crymych, Dyfed, UK), which determines height accurately (within 0.25 cm) is the most sophisticated instrument (19). However other devices are less expensive and/ or are comparable in accuracy to the more expensive Harpenden stadiometer (20). Thus previous height and weight data are useful and very important in the assessment, if these measurements are accurate. The data must be plotted on standard growth charts to evaluate the pattern of growth. A normal pattern of growth may be defined as a pattern of progression of height and weight compatible with established standards for age, and that is appropriate for the genetic potential of the individual. It should also be appropriate for the

Worrisome Growth

various growth patterns of specific patients, stages of development, racial groups and population types (19–28) (Chapter 43). On the other hand, pathological growth should always be considered in children who do not grow well regardless of height (Fig. 1). Any child who falls behind in growth across major percentiles in the chart should be evaluated, even when the height is not below the 3rd percentile (29). It must be kept in mind that growth is not continuously linear, but instead occurs in steps between saltation and stasis (30). Therefore, growth progression over a long period of time is more informative than extrapolations based on shorter periods of time. The growth rate varies according to the seasons, generally being fastest in the spring and summer. The growth rate in the fastest 3-month period is two to three times higher, but could be up to seven times the height increment during the slowest growth period in the other months (31, 32). Therefore, growth progression should be evaluated over a period of at least 6 months to 1 year (15). In addition, there is a great variation in the growth at different stages of life. In the first year of life, linear growth is very fast: a total of approximately 25 cm is gained. However, the rate of growth declines rapidly over the first year, from 38 cm/year in

5

the first 2 months to 28 cm/year at 4 months of age and 12 cm/year at 1 year of age (33). In the second year of life it is 10 cm/year, in the third through fourth years 7 cm/year, and in the fifth through sixth years 6 cm/year. From then on to puberty it is 5 cm/year (31, 32). Guidelines for abnormal growth rates adjusted for chronological age are as follows: fewer than 7 cm/year under age 4 years, fewer than 6 cm before age 6, and fewer than 4.5 cm from 6 years until puberty. At this stage growth acceleration ensues. Pubertal growth spurt occurs during early puberty and before menarche in girls (Tanner stages II–III), during which time they grow at a mean velocity of 10.3 cm per year. The pubertal growth period is longer in boys than in girls. The growth data of each patient must be plotted on the appropriate chart for that particular child. As mentioned above, new standards for the general population have been established and the recent CDC growth charts are recommended for use (5). In addition, growth velocity charts may be helpful because these take into account different stages of growth such as pubertal growth spurt. As mentioned above, the Eurogrowth Program is an excellent tool for use in infants up to 36 months of age, as it considers most variables that may influence growth progression at this stage in life (7–11). However, monitoring weight gain in short-stature patients is as important as following the height progression. Changes in weight progression may precede alterations in height increments in certain conditions such as nutritional dwarfing and obesity (34–37). Therefore, monitoring height alone does not provide sufficient information to assess a growth pattern, as discussed in the section of nutritional growth retardation. Accurate weight measurements should be made on a regular hospital weighing scale. An infant should be stripped of clothes and diapers, and older children should wear a hospital gown or light clothing. These measures minimize inaccuracies resulting from variability in clothing weight, which varies with season. Adherence to these rules is important if we are to take note of changes in weight over time.

B.

Genetic Potential

The genetic potential of the child should be considered in the evaluation of the present growth pattern. Any deviation from the expected height for the family should be worrisome (38). For this purpose, formulas and standards for target height for the family and predicted adult height have been developed. The following formulas provide an easy way of estimating the target height:

Figure 1 The growth patterns of three patients with short stature and one patient with pathological growth disorder who nevertheless was of normal height. The patient with pathological short stature received treatment at age 17 and attained catch-up growth. (From Ref. 13.)

For males: (mother’s height ⫹ 13 cm ⫹ father’s height) divided by 2 For females: (father’s height ⫺ 13 cm ⫹ mother’s height) divided by 2 This formula provides the midparental height ⫾2 SD (1 SD would be equivalent of about 5 cm). However, It

6

is important to remember that the parents’ heights should be measured and not guessed. The target height obtained by this method is then applied to the 20-year line of the gender-appropriate growth chart. The projected height is determined by extrapolating the child’s growth along his or her own channel. If the projected final height is within 5 cm of target or midparental height, the child’s height is appropriate for the family. On the other hand, if the difference between the target and the projected height is more than 5 cm, a pathological cause should be considered. A simple way of evaluating whether a child is within the normal limits of height for the family is to compare the stature of the patient with the midparental height in charts developed specially to assess the correlation coefficient of these variables (38) (Fig. 2). This correlation coefficient changes little between ages 2 and 9 years. For this norm, a simple chart plotting the age in relation to parents’ heights can be constructed with the usual percentile for the family stature. Figure 2 depicts charts of three patients with different diagnoses. Patient A’s height falls on the third percentile, and his parents’ heights midpar-

Figure 2 The Tanner standards for height of girls and boys from 2 to 9 years in relation to parents’ height. (From Ref. 48.)

Lifshitz and Botero

ental have an average of 157 cm. The position of this patient’s stature in the chart is between the 10th and 25th percentiles. Thus, for the population at large, this patient would be small, but he would be appropriate for his immediate family. Therefore, this patient may have familial short stature. In contrast, patient B, who has the same height as patient A, has parents of average height (midparental height 167 cm). This means that patient B is actually very short for the family and requires further workup. Patient C is a more extreme case: his parents are actually tall. Although this patient’s height is equal to that of the other two patients, his stature falls more than 3 SD from the family norm. In addition to the projected target height, the predicted adult height should also be considered in the evaluation of the short child. There are three popular methods of calculating a child’s predicted adult height. These are based on the fact that in a normal individual, there is a direct correlation between the degree of skeletal maturation and the time of epiphyseal closure, which is the event that ends skeletal growth. Predictions of ultimate height consider the fact that the more delayed the bone age is for the chronological age, the longer the time before epiphyseal fusion ends further growth. However, predictions of ultimate adult height are not totally accurate and are of limited value in children with growth disorders, since the predictions vary if children do not grow at normal rates. The data also may not be accurate for short patients from very short parents’ (39). It has been shown that children from very short parents may end up taller in adult stature, and their target height and their predicted height may be underestimated. The Bayley-Pinneau method is the most commonly used method to assess the predicted height (40). This method is based on the postulate that skeletal age at the time of the radiograph study correlates well with the proportion of adult height that the child will achieve. This correlation is more accurate after 9 years of age. The Tanner-Whitehouse (TW) method utilizes TW standards for the assessment of the bone age (41). In addition to bone age, this method takes into consideration actual height, chronological age, parental heights, and, in girls, the occurrence of menarche. The third method used in predicting adult height is the Roche-Wainer-Thissen (RWT) method. This method gives attention to the weight or nutritional status of the child (42). Additionally, recumbent length is used instead of standing height. The five predictor variables in this method are recumbent length, weight, bone age, chronological age, and parental heights. One of the main sources of inaccuracy of adult height prediction is the inaccuracy of the bone age estimation. A small difference in bone age determination can lead to a great difference in height prediction, especially during the pubertal growth spurt (43). Comparability studies of the various methods of adult height prediction suggest that the RWT method is the most accurate, but it involves the

Worrisome Growth

greatest amount of calculation. Its inaccuracy increases with age, and it therefore should not be used when more than half of the bones are adult (42, 43). In general, height prediction methods differ with respect to their accuracy and their tendency to overestimate or underestimate adult height (43). However, height prediction, as such, is useful only in children with normal growth rates and has limited usefulness in children who are not growing at normal rates. The calculation of target height for the family and the predicted adult height (by all three methods) can be done by computer programs developed for this purpose (ARC Software). Currently several manufacturers of growth hormone provide software at no cost to the clinician with which to follow patients with growth problems and the means to assess the information needed for a precise diagnosis.

C.

Bone Maturation

In order to assess properly the predicted adult height, accurate bone maturation patterns are necessary. The two most commonly used methods of assessing the maturation or skeletal age are the Greutich and Pyle (G–P) (44) and the Tanner-Whitehouse (TW2) methods (41). The former method utilizes standards derived from US children living in Cleveland; the latter was derived from British children (45). The G–P method of assessing bone age is usually done by comparing an x-ray film of the frontal view of the left hand and wrist with given standards of the G–P atlas. The TW2 method is always done by assigning scores to each of the 20 hand bones, including the radius, ulna, carpals, metacarpals, and phalanges, depending on their stage of maturation. The total score determines the bone age. The advantage of the TW2 method over the G–P method is that it appears to be more objective. Moreover, it can differentiate bone age up to one-tenth of a year, whereas the G–P method gives only a rough approximation, with intervals of 6–12 months between the standards. Thus, the TW2 method is more sensitive in following small changes in bone age, but it is more timeconsuming and few clinicians used it. Studies comparing the two methods of bone age determination in the same ethnic population among children aged 2–24 years suggest that the median G–P skeletal ages were markedly greater than the corresponding chronological ages, particularly from 6 to 9 years in boys, and from 4 to 8 years in girls (45). The differences between these scales could be a result of real differences in the rates of skeletal maturation in the different populations. Studies were also done to determine whether there are significant differences among methods of evaluating skeletal age in relation to the group of bones studied. The results showed that when bone age is assessed by examining all the bones, but excluding the carpals, there is a high correlation with the bone age detected by measuring the maturation of all bones, including the carpals (45).

7

The bone maturation pattern is also helpful in differentiating the type of short stature. The bone growth in children with constitutionally delayed growth is slightly retarded (2, or at the most, 3 years), and it is usually proportional to height. When adolescence begins and the growth spurt occurs, the bone age increases proportionally to height. The bone age in patients with familial or genetic short stature is seldom retarded more than 1 year compared with chronological age, and it usually follows a normal maturation pattern. In contrast, there may be a marked bone age delay in children with pathological short stature, such as hypothyroidism, growth hormone deficiency, or chronic disease. The bone age may be even further behind than that expected for height. A short adolescent with sexual infantilism and a bone age maturation delay greater than 3 years is more likely to have pathological short stature, such as that caused by hypopituitarism or hypothyroidism. The degree of the delay may also reflect the length of time the patient has had the disease.

D.

Body Proportions

Aside from body weight, height, and bone progression, attention must be given to the changes in body proportions during growth (46). The skeleton does not grow in a completely proportional manner. At birth, the upper to lower body ratio is 1.7. As the legs grow, the ratio becomes 1.0 by 10 years of age. If growth plates close early, as in precocious puberty, the proportions are those of a child, with short limbs compared with the trunk. On the other hand, if growth is prolonged as in hypogonadism, the limbs are longer compared with the trunk (47). Various types of tubular bone alterations are often found among short patients (48). These categorize patients into specific diagnostic groups and potential treatments. Thus, aside from accurate measurement of height, weight, and target and predicted height, every child who presents with a growth problem should be evaluated for disproportionate limb or trunk shortening. This information helps to narrow the differential diagnosis, including ruling out skeletal dysplasia. A detailed anthropometric evaluation of a child’s body segments is indispensable. The arm span should be measured with the patient standing against a flat wall, the arms stretched out as far as possible to create a 90 degree angle with the torso. The distance between the distal ends of both middle phalanges is measured to determine the arm span. Normally, the arm span is shorter than the height in boys under the age of 10–11 years and in girls under 11–14 years, after which the arm span becomes longer than the height. The average adult male has an arm span about 5.3 cm greater than his height, and the adult female has an arm span 1.2 cm greater than her height (Chapter 43). Conditions that adversely affect the vertebrae may result in growth retardation and disproportionately long arms. Children with arm spans that are disproportionately longer than their heights should also be evaluated for scoliosis.

8

Determination of the upper and lower body segment is also essential because skeletal dysplasias that result in growth problems are usually characterized by disproportionate shortening of the lower limbs or spine (Chapter 4). This can be done by measuring the distance between the upper border of the symphysis pubis and the floor in a patient who is standing against a flat wall in the proper position for height measurement. This measurement is difficult to obtain accurately, because the superior border of the symphysis pubis is not easy to locate and palpate, particularly in some obese patients. Preferably, the sitting height can be measured to represent the upper segment, using a Harpenden sitting table (Holtain Ltd.). The patient is asked to sit on the table with the back of the knees touching the table edge. The vertical unit is then moved close to the patient’s back and the patient positioned so that the entire back, including the back of the head, touches the vertical surface. The sitting height is indicated by a counter, and the sitting height to standing height ratio, or relative sitting height, is calculated and multiplied by 100. The normal absolute and relative sitting heights of the different ages and sexes are listed in chapter on Reference Charts (Chaper 43). Conditions that cause disproportionate limb shortening include achondroplasia, hypochondroplasia, and Turner syndrome. On the other hand, the trunk height may be disproportionally shorter than the limbs in scoliosis or in spondyloepiphyseal dysplasia (Chapter 4). The determination of rhizomelia should be made by accurate measurements of the proximal and distal segments of the limbs. This is important to assess for skeletal dysplasias, some of which may present clinically as short stature, without any other associated feature, such as mild

Lifshitz and Botero

hypochondroplasia or short-limbed short stature of genetic or familial nature (48). Disproportion between the upper arm and forearm length may be determined by measuring the shoulder-to-elbow (SE) length and the elbow-to-metacarpal length (EMC; Fig. 3) using an anthropometer. For SE length, the blades of the anthropometer are positioned from the midshoulder to the distal end of the humerus, with the elbow at a 90 degree angle and the upper arm next to the lateral side of the chest. To obtain the EMC length, the blades are positioned from the tip of the elbow to the distal end of the third metacarpal of the closed hand. Normally, the SE/EMC ratio is about unity. Rhizomelia is present if this ratio is lower than 0.98 (48). The presence of shortening of specific bones may likewise lead to the diagnosis of certain syndromes, such as type E brachydactyly (49), Turner syndrome (50), or pseudopseudohypoparathyroidism (51). These patients may be seen by the physician because of short stature and must be differentiated from those with familial genetic and short stature in whom metacarpal bone shortening and other tubular bone shortenings are very prevalent (48, 52). To detect metacarpal shortening, a ruler is placed in front of the patient’s fist. In most of the normal population the three knuckles of the third, fourth, and fifth fingers touch the ruler simultaneously. In brachymetacarpia V, however, there is a gap of 2 mm or more between the fifth knuckle and the edge of the ruler, as shown in Figure 4. This clinical observation has been confirmed radiologically (52). In patients with Turner syndrome and pseudopseudohypoparathyroidism, fourth metacarpal shortening is frequent. This can be detected radiologically and clinically in a manner similar to that used to detect fifth metacarpal bone shortening (50, 51). There is a gap be-

Figure 3 Measurement of shoulder-to-elbow length (SE) and elbow-to-end-of-third metacarpal length (EMC) is shown using an anthropometer. SE is the distance between the shoulder and the tip of the elbow, whereas EMC is the distance between the tip of the elbow and the distal end of the third metacarpal on a closed fist. (From Ref. 48.)

Worrisome Growth

9

Figure 4 A straight ruler is applied against the distal ends of the third, fourth, and fifth metacarpals of a tightly closed fist. The clinical observation of brachymetacarpia V was confirmed radiologically when the fifth metacarpal bone failed to intercept a straight line connecting the distal ends of the third and fourth metacarpal bones by more than 2 mm. (From Ref. 52.)

tween the fourth knuckle and the edge of the ruler, which touches the third and fifth knuckles simultaneously. Standards at various ages for all body parts have been established (46), and the handbook of auxological measurements should be a part of every physician’s reference library to help in the evaluation of growth problems and other syndromes. Recently the so-called SHOX gene was located in the short arm of the sex chromosome. This acronym stands for short stature homebox and defines a deficiency of one copy of the SHOX gene (53). It is believed to be the cause of some forms of short stature, including Turner syndrome (54) and Leri Weill syndrome (55). It is believed to play a significant role in growth problems with disproportionate short limbs and tubular bones alterations, particularly in patients with Madelung deformity (i.e., shortening and bowing of the radius with dosral subluxation of the distal ulna, and partial foreleg anomalies) (53). It remains to be established whether SHOX plays a role in other more common forms of short stature, such as children with brachymetacarpia or milder forms of rhi-

zomelia. This test is now available for clinicians (www. esoterix.com).

E.

Physical and Dental Examinations

Aside from obtaining accurate anthropometric measurements, a detailed physical examination may help to elucidate the cause of short stature or growth failure. Specific stigmata are present in common dysmorphology syndromes, such as Russell–Silver syndrome, Williams syndrome, Turner syndrome, and Prader-Willi syndrome (49). Signs of chronic illness should be looked for, such as pallor, dry skin, abnormal hair texture, splenomegaly, enamel hypoplasia, or dental caries. An important part of the physical examination that may provide insight into a child’s maturational development is evaluation of dental age. Tables 2 and 3 list the ages at which primary and secondary teeth are expected to erupt (56). Remember that there are wide variations in the time of eruption, which may be affected by local and environmental factors, such as the size of the jaw, position of the unerupted teeth, and premature loss of deciduous teeth (57).

10

Lifshitz and Botero Table 2 Average Age at Eruption of Primary Teeth Tooth Central incisor Lateral incisor Canine First molar Second molar

Age (months) 6–9 7–10 16–20 12–16 20–30

Children with growth hormone deficiency or untreated hypothyroidism usually have a significantly delayed dentition or abnormal teeth (i.e., hypodontia, usually of the upper incisors), potentially associated with the epidermal growth factor gene on chromosome 4 (58–59). Mild delays in dental progress may occur in constitutional delay of growth and development.

V.

CONSTITUTIONAL GROWTH DELAY

The most common cause of short stature and sexual infantilism in the adolescent is constitutionally delayed growth and sexual development. This diagnosis constitutes a large proportion of the growth disorders seen by pediatric endocrinologists. The total incidence in the population may even be higher, because pediatricians usually do not refer these patients to an endocrinologist. This entity is characterized by short stature as a variant of normal growth. These patients are the typical ‘‘slow growers’’ and

Table 3 Average Age at Eruption of Secondary Teeth Tooth Maxilla Central incisor Lateral incisor Canine First premolar Second premolar First molar Second molar Third molar Mandible Central incisor Lateral incisor Canine First premolar Second premolar First molar Second molar Third molar

Age (years) 7–8 8–9 11–12 10–11 10–12 6–7 12–13 17–25 6–7 7–8 9–11 10–12 11–12 6–7 11–13 17–25

‘‘late bloomers,’’ with a familial prevalence. Often it is recognized long before adolescence, when sexual development is not yet a concern. The child with constitutional delay of growth and development typically is characterized by a deceleration of growth occurring during the first 2 years of life, followed by normal growth progression paralleling a lower percentile curve throughout the rest of the prepubertal years, until a late catch-up growth or growth spurt occurs in adolescence (Fig. 5). Fathers usually report a similar pattern of growth and delayed puberty. Patients with constitutional growth delay usually follow a familial pattern of growth; growth delay is itself inherited from multiple genes from both sides of the family. There may be no short stature in the family, but there may be similar growth patterns. Usually it occurs in boys, only occasionally in girls. The diagnosis of constitutional growth delay in girls should be made only after eliminating other possibilities of pathological growth patterns (60). In a longitudinal study it was clearly shown that growth progression in patients with constitutional growth delay slows within the first 3–6 months of life (61). Both height and weight gain decelerate, and infants destined to have constitutional growth delay downcross percentiles until age 2–3 years (62). Thereafter, they grow at a normal rate until adolescence. This type of recanalization of growth is also seen in infants with familial short stature (see below). However, body weight progression differs between the two types of infants. In patients with constitutional growth delay, body weight gain slows, whereas in those with familial short stature it does not. Thus, patients with constitutional growth delay appear to fail to thrive with body weight deficits for length, whereas infants with familial short stature maintain a normal, or even an excess, body weight for length. These growth patterns are maintained throughout childhood, but before puberty patients with constitutional growth delay patients exhibit body weight gain and recover the body weight deficits for height before exhibiting sexual development (62). These data suggest that in constitutional growth delay there may be an association with suboptimal nutrition at the time that weight progression decreases in infancy. Of interest is that in developing countries suboptimal nutrition was shown to produce a growth pattern similar to that of constitutional growth delay (63). In children with growth failure due to primary malnutrition, when the nutritional intake improved, growth resumed at a lower percentile, as in patients with constitutional growth delay. Once there was downregulation of the growth, the patients canalized their growth at a lower level than that before the nutritional insult. A similar pattern of growth retardation may be induced in experiments with rats subjected to suboptimal nutrition. When given a low-protein diet they ceased growing. When a normal dietary intake was provided they resumed growth at an appropriate rate, but in a lower percentile (64). In these rats there were long-

Worrisome Growth

11

Figure 5 Constitutional growth retardation. Left: Note the readjustment of the growth channel and weight percentile in early infancy. Right: Note the progression of height and weight below, but parallel to, the lower percentile. Body weight deficits for height are evident. There is delayed pubertal growth spurt eventually leading to normal predicted adult stature, which is in range for the target height. (From Lifshitz F, Tarim O, Worrisome growth patterns in children. Int Pediatr 1994; 9:181–188.)

term alternations in growth hormone and insulin secretion after the temporary dietary protein restriction in early life. These alterations in the neurosecretory axis, together with subnormal insulin secretion, likely correlated to the lack of catch-up growth. These data suggest that the downregulation of growth in the early life of patients with constitutional growth delay may also be nutritionally related, although it is not clear why these infants would ingest insufficient nutrients for growth at this stage of life. These patients appear to have failure to thrive, and the differential diagnosis may be difficult while the recanalization of growth is taking place. Patients with constitutional growth delay may also show an apparent deviation from the normal curve sometime between 10 and 14 years. However, this may represent merely the difference between the prepubertal child with constitutional delay of growth and development and the average child already having a pubertal growth spurt. There is also a 2–4 year delay in skeletal maturation, retarded sexual development, and a 60–90% incidence of a familial history of delayed growth and pubertal development (65). The mechanism of this phenomenon is still unclear. Some investigators consider it the result of a tran-

sient or partial growth hormone deficiency (66–68). Other groups believe that it is the result of permanently diminished growth hormone secretion during sleep (69) or modifications in the region of the IGF-I gene (70). Some investigators think that the growth hormone alterations in these patients are caused by a deficiency of testosterone or estrogen, which are known to stimulate the production and secretion of growth hormone (71). In most patients with constitutional growth delay, however, there are no abnormalities in growth hormone secretion, nor are there any other detectable endocrine alterations (72). However, some authors believe that there may be a partial growth hormone insensitivity (73). Although children with constitutional delay attain a normal height during adulthood, they generally end up along the lower end of the normal height for their family (74, 75). Studies have shown that in boys with untreated constitutional delay in growth and puberty, there was no significant difference between final and predicted adult height, but there was a significant difference between final height and measured midparental height. Thus, although these boys reach their predicted height, they were short for their families (74, 76). This is probably the result of

12

the lower peak height velocity attained by later maturers than normal or early maturers (77). Other factors may play a role: for example, the selection for presentation to the clinic probably accounts for the finding that children with constitutional growth delay do not, on the average, attain the average percentile of their parents as expected (74). This may indicate that only the smallest of the sibships come to the attention of the physician (65). Also, this could be due to the possible effects of suboptimal nutrition (62) on the ultimate height and bone development. Based on various data available, it can be concluded that a child with constitutional delay of growth and puberty with a target or predicted height of 3 SD below the population mean is unlikely to reach the normal adult range of height (75, 78). Most patients with constitutional growth delay are also short for genetic reasons. Children who have this type of short stature and who come to the attention of the pediatric endocrinologist have both constitutional growth delay and familial short stature. If a child is destined to be an average-sized adult (50th percentile) but has a 2 year delay as a child, at age 10 he or she is at the population fifth percentile. At 14 years, he is 5 cm below the general population’s fifth percentile. Such patients may not come to the attention of the pediatric endocrinologist, especially because one or both of the parents may remember that he or she was a late bloomer and realize what is happening. On the other hand, if a patient is destined to reach only the 10th percentile as an adult and is 2 years late as a child, then at age 14 he would be about 2–3 cm below the third percentile, that is, more than 2 SD below the mean, and therefore likely to be referred for an endocrinological work-up. The typical boy with this syndrome is otherwise healthy, 10 years of age, and with the height and bone age of an average 8 year old. At the age of 12 (2 years later), height age and bone age are appropriate for age 10 years. Linear and skeletal growth remain consistent, but delayed, until his adolescent growth spurt takes place and secondary sexual characteristics appear. This condition is often difficult to diagnose when the patient is first seen unless measurements at various earlier ages are available, and follow-up height increments are assessed. The main concern with these patients is the psychological aspect of both the short stature and the lack of secondary sexual characteristics. In severe cases there may be a defective self-image and social withdrawal. Treatment of patients with constitutional growth delay with or without familial short stature is controversial. The practicing physician is now under mounting pressure to prescribe human growth hormone (hGH) for short children who are not deficient in this hormone. The medical literature contains reports of improved growth with this treatment in ‘‘normal short children’’ who are experiencing a variety of combinations of constitutional delay and familial short stature (14, 79). To date, there is no definite evidence that even when such children transiently respond with improved growth rates with growth hormone treat-

Lifshitz and Botero

ment, or any growth-promoting agent for that matter, there will be a permanent beneficial effect on ultimate stature. Papers published in recent literature on this subject demonstrate that there may be a mild improvement of the adult height of these patients (80, 81). A randomized trial of growth hormone in short–normal girls clearly showed that those treated with growth hormone for up to 10 years attained an ultimate height of 5–10 cm above that of those who did not receive this medication (82). These data are important as the clinician now has information to base a clinical decision regarding the potential benefits of treatment. The potential gain of a few centimeters in height has to be considered with regard to the long-term treatment necessary to induce the extra height, potential side effects, and cost. For a complete review of the subject of growth hormone treatment of short children, the reader is referred to Chapter 3 on growth hormone treatment. Although puberty eventually occurs spontaneously, treatment with testosterone in boys for a limited duration is recommended primarily for amelioration of the psychological problems associated with delayed puberty (83). However, treatment is recommended only if the bone age is greater than 12 years. Before this age, there may be a risk of inappropriately advancing the bone age and thus compromising the eventual adult height (84). The recommended dosage is 50 mg intramuscular testosterone enanthate or 170 mg of the cypionate form every month for 4–6 months. The 6 month course can be repeated if puberty does not progress spontaneously. Methyltestosterone may be used, but it may have potential toxicity to the liver. The use of anabolic steroids has been utilized to stimulate growth as well as to promote sexual development (85–89). Ideally, this should promote both these objectives with minimal side effects and without danger of damage to the gonads or a decrease in the patient’s final adult height. In addition, there seems to be a psychological advantage to inducing puberty in patients who might otherwise have very delayed maturation. Treatment with these medications should be reserved for patients who have attained the psychological development appropriate for puberty. Therapy may not be indicated in any patient with a chronological age of under 12 years or a bone age under 10 years. One should always keep in mind that anabolic steroids given for short periods may accelerate growth and bone maturation, but will not increase ultimate height. In fact, they may even prevent attainment of maximum height potential. Fluoroxymesterone is an anabolic compound that seems to be the best growth-promoting agent available. Long-term studies have shown that this drug causes accelerated growth without adversely causing rapid bone maturation or compromising adult height. For a comprehensive review of the effects of oxandrolone on growth, the reader is referred to an excellent article published elsewhere (89). Aside from androgens and anabolic steroids, other pharmacological agents that have been used in the treat-

Worrisome Growth

ment of these children who are not growth hormone deficient include propranolol, clonidine, and dopaminergic drugs, such as L-dopa (levo-dopa) and bromocriptine (90– 93). Clonidine treatment of constitutional short stature improved the growth of some, but not all patients treated, nor in placebo-controlled studies (91–93). Other drugs used include luteinizing hormone-releasing hormone administration at physiological intervals to stimulate testosterone production by means of pituitary gonadotropin secretion (68). However, these regimens are expensive and cumbersome. Although these drugs have been shown to increase growth hormone secretion, the growth-promoting effects are debatable. Also, long-term studies on their effect on the final height of children treated by such drugs are not promising (89, 93). The decision to use pharmacological intervention must necessarily be based on the patient’s emotional outlook and the severity of delay. Most children with constitutional delay of growth and development are able to cope with this condition, if they are properly reassured about their ultimate height and development. This diagnosis, by definition, presages eventual normal maturity and height without medical intervention. A good deal of

13

caution is warranted when treating such a benign alteration, although the induction of more rapid maturation with medications is an immediate reward. A careful assessment of the nutritional intake is recommended, with particular attention to deficits in micronutrients, iron, and calcium, since these patients may have decreased bone density as adults (94). If deficits are uncovered, nutritional therapy is recommended.

VI.

FAMILIAL SHORT STATURE

Familial short stature has also been defined as genetic short stature. These patients are short throughout life and are short as adults, but characteristically they grow at normal rates in their own percentile (see Fig. 1); however, their height is within normal limits when allowance is made for parental heights (95). The growth of these patients in infancy reveals that growth channels were reduced some time between 6 and 18 months of age (62) (Fig. 6). After 2–3 years of age growth assumes a steady channel below the fifth percentile. This is because a child’s size at birth is mostly determined by maternal fac-

Figure 6 Familial short stature. Left: During infancy, the height progression is readjusted to growth channel, which is more appropriate for the genetic potential. Right: The new height percentile is maintained without further fall-off from the lower percentile, and the weight is appropriate for height. Note that short stature is life-long and there is no catch-up growth in puberty. The predicted height of the patient is in range for the target. (From Lifshitz F, Tarim O, Worrisome growth patterns in children. Int Pediatr 1994; 9:181–188.)

14

tors. After 6 months, the genetic influence predominates, and therefore a child who was born of average size may now shift to lower channels because his or her parents are of short stature. In contrast to patients with constitutional growth delay, these infants gain weight at a steady rate, do not exhibit weight deficits for height, and have no bone age delay (62). The bone age of patients with familial short stature is consistent with their chronological age, although usually there is a component of constitutional delay in growth and development. The diagnosis of familial short stature is made when the child’s height is normal, when allowance is made for parental heights, or the predicted adult height falls within the target range for the family. Tubular bone alterations were described as significantly more prevalent in children with familial short stature children and adults than in the normal height population (48). These tubular bone alterations include fifth metacarpal bone shortening (brachymetacarpia V, Figs. 3 and 4), rhizomelia, and disproportionate shortening of the arms and lower limbs. Most children and adults with familial short stature had two to four types of tubular bone alterations, whereas most individuals with normal stature had either none or only one type of tubular bone defect. A direct linear relationship was observed between the degree of shortening of the fifth and first metacarpal bones, but not of the other metacarpal bones (48). These findings suggest that in some patients with familial short stature there may be an inherited defect in endochondrial ossification, which is the major process involved in tubular bone elongation and increase in stature. This defect may result not only in overall decrease in stature but also in disproportionate limb shortening. Patients with familial short stature may show a heterogeneous group of conditions, which manifest as short stature, with or without minor tubular bone alterations, and with or without disproportionate limb shortening, and/or present short stature with no other stigmata. For example, patients with type E brachydactyly have no other skeletal abnormalities except short stature and metacarpal and metatarsal shortening (49). Hypochondroplasia, particularly when mild, may only manifest as short stature with a slight, disproportionate limb shortening and brachydactyly (96). Unless careful observations and measurements of the different body segments are made, these patients can be underdiagnosed as having only plain and simple familial short stature. In these cases, a detailed radiological study and segregation analysis of the family members must be done. The availability of SHOX-DNA studies for diagnostic purposes remains to be established as a valid indicator for clinical assessment of these types of patients (53–55). Although it is important to consider the parents’ heights in evaluating a child’s short stature, it should be remembered that a parent’s stature is not necessarily familial or genetic (39). Stature also depends on a multitude

Lifshitz and Botero

of environmental factors that may have affected a parent’s growth, including nutrition, drugs, and illness (97). Thus, considering the heights of the parents’ siblings and parents, as well as obtaining a medical history of the parents, are also important before making a diagnosis of simple familial short stature (95). In these patients as in children with constitutional growth delay, there is pressure to consider treatment to increase growth and attain an increased ultimate height. As mentioned above, evidence is now available demonstrating a small potential gain in height with prolonged growth hormone therapy (80–82). In normal girls with genetic short stature given this medication for up to 10 years, there was a mean gain of 5–10 cm in ultimate adult height compared with the group not treated (82). However, the cost of such prolonged therapy to gain a very modest height increment should always be kept in mind, as well as other potential side effects.

VII.

PATHOLOGICAL SHORT STATURE

Pathological short stature is the least frequently occurring but most serious cause of short stature. Pathological short stature should be suspected in children who do not grow normally, those with a growth velocity of less than 4.5 cm/year after 6 years of age, and in those with marked short stature. Bone maturation is usually quite delayed, often behind that expected for height. These patients usually fail to develop sexually, and the prognosis for ultimate height is dependent on the specific diagnosis (see Table 1). Pathological short stature has accounted for over one-third of the short patients referred to a pediatric endocrinology center (13). This incidence is high compared with the general population (12), but appropriate for a referral center. It is essential to recognize these patients. A precise diagnosis must be established for early treatment. Often the only evidence of disease is the growth abnormality. The disturbances found to account for the short stature in these children may vary depending on the interest of the pediatric endocrine center to which the patient is referred. The causes are most often endocrine, metabolic, or nutritional disturbances. Undoubtedly, other alterations known to interfere with growth in children, such as renal or cardiac, predominate in patients referred to these types of subspecialty centers. The specific pathological causes of short stature due to hypopituitarism, as well as Turner syndrome are reviewed in detail in Chapters 2 and 9. Individuals with Turner syndrome have sex chromosome abnormalities and often present because of short stature. The karyotype could be either pure 45,XO or a variety of mosaicism. In the latter case, the girl may present only with short stature with or without delayed puberty, with none of the dysmorphic features of Turner syndrome (Chapter 10). The pathogenesis of the short stature is unclear, but recent studies suggest a functional abnormality of the hypothalamic–pituitary axis. During an overnight study of

Worrisome Growth

their nocturnal growth hormone secretion patterns, children with Turner syndrome had a significantly decreased number and frequency of peaks compared with normal children. Moreover, their responses to acute growth-hormone-releasing hormone (GHRH) stimulation are lower. This abnormal growth hormone neuroregulation is thought to be caused by the absence of gonadal steroids (98). Human growth hormone, anabolic steroids, and lowdose estrogen therapy, alone or in combination, have been recommended for increasing these patients’ heights (Chapters 3 and 10) (99–101). Other chromosomal defects can lead to short stature, the most common autosomat abnormality being Down syndrome. This anomaly is also the most common malformation in humans; it occurs with an incidence of 1:600. These children follow a typical growth pattern (see Chapter 43: Growth Charts) and have obvious dysmorphic features. The average adult female height is about 57 inches, and the average adult male is about 61 inches. Patients have a tendency to be overweight beginning in late infancy and throughout the remainder of the growing years (25). Growth and weight gain may also be affected by a concomitant congenital heart defect. The underlying cause of short stature remains unexplained; however, low circulating levels of insulin-like growth factor I (IGF-I) and diminished provoked and spontaneous growth hormone secretion have been reported in some patients (102, 103). However, most of the studies performed on Down syndrome patients in regard to hGH secretion were done without consideration of body composition, excess fat being a known cause of decreased growth hormone secretion (104). Thus, caution is encouraged in interpreting the results of growth hormone testing in these patients or using them in justifying treatment with growth hormone. Growth hormone treatment of a small number of patients with Down syndrome has resulted in an accelerated shortterm linear growth and an increase in head circumference. However, careful and cautious evaluation of the safety, efficacy, and ethical ramifications of growth hormone treatment of children with Down syndrome is recommended before embarking on this form of intervention (105). Short stature associated with congenital anomalies is also seen with bone diseases classified as skeletal development disorders, which result in disproportionate short stature are discussed in Chapter 4. The primary error leading to the disease may affect either the cartilaginous or the bone-forming stage of bone development. More than 250 different types of bone dysplasia are known, but the cause of most of these is unknown. The classification is therefore based largely on morphological criteria rather than metabolic or molecular ones (106, 107). This disproportion seen in many skeletal dysplasias may have therapeutic implications because some bones grow better than others. Therefore, growth-promoting agents may accentuate the disparity among the various bones.

15

One group of conditions characterized by severe short stature and typical dysmorphic features is occasionally referred to as primordial dwarfism because no specific cause for the short stature is defined, and no skeletal dysplasia is identifiable. Short stature is prenatal in onset, these children are born small for gestational age, and skeletal age is retarded (58). The most notable among the causes of primordial dwarfism is Russell–Silver syndrome, described independently by Silver in 1953 and Russell in 1954. Skeletal asymmetry is a distinct feature of this disorder, as is clinodactyly of the fifth finger and small triangular face with downturning of the corners of the mouth. Cafe´-au-lait spots are usually present. De Lange syndrome typically is characterized by mental retardation, microbrachycephaly, bushy eyebrows and synophrys, and long, curly eyelashes. Patients have a small nose, anteverted nostrils, high arched palate, micrognathia, hirsutism, delayed dentition, micromelia, phocomelia and/or oligodactyly, hypospadias, undescended testes, and hypoplastic external genitals. There may or may not be associated endocrinopathies (108). Bloom syndrome is characterized by mild microcephaly with dolichocephaly, malar hypoplasia, and facial telangiectaticerythema. There may be a mild mental deficiency and immunoglobulin deficiency. Death is usually caused by a lymphoreticular malignancy (58). JohansonBlizzard syndrome is characterized by varying degrees of intellectual impairment. Clinical characteristics include hypoplastic or aplastic alae nasi, hypoplastic deciduous teeth, and absent permanent teeth. They may have cryptochoridism, micropenis, imperforate anus, hydronephrosis, septate or double vagina, primary hypothyroidism, and/or pancreatic insufficiency (58). Seckel syndrome is characterized by microcephaly, mental deficiency, premature synostosis, receding forehead, prominent nose, micrognathia, low-set and malformed ears, relatively large eyes with downslanting palpebrat fissures, clinodactyly of the fifth finger, and dislocation of the radial head and/or hips. These patients are referred to as bird-headed dwarfs because of the disproportionately large nose size in comparison with the mandible and face (58). Finally, Williams syndrome is characterized by varying degrees of mental retardation, medial eyebrow flare, short palpebral fissures, depressed nasal bridge, epicanthal folds, periorbital fullness of subcutaneous tissues, blue eyes, anteverted nares, long philtrum, and prominent lips with open mouth. Nails are hypoplastic, and there may be cardiovascular anomalies, including supra-alveolar aortic stenosis, pulmonary artery stenosis, ventricular or atrial septal defects. There may also be renal artery stenosis, hypertension, and hypoplasia of the aorta (58).

VIII.

INTRAUTERINE GROWTH RETARDATION

Intrauterine growth retardation (IUGR) refers to a pathological condition found in infants who have low birth

16

Lifshitz and Botero

weight (LBW) for their gestational age as a result of different genetic and/or environmental influences during gestation. The Third National Health and Nutrition Examination Survey showed an overall 8.6% prevalence of U.S. newborns who are small for gestational age (SGA) of all live births (109). Elsewhere the prevalence of this condition is approximately 3% (110). IUGR is especially important because of the higher incidence of morbidity and mortality in such children and the potential long-term complications of IUGR in adults. Infants with LBW are 5–10 times more likely to die in the first year of life than are normal birth weight infants (111, 112). Those who survive may present neurological and developmental disabilities, and have an increased risk of reduced rate of postnatal growth with ultimate short stature. Although some IUGR babies may grow and develop normally and attain normal stature as adults, about 10–15% do not exhibit catch-up growth and remain short throughout life (109). The association of IUGR with several adult-onset disorders has also been described and is currently the aim of broad research. An increased incidence of hypertension, cardiovascular and cerebrovascular disease, noninsulin-dependent diabetes mellitus (NIDDM), and lipid disorders have been reported in adults with clinical antecedent of LBW (113–120). IUGR has been defined most commonly as a birth weight of under the 10th percentile for the gestational age (121–123). This weight cutoff has been criticized for allowing an overestimation of the real incidence of this disorder, since this implies that 10% of normal infants will have a birth weight below the 10th percentile. However, there is a significant increased risk for fetal death in those with birth weights between the 10th and the 15th percentiles (124), but up to 70% of all SGA infants may be constitutionally small fetuses expressing their genetic potential, and may not be at risk for perinatal mobidity or mortality. The remaining 30% are growth-restricted infants because of various pathological conditions, and are at risk for an adverse outcome (125–128). The standards for fetal growth developed by Brenner et al. (129), which included 30,772 deliveries made at 21–44 weeks gestation, are very useful to evaluate the presence or absence of IUGR.

A.

Etiology

Normal uterine growth depends on the genetic potential of the fetus modulated by environmental, hormonal, and other biological factors, including maternal health and nutrition (130). Infants of small parents tend to be small, with maternal size having the greatest influence (131). Several factors play an important role in the etiopathogenesis of IUGR. Fetal growth failure may be due to extrinsic factors, mainly maternal, or to intrinsic fetal growth retardation. The extrinsic factors occur later in pregnancy as a result of placental disorders or maternal disease, which compromise the delivery of oxygen and nutrients

to the fetus. Of special importance is the nutritional status of the mother, as this has major implications on fetal growth. Chronic undernutrition, more prevalent in developing countries, is responsible for a large population of infants with IUGR worldwide. Different outcomes are observed according to the stage of fetal development at which maternal malnutrition takes place (132, 133). Early fetal malnutrition may affect growth permanently by reducing cell proliferation and size. A decrease of the cell size with preservation of cell population is the pathological consequence of later malnutrition, which might also result in growth deficit. Infants exposed to early fetal malnutrition have LBW and are symmetrically small (proportionate IUGR). Undernutrition in late pregnancy results in an asymmetrically growth-retarded infant whose head circumference is preserved as a result of a physiological adaptation (brain-sparing phenomenon), by which a major selective blood flow is directed to the brain (130). There is undoubtedly an association between maternal weight status and infant birth weight (134). Adequate prenatal care and improved maternal nutrition, through balanced calorie or protein supplementation, leads to an overall increase in infant birth weight and to a decreased rate of LBW deliveries in at-risk populations (135). These guidelines have been endorsed by the American College of Obstetricians and Gynecologists (136) and used by the supplement food programs for Women, Infants, and Children (137). Previous nutritional guidelines recommended a gain of 22–27 pounds for women of all weight categories. Currently, the Institute of Medicine recommends for underweight women (body mass index < 19.8 kg/m2) a weight gain of 29–40 pounds; for average women (body mass index between 19.8 and 26 kg/m2) 25–35 pounds; and for overweight women (body mass index between 26 and 29 kg/m2) 15–25 pounds (134). These recommendations for weight gain during pregnancy have been associated with a decreased incidence of LBW (133–137). Other maternal risk factors associated with IUGR include maternal short stature, early menarche, short intepregnancy interval, and high maternal parity. Maternal constraints of fetal growth that result in IUGR may be multigestational, an effect that may take several generations to correct (131). Often several other conditions overlap, such as chronic malnutrition and substance abuse, tobacco smoking, and alcohol ingestion (139). Mothers who live at high altitudes (>3000 m) may have systemic hypoxemia that could account for the LBW. Other maternal illnesses can impair the fetal growth because of systemic hypoxemia, including cardiac disease (mainly cyanotic type), sickle cell disease, or severe asthma. Proteinuric hypertension during pregnancy also is often complicated by growth retardation. Intrinisic fetal factors that tend to reduce the size of the baby for gestational age include various infectious agents. These are usually responsible for early onset of IUGR, and have more severe consequences, such as

Worrisome Growth

agents associated with the TORCH syndrome (toxoplasmosis, other infections, rubella, cytomegalovires, herpes simplex). Of these, rubella and cytomegaloviruses are the most important identifiable agents associated with marked fetal growth retardation. These viral agents reduce cell number and subsequent birth weight by simultaneously inhibiting cell division and producing cell death (140). Chromosomal abnormalities, including Down syndrome, trisomy 13, trisomy 18, Turner syndrome, and other major congenital malformations are other intrinsic factors that compromise the growth and development of the fetus (141). Chromosomal aberrations and single-gene defects often result in fetal growth failure by interfering with cell division. Several syndromes cause multiple congenital malformations and are associated with IUGR (141). As mentioned above, this group of conditions is characterized by IUGR and typical dysmorphic features, which at times are identified at birth (58). Included are patients with Russell–Silver, De Lange, Bloom, JohnsonBlizzard, and Williams syndromes. The role of imprinting genes on fetal growth is another area of interest in the causation of IUGR. Kohler et al. (142), reported the first imprinting gene (grf1) to be implicated only in postnatal growth control. It codes for a protein (Grf-1) found exclusively in the hypothalamus and acts as an important regulator of synthesis and release of growth hormone (GH). The Grf-1 protein is not detected in the fetus and is only slightly detectable at birth, but is clearly present on the second postnatal day. Analysis of heterozygous mutant mice for this gene confirmed that grf1 is an important imprinted gene whose deletion leads to a significant postnatal growth deficiency that persisted in adult mice. In contrast to other imprinting genes implicated in fetal growth, grf1 is the first to be related exclusively to postnatal growth control.

B.

Hormonal Influences

Neither growth hormone nor thyroid hormones are important regulators of fetal growth. Insulin has a major effect on growth and size at birth, mostly during the third trimester when it stimulates fetal lipogenic activity, including a rapid accumulation of adipose tissue. Insulin induces protein synthesis and hepatic glycogen deposition, increases nutrient uptake and utilization, and has a direct anabolic effect. In general, growth-restricted infants are characterized by fetal hypoglycemia, which limits insulin secretion and fetal glucose production with increased protein breakdown. This reduces protein accretion, which results in slow growth. In addition, insulin plays a permissive role in the release of different growth factors from placental tissues (143). The placental lactogen, a structural related placental peptide that has many GH-like actions, also seems to play an important role in fetal growth. Maternal serum concentrations of placental lactogen rise significantly in the third trimerster, parallel with a rise in serum IGF-I (144, 145).

17

IGF-I and IGF-II, which in the fetus function independently of pituitary GH, also have important effects on the growth and differentiation of various tissues. There is a positive correlation between the serum levels of IGF-1 and birth weight (146, 147). Insulin-like growth factor levels are regulated in a reciprocal direction by maternal nutritional status. Alterations in the GH–IGF axis have been reported in infants with IUGR (147, 148). Evidence exists that GH, IGF-I, and insulin-like growth factor-binding protein 3 (IGFBP-3) are regulated in a different way in SGA infants than in infants whose birth weight is appropriate for gestational age (147). There is an inverse relation between the levels of IGF-I, its major transporter, IGFPB-3, and birth weight. The cord levels of IGF-I and IGF-II are lower in SGA infants than in neonates whose weight is appropriate for gestational age (145). Also, higher basal levels of serum GH and a higher GH response to the growth-hormone-releasing hormone have been reported in SGA infants, which might be indicative of GH resistance or insensitivity (148). In IUGR infants who achieve catch-up growth, levels of IGF-I and IGFBP3 normalize. By midchildhood, higher serum concentrations of IGF-I have been found in this group of children than in normal control subjects. This may reflect a stage of GH resistance that could be the result of a different reprogramming of the IGF-I axis than that occuring in utero (149). Other potential factors may play a role in fetal growth. Weber et al. (150) found clear evidence of a relationship between birth month and body size at 18 years of age, with maximal height obtained in children born in spring and minimal height obtained in children born in autumn. The underlying physiological mechanism for this effect might involve the light-dependent activity of the pineal gland. Melatonin is active during the prenatal period via transplacental passage, and its cyclic production in the newborn is already established by 9–15 weeks after birth. Recent studies (151, 152) have shown that leptin, the product of the ob gene, a hormone produced in adipose tissue, may play a role in the nutritional homeostasis of the fetus and in fetal growth. The hormone has been detected in fetal blood as early as the 18th week of gestation. No relationship has been found between maternal and fetal serum leptin levels. The birth weight and the body mass index correlate strongly with the serum concentration of leptin in infants (152). Infants who are SGA have a serum leptin concentration equivalent to half of the values found in infants whose weight is appropriate for gestational age. In infants who are large for gestational age, the concentration of leptin is likewise three times higher than in infants who are SGA. Although not universally reported, there seems to be a gender correlation for leptin levels, with higher serum concentrations in female infants (151). Leptin levels are influenced significantly by fatty mass and are highly related to nutritional status during the

18

Lifshitz and Botero

fetal and neonatal periods. The role of this hormone in the postnatal growth of infants with IUGR remains to be elucidated.

C.

Assessment of Growth in Fetuses and Infants

The detection in utero of fetuses with IUGR may maximize the chance of survival and reduce their chance of morbidity and mortality. Ultrasound can detect up to 80% of fetuses with IUGR with great precision. However, there may be an incidence of 20% false-positive results (153). Several measurements have been implemented via ultrasound to make a diagnosis of IUGR: fetal abdominal circumference, biparietal diameter, head circumference, and skeletal length. In order to detect abnormalities in fetal growth, at least two serial ultrasound measurements should ideally be taken before the 26th week of gestation. Doppler ultrasound measurement of fetal cardiac output, systemic blood flow, and organ supply (particularly with respect to placental circulation) is a powerful tool in identifying IUGR fetuses at risk of acidemia. Cordocentesis to measure lactate concentration in fetal blood is one of the earliest markers of fetal distress. A significant correlation exists between elevated and midtrimester ␤-core fragment levels of human chorionic gonadotropin and IUGR, comparable to third-trimester ultrasound and superior to maternal serum analytes (154). This could be a promising new tool for the early prediction of IUGR in at-risk populations. At birth, the ponderal index (PI) (birth weight (g) ⫻ 100/length (cm)⫺3) is a measurement of proportionality that is simple and easily available. It has been used to determine the symmetry of infants with IUGR. Infants with low PIs have been exposed to short periods of malnutrition that compromises mostly the weight but not the length or the head circumference (disproportionate IUGR). On the other hand, infants with ‘‘normal’’ PIs are proportionate at birth and may have been exposed to a more chronic injury in utero. The ratio of midarm to head circumference, which reflects somatic muscle and fat stores, has been proposed as a better predictor of mobidity than PI (155).

D.

Postnatal Growth and Outcome

It is important to recognize that infants with IUGR even without any major disability may fail to catch up, and their IUGR may be a cause of short stature (156). It has been shown that 15–20% of infants with IUGR will have short stature by the age of 4 years and 7.9% will have short stature at 18 years of age. Infants with IUGR usually experience catch-up growth during the first 2 years of life, with most infants achieving this growth in the first 6 months of life (109). Of those children who do not show

catch-up growth, 50% will remain short as adults (125). However the most important determinants of the final height of infants with IUGR are unknown. Leger et al. (157) reported in a longitudinal study involving 213 SGA infants that the most important factors determining final height were parental height (especially the mother’s stature) and birth length, rather than variables such as gender, birth weight, or PI. Strauss et al. (158) evaluated a cohort of infants born with IUGR and found no differences in terms of risk factors (birth weight, birth length, head circumference, PI, maternal weight gain, maternal size, placental size, smoking, toxemia, or hypertension) between the infants who showed catch-up growth and those who did not, suggesting that genetic factors rather than environmental events account for the persistent effects of IUGR on growth. The importance of a genetic contribution is supported by the increased prevalence of IUGR within some families and the discovery of single-gene mutations in IGF-1 in some infants with IUGR (159). The Third National Health and Nutrition Examination Survey (109) showed a tendency of infants who were SGA at birth to be shorter and to have smaller head circumferences despite catch-up growth. In general, after an initial period of rapid growth, infants who were SGA at birth can be expected to attain growth around the 25th percentile in early childhood. Unlike term infants who are SGA, LBW infants who are born preterm usually show poorer progress. Infants with IUGR attain 80% of catch-up growth in the first 6–8 months of life (111). In those in whom catch-up growth does not take place, final stature may be compromised. However, the postnatal growth of IUGR infants often is compromised by failure to thrive (FTT). The incidence of FTT in IUGR infants appears to be high, and it is often difficult to determine if such infants are growing normally after birth without experiencing catch-up growth or if they have FTT. Kelleher et al. (160) reported an incidence of 19.7% of FTT in a cohort of 914 preterm infants with LBW who were evaluated for 3 years. Infants who experienced FTT remained smaller on all growth parameters (weight, length, and head circumference) at 36 months of age compared to their matched controls. On the other hand, IUGR infants who are labeled as experiencing FTT may be growing appropriately and may be subjected to unnecessary diagnostic and therapeutic studies (13). One example of normal growth in IUGR misdiagnosed as FTT is shown in Figure 7. The weight and length of this patient were plotted on a growth chart for normal children, not on the specific IUGR growth charts available for these infants. However, a simple examination of the anthropometric measurements of this patient ruled out the diagnosis of FTT. The patient tripled his weight by 1 year of age and quadrupled it by 2 years. His length likewise progressed well and remained proportional to weight throughout. A careful evaluation of the growth pattern and weight gain elucidated the differential diagnosis.

Worrisome Growth

Figure 7 Top. Growth patterns of a patient with intrauterine growth retardation. Bottom. The growth velocity is plotted against normal standards. Note that this patient did not have failure to thrive nor was it suspected because he was growing at a normal velocity. (From Ref. 13.)

The diagnosis of FTT cannot be sustained when the birth weight is tripled within the first year of life. This rate of growth is the one that occurs in normal children. However, this infant did not exhibit catch-up growth. Infants with IUGR who start with a tremendous size deficit and who do not exhibit catch-up growth may be expected to remain proportionally small thereafter. Aside from the absence of catch-up growth, these children with IUGR may undergo early puberty and be unusually short as adults (161). Often these children may be forced to increase calorie intake in order to grow more in length to no avail. However if weight gain progression does not occur at a normal rate, FTT must be considered. Because infants with IUGR often have other associated abnormalities such as neurological, cardiac, or pulmonary disorders, these may contribute and compromise growth and/or lead to

19

FTT. Frequently these patients also present oral motor dysfunction (162) resulting in ‘‘poor feeding.’’ Nutrient intake in LBW infants is difficult at best, and most often does not meet the recommended dietary intakes (163). There is an accumulated nutrient deficit during the first few weeks of life of energy, protein, and other nutrient alterations that has an impact on infants’ growth. The long-term consequences of this accumulated nutrient deficit may be important: as much as 45% of the growth variation was related to this. Thus, IUGR infants must be carefully monitored to ensure an adequate intake, which should allow for their maximum growth after birth. This is particularly important because growth hormone was recently approved for treatment of such infants, and this should not be undertaken without appropriate nutrient intake. Growth failure in IUGR children is a new Food and Drug Administration (FDA)-approved indication for HGH therapy (Chapter 3). With the availability of unlimited amounts of biosynthesized HGH, the possibility of improving the final adult stature of children with IUGR by giving daily injections of HGH has been assessed in several studies (164–173). Although long-term results of HGH therapy in children with IUGR are not yet available, some studies have shown a short-term growth benefit after 2–4 years of HGH therapy (164–173). A clear dose–response effect to HGH was also shown (169–171). Dosages from 0.4–1.2 U/kg have been implemented, with a better growth response occurring with the highest dosages of HGH. However, some studies have shown that by using high dosages of HGH (>1.2 U/kg) accelerated skeletal maturation occurs. This could minimize the long-term benefits of the initial growth response (161) and the final height of IUGR subjects may not differ with and without growth hormone treatment (174). High dosages of HGH have been used in infants with IUGR based on the hypothesis of a state of HGH insensitivities in this group of patients, which might be overcome by administering elevated dosages of the hormone. The use of high dosages of HGH in infants with IUGR is only recent and although HGH seems to be well-tolerated, long-term side effects have not been ruled out. Taking into consideration some data showing a potential risk for hyperinsulinism in infants and children with IUGR (115, 117–119), and since one of the potential side effects of GH therapy is the induction of insulin resistance, the use of high dosages of HGH in these patients must be viewed with caution. Although some of these studies have shown promising results with HGH therapy, this form of treatment has only been implemented for a relatively short period of time, and no long-term data on the beneficial effects on final adult height are yet available (169). In most of these studies administration of HGH was started in patients over 2 years of age (171). To date, it is not known if there may

20

Lifshitz and Botero

be a better chance to induce a higher level of recanlization of growth with an earlier onset of HGH therapy.

E.

Long-Term Effects

IUGR may have important long-term consequences, resulting in increased morbidity and mortality in adulthood. Experiments using animals (175, 176) indicate that transient events in fetal and early life might lead to permanent and significant changes in physiology and metabolism later in life. These studies have shown that undernutrition during critical period of rapid growth in fetal and early life may permanently modify the structure and physiology of different organs, including that of the endocrine pancreas, liver, and blood vessels, changing their structure and physiology permanently. In this way, hormonal physiology and tissue sensitivity could be definitely compromised, leading to disease in adult life, a phenomenon called ‘‘programming’’ (177). Hales and Barker (178), in their ‘‘thrifty phenotype’’ hypothesis, have pointed out how prenatal nutrition has an effect on fetal development that becomes evident in adulthood. This hypothesis has been supported by animal experiments. Pregnant rats fed with isocaloric, protein-restricted diet have offspring with lower birth weights, decreased ␤-cell mass, decreased islet vascularization, and impaired insulin response (176). This damage might be irreversible if a normal diet after birth does not restore a proper insulin response by adulthood. Thus, permanent endocrine dysfunction is one consequence of initial in utero nutritional insult. Epidemiological and long-term follow-up studies have shown an inverse relation between birth weight and several adult-onset diseases (178, 179). A higher percentage of essential hypertension, impaired glucose tolerance, NIDDM, ischemic heart disease, high serum triglycerides, and low serum high-density lipoprotein concentration (syndrome X) has been reported in adults with a clinical history of LBW (180). These studies have shown a reduction in insulin response in prepubertal children and adults with a history of IUGR. The lower sensitivity to insulin seen in infants with IUGR might indicate that insulin resistance is present during childhood even without clinical manifestations. Low birth weight secondary to malnutrition during fetal development might be associated with abnormalities in muscle structure and function, which could interfere with glucose uptake, normally induced by insulin. Thus the ␤-cells must produce larger amounts of insulin to keep serum glucose levels within the physiological range, which in the course of time could lead to their exhaustion. Previous studies (177–180) have shown an association of several cardiovascular risk factors with insulin resistance. Thus, the presence of insulin resistance in children with IUGR could be a risk factor for the development not only of adult-onset NIDDM (117– 119) but also of cardiovascular disease. A higher prevalence of arterial hypertension, high serum triglyceride concentrations, and low concentrations of high-density

lipoprotein cholesterol is found in adults with antecedent of LBW (177). A threefold increased risk of NIDDM in men over 60 years of age with the clinical antecedent of IUGR was reported in a Swedish study (118). A recent study of a cohort of 70,000 women from the Nurses’ Health Study (117) likewise found a strong inverse correlation between birth weight and NIDDM among more than 2000 confirmed cases of NIDDM. Women who weighed less than 5 pounds at birth had a relative risk for NIDDM of 1.83, compared with a risk of 0.83 in women who weighed more than 10 pounds at birth. It is evident that growth restricted newborns are not all created equally (181). In recent years HGH trials have demonstrated an apparent beneficial effect on patients with noncomplicated IUGR treated after 2 years of age for 2–4 years. Most of these studies (171) have shown recanalization and improvement of height, although longterm data demonstrating gain in adult height are lacking. Whether an improved height attained with HGH treatment could ameliorate some of the long-term sequelae of IUGR in adult life is not known at present. However, in very stunted IUGR patients, it can be expected that psychological adjustment could improve with treatment that results in increased height.

IX.

FAILURE TO THRIVE

The term, ‘‘failure to thrive’’ (FTT) is used to describe infants and young children whose body weight and weight gain are substantially less than those of their peers. It is defined as growth deceleration to a point below the third percentile in weight; a child who has fallen across two or more percentiles; or a child whose weight is less than 80% of the ideal weight for age. FTT accounts for 1–5% of tertiary hospital admissions for patients less than 1 year of age (182). Many more children, perhaps 10%, are managed as outpatients by physicians throughout the United States (183). Despite its established status in medical terminology, the concept of FTT lacks a clear definition and should be considered a sign or symptom, not a diagnosis or a disease (184). Children with FTT are typically diagnosed in the first few months of life and their illness may persist for years. All FTT infants have physiological alterations due to malnutrition, but the causes can be categorized as organic or nonorganic (185). Organic FTT (OFTT) involves infants who have specific diagnosable disorders. It is only identified in 20% to 40% of children hospitalized with FTT and even less frequently in outpatient clinics. Non-organic failure to thrive (NOFTT) is a subtype of FTT that accounts for the majority of infants with FTT, although the percentage varies from institution to institution. NOFTT does not imply a specific cause, but merely suggests that the cause is primarily external to the infant (186). In addition, there may be an overlap between OFTT

Worrisome Growth

and NOFTT owing to the presence of minor infections, vomiting, and diarrhea together with behavioral problems and altered eating behavior. Therefore, several authors have questioned the adequacy of this dichotomous view, suggesting the need for a third category: so-called mixed cause (187, 188). NOFTT is more than a growth problem. Children with NOFTT present a low rate of weight or length gain, delayed development, abnormal behavior, and distorted caretaker–infant interaction. Failure to thrive can be due to a variety of disorders that may have little in common except for poor body weight. Each one of them must be recognized and treated accordingly (189–191). However, the goals of nutritional rehabilitation are similar regardless of the cause. On the other hand, pediatricians should always be aware of different patterns of growth in the first years of life that can present as factitious failure to thrive (192). These patterns include patients with constitutional growth delay and/or familial short stature. Because the size of an infant at birth is more related to maternal size and intrauterine influences than to genetic factors, in some children an adjustment in growth velocity greater than 25% (across two percentile lines) takes place as a recanalization of normal growth. A significant decrease in growth rate in these conditions may represent a physiological event in the first years of life and does not necessarily indicate FTT. Also, patients with IUGR may mimic the symptoms of FTT as described above.

A.

The Breastfed Baby

Caution must also be taken in labeling an infant who is exclusively breastfed as having FTT. Because growth charts for breastfed infants are not usually used, a normal growth pattern of a breastfed baby may seem to be lower on the growth channel of the most frequently used growth charts, which are based on studies of infants who were mostly formulafed (193, 194). To date, no clear data would warrant discouraging breastfeeding of an infant whose growth seems to deviate across channels in such growth charts. Human milk is the ideal and most readily available nutrient, and should therefore be continued and encouraged as much as possible. However, breastfeeding alone may not be adequate for a particular child who indeed may be failing to gain weight appropriately (195– 197). Breast feeding must be closely monitored to ensure that adequate lactation is present and that the infant thrives at an appropriate rate as plotted on growth charts specific for breastfed babies (11). The effect of prolonged breastfeeding on growth is controversial. One study (194) demonstrated that exclusively breastfed infants had slower length velocity after 3 months of age than infants who were weaned early and given formula plus solids. This trend was more obvious at 9 months of age. In this study, relative weight for length had no deficit. The growth of breastfed and formulafed infants from 0 to 18 months of age was investigated in

21

the so-called DARLING study (198). The mean weight of breastfed infants was shown to drop below the median of the formulafed group between 6 and 18 months of age. In contrast, length and circumference values were similar between the two groups. The results of the study showed that breastfed infants gain weight more slowly than formulafed infants from similar socioeconomic and ethnic backgrounds during the first 9 months of life. A comprehensive assessment of the effects of prolonged breastfeeding on children’s growth was performed by Grummer-Strawn (199). In this retrospective analysis of 13 studies, eight reported negative relationships between breastfeeding and growth, two found a positive effect, and three showed mixed results. Even if prolonged breastfeeding is found to impair weight gain, the protection that breast milk offers against infection and other health benefits would argue in favor of preserving the policy of encouraging human milk feedings as the main food, (sole feeding for the first 4–6 months of life), particularly where sanitary conditions are poor. Prolonged breastfeedings also provide beneficial impact on birth spacing, mother–child interactions, infections, allergies, other morbidities, and infant mortality.

B.

Clinical Findings

In the NOFTT syndrome, both inadequate nutrition (i.e., nature) and distorted social stimulation (i.e., nurture) contribute to poor weight gain, delayed development, and abnormal behavior. The clinical characteristics of infants with this type of FTT include small for age, thin for length, wide-eyed expression or gaze aversion, thin chests, wasted buttocks, prominent abdomen, hanging folds under the arms, expressionless face, decreased vocalization, gross motor activity, and response to social stimuli; lack of cuddling, and clenched fists. There is evidence that NOFTT infants may present a combination of biological vulnerability, environmental difficulties, and be the products of parents with poor marital relationships (200, 201). Infants with this type of FTT are more passive, more likely to sleep through meals or take longer to finish their meals, and more likely to be diagnosed as hypotonic. There is also evidence that NOFTT infants receive less appropriate developmental stimulation at home and have developmental delays. Developmental delays have also been linked to oral– motor dysfunction (OMD), which is frequently found in FTT children. When children with FTT were compared with children of the same developmental age with cerebral palsy, the oral–motor profiles were remarkably similar. It has been hypothesized that children with OMD might have subtle neurodevelopmental disorders (202). At 20 months of age, FTT infants were twice as likely to show mental developmental quotients less than 80 (200). The infants also showed less sociability. The clinician evaluating a child with FTT must also consider that prenatal factors may play a role in causing the problem. The pos-

22

Lifshitz and Botero

sibility of prenatal exposure to psychoactive substances needs to be ascertained, including exposure to alcohol, tobacco, and other drugs (203). There may also be signs of neglect, abuse, or illness in infants with FTT. It should be kept in mind that confirmation of the diagnosis of NOFTT is always based on a positive growth and behavioral response to treatment.

C.

Nourishing and Nurturing

Every child who fails to thrive has either not taken, has not been offered, or has not retained adequate energy to meet his or her nutritional needs. However, FTT infants prove that nourishment involves much more than ingestion of food. In most instances NOFTT results from a disruption in nurturing practices that ultimately affects the child’s ability to obtain proper nourishment. These nurturing factors include parental beliefs and their concept of nutrition. Also the infant’s behavior or adverse social or psychological environments may contribute to an inadequate nurturing environment, leading to NOFTT. Therefore, direct observation of mother–infant feeding and their social interaction is a necessary part of the evaluation. A careful nutritional evaluation must also be performed, which should include collecting dietary intake from a 24 h dietary recall or, more accurately, a food diary for 3–7 days. It should also address meal frequency, feeding patterns, and an assessment of all fluids given. It is also valuable to determine whether any particular food was restricted or promoted i.e., ‘‘no junk food,’’ increased fruit juice consumption (204–208), or if there are vegetarian practices (209–211). Often the diet record suggests that the child is receiving adequate calories for weight and length, but not for age. This level of intake allows the infant to maintain current weight but does not provide sufficient nutrients for growth. Sometimes the dietary intake is adequate in calories and protein, but is deficient in specific nutrients, such as iron, zinc, and/or other micronutrients, resulting in growth faltering (212–215). Supplementation studies have demonstrated that improvements in nutrient intake result in improved growth, including bone mineralization and maturation (216–218). Particular attention should be paid to the presence of nonspecific symptoms, such as intermittent vomiting, spitting up, diarrhea, and frequent upper respiratory tract infections. These may be present in infants with NOFTT and in other organic conditions (i.e., gastroesophageal reflux) (219). So-called feeding difficulties may also lead to decreased nutrient intake in NOFTT infants (220). These infants exhibit unusual behaviors, such as wide-eyed staring, gaze avoidance, fist clenching, and apathy toward their caregivers. Although apathy and decreased motor activity are recognized behaviors in malnourished infants (221, 222), many of the abnormal behaviors of patients with NOFTT are not attributable to malnutrition alone. Some nutritional alterations may influence the in-

fant’s behavior. Iron deficiency during infancy has been associated with anorexia, irritability, and lack of interest in their surroundings (223, 224). Zinc deficiency may likewise compound the course of FTT and excess lead ingestion may complicate the clinical picture even before the lead blood levels reach a toxic concentration. NOFTT infants were shown to have lead blood levels in a range formerly thought to be safe (i.e., 15–20 mg/dl) (225). These elements should be monitored in all FTT patients and treatment should be given when alterations are demonstrated. If decreased nutrient intake is found to be the cause of inappropriate weight gain, the question becomes: Why are insufficient amounts of food consumed by infants with NOFTT? Are these infants simply not offered enough? Do the infants fail to signal hunger or satiety? Do they have a poor appetite or refuse food?

D.

Neglect and Deprivation

In frequent cases, parental stress affects the way infants interact with their mothers (190–192). The quantity and quality of social and emotional stimulation between mother and child may be decreased even before clinical evidence of FTT is apparent. Many mothers of NOFTT infants are depressed, come from lower socioeconomic groups, lack a support group, and/or are themselves under multiple stresses. Mothers from higher socioeconomic groups may also lack the emotional strength or motivation to interpret or respond to the needs of their infant. As more mothers become engaged in work outside of the home or involved in activities that are independent of their family responsibilities, their children may not be getting the appropriate attention to meet their needs for nurturing (226). Psychosocial deprivation may also lead to FTT in infants (227–229). It has long been known that neglect and deprivation may lead to FTT. King Frederick in Sicily was interested in learning the innate language of humans. Consequently he isolated infants to learn what language they would speak spontaneously. These children did not thrive and thereafter died due to lack of communication and attention (230, 231). Also, it has long been known that infants often died and did not thrive in foundling homes (232–236) or hospitals (237, 238). A classic example of the role of nurturing influencing somatic growth was described by Waddissom (236). She described the experience of two German orphanages run by women of different personalities. The children under the care of the unpleasant, aggressive woman who did not render nurturing care did not thrive, whereas those under the care of the woman with opposite personality traits grew well. Both groups had similar dietary intakes. These patients usually have no hormonal disturbances such as growth hormone deficiency to account for poor growth, and they usually recover when sufficient nourishment and nurturing is given.

Worrisome Growth

E.

Infantile Anorexia

An infant behavior that typically leads to FTT is infantile anorexia nervosa, which is characterized by food refusal, extreme food selectivity, and undereating despite parental efforts to increase the infant’s food intake. The onset of this disorder usually is between 6 months and 3 years of age, with peak prevalence around 9 months of age (239). The feeding difficulties stem from the infant’s thrust for autonomy; a striking observation in these infants is their willfullness. Mother and infant become embroiled in conflicts over autonomy and control, which manifest primarily during feeding time. This conflict leads to a battle of wills over the infant’s food intake. Characteristically, parents mention that they have tried ‘‘everything’’ to get the infant to eat. Chatoor and colleagues (240) hypothesized that this separation-related conflict interferes with the infant development of somatopsychological differentiation. The process of differentiating somatic sensations, such as hunger or satiety, from emotional feelings, such as affection, anger, or frustration, is clouded by noncontingent responses by the parents to cues coming from the infant. As a result of this confusion, the infant’s eating becomes controlled by emotional experiences instead of by physiological needs. The focus of the treatment is on improving communication between the parents and the infant to facilitiate the process of separation and individuality. In a cognitive–behavioral approach, the therapist explains to the parents the infant’s behavior and suggests ways to positively modify and structure mealtimes to facilitate growth.

F.

Laboratory Findings

Poor nutrition and psychosocial factors are by far the most frequent factors leading to NOFTT. Therefore, laboratory tests offer limited value in determining the causes of growth deficiency and should only be used when the findings from the history and physical examination indicate something organic or possible nutritional alterations. In some cases, the child’s bone age should be determined to facilitate the process of ruling out systemic chronic diseases or a hormonal abnormality. This measurement may also be of help as a baseline for future growth and bone development progression. Unless organic disease is suspected, detailed testing should be reserved for patients in whom management of nutritional and psychosocial problems does not result in the expected improvement in the rate of growth. It has long been known that fewer than 1% of laboratory tests showed an abnormality that helped identify the cause (241). However, laboratory evaluation of the nutritional status should be comprehensive to assess for deficiencies that are not clinically apparent (242). Such an evaluation should include iron deficiency, which may be responsible for anemia and some of the long-term complications of FTT even when there is no anemia (212–221).

23

If weight gain does not occur soon after advice is given to the parent(s) about feedings, the child needs to be evaluated more intensely. Usually these patients are admitted to the hospital to have possible organic alterations ruled out, and most importantly simultaneously to receive appropriate nutritional intake to induce weight gain and thus to verify that the patient has the capacity to grow well (243).

G.

Management

In the past, hospital care was routinely recommended as part of the initial management of FTT patients. The goals were to ensure an adequate dietary intake, to observe the child’s behavior, and watch the family–child interactions. Despite today’s economic constraints, hospital care is justified when the patient has not responded to appropriate outpatient management; the severity of the malnutrition warrants it; or abuse, neglect, or both are suspected. A meta-analysis of NOFTT found that hospitalization significantly improved growth recovery and sustained catchup growth (244). However, an aggressive outpatient management program may also be appropriate (245). The use of a multidisciplinary team usually offers special advantages in the rapid correction of undernutrition and developmental progress in children with NOFTT (246). Nutritional therapy of FTT children has several goals: (a) achieving ideal weight for height; (b) correcting nutrient deficits; (c) allowing catch-up growth; (d) restoring optimal body composition; and (e) educating parents in the nutritional requirements and feeding or the child. Regardless of why a child fails to thrive, effective nutritional management consists primarily of providing enough calories to achieve a positive energy balance and growth. The World Health Organization Expert Consultation on Energy and Protein Requirements recommended that ‘‘whenever possible, energy requirements should be based on measurement of expenditure rather than intake’’ (247). The standard energy expenditure prediction equations were all derived from data accumulated from healthy children. Thus they may underestimate about one-quarter of the true energy requirement for infants with FTT (248). Because nutritional intervention is usually the focus in treating children with FTT, high-calorie, adequate protein feeding has been advocated for many years. With this treatment the child recovers more rapidly, the stay in the hospital is shorter, and more children can be treated in a given period of time at less cost. Nurses or trained therapists should feed the infant initially to allow identification of a feeding problem and to ensure that intake will be adequate. Proper feeding of the FTT child can be achieved most often with infant formula that is given in sufficient quantities to meet the child’s specific nutrient needs. Protein and other types of supplementation are usually not needed, but some products can be used when indicated. Tube feedings are indicated only in cases of severe malnutrition or failure to induce weight gain in the hos-

24

Lifshitz and Botero

pital. They may be necessary if the child is severely debilitated, metabolically unstable, or requires immediate restoration of fluid and electrolyte balance. Tube feedings may be useful for children with NOFTT as a temporary behavior modification modality, or in patients who fail to respond to other methods of nutritional rehabilitation (249). Many clinical trials have indicated that supplementation with micronutrients improves weight gain in growth-faltering patients. Single-nutrient deficiencies are cumbersome to document and micronutrient deficiencies commonly coexist. For example, iron deficiency may be present without iron deficiency anemia, and zinc deficiency may be difficult to document by the lack of a good indicator. Yet clinical trials of iron supplementation have positive effects on weight gain, linear growth, and psychosocial behavior (212, 221, 250). Similar studies have revealed positive effects with zinc supplementation on growth as well as on morbidity and severity of infections in children. (251–256). Vitamin and mineral deficiencies sometimes become evident only after the infant starts growing and gaining weight. Therefore a multivitamin– mineral preparation that includes iron and zinc is recommended for all undernourished children. Nutritional rehabilitation for these children must accomplish catch-up growth, which is defined as the acceleration in growth that occurs when a period of growth retardation ends and favorable conditions are restored. Catch-up growth in FTT depends on the provision of calories, protein, and other nutrients in excess of normal requirements. Children need 25–30% more energy and nearly double the amount of protein for catch-up growth (257). The extent to which nutritional rehabilitation can restore normal body size and composition is a critical subject. Returning to one’s previous growth curve does not indicate achievement of a normal body composition (258).

H.

Recovery

During the recovery period, parental nutrition education programs are extremely important. When families with psychosocial maladaptations are revealed to be major contributors to FTT, the physician must discuss these behaviors in a nonjudgmental way, so that guilt is not increased or compliance endangered. Parents should be reassured, and support should be provided for correction of the problems as much as possible. To improve their infant’s eating habits, parents should be introduced to inpatient treatment programs for foodrefusing infants (259). Parents and infant may have to be separated at meal times. The nurse must feed the child with structured, time-limited meals. Parents are to be given individual therapy and afterwards be reintroduced to the feeding situation. Parents must be educated regarding the catch-up growth process and long-term growth goals for their child. The baseline appearance of a cachectic child may bias the family’s perception of recovery.

The misperception that the recovering child is too plump may result in an abrupt diet change and abandonment of high-calorie feedings. In all instances and at all stages of the evaluation and treatment of FTT, a ‘‘working alliance’’ between key family members and professionals must be established (260). Developing such relationships can be a challenge and it requires the availability and commitment of multidisciplinary teams to assist the family in the treatment of NOFTT. Continued treatment after discharge from the hospital is necessary and the infant should be evaluated at regular intervals for a long time. Growth, development, and social behavior must be carefully and continually monitored. Temporary placement in a more favorable setting within the family or in a foster care environment may be necessary if the immediate family is judged as incapable of following through on the recommended management.

I.

Long-Term Outcome

A few systematic long-term studies of growth and development in NOFTT infants have been carried out. The longest follow-up study on growth found a difference between former FTT children and control children when the relationship between the height and weight ages of the children were compared with their chronological ages (261). Of the children with FTT, 6 of 14 were 1 or more years below their chronological age for height and weight. In the comparison group it was 1 child out of 14. Studies of catch-up growth show that NOFTT children continue to do poorly developmentally despite increased weight. A study by Singer showed that even after extended hospitalization, NOFTT infants manifested persistent intellectual delays at a 3 year follow-up examination, despite maintenance of weight gains achieved during early hospitalization (262). These children remained significantly behind their control group in language development, reading age, and verbal intelligence. They also scored lower than the control group on a social maturity rating.

J.

Special Considerations

The physician faces specific additional problems when dealing with a NOFTT patient in the managed health care environment. The diagnostic coding of such children is fraught with so-called Catch-22 dilemmas (263). Medical, nutritional, developmental, and/or psychiatric diagnosis may be utilized, but no optimal classification and coding scheme exists for use in these patients. The rapid growth of managed care also has significant implications for access to care, quality of services, reimbursement, and payment for health care. The special needs of these patients amplify the issues and challenges in ensuring that managed care is an effective component of community resources that foster healthy growth and development (264). These patients are at risk for concurrent illness and ad-

Worrisome Growth

verse development outcomes. A healthier child ultimately requires fewer services and indirect benefits may also occur with fewer health care expenditures and lifelong productivity.

X.

NUTRITIONAL GROWTH RETARDATION

The single most important cause of growth retardation worldwide is poverty-related malnutrition (265). When suboptimal nutrition is continued for prolonged periods of time, stunting of growth occurs as the main clinical picture (266, 267). However, nutritional growth retardation (NGR), as found in pediatric endocrine practices in the United States, is usually not the result of poverty-related malnutrition. NGR and delayed sexual development among suburban upper middle class adolescents is most often a result of self-restrictive nutrient inake (35, 268). Also, poor growth and inadequate nutrition have been found in such systemic problems as chronic inflammatory bowel disease (CIBD) and celiac disease (CD) (269, 270). Children with NGR are generally referred to the pediatric

25

endocrinologist because of short stature or delayed puberty. Therefore, pediatricians and pediatric endocrinologists need to recognize NGR and become familiar with its causes and treatment.

A.

Diagnosis

Pediatric endocrinologists usually evaluate linear growth accurately in the assessment of patients with short stature, but often little consideration is given to body weight progression. Although the importance of evaluating the pattern of stature increments throughout life in the differential diagnosis of short stature cannot be overemphasized, the assessment of the progression of body weight is equally relevant to be able to recognize NGR. Figure 8 illustrates this point. This 15-year-old boy was referred to the endocrine clinic with short stature of unknown cause. He was healthy in all other respects, and the only presenting symptom was deteriorating linear growth. On examination, both his height of 146.9 cm and weight of 37.6 kg were below the fifth percentile. No body weight deficit for height was evident, and sexual development was de-

Figure 8 a. The patient was referred because of short stature. Initially, the heights and weights depicted were the only available data. Signs of sexual development were absent. b. Complete growth data for the patient, who began dieting at 12 years of age. (From Ref. 272.)

26

layed (Tanner stage 1). The initial measurements provided by the referring pediatrician indicated a decreasing growth rate with appropriate weight gain that was progressing just below the fifth percentile (Fig. 8a). However, after additional growth data were obtained and all height and weight records were compiled, a typical picture of nutritionally related growth retardation emerged (Fig. 8b). At 12 years of age, his weight gain ceased, which subsequently resulted in deceleration of linear growth and pubertal delay. Review of his nutritional intake showed that he was consuming only approximately 60% of his estimated energy needs based on age and gender. He was an athletic boy who described a desire to remain slim and avoid obesity, a syndrome that was discovered in 1983 (34). The Wellcome Trust classification differentiates NGR from other types of malnutrition characterized by wasting and stunting (271). The anthropometric criteria for ND stipulate low weight for age with minimal deficit in weight for height. By these criteria, it may be difficult to differentiate NGR children from those who have familial short stature or constitutional growth delay. Cross-sectional data in these normal children may also demonstrate weights below the mean for age. Only the longitudinal progression of body weight and height can more clearly reveal NGR (272), which may occur even when there is weight-for-height excess (273). In NGR there is a deteriorating linear growth and/or delayed sexual development associated with inadequate weight gain (Fig. 9a,b) (34, 268, 272). This pattern of growth is seen in organic forms of NGR, as in chronic inflammatory bowel disease (274), as well as in nonorganic forms, that is, ingestion of restrictive diets (207). Furthermore, although concern is heightened when weight or height measurements fall below the fifth percentile, deterioration across percentiles of weight and height may also indicate NGR, even when height and weight are above the fifth percentile. With nutritional rehabilitation, catch-up growth is usually achieved. The analysis of body weight progression may be the most important clue to diagnosis of NGR in patients with short stature (Fig. 9a,b). The calculation of theoretical weights and heights based on previous growth percentiles may be used to compare current anthropometric indices quantitatively with previously established patterns of weight and height progression (Fig. 9a). Theoretical weight is defined as the weight the patient should have had at the time of the examination, if the patient had continued to gain weight along the previously established percentile during the premorbid growth period (272). Body weight for height deficits are not common in NGR, but there is often a body weight deficit for theoretical weight (Fig. 9a,b). In contrast, short patients without NGR, such as those with constitutional growth delay, continue to gain weight along established percentiles and the body weight at the time of assessment is equal to the theoretical body weight (Fig. 9c).

Lifshitz and Botero

The growth patterns of NGR must also be differentiated from normal variations in growth that may occur as a result of variations in frame size, feeding practices, or constitutional factors that may resemble NGR. Most normal children exhibit minimal deficits or excesses in body weight in proportion to height and grow along established percentiles (275). These constitutional variations in body weight are usually within one or two major percentiles of the height; they represent variations in frame size and do not necessarily reflect over- or undemutrition. The body weight and height increments of a child with constitutional thinness are depicted in Figure 10. Although his body weight was two major percentile lines below the height percentile, representing more than 20% body weight deficit for height, the adolescent grew and developed normally. A body weight deficit for height that remains constant and permits normal growth to proceed along a set percentile cannot be construed as abnormal. In contrast, a fall in growth associated with a poor rate of weight gain may indicate NGR, even without an appreciable body weight deficit for height (Figs. 8b,9a). The pattern of growth and weight gain in NGR differs from that of children with constitutional growth delay or familial short stature. The latter type of patients grow at constant rates, and their weight progression is also maintained in their respective percentiles after 3 years of age, as described above. In infancy, the pattern of growth and weight gain among constitutional growth delay and NGR may be indistinguishable. However, the children with constitutional growth delay usually recanalize their growth and gain weight and height over time at appropriate levels, and do not exhibit any nutritional intake alterations. There may likewise be confusion at this stage in life between NGR and the breastfed infants. The latter gain at appropriate rates when their length and weight are plotted in specific growth charts for this type of infant as described above. Patients with nutritional growth retardation do not appear to be wasted, and the biochemical parameters of nutritional status, including serum levels of retinol-binding protein, prealbumin, albumin, transferrin, and triiodothyronine (T3) levels, do not differentiate NGR patients from those with familial or constitutional short stature (276). Other indices of malnutrition, such as the urinary creatine–height index or urinary nitrogen/creatinine ratio, do not usually reflect abnormalities. The reason is that NGR patients have adapted to their suboptimal nutritional intake and they maintain homeostasis by decreasing growth, thereby reaching an equilibrium with preservation of all nutritional markers. We also showed that IGF-1 levels could not differentiate NGR patients from those with familial constitutional short-stature (276). This is in contrast to other studies, which measured IGF levels and their binding proteins (IGFBP) in fasting and in varying levels of nutritional intake, both in rodents and in humans (277– 286).

Worrisome Growth

These studies showed that IGF-I is reduced in children with protein–calorie malnutrition and in rats chronically deprived of nutrients. Reductions in IGF-I concentrations were observed in fasted volunteers (281). However, the degree of nutritional insufficiency in NGR is not as severe as that observed in protein–calorie malnutrition or fasting. The amount of nutrient restriction in NGR may impair growth by altering other cellular mechanisms without affecting the serum IGF-I levels. Because the energy restriction is mild, and NGR children consume sufficient dietary protein, IGF-I concentrations may be preserved within a range appropriate for bone age development. Likewise, studies in rats showed IGF-I concentrations to be maintained within normal ranges or to improve rapidly when diets containing 15% protein and 90% of the total energy requirements were consumed (287, 288). Serum IGF BP-3 concentrations are likewise de-

27

creased in prolonged fasting and/or protein deficiency states (284). However, alterations in IGFPB-3 levels in more subtle forms of suboptimal nutrition like that observed in NGR have not yet been studied. On the other hand, we reported that NGR patients show decreased activity of erythrocyte Na⫹, K⫹-ATPase compared with familial short-stature children (276). This enzyme is involved with the active transport of sugars and amino acids and with cellular thermogenesis. It normally accounts for approximately one-third of the basal energy requirements (289). A diminished energy intake lowers the basal metabolic rate (290) and decreases Na, K-ATPase activity (291). Thus, it may be a good marker of NGR. Because anthropometric parameters may be lacking or inaccurate and biochemical markers may not be sufficient to detect NGR, a more sensitive test is required for diagnosis. Erythrocyte Na⫹, K⫹-ATPase activity may offer

Figure 9 Growth pattern of nutritional dwarfing (a,b) compared with constitutional growth delay (c). a. Body weight gain and height progression decreased after 10 years of age. Extrapolated weight after age 14 years revealed a body weight deficit based on previous growth percentile. However, there was no body weight deficit for height; with nutritional rehabilitation, there was recovery in weight gain and catch-up growth. b. In another patient there is a body weight deficit for height, but the deficit for theoretical weight is more marked. (From Ref. 272.)

28

Lifshitz and Botero

Figure 9 Continued. c. Patient who does not have nutritional dwarfing. This patient, with constitutional growth delay, shows a body weight gain consistently along the lower percentile, with no deviation in growth. Note that there was no body weight deficit for height or for theoretical weight based on previous growth. (From Ref. 272.)

Figure 10 Constitutional underweight for height. Note the constant progression of both height and weight in the same percentiles for at least 4 years. Even though there is body weight deficit for height, there cannot be malnutrition because there must be a positive balance for growth to occur. (From Ref. 272.)

such a diagnostic tool. To date, however, this assay has not been widely available for clinical purposes, it is cumbersome, and can be applied only on a research basis.

altered anthropometric measurements, such as weight and skinfold thickness or biochemical indices. It has been known for many years that diminished energy intake leads to a reduced metabolic rate even before there is a loss of body weight. The rate of protein synthesis may decrease in response to a reduction in energy intake, because this process is energy expensive and accounts for 10–15% of the basal metabolic rate (294, 295). Protein catabolism is also sensitive to energy deprivation. Reduction in dietary energy sources may lead to an increased nitrogen flux in which protein breakdown is accelerated to provide energy (296). Nitrogen retention markedly increases during nutritional rehabilitation of malnourished children (295, 297). In addition, nutritional recovery normalizes the excretion of amino acids (296) and increases the rate of protein synthesis (298). In NGR, the result of the altered rates of protein turnover and ni-

B.

Pathophysiology

Patients with nutritional growth retardation have reached an equilibrium between their genetic growth potential and their nutritional intake because growth deceleration is the adaptive response to suboptimal nutrition (292, 293). Diminished growth brings the nutrient demands into balance with the nutritional intake without adversely affecting biochemical or functional homeostatic measures. Of course, there are limits to these adaptive possibilities. If nutritional deprivation becomes more severe, acute malnutrition may be superimposed on the chronic state, leading to NGR. In such patients, malnutrition would be reflected by

Worrisome Growth

29

trogen retention may be the cessation of normal growth as an adaptive response to the decreased intake. In addition to suboptimal energy intake, various mineral and vitamin deficiencies have been implicated in the causes of NGR, as discussed below. However, it remains controversial whether decreased body size is an advantageous adaptation to a limited food supply or whether adverse health and functional impairments result (292, 293). It has been demonstrated that physical activity is decreased with a 20% decrease in energy consumption (299), but other functional impairments are more difficult to assess. The decreased growth velocity nevertheless constitutes a functional compromise per se, which should be detected and treated as early as possible.

C.

Endocrine Adaptation

The changes in the endocrine system in response to undernutrition are adaptive in nature and largely revert to the ‘‘normal’’ state after nutritional status is improved (300). Undernutrition may involve single or multiple micronutrient deficiencies, and thus any one or a combination of deficits could be the primary problem leading to the endocrine alterations. A detailed description of the hormonal alterations in malnutrition has been published elsewhere (272, 300). However, it must be remembered that most studies have been conducted in severely malnourished patients, which may not accurately reflect more subtle forms of suboptimal nutrition leading to NGR. For example, although circulating growth hormone (GH) levels are increased in severe malnutrition, we have shown that pubertal NGR children show decreased overnight growth hormone secretion and prepubertal subjects have an increased growth hormone response to growth-hormone-releasing hormone (GHRH) stimulation (72). An interesting finding is that body composition is a significant determinant of spontaneous growth hormone secretion. In normal children with short stature, the degree of adiposity modifies spontaneous growth hormone secretion and alters the amplitude of growth hormone pulses in puberty and the number of pulses in prepubertal children (72). Indeed, NGR may be easily confused with growth hormone deficiency or neurosecretory dysfunction if the deterioration in weight progression is overlooked (Fig. 11). These patients respond to nutritional rehabilitation and do not require HGH treatment.

D.

Causes

1. Organic Causes Various pathological conditions that lead to decreased nutritional intake or malabsorption may cause NGR (301). Crohn’s disease, celiac disease, and cystic fibrosis are some of the relatively more common pathological conditions. However, any alteration that reduces energy intake or excess energy expenditures may lead to decreased growth. Also included are cardiac or renal diseases. When

Figure 11 Nutritional dwarfing or growth hormone deficiency? The patient was diagnosed to have GH deficiency at age 10 years because of poor growth. However, because of inadequate weight gain associated with decreased growth increments, therapeutic trial with an adequate diet was tried in lieu of growth hormone. Note the catch-up growth after the initiation of nutritional rehabilitation. (From Ref. 272.)

the dietary intake is disturbed, as in patients with cleft palate or other developmental disabilities, there may also be NGR. The acquired immunodeficiency syndrome and human immunodeficiency virus (HIV) infection were also shown to be associated with short stature and poor growth, that preceded any other manifestation of disease (Chapter 37) (302). However, the growth data in HIV-infected patients clearly indicate NGR because body weight progression failed to proceed at appropriate rates even before any other symptom of the disease was apparent (303). It is very likely that anorexia and decreased intake of nutrients lead to suboptimal nutrition in HIV-infected patients and cause NGR, even before other signs and symptoms of the disease become apparent. Chronic inflammatory bowel disease (CIBD) is usually associated with impaired linear growth, retarded skeletal maturation, and delayed sexual development. This problem is estimated to occur in 5–10% of pediatric patients with ulcerative colitis and 25% of patients with Crohn’s disease (304, 305). Growth failure may be the first indication of CIBD and may precede disease-related

30

symptoms (306). Therefore, the diagnosis of CIBD should always be considered in children who cease to grow adequately, even in the absence of gastrointestinal complaints. Although the pathogenesis is influenced by age at onset, duration of disease, disease activity, and medication intake, suboptimal nutrition is now recognized as the primary factor in growth failure in Crohn’s disease (274). Multifactorial nutritional alterations include a decreased nutrient intake, impaired absorption of nutrients, specific nutrient deficiencies, and enhanced protein losses through the gastrointestinal tract. Decreased energy intake in children with CIBD has been associated with anorexia and the early satiety and discomfort that accompany eating. The total daily calorie intake of CIBD patients usually is not above the recommended dietary allowance (RDA) for height age (306). Multiple studies have documented catch-up growth when adequate energy is provided (304, 305). Various forms of nutritional support (parenteral, elemental, or complex diet) have been employed, often resulting in decreased disease activity and improved growth (307–309). In addition to energy and protein deficits, other nutritional alterations may affect growth in patients with CIBD. Iron deficiency, particularly when there is blood loss through the stools, may compound anorexia and poor growth (310). These patients also may have magnesium deficiency (311) and zinc deficiency (312). It has been shown that large enteric losses of zinc occur in CIBD patients who have diarrhea and small bowel disease. In addition, zinc absorption may be reduced. Therefore, nutritional rehabilitation is essential for the treatment of CIBD patients. This may reverse the growth retardation and even improve the disease itself (313–314). Growth failure in association with gastrointestinal symptoms is common in children with active CD. It has been shown that up to 55% of patients with CD were below the third percentile for height and up to 60% were below the same percentile for weight. Failure to thrive was present in 25% of children with celiac disease at the time of diagnosis (315, 316). However, several investigators have reported short stature as the sole manifestation of CD (270, 315–317). These asymptomatic patients were considered to have so-called occult celiac disease. The prevalence of asymptomatic CD is highly variable. It was reported to be present in up to 8% in some studies (270, 316), whereas in others it was higher: 24 and 48% (315, 317). This may be the result of geographic differences in the prevalence of the disease and/or the level of suspicion in recognizing these patients. The incidence of CD in the western New York area, estimated by serum IgA–endomysial antibody, has been reported to be 1:3752 (318). The recognition of occult CD is dependent on the alertness of the clinician to consider this entity as a cause of short stature. Many asymptornatic CD patients have a history of diarrhea at an early age or have iron deficiency. They may also have other alterations when studied (e.g.,

Lifshitz and Botero

increased stool fat, antigliadin, and antiendomysial antibodies, low serum folate and ferritin levels) that point to the possibility of CD (319–321) as the cause of short stature. Although various methods may be used for screening purposes, these are not diagnostic of CD (315, 317, 318). Therefore, a small bowel biopsy is the ‘‘gold standard’’ for the diagnosis of this disease, and should be performed in every short child showing NGR from unidentified causes. A history of diarrhea during the first year of life and/or the presence of iron deficiency in a short patient should also warrant consideration of CD and therefore of a small bowel biopsy. The diagnosis of CD should be confirmed by documentation of catch-up growth with weight and height gain after institution of a gluten-free diet, which is the only treatment available for the disease. Long-term studies of children with CD suggest that those who do not comply with the diet have significantly lower mean heights and weights and a greater abnormality of the intestinal mucosa than those who are compliant. 2. Nonorganic Causes The prevalence of nonorganic NGR leading to malnutrition and poor growth in affluent communities is unknown. Only those patients whose height is markedly impaired have been recognized thus far. However, suboptimal nutritional intake may result in a fall in height within the normal percentiles that may elude medical attention. In a survey of 1017 high school students from a middle-class parochial school, a high incidence of low-weight students was reported. More than 25% of these students weighed less than 90% of their ideal body weight for height, but only 1.8% of them had growth patterns suggestive of NGR (275). In a pediatric endocrine clinic in a referral center in the same geographic area, we detected more than 300 patients with NGR. The most common causes (73%) of nutritional alterations that resulted in NGR and delayed sexual development among adolescents referred to us were nonorganic. There were patients in whom a specific fear or health belief was identified as the cause of the poor nutritional intake leading to short stature (207, 226, 268, 272). A fear of obesity or a fear of hypercholesterolemia was specifically verbalized by some. However, most patients with nonorganic NGR expressed preoccupations that involved similar issues of body weight and cholesterol and concern with a so-called healthy dietary intake. They avoided excess dietary fat and cholesterol and what they termed junk food (272). Regardless of the reason for the inadequate nutritional intake, the result in these children was NGR. These patients with inadequate dietary intake appeared to be free of severe psychopathology. They did not meet the inclusion criteria for severe eating disorders, such as anorexia nervosa or bulimia nervosa. Moreover, in a controlled, double-blind, prospective study, it was demonstrated that these children did not have behavioral or psychosocial deviations and did not differ from a group

Worrisome Growth

of normal or short-stature children (322). Thus, we concluded that the dietary habits that led to NGR were a result of the prevalence of current health beliefs and preoccupation with slimness, weight control, and the search for longevity through the intake of idealized diets (35, 205, 207). A recent national survey found that 31% of fifth grade girls have dieted (323). Abramovitz and Birch explored 5-year-old girls’ ideas, concepts, and beliefs about dieting (324). They found that 34–64% of the girls had ideas about dieting and weight loss and understood the link with body shape. Girls’ knowledge about how people diet is inappropriate. These included descriptions of modified eating behaviors, such as drinking diet shakes, sodas, eating more fruits and vegetables, special foods, and restrictive eating behaviors. Mothers seem to be modeling both health-promoting and health-compromising eating behaviors to their daughters. Girls whose mothers reported current or recent food restrictions were more than twice as likely to have ideas about dieting (324). Another factor found to influence girls’ ideas, concepts, and beliefs about dieting is family history of overweight. The media was also mentioned by 55% if the children as a source of dieting ideas (325). Neumark recently published results from a national survey examining weight-related behaviors among 6728 American adolescents in grades 5–12 (323). Almost half of the female population (45%) and 20% of male adolescents reported dieting. Older female adolescents were significantly more likely to diet than younger ones. Dieting was reported by 31% of 5th graders and increased consistently to 62% among 12th graders. The largest increase was among female adolescents between the 8th (40%) and 9th (53%) grades. Thirteen percent of the girls and 7% of the boys reported disordered eating behaviors. In another study, Neumark found that in 3832 adults and 459 adolescents from four regions of the United States, a high percentage of them reported weight control behaviors. Based on gender, weight control behaviors were found in 56.7% of adult women, 50.3% of adult men, 44.0% of adolescent girls, and 36.8% of adolescent boys (326). Moses et al. showed that high school adolescents in an affluent suburban location were dieting at a very high rate (327). Forty-one percent of the adolescents were dieting on the day of the survey. Sixty-seven percent of all the adolescents had made on their own important dietary efforts during the past 4–8 weeks. Dieting occurred in normal-weight and underweight students. About 30% of dieters were among the underweight and normal weight for height. However, the proportion of the overweight students who were dieting was relatively low: 50–60%. Children not only diet but also worry about their body appearance and distorted proportions about weight. More and more children are concerned and dissatisfied with their body image. Studies have shown that 55% of girls and 35% of boys in grades 3–6 want to be thinner (328).

31

The Children’s Version of the Eating Attitude Test showed a negative correlation with children’s BMI. It was found that 4.8% of them had scores suggestive of anorexia nervosa. Stice et al. found that eating disturbances that emerged during childhood led to inhibited and secretive eating, overeating, and vomiting. Maternal body dissatisfaction, internalization of the thin ideal, dieting, bulimic symptoms, and maternal and paternal body mass prospectively predicted the emergence of childhood eating disturbances. Infant feeding behavior and body mass during the first month of life also predicted the emergence of eating disturbances (329). Parents who worry about their children becoming overweight may set the stage for a vicious cycle. Johnson and Birch found those parents who control what and how much their children eat may impede energy self-regulation and put these children at a higher risk for being overweight (330). Furthermore, the Framingham Children’s Study showed that children whose parents had high degrees of dietary control had greater increases in body fatness than did children whose parents had the lowest levels of dietary restraint and noninhibition (331). A distorted perception of ideal body weight, manifested as below appropriate body weight for height, is very prevalent among high school students. Adolescents often know what their ideal weight should be, but some prefer to be 10% less than their ideal weight for their height (327). Health-compromising behaviors and the fear of obesity may have detrimental consequences in children. Inappropriate nutrient intake may lead to NGR, failure to thrive, and various other nutritional problems (326). There is also a high prevalence of extreme measures taken by high school students to avoid obesity throughout the country (327, 332, 333). In addition to dieting, they may have inappropriate eating habits and purging behaviors. These data indicate just how powerful and important it is for adolescents to achieve an ideal slim and trim figure. Young persons, even when they are not overweight, diet to avoid obesity at a time when they are still growing and developing (35, 327, 332, 333). Regardless of their physical needs, they strive to reach a thin ideal, consequently developing nutritional short stature (35, 327). In addition to growth retardation, other potential medical complications may be associated with excessive dieting, binging, and purging: electrolyte disturbances, dental enamel erosion, acute gastric dilation, esophagitis, enlargement of the parotid gland, aspiration pneumonitis, and pancreatitis. However, it must be kept in mind that the population at large is also quite concerned about cholesterol and preoccupied with diets to lower cholesterol levels (334). These concerns are also prevalent among children (335). The medical profession and the American Academy of Pediatrics have also recommended a low-fat–low-cholesterol diet for the population at large in an effort to prevent adult-onset diseases. However, there are potential harmful

32

consequences of feeding children with adult diets (334). A low-fat–low-cholesterol intake may lead to nutritional short stature (35, 335) and nutrient deficits (272). A recent study confirmed our observations demonstrating that children on low-fat, low-cholesterol diets can easily ingest inadequate nutrient intake (336). Careful assessment of weight and height progression will clearly identify children who are not gaining weight and growing appropriately (204, 268, 301, 327). An awareness by health care providers and pediatric endocrinologists of the prevailing eating attitudes and behaviors among adolescents in the population of their practice’s area may help detect the adolescent at risk for more serious problems. Simple tests and questionnaires may help to identify the patient with eating disorders (337). The 24 h dietary recall may identify short-stature patients who have inappropriate dietary intake. Patients with obesity constitute another group of children who often diet. Although these children usually do not present to the pediatric endocrinologist because of poor growth, when obesity occurs in association with short stature there may be concerns about their health. A variety of endocrine disorders may affect obese children who do not grow well (Chapter 28). Diet-related growth failure may be uncovered by a careful history, thereby eliminating other concerns. Weight loss is associated with a negative balance that does not allow growth in height even if the child is obese (338). Therefore, during the treatment of obesity in children, allowances must always be made to maintain a balance between the need of a patient to lose weight and the nutritional requirements that allow growth in height. Nutritional rehabilitation for NGR of nonorganic origin requires providing the patient with adequate caloric and nutrient intake for the restoration of previous growth patterns. Initially, estimation of energy requirements should be based on the age- and gender-specific RDA using the patient’s theoretical weight. Adequate intake of protein usually accompanies sufficient caloric intake, but care should be taken that micronutrient intakes meet the RDA. If results of biochemical tests reveal specific deficiencies, such as iron or zinc, these nutrients should be supplemented. Some patients may not be willing or able to consume a completely balanced diet and may require a multivitamin and mineral supplement. A careful diet history can elucidate food preferences and eating patterns that can be used to devise an appropriate dietary plan. Our experience has been to offer general dietary suggestions rather than to prescribe a specific diet. Frequent followup visits provide an opportunity to revise and update dietary recommendations and to obtain weight and height measurements. Although the appropriate diet can be easily determined, successful intervention requires a change in dietary patterns and possibly health beliefs as well. Increasing the caloric density of the child’s diet often involves raising the dietary fat content to at least 30–35% of calories. The

Lifshitz and Botero

increase in fat consumption may concern both the child and the parent, especially in patients who fail to grow because of dieting. The assurance that an appropriate nutritional intake will result in normal growth, without producing obesity, is necessary supportive therapy. This is of particular concern in the initial stages of the treatment, when weight increases rapidly, whereas no noticeable effect on height is observed. 3. Vitamin and Mineral Deficiencies Regardless of NGR’s cause, patients may present with multiple vitamin and mineral deficiencies that contribute to growth failure (272, 335). There may be generalized malnutrition with multiple macro- and micronutrient deficits, or there may be more specific nutritional alterations, as discussed below. Vitamin A is an important nutrient for gene expression of growth hormone. Studies have shown an improvement in linear growth in some subsets of supplemented children (339). A study in Java found that children who consumed small frequent amounts of vitamin A in fortified monosodium glutamate experienced greater height gain but similar weight gain to control children (340). In the Sudan, dietary vitamin A intake, but not vitamin A supplements given once every 6 months, was positively associated with greater weight gain and with linear growth of children (341, 342). This suggests that small daily supplements of vitamin A may be beneficial over and above the benefits imparted by periodic doses of vitamin A. However, in other intervention studies, vitamin A supplements had no effect on either linear growth or weight gain even when other vitamins and nutrients in addition to vitamin A were supplemented. In a large placebo-controlled study in Tamil Nadu, India, children were visited every week and given a small dose of vitamin A or a placebo. In spite of a large protective effect against mortality, the supplements had no effect on growth (343). Multiple postulated mechanisms link other vitamin deficiencies with poor growth. These include iron, folate, and/or B12 deficiency, which lead to poor oxygen delivery to tissues, and to multiple metabolic pathways that alter protein synthesis leading to impaired growth. Furthermore, there may be anorexia and inappropriate intake in iron deficiency. Iron supplementation in school children demonstrated beneficial effects on appetite, growth, and anemia (344, 345). Vitamin-D-deficiency rickets can, of course, present with growth failure and osteomalacia. In several prospective cohort studies in developing countries, the onset of stunting coincided with dietary deficiencies of several micronutrients, including iron, zinc and iodine (346). Height deficits were associated with chronic deficits in energy and protein, as well as suboptimal zinc levels. Multiple micronutrient deficiencies may explain why supplementary feeding programs that aimed at only increasing energy and protein intake resulted in limited physical growth (347).

Worrisome Growth

Growth retardation caused by zinc deficiency in humans was first reported by Prasaad et al. in 1963. The patients had remarkably short stature and hypogonadism. They were shown to have zinc deficiency documented by decreased zinc concentrations in plasma, erythrocytes, and hair. Studies with 65Zn revealed that plasma zinc turnover was greater, the 24 h exchangeable pool was smaller, and the excretion of 65Zn in stool and urine was less in the growth-retarded subjects than in the controls (348). Further studies showed that the rate of growth was greater in patients who received supplemental zinc than in those receiving only an adequate animal protein diet (349). Since then, many cases of marginal or moderate growth impairment in children with zinc deficiency as a consequence of inadequate zinc intake have been reported from various parts of the world (350, 351). It appears that zinc deficiency is prevalent throughout the world in both developed and developing countries. Favier indicated that, depending on the country, 5–30% of children had moderate zinc deficiency, responsible for small-for-age height (352). Those reports showed positive effects of oral zinc supplementation on growth velocity in children with zinc deficiency (349–352). It is also well known that zinc deficiency in pregnant women causes fetal growth retardation. Kirksey et al. revealed a significant correlation between maternal plasma zinc concentrations measured at midpregnancy and birth weight (353). Neggers et al. reported that the prevalence of low birth weight (LBW) infants was significantly higher (eight times) among women with serum zinc concentrations in the lowest quartile in early pregnancy, independent of other risk factors (354). However, the effects of zinc supplementation in pregnancy are not clear. It is now speculated that zinc supplementation during pregnancy might be beneficial only in populations that are zinc deficient and at high risk of poor fetal growth (355). Marginal zinc deficiency seems to be prevalent in infancy. Michaelsen et al. examined zinc intake and status in healthy term infants from birth to 12 months of age in Denmark, and found suboptimal zinc status in many subjects during late infancy. They also reported that serum zinc level at 9 months was positively associated with growth velocity during the period from 6 to 9 months (356). The zinc status in short-stature patients with normal GH secretion was tested by body zinc clearance studies to detect the marginal zinc nutriture, and to evaluate the effects of oral zinc supplementation (357). This Japanese study indicated that about 60% of short children had marginal zinc deficiency. Oral zinc supplementation was effective on height gain in short boys with marginal zinc deficiency, but not in girls. There was also a significant correlation between the body zinc clearance values and percentage increases in the growth velocity after oral zinc supplementation, indicating that oral zinc supplementation was most effective on height gain (357). The reason for

33

such a high incidence of marginal zinc deficiency in Japanese short children may be mainly the recent prevalence of precooked food, snacks, and convenience foods in their diets. In 1993 Nakamura et al. conducted an age-matched control study showing that oral zinc supplementation was effective in improving the growth rate in short children with marginal zinc deficiency. They reported that oral zinc supplementation induced increases of serum IGF-1, osetocalcin, and alkaline phosphatase activity (358). There have been a few reports on the relationship between zinc deficiency and GH secretory insufficiency. Nishi et al. described a 13-year-old Japanese boy with growth disturbance who had partial GH deficiency due to chronic mild zinc deficiency. His diet was low in animal protein and consisted primarily of rice and vegetables, because he disliked meats, fish, eggs, and dairy products that were rich sources of zinc. His plasma zinc level and GH responses to the pharmacological stimulation tests were low. After 3 months of oral zinc supplementation, however, his growth velocity improved without GH replacement therapy, and his plasma zinc levels and GH responses to those tests increased to the normal range (359). The mechanism by which zinc deficiency causes growth disturbance has been controversial. Zinc is required for activities of more than 300 enzymes (zinc metalloenzymes), in which zinc is located at the active site, including DNA polymerase, RNA polymerase, and thymidine kinase. Because these enzymes are important for nucleic acid and protein synthesis and cell division, zinc may be essential for growth. Furthermore, several hundred zinc-containing nucleoproteins are probably involved in gene expression of various proteins (349, 360). Zinc deficiency may adversely affect GH production and/or secretion (359). Since zinc has an important role in protein synthesis, IGF-1 synthesis can be impaired by zinc deficiency. Ninh et al. reported that low IGF-1 levels in zinc-deprived rats were closely associated with decreased hepatic IGF-1 gene expression and with a diminuation of liver GH receptors and circulating GH-binding protein (GHBP). They also suggested that decreased hepatic GH receptors and/or GHBP concentrations might be responsible for the decline of circulating IGF-1 in zincdeficient animals (361). The presence of a large amount of zinc in bone tissue suggests that zinc plays an important role in the development of skeletal systems (362). Retardation of bone growth is a common finding in various conditions associated with zinc deficiency. Zinc has a stimulatory effect on bone formation and mineralization (363). Zinc is required for alkaline phosphatase activity and the enzyme is mainly produced by osteoblasts whose major function is to provide calcium deposition in bone diaphysis. The administration of vitamin D3 or zinc produced a significant increase in bone alkaline phosphatase activity and DNA content was synergistically enhanced by the simul-

34

Lifshitz and Botero

taneous treatment with zinc (363). The receptors for 1,25dihydroxyvitamin D3 were shown to have two zinc fingers at the site of interaction with DNA (364). One possible function of zinc is to potentiate the interaction of the 1,25-dihydroxyvitamin D3 receptor complex with DNA at that site. Zinc also directly activates aminoacyltRNA synthetase in osteoblasts, and it stimulates cellular protein synthesis. Moreover, zinc has an inhibitory effect on osteoclastic bone resorption by suppressing osteoclastlike cell formation from marrow cells (362). Zinc deficiency should be considered as a causative factor in some children with unexplained short stature. Oral zinc supplementation should be considered as the growth-promoting therapy for children with short stature once the status of their zinc nutrition is established. Not all zinc intervention studies have found improved growth patterns in subjects receiving supplements. Rosado et al. performed a randomized clinical trial among young Mexican children, comparing daily doses of iron, zinc, both, or placebo (365). Others have also reported no effect of zinc supplementation on growth rates (366, 367), and some have hypothesized that the presence of multiple micronutrient deficiencies may be at least in part to blame (368, 369). Prentice reported that zinc supplementation failed to show beneficial effects on height gain in Guatemalan children, although the relatively short supplementation period of 25 weeks might have been insufficient to detect subtle changes in growth velocity (370). A systematic review of 25 clinical trials that evaluated the impact of zinc supplementation on growth found a significant pooled effect of an increment of 0.22 standard deviations (SD) on height and 0.26 SD on weight (371). The greatest impact of zinc supplementation was found in stunted children (in whom an increase of 0.49 SD was found in height), and in those with low initial zinc concentrations.

XI.

LABORATORY AIDS IN DIFFERENTIATING SHORT STATURE

Any patient who falls below the third percentile in height and/or has decreased growth rates (falling across the major percentiles) should receive a complete diagnostic evaluation. Because there are multiple causes of short stature and growth retardation, laboratory investigation should be geared toward confirming or ruling out the differential diagnoses based on information obtained from history and physical examination. It is important to assess, in addition to the growth rates: history of chronic illness and medications, midparental and target height, birth size, growth pattern, nutritional state, pubertal stage, body segment proportions, bone age, and predicted adult height. The following simple laboratory screening tests may be performed: urinalysis, urine metabolic screening, hemoglobin, hematocrit and ferritin levels, measurement of sedimentation rate and creatine phosphokinase (CPK), ve-

nous blood gases with simultaneous urine pH, liver and kidney function tests, and antigliadin and antiendomyacil antibodies. A karyotype is imperative in every girl with short stature, even in the absence of the stigmata of Turner syndrome. Children who demonstrate skeletal abnormalities on physical examination deserve evaluation for metabolic bone disease, such as mucopolysaccharidosis, mucolipidosis, and gangliosidosis (Chapter 4). In addition, skeletal abnormalities should be looked for in accordance with body proportion alterations detected on physical examination (i.e., hypochrondroplasia) (46, 58, 95). Endocrine causes of short stature and/or poor growth may be determined by evaluating thyroid function and assessing the hypothalamic–pituitary axis (Chapters 2, 3, and 38). Examination of the eye grounds and visual fields should be done, but a magnetic resonance imaging (MRI) scan may be necessary if hypopituitarism is considered. A thorough nutritional assessment should be made if there is a growth pattern of NGR. If zinc deficiency is suspected, serum zinc levels may be obtained, but they are usually not sufficient to establish the diagnosis. Other tests may be necessary before treatment is instituted as described above. A number of tests to assess growth hormone status have been devised using various provocative tests: insulin, L-dopa, arginine, clonidine, and other agents (372). Growth hormone is secreted at intervals and random growth hormone measurements are useless. Estrogen and/ or androgen priming before provocative testing is also useful in Tanner I or Tanner II children to differentiate between GH deficiency and constitutional growth delay (373, 374). A frequent test is to measure GH after exercise (375). Pituitary function may also be evaluated comprehensively using a combined hormonal stimulation test (376). This utilizes sequentially administered insulin or arginine or L-dopa, thyrotropin-releasing hormone, and gonadotropin-releasing hormone. In addition, deficiency of GHRH may be ruled out by giving human pituitary GHRH and evaluating the patient’s growth hormone response. So-called neurosecretory growth hormone dysfunction can be determined by performing an overnight growth hormone study and assessing growth hormone pulsatile secretions under physiological conditions, such as sleep. The indications for this test are for those patients who may demonstrate a normal growth hormone response to pharmacological stimuli, but may not be able to secrete growth hormone under physiological conditions (377– 379). However, there is no completely reliable test for diagnosing or excluding growth hormone deficiency in short children (Chapters 2, 3). IGF-I and IGFBP levels are decreased in growth hormone deficiency and may help in differentiating short children with growth hormone deficiency (380–383). However, these tests are not useful in NGR or younger patients. Measuring levels of GHBP or

Worrisome Growth

35

IGFBP may also help differentiate the different conditions, as well as IGF levels and their response to exogenous growth hormone administration. Details of the foregoing tests and procedures are described in Chapter 41. However, it should be kept in mind that growth measurements over time are better guidelines than many of the tests mentioned above. Indeed without the clinical growth data, the results of the tests are hard to interpret.

son Drive, Cherry Lane, MD 20815; or Magic, 1327 North Harlem Drive, Oak Park, IL 60302. They may legitimately hope for romance, marriage, and a successful sex life and should consider help regarding their height through the use of footwear that may increase their size without other major procedures or therapies (Elevators, Richlee Shoe Co., P.O. Box 3566, Frederick, MD 21705, Tel 1-800-290TALL).

XII.

ACKNOWLEDGMENT

FINAL CONSIDERATIONS

Short children and their parents face a number of specific psychosocial problems. These problems are frequently associated with the developmental stage of (384) the child’s life. The parents frequently have difficulty in accepting the child’s height and in treating the child according to age level. By 7 or 8 years of age the child usually has become acutely aware of his or her short stature. The teenage years are much more difficult for the short-stature child than for the child of normal or mildly abnormal height. The problems of short stature are often compounded by lack of sexual development and withdrawal from heterosexual social activities or by other transition periods, such as moving to a new school or community. Despite these developmental problems, the short individual frequently makes an adequate adjustment to life as an adult (384). Other issues transcend the purely developmental aspects of short stature, such as the general personality mechanisms of the small child and his or her parents. Of importance are the school achievements of such children and the specific techniques they develop in coping more effectively with their environment. One of the most important problems of short people is being treated in an infantile manner, appropriate for their size, but not for their age. Some short people respond to being treated as a younger child by behaving immaturely (Peter Pan reaction). Others rebel against being pampered and sometimes develop various neurotic and psychosomatic symptoms, including denial, withdrawal, phobias, and compensatory fantasies. Still others find a more satisfactory solution in the reaction of ‘‘mascotism.’’ Frankness (diplomatic rather than brutal) is desirable in counseling short and dwarfed people about their situation in life. They are then able to plan the future realistically, to discuss the taboos that beset them, and to perfect techniques in dealing with silly comments about their size and age. Emotional deprivation and neglect may cause a certain type of dwarfism (385). This may be the primary problem and, when resolved, growth occurs. Short stature is not typically associated with intellectual defect (386). Dwarfed people may expect to be employed and, under some circumstances, graduate from college. Short people can meet one another by joining such organizations as Little People of America, P.O. Box 622, San Bruno, CA 94006; the Human Growth Foundation, Inc., 4607 David-

This work was supported in part by Pediatric Sunshine Academics.

REFERENCES 1.

2. 3. 4. 5. 6. 7.

8.

9.

10.

11.

12. 13.

Kranzler JH, Rosenbloom AL, Proctor B, Diamond F, Watson M. Is short stature a handicap? A comparison of the psychosocial functioning of referred and non-referred children with normal stature and children with short stature. J Pediatr 2000; 136:96–102. Sandberg DE, Brook AE, Campos SP. Short stature: a psychosocial burden requiring growth hormone therapy? Pediatrics 1994; 94:832–840. Sanberg DE. The quality-of-life benefits of growth hormone-increased final height: what do we know? Endocrinologist 2001; 11:8S–14S. Bort LLE, Mul D. Growth hormone in short children: beyond medicine? Acta Paediatr 2001; 90:69–73. Macklin R. Growth hormone in short children: medically appropriate treatment. Acta Paediatr 2001, 90:5–6. Roberts SB, Dallal GE. The new childhood growth charts. Nutr Rev 2001; 59:31–36. Haschke F, van’t Hof MA, the Euro-Growth Study Group. Euro-Growth references for length, weight and body circumferences. J Pediatr Gastroenterol Nutr 2000; 31 (suppl 1) S14–38. Van’t Hof MA, Haschke F, the Euro-Growth Study Group. Euro-Growth References for body mass index (BMI) and weight for length (WfL). J Pediatr Gastroenterol Nutr 2000; 31 (suppl 1) S48–59. Van’t Hof MA, Haschke F, Darvay S, the Euro-Growth Study Group. Euro-Growth references on increments in length, weight, head- and arm circumference during the first three years of life. J Pediatr Gastroenterol Nutr 2000; 31 (suppl 1) S39–47. Freeman V, van’t Hof MA, Haschke F, the Euro-GrowthStudy Group. Patterns of milk and food intake during the first three years of life. The Euro-Growth Study. J Pediatr Gastroenterol Nutr 2000; 31 (suppl 1) S76–85. Haschke F, van’t Hof MA, the Euro-Growth-Study Group. Euro-Growth references for breastfed boys and girls: the influence of breastfeeding and solids on growth until 36 months of age. J Pediatr Gastroenterol Nutr 2000; 31 (suppl 1) S60–71. Lacey KA, Parkin JM. Causes of short stature. A community study of children in Newcastle-upon-Tyne. Lancet 1974; 1:42–45. Lifshitz F, Cervantes C. Short stature. In: Lifshitz F, ed. Pediatric Endocrinology, 3rd ed. New York: Marcel Dekker, 1996:1–18.

36 14.

15.

16.

17.

18.

19. 20. 21.

22. 23. 24. 25.

26. 27.

28. 29. 30. 31.

32. 33.

Lifshitz and Botero Rudman D, Kutner MH, Blackstone RD, Cushman RA, Bain RP, Patterson JH. Children with normal variance short stature: treatment with human growth hormone for six months. N Engl J Med 1981; 305:123–131. Rekers-Mombarg LT, Karel GH, Massa GG, Wit JM. Influence of growth hormone treatment on pubertal timing and pubertal growth in children with idiopathic short stature. J Pediatr Endocrinol Metab 1999; 12:611–616. Hebert PR, Rich-Edwards JW, Manson JE, Ridker PM, Cook NR, O’Connor GT, Buring JE, Hennekens CH. Height and incidence of cardiovascular disease in male physicians. Circulation 1993; 88:1437–1443. Kannam JP, Levy D, Larson M, Wilson PW. Short stature and risk for mortality and cardiovascular disease events. The Framingham Heart Study. Circulation 1994; 90: 2241–2247. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. Evidence that height is an independent risk factor for coronary artery disease (the Manitoba Follow-Up Study). Am J Cardiology 1994; 74:398–399. Tanner JM, Whitehouse RH, Marubini E, Resele L. The adolescent growth spurt of the boys and girls of the Harpenden Growth Study. Ann Hum Biol 1976; 3:109–126. Roche AF, Guo S, Baumgartner RM, Falls RA. The measurement of stature. Am J Clin Nutr 1988; 47:922. Taranger J, Bruning B, Claesson I, et al. Skeletal development from birth to 7 years. In: Taranger J, ed. The Somatic Development of Children in a Swedish Urban Community. Acta Paediatr Scand (Suppl) 1967; 258:98– 108. Tuddenham RD, Snyder MM. Physical growth of California boys and girls from birth to eighteen years. Univ Calif Pubi Child Dev 1954; 1:183–364. Horton WA, Rotter JI, Rimoin DL. Standard growth curve for achondroplasia. J Pediatr 1978; 93:435–438. Babson SO, Benda GI. Growth graphs for the clinical assessment of infants of varying gestational age. J Pediatr 1976; 89:814–820. Cronk C, Crocker AC, Pueschel SM, Shea AM, Zackai E, Pickens G, Reed RB. Growth charts for children with Down syndrome: 1 month to 18 years of age. Pediatrics 1988; 81:102–110. Lyon AJ, Preece MA, Grant DB. Growth curve for girls with Turner syndrome. Arch Dis Child 1985; 60:932– 935. Horton WA, Hall JG, Scott CI. Growth curves for diastrophic dysplasia, spondyloepiphyseal dysplasia and pseudoachondroplasia. Am J Dis Child 1982; 136:316– 319. Witt DR, Keena BA, Hall JG, Allanson JE. Growth curves for height in Noonan syndrome. Clin Genet 1986; 30:150–153. Brook GGD, Hindmarsh PC, Healy MJR. A better way to detect growth failure. Br Med J 1986; 293:1186. Lampl M, Veldhuis JD, Johnson ML. Saltation and stasis: a model of human growth. Science 1992; 258:801–803. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity and weight velocity in British children. Arch Dis Child 1966; 41:613–616. Tanner JM, Whitehouse RH. Clinical longitudinal standard for height, weight, height velocity, weight velocity and stages of puberty. Arch Dis Child 1976; 51:170–171. Guo S, Roche AF, Fomon SJ, Nelson SE, Chumlea WC, Rogers RR, Baumgartner RN, Ziegler EE, Siervogel RM.

34. 35. 36.

37.

38.

39. 40. 41.

42. 43. 44. 45. 46. 47. 48. 49. 50. 51.

52.

Reference data on gains in weight and length during the first two years of life. J Pediatr 1991; 119:355–362. Pugliese MT, Lifshitz F, Grad G, Fort P, Marks-Katz M. Fear of obesity: a cause of short stature and delayed puberty. N Engl J Med 1983; 309:513–518. Lifshitz F, Moses N, Cervantes C, Ginsberg L. Nutritional dwarfing in adolescence. Semin Adolesc Med 1987; 3: 255–266. Desai ID, Garcia-Tavares ML, Dutra de Oliveira BS, Desai MI, Romero LS, Vichi FL, Duarte FA, Dutra de Oliveira JE. Anthropometric and cycloergometric assessment of the nutritional status of the children of agricultural migrant workers in Southern Brazil. Am J Clin Nutr 1981; 34:1925–1934. Trowbridge FL, Marks JS, Lopez de Romana G, Madrid S, Boutton TW, Klein PD. Body composition of Peruvian children with short stature and high weight-for-height. Implications for the interpretation of weight-for-height as an indicator of nutritional status. Am J Clin Nutr 1987; 46:411–418. Tanner JM, Whitehouse RH, Marshall WA, Carter BS. Prediction of adult height from height, bone age, and occurrence of menarche, at ages 4 to 16, with allowance for midparent height. Arch Dis Child 1975; 50:14–26. Luo ZC, Albertsson-Wikland K, Karlberg J. Target height as predicted by parental heights in a population-based study. Pediatr Res 1998; 44:563–571. Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standard. J Pediatr 1952; 40:423–441. Tanner JM, Whitehouse RH, Cameron N, Marshall WA, Healy MJR, Goldstein H. Assessment of Skeletal Maturity and Prediction of Adult Height (TW2 Method). London: Academic Press, 1983. Roche AF, Wainer H, Thissen D. The RWT method for the prediction of adult stature. Pediatrics 1975; 56:1026– 1033. Lenko HL. Prediction of adult height with various methods in Finnish children. Acta Pediatr Scand 1979; 68:85– 92. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford, CA: Stanford University Press, 1950. Roche AF, Davila GH, Leyman SL. A comparison between Greulich-Pyle and Tanner-Whitehouse assessment of skeletal maturity. Radiology 1971; 98:273–280. Hall JG, Froster-Iskenius U, Allanson J. Handbook of Normal Physical Measurements. Oxford, UK: Oxford University Press, 1989. Albanses A, Stanhope R. Does constitutional delayed puberty cause segmental disproportion and short stature? Eur J Pediatr 1993; 152:293–296. Cervantes C, Lifshitz F. Tubular bone alterations in familial short stature. Hum Biol 1988; 60:151–165. Beresma D. Birth Defects Compendium, 2nd ed. The National Foundation March of Dimes. New York: Alan R. Liss, 1982:151–152. Archibald RM, Findy N, DeVito F. Endocrine significance of short metacarpals. J Clin Endocrinol Metab 1959; 19:1312–1322. Van der Werf Ten Rosch JJ. The syndrome of brachymetacarpal dwarfism (‘‘pseudopseudohypoparathyroidism’’) with and without gonadal dysgenesis. Lancet 1959; 1:69–71. Cervantes CD, Lifshitz F, Levenbrown J. Radiologic an-

Worrisome Growth

53.

54.

55.

56.

57. 58. 59.

60.

61. 62.

63.

64.

65. 66. 67.

68. 69.

thropometry of the hand in patients with familial short stature. Pediatr Radiol 1988; 18:210–214. Musebeck J, Mohnike K, Beye P, Tonnies H, Neitzel H, Schnabel D, Gruters A, Wieacker PF, Stumm M. Short stature homebox-containing gene deletion screening by fluorescence in situ hybridisation in patients with short stature. J Pediatr 2001; 160:561–565. Ballabio A, Bardoni B, Carrozzo R, Andria G, Bick D, Campbell L, Hamel B, Ferguson-Smith MA, Gimelli G, Fraccaro M, Maraschio P, Zuffardi O, Guioli S, Camerino G. Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome. Proc Natl Acad Sci USA 1989; 86:10001–10005. Belin V, Cusin V, Viot G, Girlich D, Toutain A, Moncla A, Vekemans M, Le Merrer M, Munnich A, CormierDaire V. SHOX mutations in dyschondrosteosis (LeriWeill syndrome). Nat Genet 1998; 19:67–69. Stewart RE, Horton WA, Eteson DJ. General concepts of growth and development. In: Stewart RE, Barber TK, Troutman KC, Wei SHY, eds. Pediatric Dentistry: Scientific Foundations and Clinical Practice. St. Louis: CV Mosby, 1982:3–34. Duterloo HS. An Atlas of Dentition in Childhood. London: Wolfe Publishing, 1991:93–96. Jones KL: Smith’s Recognizable Patterns of Human Malformation, 5th ed. Philadelphia: WB Saunders, 1997:592. Murray JC, Bennett SR, Kwitek AE, Small KW, Schinzel A, Alward WL, Weber JL, Bell GI, Buetow KH. Linkage of Rieger syndrome to the region of the epidermal growth factor gene on chromosome 4. Nat Genet 1992; 2:46–49. Veitia R, Ion A, Babaux S, Jobling MA, Souleyreaux N, Ennis K, Ostrer H, Tosi M, Meo T, Chibani J, Fellous M, McElreary K. Mutation and sequence variants in the testes-determining region of the 4 chormosome in individuals with a 46XY female phenotype. Hum Genet 1997; 99:648–652. Horner JM, Thorsson AV, Hinz RI. Growth deceleration patterns in children with constitutional short stature: an aid to diagnosis. Pediatrics 1978; 62:529–534. Vaquero-Solans C, Lifshitz F. Body weight progression and nutritional status of patients with familial short stature with and without constitutional delay in growth. Am J Dis Child 1991; 146:296–302. Galler JR, Ramsey F, Solimano G. A follow-up study of the effects of early malnutrition in subsequent development in physical growth and sexual maturation during adolescence. Pediatr Res 1985; 19:518–523. Harel Z, Tannenbaum GS. Long-term alterations in growth hormone and insulin secretion after temporary dietary protein restriction in early life in the rat. Pediatr Res 1995; 38:747–753. Bierich JR. Constitutional delay of growth and development. Growth Genet Horm 1987; 3:9–12. Gourmelen M, Pham-Huu-Trung MT, Girard F. Transient partial hGH deficiency in prepubertal children with delay of growth. Pediatr Res 1979; 13:221–224. Kastrup KW, Andersen H, Eskildsen PC, Jacobsen BB, Krabbe S, Petersen KE. Combined test of hypothalmic– pituitary function in growth-retarded children treated with growth hormone. Acta Paediatr Scand (Suppl) 1979; 227: 9–13. Clayton PE, Shalet SM, Price DA. Endocrine manipulation of constitutional delay in growth and puberty. J Endocrinol 1988; 116:321–323. Bierich JR, Brogmann G, Schippert R. Assessment of

37

70.

71.

72.

73.

74. 75. 76.

77.

78. 79. 80.

81.

82. 83.

84. 85.

86.

sleep-associated HGH secretion in normal children and in endocrine disorders. Pediatr Res 1985; 19:609. Schneid H, Le Bouc Y, Seurin D, Gourmelen M, Cabrol S, Raux-Demay MC, Girard F, Binoux M. Insulin-like growth factor-I gene analysis in subjects with constitutionally variant stature. Pediatr Res 1990; 27:488–491. Link K, Blizzard RM, Evans WS, Kaiser DL, Parker MW, Rogol AD. The effect of androgens on the pulsatile release and the twenty-four-hour mean concentration of growth hormone in pre-pubertal males. J Clin Endocrinol Metab 1986; 62:159–164. Abdenur JE, Publiese MT, Cervantes C, Fort P, Lifshitz F. Alterations in spontaneous growth hormone secretion and the response to GH-releasing hormone in children with non-organic nutritional dwarfing. J Clin Encocrinol Metab 1992; 75:930–934. Attie KM, Carlsson LM, Rundle AC, Sherman BM. Evidence for partial growth hormone insensitivity among patients with idiopathic short stature. J Pediatr 1995; 127: 244–250. Preece MA, Greco L, Savage MD, Cameron N, Tanner JM. The auxology of growth delay. Pediatrics 1981; 15– 76. LaFranchi S, Hanna CE, Mandel SH. Constitutional delay of growth: expected versus final adult height. Pediatrics 1991; 87:82–87. Crowne EC, Shalet SM, Wallace WHB, Eminson DM, Price DA. Final height in boys with untreated constitutional growth delay in growth and puberty. Arch Dis Child 1990; 65:1109–1112. Hagg U, Taranger J. Pubertal growth and maturity pattern in early and late maturers. A prospective longitudinal study of Swedish urban children. Swed Dent J 1992; 16: 199–209. Ranke MB, Aronson AS. Adult height in children with constitutional short stature. Acta Paediatr Scand (Suppl) 1989; 362:27–31. Von Vliet G, Styne PN, Kaplan SL, Grumbach MM. Growth hormone treatment for short stature in children. N Engl J Med 1983; 309:1016–1023. Hintz RL, Attie KM, Baptista J, Roche A, for the Genentech Collaborative Group. Effect of growth hormone treatment on adult height of children with idiopathic short stature. N Engl J Med 1999; 340:502–507. Buchlis JG, Irizarry L, Crotzer BC, Shine BJ, Allen L, MacGillivray MH. Comparison of final heights of growth-hormone-treated vs. untreated children with idiopathic short stature. J Clin Endocrinol Metab 1998; 83: 1075–1079. McCaughey ES, Mulligan J, Voss LD, Betts PR. Randomised trial of growth hormone in short normal girls. Lancet 1998; 351:940–944. Rosenfeld RG, Northcraft GB, Hintz RL. A prospective, randomized study of testosterone treatment of constitutional delay of growth and development in male adolescents. Pediatrics 1982; 69:681–687. Lee PA, O’Dea L. Primary and secondary testicular insufficiency. Pediatr Clin North Am 1990: 37:1359–1387. Strickland AI. Long-term results of treatment with lowdose fluoxymesterone in constitutional delay of growth and puberty and in genetic short stature. Pediatrics 1993; 91:716–720. Bettmann HK, Goldman HS, Abramowics MN, Sobel EH. Oxandrolone treatment of short stature, effect on predicted matrix adult height. J Pediatr 1971; 79:1018–1023.

38 87.

88. 89. 90.

91. 92.

93.

94.

95. 96. 97. 98. 99.

100.

101.

102.

103.

104.

Lifshitz and Botero Buyukgebiz A, Hindmarsh PC, Stanhope R, Preece MA, Brook CGD. Long term outcome of oxandrolone treatment in boys with constitutional delay of growth and puberty. J Pediatr 1990; 117:588–591. Blethen SL, Gaines S, Welden V. Comparison of predicted and adult heights in short boys: effects of androgen therapy. Pediatr Res 1984; 18:467–469. Blizzard RM, Hindmarsh PC, Stanhope R. Oxandrolone therapy: 25 years experience. Growth Genet Horm 1991; 4:1–6. Chihara K, Kodama H, Kaji H, Kita T, Kashio Y, Okimura Y, Abe H, Fujita T. Augmentation by propanolol of growth hormone-releasing hormone-(1-44)-NH2-induced growth hormone release in normal short and normal children. J Clin Endocrinol Metab 1985; 61:229–233. Pintor C, Cella SC, Loche S, Puggioni R, Corda R. Locatelli V, Muller EE. Clonidine treatment for short stature. Lancet 1987; 1:1226–1230. Allen DB. Effects of nightly clonidine administration on growth velocity in short children without growth hormone deficiency: a double-blind, placebo-controlled study. J Pediatr 1993; 122:32–36. Pescovitz OH, Tan E. Lack of benefit of clonidine treatment for short stature: a clonidine therapy of non-growth hormone deficient patients: double-blind, placebo trial. Lancet 1988; 2:874–877. Finkelstein JS, Klibanski A, Neer R. A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty. J Clin Endocrinol Metab 1996; 81: 1152–1155. Tanner JM, Goldstein H, Whitehouse RH. Standards of children’s height at ages 2 to 9 years allowing for height of parents. Arch Dis Child 1970; 45:755–762. Hall B, Spranger J. Hypochondroplasia: clinical and radiological aspects in 39 cases. Radiology 1979; 133:95– 100. Gebhardt-Henrich SG. Heritability of growth curve parameters and heritability of final size: a simulation study. Growth Dev Aging 1992; 56:23–34. Bermasconi S, Ghizzoni L, Volta C, Morano M, Giovanelli G. Spontaneous growth hormone secretion in Turner’s syndrome. J Pediatr Endocrinol 1992; 5:101–105. Raiti S, Moore WV, Van Vliet G, Kaplan SL. Growthstimulating effects of human growth hormone therapy in patients with Turner syndrome. J Pediatr 1986; 109:944– 949. Ross JL, Long lM, Skerda M, Cassorla F, Kurtz D, Loriaux DL, Cutler GB Jr. Effect of low doses of estradiol on 6-month growth rates and predicted height in patients with Turner’s syndrome. J Pediatr 1986; 109:950–953. Rosenfeld RG, Frane J, Attie KM, Brasel JA, Burstein S, Cara JF, Chernausek S, Gotlin RW, Kuntze J, Lippe BM, et al. Six-year results of a randomized, prospective trial of human growth hormone and oxandrolone in Turner syndrome. J Pediatr 1992; 121:49–55. Anneren G, Gustavson KH, Sara VR, Tunemo T. Growth retardation in Down syndrome in relation to insulin-like growth factors and growth hormone. Am J Med Genet (Suppl) 1990; 7:59–62. Torrado C, Bastian W, Wisniewski KE, Castells S. Treatment of children with Down syndrome and growth retardation with recombinant human growth hormone. J Pediatr 1991; 119:478–483. Lifshitz F. Commentary. Growth Genet Horm 1993; 9: 1011.

105. 106. 107.

108. 109.

110. 111. 112. 113. 114. 115.

116. 117.

118.

119.

120. 121. 122.

123.

Allen DB, Frasier SD, Foley TP Jr, Pescovitz OH. Growth hormone for children with Down syndrome. J Pediatr 1993; 123:742–743. Spranger J. Classification of skeletal dysplasias. Acta Paediatr Scand (Suppl) 1991; 377:138–142. Rimoin DL. International nomenclature and classification of the osteochondrodysplasias. International Working Group on Constitutional Diseases of Bone. Am J Med Genet 1998; 79:376–382. Schwartz ID, Schwarts KJ, Kouseff BG, Becru BB, Root AW. Endocrinopathies in Cornelia de Lange syndrome. J Pediatr 1990; 117:920–922. Hediger, MI, Overpeck MD, Maurer KR, Kuczmanski, RJ, McGlynn A, Davis WW. Growth of infants and young children born small or large for gestational age: findings from the third national health and nutrition examination survey. Arch Pediatr Adolesc Med 1998; 152:1225–1231. Albertsson-Wikland K, Karlberg J. Natural growth in children born small for gestational age with and without catch-up growth. Acta Paediatr Suppl 1994; 399:64–70. McCormick M. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985; 312:82–90. McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999; 340:1234–1238. Barker DJP, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular diseases in adult life. Lancet 1993; 341:938–941. Williams S, St. George IM, Silva PA. Intrauterine growth retardation and blood pressure at age seven and eighteen. J Clin Epidemiology 1992; 45:1257–1263. Leger J, Levy-Marchal C, Bloch J, Pinet A, Chevenne D, Porquet D, Collin D, Czernichow P. Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. Br Med J 1997; 315:341–347. Laor A, Stevenson DK, Shemer JG, Rena S, Daniel S. Size at birth: maternal nutritional status in pregnancy, and blood pressure at age 17. Br Med J 1997; 315:449–453. Rich-Edwards JW, Colditz GA, Stampfer MJ, Willett WC, Gillman MW, Hennekens CH. Birthweight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med 1999; 130:278–284. Litheil HO, McKeigue PM, Berglund L, Mohsen R, Lithell UB, Leon DA. Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50–60 years. Br Med J 1996; 312:406–410. Hofman PL, Cutfield WS, Robinson EM, Bergman RN, Menon RK, Sperling MA, Gluckman PD. Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab 1997; 82:402–406. Barker DJP, Gluckman PD, Robinson JS. Fetal origins of adult disease: report of the first study group. Sydney, 29– 30 October, 1994. Placenta 1995; 16:317–320. Lubchenko LO, Hanaman C, Dressler BE. Intrauterine growth as estimated from live born birth weight data at 24–42 weeks of gestation. Pediatrics 1963; 32:793–800. Usher R, McLean F. Intrauterine growth of live born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. Pediatrics 1969; 74:901–910. Goldberg RL, Cutter GR, Hoffman HJ, Foster JM, Nelson KG, Hauth JC. Intrauterine growth retardation: standards for diagnosis. Am J Obstet Gynecol 1989; 161:271–277.

Worrisome Growth 124. 125. 126. 127. 128.

129. 130.

131. 132.

133.

134. 135. 136.

137.

138.

139. 140.

141. 142. 143.

Seeds JW, Peng T. Impaired growth and risk of fetal death: is the tenth percentile the appropriate standard? Am J Obstet Gynecol 1998; 178:658–667. Karlberg J, Albertsson-Wikland K. Growth in full-term small-for-gestational-age infants: from birth to final height. Pediatr Res 1995; 38:733–739. Wright K, Dawson JP, Fallis D, Vogt E, Lorch V. New postnatal growth grids for very low birth weight infants. Pediatrics 1993; 91:922–926. Cooke RJ, Ford A, Werkman S, Conner C, Watson D. Postnatal growth in infants born between 700 and 1,500 g. J Pediatr Gastroenterol Nutr 1993; 16:130–135. Casey PH, Kraemer HC, Bernbaum J, Tyson JE, Sells JC, Yogman MW, Bauer CR. Growth patterns of low birth weight preterm infants: a longitudinal analysis of a large, varied sample. J Pediatr 1990; 117:298–307. Brenner WE, Edelman DA, Hendricks CH. A standard for fetal growth for the United States of America. Am J Obstet Gynecol 1976, 126:555–564. Singer DB, Sung CJ, Wigglesworth JS. Fetal growth and maturation: with standards for body and organ development. In: Wigglesworth JS, Singer DB, eds. Textbook of Fetal and Perinatal Pathology. Boston: Blackwell Scientific Publications, 1996:11–47. Klebanoff MA, Mairik O, Berendes HW. Second generation consequences of small-for-dates birth. Pediatrics 1989; 84:343–347. Godfrey K, Robinson S, Barker, DJP, Osmond C, Cox V. Maternal nutrition in early and late pregnancy in relation to placental and fetal growth. Br Med J 1996; 312:410– 414. Luke S, Gillespie B, Min S-J, Avni M, Witter FR, O’Sullivan MJ. Critical periods of maternal weight gain: effect on twin birth weight. Am J Obstet Gynecol 1997; 177:1055–1062. Abrams B, Selvin S. Maternal weight gain pattern and birth weight. Obstet Gynecol 1995; 86:163–169. Food and Nutrition Board, Institute of Medicine (United States). Nutrition During Pregnancy and Lactation. Washington: National Academy Press, 1990:1–233. American College of Obstetricians and Gynecologists. Nutrition During Pregnancy. Washington: American College of Obstetricians and Gynecologists, 1993 (Technical bulletin no. 179). Brown HL, Watkings K, Hiett KA. Fetus–placenta–newborn; the impact of the women, infants and children food supplement program on birth outcome. Am J Obstet Gynecol 1996; 174:279–283. Cogswell ME, Serdula MK, Hungerford DW, Yip R. Gestational weight gain among average-weight and overweight women—what is excessive? Am J Obstet Gynecol 1994; 172:705–712. Tudehope DI. Neonatal aspects of intrauterine growth retardation. Fetal Med Rev 1991; 3:73–85. Berge P, Stagno S, Federer W, Cloud G, Foster J, Utermohlen V, Armstrong D. Impact of asymptomatic congenital cytomegalovirus infection on size at birth and gestational duration. Pediatr Infect Dis J 1990; 9:170–175. Khoury MJ, Erickson JD, Cordero JF, McCarthy BJ. Congenital malformations and intrauterine growth retardation: a population study. Pediatrics 1988; 82:83–90. Kohler M, Moya-Sola S, Autusti J. Imprinted gene in postnatal growth role. Nature 1998; 393:125–126. Krook A, Brueton L, O’Rahilly S. Homozygous nonsense mutation in the insulin receptor gene in infant with leprechaunism. Lancet 1993, 342:227–228.

39 144.

145.

146.

147.

148.

149.

150. 151.

152. 153.

154.

155.

156.

157.

158.

Furlanetto RW, Underwood LE, Van Wyk JJ, Hanweger S. Serum immunoreactive somatomedine-C is elevated in late pregnancy. J Clin Endocrinol Metab 1979; 47:695– 698. Freemark M, Comer M, Mularoni T, D’Ercole AJ, Granois A, Kodack L. Nutritional regulation of the placental lactogen receptor in fetal liver: implications for fetal metabolism and growth. Endocrinology 1989; 125:1504– 1512. Leger J, Noel M, Limal JM, Czernichow P, for the Study group of IUGR. Growth factors and intrauterine growth retardation: II: serum growth hormone, insulin-like growth factor (IGF)-1 and IGF binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects: prospective study from birth to two years of age. Pediatr Res 1996; 40:101–107. Cance-Rouzaud A, Laborie S, Bieth E, Tricoire J, Rolland M, Grandjean H, Rochiccioli P, Tauber M. Growth hormone, insulin like growth factor-1 and insulin-like growth factor binding protein-3 are regulated differently in smallfor-gestational-age and appropriate-for-gestational-age neonates. Biol Neonate 1998; 73:347–355. Lassarre C, Hardouing S, Daffos F, Forestier F, Frankenne F, Binoux M. Serum insulin-like growth factors and insulin-like growth factor binding proteins in normal subjects and in subjects with intrauterine growth retardation. Pediatr Res 1991; 29:219–225. Job JC, Chatelain P, Rochiccioli P, Ponte C, Oliver M, Sagard L. Growth hormone response to a bolus injection of 1-44 growth-hormone-releasing hormone in very short children with intrauterine onset growth failure. Horm Res 1990; 33:161–165. Weber GW, Prossinger H, Horst S. Height depends on month of birth. Nature 1998; 39:754–755. Jaquet D, Leger J, Levy-Marchal C, Oury JF, Czernichow P. Ontogeny of leptin in human fetuses and newborns effect of intrauterine growth retardation on serum leptin concentrations. J Clin Endocrinol Metab 1998; 83:243– 246. Marchini G, Fried G, Ostlund E, Gagenas L. Plasma leptin in infants: relations to birth weight and weight loss. Pediatrics 1998; 101:429–432. Chang TC, Robson SC, Boys RJ, Spencer JAD. Prediction of the small for gestational age infant: which ultrasonic measurement is best? Obstet Gynecol 1992; 80: 1030–1038. Bahado-Singh R, Oz U, Kovanchi E, Lernik E, Flores D, Singh-Basra D, et al. Mid-trimester maternal uterine marker for the prediction of subsequent IUGR. Am J Obstet Gynecol 1999; 180 (suppl II):174–175. Georgieff MK, Sasanow SR, Chockalingam UM, Pereira GR. A comparison of the mid-arm circumference/head circumference ratio and the ponderal index for the evaluation of newborn infants after abnormal intrauterine growth. Acta Paediatr Scand 1988; 77:214–219. Peralta-Carcelen M, Jackson DS, Goran MI, Royal SA, Mayo MS, Nelson KG. Growth of adolescents who were born at extremely low birth weight without major disability. J Pediatr 2000; 136:633–640. Leger J, Limoni C, Collin D, Czernichow P. Prediction factors in the determination of final height in subjects born small for gestational age. Pediatr Res 1998; 43:808– 812. Strauss RS, Dietz WH. Growth and development of term children born with low birth weight: effects of genetic and environmental factors. J Pediatr 1998; 133:67–72.

40 159.

160.

161.

162. 163.

164.

165.

166.

167.

168.

169.

170.

171. 172. 173.

Lifshitz and Botero Woods KA, Camacho-Hubner C, Savage MO, Clark AJL. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 1996; 335:1363–1367. Kelleher KJ, Casey PH, Bradley RH, Pope SK, Whiteside L, Barret KW, et al. Risk factors and outcomes for failure to thrive in low birth weight preterm infants. Pediatrics 1993; 91:941–948. Arisaka G, Arisaka M, Kiyokawa N, Shimizu T, Nakayama Y, Yabuta K. Intrauterine growth retardation and early adolescent growth spurt in 2 sisters. Clin Pediatr 1986; 25:559–561. Reilley SM, Skuse DH, Wolke D, Stevenson J. Oral-motor dysfunction in children who fail to thrive: organic or non-organic. Dev Med Child Neurol 1999; 41:115–122. Embleton NE, Pang N, Cook RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001; 107:270–273. Fjellestad-Paulsen A, Czernichow P, Brauner R, Bost M, Colle M, Lebouc JY, Lecronu M, Leheup B, Limal JM, Raux MC, Toublanc JE, Rappaport R. Three-year data from a comparative study with recombinant human growth hormone in the treatment of short stature in young children with intrauterine growth retardation. Acta Paediatr 1998; 87:511–517. Chaussain JL, Colle M, Landier F. Effects of growth hormone therapy in prepubertal children with short stature secondary to intrauterine growth retardation. Acta Paediatr Suppl 1994; 399:74–75. Coutant R, Carel JC, Letrait M, Bouvattier C, Chatelain P, Coste J, Chaussain JL. Short stature associated with intrauterine growth retardation: final height of untreated and growth-hormone-treated children. J Clin Endocrinol Metab 1998; 83:1070–1074. Boguszewski M, Albertsson-Wikland K, Aronsson S, Gustafsson J, Hagenas L, Westgren U, Westphal O, Lipsanen-Nyman M, Sipila I, Gellert P, Muller J, Madsen B. Growth hormone treatment of short children born smallfor-gestational-age: the Nordic Multicentre Trial. Acta Paediatr 1998; 87:257–263. Chernausek SD, Breen TJ, Frank GR. Linear growth in response to growth hormone treatment in children with short stature associated with intrauterine growth retardation: The National Cooperative Growth Study experience. J Pediatr 1996; 128(suppl):22–27. de Zegher F, Albertsson-Wikland K, Wilton P, Chatelain P, Jonsson B, Lofstrom A, Butenandt O, Chaussain JL. Growth hormone treatment of short children born small for gestational age: metanalysis of four independent, randomized, controlled, multicentre studies. Acta Paediatr Suppl 1996; 417:27–31. Job JC, Chaussain JL, Job B, Ducret JP, Maes M, Oliver M, Ponte C, Rochiccioli P, Vanderschueren-Lodeweycks M, Chatelain P. Follow-up of three years of treatment with growth hormone and one of post-treatment year, in children with severe growth retardation of intrauterine onset. Pediatr Res 1996; 39:354–359. Botero D, Lifshitz F. Intrauterine growth retardation and long-term effects on growth. Curr Opin Pediatr 1999; 11: 340–347. Butenandt O, Lang G. Recombinant human growth hormone in short children born small for gestational age. J Pediatr Endocrinol Metab 1997; 10:275–282. de Zegher F, Maes M, Gargosky SE, Heinrichs C, Caju M, Thiry G, De Schepper J, Craen M, Breysem L, Lof-

174.

175. 176.

177.

178. 179.

180.

181. 182. 183. 184. 185. 186. 187. 188. 189.

190. 191. 192.

strom A, Jonsson P, Bourguignon JP, Malvaux P, Rosenfeld RG. High-dose growth hormone treatment of short children born small for gestational age. J Clin Endocrinol Metab 1996; 81:1887–1892. Zucchini S, Cacciari E, Balsamo A, Cicognani A, Tassinari D, Barbieri E, Gualandi S. Final height of short subjects of low birth weight with and without growth hormone treatment. Arch Dis Child 2001; 84:340–343. Persson E, Jansson T. Low birthweight is associated with elevated adult blood pressure in the chronically catheterized guinea pig. Acta Physiol Scand 1992; 145:195–196. Dahri S, Snoeck A, Reusens-Billen B, Hoet JJ. Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. Biol Neonate 1991; 40(suppl 2):115– 120. Lucas A. Programming by early nutrition in man. In: Barker DJP, ed. The Childhood Environment and Adult Disease: CIBA Symposium 156. Chichester, UK: John Wiley, 1991:38–55. Hales CN, Barker DJ. Type 2 (non-insulin dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35:444–446. Barker DJP, Hales CN, Fall CHD, Osmond C, Phipps K, Clark PMS. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993; 36:62– 67. Bao W, Srinivasan SR, Wattigney WA, Berenson GS. Persistence of multiple cardiovascular risk clustering related to syndrome X from childhood to going adulthood: the Bogalusa Heart Study. Arch Intern Med 1994; 154:1842– 1847. Kramer MS, Platt R, Yang H, McNamara H, Usher RH. Are all growth-restricted newborns created equal(ly)? Pediatrics 1999; 103:599–602. Porter B, Skuse D. When does slow weight gain become ‘failure to thrive’? Arch Dis Child 1991; 66:905–906. Mitchell WG, Gorrell RW, Greenberg RA. Failure-tothrive: a study in a primary care setting. Epidemiology and follow-up. Pediatrics 1980; 65:971–977. Wilcox WD, Nieburg P, Miller DS. Failure to thrive: a continuing problem of definition. Clin Pediatr 1989; 28: 391–394. Rosenn DW, Loeb LS, Jura MB. Differentiation of organic from non-organic failure to thrive syndrome in infancy. Pediatrics 1980; 66:698–704. Frank DA, Zeisel SH. Failure to thrive: mystery, myth and method. Contemp Pediatr 1993; 2:114. Edwards AGK, Halse PC, Parkin JM, Waterson AJ. Recognizing failure to thrive in early childhood. Arch Dis Child 1990; 65:1263–1265. Skuse DH. Non-organic failure to thrive: a reappraisal. Arch Dis Child 1985; 60:173–178. Kirkland RT. Failure to Thrive. In: Oski FA, De Angelis CD, McMillan JA, Feigin RD, Warshaw JB, eds. Principles and Practice of Pediatrics, 2nd ed. Philadelphia: JB Lippincott, 1994:1048–1050. Leung AK, Robson WL, Fagan JE. Assessment of the child with failure to thrive. Am Fam Phys 1993; 48: 1432–1438. Powell GF. Failure to thrive. In: Lifshitz F, ed. Pediatric Endocrinology, 3rd ed. New York: Marcel Dekker, 1996: 121–130. Lifshitz JZ, Lifshitz F. Failure to thrive. In: Lifschitz CL, ed. Pediatric Gastroenterology and Nutrition. New York: Marcel Dekker, 2001:301–326.

Worrisome Growth 193. 194. 195. 196.

197.

198.

199. 200.

201. 202. 203.

204. 205. 206. 207. 208. 209. 210. 211. 212.

213.

Sheard NF. Growth pattens in the first year of life: what is the norm? Nutr Rev 1993; 51:52–54. Salmenpera L, Peerheentupa J, Slimes MA, Exclusively breast-fed healthy infants grow slower than reference infants. Pediatr Res 1985; 19:307–312. Hill PD. Insufficient milk supply syndrome. Clin Issues Perinat Womens Health Nurs 1992; 3:605–612. Motil KJ, Sheng HP, Montandon CM. Case report: failure to thrive in a breast-fed infant is associated with maternal dietary protein and energy restriction. J Am Col Nutr 1994; 13:203–208. Weston JA, Stage AF, Hathaway P, Andrews DL, Stonington JA, McCabe EB. Prolonged breast-feeding and nonorganic failure to thrive. Am J Dis Child 1987; 141: 242–243. Dewey KG, Heining MJ, Nommsen LA, Peerson JM, Lonnerdal B. Growth of breast-fed infants from 0 to 19 months: the DARLING Study. Pediatrics 1992; 89:1035– 1041. Grummer-Strawn LM. Does prolonged breast-feeding impair child growth? A critical review. Pediatrics 1993; 91: 766–771. Wilensky DS, Ginsberg G, Altman M, Tullchinsky TH, Ben Yishay F, Auerbach JA. A community-based study of failure to thrive in Israel. Arch Dis Child 1996; 75: 145–148. Altemeier WA, O’Connor SM, Sherrod KB, Vietze PM. Prospective study of antecedents of nonorganic failure to thrive. J Pediatr 1985; 106:360–365. Reilly SM, Skuse DH, Wolke D, Stevenson J. Oral–motor dysfunction in children who fail to thrive: organic or nonorganic? Dev Med Child Neurol 1999; 41:115–122. Frank DA, Wong F. Effects of prenatal exposures to alcohol, tobacco and other drugs. In: Kessler DB, Dawson P, eds. Failure to Thrive and Pediatric Undernutrition— A Transdisciplinary Approach. Baltimore: Brookes Publishing Co., 1999:275–280. Pugliese MT, Weyman-Daum M, Moses N, Lifshitz F. Parental health benefits as a cause of non-organic failure to thrive. Pediatrics 1987; 80:175–182. Lifshitz F. Children on adult diets. Is it harmful? Is it healthful? J Am Coll Nutr 1992; 11:845–905. McCann JB, Stein A, Fairburn CG, Dunger DB. Eating habits and attitudes of mothers of children with non-organic failure to thrive. Arch Dis Child 1994; 70:234–236. Lifshitz F, Tarim O. Nutritional dwarfing. Curr Probl Pediatr 1993; 23:322–326. Smith MM, Lifshitz F. Excessive fruit juice consumption as a contributing factor in non-organic failure to thrive. Pediatrics 1993; 93:438–443. Campbell M, Lofters WS, Gibbs W. Rastafarianism and the vegan syndrome. Br Med J 1982; 285:1617–1618. Roberts IF, West RJ, Ogilvie D, Dillon MJ. Malnutrition in infants receiving cult diets: a form of child abuse. Br Med J 1979; 1:296–298. Sanders TA, Reddy S. Vegetarian diets and children. Am J Clin Nutr 1994; 59 (suppl): 1176S–1181S. Latham MC, Stephenson LS, Kinoti SN, Zaman MS, Kurz KM. Improvements in growth following iron supplementation in young Kenyan school children. Nutrition 1990; 6:159–165. Cavan KR, Gibson RS, Grazioso CR, Isalgue AM, Ruz M, Solomons NW. Growth and body composition of periurban Guatemalan children in relation to zinc status: a cross-sectional study. Am J Clin Nutr 1993; 57:334–352.

41 214.

215. 216. 217. 218.

219.

220. 221. 222. 223. 224. 225. 226. 227. 228. 229. 230.

231. 232. 233.

Hadi H, Stoltzfus R, Dibley MJ, Moulton LH, West KP Jr, Kjolhede CL, Sadjimin T. Vitamin A supplementation selectively improves the linear growth of Indonesian preschool children: results from a randomized controlled trial. Am J Clin Nutr 2000; 71:507–513. Allen LH. Nutritional influences on linear growth: a general review. Euro J Clin Nutr 1994; 48 (Suppl 1):S75– S89. Martorell R. Results and implications of the INCAP follow-up study. J Nutr 1995; 125:1127S–1138S. Caulfield LE, Himes JH, Rivera JA. Nutritional supplementation during early childhood and bone mineralization during adolescence. J Nutr 1995; 125:1104S–1110S. Pickett KE, Haas JD, Murdoch S, Rivera JA, Martorell R. Early nutritional supplementation and skeletal maturation in Guatemalan adolescents. Nutrition 1995; 125: 1097S–1103S. Vandenplas Y, Lifshitz JZ, Orenstein S, Lifschitz CL, Shepherd RW, Casaubon PR, Muinos RI, Fagundes-Neto U, Garcia Aranda JA, Gentles M, Santiago JD, Vanderhoof J, Yeung CY, Moran JR, Lifshitz F. Nutritional management of regurgitation in infants. J Am Coll Nutr 1998; 17:308–316. Ramsay M, Gisel EG, Boutry M. Non-organic failure to thrive: Growth failure secondary to feeding-skills disorder. Dev Med Child Neurol 1993; 35:285–297. Dobbing J. Vulnerable periods in developing brain. In: Dobbing J, ed. Brain, Behavior and Iron in the Infant Diet. New York: Springer-Verlag, 1990. Wachs TD. Relation of mild-to-moderate malnutrition to human development: Correlational studies. J Nutr 1995; 125 (8 Suppl.):2245S–2254S. Idjradinata P, Pollitt E. Reversal of developmental delays in iron-deficient anemic infants treated with iron. Lancet 1993; 341:1–4. Pollitt E, Oh S. Early supplementary feeding, child development and health policy. Food Nutr Bull 1994; 15: 208–214. Bithoney WG. Elevated lead levels in children with nonorganic failure to thrive. Pediatrics 1986; 78:891–895. Lifshitz F, Moses-Finch N, Lifshitz JZ. Failure to Thrive in Children’s Nutrition. Boston: Jones & Bartlett, 1991: 253–270. Krieger I. Food restriction as a form of child abuse in 10 cases of psychosocial deprivation dwarfism. Clin Pediatr (Phila) 1974; 13:127–133. Krieger I, Mellinger RC. Pituitary function in the deprivation syndrome. J Pediatr 1971; 79:216–225. Whitten C, Fischoff J. Evidence that growth failure from maternal deprivation is secondary to undereating. JAMA 1969; 209:1675–1682. Krieger I. Endocrines and nutrition in psychosocial deprivation in the USA: comparison with growth failure due to malnutrition on an organic basis. In: Gardner LI, Amacher P, eds. Endocrine Aspects of Malnutrition: Marasmus, Kwashiorkor and Psychosocial Deprivation. Santa Ynez, CA: Kroc Foundation, 1973:129–162. Krieger I, Whitten CF. Energy metabolism in infants with growth failure due to maternal deprivation under-nutrition, or causes unknown. J Pediatr 1969; 75:374–379. Gardner LI. Deprivation dwarfism. Sci Am 1972; 227: 76–82. Green WH. Psychosocial dwarfism: psychological and etiological considerations. Adv Clin Child Psychol 1986; 9:245–278.

42 234. 235.

236. 237. 238. 239. 240. 241. 242.

243. 244. 245.

246.

247.

248.

249. 250.

251. 252.

253.

Lifshitz and Botero Bakwin H. Loneliness in infants. Am J Dis Child 1942; 62:30–40. Talbot NB, Sobel EH, Burke BS, Lindemann E, Kaufman SB. Dwarfism in healthy children, its possible relation to emotional, nutritional and endocrine disturbances. N Engl J Med 1947; 236:783–793. Widdowson EM. Mental contentment and physical growth. Lancet 1951; 1:1316–1318. Spitz R. Hospitalism, an inquiry into the genesis of psychiatric conditions in early childhood. Psychoanal Study Child 1945; 1:53–74. Spitz R. Hospitalism, a follow-up report. Psychoanal Study Child 1946; 2:113–117. Chatoor I, Egan J. Non-organic failure to thrive and dwarfism due to food refusal: a separation disorder. J Am Acad Child Psychiatry 1983; 22:294–301. Chatoor I, Egan J, Getson P, Menvielle E, O’Donnell R. Mother–infant interactions in anorexia nervosa. J Am Acad Child Adolesc Psychiatry 1988; 27:535–540. Benjamin DR. Laboratory tests and nutritional assessment. Protein–energy status. Pediatr Clin North Am 1989: 36:139–161. Figueroa-Colon R. Clinical and laboratory assessment of the malnourished child. In: Suskind RM, Lewinter-Susking L, eds. Textbook of Pediatric Nutrition, ed. 2. New York: Raven Press, 1993:191–205. Berwick DM, Levy JC, Kleinerman R. Failure to thrive. Diagnostic yield to hospitalization. Arch Dis Child 1982; 57:347–351. Fryer GE Jr. The efficacy of hospitalization of non-organic failure to thrive children: a meta-analysis. Child Abuse Neglect 1988; 12:375–381. Casey PH, Wortham B, Nelson JY. Management of children with failure to thrive in a rural ambulatory setting: epidemiology and growth outcomes. Clin Pediatr 1984; 23:325–330. Bithoney WG, McJunkin J, Michalek J, Snyder J, Egan H, Epstein D. The effect of a multidisciplinary team approach on weight gain in non-organic failure-to-thrive children. J Dev Behav Pediatr 1991; 12:254–258. World Health Organization. Energy and Protein Requirements. Report of a Joint FAO/WHO/UNU Expert Consultation. WHO Technical Report Series No. 724. Geneva: World Health Organization, 1985. Sentongo TA, Tershakovec AM, Mascarenhas MR, Watson MH, Stallings VA. Resting energy expenditure and prediction equations in young children with failure to thrive. J Pediatr 2000; 136:345–350. Ramsay M, Zelaso PR. Food refusal in failure to thrive infants: nasogastric feeding combined with interactive-behavioral treatment. J Pediatr Psychol 1988; 13:329–347. Angeles IT, Schultnick WJ, Matulessi P, Gross R, Sastroamidjojo S. Decreased rate of stunting among anemic Indonesian preschool children through iron supplementation. Am J Clin Nutr 1993; 58:339–342. Black RE. Therapeutic and preventive effects of zinc on serious childhood infectious diseases in developing countries. Am J Clin Nutr 1998; 68:476S–479S. Sazawal S, Black RE, Jalla S, Mazumdar S, Sinha A, Bhan MK. Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double-blind controlled trial. Pediatrics 1998; 102:1–5. Muhe L, Lulseged S, Mason KE, Simoes EA. Case–control study of the role of nutritional rickets in the risk of

254.

255.

256.

257.

258.

259. 260.

261. 262. 263.

264.

265. 266. 267. 268. 269.

270.

developing pneumonia in Ethiopian children. Lancet 1997; 349:1801–1804. Umeta M, West CE, Haidar J, Deurenberg P, Hautvast JG. Zinc supplementation and stunted infants in Ethiopia: a randomised controlled trial. Lancet 2000; 355:2021– 2026. Bhutta ZA, Black RE, Brown KH, Gardner JM, Gore S, Hidayat A, Khatun F, Martorell R, Ninh NX, Penny ME, Rosado JL, Roy SK, Ruel M, Sazawal S, Shankar A. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Zinc Investigators’ Collaborative Group. J Pediatr 1999; 35:689–697. Rosado JL, Lopez P, Munoz E, Martinez H, Allen LH. Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexian preschoolers. Am J Clin Nutr 1997; 65:13–19. Whitehead RG, Biol FL. Protein and energy requirement of young children living in the developing countries allow for catch-up growth after infections. Am J Clin Nutr 1977; 30:1545–1547. Reeds PJ, Jackson AA, Picou D, Poulter N. Muscle mass and composition in malnourished infants and children and changes seen after recovery. Pediatr Res 1978; 12:613– 618. Chatoor I. Infantile anorexia nervosa: a developmental disorder of separation and individuation. J Am Acad Psychoanal 1989; 17:43–46. Sturm L, Dawson P. Working with families—an overview for providers. In: Kessler DB, Dawson P, eds. Failure to Thrive and Pediatric Undernutrition—A Transdisciplinary Approach. Baltimore: Brookes Publishing Co., 1999:65– 76. Oates RK, Peacock A, Forrest D. Long-term effects of non-organic failure to thrive. Pediatrics 1985; 75:36–40. Singer L. Long-term hospitalization of non-organic failure-to-thrive infants: patient characteristics and hospital course. J Dev Behav Pediatr 1987; 8:25–31. Casey PH. Diagnostic coding of children with failure to thrive. In: Kessler DB, Dawson P, eds. Failure to Thrive and Pediatric Undernutrition—A Transdisciplinary Approach. Baltimore: Brookes Publishing, 1999:281–286. Hess CA. Managed care as part of family-centered service systems. In: Kessler DB, Dawson P, eds. Failure to Thrive and Pediatric Undernutrition—A Transdisciplinary Approach. Baltimore: Brookes Publishing, 1999:287– 302. Torun B, Viteri FE. Protein energy malnutrition. In: Shils ME, Young VR, eds. Modern Nutrition in Health and Disease, 7th ed. Philadelphia: Lea & Febiger, 1988:746–773. Nikens PR. Stature reduction as an adaptive response to food production in Mesoamerica. J Archaeol Sci 1976; 3: 21–41. Stin WA. Evolutionary implications of changing nutritional patterns in human populations. Am Anthropol 1971; 73:1019–1030. Lifshitz F. Nutrition and growth. In: Paige DM, ed. Clinical Nutrition. Nutrition and Growth Supplement 4. St Louis: CV Mosby, 1985:40–47. Kelts DO, Grand RJ, Shen G, Watkins JB, Werlin SL, Boehme C. Nutritional basis of growth failure in children and adolescents with Crohn’s disease. Gastroenterology 1979; 76:720–727. Stenhammar L, Fallstrom SP, Jansson G, Jansson U, Lindberg T. Cocliac disease in children of short stature

Worrisome Growth

271. 272. 273.

274. 275. 276.

277. 278.

279.

280.

281. 282.

283.

284.

285.

286. 287.

without gastrointestinal symptoms. Eur J Pediatr 1986; 145:185–186. Keller W, Fillynore CM. Prevalence of protein–energy malnutrition. World Health Stat Q 1983; 36:129–167. Lifshitz F, Tarim O, Smith MM. Nutrtional growth retardation. In: Lifshitz F, ed. Pediatric Endocrinology, 3rd ed. New York: Marcel Dekker, 1996:103–120. Trowbridge FL, Marks JS, Lopez de Romana G, Madrid S, Boutton TW, Klein PD. Body composition of Peruvian children with short stature and high weight-for-height: implication for the interpretation for weight-for-height as an indicator of nutritional status. Am J Clin Nutr 1987; 46:411–418. Kirschner BS. Nutritional consequences of inflammatory bowel disease on growth. J Am Coll Nutr 1988; 7:301– 308. Pugliese MT, Lifshitz F, Grad G, Fort P, Marks-Katz M. Fear of obesity: a cause of short stature and delayed puberty. N Engl J Med 1983; 309:513–518. Lifshitz F, Friedman S, Smith MM, Cervantes C, Recker B, O’Connor M. Nutritional dwarfing: a growth abnormality associated with reduced erythrocyte Na⫹, K⫹ ATPase activity. Am J Clin Nutr 1991; 54:1–7. Clemmons DR, Underwood LE. Nutritional regulation of IGF-I and IGF binding proteins. Annu Rev Nutr 1991; 11:393–412. Thissen JP, Underwood IE, Maiter D, Maes M, Clemmons DR, Ketelslegers JM. Failure of insulin-like growth factor-1 (IGF-I) infusion to promote growth in proteinrestricted rats despite normalization of serum IGF-I concentrations. Endocrinology 1991; 128:885–890. Clemmons DR, Thissen JP, Maes M, Ketelslegers JM, Underwood LE. Insulin-like growth factor-I (IGF-1) infusion into hypophysectomized or protein-deprived rats induces specific IGF binding proteins in serum. Endocrinology 1989; 125:2967–2972. Clemmons DR, Underwood LE, Dickerson RN, Brown RO, Hak LJ, MacPhee RD, Heizer WD. Use of somatomedin-C/insulin-like growth factor I measurements to monitor the response to nutritional repletion in malnourished patients. Am J Clin Nutr 1985; 41:192–198. Merimee TJ, Zapf J, Froesch ER. Insulin-like growth factors in the fed and fasted states. J Clin Endocrinol Metab 1982; 55:999–1002. Underwood LE, Thissen JP, Moats-Staats BM, et al. Nutritional regulation of IGF-I and postnatal growth. In: Spencer EM, ed. Modern Concepts of Insulin-like Growth Factors. New York: Elsevier, 1991:37–47. Donhue SP, Phillips LS. Response of IGF-I to nutritional support in malnourished hospital patients: a possible marker of short-term changes in nutritional status. Am J Clin Nutr 1989; 50:962–969. Ranke MB, Blum WF, Frisch H. The acid-stable subunit of insulin-like growth factor binding protein (IGFBP-3) in disorders of growth. In: Drop SLS, Hintz RL, eds. Insulin-like Growth Factor Binding Proteins. Amsterdam: Excerpta Medica, 1989:103–113. Guler HP, Zapf J, Schmid C, Froesch ER. Insulin-like growth factors I & 11 in healthy man. Estimations of halflives and production rates. Acta Endocrinol (Copenh) 1989; 121:753–758. Phillips LS, Unterman TG. Somatomedin activity in disorders of nutrition and metabolism. Clin Endocrinol Metab 1984; 13:145–189. Phillips LS, Young HS. Nutrition and somatomedin. 1. Effect of fasting and re-feeding on serum somatomedin

43

288.

289.

290. 291. 292. 293.

294. 295. 296. 297.

298.

299.

300.

301.

302.

303.

304.

activity and cartilage growth activity in rats. Endocrinology 1976; 99:304–314. Phillips LS, Orawski AT, Belosky DC. Somatomedin and nutrition. IV. Regulation of somatomedin activity and growth cartilage activity by quantity and composition of diet in rats. Endocrinology 1978; 103:121–124. Golden M, Jackson AA. Chronic severe under-nutrition. In: Olson RE, Broquist HP, Chichester CO, Darby WJ, Kolbye AC Jr, Stalvey RM, eds. Present Knowledge in Nutrition. Washington, DC: Nutrition Foundation, 1984: 57–67. Byung PY. Update on food restriction and aging. Rev Biol Res Aging 1985; 2:435–443. Patrick J, Golden M. Leukocyte electrolytes and sodium transport in protein energy malnutrition. Am J Clin Nutr 1977; 30:1478–1481. Montage A, Brace C. Human Evolution, 2nd ed. New York: Macmillan, 1977. Beaton GH. The significance of adaptation in the definition of nutrient requirements and for nutrition policy. In: Blaxter KL, Waterlow JC, eds. Nutritional Adaptation in Man. London: Libbey, 1985:219–232. Poehlman F, Melby CL, Badylak SF. Resting metabolic rate and post-prandial thermogenesis in highly trained and untrained males. Am J Clin Nutr 1988; 47:793–798. Waterlow JC, Golder M, Picou D. Protein turnover in man. Am J Clin Nutr 1977; 30:1333–1339. Read WW, McLaren DS, Tchalian M, Nassar S. Studies with 15 N-labelled ammonia and urea in the malnourished child. J Clin Invest 1969; 48:1143–1149. Waterlow JC, Golden MH, Garlick PJ. Protein turnover in man measured with 15N-Comparison of end products and dose regimens. Am J Physiol 1978; 235(2):EI65– EI74. Golden M, Waterlow JC, Pilou D. The relationship between dietary intake, weight change, nitrogen balance, and protein turnover in man. Am J Clin Nutr 1977; 30: 1345–1348. Viteri FE, Torun B. Nutrition, physical activity and growth. In: Ritzer M, Apsia A, Hall K, eds. The Biology of Normal Human Growth. New York: Raven Press, 1981:269–273. Lifshitz F, Brasel JA. Nutrition and Endocrine Disease. In: Kappy MS, Blizzard RM, Migeon C, eds. Wilkins Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. Springfield, IL: Charles C Thomas, 1994:535–573. Alemzadeh R, Pugliese M, Lifshitz F. Disorders of puberty. In: Friedman SB, Fisher M, Shonberg SK, eds. Comprehensive Adolescent Health Care. St. Louis: Quality Medical Publishing, 1992:187–205. Brettler DB, Forsberg A, Bolivar E, Brewster F, Sullivan J. Growth failure as a prognostic indicator for progression to acquired immunodeficiency syndrome in children with hemophilia. J Pediatr 1990; 117:584–588. Gertner JM, Kaufman FR, Donfield SM, Sleeper LA, Shapiro AD, Howard C, Gomperts ED, Hilgartner MW. Delayed somatic growth and pubertal development in human immunodeficiency virus-infected hemophiliac boys: hemophilia growth and development study. J Pediatr 1994; 124:896–902. Kirschner BS, Sutton MM. Somatomedin C levels in growth impaired children and adolescents with chronic inflammatory bowel disease. Gastroenterology 1986; 91: 830–836.

44 305.

306.

307.

308.

309.

310.

311.

312.

313.

314.

315. 316.

317. 318.

319. 320. 321. 322.

Lifshitz and Botero Belli DC, Seidman E, Bouthillier L, Weber AM, Roy CC, Pletinex M, Beaulieu M, Morin CL. Chronic intermittent elemental diet improves growth failure in children with Crohn’s disease. Gastroenterology 1988; 94:603–610. Kanoff ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn’s disease. Gastroenterology 1988; 94:1523– 1527. Seidman E, LeLeiko N, Ament M, Berman W, Caplan D, Evans J, Kocoshis S, Lake A, Motil K, Sutphen J, et al. Nutritional issues in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1991; 12:424–438. Lindor KD, Fleming CR, Burnes JU, Neslon JK, Listrup DM. A randomized prospective trial comparing a defined formula diet, corticosteroids, and a defined formula diet, corticosteroids, and a defined formula diet plus corticosteroids in active Crohn’s disease. Mayo Clin Proc 1992; 67:328–333. Logan RF, Gillon J, Ferrington C, Ferguson A. Reduction of gastrointestinal protein loss by elemental diet in Crohn’s disease of the small bowel. Gut 1981; 22:383– 387. Daum F, Aiges KW. Inflammatory bowel disease in children. In: Lifshitz F, ed. Clinical Disorders in Pediatric Gastroenterology and Nutrition. New York: Marcel Dekker, 1980:145–168. LaSala MA, Lifshitz F, Silverberg M, Wapnir RA, Carrera E. Magnesium metabolism studies in children with chronic inflammatory disease of the bowel. J Pediatr Gastroenterol Nutr 1985; 4:75–81. Nishi Y, Lifshitz F, Bayne MA, Daum F, Silverberg M, Aiges H. Zinc status and its relation to growth retardation in children with chronic inflammatory bowel disease. Am J Clin Nutr 1980; 33:2613–2621. Morin CL, Roulet M, Roy CC, Weber A. Continuous elemental enteral alimentation in children with Crohn’s disease and growth failure. Gastroenterology 1980; 79: 1205–1210. Motil KJ, Grand RJ, Maletskos CJ, Young VR. The effect of disease, drug and diet on whole body protein metabolism in adolescents with Crohn’s disease and growth failure. J Pediatr 1982; 101:345–351. Groll A, Candy DCA, Preece MA, Tanner JM, Harries JT. Short stature as the primary manifestation of coeliac disease. Lancet 1980: 22:1097–1099. Cacciari E, Salardi S, Volta U, Biasco G, Lazzari R, Corazza GR, Feliciani M, Cicognani A, Partesotti S, Azzaroni D, et al. Can antigliadin antibody detect symptomless coeliac disease in children with short stature? Lancet 1985; 1:1469–1471. Rosenbach Y, Dinari G, Zahavi I, Nitzan M. Short stature as the major manifestation of celiac disease in older children. Clin Pediatr (Phila) 1986; 25:13–16. Rossi TM, Albini CH, Kumar V. Incidence of celiac disease identified by the presence of serum endomysial antibodies in children with chronic diarrhea, short stature, or insulin-dependent diabetes mellitus. J Pediatr 1993; 123:262–264. Ashkenazi A, Branski D. Pathogenesis of celiac disease. Part 1. Immunol Allergy Pract 1988; 10:227–234. Ashkenazi A, Branski D. Pathogenesis of celiac disease. Part 2. Immunol Allergy Pract 1988; 10:268–277. Ashkenazi A, Branski D. Pathogenesis of celiac disease. Part 3. Immunol Allergy Pract 1988; 10:315–323. Sandberg DE, Smith MM, Fornari V, Goldstein M, Lifshitz F. Nutritional dwarfing: is it a consequence of dis-

323. 324. 325. 326.

327. 328. 329. 330. 331.

332. 333.

334.

335. 336.

337. 338. 339.

340.

341. 342.

turbed psychosocial functioning? Pediatrics 1991; 88: 926–933. Neumark-Sztainer D, Hannan P. Weight-related behaviors among adolescent girls and boys: results from a national survey. Arch Pediatr Adolesc Med 2000; 154:569–577. Abramovitz B, Birch L. Five-year-old girls’ ideas about dieting are predicted by their mothers’ dieting. J Am Diet Assoc 2000; 100:1157–1163. Schur E, Sanders M, Steiner H. Body dissatisfaction and dieting in young children. Int J Eat Disord 2000; 27:74– 82. Neumark-Sztainer D, Rock CL, Thornquist MD, Cheskin LJ, Neuhoser ML, Barnett MJ. Weight-control behaviors among adults and adolescents: associations with dietary intake. Prev Med 2000; 5:381–391. Moses N, Banilvy M, Lifshitz F. Fear of obesity among adolescent girls. Pediatrics 1989; 83:33–398. Vanderwall JG, Thelen MH. Eating and body image concerning obese and average weight children. Addiction Behav 2000; 25:775–778. Stice E, Agras W, Hammer L. Risk factors for the emergence of childhood eating disturbances: a five-year prospective study. Int J Eat Disord 1999; 25:375–387. Johnson S, Birch L. Parents’ and children’s adiposity and eating style. Pediatrics 1994:653–661. Hood MY, Moore LL, Sundarajan-Ramamurti A, Singer M, Cupples LA, Ellison RC. Parental eating attitudes and the development of obesity in children. The Framingham Children’s Study. Int J Obes 2000; 24:1319–1325. Storz NS, Greene WI. Body weight, body image and perception of fad diets in adolescent girls. J Nutr Ed 1983; 15:15–18. Killen JD, Taylor CB, Telch MJ, Saylor KE, Maron DJ, Robinson TN. Self-induced vomiting and laxative and diuretic use among teenagers: precursors of the binge– purge syndrome. JAMA 1986; 255:1447–1449. Tarim O, Newman TB, Lifshitz F. Cholesterol screening and dietary intervention for prevention of adult-onset cardiovascular disease. In: Lifshitz F, ed. Childhood Nutrition. Boca Raton, FL: CRC Press, 1995:13–20. Lifshitz F, Moses N. Nutritional dwarfing: growth, dieting and fear of obesity. J Am Coll Nutr 1988; 7:368–376. Kaistha A, Deckelbaum RJ, Starc TJ, Couch SC. Overrestriction of dietary fat intake before formal nutritional counseling in children with hyperlipidemia. Arch Pediatr Adolesc Med 2001; 155:1225–1230. Garner DM, Garfunkel PE. The eating attitudes test: an index of the symptoms of anorexia nervosa. Psychol Med 1979; 9:273–279. Dietz WH, Hartung R. Changes in height velocity of obese pre-adolescents during weight reduction. Am J Dis Child 1985; 139:704–708. Hadi H, Stoltzfus RJ, Dibley MJ, Moulton LH, West KP Jr, Kjolhede CL, Sadjimin T. Vitamin A supplementation selectively improves the linear growth of Indonesian preschool children: results from a randomized, controlled trial. Am J Clin Nutr 2000; 71:507–513. Muhilal-Permeisih HD, Idjradinata YR, Muherdiyantiningsih D. Vitamin A-fortified monosodium glutamate and health, growth and survival of children: a controlled field trial. Am J Clin Nutr 1988; 48:1271–1276. Fawzi WW, Herrera MG, Willett WC, Nestel P, el Amin A, Mohamed KA. Dietary vitamin A intake in relation to child growth. Epidemiology 1997; 8:402–407. Fawzi WW, Herrera MG, Wilett WC, Nestel P, el Amin A, Mohamed KA. The effect of vitamin A supplementa-

Worrisome Growth

343.

344.

345.

346. 347. 348.

349. 350. 351.

352. 353.

354.

355.

356.

357.

358.

359.

tion on the growth of preschool children in the Sudan. Am J Public Health 1997; 87:1359–1362. Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC. Diarrhea, respiratory infections, and growth are not affected by a weekly low-dose vitamin A supplement: a masked, controlled field trial in children in southern India. Am J Clin Nutr 1991: 54:568–577. Latham MC, Stephenson LS, Kinoti SN, Zaman MS, Kurz KM. Improvements in growth following iron supplementation in young Kenyan school children. Nutrition 1990; 6:159–165. Lawless JW, Latham MC, Stephenson LS, Kinoti SN, Pertet AM. Iron supplementation improves appetite and growth in anemic Kenyan primary school children. J Nutr 1994; 124:645–654. Allen LH. Malnutrition and human function: a comparison of conclusions from the INCAP and nutrition CRSP studies. J Nutr 1995; 125:1119S–1126S. Beaton G, Ghassemi H. Supplementary feeding programs for young children in developing countries. Am J Clin Nutr 1982; 35:864–916. Prasad AS, Miale A, Farid Z, Sandstead HH, Schulert AR. Zinc metabolism in patients with the syndrome or iron deficiency anemia, hepatosplenomegaly, dwarfism and hypogonadism. J Lab Clin Med 1963; 61:537–549. Prasad AS. Zinc deficiency in women, infants and children. J Am Coll Nutr 1996; 15:113–120. Hambidge KM, Hambidge C, Jacobs M, Baum JD. Low levels of zinc in hair, anorexia, poor growth, and hypogeusia in children. Pediatr Res 1972; 6:868–874. Slonim AE, Sadick N, Pugliese M, Meyers-Seifer CH. Clinical response of alopecia, trichorrhexis nodosa, and dry, scaly skin to zinc supplementation. J Pediatr 1992; 121:890–895. Favier AE. Hormonal effects of zinc on growth in children. Biol Trace Elem Res 1992; 32:383–398. Kirksey A, Wachs TD, Yunis F, Srinath U, Rahmanifar A, McCabe GP, Galal OM, Harrison GG, Jerome NW. Relation of maternal zinc nutriture to pregnancy outcome and infant development in an Egyptian village. Am J Clin Nutr 1994: 60:782–792. Neggers YH, Cutter GR, Acton RT, Alvarez JO, Bonner JL, Goldenberg RL, Go RC, Roseman JM. A positive association between maternal serum zinc concentration and birth weight. Am J Clin Nutr 1990; 51:678–684. Osendarp SJM, van Raaij JMA, Arifeen SE, Wahed MA, Baqui AH, Fuchs GJ. A randomized, placebo-controlled trial of the effect of zinc supplementation during pregnancy on pregnancy outcome in Bangladeshi urban poor. Am J Clin Nutr 2000: 71:114–119. Michaelsen KF, Samuelson G, Graham TW, Lonnerdal B. Zinc intake, zinc status and growth in a longitudinal study of healthy Danish infants. Acta Paediatr 1994; 83:1115– 1121. Kaji M, Gotoh M, Takagi Y, Masuda H, Kimura Y, Uenoyama Y. Studies to determine the usefulness of the zinc clearance test to diagnose marginal zinc deficiency and the effects of oral zinc supplementation for short children. J Am Coll Nutr 1998; 17:388–391. Nakamura T, Nishiyama S, Futagoishi-Suginohara Y, Matsuda I, Higashi A. Mild to moderate zinc deficiency in short children: effect of zinc supplementation on linear growth velocity. J Pediatr 1993; 123:65–69. Nishi Y, Hatano S, Aihara K, Fujie A, Kihara M. Transient partial growth hormone deficiency due to zinc deficiency. J Am Coll Nutr 1989; 8:93–97.

45 360. 361.

362. 363.

364.

365.

366.

367.

368. 369. 370. 371. 372. 373.

374. 375. 376.

377.

378.

Nishi Y. Zinc and growth. J Am Coll Nutr 1996; 15:340– 344. Ninh NX, Thissen JP, Maiter D, Adam E, Mulumba N, Ketelslegers JM. Reduced liver insulin-like growth factorI gene expression in young zinc-deprived rats is associated with a decrease in liver growth hormone (GH) receptors and serum GH-binding protein. J Endocrinol 1995; 144:449–456. Yamaguchi M. Role of zinc in bone formation and bone resorption. J Trace Elem Exp Med 1998; 11:119– 135. Yamaguchi M, Inamoto K. Differential effects of calciumregulating sulfate hormones on bone metabolism on weanling rats orally administered zinc sulfate. Metabolism 1986; 35:1044–1047. McDonell DP, Mongelsdorf DJ, Pike JW, Haussler MR, O’Malley BW. Molecular cloning of complementary DNA encoding the avian receptor for vitamin D. Science 1987; 235:1214–1217. Rosado JL, Lopez P, Munoz E, Martinez H, Allen LH. Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers. Am J Clin Nutr 1997; 65:13–19. Bates CJ, Evans PH, Dardenne M, Prentice A, Lunn PG, Northrop-Clewes CA, Hoare S, Cole TJ, Horan SJ, Longman SC. A trial of zinc supplementation in young rural Gambian children. Br J Nutr 1993; 69:243–255. Meeks Gardner J, Witter MM, Ramdath DD. Zinc supplementation: effects on the growth and morbidity of undernourished Jamaican children. Eur J Clin Nutr 1998; 52:34–39. Rosado JL. Separate and joint effects of micronutrient deificiencies on linear growth. J Nutr 1999; 129:531S– 533S. Hambidge MK. Zinc deficiency in young children. Am J Clin Nutr 1997; 65:160–161. Prentice A. Does mild zinc deficiency contribute to poor growth performance? Nutr Rev 1993; 51:268–270. Brown KH, Peerson JM, Allen LH. Effect of zinc supplementation on children’s growth: a meta-analysis of intervention trials. Bibl Nutr Dieta 1998; 54:76–83. Shalet SM, Toogood A, Rahim A, Brennan BM. The diagnosis of growth hormone deficiency in children and adults. Endocr Rev 1998; 19(2):203–223. Deller JJ, Boulis MW, Harriss WE, Hutsell TC, Garcia JF, Linfoot JA. Growth hormone response patterns to sex hormone administration in growth retardation. Am J Med Sci 1979; 259:292–296. Martin LG, Clark JW, Connor TB. Growth hormone secretion enhanced by androgens. J Clin Endocrinol Meta 1968; 28:425–428. Greene SA, Torresani T, Prader A. Growth hormone response to a standardized exercise test in relation to puberty and stature. Arch Dis Child 1987; 62:53–56. Pugliese M, Lifshitz F, Fort P, Cervantes C, Recker B, Ginsberg L. Pituitary assessment in short stature by a combined hormone stimulation test. Am J Dis Child 1587; 141:556–561. Bercu BB, Shulman DJ, Root AW, Spiliotis BE. Growth hormone provocative testing frequently does not reflect endogenous GH secretion. J Clin Enocrinol Metab 1986; 63:709–716. Rose SR, Ross JL, Uriarte M, Barnes KM, Cassorla FG, Cutler JB Jr. The advantage of measuring stimulated as

46

379. 380.

381.

382.

Lifshitz and Botero compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency. N Engl J Med 1988; 319:201–207. Lanes R. Diagnostic limitations of spontaneous growth hormone measurements in normally growing prepubertal children. Am J Dis Child 1989; 143:1284–1286. Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR. A specific radioimmunoassay for the growth hormone-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J Clin Endocrinol Metab 1990; 70:1292–1298. Hasegawa Y, Hasegawa T, Aso T, Kotoh S, Tsuchiya Y, Nose O, Ohyama Y, Araki K, Taranka T, Saisyo S, et al. Usefulness and limitation of measurement of insulin-like growth factor binding protein-3 (IGFBP-3) for diagnosis of growth hormone deficieiency. Endocrinol Jpn 1992; 39:585–591. Sklar C, Sarafoglou K, Whittam E. Efficacy of insulin-

383.

384. 385. 386.

like growth factor-I and IGF-binding protein-3 in predicting the growth hormone response to provocative testing in children treated with cranial irradiation. Acta Endocrinol (Copenh) 1993; 129:511–515. Smith WJ, Nam TJ, Underwood LE, Busby WH, Celnicker A, Clemmons DR. Use of insulin-like growth factor binding protein-2 (IGFBP-2), IGFBP-3 and IGF-1 for assessing growth hormone status in short children. J Clin Endocrinol Metab 1993; 77:1294–1299. Sandberg DE. Short stature: intellectual and behavioral aspects. In: Lifshitz F, ed. Pediatric Endocrinology, 3rd ed. New York: Marcel Dekker, 1996:149–162. Blizzard RM, Bulatovic A. Syndromes of psychosocial short stature. In: Lifshitz F, ed. Pediatric Endocrinology, 3rd ed. New York: Marcel Dekker, 1996:83–94. Meyer-Bahlburg HFL. Short stature: psychological issues. In: Lifshitz F, ed. Pediatric Endocrinology, 2nd ed. New York: Marcel Dekker, 1990:173–196.

2 Hypopituitarism and Other Disorders of the Growth Hormone and Insulin-Like Growth Factor Axis Arlan L. Rosenbloom University of Florida College of Medicine, Gainesville, Florida, U.S.A.

Ellen Lancon Connor University of Wisconsin, Madison, Wisconsin, U.S.A.

I.

cause. Nearly half of these (47%) were central nervous system (CNS) tumors, including craniopharyngioma, 15% were CNS malformations, 14% septo-optic dysplasia, 9% leukemia, 9% CNS radiation, 3% trauma, 2% histiocytosis, and 1% CNS infection (3). Comparable findings were obtained in the European postmarketing surveillance study (Kabi International Growth Study; KIGS). Some 22% of approximately 15,500 children with GHD had an organic cause, congenital in 24% of this subgroup. The most common central malformation was empty sella, accounting for 37%, followed by septo-optic dysplasia in 24% of those with congenital organic GHD. Among the 76% of patients with organic GHD considered acquired, craniopharyngioma accounted for 24% and other CNS tumors for 30%, leukemia 16%, histiocytosis 3.5%, trauma 3%, and CNS infection 1% (4).

INTRODUCTION

Disorders involving the growth hormone (GH) pathway result in insulin like growth factor-I (IGF-I) deficiency or ineffectiveness and may be congenital or acquired. Congenital GH deficiency is associated with structural malformations of the central nervous system, hypothalamus, or pituitary. IGF-I deficiency/resistance may result from genetic defects involving critical factors in the embryological development of the pituitary or in the cascade from hypothalamic stimulation of GH release to completion of IGF effects on growth. Acquired abnormalities affecting the GH/IGF axis range from damage to the hypothalamic–pituitary region from tumors, infection, autoimmune disease, or radiation to a broad spectrum of chronic conditions characterized by catabolism. The frequency of GH deficiency (GHD) has been estimated in various studies to range from 1:4000 to 1:10,000 (1). Estimates based on clinic referral populations are inherently biased. An excellent population-based study of 80,000 schoolchildren in Salt Lake City documented growth rates over 1 year; of the 555 children who were below the third percentile in height and had growth rates 20,000 children being treated with rhGH registered in the National Cooperative Growth Study, ⬃25% of those with proven GHD had an organic

II.

PITUITARY GLAND, GROWTH HORMONE, AND IGF-I

A.

Embryology of the Pituitary Gland

The pituitary, traditionally considered the ‘‘master gland,’’ appears early in embryonic life. At 3 weeks’ gestation, the ectodermal stomodeum of the embryo develops an outpouching anterior to the buccopharyngeal membrane. This outpocketing is Rathke’s pouch, which usually separates from the oral cavity and will give rise to the adenohypophysis of the pituitary gland. An evagination of the diencephalon then gives rise to the neurohypophysis of the pituitary gland. In rare cases, the primitive oral cavity origin of the pituitary results in a functional pharyngeal adenohypothesis (5). The fetal pituitary gland consists of the 47

48

Rosenbloom and Connor

pars distalis (anterior lobe), pars nervosa (posterior lobe), and the pars intermedia (6). Secretion of pituitary hormones can be detected as early as week 12 in the fetus, and some of these hormones are found within the pituitary by 8 weeks’ gestation (7). Average newborn pituitary weight is 100 mg. Differentiation of the primordial pituitary gland requires a cascade of factors to be expressed in critical temporal and spatial relationships. These include extracellular signaling factors from the adjacent diencephalon that initiate anterior pituitary gland development from the oral ectoderm, and transcription factors that control pituitary cell differentiation and specification. Several homeodomain transcription factors directing embryological development of the anterior pituitary have been found to have mutations that result in congenital defects affecting the synthesis of GH and one or more additional pituitary hormones (9, 10). The homeobox gene expressed in embryonic stem cells (HESX1) is important in development of the optic nerve, as well as of the anterior pituitary. HESX1 has also been referred to as the Rathke’s pouch homeobox gene (Rpx). The three mutations that have been described account for a small minority of instances of septo-optic dysplasia with variable GH and other pituitary deficiencies (11). LIM-type homeodomain proteins (named for the 3 homeodomain proteins lin-11, Islet-1, and mec-3), known as LHX3 accumulate in the Rathke pouch and the primordium of the pituitary and are thought to be involved in the establishment and maintenance of the differentiated cell types (12). Only four patients in two families have been described with mutations of this transcription factor, which results in deficiencies of all pituitary hormones except adrenocorticotropin, and cervical spine rigidity indicating extrapituitary function for this factor (13). Prophet of Pit1 (PROP1) represses HESX1 expression at the appropriate time and is required for initial determination of pituitary cell lineages, including gonadotropes and those of Pit1 (GH, thyroid-stimulating hormone [TSH], prolactin [PRL]). Nine recessive mutations have been described in PROP1 that result in GH, PRL, TSH, gonadotropin, and variable adrenocorticotropin (ACTH) deficiency. Eleven recessive and four dominant mutations have been reported affecting the Pit1 gene, with resultant GH, PRL, and TSH deficiency (10, 14). Somatotroph development is also dependent on hypothalamic GH-releasing hormone (GHRH). Mutation in the gene encoding the GHRH receptor results in severe GH deficiency (15, 16).

B.

Functional Anatomy of the Pituitary Gland

The adult pituitary weighs 0.5 g and has average dimensions of 10 ⫻ 13 ⫻ 6 mm (Fig. 1). The pars intermedia is vestigial in the adult, except in pregnancy. The adeno-

hypophysis receives hormonal modulating signals from the hypothalamus, transmitted from ventromedial and infundibular nuclei axons that terminate in the hypophyseal portal system. These signals result in production of specialized cells of the pars distalis of ACTH by 8 weeks gestation, TSH by 15 weeks gestation, somatotropin (GH) by 10–11 weeks gestation, prolactin by 12 weeks, and the gonadotropes, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by 11 weeks,. The pars distalis has at least three distinct hormone-producing cell populations classified by staining characteristics (8). Fifty percent of the cells are chromophobes, 40% are characterized as acidophils, and the remainder as basophils. Acidophils secrete GH or prolactin. Basophils secrete TSH, LH, FSH, or ACTH. Some basophils have a positive periodic acid– Schiff (PAS) base reaction: these are the cells that secrete the glycoproteins LH, FSH, or TSH. Although chromophobe cells are known to produce ACTH in the rat pituitary, the role of these cells in the human pituitary remains unclear. Anterior pituitary hormones enter the portal venous system to drain into the cavernous sinus, enter the general circulation, and ultimately exert long-distance influence over their respective target organs. PRL has an effect on lactation through direct effects on breast ductal tissue. ACTH stimulates the adrenal cortical production of cortisol and affects renal reabsorption of water. TSH promotes growth of the thyroid and production of thyroxine. LH and FSH stimulate gonadal maturation and hormonal cycling. GH exerts indirect growth effects through the elaboration of IGF-I in the liver, direct growth effects on bone, and direct metabolic effects, primarily in adipose tissue. Although the pars intermedia had been identified as a site of possible melanocyte-stimulating hormone (MSH) production, more recent studies suggest that MSH is actually being produced in the pars distalis and enters the portal venous system to exert a distant effect on skin pigmentation (17). The pars nervosa, or infundibular process, and the infundibulum, or neural stalk, comprise the neurohypophysis. The infundibulum consists of the pituitary stalk and median eminence and is the direct connection to the hypothalamus. The neurohypophysis receives, stores, and releases two important hormones produced in the hypothalamus. These hormones, oxytocin and arginine vasopressin, originate in the supraoptic and paraventricular nuclei of the hypothalamus. The 100,000 axons of these nuclei are unmyelinated and form the supraopticohypophyseal tract that transports oxytocin and vasopressin to be stored in the posterior lobe of the pitutitary (7, 18). The rich blood supply of the pituitary gland is subject to interruption during periods of severe hypotensive stress and hypoxia, resulting in the Sheehan syndrome of hypopituitarism. This is classically described after intrapartum hypotension, but is possible in any hypovolemic crisis or increased intracranial pressure episode, as in hypopi-

Hypopituitarism

Figure 1

49

Diagrammatic illustration of the pituitary gland, showing anatomical divisions. (From Ref. 20.)

50

Rosenbloom and Connor

tuitarism following recovery from cerebral edema (19). The internal carotid arteries supply the vascular branches that bathe the pituitary. The right and left superior hypophyseal arteries, which branch into anterior and posterior divisions, supply the median eminence and infundib-

Figure 2

ulum. The neurohypophysis and stalk are supplied by the right and left inferior hypophyseal arteries. The hypophyseal portal vessels, which originate from capillary beds in the median eminence and infundibular stem, supply the pars distalis (Fig. 2) (18, 20).

Diagrammatic illustration of pituitary blood supply. (From Ref. 20.)

Hypopituitarism

51

Figure 3 Simplified diagram of the GH-IGF-I axis involving hypophysiotropic hormones controlling pituitary GH release, circulating GH binding protein and its GH receptor source, IGF-I and its largely GH-dependent binding proteins, and cellular responsiveness to GH and IGF-I interacting with their specific receptors. (Reprinted from Trends in Endocrinology and Metabolism, vol. 5, Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Pollock BH, Growth in growth hormone insensitivity, pages 296–303. 䉷 1994, with permission from Elsevier Science.)

C.

Biochemistry and Physiology of the GH/IGF-I/IGF-Binding Protein Axis

1. GH Human GH is a single-chain, 191 amino acid, 22 kD protein, containing two intramolecular disulfide bonds (21). Release of GH from the anterior pituitary somatotrophs is controlled by the balance between stimulatory GHRH and inhibitory somatostatin (SS) from the hypothalamus (Fig. 3). This balance is regulated by a variety of neurological, metabolic, and hormonal influences; numerous neurotransmitters and neuropeptides are involved. These include vasopressin, corticotropin-releasing hormone, thyrotropin-releasing hormone, neuropeptide Y, dopamine, serotonin, histamine, norepinephrine, and acetylcholine, which respond to various circumstances that affect GH secretion such as sleep, fed–fasting state, stress, and exercise. Other hormones including glucocorticoids, sex steroids, and thyroid hormone also influence secretion of GH. These various influences are important in the evaluation of GH secretion, which may give abnormal results despite normal somatotroph function.

Stimulation of GH release by GHRH is via specific GHRH receptors. A number of synthetic hexapeptides, referred to as GH-releasing peptides (GHRPs), have been developed that act on other receptors to stimulate GH release (22, 23). The naturally occurring ligand for the GHRP receptor, ghrelin, has been isolated and cloned (24). Ghrelin is unique among mammalian peptides in its requirement of a posttranslational modification for activation. This involves addition of a straight chain octanyl group conferring a hydrophobic property on the N terminus that may permit entry of the molecule into the brain. Similarly to synthetic GHRPs, ghrelin binds with high affinity and specificity to a distinct G protein-coupled receptor (25). Unlike GHRH, ghrelin is synthesized primarily in the fundus of the stomach (24), as well as in the hypothalamus (26) and its receptor is more widely distributed than that of GHRH. Ghrelin may have widespread metabolic effects in addition to being synergistic with GHRH in the stimulation of GH release. Some 75% of circulating GH is in the 22 kD form. Alternative splicing of codon 2 results in a deletion of 11 amino acids and formation of a 20 kD fragment account-

52

ing for 5–10% of secreted GH. Other circulating forms include deamidated, N-acetylated, and oligomeric GH. About 50% of GH circulates in the free state, the rest bound principally to GH binding protein (GHBP). Because the binding sites for the radioimmunoassay of GH are not affected by the GHBP, both bound and unbound GH are measured (27). 2. GHBP A high-affinity GHBP was identified in rabbit and human serum in the mid-1980s (28), and separate reports in 1987 found this binding protein to be absent in the sera of patients with GH resistance (29, 30), who were identified by high circulating GH concentration with a clinical picture of severe GH deficiency. The recognition that circulating GHBP in rabbit serum corresponded to liver cytosolic GHBP was followed by the purification, cloning, and sequencing of human GHBP (31). The human GHBP was found to be structurally identical to the extracellular hormone-binding domain of the membrane bound GH receptor (GHR). The entire human GHR gene, localized to the proximal short arm of chromosome 5, was subsequently characterized (32). The GHR was the first to be cloned of a family of receptors that includes the receptor for prolactin and numerous cytokine receptors. Members of this family share ligand and receptor structure similarities, in particular the requirement that the ligand bind to two or more receptors or receptor subunits and interact with signal transducer proteins to activate tyrosine kinases (33). In humans, GHBP is the proteolytic product of the extracellular domain of the GHR. This characteristic permits the assaying of circulating GHBP as a measure of cellular-bound GHR, which usually correlates with GHR function. The GH molecule binds to cell surface GHR, which dimerizes with another GHR so that a single GH molecule is enveloped by two GHR molecules (34). The intact receptor lacks tyrosine kinase activity, but is closely associated with JAK2, a member of the Janus kinase family. JAK2 is activated by binding of GH with the GHR dimer, which results in self-phosphorylation of the JAK2 and a cascade of phosphorylation of cellular proteins. Included in this cascade are signal transducers and activators of transcription (STATs), which couple ligand binding to the activation of gene expression, and mitogen-activated protein kinases (MAPK). Other effector proteins have also been examined in various systems. This is a mechanism typical of the growth hormone/prolactin/cytokine receptor family (27, 35). The GH receptor in humans is also synthesized in a truncated form (GHRtr) lacking most of the intracellular domain. Although the quantity of this GHRtr is small relative to the full-length GHR, release of GHBP from this isoform is increased (36). Some of the changes in body composition that occur with GH treatment in GH deficiency may be related to changes in the relative expression of GHR and GHRtr (37).

Rosenbloom and Connor

3. IGF-I Most of the growth effect that gives GH its name is indirect, via stimulation of IGF-I production, primarily in the liver (38). IGF-I is a 70 residue single-chain basic peptide, and IGF-II a slightly acidic 67 residue peptide. Their structure is similar to that of proinsulin: A and B chains connected by disulfide bonds and a connecting Cpeptide, but unlike the posttranslational processing of insulin, there is no cleavage of the C-peptide. The two IGFs share approximately two-thirds of their possible amino acid positions and are 50% homologous to insulin (39, 40). The connecting C-peptide is 12 amino acids long in the IGF-I molecule and 8 amino acids long in IGF-II, and has no homology with the comparable region in the proinsulin molecule. The IGFs also differ from proinsulin in having carboxy terminal extensions. These similarities and differences from insulin explain the ability of IGFs to bind to the insulin receptor and insulin’s ability to bind to the type 1 IGF receptor, as well as the specificity of IGF binding to the IGFBPs. 4. IGFBPs Hepatic IGF-I circulates almost entirely bound to IGFbinding proteins (IGFBPs), with 2 standard deviations (SD) below the mean (112). 3. IGHD II is differentiated from IGHD I because it is inherited in an autosomal dominant mode, the result of dominant negative mutations of the GH1 gene. Affected individuals typically have an affected parent and respond well to rhGH administration. Most of the mutations that have been described associated with this form

Rosenbloom and Connor

of IGHD are in intron 3 of the GH gene and alter splicing of GH mRNA with skipping or deletion of exon 3. It is not clear why these mutations prevent expression of normal GH from the unaffected allele (the dominant negative phenomenon) (113–115). With one of the splice mutations, resulting in del32-71-GH, transfection studies in neuroendocrine cell lines demonstrated suppression of wild-type GH by the mutant as a posttranslational effect caused by decreased stability rather than decreased synthesis of the wild-type GH (116). 4. IGHD III is inherited in an X-linked manner. It is associated with agammaglobulinemia in some but not all families, suggesting contiguous gene defects on the long arm of the X chromosome as a cause of some instances of IGHD III (117). 5. Bioinactive GH. The presence of immunologically detectable but biologically ineffective GH has been proposed for a number of reported patients with the appearance of GHD, normal levels of radioimmunoassayable GH in the circulation, and low concentrations of IGFI (118). Radioreceptor assay for GH in these cases has indicated lower concentrations than in the radioimmunoassay, and therapeutic response to rhGH is comparable to that in IGHD (118, 119). A mutation resulting in a heterozygous single amino acid substitution in the GH1 gene has been described in a patient thought to have bioinactive GH. Although there was an abnormal GH peak on isoelectric focusing, there was also a normal one and the patient shared this mutation with his normal father, suggesting that it was not pathological (120). In quest of a molecular defect in such patients, 200 children with short stature found to have GH sufficiency were reviewed. Three were identified who had short stature and growth velocities consistent with GHD, but elevated basal and stimulated levels of immunoassayable GH, and low concentrations of IGF-I and IGFBP-3 in the serum. A rat lymphoma cell proliferation assay and an immunofunctional assay for GH gave abnormally low responses compared to results on the radioimmunoassay (RIA). High-resolution sequencing of both strands of the coating region and display sites of genomic DNA and sequencing of the CD did not reveal GH-1 gene mutation in any of the patients. It was postulated that the reduced biological activity of abnormal translation product could be due to posttranslational processing in these patients (121).

V.

ACQUIRED GH DEFICIENCY

A.

Tumors

By far the most common cause of acquired GH deficiency in children is tumor. Craniopharyngiomas account for the greatest number of tumors causing GH deficiency, but several other benign or malignant tumors can also be responsible for the deficient state (122–124). Benign lesions that damage the hypothalamic–pituitary axis include pi-

Hypopituitarism

59

Figure 6 Comparison of patients with GHRD and GHRH receptor deficiency. Upper left: 30-year-old man with GHRD (Laron syndrome), height 106 cm (⫺10.8 SDS), with 17-year-old brother, height 162 cm (⫺2.1 SDS). Upper right: 21-year-old twins with GHRH receptor deficiency, heights 119 and 118 cm (⫺8.8, 8.9 SDS) and normal adult from region (height 168 cm). Lower: 27-year-old woman with GHRD, height 106 cm (⫺9.4 SDS), 24-year-old unaffected sister, height 155 cm (⫺1.4 SDS), and 25-year-old affected sister, height 112 cm (⫺8.4 SDS). Note in patients with GHRD family resemblance but with marked foreshortening of the face, prominence of the forehead, obesity, in men, frontotemporal baldness, and relatively short upper extremities. In contrast, the men with GHRH receptor deficiency have normal facies and body proportions, without obesity. (Upper right photo reprinted from Maheshwari HG, Silverman BL, Dupuis J, Baumann G. Phenotypic and genetic analysis of a syndrome caused by an inactivating mutation in the GH-releasing hormone receptor: dwarfism of Sindh. J Clin Endocrinol Metab 1998; 1983:4065–4074; 䉷 The Endocrine Society.)

tuitary adenoma, Rathke’s cleft cyst, and arachnoid cyst (125). Primary malignant tumors that can affect this region include dysgerminomas, germinomas, meningiomas, and gliomas (126). Although metastatic tumor is a more common cause of GH deficiency in adults than in children, childhood Hodgkin’s disease or nasopharyngeal carcinoma can metastasize to the pituitary or hypothalamus (126). Signs and symptoms of primary or metastatic malignancies and benign intracranial lesions can be visual loss (particularly bitemporal hemianopsia, for optic chiasm lesions), papilledema, headache with sleep or on awakening, emesis, and behavioral changes (126). Lesions

in the hypothalamus may additionally cause hypersomnolence, appetite changes, or diabetes insipidus (127). Weight loss may result from appetite loss or excess fluid losses from diabetes insipidus. Symptoms of prolactin excess, including amenorrhea or galactorrhea, may occur, because of the loss of dopamine inhibition from the hypothalamus. 1. Craniopharyngioma Two-thirds of craniopharyngiomas are found in a suprasellar location. The tumor most likely arises from rem-

60

Rosenbloom and Connor

Figure 7 Top: 7-year-old boy with GHRH receptor deficiency, height 95 cm (⫺5.2 SDS) and weight 12 kg (5th percentile for height) with bone age 3 years, spontaneous and stimulated GH concentrations 3 month) LHRH analog treatment suppresses ovarian androgen secretion in these patients (182). The definitive differential diagnosis of these three conditions requires ovarian hormonal dynamic studies, radiological evaluation, gynecological examination, and possibly laparoscopic examination in some cases. Laparotomy may also have to be carried out if there is a high suspicion of tumorous lesions in the ovary.

VI.

TREATMENT OF HIRSUTISM AND POLYCYSTIC OVARY SYNDROME

The specific and nonspecific therapies for the various causes of hirsutism described here are based partly on the author’s experience and a review of the literature (Table 6). The treatment of hirsute symptoms is most effective if aimed at correcting the primary pathogenic mechanism. This is not always straightforward in patients with PCOS, ovarian hyperthecosis, or idiopathic hirsutism. Both specific and nonspecific therapy will be discussed for each disorder.

A.

Mild Nonclassic 21-Hydroxylase Deficiency, 3␤-HSD Deficiency, and Idiopathic Adrenal Hyperandrogenism

Suppression of excess adrenal androgen production for these conditions can easily be achieved by administration of a relatively low dosage of glucocorticoid hormone. We have used prednisone in a dosage of 2.5 mg twice daily or 5 mg a.m. and 2.5 mg p.m., or dexamethasone 0.25– 0.375 mg at bedtime. The dosage of glucocorticoid should be adjusted based on the patient’s clinical and hormonal response, as well as side effects of glucocorticoid, such as weight gain, striae, and Cushingoid features. Use of dexamethasone 0.5 mg at bedtime caused Cushingoid fea-

tures in some women with nonclassic CAH within 4–8 weeks in the author’s experience as well as in PCOS patients with elevated adrenal androgens (245). The aim of treatment is to reduce adrenal androgen secretion to a low-normal level, not complete adrenal suppression, thereby minimizing the side effects. Our experience indicates that marginal to significant clinical improvement of hirsutism in a large number of women with these increased adrenal androgen-producing conditions occurred within 8 months to 1 year of treatment. By the second year of treatment, a majority of the patients showed good improvement in hirsutism. In almost all cases recovery of menses occurred in 2–3 months following adequate suppression of excess adrenal androgen secretion. Therapeutic monitoring of 21-hydroxylase deficiency requires periodic follow-up measurement of 17-OHP, ⌬4-A, and T levels. Periodic measurement of DHEA, DHEA-S, ⌬4-A, and T is necessary to monitor 3␤-HSD deficiency and idiopathic adrenal hyperandrogenism. Antiandrogen drug therapy as depicted later in Table 8 may be necessary in those patients whose hirsutism symptoms do not improve significantly despite lowered adrenal androgen levels. Use of spironolactone in nonclassic CAH is, however, not desirable due to its potential salt-wasting effect.

B.

Primary PCOS and Stromal Hyperthecosis

Primary PCOS is a more difficult condition to treat successfully for both hirsutism and menstrual disorders (amenorrhea/oligomenorrhea or dysfunctional bleeding). In patients with insulin resistance and/or obesity, additional risk of glucose intolerance or type 2 diabetes and complications of obesity need to be dealt with. In PCOS females with insulin resistance with or without obesity and menstrual disorder, treatment for hyperinsulinemia secondary to insulin resistance is the approach of choice. This is because the pathophysiology of ovarian hyperandrogenism and menstrual disorder is related to a peripheral defect in either the insulin-signaling pathway or glucose metabolic pathway as described earlier. Thus, weight control and weight loss measures in obese patients, including nutritionally healthy eating, controls on both the amount and kinds of food, coupled with a physically active lifestyle in the long term is needed to reduce or prevent ovarian hyperandrogenism, glucose intolerance, type 2 diabetes, hyperlipidemia, and hypertension. Insulin-sensitizing pharmacological agents used in the past few years and currently available on the market are summarized in Table 6. Metformin hydrochloride (Glucophage) decreases hepatic glucose production, decreases intestinal glucose absorption, increases peripheral glucose uptake/utilization (nonhypoglycemic agent), and has been more widely used than other insulin-sensitizing agents for PCOS females. At a dosage of 1000–2000 mg per day in two to three divided doses, it is effective in improving glycemic parameters, lowering insulin levels, and improv-

299

Acarbose, 300 mg/d in 3 divided doses

Leuprolide depot, Triptorelin, decapeptyl 3.75–7.5 mg/q m IM ⫾ COC Goserelen, 3.75 mg/q m IM ⫾ COC Metformin, 1000–2000 mg/d in 2–3 divided doses

EE, 35 ␮g ⫹ CPA 2 mg/d

Triphasic OC

↓ F-G score ↓ T/free T/DHEAS ↓ LH and FSH ↓ Androgen ↔ F-G score ↓, ↔ F-G score ↓ T/free T index ↔ LH and FSH ↓ or ↔ DHEA/DS

↓ F-G score ↓ T/free T ↓ DHEA, A

↓ Acne/seborrhea ↓ Androgen

↓ F-G score ↓ only in lean PCOS ↓ T/free T ↓ LH and FSH

↓ F-G score

53% normal cycle recovery

Improved menstrual cyclicity/regularity, less for patients with ↑ DHEA-S

Anovulatory cycle regularity

Anovulatory cycle regularity

Recovery of spontaneous/ clomid-induced ovulation

Improved insulin sensitivity ↓ fasting insulin ↓ fasting glucose ↓ insulin response to glucose ↓ insulin to glucose

Variable effects No significant changes

↑ ↑ ↑ ↑

↓ free fatty acids

TC HDL LDL TG

255

246, 247, 249, 250, 252, 259

256

262–265

252, 256– 261

267, 233

↓ F-G score ↓ T/Free T ↓ DHEA-S ↓ All androgens

Dexamethasone, 0.375 mg/d ⫹ spironolactone 100 mg/d, Dexamethasone 0.5 mg po qd Low dose COC, 35 ␮g EE ⫹ progestin No effect

262, 270, 276, 277

↓ F-G score ↔, ↑ Total T ↓ DHT, 3␣-AG

↓ F-G score ↔ or ↑ T/E2 ↓ DHT, 3␣-AG, DHEA-S

263, 270, 272, 275, 276

↓ F-G score ↔ T, DHT, 3␣AG

↓ F-G score ↔ T, DHT, 3␣AG

Finasteride, 5 mg/d ⫾ COC, 0.25% finasteride cream

257, 263, 270, 272, 275

↓ F-G score ↓ Androgens

257, 267– 272

Ref.

↓ F-G score ↓ Androgens

Lipid changes

CPA, 50–100 mg/1– 10 days of use ⫹ COC or 25–50 mg/ day ⫹ COC Flutamide, 62.5–250 mg/d, 250 mg bid ⫾ COC

Insulin resistance, glucose intolerance

↓ F-G score ↓ Free T

Anovulation

↓ F-G score ↔ Androgens

Cycle regulation

Spironolactone, 100– 200 mg/d ⫾ COC

Idiopathic

Menstrual disorders

PCOS

GI side effects, flatulence, pain, diarrhea, do not use in liver disorder, GI disorders, renal failure

Contraindicated for renal/hepatic dysfunction—monitor function yearly, GI side effects, lactic acidosis precaution

↑ risk of venous thrombosis in coagulation factor V cases, ↑ risk of arterial thrombosis in hypertensive patients, smoker and >35 yrs age, weight gain, breakthrough bleeding, GI SYS, breast tenderness, and mood swing Temporary ↑ in LH/FSH, COC Rx to prevent osteoporosis, costly Rx

Cushingoid side effect/weight gain at 0.5 mg/day dose

Contraception precaution, liver function monitoring a must; fulminant liver failure reported Contraception precaution

Need of contraception/longterm therapy for efficacy, gradual dose increase from 25 to 100 mg over time, K⫹ level monitoring, breast tenderness, irregular bleeding, mild volume deletion Same as COC below

Precautions

F-G, Ferriman-Gallwey hirsutism score; EE, ethinyl estradiol; CPA, cyproterone acetate; ↑, increase; ↓, decrease; ↔, no change; 3␣-AG, 3␣-androstanediol gluconate; A, androstenedione; COC, combined estrogen/progesterone oral contraceptives.

Insulin-sensitizing agents

GnRH analog

COC

Glucocorticoids

Antiandrogens

Drugs and dosage

Hyperandrogenic causes

Hirsutism and androgen levels

Reported Effects of Pharmacological Therapies for Hirsutism and Polycystic Ovary Syndrome

Classification of therapy

Table 6

300

ing or recovering regular menstrual cyclicity in women with PCOS (246–250) and decreased visceral adiposity (248, 251, 252). The effect of metformin on the FerrimanGallwey Hirsutism Score has been inconsistent (247, 250) and appears less effective in patients with elevated DHEA and DHEA-S levels (246). Troglitazone (Rezulin: no longer on the market) is an insulin-sensitizing agent of the thiazolidinedione family. It has the pharmacological action of decreasing hepatic glucose output and increasing insulin-dependent glucose disposal in skeletal muscle via its binding to peroxisome proliferator-activated receptors (253, 254). At a dosage of 400–600 mg per day it improved all glycemic parameters and the ovulatory cycle in PCOS females (253, 254). The drug was removed from the market due to a potential for liver toxicity. Its effect on hirsutism, however, was only slight (253, 254). Rosiglitazone (Avandia) and Pioglitazone (Actos) are potent agonists for peroxisome proliferator-activated receptorgamma and have pharmacological actions similar to Troglitazone. Both are available on the market, but their use for PCOS females is limited. Acarbose (Precose) is an agent of alpha-glucodase inhibitor that delays digestion of ingested carbohydrates and minimizes glucose use. A dosage of 300 mg per day was reported to be effective in lowering insulin levels and in the recovery of the normal menstrual cycle in 53% of PCOS females. Improved acne has also been reported (255). If the patient desires mainly hirsutism treatment, as is the case with many adolescent girls with PCOS or hyperandrogenism, the antiandrogen therapies in Table 6 may be considered as well as combined estrogen/progesterone oral contraceptive (COC) therapy. Because all of the antiandrogen agents are potentially teratogenic for the male fetus, women of reproductive age should take contraceptive precautions using either COC or barrier contraceptives during this treatment. Additive effects of an antiandrogen agent and COC are likely to result in a greater degree of improvement in hirsutism. Use of antiandrogen compounds in the treatment of hirsutism is described in greater detail in the section on Idiopathic Hirsutism below. COC treatment alone in PCOS patients is often partially effective in hirsutism improvement and suppression of ovarian androgen secretion and free T levels (252, 256– 261). Cyclic COC therapy in PCOS patients, however, has a long-term benefit from the prevention of endometrial hyperplasia to an unopposed effect of increased free estrogen in PCOS. COC has no discernable effect on insulin sensitivity and has variable influence on HDL and LDL, and total cholesterol and triglyceride levels (256–259). Thus, the long-term benefits of COC on lipids are difficult to predict in young women (Table 6). In women with severe PCOS or stromal ovarian hyperthecosis with a greater degree of elevated ovarian testosterone level associated with increased LH secretion, use of a GnRH analog at a dosage of 3.75–7.5 mg intramuscularly (IM) every 28 days is highly effective in near-

Pang

total suppression of gonadotropin and ovarian androgen secretion (182, 262–265). GnRH analog therapy is often combined with COC to prevent any undesirable effect on bone mineral density in these patients. The combined therapies of GnRH analog and COC thus have the effect of decreasing ovarian androgen levels, having antiandrogen action in the androgen-sensitive tissue, and increasing SHBG. They were also very effective in the treatment of hirsutism in PCOS and stromal hyperthecosis. The drawback of these therapies, however, is recurrence of ovarian hyperandrogenism and symptoms shortly after the drug therapies are discontinued (182, 260). Although ketoconazole has been reported to be effective in decreasing serum androgen levels and hirsutism (257, 266), this compound has not been widely accepted in the treatment of hirsutism.

C.

Idiopathic Hirsutism

In the treatment of idiopathic hirsutism, the antiandrogen agents shown in Table 6 are predicted to be more specific therapeutic agents. However all antiandrogenic agents entail the risk of teratogenic effects. Therefore, absolute contraceptive measures are a must in women receiving antiandrogenic therapy. During the past several years, wider experience with four different antiandrogenic agents for treatment of idiopathic and hyperandrogenic hirsutism have been reported (Table 6), although the Food and Drug Administration has approved of none of these agents for treatment of hirsutism. Spironolactone (100–400 mg/day) interferes with DHT binding to its receptor and forms inactive complexes at the nuclear level, minimizing the androgen effect on hair growth. Spironolactone treatment has variable results in hirsute females and other cosmetic hair removal care is often necessary. In our experience, spironolactone alone or combined therapy with spironolactone and COC was more effective in women with idiopathic hirsutism defined by normal androgen levels than in women with elevated androgen levels. Recent reports using a lower dosage of spironolactone (at 100–200 mg per day) showed as effective results in decreasing the Ferriman-Gallwey score as COC alone or cyproterone acetate combined with COC or ketoconazole therapy (257, 267–272) or flutamide or finasteride (270). Cyproterone acetate is a synthetic steroid derivative of 17-OHP and has both antiandrogenic and antigonadotropic action (273). This agent is effective not only in the treatment of idiopathic hirsutism but also in other causes of androgen excess due to its antiandrogenic properties and by reducing androgen production via suppression of gonadotropin secretion (274). Overall, the combination of cyproterone acetate at 50–100 mg from cycle days 1–10, or a daily dose of 25–50 mg together with low-dosage estrogen therapy reduces the production, transport, metabolism, and action of androgens (257, 263, 270, 272, 273, 275). As shown in Table 6, numerous European sources

Hirsutism, POS, Menstrual Disorders

301

indicate successful treatment of hirsutism of various causes using these combinations. 5␣-reductase inhibitor should theoretically be an effective agent in the treatment of hirsutism. The type 1 5␣reductase isoenzyme predominates in peripheral tissue and type 2 isoenzyme in the reproductive system. Recently, type 2 isoenzyme has also been demonstrated in the hair follicle tissue and was described earlier. Of several steroidal and nonsteroidal 5␣-reductase inhibitors, only finasteride has been extensively used for the treatment of hirsutism (262, 270, 276, 277). Finasteride at a daily dosage of 5 mg orally has been reported to decrease hirsutism scores in patients with both idiopathic and hyperandrogenic hirsutism (262, 270, 276, 277). Its effect on circulating androgen levels appears variable. The effect of finasteride in decreasing hirsutism has been reported to be either similar to the effect of cyproterone acetate or flutamide (275) or less than the effect of flutamide (276). Flutamide is a nonsteroidal antiandrogen and prevents androgen from binding to the androgen receptor by its competitive binding without androgenic activity. Variable dosages of flutamide from 62.5 to 500 mg in two divided doses daily have been reported as effective in the treatment of hirsutism in both the idiopathic and hyperandrogenic causes (263, 270, 272, 275, 276, 278). A concern about this drug derives from a few reports of related fulminant hepatic failure (279–281). Thus, close monitoring of liver function is mandatory during the course of flutamide therapy. COC treatment alone or combined COC and GnRH analog therapy in idiopathic hirsutism decreased the hirsutism score in a few reports (260, 261) (Table 6). The beneficial effects of COC and GnRH were described earlier. In summary, most of the antiandrogenic drug therapies have been reported as effective in decreasing the amount of hirsutism in patients with either idiopathic or hyperandrogenic cases. However, the drawbacks of these therapies are their temporary effectiveness during the drug treatment course. Cessation of drug therapies almost invariably results in recurrent hyperandrogenic symptoms with time. In addition, there are known potential side effects with all drug therapies, as summarized in Table 6. Evaluation of renal and hepatic function prior to and during administration of many of these pharmacological compounds and providing precautionary information to the patient with regard to potential side effects of the compounds are prudent measures in clinical practice.

include shaving, waxing, tweezing, depilatory creams, and electrolysis. Recently, hair removal methods based on light technology such as lasers or intense pulsed light have been used in darker-skinned patients (282). This was reported to be a useful method when proper patient selection was employed in both darker- and lighter-skinned subjects (282–284). Both cosmetic and medical therapies need to be considered for hirsute females to minimize emotional embarrassment.

D.

Primary amenorrhea is defined by the absence of menarche by age 16 years with normal pubertal development; by 2 years after completed sexual maturation; or without the onset of pubertal development by age 14 years. Secondary amenorrhea is defined by the absence of menstruation for 3 cycle lengths in the setting of oligomenorrhea, for 6 months after establishing regular menses or by 18

Cosmetic Treatment of Hirsutism

Psychological embarrassment as a result of hirsutism and/ or acne in adolescents and young adult women is a common observation in clinical practice. Thus, many patients undertake immediate methods of hair elimination prior to seeking medical help. Traditional methods of hair removal

VII. A.

MENSTRUAL DISORDERS IN ADOLESCENTS Physiology of the Menstrual Cycle

Maturation of the normal ovulatory menstrual cycle requires intact development and function of the cascade of the system, including maturation of cyclic hypothalamic gonadotropin-releasing hormone secretion in the basal hypothalamus; its effect on the sequence and magnitude of gonadotropin secretion in the anterior pituitary; proper quantity and sequence of ovarian steroidogenesis, which interacts in a positive manner for induction of ovulatory cyclic changes of LH and FSH; evolving spectrum of follicle development, ovulation, and corpus luteum function; and development and cyclic changes of the endometrium in relation to the ovarian steroidogenic and follicular life cycle (Fig. 7). The entire system is regulated by a complex mechanism that integrates biophysical and biochemical information composed of interactive levels of hormonal signals, autocrine and paracrine factors, and target cell reactions (285, 286). In addition, the normal anatomy of menstrual outflow that connects the internal genital source of flow with the outside provides patency and continuity of the endocervix with the uterine cavity, vaginal canal, and orifice. The average age of menarche in the U.S. is 12.8 years for white girls and 12.6 years for African-American girls, with a range from 9 to 16 years in the normal spectrum. Age of menarche is associated with race, nutritional status, amount of body fat, and maternal age at menarche. Menarche usually occurs 2–2.5 years after thelarche and 1 year after the growth spurt. Normal menstrual cycles vary from 21 to 45 days but remain fairly constant within a given individual. Normal flow lasts 2–7 days with an average blood flow of 30–40 ml. Ovulation may not begin until as late as 2 years after menarche (286, 287).

B.

Definition of Menstrual Disorder

302

Pang

Figure 7 Normal menstrual cycle of hormonal follicular and endometrial changes. (From Carr BR and Wilson JD, Disorders of the Ovary and Female Reproductive Tract in Harrison’s Principles of Internal Medicine, 11th Edition, 1987:1818–1837. Reproduced with permission from McGraw-Hill, New York, NY.)

months after menarche (285). Oligomenorrhea is defined by significantly diminished menstrual flow. Polymenorrhea, or intermenorrhea indicates a too frequent menstrual flow cycle (less than 21 days). Menorrhagia indicates excessive uterine bleeding occurring at the regular intervals of menstruation, and menometrorrhagia indicates excessive uterine bleeding occurring at regular or irregular intervals. Table 7 depicts the causes of menstrual disorders/ alteration in young women with apparent normal external genitalia.

C.

Causes of Menstrual Disorders

1. Primary Amenorrhea Primary amenorrhea may be caused by a congenital or acquired pathology of a significant degree in the CNS– hypothalamic–pituitary–ovarian (H–P–O) axes; in the genital anatomy; as well as other systemic and/or hormonal factors affecting the H–P–O axes; and rarely but not impossibly by pregnancy. Complete absence of sec-

ondary sex characteristic development, including amenorrhea in the absence of hyperandrogenic symptoms or signs, generally signifies complete or near complete failure of either ovarian or hypothalamic–pituitary gonadotrope function of either congenital or inherited causes or causes acquired prior to adolescence. The classification of the causes of primary amenorrhea depicted in Table 7 helps to identify the pathogenic site of this disorder. a. Normal Anatomy of the Genital Outflow Tract. Primary ovarian failure results in a hypergonadotropic state with a greater increase in FSH than LH from peripubertal age (288). Congenital causes include gonadal dysgenesis due to an abnormal X chromosome typified by a deletion of an X chromosome during meiosis, resulting in features of classic Turner syndrome including sexual infantilism, short stature, cardiovascular defects, webbed neck, shield chest, short fourth and fifth metacarpals, increased carrying angles of arms, and other associated features. In Turner syndrome, germ cells are absent in the

Hirsutism, POS, Menstrual Disorders Table 7

303

Causes of Menstrual Disorders with Apparent Female External Genitalia in Adolescent Girls

Primary amenorrhea 1. Primary ovarian failure (Hypergonadotropic hypogonadism): Congenital Gonadal dysgenesis (Turner syndrome/mosaicism, pure 46 XX or XY dysgenesis, other X chromosome abnormalities) 17␣-hydroxylase/17, 20 lyase deficiency Other congenital FSH receptor gene mutation LH receptor gene mutation Acquired Autoimmune oophoritis Mumps oophoritis Irradiation Chemotherapy Galactosemia complication 2. Gonadatropin deficiency: Congenital GnRH deficiency (Kallman syndrome) Hypopituitarism/empty sella syndrome GnRH receptor gene mutation Prader-Willi syndrome Bardet-Biedel syndrome Acquired CNS trauma CNS histiocystosis X Suprasella tumors Eating disorders Rigorous exercise 3. Genital structure abnormalities: Congenital in genetic females Agenesis of mullerian structure (MayerRobitansky-Kuster-Hauser syndrome) Agenesis of vagina Agenesis of cervix/endometrium Hymen imperforation Labial agglutination Congenital in genetic males Complete androgen insensitivity 17␣-hydroxylase/17, 20 lyase deficiency Acquired Uterine synechia secondary to irradiation/infection 4. Hyperandrogenic disorders: Stromal hyperthecosis/PCOS Congenital adrenal hyperplasia Androgen-producing tumor 5. Pregnancy

Secondary amenorrhea Pregnancy Hypothalamic amenorrhea PCOS/stromal hyperthecosis Hyperprolactinemia Hypo/hyperthyroidism Turner mosaicism Other X chromosome abnormalities All acquired causes of hyper/ hypogonadotropism All acquired virilizing disorders including Cushing syndrome

Oligomenorrhea and menometrorrhagia Pregnancy PCOS Hyperprolactinemia Functional hypothalamic anovulation Thyroid disorder

304

ovary and are replaced by a fibrous streak. The variants of Turner syndrome are termed Turner mosaicism, with X-chromosome abnormalities such as 45 X/46 XX; and iso or ring X-chromosome. 46 XX/XXX abnormality is also a cause of ovarian failure (289). In subjects with Turner mosaicism, the degree of ovarian failure may be complete or partial, thus development of some secondary sex characteristics may be present despite primary amenorrhea (289). Gonadal dysgenesis is the most common cause of primary amenorrhea. Pure gonadal dysgenesis with a 46 XY karyotype (Swyer syndrome) is a rare cause of primary gonadal failure and is associated with increased risk of gondaoblastoma development from the streak gonads (290). A recent cytogenetic study of adolescent patients with primary amenorrhea revealed a pathologicical or male karyotype in 26.4% (18/68) of patients (289). Pure gonadal dysgenesis with 46 XX karyotype may result from a single gene defect or destruction of germinal tissues in utero by environmental or infectious processes (291, 292). Both genetic females and males with gonadal/adrenal combined 17-␣-hydroxylase/17,20 lyase deficiencies of significant degrees are phenotypically feminized and fail to develop female secondary sex characteristics (293, 294). A characteristic clinical clue for this enzyme deficiency is hypertension; biochemical evaluation would verify elevated progesterone and deoxycorticosterone levels and decreased 17-hydroxysteroids, DHEA, other androgens and estrogen levels. Feminized genetic males with this enzyme deficiency do not have the mullerian structure. Acquired causes of primary ovarian failure include mumps oophoritis; autoimmune oophoritis; destruction of ovarian tissue by trauma, irradiation, or chemotherapeutic complications; or by excessive accumulation of galactose1-phosphate or deficiency of galactose-containing compounds in the ovary of patients with galactosemia (295); as well as idiopathic cause for primary amenorrhea. Depending on the age at which the disease is acquired, primary amenorrhea may or may not be associated with secondary sex characteristic development. Other rare genetic causes of hypergonadotropic primary amenorrhea include inactivating mutations of the FSH receptor gene in females with normal pubertal development, high plasma FSH level and numerous ovarian follicles (296), and inactivating mutations of the LH receptor gene in females with normal breast development (297, 298). Gonadotropin deficiency due to a congenital or inherited disorder or acquired cause results in hypogonadotropic hypogonadism and primary amenorrhea. A cause of inherited hypogonadotropic hypogonadism is Kallman syndrome resulting from congenital deficiency of GnRH in the presence or absence of agenesis of olfactory bulbs causing anosmia. This disorder is transmitted by an X-linked gene mutation but may also be transmitted by an autosomal dominant trait (299, 300). Thus, this disorder occurs in both females and males. GnRH receptor

Pang

gene mutation has recently been characterized and results in hypogonadotropic hypogonadism and primary amenorrhea in females with normal breast development (301). Other congenital syndromes that have been reported to be associated with hypogonadotropic hypogonadism include Bardet-Biedel syndrome and Prader-Willi syndrome. Other congenital causes of hypogonadotropic hypogonadism are empty sella syndrome, which causes varying degrees of hypopituitarism and idiopathic gonadotropindeficient hypogonadism. An acquired cause of gonadotropin deficiency causing primary amenorrhea is chronic debilitating systemic disease, which is often associated with overall delayed development of secondary sex characteristics. This delay is seen in patients with congenital hemoglobinopathy, malabsorption, human immunovirus (HIV), chronic nutritional deprivation, malnutrition, or due to eating disorders including anorexia nervosa and bulimia with or without rigorous exercise. Organic and anatomical pathologies in the hypothalamic–pituitary region, including suprasella tumors (craniopharyngioma, germinoma, teratoma, histoliocytosis, etc.); or other inflammatory processes (sarcoidosis, meningitis, tuberculosis, etc.) in the hypothalamic region; pituitary tumors, pituitary infarction or necrosis, or pituitary hemachromatosis or sarcoidosis; or trauma in the pituitary stalk or hypothalamic–pituitary axis region are well-known causes of hypopituitarism and hypogonadism. Primary amenorrhea may be related to hyperandrogenic disorders including ovarian hyperthecosis and PCOS, CAH, Cushing syndrome, or androgen-producing tumors, as discussed earlier in this chapter. The clinical presentation of these disorders is often associated with hyperandrogenic symptoms. Excess androgens, progesterone, or cyclic production of estrone by extraglandular aromatization of excess androgens is likely to be altering the feedback loop of the H–P–O axis in these disorders. Thyroid disorders including hyper- or hypothyroidism are a cause of amenorrhea of primary and secondary natures and may be associated with estrogen-positive anovulation. Other gonadal and endocrine disorders to be considered for primary amenorrhea include mixed gonadal dysgenesis, true hermaphroditism, and androgen resistance syndrome in genetic males with complete or near complete female phenotypic presentation. Any slight suspicion of genital ambiguity with or without signs of virilization or palpable gonadal mass in the inguinal or labial region in the female is often a clue for these causes (See Chapter 13 on Ambiguous Genitalia and Sexological Considerations). A varying degree of internal genital abnormality is associated with these causes of sexual ambiguity. b. Anatomical Defect in the Outflow Genital Tract and Uterus. Characteristically, females with anatomical defects in the genital tract present with normal development of secondary sex characteristics and normal maturation of the H–P–O axis including ovulatory function. Due to an obstruction in the genital tract, menstrual blood

Hirsutism, POS, Menstrual Disorders

accumulates behind the obstruction site. Cyclic and predicted episodes of pain in the absence of menses are a typical presentation and the patient may develop hematocolpos, hematometra, or hematoperitoneum. If undiagnosed, these disorders may lead to endometriosis, adhesion, and eventually infertility. Causes of the obstruction defect in the female tract are many and include agenesis or imperforation at various sites of the anatomy (Table 7). Agenesis of the mullerian structure (Mayer– Rokitansky–Hauser syndrome) is the second most common cause of primary amenorrhea and results in the absence of the vagina and aplasia or hypoplasia of the uterus, such as rudimentary bicornuate cords (302). This syndrome occurs in 1:4000–5000 girls. Renal abnormalities occur in 30–40% of subjects with this syndrome (303) and spinal abnormality has also been reported. Defects in the fusion of the mullerian structure caudally or with the urogenital sinus results in abnormal development of the uterus or uterine septum and failure to discharge outflow. Agenesis of the vagina or cervix, transverse vaginal septum or imperforate hymen, idiopathic labial fusion, and adhesion or secondary labial agglutination are known causes of menstrual outflow obstruction. Endometrial hypoplasia or aplasia is a rare cause of primary amenorrhea. 2. Secondary Amenorrhea Secondary amenorrhea in otherwise sexually healthy adolescents and young women warrants pregnancy testing. Secondary amenorrhea in patients with hyperandrogenic disorders including PCOS, ovarian hyperthecosis, adrenal causes of excess androgen-producing pathology, hyperprolactinemia, and thyroid disorders were discussed in the previous section. Almost all known causes of hypergonadotropic hypogonadism including Turner mosaicism and other X-chromosome abnormalities and all acquired causes of primary amenorrhea are also causes of secondary amenorrhea. Acquired causes of hypogonadotropic hypogonadism of primary amenorrhea are also causes of secondary amenorrhea. Hypothalamic amenorrhea represents a spectrum of disordered GnRH secretion that can vary over time, from apulsatile to low frequency/amplitude to low amplitude with normal frequency of LH pulses, low frequency and normal amplitude, and normal amplitude and frequency of LH pulses (304). The causes of hypothalamic amenorrhea may be psychological in nature, related to stress, weight loss, eating disorders such as anorexia nervosa and bulimia nervosa (305, 306), chronic, high-intensity physical exercises (307), or idiopathic. The diagnosis of hypothalamic amenorrhea is made by exclusion of other probable causes and normal imaging studies of the hypothalamic–pituitary anatomy. 3. Oligomenorrhea and Menometrarrhagia Both decreased and increased menstrual volume with regular or irregular cycles may be caused by pregnancy com-

305

plications or by all of the known causes of endocrine abnormalities for secondary amenorrhea including PCOS, hyperprolactinemia, thyroid disorder, Cushing syndrome, and functional hypothalamic anovulation. Additional causes of menometrorrhagia in adolescent females include bleeding disorders and complications of the genital tract such as trauma, dysplasia, polyps, foreign bodies, and infection.

D.

Evaluation of Menstrual Disorder

In all adolescents with menstrual disorders, a detailed history with regard to growth and secondary sex characteristic maturation is helpful in identifying the cause of the abnormality. Careful history of age at thelarche, pubarche, and menarche, menstrual history, flow of menses, presence or absence of excessive weight gain during peripubertal age, dysmenorrhea, cyclic pelvic pain, cyclic breast changes, and the presence or absence of hirsutism/acne are helpful in determining the likely cause of the menstrual disorder. Histories with regard to nutrition, physical training, sexual activity, weight change, dieting, body image, and emotional and family dynamics are also essential in evaluating the patient with primary or secondary amenorrhea or oligomenorrhea. Childhood history of illness, chronic disease, or therapies (chemotherapy/radiation therapy) may determine the causative factor. History-taking should also include vasomotor symptoms (hot flashes), virilizing signs, galactorrhea, symptoms of hypothyroidism, hyperthyroidism, and CNS symptoms including headache, hearing changes, and mood changes. Family history including maternal menstrual history, primary or secondary amenorrhea history in siblings or relatives, and hyperandrogenic history are also useful. Focus on physical examination pertinent to menstrual disorders includes anthropometric data, vital signs, androgen excess, Turner stigmata, acanthosis nigricans in the skin, thyroid gland, sexual maturation stage, breast discharge, presence or absence of sexual hair and genital ambiguity, pelvic mass or fullness in the patient with primary amenorrhea, and a careful gynecological patency examination in those with normal pubertal development despite primary amenorrhea. A guideline for a logical and stepwise approach for evaluation of primary amenorrhea, secondary amenorrhea, oligomenorrhea, and menometrorrhagia is provided in Figure 8. Excluding those with obvious hyperandrogenic manifestation and sexual ambiguity, the first work-up for both primary and secondary amenorrhea is random gonadotropin level measurements. Those with unquestionably elevated FSH and LH levels have primary ovarian failure (>20 miu/ml). A karyotype study would differentiate gonadal dysgenesis from other causes of primary ovarian failure. A positive antiovarian antibody study with established specificity and sensitivity indicates autoimmune, oophoritis while a negative antiovarian antibody finding cannot rule out the autoimmune disorder unequivocally.

Figure 8

Guideline for evaluation of menstrual disorders. NL, normal; T, testosterone.

306 Pang

Hirsutism, POS, Menstrual Disorders

Patients with apparently normal karyotypes and a negative antiovarian antibody may have a micro X-chromosome abnormality that cannot be detected by the karyotype study. In amenorrheic patients with mildly elevated LH levels (>10–36 (normal, 8–16). Serum plasma LH levels are elevated, suggesting a role for DHT in negative feedback at the level of the hypothalamus. FSH levels are normal or high, reflecting damage to seminiferous tubules. In the newborn period, the T/DHT ratio is high. During infancy and childhood, hCG stimulation also results in normal serum levels of testosterone, but subnormal serum levels of DHT. In the first few months of life, when plasma levels of testosterone and DHT are detectable, the normal T/DHT ratio is a value less than 12. Following hCG stimulation, normal boys from 17 days to 6 months have a T/DHT ratio of 5.2⫾1.5. T/DHT ratio of 11⫾4.4 is considered normal in boys from 6 months to 14 years. Abnormally high T/DHT ratios indicate 5␣ reductase deficiency (84). 46,XX subjects with 5␣-reductase deficiency have a normal female phenotype and normal puberty, but decreased axillary and pubic hair. Although menarche is delayed, fertility is normal (83). The pattern of inheritance in 5␣-reductase deficiency is autosomal recessive involving homozygous or compound heterozygous mutations. However, paternal uniparental disomy was found in one patient (85). All cases of steroid 5␣-reductase deficiency are related to mutations in the coding region of the 5␣-reductase 2 gene. Mutations are found in all five exons of the gene. The majority of subjects have missense mutations (86). Other individuals have deletions, splice-junction, and nonsense mutations. The end product is a nonfunctional or subfunctional protein with decreased affinity of the enzyme to NADPH or decreased binding to testosterone. If affected babies are raised as males, surgical correction of the external genitalia and cryptorchidism should be performed. Prior to surgery, administration of androgens is recommended to increase phallic length and facilitate hypospadias repair. Normal levels of DHT have been achieved in adults following pharmacological doses of testosterone, presumably though activity of 5␣-reductase 1. If the child is raised as a female, surgical correction

Disorders of Sexual Differentiation

of external genitalia should be performed and gonadal tissue removed before puberty. Cyclic hormonal therapy at puberty for development of secondary sexual characteristics is required (83). b. Androgen Insensitivity Syndrome. Androgen insensitivity syndrome (AIS) is comprised of four conditions with distinct phenotypes: complete AIS (CAIS), partial AIS (PAIS), androgen insensitivity associated with the infertile man syndrome, and Kennedy syndrome. Clinical phenotype 1. Complete Androgen Insensitivity (CAIS) is an Xlinked trait with an incidence of 1:20.000–1:64000 male births (87). This condition has also been referred to as the testicular feminization syndrome (88). CAIS is characterized by a normal 46,XY karyotype, female external genitalia with short vagina, absence of mu¨llerian structures, and absent or vestigial wolffian structures. Gonads may be located in the inguinal canal or may be intra-abdominal. Some subjects with CAIS present in infancy or childhood when surgery for inguinal hernia reveals testis in the hernia sack. If gonadectomy is not performed in infancy or childhood, affected subjects have breast development at puberty but little or no axillary hair. Although the clitoris or labia majora are normal, the labia minora may be underdeveloped. Patients usually present in their teens or early 20s because of amenorrhea. Serum levels of LH and testosterone are abnormally elevated. Estradiol, which comes from peripheral conversion of testosterone and from testicular secretion, tends to be in the normal female range. Serum AMH is abnormally high in women with CAIS because the physiological suppression of AMH by testosterone does not occur (89). Women with CAIS have a greater incidence of testicular tumor, with risk increasing significantly after puberty. Management of adult women with CAIS involves gonadectomy and sex hormone supplementation. In some women vaginoplasty may be necessary to improve the length of the vagina. Wisniewski et al. (90) examined long-term outcome of women with CAIS. Fourteen women were studied using questionnaires and follow-up physical examination. These women considered their development of secondary sexual characteristics to be satisfactory. Furthermore, most patients were satisfied with sexual function. All of the women studied were satisfied with sex of rearing. Nonetheless, the study indicated that more two-thirds of the women had incomplete understanding of their condition. 2. Subjects with Partial Androgen Insensitivity (PAIS) usually present in the newborn period with ambiguous genitalia. Mu¨llerian structures are absent and development of wolffian ducts is usually abnormal. The diagnosis is suspected if there are normal levels of testosterone and a normal testosterone/DHT ratio. Several approaches have been suggested to differentiate PAIS from other conditions with a similar hormonal profile. Some authors have suggested that the extent of penile growth after administration of testosterone or hCG provides an indicator

331

of responsiveness to androgens. Others have advocated determination of sex hormone-binding globulin (SHBG) levels in blood to identify subjects with PAIS. This is based on the fact that androgen secretion typically results in a diminution of SHBG levels. Hence, higher than normal levels of SHBG in an individual with normal male testosterone and DHT concentration might indicate androgen insensitivity (91). Blood levels of AMH are also suppressed by androgens. Hence the combination of male levels of testosterone and DHT in the face of unsuppressed AMH might indicate PAIS (92). At puberty, serum levels of LH and testosterone are abnormally elevated, although the T/DTH ratio remains normal. There is enlargement of the penis at puberty, but the penis usually remains small. Serum levels of estradiol are abnormally elevated and gynecomastia is almost always present. Testes are small and there is azoospermia. 3. Subjects with androgen insensitivity associated with infertile men present various phenotypes. Some subjects have mild hypospadias, although many have normal male external genitalia. Like subjects with other forms of AIS, these men have elevated levels of serum LH and testosterone. Subjects are typically ascertained during evaluation for infertility (93). 4. Kennedy syndrome is an X-linked from of spinal and bulbar atrophy, which appears in mid to late adulthood. The association of gynecomastia and the variable presence of impotence and infertility suggest a form of androgen insensitivity and subsequent studies identified a defect in the AR gene (94). Genetic abnormalities related to AIS. Most cases of CAIS and PAIS are related to mutations in the AR gene and the majority of them are point mutations. Relatively few mutations have been detected in the amino terminal domain. Mutations that result in stop codons in this region are typically associated with CAIS. Deletions of polyglutamine repeats are associated with PAIS. Kennedy syndrome results from expansion of polyglutamine repeats to a number greater than 42 (95). Within the DNA-binding domain, mutations that result in stop codons or in the deletion of the second zinc finger are associated with CAIS (96). Mutations in the phosphorylation site are associated with both CAIS and PAIS. Mutations in the hormone-binding domain can result in both complete and partial AIS. Frame shift or point mutations that result in premature termination are associated with CAIS. By contrast, mutations causing less severe defects in hormone binding are more likely to be found in patients with PAIS. Splicing mutations in the AR gene have also been reported in PAIS. They result in transcription of mRNA encoding mutant AR as well as lower levels of mRNA encoding normal AR (97). AR gene mutations have been identified in some subjects with the androgen insensitivity of infertile men. In a group of nearly 200 infertile men, three unrelated subjects

332

had mutations of AR gene. Two of these mutations were in the transactivation domain and one was in the DNAbinding domain (93). In another study, a subject with this condition had a point mutation in the hormone-binding domain that did not diminish steroid binding but resulted in defective transactivation (98). In additional studies Giwercman identified an unusual subject with mutation in the AR gene and phenotypic features of AIS, but normal fertility (99). Despite correlations between phenotype and genotype that have been made in the AIS, many cases indicate that these relationships do not always apply. For example, most mutations that result in absence of androgen-receptor binding in cultured cells result in CAIS. However, some of these mutations are also associated with PAIS. Most mutations that are associated with intact AR binding in cultured cells are likewise associated with PAIS. Nonetheless, some of them are associated also with CAIS. More surprising is the observation that CAIS and PAIS have been associated with the same mutation in the AR, suggesting that other factors play a role in AR function (95). Recent reports explain the lack of phenotype–genotype correlation in some patients. In 1997, Holterhus described a patient with PAIS who had a mutation in the AR that resulted in a premature stop codon. Such mutations are usually associated with CAIS. The unexpected mild phenotype in this report was the result of somatic mosaicism (100). The AR was also studied in another family who had AIS and a range of phenotypic appearance among affected members. Studies of this kindred indicated that transactivation of the AR varied over a range of DHT concentrations, suggesting that the range in phenotype might have resulted from variable levels of DHT in each of the individuals in utero (101). More recently Boehmer et al. described a kindred in which one sibling had CAIS and another had PAIS. The differences in phenotype were correlated with differences in 5-reductase activity in the two siblings (102). AIS has also been attributed to abnormalities in the interaction of coactivators with the AR. In one study CAIS was associated with inability of the AR to interact with AF1 (103). Expansion of the polyglutamine repeats results in decreased binding of ARA 24 and subsequent decreased coactivation, providing a possible explanation for the AIS associated with Kennedy syndrome (44, 94). 4.

Male Pseudohermaphroditism Associated with Multiple Congenital Anomalies Some subjects have well-described syndromes in which there is abnormal sex differentiation in association with other congenital anomalies, but no obvious defect in gonadal differentiation, testosterone biosynthesis, or androgen effect (53). Some examples include Opitz-Frias syndrome, Rieger’s syndrome, Rapp-Hodgkin ectodermal dysplasia, the CHARGE association and VATER syn-

Carrillo et al.

drome. Many cases of male pseudohermaphroditism and multiple congenital anomalies are sporadic, but they frequently involve other defects in the genitourinary system. In addition, maternal exposure to certain drugs, such as dilantin, trimethadione, and progesterone, have been implicated in abnormal sex differentiation. 5.

Timing Defect and Idiopathic Male Pseudohermaphroditism Several patients have been reported who had a 46,XY karyotype and ambiguous genitalia, but normal production of testosterone and DHT at puberty and normal responsiveness to androgens. It was suggested that these subjects had delayed differentiation of Leydig cells and the term timing defect was applied to this condition (104). It is possible that subjects with so-called idiopathic male pseudohermaphroditism have such a timing defect. 6. Persistent Mu¨llerian Duct Syndrome The persistent mu¨llerian duct syndrome (PMDS) is defined by the presence of mu¨llerian derivatives (uterus, fallopian tubes, and superior two-thirds of the vagina) in otherwise normal 46,XY subjects (105). This rare form of male pseudohermaphroditism has been reported in approximately 150 subjects. Patients with PMDS present with cryptorchidism, inguinal hernias, or both. Herniation of the mu¨llerian structures through the inguinal ring and transverse testicular ectopia are frequent associations. Persistent mu¨llerian duct syndrome occurs in two different anatomical forms. The form characterized by partially descended testes (80–90% of reported cases) occurs with unilateral cryptorchidism and contralateral inguinal hernia. Typically, the undescended testis is in the inguinal canal. This condition is termed hernia uteri inguinalis. Sometimes the opposite testis is in the hemiscrotum with hernia (transverse testicular ectopia). The second form is characterized by undescended testes. The gonads are located in a high position, the uterus is fixed in the pelvis, and both testes are embedded in the round ligament. The round ligament is usually distended in PMDS, leading to abnormal mobility of mu¨llerian derivatives. Furthermore, the testis itself is abnormally mobile because it is not connected to the base of the scrotum. The testes of these males contain germ cells, but are not properly connected to male excretory ducts. Aplasia of the epididymis, as well as aplasia of the upper part of the vas deferens, has been reported. The mu¨llerian segment of the vagina contacts the posterior urethra at the veru montanum, but communication is usually not patent and retrograde urethrography shows a normal male urethra (105). Affected subjects frequently present for evaluation of undescended testes or inguinal hernia. The diagnosis can be made by sonogram during the evaluation of newborns or infants with cryptorchidism and during surgical exploration. In subjects with bilateral nonpalpable gonads, con-

Disorders of Sexual Differentiation

genital adrenal hyperplasia in a female must also be excluded. Serum levels of testosterone are typically normal in these patients, but should be assessed. The level of AMH should be measured to help determine the specific problem (abnormality of AMH or receptor) (36). Although pelvic ultrasonography may be useful to detect mu¨llerian structures, false-negative results can occur. PMDS is inherited either as a sex-limited autosomal recessive trait (the most common) or as a sex-linked recessive trait. Mutations in either the gene for AMH or its receptor are responsible for the lack of regression of the mu¨llerian ducts. Patients with a serum level of AMH in the upper limit of normal are referred to as being AMHpositive. Patients with very low AMH levels, are called AMH-negative. The most common genetic anomaly causing PMDS is a 27 base-pair deletion in exon 10 of the antimu¨llerian type II receptor gene. This deletion is implicated in approximately 25% of patients presenting with PMDS (106). The surgical management of patients with PMDS is controversial due to the potential morbidity associated with both the retention and the removal of the mu¨llerian structures. Controversy also exists regarding the malignant potential of the PMDS testes. Surgical excision of persistent mu¨llerian duct structures may result in ischemic and/or traumatic damage to the vas deferens and testes. Optimal management is orchiopexy, leaving the uterus and fallopian tubes in situ. Orchiectomy is indicated for testes that cannot be mobilized to a palpable location. Careful identification of the vas deferens with meticulous dissection of the mu¨llerian structures facilitates intrascrotal placement of the testes. There is an increased risk of malignancy associated with the cryptorchidism (3% to 18%), but not with the retained mu¨llerian structures. These structures remain infantile, and neither cyclic hematuria nor endometrial malignancy occurs. Most of these patients are infertile.

C.

Female Pseudohermaphroditism

Female pseudohermaphroditism describes one-third to one-half of patients with ambiguous genitalia. Subjects have 46,XX karyotype, normal mu¨llerian ducts, and masculinization of the external genitalia and urogenital sinus (see Table 3). Wolffian ducts (epididymis, vas deferens, and seminal vesicles) are absent. The degree of masculinization of external genitalia is determined by the extent of androgen secretion and the timing of androgen production. Once female sex differentiation is complete, androgen exposure causes clitoral hypertrophy but no other masculinization of genitalia. 1. Congenital Adrenal Hyperplasia The most common cause of female pseudohermaphroditism is congenital adrenal hyperplasia (CAH). In these conditions there is an abnormality in the biosynthesis of cortisol and aldosterone. Diminished secretion of cortisol

333 Table 3 Classification of Female Pseudohermaphroditism Congenital adrenal hyperplasia CYP21 (21-hydroxylase) deficiency CYP11 (11␤-hydroxylase) deficiency 3␤HSD II deficiency Exposure to maternal androgens excess Iatrogenic: androgens and progestins Virilizing ovarian or adrenal tumor Luteoma of pregnancy CYP19 (aromatase) deficiency Congenital abnormalities

results in marked elevation of plasma ACTH that subsequently stimulates increased production of adrenal androgens and hence masculinization of external genitalia. CYP21 (21 hydroxylase) deficiency is the most common cause of CAH. Two other virilizing forms of CAH are 11␤hydroxylase and 3-␤ hydroxysteroid dehydrogenase deficiencies. (These conditions are discussed at greater length in Chapter 7). A brief summary is presented below. a. CYP21 (21 Hydroxylase) Deficiency. CYP21 is required for conversion of 17-hydroxyprogesterone to 11deoxycortisol and progesterone to deoxycorticosterone. Hence CYP21 deficiency decreases both mineralocorticoid and glucocorticoid production. Females with this condition present ambiguous genitalia, or, later in life, virilization. Salt-losing crisis is a potentially life-threatening complication of the severe form of this disorder. Serum levels of 17-hydroxyprogesterone are markedly elevated (3000–40,000 ng/dl), the level depending upon age and severity of the enzyme defect. Androstenedione levels are abnormally high (107, 108). b. CYP11 (11 Hydroxylase) Deficiency. This condition is characterized by lack of conversion of 11-deoxycortisol to cortisol and conversion of DOC to corticosterone. High blood pressure occurs due to increased levels of DOC (107, 108). c. 3␤-Hydroxysteroid Dehydrogenase/⌬4–5 Isomerase Deficiency. This is characterized by lack of conversion of ⌬5 3␤hydroxysteroids to 3 ketosteroids. The synthesis of both aldosterone and cortisol is impaired. Salt-wasting and adrenal crisis can occur in severe forms of this condition. Serum levels of 17-hydroxypregnenolone may be increased due to impaired conversion of 17-hydroxypregnelonone to 17-hydroxyprogesterone. In addition, the ratio of 17-hydroxypregenelonone to 17hydroxyprogesterone is elevated in these patients (107, 108). 2.

Maternal Androgens

a. Iatrogenic. Several drugs have been associated in the past with female pseudohermaphroditism. Proges-

334

Carrillo et al.

tins such as norethindrone and ethisterone can cause some degree of masculinization of external genitalia. Danazol, used for treatment of endometriosis, has also been implicated as a cause of female pseudohermaphroditism. Stilbestrol and its metabolites are also related to masculinization of female external genitalia through inhibition of 3-␤ hydroxysteroid dehydrogenase (47). b. Androgen-Secreting Tumors. These occurring in the mother can also cause masculinization of the female fetus. Luteoma of pregnancy is a rare tumorlike mass that emerges during pregnancy and regresses spontaneously after delivery. Absence of maternal virilization does not exclude the diagnosis of luteoma of pregnancy. Other androgen-secreting tumors of both the ovary and adrenal have also been reported. Ovarian tumors include Brenner tumor and thecoma, among others. Adrenal tumors causing female pseudohermaphroditism are extremely rare (109). 3. Placental Aromatase Deficiency Human CYP450 aromatase is expressed in placental syncytiothrophoblast and many other fetal tissues. After the 9th week of gestation, the placenta provides the primary source of circulating estrogens. Lack of placental aromatase exposes the fetus to androgen excess and can result in ambiguous genitalia in females. Diagnosis should be suspected in an infant with female pseudohermaphroditism in whom CAH has been excluded. The diagnosis is suggested by maternal virilization during pregnancy, and abnormally high serum levels of ⌬4 androstenedione, testosterone, and DHT. Low plasma levels of estriol, as well as low urinary estriol concentration, are present. Amniotic fluid concentrations of ⌬4 androstenedione and testosterone are high, while estrone, estradiol, and estriol levels are low (110). 4.

Syndromes of Multiple Congenital Abnormalities Association of female pseudohermaphroditism with cloacal anomalies, renal agenesis or dysplasia, and gastrointestinal and urinary tract anomalies has been reported. The mu¨llerian structures in these patients may be poorly developed and dysplastic. The cause of this defect is uncertain. There is a disorganized differentiation of the caudal development including perineum, genital tubercle, and genital folds (111). Maternal alcohol use during pregnancy has been associated with clitoral hypertrophy.

V.

DIAGNOSTIC EVALUATION FOR AMBIGUOUS GENITALIA

When a child is born with ambiguous genitalia, a specialized care team should be convened. A rapid and organized evaluation should be initiated to garner infor-

mation about karyotype, gonadal function, androgen biosynthesis, and internal anatomy.

A.

Diagnostic Evaluation

1. History A thorough family history is important with respect to previous perinatal or neonatal deaths, infertility, consanguinity, or history of infants with ambiguous genitalia. The patterns of inheritance in the various intersex disorders must be considered. A maternal history should focus on complications of pregnancy, especially during the first trimester, and should include information regarding drug and alcohol use as well as hormone administration. 2. Physical Examination The physical examination should determine whether the infant has dysmorphic features, since many syndromes are associated with ambiguous genitalia. Intrauterine growth retardation suggests a chromosomal anomaly. Abnormal body proportions suggest an associated syndrome of bone dysplasia. Stigmata, such as webbed neck and edematous hands and feet, may be present in mixed gonadal dysgenesis (45,X/46,XY). Table 4 includes some of the conditions associated with genital ambiguity. The stretched phallic length should be measured along the dorsum from the pubic ramus to the tip of the glans. The degree of development of the corpora may be assessed by palpation of the shaft. Normal values for stretched penile length in neonates and preterm infants are available, as are normal values for clitoral length (Chap. 42). It is important to note that premature female infants may appear to have clitoromegaly because they have a larger clitoral breadth compared to body size. Urethral opening is assessed by careful examination of the ventral area of the phallus for grooves and chordees. The urethral meatus may be anywhere from the tip of the phallus to the perineum. A single opening on the perineum indicates the presence of a urogenital sinus. Fusion of the labia majora should also be assessed. The labioscrotal folds are examined for degree of fusion, development of rugae, and pigmentation. The presence of gonadal tissue must be carefully assessed. Each gonad is evaluated for size, texture, and presence of an epididymis. Minimal enlargement of the phallus and only mild posterior fusion may be associated with a mild form of masculinization in an XX individual or a severe form of undermasculinization in an individual with an XY karyotype. Phallic enlargement with nearly complete fusion of the labioscrotal folds may likewise be associated with a minimal defect of masculinization in an individual with a XY karyotype or a very severe abnormality of sexual differentiation in an individual with an XX karyotype. Hence, the extent of masculinization of the external genitalia does not provide information about the underlying diagnosis but merely provides information about the extent of the abnormality once the karyotype is known.

Disorders of Sexual Differentiation Table 4

335

Syndromes and Chromosomal Abnormalities Associated with Ambiguous Genitalia

Abnormalities Chromosomal Trisomy 13 Trisomy 18 Triploidy syndrome 4p⫺ 13q⫺ Syndromes Aaskog Campomelic Dysplasia Carpenter CHARGE Curradino Ellis-Van Crevel Fraser SCARF

Lissencephaly X-linked Meckel-Gruber Oral–facial–digital Rieger’s Robinow Short rib polydactylia Smith-Lemli-Opitz, type II

Smith-Lemli-Opitz, type I

VACTER WAGR

Clinical findings Holoprosencephalia, polydactyly, cleft lip, hypospadias, cryptorchidism Clenched hand, short sternum, malformated auricles, male cryptorchidism, virilized females Prenatal growth failure, microphtalmia, congenital heart defects, hypospadias, micropenis Supreorbital ridges, synophrys, large ears, incomplete masculinization Mycrocephaly, colobatoma, thumb hypoplasia, incomplete masculinization Hypertelorism, brachydactyly, shawl scrotum, cryptorchidism Flat facies, bowed tibiae, hypoplastic scapulae, 46, XY partial gonadal dysgenesis Acrocephaly, polydactyly, and syndactyly of the feet, lateral displacement of inner canthi, mental retardation, hypogonadism Colobomata, heart defect, choanal atresia, retarded growth, genital hypoplasia, ear anomalies Partial sacral agenesis with intact first sacral vertebra (‘‘sickle-shaped sacrum’’), a presacral mass, and anorectal malformation (Currarino triad) Mesomelic dwarfism, polydactyly, cardiac anomalies, cryptorchidism Cryptophthalmos (eye hidden, fused lids, absence of palpebral fissure), defect of auricle, males with cryptorchidism and hypospadias, females with vaginal atresia Lax skin, joint hyperextensibility, umbilical and inguinal hernias, craniosynostosis, pectus carinatum, abnormally shaped vertebrae, enamel hypoplasia with hypocalcification of the teeth, facial abnormalities, wide webbed neck, ambiguous genitalia, multiple nodular liver tumors, and mild psychomotor retardation Lissencephaly with ambiguous genitalia Encephalocele, polydactyly, renal cystic dysplasia, ambiguous genitalia Polydactyly, campomelia, ambiguous genitalia, cystic dysplastic kidneys, and cerebral malformation Iris dysplasia, maxillar hypoplasia, hypospadias Short stature, mesomelic and acromelic brachymelia, hypertelorism, wide palpebral fissures, midface hypoplasia and large mouth, and hypogenitalism Cleft lip, malformed larynx with hypoplastic epiglottis, pulmonary hypoplasia, renal cysts, ambiguous genitalia, pachygyria, and small cerebellar vermis Mutations in the delta-7-dehydrocholesterol reductase gene in chromosome Failure to thrive, facial dysmorphism, ambiguous genitalia, syndactyly, postaxial polydactyly, and internal developmental anomalies (Hirschsprung’s disease and cardiac and renal malformations) Failure of masculinization, intra-abdominal testes, a normally shaped uterus and vagina, polydactyly, cleft palate, blepharoptosis, and abnormalities of the kidneys, liver, and lungs Vertebral anomalies, Anal atresia, Tracheo-Esophageal fistula, Radial and Renal dysplasia, bifid scrotum Contiguous gene syndrome: Wilms tumor, Aniridia, cataract, ambiguous Genitalia, gonadoblastoma, genitourinary abnormalities, mental Retardation

3. Etiologic Evaluation Adrenal hyperplasia is always a possibility in an infant who presents with ambiguous genitalia. Therefore, throughout the period in which diagnostic tests are performed, careful attention must be paid to blood chemistry and vital signs to ensure that early and appropriate treatment is started if clinical presentation suggests congenital adrenal hyperplasia.

Migeon et al. have described a program for the evaluation of the ambiguous genitalia in the first week (54). A karyotype is obtained on the first day of life and is usually done using peripheral lymphocytes. Occasionally chromosome analysis from other tissues may be necessary to exclude mosaicism. Plasma levels of testosterone and dihydrotestosterone are determined on day 1–2 since there is a physiological peak of testosterone secretion in

336

normal boys at this time. Occasionally, assay of other plasma steroids precursors of testosterone synthesis may be indicated. Plasma levels of 17-hydroxyprogesterone and 17-hydroxypregnelonone should be determined on day 3–4. It is necessary to obtain the blood sample until day 3–4, because contaminating plasma steroids result in spuriously high levels. Assays of both testosterone and 17hydroxyprogesterone require a chromatographic step prior to assay to prevent additional artifacts (112). If the baby is clinically stable, imaging studies should de performed on day 5 of life. A genitogram with retrograde injection of contrast media into the urogenital sinus should be performed to detect the presence of mu¨llerian structures, as well as to outline the anatomy of the urethra. Sonography may also be performed to detect mu¨llerian structures. In some instances sonography may be useful to identify abdominal or inguinal gonads. Occasionally an MRI of the pelvis may also be needed. 4. Diagnosis of Ambiguous Genitalia Migeon and Berkovitz have proposed an algorithm for the diagnosis of ambiguous genitalia in the newborn period (54). If the karyotype indicates mosaicism or possible chimerism involving a Y chromosome, the abnormality of sex differentiation is considered to be a function of the cloning of the various cell types in the gonad. If the karyotype is 46,XX or 46,XY the diagnosis will be established by the hormonal profile, the presence of specific internal duct structures, and, in some cases, by gonadal histological results. In patients with a 46,XY karyotype and a subnormal plasma level of testosterone, abnormally low levels of steroid precursors of testosterone indicate the possibility of 46,XY gonadal dysgenesis, 46,XY true hermaphroditism, and Leydig cell aplasia hypoplasia. Subnormal levels of plasma testosterone, but abnormal elevation of plasma precursors of testosterone, indicate a defect in the biosynthesis of testosterone. If levels of plasma testosterone and DHT are normal or elevated but the ratio of T to DHT is abnormally elevated, a diagnosis of 5␣-reductase deficiency is made. If plasma concentration of T and DHT is both normal the differential diagnosis includes androgen insensitivity, syndromes of multiple congenital anomalies, and idiopatic or timing defects. In subjects with a 46,XX karyotype, diagnostic considerations include abnormalities of gonadal differentiation and those resulting from exposure of the fetus to excess androgen. The former group comprises 46,XX true hermaphroditism and the XX maleness. When normal ovarian differentiation has occurred, masculinization may have resulted from congenital adrenal hyperplasia (deficiency of 21-hydroxylase, 3␤ HSD, and 11-hydroxylase), androgen-secreting tumors in the mother, placental aromatase deficiency, various drugs, and syndromes of multiple congenital anomalies.

Carrillo et al.

VI. A.

MANAGEMENT OF INTERSEX Introduction

The management of children born with ambiguous genitalia has been guided by the traditional policy developed by psychologists in collaboration with pediatric endocrinologists and other health care professionals (113). This management has been based on assessment of the anatomy of sex organs, on likely cosmetic appearance of the reconstructed genitalia, on the potential for normal sex steroid secretion at puberty, the potential for normal sexual intercourse, and on the potential for fertility. It has also been referred to as the optimal-gender policy. Gender assignment has been recommended as early as possible to minimize the period of gender uncertainty. Surgery of the external genitalia has been recommended to facilitate consistent gender-typical rearing by the family. As an example, female gender has been considered appropriate for girls with the masculinized form of CAH. This has been based on the consideration that adequate replacement therapy will permit ovarian sex hormone secretion and normal fertility and because reconstructive surgery will allow for sexual intercourse later in life. Over the past few years, patient activists have questioned aspects of the traditional policy for gender assignment at the earliest age possible and have emphasized the risk of early genital surgery. The Intersex Society of North America was established to involve the public in an open discussion about management of intersex patients. They have objected to early genital surgery on the grounds that the patient is too young to provide informed consent (114). Another critique of the traditional approach to intersex management comes from biological determinists who claim that prenatal androgens play a critical role in the masculinization of the fetal brain, and therefore influence behavior and gender identity later in life. Improved understanding regarding the long-term outcome of intersex patient management is helping to guide changes in the traditional policy (90, 115).

B.

Gender Assignment at Birth

Gender assignment of infants with ambiguous genitalia at birth requires open and intense communication between the medical team and the family. Counseling requires avoidance of oversimplification. However, complete information must be provided and presented in a way that can be assimilated by the family. The physician must be open to new information. For example, recent data show that penile growth potential in newborns with micropenis is greater than previously thought. As a consequence, reassignment in the baby with full male differentiation and micropenis is no longer recommended (116). The American Academy of Pediatrics has published a statement concerning evaluation of the newborn with

Disorders of Sexual Differentiation

developmental anomalies of the external genitalia. It emphasizes that sex of rearing be based on the potential for fertility, capacity for normal sexual function, endocrine function, potential malignant change, and testosterone imprinting. It is useful for health care professionals to develop a sex-assignment team where a multidisciplinary approach that includes parental involvement can be provided for the management of the intersex patient (117). Pediatric endocrine societies are also in the process of developing consensus guidelines for gender assignment. Such guidelines should be revised at regular intervals or whenever major new evidence comes to light.

C.

Gender Reassignment in Childhood

Gender reassignment must take into consideration the child’s development, the family’s beliefs, and the cultural environment. Uncertainty exists regarding the latest time for gender reassignment without an increased risk of conflict in the child’s emerging sense of gender identity. Early studies suggested a cut-off age of 18 months. Newer data suggest an earlier cut-off date, perhaps around 9 months of age. After that age, the child’s emerging habitual gender-role behavior and identity must be carefully evaluated for compatibility with the recommended gender. Such an evaluation can be an arduous task because of the child’s cognitive limitations at this stage of development and because of the potential for emotional sensitivity (118). In addition to considering the child’s gender development, the clinician must evaluate the family’s expectations, the family’s flexibility, and the societal context. The child and the family must be able to cope with the gender reassignment. Clinicians should be careful not to superimpose their own cultural values.

D.

Gender Assignment and Reassignment in CAH

Almost all female CAH patients, when appropriately diagnosed, are raised as girls. However, some patients who are born with markedly masculinized external genitalia have been inadvertently assigned to the male gender. In cases in which the diagnosis was made later, many physicians have recommended reassignment to the female gender after appropriate parental consent. Most 46,XX patients with CAH who have been assigned or reassigned to the female gender at an early age remain females lifelong. A small group of patients self-initiate gender reassignment at around puberty or later, and sometimes even as late as in midadulthood. Patients with CAH and 46,XX karyotype who have been reared in the male gender until late childhood or early adolescence usually elect to remain boys even after CAH is diagnosed. However, occasional patient-initiated reassignments to the female gender have been reported. Thus, an apparently stable gender identity in childhood does not necessarily preclude gender change

337

at a later age, nor does a successful gender reassignment in childhood exclude gender problems later in life (118). Assigning newborns with CAH and penile urethra to the male gender has also been discussed but remains extremely controversial. Arguments in favor of male gender assignment include the consideration that a well-formed penis with a penile urethra does not require surgery, whereas reconstruction along female lines may not produce a vagina adequate for sexual intercourse, and may damage neuronal connection and vascular supply to the clitoris. Arguments against male gender assignment include the observation that the obligatory gonadectomy will be accompanied by loss of fertility and that there may be a need for sex hormone therapy at puberty. Studies involving large numbers of patients are needed before a change in policy can be made regarding gender assignment in patients with CAH with marked genital masculinization.

E.

Gender Identity

Gender identity refers to the sense of belonging to or fitting into the male or female gender. Gender-role behavior denotes the behavior typical of one gender or the other in a given historical time and place. Considerable information on the influence of prenatal androgen exposure on gender role behavior comes from studies of CAH. Various categories of sexually dimorphic behaviors are affected in girls with CAH. They include toy preferences, rough-and-tumble play, aggressiveness, interest in sports, maternal behavior, and vocational preferences. It has been suggested that the most important factor accounting for the difference in sexually dimorphic behavior between CAH girls and controls appears to be the effect of the prenatal androgens on sexual differentiation of the brain. Several researchers have indicated that the degree of genital masculinization is an indicator of the degree of masculinization of the brain. Indeed masculinized behavior is more prevalent among girls with saltwasting CAH than it is in the simple virilizing form (119). If, as expected, much of the shift toward increased masculinization of behavior in CAH is due to the atypical prenatal androgen milieu, a reduction in prenatal androgen levels by prenatal dexamethasone treatment should reduce the degree of masculinization on the brain. However, concerns about the potential behavioral side effects of this treatment have been raised and are being addressed in continuing studies (120). Many parents become anxious and uncomfortable when their daughter with CAH shows markedly genderatypical behavior. Children with CAH should be monitored regularly and assessed unobtrusively for the degree of gender-atypical behavior. In addition, family milieu should be evaluated for acceptance of such behavior. In this regard appropriate psychological/psychiatric counseling promoting the acceptance of the behavior can be undertaken. Girls with CAH with markedly gender-atypical

338

Carrillo et al.

behavior persisting into late childhood and early to midadolescence may become alienated from their gender-typical peer group. The alienation can lead to isolation, selfdoubts, and depressive features. Such girls may profit from individual counseling and from contact with other girls in support groups. There is a published counseling guide in the intersex area, which is strongly recommended to patients and health care providers. Women with saltlosing CAH have an increased rate of bisexual or homosexual orientation, as demonstrated in sexual imagery such as erotic and romantic fantasies and dreams and sexual attractions; many of these women consider themselves lesbians. Long-term studies of outcome in large numbers of subjects with 46,XY karyotypes and ambiguous genitalia are now being performed. Physical and psychological aspects are being explored. Such studies will provide additional perspective on the relative influence of prenatal androgens and environment.

F.

Surgery During Infancy and Childhood

The timing of genital surgery in the course of a child’s development is likely to have important psychological implications. In infancy, the decision must be made by the parents in consultation with physicians. Parents must have unequivocal commitment to the decision. Comprehensive genital surgery in infancy without any need for later procedures is intuitively beneficial, but no systematic data are available on the differences in psychological consequences of early vs. late surgery. Parents of newborns not only want to reach a decision about sex of rearing as soon as possible but also want the genitalia to appear similar to other children of the same sex and age. Surgical techniques have advanced dramatically and skillful surgeons have achieved satisfactory outcomes in the majority of intersex patients. In particular, advances in techniques for reconstruction of male external genitalia have allowed definitive repair in infancy and early childhood. Timing of genital reconstruction in female subjects is more problematic. For example, it is not clear whether it is easier for an adolescent woman to undergo vaginal reconstruction just before she is ready to become sexually active or whether is preferable to perform surgery earlier, with the obligation to use dilators until the patient starts engaging in regular sexual intercourse. Prescribing vaginal dilatation during middle childhood presents difficulties. Cessation of early surgical intervention has been advised in several cases because of the emotional effect on the child. However, no systematic data on psychosocial acceptability and outcome are available. Individuals vary widely in the timing and pattern of sexual socialization. However, it is likely that an inadequate vagina and a reduction in erotic sensitivity, orgasmic capacity, and sexual satisfaction will inhibit courtship and perhaps reduce interest in sexual activity altogether.

Esthetic and gender-typical appearance continue to be useful criteria for surgical outcome, although attention must also be paid to long-term sexual functioning. Quality-of-life considerations, including sexual life in adolescence and adulthood, must be considered. In this regard as well, there is a major need for pediatric societies to develop consensus guidelines. The performance of genital surgery without the child’s fully informed consent has been severely criticized by the Intersex Society of North America. This point of view must be weighed against the complexities regarding the need for sex definition (121).

G.

Examination of the Genitalia

Examination of the genitalia is crucial in evaluating the need for surgery, the outcome of surgery, and the impact of lapses in hormonal treatment. The physician must be aware of the potentially adverse psychological consequences of such examinations, even if the child seems overtly compliant. Genital examinations have more significant psychological implications than examinations of other body parts. Many patients become oversensitized by frequent examination. Hence, such examinations must be performed with psychological sensitivity. Their repetition by multiple trainees should be avoided. Alternative training strategies should be developed that do not adversely affect the patient.

H.

Psychological Counseling

Most authors recommend an annual visit particularly during adolescence, with a mental health professional who is familiar with the psychosocial and sexual problems of intersex patients. It can be beneficial to have the same person involved in this capacity over the years, provided that the rapport with the patient is generally good. In addition, meeting one or more patients with the same or similar condition can be extremely helpful for patients with an uncommon disorder. The creation of clinic-affiliated support groups is recommended. Patient support groups on the Internet can also be useful. When recommending support-group affiliation, one should always make the patient aware of the risks, including biases, of these groups. The patient should be encouraged to discuss novel information acquired from support groups with his or her physician or mental health specialist. Patients with specific sexual dysfunction may need to be evaluated by a specialist who can review all endocrine, anatomical, surgical, and psychological factors that may be involved and who can plan an intervention in consultation with the respective specialists. Given the scarcity of mental health personnel familiar with intersex problems, physicians and patient organizations should press for appropriate training of mental health liaison personnel and for third-party coverage of the respective services.

Disorders of Sexual Differentiation Table 5

339

Stretched Penile Length in Normal Males

Age

Mean ⫾ SD (cm)

Mean ⫾ SD (cm)

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

1.5 2.0 2.4 1.9 2.3 2.6 2.9 3.3 3.5 3.8 3.9 3.7 3.8 3.8 3.7 9.3

Newborn, 30 wk Newborn, 34 wk Newborn, term 0–5 months 6–12 months 1–2 yr 2–3 yr 3–4 yr 4–5 yr 5–6 yr 6–7 yr 7–8 yr 8–9 yr 9–10 yr 10–11 yr Adult

2.5 3.0 3.5 3.9 4.3 4.7 5.1 5.5 5.7 6.0 6.1 6.2 6.3 6.3 6.4 13.3

0.4 0.4 0.4 0.8 0.8 0.8 0.9 0.9 0.9 0.9 0.9 1.0 1.0 1.0 1.1 1.6

Source: Adapted from Ref. 29.

VII.

MICROPENIS

Micropenis is characterized by a normally formed penis with a stretched penile length more than 2.5 standard deviations below the mean for age. Normative data are provided in Table 5 and in Chapter 42 (29). The mean stretched penile length in newborns is 3.5 cm (minus 2.5 standard deviation: 1.9 cm). Ethnic differences have been reported, with a smaller mean penile length in newborns of Chinese origin than in newborns of White and EastIndian origins (122). Measurement of penile length should be made on the fully stretched rather than flaccid penis. A ruler should be pressed against the pubic ramus, depressing the suprapubic fat pad as completely as possible. The penis should be stretched by grasping the glans between the thumb and forefinger. The measurement is made along the dorsum to the tip of the glans without including the foreskin, if present. Accurate examination and measurement are essential in determining the presence of micropenis. Micropenis must be differentiated from so-called hidden penis, defined as a normal penis obscured by excessive suprapubic fat, and from a penis held down by marked chordee, in which it has a downward bowing as a result of a congenital anomaly (123). Patients with micropenis may be classified in four major groups: 1. Hypogonadotropic hypogonadism is characterized by an abnormality in the hypothalamic–pituitary axis, resulting in inadequate androgen production. Syndromes in this category include Kallmann syndrome, Prader-Willi syndrome, Laurence-Moon syndrome, Rud syndrome, and conditions with multiple pituitary hormone deficiency.

2. Hypergonadotropic hypogonadism is characterized by primary gonadal failure. Conditions included in this category are Klinefelter syndrome, other X polysomies, Robinow syndrome, trisomy 21, Noonan syndrome, and Laurence-Moon syndrome. 3. Failure of androgens’ action includes subjects with mild partial androgen insensitivity. 4. Idiopathic micropenis: Subjects in this category have normal hypothalamic–pituitary–gonadal function. Very rarely the entire penis is absent, a condition named aphallia (124). The work-up of patients with micropenis should be directed toward early diagnosis and therapy. Other potential dangerous conditions that may be associated with gonadotropin deficiency, such as hypothyroidism, hypocortisolemia, growth hormone deficiency, and diabetes insipidus should be excluded and treated. In particular, infants should be carefully monitored. Plasma levels of FSH, LH, and testosterone should be determined. A gonadotropin-releasing hormone stimulation test and/or an hCG stimulation test may also be helpful in establishing the cause of the micropenis. The ability of the penis to respond to androgens can be assessed following administration of testosterone or hCG in the newborn period. Treatment with intramuscular testosterone in infancy and childhood has been recommended to improve the appearance of the penis and to facilitate toilet training. The side effects of this treatment are minimal, and include temporary acceleration in growth and advancement of bone age, in addition to some others. Replacement therapy at puberty may be necessary in some individuals. Wisniewski et al. examined long-term outcome among subjects with congenital micropenis (13 raised as males and 5 raised as females). Subjects were studied with questionnaires and physical examination. Penile length in individuals raised male was below the mean in all subjects. Many men reported dissatisfaction with the appearance of their genitalia. Both males and females were satisfied with their sex of rearing. Nonetheless, subjects raised female required several surgical procedures for reconstruction of their genitalia (115).

VIII.

HYPOSPADIAS

Hypospadias is defined as abnormal placement of the urethral meatus. Isolated hypospadias is the most common congenital malformation in males, with an estimated incidence of 1:300 live male births. In the United States, the incidence of hypospadias has increased over the past years (125). There is a familial tendency with an increased risk among certain ethnic groups. It has been reported that 21% of subjects with isolated hypospadias had another family member with hypospadias: 14% having an affected brother and 7% having an affected father (126).

340

Carrillo et al.

Formation of the ventral foreskin of the penis is related to normal urethral development. Failure of the urethra to reach the tip of the glans is accompanied by absence of the ventral foreskin. This absence causes ventral curvature of the penis known as chordee, which frequently accompanies hypospadias. If normal development of the urethra is arrested and the urethral folds fail to fuse, the meatus may be found anywhere along the course of the penis from the perineum to the glans. Hypospadias is classified based on the location of the urethral meatus after ventral curve has been surgically corrected. The most common form is the anterior hypospadias (glandular or coronal types), which accounts for 50% of all cases of hypospadias. The distal penile, midshaft, and proximal penile forms make up 30%. The remaining 20% are posterior forms (penoscrotal and perineal) (127). The cause of hypopadias is multifactorial. In the majority of cases of isolated hypopadias the cause remains unknown. Hypospadias has been also associated with disorders of male sexual differentiation (127, 128). Environmental estrogens and antiandrogens have also been associated with isolated hypospadias. Hypospadias may be associated with syndromes of human malformation, such as Smith-Lemli-Opitz syndrome and cerebrohepatorenal syndrome. Subjects with severe hypospadias with and without cryptorchidism required a complete evaluation of ambiguous genitalia (see above). Surgical reconstruction of hypospadias requires correction of chordee when present. It is recommended that boys with hypospadias not be circumcised, because the foreskin may be used in the urethroplasty. If hypospadias is associated with micropenis, treatment with testosterone is usually performed before surgery.

IX.

CRYPTORCHIDISM

A.

Definition

Cryptorchidism, defined as failure of the testis to descend into the scrotum, is another common disorder in boys. Undescended testis has a prevalence of 4–5% in full-term boys and 9–30% in premature boys (30). Spontaneous testicular descent usually occurs by the first year of life, when the prevalence of cryptorchidism declines to 1%. Undescended testis is usually unilateral (90%) and most often right-sided. The undescended testis can be located along of the inguinal canal (72%), just distal to the external ring (20%), or intra-abdominally (8%). In rare instances, the testis deviates from the normal pathway, a condition referred to as ectopic testis. The ectopic testis may be located in the superficial inguinal pouch, perineum, femoral canal, prepenile scrotum, or contralateral scrotum. The true undescended testis must be differentiated from conditions such as the so-called retractile testis: a

normal testis that has an active cremasteric reflex that pulls it back into the groin. In this condition, the testis can be brought into the scrotum without the testis being under tension. A retractile testis can often be more easily brought into the scrotum when the child assumes a squatting position. Alternatively, it may be seen in the scrotum when the child is in a warm bath.

B.

Etiology

Undescended testis results from a disruption in physiological testicular descent. Decreased androgen production as a consequence of abnormalities of the hypothalamic–pituitary axis, such as anencephaly, pituitary aplasia, and Kallmann syndrome, is associated with the occurrence of undescended testis. Defects of androgen synthesis and androgen-receptor insensitivity are also associated with the presence of undescended testis (129, 130). Mechanical anomalies related to urogenital obstruction including prune belly syndrome, posterior urethral valves, and defects of the abdominal wall such as gastrochisis and omphalocele cause undescended testis (131). Several syndromes with different chromosomal abnormalities (deletions, duplications, trisomies) include undescended testis among their features. Genetic factors may play a role, this being suggested by the occurrence of undescended testis in 1.5–4% of fathers and 6.2% of brothers of patients with cryptorchidism (30). Insulin-like hormone-3 (INSL-3), also known as Leydig insulin-like protein, is involved in testicular descent. Mice with mutations of INSL-3 have bilateral undescended testis with abnormal development of the gubernaculums (132). Tomboc et al. reported the presence of two mutations in the connecting peptide region of the protein in 2 of 145 patients with undescended testis (133).

C.

Evaluation of Undescended Testes

In newborns with male external genitalia and bilateral undescended testis, salt-losing congenital adrenal hyperplasia in a female infant must be excluded. If the karyotype is 46,XY, the presence of dysmorphic features may indicate a specific syndrome. Radiological studies may be warranted in the diagnosis of undescended testis. Testes located in the external inguinal canal or just adjacent to the external inguinal ring are easily detected by a high-resolution ultrasound scan (134). In a 46,XY subject with unilateral undescended testis, evaluation is advised at 1 year of age. In older children with undescended testis, hormonal evaluation, including evaluation of LH, FSH, and AMH is recommended. In children with hypogonadotropic hypogonadism, complete hormonal evaluation is indicated as discussed in the section on micropenis.

Disorders of Sexual Differentiation

D.

Consequences of Cryptorchidism

Testicular neoplasm, infertility, testicular torsion, and inguinal hernia are the most common complications of undescended testis. The risk of testicular malignancy in the general population is 1 in 45,000 males. However, 10% of adult testicular tumors occur in men with a history of undescended testis. The risk of testicular tumor in subjects with unilateral and bilateral undescended testis is 15 and 33 times greater, respectively, than that of subjects with normal testes. Intra-abdominal testes are five times more likely to develop a tumor. Germ-cell degeneration and dysplasia are considered the causes of malignancy. Seminomas are the most common type of malignancy, followed by embryonal cell carcinoma. Most studies indicate that bringing the testis down into the scrotum does not reduce the risk of subsequent malignancy. Malignancy may occur after orchiopexy or in the contralateral normally descended testis (30). Infertility is due to lack of or decrease in the number of germ cells as a consequence of temperature-induced degeneration. Histological abnormalities with decreased number of the spermatogonia in undescended testis are reported as early as 3 months of age (135). By 2 years of age the germ cells have decreased to 40% of normal. There is also an increase in interstitial fibrosis and collagenization in peritubular connective tissue. There is indirect evidence that the abnormality in the contralateral descended testis occurs at an early age. Autoantibodies to the undescended testis may be produced and can cause degenerative changes in the descended testis. Paternity rates are lower in men with history of bilateral cryptorchidism than in men with a history of unilateral cryptorchidism. Sudden painful inguinal swelling in association with cryptorchidism can represent testicular torsion or hernia with incarceration, both of which indicate the need for urgent intervention.

E.

Treatment

The therapeutic goals in treating cryptorchidism are to prevent infertility, avoid malignancy, correct an associated hernia, if present, and alleviate psychological stress caused by the empty scrotum. 1. Hormonal Therapy Different protocols with hCG and/or pharmacological preparation of gonadotropin-releasing hormone (GnRH) have been used with a range of success. The World Health Organization recommends hCG 250 IU twice a week for 5 weeks in boys up to 1 year of age. From 1 to 5 years of age, 500 IU is recommended twice weekly for 5 weeks. In older boys, 1000 IU twice weekly is suggested for 5 weeks. Nonetheless, published dosages and treatment schedules have varied from 100 to 4000 IU per injection given 2–3 days per week for 1–5 weeks. Combined treatment using hCG and GnRH analogs for a total of 4 weeks

341

has been reported to improve response in nonpalpable testis (136). Successful treatment of the true undescended testis with hCG has varied from 6 to 65%. Hormonal treatment is more effective in the treatment of testis located immediately prescrotally. However, some reports suggest that hormonal therapy is only successful for those testes that would have ultimately descended without surgery. 2. Surgical Therapy The optimal time to operate is unknown, considering that evidence that histological changes in the testis occur early as 2–3 months of age. However, the recommendation of the Action Committee on Surgery of the Genitalia is to perform orchiopexy at 12 months of age. Numerous studies have reported that 75% of testes descend spontaneously by this age without further chance of descent thereafter. Anesthesia risk by this age is minimal when administered by experienced pediatric anesthesiologists. Most orchiopexies are performed as outpatient procedures. Ectopic testes and testes in the inguinal canal are brought into the scrotum by a small inguinal crease incision. The gubernaculum and cremasteric muscle are separated from the testis, and the lateral Prentiss fibers are divided, thereby allowing the testis a more direct route into the scrotum. The testis is then fixed in place with a suture. There is a 90% incidence of inguinal hernia with undescended testis, which is usually repaired simultaneously. The success rate of this operation is reported to be over 95%. Bilateral inguinal testes can be operated on at the same time. Nonpalpable undescended testis can now be located by laparoscopy to inspect the peritoneal cavity. Of nonpalpable testes, 20% are atrophic, and blind-ending spermatic vessels and vas deferens are noted intra-abdominally. Numerous radiological investigations have been performed, including sonograms, CT scans, venography of the spermatic vessels, and, recently, MRI. If, at the time of laparoscopy, the testis is located, an orchiopexy can be performed. Most testes can be placed within the scrotal sac by one procedure. However, when the spermatic vessels are extremely short, a two-stage orchiopexy can be performed. The spermatic vessels are ligated or divided during the first stage, allowing collateral blood supply via the vasal artery to develop. Then, 4–6 months later, the testis can be brought into the scrotal sac and nourished with the vasal blood supply with a success rate of 90%. In bilateral nonpalpable testis, hCG stimulation tests should be performed before laparoscopy to rule out testicular agenesis. Laparoscopy in children has been shown to be safe by the age of 1 year and can be done as an outpatient procedure (30).

ACKNOWLEDGMENTS We gratefully acknowledge the excellent editorial assistance of Kaitlin K. Blazejack.

342

Carrillo et al.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

14. 15.

16. 17. 18.

19. 20. 21. 22. 23. 24.

Drews U. Local mechanisms in sex specific morphogenesis. Cytogenet Cell Genet 2000; 91:72–80. Hughes IA. Minireview: sex differention. Endocrinology 2001; 142(8):3281–3287. Ostrer H. Sexual differentiation. Semin Reprod Med 2000; 18:41–49. Swain A, Lovell-Badge R. Mammalian sex determination: a molecular drama. Genes Dev 1999; 13:755–767. Teixeira J, et al. Mullerian-inhibiting substance regulates androgen synthesis at the transcriptional level. Endocrinology 1999; 140:4732–4738. McLaren A. Gonad development. Curr Biol 1998; 8(5): R175–R177. Lejeune H, Habert R, Saez JM. Origin, proliferation and differentiation of Leydig cells. J Mol Endocrinol 1998; 20:1–25. Martineau J, et al. Male-specific cell migration into the developing gonad. Curr Biol 1997; 7:958–968. Jirasek JE. Germ cells and the indifferent gonad (genital ridge). In Polin RA, ed. Fetal and Neonatal Physiology. Philadelphia: WB Saunders 1992:1854–1864. Greenfield A. Genes, cells and organs: recent developments in the molecular genetics of mammalian sex determination. Mammal Genome 1998; 9:683–687. Capel B. The battle of sexes. Mechanisms Dev 2000; 92: 89–103. Birk OS, et al. The LIM homebox gene Lhx9 is essential for mouse gonad formation. Nature 2000; 403:909–913. Ottolenghi C, et al. Absence of mutations involving the Lim homeobox domain gene LHX9 in 46,XY gonadal agenesis and dysgenesis. J Clin Endocrinol Metab 2001; 86:2465–2469. Hammer GD, Ingraham HA. Steroidogenic factor-1: its role in endocrine organ development and differentiation. Front Neuroendocrinol 1999; 20:199–223. Berkovitz GD, Seeherunvong T. Molecular basis of sexual differentiation. In Handwerger S, ed. Molecular and Cellular Pediatric Endocrinology. Towota, NJ: Humana Press 1997:1–8. Sinclair AH, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 1990; 346:240–244. Marshall OJ, Harley VR. Molecular mechanisms of SOX9 action. Mol Gen Metabol 2000; 71:455–462. De Santa B, et al. Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene. Mol Cell Biol 1998; 18(11):6653–6655. Goodfellow PN, Camerino G. DAX-1, an ‘‘anti-testis’’ gene. EXS 2001; 91:57–69. Nachtigal MW, et al. Wilms’ tumor 1 and DAX-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell 1998; 93:445–454. Parker KL, Schimmer BP, Schedl A. Genes essential for early events in gonadal development. Cell Mol Life Sci 1999; 55:831–838. Veitia RA, et al. Testis determination in mammals: more questions than answers. Mol Cell Endocrinol 2001; 179: 3–16. Vainio S, et al. Female development in mammals is regulated by the Wnt-4 signaling. Nature 1999; 397:405– 409. MacLaughlin DT, Teixeira J, Donahoe PK. Perspective: reproductive tract development-New discoveries and future directions. Endocrinology 2001; 142:2167–2172.

25. 26. 27. 28. 29. 30. 31. 32. 33.

34. 35. 36. 37. 38. 39. 40. 41. 42. 43.

44.

45. 46.

Kuschert S, et al. Characterization of Pax-2 regulatory sequences that direct transgene expression in the Wolffian duct and its derivatives. Devel Biol 2001; 229:128–140. Parr B, McMahon A. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature 1998; 395:707–710. Trelstad RL, et al. The epithelial mesenchyme interface of the male rate Mullerian duct: loss of membrane integrity and ductal regression. Dev Biol 1982; 92:27–40. Gleinster TW. The development of the utricle and the socalled ‘‘middle’’ or ‘‘median’’ lobe of the human prostate. J Ant 1962; 96:443–445. Feldman KW, Smith DW. Fetal phallic growth and penile standards for newborn male infants. J Pediatr 1975; 86: 395–398. Hutson JM, Hasthorpe S, Heyns CF. Anatomical and functional aspects of testicular descent and cryptorchidism. Endocr Rev 1997; 18(2):259–280. Jost A, Magre S. Control mechanisms of testicular differentiation. Phil Trans R Soc Lond 1988; 322:55–61. Joss N, di Clemente N. TGF-␤ family members and gonadal development. Trends Endocrinol Metab 1999; 10: 216–222. Gouedard L, et al. Engagement of bone morphogenetic protein type IB receptor and Smad1 signaling by antiMullerian hormone and its type II receptor. J Biol Chem 2000; 36:27973–27978. Parr BA, McMahon AP. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature 1998; 395:707–710. Josso N, di Clemente N, Gouedard L. Anti-Mullerian hormone and its receptors. Mol Cell Endocrinol 2001; 179: 25–32. Lane AH, Lee MM. Clinical applications of Mullerian inhibiting substance in patients with gonadal disorders. Endocrinologist 1999; 9:208–215. Prince FP. The triphasic nature of Leydig cell development in humans, and comments on nomenclature. J Endocrinol 2001; 168:213–216. Jenkins EP, et al. Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase. J Clin Invest 1992; 89:293–300. Kuiper GG, et al. Structural organization of the human androgen receptor gene. J Mol Endocrinol 1989; 2(3): R1–4. McKenna NJ, O’Malley BW. From ligand to response: generating diversity in nuclear receptor coregulator function. J Steroid Biochem Mol 2000; 74:351–356. Brinkmann AO, et al. Mechanisms of androgen receptor activation and function. J Steroid Mol Biol 1999; 69:307– 313. Brinkmann AO. Lessons to be learned from the androgen receptor. Eur J Dermatol 2001; 11(4):301–303. Poukka H, et al. Coregulator small nuclear RING finger protein (SNURF) enhances Sp1- and steroid receptor-mediated transcription by different mechanisms. J Biol Chem 2000; 275:571–579. Mongan NP, Lim HN, Hughes IA. Genetic evidence to exclude the androgen receptor-polyglutamine associated coactivator, ARA-24, as a cause of male undermasculinization. Eur J Endocrinol 2001; 145:809–811. Cooke PS, et al. Mechanism of estrogen action: lessons from the estrogen receptor-alpha knockout mouse. Biol Reprod 1998; 59:470–475. Hess RA, Bunick D, Bahr J. Oestrogen, its receptors and function in the male reproductive tract—a review. Mol Cell Endocrinol 2001; 178:29–38.

Disorders of Sexual Differentiation 47. 48. 49. 50.

51.

52. 53. 54.

55. 56. 57. 58. 59.

60.

61.

62.

63.

64. 65. 66.

McLahlan JA. Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals. Endocr Rev 2001; 22:319–341. Kelce WR, Wilson EM. Environmental antiandrogens: developmental effects, molecular mechanisms, and clinical implications. J Mol Med 1997; 75:198–207. Sultan C, et al. Environmental xenoestrogens, antiandrogens and disorders of male sexual differentiation. Mol Cel Endocrinol 2001; 178:99–105. Berkovitz GD, et al. Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation. Medicine 1991; 70(8): 375–383. Grumbach MM, Conte FA. Disorders of sex differentiation. In Wilson JD, et al., eds. Williams textbook of Endocrinology. Philadelphia: WB Saunders 1998:1303– 1425. Verp MS, Simpson JL. Abnormal sexual differentiation and neoplasia. Cancer Genet Cytogenet 1987; 25:191. Neri G, Opitz J. Syndromal (and nonsyndromal) forms of male pseudohermaphroditism. Am J Med Genet 1999; 89: 201–209. Migeon CJ, Berkovitz GD. Sexual differentiation and ambiguity. In Kappy MS, Blizzard RM, Migeon CJ, eds. Wilkins the Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. Springfield: Charles C Thomas, 1994:573–715. Berkovitz GD, Rock JA, Urban MD. True hermaphroditism. Johns Hopkins Med J 1982; 151:290. Marcantonio SM, et al. Embryonic testicular regression sequence: a part of the clinical spectrum of 46, XY gonadal dysgenesis. Am J Med Genet 1994; 49:1–5. Josso N, Briard ML. Embryonic testicular regression syndrome: variable phenotypic expression in siblings. J Pediatr 1980; 97:200–2004. Corrado F, Stella NC, Triolo O. Testicular regression syndrome. A case report. J Reprod Med 1991; 36:549–50. Hawkins JR, et al. Evidence of increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J Hum Genet 1992; 51(5): 979–984. Canto P, et al. A mutation in the 5⬘ non-high mobility group box region of the SRY gene in patients with Turner syndrome and Y mosaicism. J Clin Endocrinol Metab 2000; 85:1908–1911. McElreavey K, et al. Loss of sequences 3⬘ to the testisdetermining gene, SRY, including the Y pseudoautosomal boundary associated with partial testicular determination. Proc Natl Acad Sci USA 1996; 93(16):8590–8594. Domenice S, et al. A novel missense mutation (S18N) in the 5⬘ non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal relatives. Hum Genet 1998; 102:213–215. Braun A, et al. True hermaphroditism in a 46,XY individual, caused by a postzygotic somatic point mutation in the male gonadal sex-determining locus (SRY): molecular genetic and histologic findings in a sporadic case. Am J Hum Genet 1993; 52:578–585. Hammes A, et al. Two splice variants of the Wilms tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 2001; 106:319–329. Achermann JC, Meeks JJ, Jameson LJ. Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol 2000; 185:17–25. Preiss S, et al. Compound effects of point mutations causing campomelic dysplasia/autosomal sex reversal upon

343

67. 68.

69. 70.

71.

72. 73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83. 84.

SOX9 structure, nuclear transport, DNA binding, and transcriptional activation. J Biol Chem 2001; 276:27864– 27872. Telvi L, et al. 45,X/46,XY mosaicism: report of 27 cases. Pediatrics 1999; 104:304–308. Reindollar RH, et al. A cytogenetic and endocrinologic study of a set of monozygotic isokaryotic 45,X/46,XY twins discordant for phenotypic sex: mosaicism versus chimerism. Fertil Steril 1987; 47:626–633. Zenteno-Ruiz JC, Kofman-Alfaro S, Mendez JP. 46,XX sex reversal. Arch Med Res 2001; (32):559–566. McElreavey K, et al. A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development. Proc Natl Acad Sci USA 1993; 90:3368–3372. Seeherunvong T, et al. 46, XX sex reversal with duplications of chromosome 22q. In Endocrine Society’s 82nd Annual Meeting, June 21–24, 2000, Toronto, Canada. Somkuti S, et al. 46,XY monozygotic twins with discordant sex phenotype. Fertil Steril 2000; 74:1254–1256. Themmen APN, Huhtaniemi IT. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and patophysiology of pituitary-gonadal function. Endocr Rev 2000; 21:551–583. Bose HS, et al. Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 2000; 85(10):3636–3639. Tajima T, et al. Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency. J Clin Endocrinol Metab 2001; 86:3820–3825. Pang S. Congenital adrenal hyperplasia owing to 3 betahydroxysteroid dehydrogenase deficiency. Endocrinol Metab Clin North 2001; 30:81–99. Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am 2001; 30:101–119. Miller WL, Geller DH, Auchus RJ. The molecular basis of isolated 17,20 lyase deficiency. Endocr Res 1998; 24: 817–825. Auchus RJ. Congenital adrenal hyperplasia: The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metabol Clin North Am 2001; 30:101–119. Gupta MK, Geller DH, Auchus RJ. Pitfallas in characterizing P450c17 mutations associated with isolated 17,20lyase deficiency. J Clin Endocrinol Metab 2001; 86: 4416–4423. Boehmer ALM, et al. 17Beta-hydroxy dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clinic Endocrinol Metab 1999; 84: 4713–4721. Lindqvist A, Hughes IA, Andersson S. Substitution mutation C268Y causes 17Beta-hydroxysteroid dehydrogenase 3 deficiency. J Clin Endocrinol Metab 2001; 86: 921–923. Fratianni CM, J I-M. The syndrome of 5 alpha-reductase deficiency. Endocrinologist 1994; 4:302–314. Imperato-McGinley J, Peterson RE, Gautier T. Primary and secondary 5 alpha-reductase deficiency. In Serio M, et al., eds. Sexual Differentiation: Basic and Clinical Aspects. New York: Raven Press, 1984:233.

344 85. 86.

87.

88. 89. 90.

91.

92.

93. 94.

95. 96.

97.

98.

99.

100.

101.

102.

Carrillo et al. Chavez B, VE, Vilchis F. Uniparental disomy in steroid 5alpha-reductase 2 deficiency. J Clin Endocrinol Metab 2000; 85:3147–3150. Vilchis F, et al. Identification of missense mutations in the SRD5A2 gene from patients with steroid 5alpha-reductase 2 deficiency. Clin Endocrinol (Oxf) 2000; 52: 383–387. Ahmed SF, et al. Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome. J Clin Endocrinol Metab 2000; 85:658–665. Morris JM. The syndrome of testicular feminization in male pseudohermaphroditism. Am J Obstet Gynecol 1953; 65:1192–1953. Rey R, et al. Anti-Mullerian hormone in children with androgen insensitivity. J Clin Endocrinol Metab 1994; 79: 960–964. Wisniewski AB, et al. Complete androgen insensitivity syndrome: Long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab 2000; 85:2664– 2669. Bertelloni S, et al. Biochemical selection of prepubertal patients with androgen insensitivity syndrome by sex hormone-binding globulin response to the human chorionic gonadotropin test. Pediatr Res 1997; 41:266–271. Rey RA, et al. Evaluation of gonadal function in 107 intersex patients by means of serum anti-Mu¨llerian hormone measurement. J Clin Endocrinol Metab 1999; 84: 627–631. Hiort O, et al. Significance of mutations in the androgen receptor gene in males with idiopathic infertility. J Clin Endocrinol Metab 2000; 85:2810–2815. Hsiao PW, et al. The linkage of Kennedy’s neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. J Biol Chem 1999; 274(29):20229–20234. Brinkmann AO. Molecular basis of androgen insensitivity. Mol Cell Endocrinol 2001; 179:105–109. Matias PM, et al. Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations. J Biol Chem 2000; 275(34):26164–26171. Hellwinkel OJ, et al. A unique exonic splicing mutation in the human androgen receptor gene indicates a physiologic relevance of regular androgen receptor transcript variants. J Clin Endocrinol Metab 2001; 86:2569– 2575. Wang Q, et al. Azoospermia associated with a mutation in the ligand-binding domain of an androgen receptor displaying normal ligand binding, but defective trans-activation. J Clin Endocrinol Metab 1998; 83:4303–4309. Giwercman A, et al. Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene. J Clin Endocrinol Metab 2000; 85:2253–2259. Holterhus PM, et al. Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome. J Clin Endocrinol Metab 1997; 82:3584–3589. Hellwinkel OJ, Bassler J, Hiort O. Transcription of androgen receptor and 5 alpha reductase II in genital fibroblasts from patients with androgen insensitivity syndrome. J Steroid Biochem Mol 2000; 75:213–218. Boehmer AL, et al. Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5alpha dihydrotestosterone availability. J Clin Endocrinol Metab 2001; 86:1240–1246.

103. 104. 105. 106. 107. 108. 109. 110. 111.

112.

113.

114. 115. 116.

117.

118. 119.

120. 121. 122. 123. 124.

Adachi M, et al. Androgen-insensitivity syndrome as a possible coactivator disease. N Engl J Med 2000; 343(12):856–862. Walsh PC, Migeon CJ. The phenotypic expression of selective disorders of male sexual differentiation. J Urol 1978; 119:627–629. Diaz A, et al. Persistent Mu¨llerian duct syndrome in an infant with initial bilateral cryptorchidism. Int Pediatr 2000; 15:41–43. Lee MM, et al. Measurements of serum Mu¨llerian inhibiting substance in the evaluation of children with nonpalpable gonads. N Engl J Med 1997; 336:1480–1486. Collett-Solberg PF. Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice, part 2. Clin Pediatr (Phila) 2001; 40:125–132. Collett-Solberg PF. Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice, part 1. Clin Pediatr (Phila) 2001; 40:1–16. Mazza V, et al. Prenatal diagnosis of female pseudohermaphroditism associated with bilateral luteoma of pregnancy: case report. Hum Reprod 2002; 17:821–824. Bulun SE. Clinical review 78: Aromatase deficiency in women and men: would you have predicted the phenotypes? J Clin Endocrinol Metab 1996; 81:867–871. Chadha R, et al. Female pseudohermaphroditism associated with cloacal anomalies: faulty differentiation in the caudal developmental field. J Pediatr Surg 2001; 36(7): E9. Fuqua JS, et al. Assay of plasma testosterone during the first six months of life: importance of chromatographic purification of steroids. Clin Chem 1995; 41: 1146–1149. Money J, Danon M. Sexological considerations in patients with history of ambisexual birth defects. In Lifshitz F, ed. Pediatric Endocrinology. New York: Marcel Dekker, Inc, 1996:347–353. Intersex Society of North America (ISNA). http:// www.isna.org. Wisniewski AB, et al. Congenital micropenis: long-term medical, surgical and psychosexual follow-up of individuals raised male or female. Horm Res 2001; 56:3–11. Bin-Abbas B, et al. Congenital hypogonadotropic hypogonadism and micropenis: effects of testosterone treatment on adult penile size—why sex reversal id not indicated. J Pediatr 1999; 134:579–583. American Academy of Pediatrics Committee of Genetics. Evaluation of the newborn with developmental anomalies of the external genitalia. Pediatrics 2000; 106: 138–142. Meyer-Bahlburg HF. Gender and sexuality in classic congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001; 30. Berenbaum SA, Duck SC, Bryk K. Behavioral effects of prenatal versus postnatal androgen excess in children with 21-hydroxylase-deficient congenital adrenal hyperplasia. J Clin Endocrinol Metab 2000; 85:727–733. Carlson AD, et al. Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment. J Steroid Biochem Mol Biol 1999; 19–29. Lee PA. Should we change our approach to ambiguous genitalia? The Endocrinologist 2001; 11:118–123. Cheng PS, Chanoine J-P. Should the definition of micropenis vary according top ethnicity? Horm Res 2001; 55: 278–281. Bergeson PS, et al. The inconspicuous penis. Pediatrics 1993; 92:794–799. Skoog SJ, Belman AB. Aphallia: its classification and management. J Urol 1989; 141:589.

Disorders of Sexual Differentiation 125. 126. 127. 128. 129. 130.

Baskin LS, Himes K, Colborn T. Hypospadias and endocrine disruption: is there a connection? Environ Health Perspect 2001; 109:1175–1183. Boehmer ALM, et al. Etiological studies of severe or familial hypospadias. J Urology 2001; 165:1246–1254. Albers N, et al. Etiologic classification of severe hypospadias: implications for prognosis and management. J Pediatr 1997; 131:386–392. Nordenskjold A, et al. Screening mutations in candidate genes for hypospadias. Urol Res 1999; 27:49–55. Timohiro I, et al. Micropenis and the AR gene: mutation and CAG repeat-length analysis. J Clin Endocrinol Metab 2001; 86:5372–5378. Lim HN, Hughes IA, Hawkins JR. Clinical and molecular evidence for the role of androgens and WT1 in testis descent. Mol Cel Endocrinol 2001; 185:43–50.

345 131. 132. 133. 134. 135. 136.

Koivusalo A, Taskinen S, Rintala RJ. Cryptorchidism in boys with congenital abdominal wall defects. Pediatr Surg Int 1998; 13:143–145. Adham IM, Emmen JMA, Engel W. The role of testicular factor INSL3 in establishing the gonadal position. Mol Cell Endocrinol 2000; 160:11–16. Tomboc M, et al. Insulin-like 3/relaxin-like factor gene mutations are associated with cryptorchidism. J Clin Endocrinol Metab 2000; 85:4013–4018. Nguyen HT, Coakley F, Hricak H. Cryptorchidism: strategies in detection. Eur Radiol 1999; 9:336–343. Huff DS, et al. Abnormal germ cell development in cryptorchidism. Horm Res 2001; 55:11–17. Giannopoulus MF, Viachakis IG, Charissis GC. 13 years’ experience with the combined hormonal therapy of cryptorchidism. Horm Res 2001; 55:33–37.

14 Thyroid Disorders in Infancy Guy Van Vliet University of Montreal and Sainte-Justine Hospital, Montreal, Quebec, Canada

I.

INTRODUCTION

Around the time of birth and during the first few years of life, thyroid hormone economy undergoes major changes that need to be understood for the proper investigation and treatment of thyroid dysfunction. The dramatic consequences of congenital hypothyroidism (CH) that is not diagnosed during the neonatal period for later brain development underline the importance of prompt recognition of abnormal thyroid function test results. Although congenital hyperthyroidism is a much less common and usually self-limited entity, it may also lead to dramatic consequences. Heart failure and even death from this condition have been reported in hyperthyroid newborns, and later developmental problems may occur as well. The most striking changes in plasma thyroid-stimulating hormone (TSH) and thyroid hormone levels occur immediately after birth. It is therefore important to know about the neonatal TSH surge, which reaches its maximum in the first few hours of life, and is followed by a peak in plasma thyroxine (T4) approximately 24 h later. An isolated TSH measurement in the first 24 h of life may therefore lead to an erroneous diagnosis of primary hypothyroidism, while an isolated measurement of T4 on the second day of life may lead to an incorrect diagnosis of hyperthyroidism. However, it is also important to recognize that several parameters of thyroid function, such as the normal ranges of free T4 and of total T3, extend to much higher levels in infancy than in older children or adults. The mechanisms underlying these age-related changes in thyroid hormone levels are briefly reviewed in the following section, and the clinical problems are discussed next in order of frequency and importance. The vast majority of these problems present as abnormalities of thyroid function, but some structural thyroid problems may also present in infancy.

II.

CHANGES IN THYROID HORMONE ECONOMY FROM CONCEPTION TO 3 YEARS OF AGE

A.

Embryonic Period

The median anlage of the thyroid migrates from the lingual area to its normal location in the neck between the 5th and 7th week of embryonic life. Once migration is complete, the median anlage connects with the lateral lobes that are derived from the fourth and fifth pharyngeal pouches. However, from the functional standpoint, the capacity to concentrate iodine only appears at about 12 weeks and control of thyroid function by the hypothalamopituitary axis is only established at 18 weeks. Because of this, the low amount of T4 that can be measured in amniotic cavities in the first trimester must be of maternal origin, suggesting that some transplacental passage of T4 already occurs at that stage (1). This may explain the deleterious effects of maternal hypothyroidism (which has been most dramatically illustrated in severe iodine deficiency) on the intellectual development of the offspring. This may justify biochemical screening of women who have a personal or family history of thyroid disease and who are contemplating becoming pregnant (2).

B.

Fetal Period

In fetal blood, T3 is low because of the presence of the placenta, with its very rich content in type III deiodinase (which transforms the prohormone T4 in the inactive hormone reverse T3 [(rT3)] and T3 itself into the inactive T2). The low T3 milieu may be responsible for the maintenance of a low level of in utero thermogenesis. TSH is high, probably because of extrahypothalamic sources of TRH, such as the pancreas and the placenta. Between 20 weeks and term, fetal plasma free T4 increases progressively because of increased secretion by the fetal thyroid (3). However, even in the complete absence of fetal thyroid func347

348

Van Vliet

tion, cord blood T4 is 20–50% of the mean value of euthyroid neonates (4). This suggests that the transplacental passage of T4 alluded to above may become substantial in the third trimester and allow some protection of the fetal brain against defective function of the fetal thyroid. The fetal brain is also protected against hypothyroidism by its rich content of type II deiodinase, the enzyme that converts T4 into the active hormone T3, which is upregulated in hypothyroidism. These two protective mechanisms provide the framework supporting the concept that complete salvage of intellectual potential is possible even in cases of severe congenital hypothyroidism provided effective treatment is administered soon after birth (see below). Another important consideration deriving from the above is that prenatal screening of all pregnant women for fetal hypothyroidism is probably not justified. At present, it would require amniocentesis, and the risks of this procedure would outweigh the possible benefits of diagnosing hypothyroidism in the fetus. However, in utero diagnosis of hypothyroidism by cordocentesis and treatment of the fetus by intraamniotic injections of levothyroxine have been reported (5). The major indication is to determine the cause of a fetal goiter discovered by ultrasonography (if it cannot be reasonably guessed from the clinical context), so as to choose the most appropriate treatment to decrease its size. Indeed, a large goiter in the fetus entails potential risks during labor (face presentation) or after birth (respiratory distress).

C.

Neonatal Period

Presumably as a consequence of the precipitous drop in ambient temperature, plasma TSH increases markedly in normal newborns, with a peak in the first 24 h of life. This is followed by a more shallow increase in plasma T4, peaking during the second day of life. Thus, screening for congenital hypothyroidism using TSH as the primary method should be delayed until after 24 h of life, otherwise the number of false positive tests would become unacceptably high. In premature newborns, the postnatal peaks of TSH and of T4 occur within the same time frame, but their amplitude is somewhat lower than that observed in term newborns.

D.

Infancy

The relative dosage (in ␮g/kg/day) of thyroxine needed to maintain euthyroidism in hypothyroid subjects decreases exponentially during the first 2 years of life from about 10 to about 5 ␮g/kg/day (6). In absolute terms, the ⬃50 ␮g thyroxine needed by a newborn correspond to about 15% of the neonatal intrathyroidal iodine pool, whereas the 150 ␮g needed by an adult correspond to only 1% of the mature intrathyroidal iodine pool. A higher iodine turnover is in general associated with higher plasma T3 (7) and, accordingly, the normal range of plasma T3

extends to higher values in infancy than in adulthood (8) (Table 1).

III. A.

CONGENITAL HYPOTHYROIDISM Nomenclature

As is the case at later ages, hypothyroidism in infancy can be congenital or acquired, peripheral (primary) or central (secondary or tertiary), and permanent or transient in nature (Table 2). Because the most common and most potentially deleterious for long-term intellectual outcome is permanent primary congenital hypothyroidism (PPCH), PPCH will be the focus of this section. On the other hand, transient hypothyroxinemia without elevation of plasma TSH is very common in premature infants. Yet there is still controversy as to whether this is a disease entity requiring treatment or whether it is one of the many mechanisms by which the premature infant adjusts to extrauterine life. Transient hypothyroxinemia is therefore the subject of a section separate from congenital hypothyroidism. Likewise, newborns are very sensitive to iodine deficiency and this remains a major cause of congenital hypothyroidism worldwide. The distribution of neonatal TSH levels and the percentage of newborns with TSH > 5 mIU/l on neonatal blood spot samples has been proposed as a means to evaluate the extent of iodine deficiency in a population (9). This major public health problem is beyond the scope of the present chapter. The prevalence of permanent primary CH is not increased in preterm infants (10). However, an increased prevalence of transient primary CH has been reported in some studies of premature newborns. The best characterized is due to the Wolff-Chaikoff effect: the induction of hypothyroidism by acute iodine overload (most often from iodine-containing antiseptic agents) (11). This condition has been mostly reported from areas of Europe where there is mild iodine deficiency and does not appear to occur in North America (12), presumably because the iodine intake of pregnant women in this area remains, on average, above a critical threshold. Finally, the hypothyroidism resulting from dominantly inherited mutations that inactivate the T3 receptor can sometimes be severe enough to be recognized in the neonatal period. Molecular confirmation of this diagnosis has now been obtained in over 200 pedigrees, but this condition will not be discussed further in this chapter and the reader is referred elsewhere (13).

B.

Epidemiology and Causes of PPCH

PPCH affects 1:2500–4000 newborns. On the basis of newborn screening programs, its worldwide incidence is relatively similar over a wide range of ethnic groups and geographical areas. The only possible exception to this rule is a lower prevalence among black populations (14).

Thyroid Disorders in Infancy Table 1

349

Pediatric Reference Intervals for T4, T3, TSH, and Free T4 Females

Analyte

Age

T4, nmol/La

1–11 months 1–5 years 6–10 years 11–15 years 16–20 years Total 1–11 months 1–5 years 6–10 years 11–15 years 16–20 years Total 1–11 months 1–5 years 6–10 years 11–15 years 16–20 years Total

T3, nmol/Lb

TSH, mIU/L

Mean 122 120 115 109 104

Males

Reference interval

n

82–162 79–160 75–154 69–149 64–144

116 471 462 799 565 2413 70 262 255 483 346 1416 131 523 562 1057 809 3082

2.46 2.37 2.20 2.03 1.84

1.52–3.39 1.43–3.30 1.62–3.12 1.09–2.95 0.92–2.78

2.2 2.0 1.8 1.5 1.3

0.8–6.3 0.7–5.9 0.6–5.1 0.5–4.4 0.5–3.9

Mean

Reference interval

n

79–161 75–158 69–152 63–147 58–142

135 589 600 614 200 2138 93 340 362 341 131 1267 158 659 698 738 223 2476

120 116 111 106 99 2.46 2.38 2.26 2.12 1.98

1.58–3.35 1.54–3.27 1.37–3.13 1.24–3.00 1.11–2.86

2.2 2.1 1.9 1.7 1.6

0.8–6.3 0.7–6.0 0.7–5.4 0.6–4.9 0.5–4.4

Females and Males Free T4, pmol/L

c

1–11 months 1–5 years 6–10 years 11–15 years 16–20 years Total

19.5 18.4 16.9 15.5 14.1

9.5–39.5 9.0–37.2 8.3–34.1 7.6–31.5 7.0–28.7

47 91 57 88 70 353

To convert nmol/L to ␮g/dl, divide by 12.87. To convert nmol/L to ng/dl, multiply by 65.1. c To convert pmol/L to ng/dl, divide by 12.87. Source: From Ref. 8. Reference values were obtained with the AutoDelfia analyzer (Wallac, Finland); different values may be expected with other methods. a b

Eighty to 90% of PPCH cases are due to developmental defects of the thyroid gland (thyroid dysgenesis), such as arrested migration of the embryonic thyroid in the sublingual area (ectopic thyroid) or an apparently complete absence of thyroid tissue on scan with sodium pertechnetate (athyreosis). Renewed interest in thyroid development has stemmed from the identification of transcription factors that are relatively thyroid-specific and from the generation of knock-out mice for these transcription factors. In humans, a few single gene defects have been shown to account for some cases of familial thyroid dysgenesis, but the vast majority of cases are sporadic and result from as yet unknown mechanisms (15). The remaining 10–20% of PPCH cases have functional defects in one of the steps involved in thyroid hormone biosynthesis (thyroid dyshormonogenesis), which follow an autosomal recessive mode of inheritance.

Recent studies have reevaluated whether genetic factors are involved in thyroid dysgenesis. Thus, a nationwide study of cases diagnosed by neonatal screening in France identified 48 familial cases out of 2472 (2%), which is 15-fold more than expected by chance. Analysis of the most typical pedigrees suggested autosomal dominant inheritance with incomplete penetrance, although there was also evidence for genetic heterogeneity (16). Ectopy and athyreosis are generally considered as part of a spectrum. Recent arguments in favor of this view are that athyreosis and ectopy can coexist in the same pedigree (16) and that ttf 2 -/- mice can have either ectopy or athyreosis, with a 50/50 distribution between the two phenotypes (17). On the other hand, the female preponderance classically described for thyroid dysgenesis as a whole is in fact only significant for ectopy, according to the results of two large recent surveys (15,18) (Table 3).

350

Van Vliet

Table 2 Classification of Causes of Congenital Hypothyroidism Central: Rare Mutation of the TRH receptor Mutation of beta-TSH Mutation of (PROP)PIT-1 So-called idiopathic hypopituitarism (usually with classic triad on MRI, see text) Peripheral: Frequent (1:2500–4000 newborns) Ectopic thyroid (most often sublingual): ⬃70% of cases Mutations inactivating PAX-8 Other mechanisms (postzygotic stochastic events) Athyreosis ⬃15% of cases True (undetectable plasma thyroglobulin) Mutations inactivating TTF-2 Other mechanisms Apparent Permanent Mutations inactivating TSHR or NIS Other mechanisms Transient: maternal TSH-receptor blocking antibodies Dyshormonogenesis (leading to goiter): ⬃10–20% of cases Thyroid of normal shape, position and size: ⬃5% of cases Source: See Refs. 15 and 25 for discussion.

This may suggest distinct molecular mechanisms for the two forms of thyroid dysgenesis, or sex-specific modifiers of a common initial event (15). The fetal sex ratio in studies of various embryopathies is seldom reported (19), and indeed was not reported for the ttf 2 -/- mice. It should also be kept in mind that athyreosis itself may be heterogeneous (Table 2). Undetectable uptake on scan may represent so-called true athyreosis (a diagnosis that should be validated by an undetectable plasma thyroglobulin) or apparent athyreosis from transplacental transfer of TSH-receptor blocking antibodies; Na/I sym-

Table 3 Proportion of Girls with Ectopy or Athyreosis from Quebec and Toronto

Ectopy: Proportion of girls 95% confidence interval Number of subjects Athyreosis: Proportion of girls 95% confidence interval Number of subjects

Quebec

Toronto

0.74 0.67–0.81 141

0.78 0.67–0.89 54

0.58 0.42–0.74 36

0.61 0.44–0.78 31

porter mutations; or ectopic tissue too small for the limit of detection of nuclear medicine scans. The differentiation between athyreosis and ectopy is of more than academic interest. Apparent athyreosis from transplacental transfer of TSH-receptor blocking antibodies leads to transient CH but has a very high risk of recurrence in subsequent pregnancies (20). The observation that PPCH from athyreosis does not have a sex ratio that is significantly different from 0.5 (Table 3) suggests that autosomal recessive mechanisms may be involved in a significant proportion of cases. Indeed, several pedigrees have been described in which apparent athyreosis was due to either compound heterozygosity (21) or homozygosity (22) for mutations that result in complete inactivation of the TSH receptor. Anatomically, the absent uptake was due to the fact that the gland was severely hypofunctional, but careful ultrasonography demonstrated that a hypoplastic gland was present and was of normal shape and position. This is consistent with the concept that TSH and its receptor are necessary for growth and function of the thyroid, but not involved in the initial differentiation of thyroid cells or in the migration of the thyroid anlage. A milder form of TSH resistance can be seen in pseudohypoparathyroidism, in which an increased level of TSH at neonatal screening or during infancy may be the presenting sign (23), before obvious phenotypic features are recognized; and in non-TSH-receptor-related TSH resistance, with a consistently normal plasma T4, a normal orthotopic gland on 99mTc imaging, and a dominant pattern of inheritance (24). Permanent or transient hyperthyrotropinemia of infancy, with normal plasma T4 and normal thyroid anatomy, can also be seen without a family history and its mechanisms remain to be elucidated. It may occur in otherwise normal children or in children with other phenotypic abnormalities, such as respiratory distress and developmental delay (as in patients with mutations in TTF-1; see Table 4). It can also be seen in Down syndrome (see below). Aside from TSH receptor mutations in athyreosis, a search for mutations in the genes coding for thyroid transcription factor-1 (TTF-1), for TTF-2 or for the paired domain factor PAX 8 has so far yielded only a handful of positive results. The careful description of the phenotypes of these naturally occurring mutation in humans and of the corresponding knock-out experiments in mice is of great importance for our understanding of thyroid gland development, but is beyond the scope of this chapter. The reader is referred elsewhere for this aspect (25). For clinical purposes, Table 4 proposes guidelines for when a specific gene should be examined.

C.

Source: Adapted from Refs. 15 and 18

Clinical Aspects and Rationale for Biochemical Screening

Signs and symptoms of hypothyroidism in the newborn period are almost always overlooked, yet this is when irreversible brain damage occurs. In the experience of the

Thyroid Disorders in Infancy Table 4

351

Transcription Factor Mutations and Congenital Hypothyroidism

Thyroid phenotype

Other features

Gene

Type of genetic lesion

Transmission

Mildly ↑ TSH Gland normal in shape, size, and position Athyreosis

RDS Developmental delay Ataxia Cleft palate Choanal atresia Kinky hair Cysts within thyroid remnants

TTF-1

Chromosomal deletion Missense

de novo or inherited de novo

TTF-2

Missense

AR

PAX-8

Missense

AD or de novo

Ectopy or orthotopic hypoplasia

RDS, respiratory distress syndrome; TTF, thyroid transcription factor; AR, autosomal recessive; AD, autosomal dominant.

last 12 years at the author’s institution, the diagnosis was suspected clinically in only 2 of more than 150 newborns. For this reason, systematic biochemical screening of newborns was undertaken in the 1970s and is becoming the standard of care in an ever-increasing number of countries. The screening strategy is based on primary TSH measurements in most countries, followed by T4 measurement if TSH is raised above a certain cutoff. As an alternative, the so-called primary T4 strategy is still used in most American states. The time at which the sample is taken may also vary between centers, with some taking cord blood, but the majority take blood from a heel prick after 24 h of age, to avoid an unacceptable percentage of recall due to the neonatal TSH surge alluded to above. Therefore, the practice of discharging newborns on the day of birth represents an organizational challenge to screening for CH.

Table 5

Knowledge of the specific technique and cutoff levels used by the screening program is not as important as the clinician’s awareness that a positive screening result should prompt immediate action and that continuous auditing of the turnaround time of the screening program is essential. Many individuals are involved between the time the sample is taken and sent to the screening laboratory and when the laboratory technician reports an abnormal result to the clinician. Human errors are the single most important factor in delayed or missed diagnoses of CH. The current guidelines used by the Quebec screening program are given in Table 5. Aside from human errors, truly normal screening TSH and T4 values have been found in infants who developed severe hypothyroidism during infancy. Thus, for unknown reasons, children with thyroid dyshormonogenesis can have normal TSH and T4 as newborns and yet

Screening and Evaluation Strategies for CH: Quebec Guidelines, 2001

Heel prick after 24 h of life except if Transfer to another hospital (sample should be taken at hospital of birth) Exchange blood transfusion Death within 24 h Note: entire surface of the spot should be filled (avoid soiling) Samples should be sent to screening laboratory every weekday Assay for TSH by time-resolved fluorometric assay technique If TSH is less than 15 mIU/L: normal If TSH between 15 and 29 mIU/L, total T4 is measured on blood spot: If total T4 is less than 87 mmol/l,a immediate referral If total T4 is greater than 87 nmol/l,a a second blood spot is requested and the infant is referred if TSH is still 15 mIU/l or above If TSH is greater than 30 mIU/l, immediate referral Upon referral: History and physical examination Anteroposterior x-ray of knee 99m Tc scintigraphy of cervical, lingual, and mediastinal area blood for TSH, free T4, T3, antithyroperoxidase antibodies in mother and baby plasma thyroglobulin in baby if apparent athyreosis on scan Start treatment without waiting for results of blood tests a

65 nmol/l if birthweight less than 2.5 kg.

352

Van Vliet

present in the first 2 years of life with clinical and biochemical evidence of severe hypothyroidism (10, 26). The second situation arises from the fact that monozygotic twins are generally discordant for thyroid dysgenesis and that the affected twin may have normal screening values because of subtle blood mixing between the euthyroid and the hypothyroid fetus (27). Lastly, dopamine infusions may lead to a false-normal plasma TSH result in spite of primary hypothyroidism (28). Thus, in spite of normal neonatal screening results, the appearance of signs and symptoms suggestive of hypothyroidism in an infant justifies repeating the determination of TSH and T4.

D.

Diagnostic Evaluation of the Hypothyroid Newborn

As stated above, a clinical diagnosis is almost never made in the newborn period. However, when a baby is referred for evaluation of a positive test, it is sometimes possible to elicit a history of increased sleepiness, poor feeding, or constipation. The family history should focus on whether there are other cases of CH or whether the mother is known to have autoimmune thyroid disease. On physical examination, prolonged icterus and large fontanelles are the most frequently encountered signs. A careful inspection of the cervical area, with the neck hyperextended, is important to detect a goiter. However, even obvious goiters on nuclear medicine scanning can be missed by experienced clinicians and imaging studies are almost always necessary. Extrathyroid abnormalities should be noted: congenital hypothyroidism can be part of a polymalformative syndrome (Table 4) and a fivefold increase in the prevalence of minor defects in septation of the embryonic heart has been reported in children with thyroid dysgenesis (15). Blood is taken to confirm the positive screening results. In addition to TSH, we routinely measure free T4, total T3, and thyroglobulin from this sample. Although the prevalence of transient CH from transplacental transfer of TSH receptor-blocking antibodies is low (29), this possibility should be investigated in cases with apparent athyreosis or with a gland of normal shape and size but decreased uptake. Because of the importance of a precise diagnosis in establishing that CH is permanent (as in true athyreosis and ectopy) or that it has a 25% recurrence risk in subsequent siblings (as in dyshormonogenesis), a nuclear medicine scan should be obtained. This should ideally be carried out on the day of the initial diagnostic evaluation, but can be performed during the first few days of thyroxine treatment because, as long as plasma TSH is still elevated, there will be uptake of the tracer by thyroid tissue. The isotope of choice is sodium pertechnetate (99mTc), which is available daily in most nuclear medicine services. However, difficulties in arranging for imaging studies should never be taken as an excuse for not initiating treat-

ment on the first visit. A nuclear medicine scan can always be obtained after withdrawing treatment for a month at 3 years of age (when hypothyroidism no longer has permanent consequences for brain development); however, obtaining good imaging is easier in a newborn than in a toddler. Lastly, one should not wait for the results of confirmatory blood tests before starting treatment. The technical quality of nuclear medicine scans is important (30). The unequivocal demonstration of ectopic sublingual tissue requires that the salivary glands be empty (which can easily be achieved in newborns by feeding them between the intravenous [IV] injection of technetium and scanning, and in toddlers by giving them a piece of candy). Ascertaining that the technetium has been injected in the vein is also essential. Because of these pitfalls of nuclear medicine imaging (and the radiation involved, although the dosage is minimal), ultrasound scanning has been evaluated for the etiological diagnosis of CH. The differentiation between normal thyroid lobes and the hyperechogenic structures (likely the ultimobranchial bodies) in the same location when there is no orthotopic thyroid is difficult and requires a highly skilled pediatric radiologist (31). Ultrasound scanning has therefore not replaced nuclear medicine imaging at most centers.

E.

Treatment and Outcome of Congenital Hypothyroidism

Before systematic biochemical screening of newborns, the mean IQ of CH children was 76 (32) and 40% required special education (33). Even in those with normal IQs, specific cognitive deficits were common (34). These numbers provide the historical background against which to gauge the success of biochemical screening and different treatment regimens. In the first generation of screened CH newborns, treatment was started at a mean age of 23–30 days and the starting dosage of levothyroxine was 5–6 ␮g/kg ⭈ day. While it was recognized that such a dosage did not normalize plasma TSH for weeks or even months, this was thought to reflect resistance to the normal feedback control mechanisms. However, such a resistance occurs only in a minority of CH newborns (35). The first report of developmental outcome of screened CH children suggested that intellectual impairment had been completely eliminated (36). This first report also found no impact of the initial severity of hypothyroidism at diagnosis. However, a meta-analysis published 15 years later and including 675 children with CH and 570 controls from 7 studies clearly showed that initial disease severity was an important determinant of outcome. Specifically, the subgroup of children with severe CH had a mean loss of six IQ points compared to controls, and in some studies the difference was in the range of 10–20 IQ points, which is not only statistically but also clinically significant (37).

Thyroid Disorders in Infancy

Severity of CH at diagnosis can be evaluated in a number of different ways (38). Most commonly, this has been done on the basis of the plasma level of T4, of the bone maturation, or of the cause (athyreosis vs. ectopy). An important concept is that the impact of severity of CH on developmental outcome does not appear linear: rather, there seems to be a threshold below which an infant with CH was at greater risk of developmental problems. This has been most convincingly demonstrated by Tillotson et al. (33), who defined a plasma total T4 at diagnosis of 43 nmol/l as the critical point below which the IQ became affected by CH. A more detailed description of these studies mostly carried out in the eighties does not seem necessary, because age at starting treatment and initial dosage of levothyroxine have changed substantially since then. In the last decade, most centers have been able to start treatment at a mean age of 9–14 days. Also in the last decade, because several lines of evidence suggested that the dosage used was suboptimal (not only persistent elevation of TSH, but also persistent delay in bone maturation at 3 years were observed [39]), the starting dosage of levothyroxine has been increased at many centers to 10–15 ␮g/ kg ⭈ day. This regimen promptly normalizes plasma TSH, but is associated with plasma free T4 levels above the reference range of most laboratories. However, as reviewed above, the normal range of plasma free T4 extends to much higher levels in infants than in older children or adults (Table 1). In addition, the mean plasma level of T3 remains within the normal range and objective signs of hyperthyroidism have not been documented. Frequent monitoring of thyroid function (i.e., every 1–3 months) was recommended by the American Academy of Pediatrics in 1993 (40). With frequent monitoring, the dosage of levothyroxine will be titrated upwards in a timely fashion when the starting dosage is low (41) and may be titrated downwards if TSH is consistently below the normal range and/or if T3 is high. Infants with dyshormonogenesis appear to need less levothyroxine than those with dysgenesis (18). Thus, further studies on the biochemical endpoints of treatment and the development of guidelines for change in dosage are needed with the high initial dosages currently used at many centers. However, the most important aspect of outcome is developmental and several recent studies have shown that the developmental gap that existed between severe CH children and controls has now been closed (6). Both early and high-dosage treatment appear necessary (42). Detailed studies of neurophysiological functions that may be more sensitive to the effects of both over- and undertreatment than the measurement of IQ may lead to greater individualization of initial dosage recommendations. In the meantime, starting as early as possible with 10–15 ␮g/ kg ⭈ day appears safe and effective in achieving the major goal of neonatal screening: to allow all CH children, including those with a severe form of the disease, to achieve their full intellectual potential (43).

353

IV.

HYPOTHYROXINEMIA OF THE NEWBORN

It is essential to define whether one is discussing decreased total or decreased free T4. The first condition that needs to be ruled out in a newborn with low total T4 concentrations associated with normal plasma TSH is thyroxin-binding globulin (TBG) deficiency. This X-linked condition is discovered only by screening programs using a primary T4 approach (for technical reasons, total and not free T4 is measured on the neonatal blood spot). It does not require treatment, since the plasma levels of free thyroid hormones are normal and the subjects are euthyroid. Loss of protein from nephrotic syndrome may also lead to low total T4. With the generalization of free T4 assays, unnecessary investigation and treatment of TBG deficiency has become rarer. In a term neonate with a low free T4 but normal TSH level, true central hypothyroidism needs to be ruled out. Isolated central hypothyroidism is exceedingly rare but may also have profound long-term deleterious effects on later development: it can be caused by mutations that inactivate the gene coding for the beta-subunit of TSH (44) or the gene coding for the TRH receptor (45). More commonly, central hypothyroidism occurs in association with other anterior pituitary hormone deficiencies: hypoglycemia, prolonged conjugated hyperbilirubinemia, and microphallus and/or cryptorchidism will suggest associated deficiencies in growth hormone, adrenocorticotropin (ACTH) and luteinizing hormone (LH), respectively. Clinical clues to a midline defect include cleft lip and palate and optic nerve hypoplasia. Magnetic resonance imaging reveals the classic triad of ectopic posterior pituitary; thin, interrupted, or absent stalk; and hypoplastic anterior pituitary in most cases of congenital hypopituitarism. A normal pituitary anatomy should lead to consideration of mutations in PIT-1 or in PROP-1 (46). On the other hand, hypothyroxinemia relative to term values, but with normal TSH, is a very common finding in premature newborns (10). It does not only reflect low TBG levels because free T4 levels are low as well. This should probably be considered as a situation akin to that seen at later ages in the presence of severe nonthyroidal illness. Indeed, numerous studies have shown that there is a correlation between the degree of lowering of T4 and negative outcomes, both short-term (mortality) and longterm (developmental problems). However, correlation does not imply causation: indeed, randomized, doubleblind, placebo-controlled studies of thyroxin supplementation have not shown an overall benefit in terms of morbidity, mortality, or developmental outcome. In fact, lower IQs were observed in levothyroxine-treated infants born after 27 weeks of gestation. Further research is underway to determine if the apparent benefit from thyroxin supplementation in extremely premature (isoleucine) in the extracellular domain of the thyrotropin receptor. J Clin Invest 1997; 100:1634–1639. Foley TP Jr, Abbassi V, Copeland KC, Draznin MB. Hypothyroidism caused by chronic autoimmune thyroiditis in very young infants. N Engl J Med 1994; 330:466–468. Ward L, Huot C, Lambert R, Deal C, Collu R, Van Vliet G. Outcome of pediatric Graves’ disease after treatment with antithyroid medication and radioiodine. Clin Invest Med. 1999; 22:132–139. van Trotsenburg AS, Vulsma T, van Santen HM, de Vijlder JJM. Are young Down syndrome infants hypothyroid? Horm Res 2000; 53(suppl 2):115. Konings CH, van Trotsenburg AS, Ris-Stalpers C, Vulsma T, Wiedijk BM, de Vijlder JJ. Plasma thyrotropin bioactivity in Down’s syndrome children with subclinical hypothyroidism. Eur J Endocrinol. 2001; 144:1–4. Tirosh E, Taub Y, Scher A, Jaffe M, Hochberg Z. Shortterm efficacy of thyroid hormone supplementation for patients with Down syndrome and low-borderline thyroid function. Am J Ment Retard 1989; 93:652–656. Sprinzl GM, Koebke J, Wimmers-Klick J, Eckel HE, Thumfart WF. Morphology of the human thyroglossal tract: a histologic and macroscopic study in infants and children. Ann Otol Rhinol Laryngol 2000; 109:1135–1139. Van Vliet G, Glinoer D, Verelst J, Spehl M, Gompel C, Delange F. Cold thyroid nodules in childhood: is surgery always necessary? Eur J Pediatr 1987; 146:378–382. Geva T, Theodor R. Atypical presentation of subacute thyroiditis. Arch Dis Child 1988; 63:845–846. Lallier M, St-Vil D, Giroux M, Huot C, Gaboury L, Oligny L, Desjardins JG. Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome. J Pediatr Surg 1998; 33:846–848.

15 Hypothyroidism John S. Dallas University of Texas Medical Branch–Galveston, Galveston, Texas, U.S.A.

Thomas P. Foley, Jr. University of Pittsburgh and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

I.

tried; then Murray used an extract subcutaneously. Hector Mackenzie in London and Howitz in Copenhagen introduced the method of feeding. We now know that the gland, taken either fresh, or as the watery or glycerin extract, or dried and powdered, is equally efficacious in a majority of all the cases of myxoedema in infants or adults . . . The results, as a rule, are most astounding—Unparalleled by anything in the whole range of curative measures. Within 6 weeks a poor, feeble-minded, toad-like caricature of humanity may be restored to mental and bodily health’’ (9).

HISTORICAL BACKGROUND

For more than 2000 years, endemic goiter and cretinism have been prevalent in iodine-deficient regions of the world, as evidenced by Andean sculptures of goitrous dwarfs dating from the 4th century BCE (1) and by descriptions recorded in Europe during the 1st century BCE (2, 3). Nonendemic cretinism, however, was not reported until 1850 when Curling described two children who had no detectable thyroid tissue at autopsy (4). In 1871, Fagge used the term ‘‘sporadic cretinism’’ to describe four children with cretinism, one being a 16-year-old girl with classic symptoms and signs of hypothyroidism, absence of thyromegaly, and ‘‘mental faculties unimpaired’’ (5). In 1878, W.M. Ord associated the term ‘‘myxoedema’’ with his descriptions of the supraclavicular ’’fatty tumours‘‘ found in hypothyroid middle-aged women (6). The Committee of the Clinical Society of London was nominated in 1883 to study hypothyroidism and presented its report in 1888 describing lymphocytic infiltration and atrophy of the thyroid gland (7) (Fig. 1). This first description of chronic lymphocytic thyroiditis preceded Hashimoto’s classic description of asymptomatic goiter (8) by 24 years. During the last decade of the 19th century several reports of successful treatment of hypothyroidism with thyroid gland extracts were reported. These therapeutic achievements were summarized in 1898 so elegantly by Sir William Osler:

Photographs depicting hypothyroid children before and after the initiation of thyroid extract therapy began to appear in textbooks soon thereafter (10) (Fig. 2). During the 20th century our understanding of the biochemical and physiological functions of the thyroid gland expanded considerably. The discovery of the structures of the iodothyronines, the need for adequate dietary intake of iodine, and the identity of the types of familial goiter and their causes have improved our ability to diagnose and treat hypothyroidism more accurately. The pathogenesis of autoimmunity, which is the most common cause of hypothyroidism in nonendemic goiter regions of the world, has been elucidated with the pioneering serological studies of Roitt and Doniach (11) and the experimental studies of Rose and Witebsky (12). More recently, competitive binding assays, thyroid epithelial cell culture systems, and advances in molecular biology have provided improved methods to study thyroid hormone secretion and action. They have also expanded our knowledge into the causes and pathogenesis of autoimmunity, inborn errors of thyroid hormone synthesis, regulation and metabolism, and other causes of hypothyroidism.

‘‘That we can to-day rescue children otherwise doomed to helpless idiocy—that we can restore to life the hopeless victims of myxoedema—is a triumph of experimental medicine for which we are indebted very largely to Victor Horsley and to his pupil Murray. Transplantation of the gland was first 359

360

Dallas and Foley

Figure 1 Lymphocytic infiltration of the thyroid gland of an adult with myxedema reported in 1888, or 24 years before the description by Hashimoto. (From Refs. 7, 8).

II.

CLASSIFICATION AND CAUSES

A.

Classification

Normal thyroid hormone secretion depends on an intact hypothalamic–pituitary–thyroid axis. In normals, thyrotropin-releasing hormone (TRH) modulates the release of thyrotropin (TSH) from the pituitary gland. TSH then binds to plasma membrane receptors on the thyrocyte and stimulates a cascade of biochemical processes that result in the production and release of primarily L-thyroxine (T4) and, in smaller molar concentrations, 3, 3⬘, 5-L-triiodothyronine (T3). An abnormality at any point within this axis can lead to decreased thyroid hormone secretion and result in hypothyroidism. By convention, hypothyroidism is classified according to the anatomical location within this axis where the abnormality occurs (13). For example, hypothyroidism resulting from thyroid gland failure, such as occurs with autoimmune destruction in Hashimoto’s thyroiditis, is referred to as primary hypothyroidism. Likewise, secondary and tertiary hypothyroidism refer to hy-

pothyroidism resulting from disorders at the level of the pituitary and hypothalamus, respectively. These diseases also are referred to as pituitary and hypothalamic hypothyroidism, and, in patients at all ages, they are much less common than primary hypothyroidism. Selective peripheral resistance to thyroid hormone is a very rare cause of hypothyroidism (14). In this syndrome, the hypothalamic–pituitary–thyroid axis is normal, but nuclear thyroid hormone receptors in peripheral tissues do not respond adequately to T3. Affected patients have symptoms and signs of hypothyroidism from an early age. Basal serum TSH, thyroid hormone levels, and TSH responses to TRH are normal. Why the resistance to thyroid hormone is present only in the peripheral tissues, and not also in the pituitary, remains to be fully elucidated.

B.

Causes

Hypothyroidism during childhood and adolescence can result from a variety of congenital or acquired defects (Table

Hypothyroidism

361

Figure 2 An early example of the effects of thyroid hormone therapy in a 7-year-old girl with the onset of hypothyroidism around age 3 years.

1). In economically advantaged countries, the majority of children with congenital primary hypothyroidism will be detected through neonatal thyroid screening programs. Rarely, however, patients with hypothyroidism caused by ectopic or hypoplastic thyroid glands, or with inborn errors of thyroid hormone synthesis (Fig. 3), may not be recognized until later in infancy or childhood. In general, ectopic and hypoplastic glands occur sporadically, whereas the inborn errors of hormone synthesis (thyroid dyshormonogenesis) are inherited as autosomal recessive disorders (15). Specific mutations have been identified in the genes that regulate the synthesis of proteins (usually enzymes) involved in the specific steps of hormonogenesis (16). Autoimmune chronic lymphocytic thyroiditis is the most common cause of acquired primary hypothyroidism in nonendemic goiter regions of the world. The disease occurs most often during childhood or adolescence and more frequently in girls than boys. However, it may pre-

sent during infancy (as early as 6–9 months of age) with subtle symptoms and signs of hypothyroidism of short duration (17). The disease also occurs with increased frequency in patients with other autoimmune-mediated diseases, especially insulin-dependent diabetes mellitus and the polyglandular autoimmune syndromes and in Down, Turner, and Klinefelter syndromes. In a recent study, serum thyroid antibodies were found in 52% of girls with Turner syndrome compared to 17% in age-matched normal girls (18). Thyroid autoimmune disease is most commonly associated with an X-isochromosome karyotype, but is also common with a 45,X karyotype (19). This association suggests that the loss of one or more genes, known as haploinsufficiency, on the short arm of the X or Y chromosome that normally are not inactivated play an important role in the pathogenesis of autoimmune thyroid disease. Other causes of primary hypothyroidism include irradiation of the thyroid, surgical removal of thyroid tissue,

362

Dallas and Foley

Table 1

Causes of Juvenile Primary Hypothyroidism

Congenital hypothyroidism: mild, late-onset Ectopic thyroid dysgenesis Familial thyroid dyshormonogenesis Peripheral resistance to thyroid hormone action Acquired primary hypothyroidism Chronic autoimmune thyroiditis Lymphocytic thyroiditis of childhood and adolescence with thyromegaly Hashimoto’s thyroiditis with thyromegaly (struma lymphomatosa) Chronic fibrous variant Drug-induced hypothyroidism Endemic goiter Iodine deficiency Environmental goitrogens Irradiation of the thyroid Therapeutic radioiodine External irradiation of nonthyroid tumors Surgical excision Nephropathic cystinosis Subacute thyroiditis: transient phase

goitrogen ingestion, iodine deficiency, and nephropathic cystinosis (Table 1). Transient primary hypothyroidism may occur during the recovery phase from subacute and toxic thyroiditis. Secondary and tertiary hypothyroidism result from deficiencies in TSH and TRH, respectively. Most children with secondary or tertiary (also known as central) hypothyroidism will have other pituitary or hypothalamic hormone deficiencies, but an isolated deficiency of either TSH or TRH secretion can occur as familial or sporadic diseases (20), and mutations have been found in the genes that control the synthesis of the TSH beta chain and the TSH and TRH receptors (21). Malformation syndromes, such as septo-optic dysplasia, or midline facial anomalies, such as cleft lip or palate, can be associated with central hypothyroidism. Trauma, neoplasms, infectious or inflammatory processes, irradiation, and surgery can damage the hypothalamus or pituitary and cause TRH, TSH, and other hormone deficiencies. These diseases are discussed in further detail elsewhere. In very low birth weight (VLBW) preterm infants less than 27 weeks of gestation, and in critically ill infants and children, hypothalamic hypothyroidism may occur as a progression of the nonthyroidal illness state and inhibition by certain therapeutic modalities.

III.

PATHOPHYSIOLOGY

In primary hypothyroidism, abnormalities of the thyroid gland or of thyroid gland function impair thyroid hormone production and/or release. Early in the course of thyroid

gland failure, a slight decrease in the serum free T4 (FT4) concentration occurs, but in most cases the level usually remains within the normal range for age. A decrease in FT4 leads to minor reductions in pituitary FT4 concentrations and the intrapituitary conversion of T4 to T3 (22). With a decrease in the pituitary free T3 (FT3) concentration, TSH production and release increase. The subsequent increase in serum TSH that causes further stimulation of the TSH receptor results in an increase in thyroid hormone synthesis and release in an attempt to maintain normal serum FT4 and FT3 levels. However, as thyroid gland failure progresses, increased TSH secretion no longer is able to maintain normal thyroid hormone synthesis, and serum FT4 and FT3 levels decrease to abnormal levels. Since serum TSH rises before serum thyroid hormone levels decrease below the normal range, the measurement of serum TSH is the most sensitive test for the early detection of primary hypothyroidism. Pituitary TSH synthesis and secretion are directly controlled by serum levels of free or unbound T4 (FT4) and FT3. This control occurs by negative feedback; that is, rising serum levels of FT4 and FT3 inhibit, whereas decreasing FT4 and FT3 levels enhance, TSH synthesis and secretion. Through TRH and somatostatin secretion, the hypothalamus modulates this negative feedback system, and the so-called set point of the molar concentrations of FT4/FT3 for TSH secretion is fine-tuned (23). TRH secretion enhances and somatostatin inhibits TSH release. Thus, patients with TRH deficiency have a decreased release of TSH causing a decrease in thyroid hormone production. However, TRH deficiency is associated with increased pituitary stores of TSH because low intrapituitary FT4 and FT3 concentrations continue to stimulate TSH synthesis. Therefore, TSH responses to TRH in experimental animals and patients often are exaggerated and the TSH rise is usually delayed, a pattern that is diagnostic of hypothalamic TRH deficiency (see below) (24).

IV.

CLINICAL PRESENTATION

Children with hypothyroidism may have a variety of clinical presentations (Table 2) and often a family history of thyroid or pituitary disease. Some children present with an asymptomatic goiter, whereas others may present with mild tenderness or a sensation of fullness in the anterior neck. Other presenting symptoms are often nonspecific and include weakness, lethargy, decreased appetite, cold intolerance, constipation, and dry skin. Although children with hypothyroidism may have mild obesity, hypothyroidism generally does not cause morbid obesity. The course of hypothyroidism is often so insidious that neither the child nor his or her parents are aware of the physical changes that have occurred. These children often experience marked growth retardation before the disease is recognized, and this expected effect on linear growth emphasizes the importance of serial growth measurements in

Hypothyroidism

363

Figure 3 Schematic representation of thyroid hormone synthesis and the sites of the most frequent abnormalities seen in patients with familial dyshormonogenesis (15, 16). A. Impaired thyroid response to TSH. B. Iodide transport defect. C. Iodide oxidation and tyrosyl iodination defects, including Pendred syndrome. D. Iodotyrosine coupling defect. E. Thyroglobulin synthetic defects. F. Iodotyrosine deiodinase defect. Each defect is associated with thyromegaly, except A. An increase in [123]Iiodide uptake occurs in each defect, except A and B. A rapid discharge of [123]I-iodide from the thyroid after oral perchlorate occurs in the iodide oxidation and tyrosyl iodination defects.

all children. Whereas children who develop hypothyroidism before age 2 years may suffer some irreversible central nervous system damage and developmental delay, the onset of hypothyroidism after age 2 years does not cause mental retardation. Infants with acquired autoimmune-mediated infantile hypothyroidism present between 6 and 24 months of age with symptoms and signs similar to those in infants with congenital hypothyroidism (17). Deceleration of linear growth is an important sign that is helpful in the early recognition of this disease. Most adolescents with untreated primary hypothyroidism will have delayed pubertal development, although

an occasional patient will present with precocious puberty. Girls may have galactorrhea that usually is associated with an elevated serum prolactin level; boys may have macroorchidism. The cause of precocious puberty in primary hypothyroidism originally was postulated to occur as a result of increased LH and FSH secretion through an overlap in the pituitary regulation of TSH secretion (25). Other studies suggest that hyperprolactinemia, which presumably results from chronic TRH stimulation of the pituitary, may play a role in this syndrome through an inhibition of gonadal stimulation by luteinizing hormone (LH), but not follicle-stimulating hormone (FSH), thereby resulting in sustained stimulation of the gonad by FSH (26). More

364 Table 2 Clinical Features Unique to Juvenile Hypothyroidism Growth retardation with delayed skeletal maturation Delayed dental development and tooth eruption Onset of puberty usually delayed; rarely precocious Galactorrhea: elevated prolactin Increased skin pigmentation Sellar enlargement Pseudotumor cerebri Myopathy and muscular hypertrophy

Dallas and Foley

dentition, mild obesity, facial puffiness and dull facial expression, coarse hair, cool and dry carotenemic skin, and delayed relaxation of deep tendon reflexes. The majority of patients with primary hypothyroidism will have thyromegaly, but some patients with autoimmune thyroiditis and ectopic or hypoplastic glands will not have detectable thyroid enlargement. Thyromegaly is not associated with hypothalamic and pituitary hypothyroidism. These children may have an abnormal optic fundus examination (i.e., papilledema), and visual field defects may be found.

V. recently, studies involving the use of mammalian cells transfected with the cDNA of either the LH/chorionic gonadotropin (CG) receptor or the FSH receptor have shown that TSH can bind to and activate both the LH and FSH receptors (27, 28). Based on these studies, elevated TSH levels associated with severe primary hypothyroidism may result in stimulation of both LH and FSH receptors and contribute to the development of precocious puberty (27, 28). The adolescent girl who acquires hypothyroidism after menarche often experiences excessive and irregular menstrual bleeding. The child with severe primary hypothyroidism may develop enlargement of the sella turcica. When this is identified by skull x-rays, computed tomographic (CT) scan, or magnetic resonance image (MRI) of the head, the child may be referred to a neurosurgeon or an endocrinologist for evaluation of suspected pituitary tumor. This pituitary mass represents hypertrophy and hyperplasia of thyrotrophs in response to the lack of negative feedback by thyroid hormones (29). Therefore, these patients with primary hypothyroidism usually have markedly elevated serum TSH levels and low serum levels of thyroid hormones; patients with hypothalamic and pituitary hypothyroidism usually have normal or very mildly elevated serum TSH levels (30) and low serum FT4 values. Pituitary enlargement usually resolves with adequate thyroid hormone replacement therapy. Primary hypothyroidism with enlargement of the sella and pituitary gland was reported in a boy in whom an empty sella and hypopituitarism occurred after thyroid hormone replacement (31). Visual field defects also may be detected in these patients (32). Children with hypothalamic and pituitary hypothyroidism can present with the same nonspecific symptoms found in primary hypothyroidism, as well as with symptoms suggestive of other hormone deficiencies. Patients with organic defects also may present with symptoms of increased intracranial pressure, such as headaches, morning vomiting, and decreased visual acuity. Features of hypothyroidism on physical examination include bradycardia, decreased pulse pressure, short stature with an increased upper-to-lower body ratio, delayed

DIAGNOSTIC EVALUATION

Patients with nongoitrous, acquired primary hypothyroidism require very few diagnostic tests prior to therapy. Serum determinations of TSH, FT4 and thyroid antibodies, thyroperoxidase antibodies (TPOAb), and thyroglobulin antibodies (TGAb), should be obtained. The presence of thyroid antibodies permits a presumptive diagnosis of autoimmune thyroiditis. Some patients with autoimmune thyroiditis have negative thyroid antibodies on initial evaluation, but, on repeat determinations 3–6 months later, have elevated thyroid antibody titers (11, 33). Thyroid antibodies may be positive in other forms of thyroiditis (34), although the levels tend to be lower and not as persistently elevated as in patients with autoimmune thyroiditis. Similar thyroid function tests should be performed in patients with goitrous hypothyroidism since the most common cause is autoimmune thyroiditis. However, if thyroid antibodies are negative on repeated determinations in a child with persistent thyromegaly, these additional tests may be useful to determine the cause of hypothyroidism: 1.

2. 3.

Radioiodide uptake test with perchlorate discharge at 2–4 h after dose, salivary-to-plasma ratio of radioiodide 2 h after the dose, and serum thyroglobulin (to identify inborn errors of thyroid hormone synthesis) Urinary iodine excretion (to identify iodine deficiency) Fine-needle aspiration (FNA) biopsy of the thyroid nodule(s) or tissue, if progressive asymptomatic enlargement of the thyroid occurs despite treatment with full replacement or suppressive dosages of L-thyroxine (to identify rare malignant infiltrative diseases).

In addition to serum thyroid function tests, a TRH test often is indicated for patients with suspected hypothalamic or pituitary hypothyroidism. In children with hypothalamic hypothyroidism the peak serum TSH response to TRH often is delayed beyond 30 min, and the TSH response may be prolonged with serum TSH values that remain elevated for 2–3 h. The TSH response to TRH is

Hypothyroidism

low or absent in patients with pituitary thyrotroph deficiency (24, 35). The nonthyroidal illness (NTI) syndrome refers to the various alterations in thyroid function often seen in preterm and VLBW infants, as well as in older children in association with a variety of conditions such as acute or chronic illnesses, surgery, trauma, malnutrition, and starvation. The magnitude of change in thyroid function tends to correlate directly with the severity of systemic illness or tissue injury. Although there are exceptions, the typical pattern of serum thyroid function tests that allows the diagnosis of this syndrome includes low total and free T3, low to normal T4, normal to high 3,3⬘,5⬘-L-triiodothyronine [known as reverse T3 (rT3)], increased T3 resin uptake, and normal TSH (36). The serum FT4 is usually normal and often in the high–normal range. Low serum FT4 values have been reported, especially in the most severely ill patients (37). The direct dialysis method to measure FT4 in serum is the most accurate determination and rarely is associated with false-positive or false-negative results (38). However, heparin use in infants and children, such as occurs with heparin-supplemented total parenteral nutrition, can cause spurious elevations in FT4 levels measured by direct dialysis methods (39). Various factors contribute to the changes in thyroid hormone economy that occur in patients with this syndrome. In the normal state, peripheral tissue conversion of T4 to T3 is the major source of circulating T3, and conversion occurs through monodeiodination via the 5⬘deiodinase pathway. This pathway also converts rT3 to T2. In the NTI syndrome, 5⬘-deiodinase activity is decreased in peripheral tissues, causing a decreased production of T3 and decreased clearance of rT3. Therefore, decreased 5⬘deiodinase activity accounts for the low serum T3 and elevated serum rT3 levels in these patients. The increased T3 resin uptake indicates a reduction in available serum thyroid hormone binding sites. The concentrations of thyroxin-binding globulin (TBG) and transthyretin (TTR), and the binding capacity of TBG, are decreased. These changes are largely responsible for the reduction in available binding sites. Nondialyzable substances, shown to be specific lipoproteins, inhibit thyroid hormone binding to TBG and TTR, and are detectable in serum during severe illness (40). Decreased T4 binding to serum proteins leads to an increased percentage of FT4 in serum and accounts for normal FT4 levels even when TT4 levels are low. The factors responsible for low TT4 levels are less well understood. Although decreased serum binding of T4 and inhibitors of binding to serum proteins may contribute, accelerated disposal of T4 and decreased TSH secretion are factors that contribute to the low T4 levels. Accelerated disposal of T4 occurs through the 5-deiodinase pathway, which converts T4 to rT3, and through nondeiodinative pathways (36). Inhibition of TSH release occurs when patients become severely ill. Abnormal hypothalamic–pituitary function during severe illness results in hypo-

365

thalamic hypothyroidism that is evident when FT4 levels become low (41). Thyroid function tests are often obtained in severely ill infants and children who are evaluated for such clinical findings as hypothermia, weakness, lethargy, and growth failure. Not only can the underlying illness or injury produce alterations in thyroid function, but the severely ill child may also be receiving medications such as dopamine, glucocorticoids, and phenytoin that can alter thyroid hormone economy (36). Cytokines also may interfere with TSH synthesis and release. Whereas the ill child with low serum T3 but normal serum TT4 and FT4 levels usually does not pose a diagnostic problem, the question of hypothyroidism frequently arises in the ill child with low serum levels of T3 and T4. In this situation a normal serum FT4 level is used as evidence against central hypothyroidism, especially when measured by direct dialysis methods (38). In the child with a low serum T4, an elevated rT3, and normal TSH, the diagnosis of the NTI syndrome is very likely, and is differentiated from hypothyroidism by normal FT4 and TSH levels. An elevated serum TSH level in a severely ill patient usually indicates primary hypothyroidism, especially when FT4 levels by direct dialysis are low (36, 37). However, modest elevations of TSH may occur during recovery from illness (36), and serial TSH measurements may be required to establish the correct diagnosis (37, 41). Children with hypothalamic or pituitary hypothyroidism generally have normal TSH and low serum FT4 and rT3 levels. These children may develop severe systemic illness, and it may be difficult to differentiate them from severely ill patients with the NTI syndrome. The history and physical examination may help to differentiate between the two disorders, but a more extensive evaluation including a MRI study of the hypothalamic–pituitary region and pituitary function testing may be necessary. The TSH response to TRH in the NTI syndrome can be normal, delayed, or blunted, and may not be useful in differentiating the NTI syndrome from hypothalamic or pituitary hypothyroidism (36, 37). Determination of rT3 is not always helpful because the level may be normal in sick hypothyroid children (36, 37). Thyroid hormone replacement is not recommended in the treatment of the NTI syndrome unless the FT4, preferably measured by direct dialysis, is low, and especially when the serum TSH is elevated. Management should be directed towards supportive or specific treatment of the underlying illness. To date, studies that have evaluated the effects of T4 or T3 replacement in patients with this syndrome have not demonstrated increased survival with replacement therapy (42–44). However, controversy still exists as to whether the NTI syndrome represents an adaptive and beneficial response to severe illness or whether, in its most advanced stage, it represents a functional type of secondary hypothyroidism as a result of a prolonged,

366

Dallas and Foley

severe illness that responds to thyroxine replacement therapy (36, 44).

VI. A.

CLINICAL COURSE AND MANAGEMENT Primary Hypothyroidism

L-thyroxine is the safest and most efficacious thyroid medication for treatment of hypothyroidism in children and adolescents (35, 37, 45, 46). Other thyroid preparations, such as thyroid extract, desiccated thyroid, and T4 – T3 combination drugs, offer no advantage over L-thyroxine and may have some disadvantages when therapy is monitored by thyroid function tests. Recent claims that T3 therapy is clinically efficacious in the treatment of an entity described on a web site as Wilson’s syndrome, caused by a reduced T4 to T3 conversion disorder, cannot be substantiated by studies reported in the literature. In these patients, any perceived benefits of T3 replacement likely result from mild hyperthyroidism induced by the T3 therapy. Approximately 20% of patients who are prescribed L-thyroxine after total thyroidectomy for thyroid cancer report symptoms of hypothyroidism despite normal results of thyroid function tests. These symptoms improve with higher dosages of L-thyroxine and mildly elevated T4 values and suppressed TSH; it is yet to be determined if instances of reduced T4 to T3 conversion occur in these patients. Generic preparations of L-thyroxine should be prescribed cautiously as some may have variable potencies and, therefore, may provide inconsistent replacement therapy (46). The importance of prescribing reliable L-

Table 3

thyroxine preparations for treatment of hypothyroidism is essential for restoration of the euthyroid state. L-thyroxine is prescribed orally as a single daily dose and should be taken at least 30 min before food intake to maximize absorption. The estimated dosage for children and adolescents is based on age and body weight (Table 3). To minimize central nervous system damage, children who are less than 2 years of age require prompt treatment with L-thyroxine in full replacement dosages. Rapid achievement of euthyroidism is not as essential in the older child and adolescent; in fact, children with chronic or severe hypothyroidism often experience undesirable side effects, such as irritability, restlessness, decreased attention span, and restless sleep or insomnia when L-thyroxine is prescribed in full replacement dosages at diagnosis. For these children it is preferable to restore euthyroidism gradually by initiating treatment with 25 ␮g daily for 2 weeks, and thereafter increasing the dose by 25 ␮g daily every 2–4 weeks until the desired dosage is achieved. This regimen is not necessary for children with mild hypothyroidism, or those with clinical symptoms of short duration. On initiation of therapy in older children and adolescents, it is important, however, to avoid excessive replacement and prudent to begin with the lower dosage per kilogram body weight for age. In patients with compensated, or subclinical, hypothyroidism, defined as an elevated serum TSH level (47), but normal concentrations of TT4 and FT4, it is worthwhile to confirm that the process is persistent by repeating the serum TSH evaluation before initiating long-term therapy. This is especially important in patients with negative thyroid antibodies and no apparent cause for the elevated

Guidelines for Maintenance Sodium L-Thyroxine Therapy

Age 20 mU/l) on at least two separate occasions and requires an increase in his/her L-thyroxine replacement does not have transient hypothyroidism that will recover spontaneously. Therefore, this child should be treated with L-thyroxine indefinitely. On the other hand, reports indicate that approximately 20% of patients with autoimmune goitrous hypothyroidism may revert to the euthyroid state (52, 53). These children may be given a 2–3 month trial off Lthyroxine treatment if the thyroid size and consistency become normal during treatment. The serum TSH level should be determined at the end of this trial, or sooner if symptoms of hypothyroidism develop. If the serum TSH

367

level is normal, the child should be monitored every 3 months for a year and then annually thereafter if thyroid antibody titers remain abnormal. If the TSH level becomes abnormal, L-thyroxine therapy should be resumed indefinitely. Serum TSH should be monitored in children receiving lithium carbonate or similar drugs that block thyroid function (54). If these children also have autoimmune thyroiditis, they very likely will develop primary hypothyroidism during lithium treatment (55). Patients should not take iron-containing (56) or calcium-containing (57) medications at the same time as thyroxine tablets. These and other medications, like certain soy-based infant formulas and high-fiber diets, very effectively block the absorption of thyroxine from the intestine (58). Other drugs, such as phenobarbital, phenytoin, carbamazepine, and rifampin, induce accelerated hepatic metabolism of L-thyroxine and can increase dosage requirements in hypothyroid patients (59). Some adolescent girls and young women with hypothyroidism receiving estrogen replacement therapy have an increase requirement for thyroxine and need to increase their dosages of thyroxine if serum TSH becomes elevated (60). During pregnancy, women with hypothyroidism require an average of 45% more thyroxine to maintain serum TSH values in the normal range (60) as a result of an increase in thyroxine-binding globulin levels (61). Estrogen stimulates glycosylation of TBG and this reduces the metabolic clearance of thyroxine (61). Maintenance of euthyroidism in the mother during early pregnancy is necessary to protect the fetus from the adverse effects of maternal hypothyroxinemia on fetal thyroxine levels that are necessary for normal central nervous system maturation (61, 62). Prepubertal children with severe hypothyroidism and short stature usually experience a period of catch-up growth after initiation of L-thyroxine replacement therapy, but, despite adequate treatment, some have incomplete catch-up and never reach their full genetic growth potential (63). The mechanisms responsible for this incomplete catch-up growth have not been clearly defined, but delay in treatment of hypothyroidism may be a critical factor (63).

B.

Disorders of Thyrotropin Secretion

Hypothyroidism, either hypothalamic or pituitary, may be present at the time of an initial diagnosis of hypopituitarism, or hypothyroidism may occur at a later time during growth hormone replacement therapy. To avoid any confusion in the differential diagnosis between hypothalamic or pituitary hypothyroidism and the NTI syndrome that occurs during severe illnesses or severe caloric/carbohydrate deprivation states, serum FT4 and, if possible, rT3 levels should be measured. The FT4 and rT3 levels are low in hypothyroidism whereas the FT4 is usually normal (37) and the rT3 is normal or elevated (36) in the NTI syn-

368

Dallas and Foley

drome. These measurements may be extremely helpful in patients with CNS tumors who are in a catabolic state following surgery. In general, patients with the NTI syndrome do not require L-thyroxine replacement, whereas patients with hypothyroidism do. As previously mentioned, results of TRH tests may differentiate between hypothalamic and pituitary hypothyroidism (35). Children with hypothalamic or pituitary hypothyroidism usually require lower dosages of L-thyroxine than children with congenital and acquired primary hypothyroidism. Serum levels of FT4 should be monitored during L-thyroxine therapy. It is unnecessary to monitor TSH levels, however, since patients with hypothalamic or pituitary hypothyroidism will have normal or low TSH values on thyroxine therapy. Once the dosage has been established and the patient is clinically and biochemically euthyroid, further serum thyroid function tests only need to be obtained annually to ensure compliance and reliability of the medication. Although children with hypothalamic or pituitary hypothyroidism and short stature may exhibit a period of catch-up growth after initiation of L-thyroxine therapy, their course is often complicated by deficiencies of growth hormone, gonadotropins, and sex hormones, and many fail to reach their full genetic height potential. Further discussion of the treatment of hypopituitarism may be found in Chapter 3. Because L-thyroxine therapy increases the metabolic clearance rate of cortisol, patients with deficiencies of hypothalamic–pituitary–adrenal and thyroid function should begin cortisol replacement with initiation of L-thyroxine replacement to avoid the precipitation of hypocortisolism and an adrenal crisis.

REFERENCES 1.

2. 3. 4. 5. 6.

7.

8.

Gaitan E. Iodine deficiency and toxicity. In: White PL, Selvey N, eds. Proceedings, Western Hemisphere Nutrition Congress-IV. Acton, MA: Publishing Sciences Group, 1975:56–63. Cranefield PF. The discovery of cretinism. Bull Hist Med 1962; 36:489. Thompson J. Historical Notes. In: Smithers D, ed. Tumours of the Thyroid, vol. 6, Neoplastic Diseases at Various Sites. Edinburgh: Livingstone, 1970. Curling TB. Two cases of absence of the thyroid body. Med Chir Trans 1850;33:303. Fagge CH. On sporadic cretinism, occurring in England. R Med Chir Soc London 1871;54:155. Ord WM. On myxoedema, a term proposed to be applied to an essential condition in the ‘‘cretinoid’’ affection occasionally observed in middle-aged women. Med Chir Trans 1878;61:57. Report of a Committee of the Clinical Society of London, nominated December 14, 1883, to investigate the subject of myxedema. Trans Clin Soc London (suppl) 1888;21:1– 202. Hashimoto H. Zur Kenntniss der lymphomato¨sen Vera¨nderung der Schilddru¨se (struma lymphomatosa). Arch Klin Chir 1912;97:219.

9. 10. 11. 12.

13.

14. 15.

16. 17.

18. 19. 20. 21. 22. 23.

24.

25.

26. 27.

28.

Osler W. The Principles and Practice of Medicine, 3rd Ed. D. Appleton and Co, 1898:843. Sajous CE de M. The Internal Secretions and the Principles of Medicine, 8th Ed. London: F. A. Davis, 1919:198–201. Roitt IM, Doniach D, Campbell RN, Hudson RV. Autoantibodies in Hashimoto’s disease. Lancet 1956;2:820. Rose NR, Witebsky E. Studies on organ-specificity. V. Changes in the thyroid glands of rabbits following active immunization with rabbit thyroid extract. J Immunol 1956; 76:417. Braverman LE, Utiger RD. Introduction to hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 8th ed. Philadelphia: Lippincott Williams & Wilkins, 2000:719–720. Kaplan MM, Swartz SL, Larsen PR. Partial peripheral resistance to thyroid hormone. Am J Med 1981;70:1115. Refetoff S, Dumont JE, Vassart G. Thyroid disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York: McGraw-Hill, 2001:4029–4075. Medeiros-Neto GA, Billerbeck AEC, Wajchenberg BL, Targovnik HM. Defective organification of iodide causing hereditary goitrous hypothyroidism. Thyroid 1993;3:143. Foley TP Jr, Abbassi V, Copeland KC, Draznin MB. Acquired autoimmune mediated infantile hypothyroidism: a pathologic entity distinct from congenital hypothyroidism. N Engl J Med 1994;330:466. Ivarrson SA, Ericsson UB, Nilsson KO, et al. Thyroid autoantibodies, Turner’s syndrome and growth hormone therapy. Acta Pediatr 1995;84:63. Elsheikh M, Wass JAH, Conway GS. Autoimmune thyroid syndrome in women with Turner’s syndrome—the association with karyotype. Clin Endocrinol 2001;55:223. Foley TP Jr. Congenital hypopituitarism. In: Dussault JH, Walker P, eds. Congenital Hypothyroidism. New York: Marcel Dekker, 1983:331–348. Tatsumi K-I, Miyai K, Tsugunori N, et al. Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet 1992;1:56. Larsen PR. Thyroid–pituitary interaction. N Engl J Med 1982;306:23. Scanlon MF, Toft AD. Regulation of thyrotropin secretion. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 8th ed. Philadelphia: Lippincott Williams & Wilkins, 2000:234–253. Foley TP Jr, Owings J, Hayford JR, Blizzard RM. Serum thyrotropin (TSH) responses to synthetic thyrotropin releasing hormone (TRH) in normal children and hypopituitary patients: a new test to distinguish primary pituitary hormone deficiency. J Clin Invest 1972;51:431. Van Wyk JJ, Grumbach MM. Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. J Pediatr 1960;59:416. Castro-Magana M, Angulo M, Canas A, et al. Hypothalamic-pituitary-gonadal axis in boys with primary hypothyroidism and macroorchidism. J Pediatr 1988;112:397. Hidaka A, Minegishi T, Kohn LD. Thyrotropin, like luteinizing hormone (LH) and chorionic gonadotropin (CG) increases cAMP and inositol phosphate levels in cells with recombinant human LH/CG receptor. Biochem Biophys Res Commun 1993;196:187. Anasti JN, Flack MR, Froehlich J, et al. A potential novel mechanism for precocious puberty in juvenile hypothyroidism. J Clin Endocrinol Metab 1995;80:2543.

Hypothyroidism 29.

30.

31. 32. 33. 34.

35.

36. 37.

38.

39.

40.

41. 42. 43.

Yamada T, Tsukaii T, Ikejiri K, et al. Volume of sella turcica in normal subjects and in patients with primary hypothyroidism and hyperthyroidism. J Clin Endocrinol Metab 1976;42:817. Illig R, Krawczy’nska H, Torresani T, Prader, A. Elevated plasma TSH and hypothyroidism in children with hypothalamic hypopituitarism. J Clin Endocrinol Metab 1975; 41:722. LaFranchi SH, Hanna CE, Krainz PL. Primary hypothyroidism, empty sella, and hypothyroidism. J Pediatr 1986; 108:571. Yamamoto K, Saito K, Takai T, et al. Visual field defects and pituitary enlargement in primary hypothyroidism. J Clin Endocrinol Metab 1983;57:283. Foley TP Jr. Acute, subacute, and chronic thyroiditis. In: Kaplan SA, ed. Clinical Pediatric and Adolescent Endocrinology. Philadelphia: WB Saunders, 1982:96–109. Emerson CH, Farwell AP. Sporadic silent thyroiditis, postpartum thyroiditis, and subacute thyroiditis. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 8th ed. Philadelphia: Lippincott Williams & Wilkins, 2000: 578–589. Foley TP Jr. Acquired hypothyroidism during infancy, childhood, and adolescence. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 8th ed. Philadelphia: Lippincott Williams & Wilkins, 2000:983–988. Fisher DA. Euthyroid low thyroxine (T4) and triiodothyronine states in prematures and sick neonates. Pediatr Clin North Am 1990;37:1297. Foley TP Jr, Malvaux P, Blizzard RM. Thyroid Disease. In: Kappy MS, Blizzard RM, Migeon CJ, eds. Wilkins The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, 4th ed. Springfield: Charles C Thomas, 1994:513–515. Nelson JC, Wilcox RB, Pandian MR. Dependence of free thyroxine estimates obtained with equilibrium tracer dialysis on the concentration of thyroxine-binding globulin. Clin Chem 1992;38:1294. Dallas JS, Dallas DV, Frost PH, et al. Measurement of free T4 levels in preterm infants receiving heparin-supplemented parenteral nutrition: comparison between equilibrium dialysis and a two-step RIA method. Program and Abstracts, 73rd Annual Meeting of the American Thyroid Association, Washington, D.C., 2001:167. Oppenheimer JH, Schwartz HL, Mariash CN, Kaiser FE. Evidence for a factor in the sera of patients with nonthyroidal disease which inhibits iodothyronine binding by solid matrices, serum proteins, and rat hepatocytes. J Clin Endocrinol Metab 1982;54:757. Wehmann RE, Gregerman RI, Burns WH, et al. Suppression of thyrotropin in the low-thyroxine state of severe nonthyroidal illness. N Engl J Med 1985;312:546. Becker RA, Vaughan GM, Ziegler MG, et al. Hypermetabolic low triiodothyronine syndrome of burn injury. Crit Care Med 1982;10:870. Rapaport R, Rose SR, Freemark M. Hypothyroxinemia in the preterm infant: the benefits and risks of thyroxine treatment. J Pediatr 2001;139:182.

369 44.

45. 46. 47. 48. 49.

50. 51. 52. 53. 54. 55. 56.

57. 58. 59. 60. 61. 62. 63.

Wiersinga WM. Nonthyroidal illness. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s The Thyroid, 8th ed. Philadelphia: Lippincott Williams & Wilkins, 2000:281– 295. Foley TP Jr. Pediatric thyroid disorders. In: Cooper DS, ed. Medical Management of Thyroid Disease. New York: Marcel Dekker, 2001:313–344. Rees-Jones RW, Rolla AR, Larsen PR. Hormone content of thyroid replacement preparations. JAMA 1980;243:549. Cooper DS. Subclinical hypothyroidism. N Engl J Med 2001;345:260. LaFranchi S. Thyroiditis and acquired hypothyroidism. Pediatr Ann 1992;21:29. Rubello D, Pozzan GB, Casara D, et al. Natural course of subclinical hypothyroidism in Down’s syndrome: prospective study results and therapeutic considerations. J Endocrinol Invest 1995;18:35. Bucci I, Napolitano G, Giuliani C, et al. Zinc sulfate supplementation improves thyroid function in hypozincemic Down children. Biol Trace Elem Res 1999;73:93. Kanavin OJ, Aaseth J, Birketvedt GS. Thyroid hypofunction in Down’s syndrome: is it related to oxidative stress? Biol Trace Elem Res 2000;78:35. Sklar CA, Qazi R, David R. Juvenile autoimmune thyroiditis: hormonal status at presentation and after long-term follow-up. Am J Dis Child 1986;140:877. Maenpaa J, Raatikka M, Rasanen J, et al. Natural course of juvenile autoimmune thyroiditis. J Pediatr 1985;107: 898. Levy RP, Jensen JB, Laus VG, et al. Serum thyroid hormone abnormalities in psychiatric disease. Metabolism 1981;38:1060. Bocchetta A, Bernardi F, Burrai C, et al. The course of thyroid abnormalities during lithium treatment: a two-year follow-up study. Acta Psychiatr Scand 1992;86:38. Shakir KMM, Chute JP, Aprill BS, Lazarus AA. Ferrous sulfate-induced increase in requirement for thyroxine in a patient with primary hypothyroidism. South Med J 1997; 90:637. Singh N, Weisler SL, Hershman JM. The acute effect of calcium carbonate on the intestinal absorption of levothyroxine. Thyroid 2001;11:967. Chiu AC, Sherman SI. Effects of pharmacological fiber supplements on levothyroxine absorption. Thyroid 1998;8: 667. Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995;333:1688. Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 2001;344:1743. Utiger RD. Estrogen, thyroxine binding in serum, and thyroxine therapy. N Engl J Med 2001;344:1784. Smallridge RC, Ladenson PW. Hypothyroidism in pregnancy: consequences to neonatal health. J Clin Endocrinol Metab 2001;86:2349. Rivkees SA, Bode HH, Crawford JD. Long-term growth in juvenile acquired hypothyroidism: the failure to achieve normal adult stature. N Engl J Med 1988;318:599.

16 Hyperthyroidism John S. Dallas University of Texas Medical Branch–Galveston, Galveston, Texas, U.S.A.

Thomas P. Foley, Jr. University of Pittsburgh and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

I.

can lead to hyperthyroidism (4, 5). Although extremely rare, the possibility of a molar pregnancy should be considered in adolescent girls with thyrotoxicosis. Inflammation of thyroid follicular cells can be associated with viral or autoimmune processes, and extensive destruction can release large amounts of preformed T4 and T3 into the circulation. The resultant thyrotoxicosis tends to be mild and transient, usually only lasting a few weeks to a few months. Examples include the toxic thyroiditis of Hashimoto’s disease and subacute thyroiditis. Acute or chronic ingestion of thyroid hormone preparations such as L-thyroxine or desiccated thyroid can produce excessive levels of circulating thyroid hormones. Ingestion may be surreptitious, iatrogenic, or accidental. Ingestion or parenteral administration of iodides may also result in thyrotoxicosis. This phenomenon, known as jodbasedow, most frequently occurs in iodine-deficient areas when supplemental iodides are added to the diet. Iodineinduced hyperthyroidism generally occurs in thyroid glands that are functioning independently of TSH stimulation (6, 7). However, iodine-induced hyperthyroidism has also been described both in adults (6, 7) and in a neonate (8) with apparently normal thyroid glands who were exposed to high concentrations of iodine over prolonged periods.

PATHOGENESIS AND ETIOLOGY

Thyrotoxicosis is an uncommon disorder of childhood characterized by accelerated metabolism of body tissues resulting from excessive levels of unbound circulating thyroid hormones. Graves’ disease accounts for at least 95% of cases in children (1). Other causes are rare and are listed in Table 1. Mechanisms that can produce thyrotoxicosis include thyroid follicular cell hyperfunction with increased synthesis and secretion of T4 and T3, thyroid follicular cell destruction with release of preformed T4 and T3, and ingestion or administration of thyroid hormone or iodide preparations. Hyperfunction of thyroid follicular cells can either be autonomous or mediated through stimulation of thyrotropin receptors by substances such as thyrotropin (TSH) or thyrotropin receptor antibodies (TSHrAb). Autonomous hyperfunction of thyroid follicular cells is rarely seen during childhood and is represented by toxic adenoma, familial nonautoimmune hyperthyroidism, hyperfunctioning thyroid carcinoma, and the hyperthyroidism of the McCune-Albright syndrome. Stimulation of thyrotropin receptors by TSHrAb produces the diffuse toxic goiter of Graves’ disease and accounts for the majority of childhood thyrotoxicosis. In rare cases, increased TSH secretion resulting either from a TSH-producing pituitary adenoma or from pituitary resistance to thyroid hormone can produce thyrotoxicosis. Another glycoprotein hormone, human chorionic gonadotropin (hCG), also binds to the TSH receptor and stimulates thyroid cell function (2, 3). The thyrotropic potency of hCG is much less than that of TSH, but extremely high serum levels of hCG, such as those seen in individuals with hydatidiform moles or other trophoblastic tumors,

II.

GRAVES’ DISEASE

A.

Introduction

Graves’ disease is an immunogenetic disorder characterized clinically by thyromegaly, hyperthyroidism, and infiltrative ophthalmopathy. A family history of autoimmune thyroid disease is present in up to 60% of patients (9). 371

372 Table 1 Causes of Thyrotoxicosis in Childhood and Adolescence Graves’ disease Autonomous functioning nodule(s) Toxic adenoma Hyperfunctioning papillary or follicular carcinoma McCune-Albright syndrome Familial nonautoimmune hyperthyroidism TSH-induced hyperthyroidism TSH-producing pituitary adenoma Pituitary resistance to thyroid hormone Thyroiditis Subacute thyroiditis Toxic thyroiditis of Hashimoto’s disease Exogenous thyroid hormone Iodine-induced hyperthyroidism ( jodbasedow) Tumor-produced thyroid stimulators Hydatidiform mole Choriocarcinoma

Genetic studies have shown it to be a polygenic disorder, and most of the genes that have been implicated appear to be involved in immunoregulation (10). Human leukocyte antigens (HLA) and the CTLA-4 gene region have been established as susceptibility loci, although the magnitude of their contributions seems to vary depending on age of onset and racial background (11, 12). Recent reports indicate that HLA-DRB1*03 and -DRB1*08 are positively associated with Graves’ disease in White children, whereas the DRB1*07 haplotype is protective (13, 14). For the Japanese population, HLA-DPB1*0501 is significantly increased in children with Graves’ disease (15). Recently, genome-wide linkage analysis studies have identified regions on chromosomes 14q31, 18q21, 20q11.2, and Xq21.33–22 that appear to represent susceptibility loci for Graves’ disease (12, 16). The concordance rate between monozygotic twins has been reported to range between 20 and 60% (11–13), thus implying that environmental factors play a significant role in the development of the disease. The extent to which chemicals, drugs, infections, and psychological stress can alter immunoregulatory genes is unknown. However, the existence of a two-way interaction between the immune and neuroendocrine systems may provide a mechanism by which biological and psychological stresses can affect lymphocyte subpopulations and immunoregulation (17). The exact incidence of Graves’ disease during childhood in North America is unknown, but it is uncommon and has been reported to account for fewer than 5% of cases seen in most thyroid clinics (18). A recent study has estimated the incidence of childhood thyrotoxicosis in Denmark to be 0.1:100,000 in the very young increasing with age to 3:100,000 by 14 years old (19). Just as in North America, the vast majority (>95%) of childhood thyrotoxicosis in Denmark is due to Graves’ disease (19).

Dallas and Foley

More than two-thirds of childhood cases in North America occur between the ages of 10 and 15 years (1), and it occurs more frequently in girls in a ratio of 3:1 to 5:1 (9).

B.

Pathogenesis: Thyrotropin Receptor and Thyrotropin Receptor Antibodies

The thyrotropin (TSH) receptor is a member of the large family of guanine-nucleotide-binding (G) protein-coupled receptors and represents the primary target antigen for autoantibodies that mediate the hyperthyroidism and thyromegaly of Graves’ disease. The cDNA encoding the human TSH receptor has been cloned and characterized (20, 21). As deduced from the cDNA sequence, the mature receptor is a glycoprotein with a single polypeptide chain of 744 amino acids. Like all other G-protein-coupled receptors, the TSH receptor has an extracellular domain, seven transmembrane domains, and an intracellular domain. The TSH and other glycoprotein hormone (i.e., luteinizing hormone [LH]/chorionic gonadotropin [CG] and follicle-stimulating hormone [FSH]) receptors each have relatively large extracellular domains, and this characteristic differentiates them from the other G-protein-coupled receptors. The TSH, LH/CG, and FSH receptors are closely related structurally and share about 70% and 45% homology in their transmembrane and extracellular domains, respectively (22). The extracellular domain of the TSH receptor (398 amino acids) represents the amino-terminal end, and the transmembrane and intracellular domains (346 amino acids) represent the carboxyl-terminal end of the protein. The extracellular domain contains six potential N-glycosylation sites and nine leucine-rich repeats of a loosely conserved 25 amino acid residue motif. Proper glycosylation appears to be important both for normal expression of the receptor on the thyroid cell membrane and for normal hormone–receptor interactions (20, 21). The leucinerich repeats, which have the potential to form amphipathic ␣-helices, are believed to be involved in protein–protein or protein–membrane interactions. Recent studies have confirmed that both TSH and autoantibodies to the TSH receptor (TSHrAb) bind to the extracellular domain (20, 21). The transmembrane and intracellular domains are involved in signal transduction, acting through G-protein to stimulate the production of cyclic AMP by adenylyl cyclase (20, 21). The hyperthyroidism and thyromegaly of Graves’ disease are mediated through immunoglobulin G (IgG) that binds to the extracellular domain of the TSH receptor and stimulates follicular cell function and growth. In addition to the stimulating TSHrAbs, sera from patients with Graves’ disease may also contain other IgG to the TSH receptor that block thyroid cell function and growth. Stimulating TSHrAbs are restricted to the IgG1 subclass, suggesting that they are either oligo- or monoclonal in origin (23). On the other hand, blocking TSHrAbs appear to be polyclonal in origin and may be of IgG1, IgG2, IgG3, or

Hyperthyroidism

IgG4 subclass (24). Current evidence suggests that disease caused by the immune system (i.e., autoimmune disease) appears to result from a restricted immune response involving B and/or T lymphocytes against one or a few epitopes of the target antigen (25). These observations, therefore, support the importance of stimulating TSHrAbs in the cause of Graves’ disease and imply that blocking TSHrAbs, much like antithyroglobulin and antithyroid peroxidase, arise as a result of thyroid tissue damage. Nevertheless, blocking TSHrAbs can still modulate the biological effects of stimulating TSHrAbs. Therefore, a patient’s clinical presentation and course may be determined by the net biological effect of the simultaneous interaction of various stimulating and blocking TSHrAbs with the TSH receptor. Several investigators have proposed that the functional effect(s) a particular TSHrAb exhibits is determined by the specific region to which the antibody binds on the TSH receptor (26, 27). Following the successful cloning of the TSH receptor, numerous studies have attempted to identify binding sites for the various TSHrAbs. To date, the major experimental approaches to defining TSHrAb epitopes have included transfecting mammalian cells with mutant cDNA of the TSH receptor and using synthetic peptides derived from the predicted amino acid sequence of the TSH receptor (reviewed in 21, 28–30). Although some of these studies have localized functional epitopes to a few relatively narrow regions of the extracellular domain (31), others have identified multiple regions throughout the entire extracellular domain that appear to be involved in TSHrAb binding (32). Although controversy still exists regarding the specific sites that compose TSHrAb epitopes, current evidence supports the concept that the antibodies bind to conformational epitopes made up of discontinuous segments across the extracellular domain (11). The amino acid region 55–254 contains residues important for the binding of at least some stimulating TSHrAbs (33–35), whereas the amino acid region 370– 400 contains residues important for the binding of some inhibitory TSHrAbs (20, 31, 36). Despite these recent advances, the exact mechanisms by which stimulating and blocking TSHrAbs exert their biological effects remain unknown. The precise determination of TSHrAb epitopes, as well as the study of molecular mechanisms, will require the development of human, disease-associated monoclonal antibodies. The major source of TSHrAb production appears to be intrathyroidal lymphocytes (27), but lymphocytes in the spleen, lymph nodes, bone marrow, and peripheral blood may also produce these antibodies (37, 38). The mechanisms and control of stimulating TSHrAb production are uncertain, but several hypotheses have been proposed. One hypothesis suggests that a deficiency of specific suppressor T-cell function accounts for TSHrAb production (39); a second hypothesis suggests that a breakdown in the idiotype–anti-idiotype network of B

373

lymphocyte immunoregulation may be responsible (40). An increased frequency of antibodies to certain serotypes of Yersinia enterocolitica has been reported in patients with Graves’ disease (41), and infection with this bacterium has been proposed as an important initiating event in the development of the disease (42). Y. enterocolitica has a specific, saturable binding site for TSH, and antibodies produced against this site may cross react with the TSH receptor on the thyroid follicular cell membrane (41). A fourth hypothesis relies on the fact that thyroid follicular cells can express HLA-DR antigens and are, therefore, endowed with the capacity to present other antigenic material to primed T lymphocytes. Through this mechanism, the follicular cell could present the TSH receptor as antigen and direct the synthesis of TSHrAb (43). Although experimental evidence exists for each of the above hypotheses, none can fully account for all aspects of TSHrAb production; further studies will be necessary to identify the responsible mechanisms. Currently, two major types of assays are used to measure TSHrAbs (44). Receptor assays assess the ability of Graves’ IgG to inhibit labeled TSH from binding to the TSH receptor, and antibodies detected by this method have been designated thyrotropin-binding inhibitory immunoglobulins (TBII). It should be emphasized that receptor assays do not differentiate TSHrAb that stimulate thyroid cell function from TSHrAb that inhibit thyroid cell function; both types of TSHrAbs can be detected as long as they inhibit TSH from binding to its receptor. Receptor assays that employ a combination of detergent-solubilized porcine TSH receptors and receptor-purified [125I]-labeled bovine TSH (referred to as first-generation TSH receptor assays) are both sensitive and specific, and they provide a reproducible, inexpensive means of measuring TSHrAb in unextracted serum (27, 45). Studies using these receptor assays have detected TSHrAb in 82–100% of adults (27) and 93% of children (46) with untreated active Graves’ disease. TSHrAb can also be detected by receptor assays in small numbers (10–20%) of patients with Hashimoto’s thyroiditis (27, 46, 47). A newer second-generation TSH receptor antibody assay is now commercially available (48) that utilizes purified labeled bovine TSH and an immobilized recombinant human TSH receptor protein (48). Recent reports show that this assay retains very high specificity and is more sensitive than the first-generation receptor assay (48, 49). In one report (49), the second-generation assay detected TSHrAb in 41 of 46 patients with Graves’ disease who had negative results with the standard first-generation assay. Bioassay methods constitute the other major type of assay currently used to measure TSHrAb. Most commonly, these assays employ isolated thyroid cells in culture to assess the ability of immunoglobulin concentrates from patient sera to stimulate thyroid cell production of cAMP. Antibodies detected by these assays have been designated thyroid-stimulating immunoglobulins (TSI).

374

Dallas and Foley

These assays can be performed using cells taken from human or porcine thyroid tissue as well as from the immortal rat thyroid line: the FRTL-5 cells. More recently, transfected mammalian cells (e.g., Cos-7 and CHO cells) expressing the recombinant human TSH receptor have been used to detect stimulating TSHrAbs (20, 50). Recently, a bioassay method utilizing CHO cells transfected with the human TSH receptor was found to detect TSI in 10 of 11 (91%) children with active Graves’ disease, whereas TSI were not detected by this assay in 13 normal children, 2 children in remission from Graves’ disease, and 11 children with chronic lymphocytic thyroiditis (51). Although the bioassays possess high sensitivity and specificity, they are less precise and are more expensive and time-consuming to perform than the receptor assays (26, 27, 44, 51). Although some reports have demonstrated highly positive correlations between TSHrAb levels detected by the receptor and bioassay methods (52), most have demonstrated no such correlation (26). Some investigators suggest that the lack of correlation between TBII and TSI levels in patient sera is due to the presence of different populations of TSHrAbs that exhibit different degrees of TSH agonist activity (53). Others suggest that the poor correlation results from the coexistence of both stimulating and blocking TSHrAb in some patients’ sera (54).

C.

Clinical Manifestations

During childhood and adolescence most patients with Graves’ disease present with the classic symptoms and signs (9). Early during the course of the disease the symptoms and signs specific to children (Table 2) may be minimal since the disease usually develops insidiously over several months (9). Often the initial awareness of any problem is in school, where teachers notice changes in behavior and academic performance. Insomnia, restless sleep, and nocturia are common and often are associated

Table 2 Common Symptoms and Signs of Graves’ Disease in 290 Children and Adolescents Percentage affected Goiter Tachycardia Nervousness Increased pulse pressure Proptosis Increased appetite Tremor Weight loss Heat intolerance Source: Ref. 9.

98 82 82 80 65 60 52 50 30

with easy fatigability and lethargy during the day. Other clinical manifestations include palpitations, increased stool frequency, increased sweating, and proximal muscle weakness. Children who develop Graves’ disease before the age of 3–4 years can experience transitory speech and language delays, mental retardation, and craniosynostosis (55). The symptoms of hyperthyroidism in Graves’ disease, although variable, tend to be more severe than in other causes of hyperthyroidism. Ophthalmic abnormalities are present in over one-half of patients (refer to Chapter 16, Sec. X), and thyromegaly is almost invariably present. In fact, the absence of goiter raises serious doubt about the diagnosis of Graves’ disease, and other causes of hyperthyroidism should be sought. The thyroid gland usually is symmetrically enlarged, smooth, soft, and nontender. A palpable thrill or an audible bruit may be present and reflects increased blood flow through the gland. Less often, and usually in association with coexisting Hashimoto’s thyroiditis, the gland may be firm, bosselated, and asymmetrically enlarged. Although pretibial myxedema is observed in 1– 2% of adults with Graves’ disease (11), it rarely, if ever, occurs in children. Other diseases have been observed in association with Graves’ disease and include Hashimoto’s thyroiditis, vitiligo, systemic lupus erythematosus, rheumatoid arthritis, Addison’s disease, insulin-dependent diabetes mellitus, myasthenia gravis, and pernicious anemia (1). Although their occurrence is extremely rare, thyroid storm and thyrotoxic periodic paralysis (TPP) are two endocrine emergencies that have been reported in children/ adolescents with hyperthyroidism. Although most reported patients have had Graves’ disease, these situations can also occur with other causes of hyperthyroidism (56– 59). Thyroid storm is a life-threatening manifestation of thyrotoxicosis characterized by fever (generally greater than 38.5⬚C), tachycardia out of proportion to the fever, high-output cardiac failure, gastrointestinal dysfunction (such as vomiting, diarrhea, and jaundice), and neurological changes (such as confusion, obtundation, seizures, and coma). The diagnosis of thyroid storm requires a high index of suspicion. The syndrome complex may occur either in previously undiagnosed patients or in patients with poorly controlled hyperthyroidism. If left untreated, mortality rates of up to 90% have been reported (60). The exact mechanisms underlying the clinical progression from uncomplicated thyrotoxicosis to storm have not been determined. A number of precipitating factors have been identified and include infection, trauma, surgery, concomitant ingestion of sympathomimetic agents (e.g., pseudoephedrine), withdrawal of antithyroid medication, and radioactive iodine therapy (56, 61–65). Therapeutic intervention includes emergency and supportive care to maintain adequate respiratory and cardiovascular functions and to control body temperature; management of precipitating factors, if indicated; and limiting the amount of thyroid

Hyperthyroidism

hormones available to the peripheral body tissues, by using propylthiouracil (PTU), iodide, ␤-adrenergic blockers, and glucocorticoids (64, 65). PTU inhibits production of new thyroid hormone and blocks conversion of T4 to T3 in peripheral tissues. During the first 24–48 h of management, PTU can be administered orally, rectally, or by nasogastric tube in dosages ranging from 100 to 200 mg every 4–6 h (66). Once initial control of thyrotoxicosis has been achieved, PTU dosages can be reduced to 5–10 mg/kg/day in divided oral doses every 6–8 h. Iodides (SSKI, 5–6 drops orally every 8 h) inhibit release of preformed hormones from the thyroid, acutely impair organification of T4, and inhibit T4 to T3 conversion. Preferably, iodides should be used only after PTU has been administered to avoid an increase in new thyroid hormone production. Propranolol (2 mg/kg/day in divided oral doses every 6–8 h) and hydrocortisone (2 mg/kg as an intravenous [IV] bolus, then 36–45 mg/m2/day in divided IV doses every 6 h) are used to treat the exaggerated adrenergic effects and possible relative glucocorticoid insufficiency, respectively, that accompany thyroid storm. Both also inhibit conversion of T4 to T3. TPP is a reversible cause of sudden-onset weakness that most commonly affects hyperthyroid patients of Asian descent. However, TPP has also been observed in susceptible White, African-American, Hispanic, and Native American persons (59). The disorder affects 1–2% of hyperthyroid patients in Asian populations, but only 0.1– 0.2% of hyperthyroid patients in North America (67, 68). A very strong male preponderance has been observed, but the mode of inheritance is unknown and the majority of affected individuals do not have a family history of periodic paralysis. Most patients present between the ages of 20 and 39 years, but older adolescents with TPP have been reported (69). At presentation, the clinical signs and symptoms of thyrotoxicosis are often subtle and may be overlooked. In the majority of patients, episodes of weakness usually occur precipitously and vary from mild weakness to total paralysis of affected muscle groups. Weakness usually involves the limbs, with proximal muscles being more severely affected than distal muscles. Mental function, sensory function, respiratory, ocular, and bulbar muscle groups are not affected. However, cardiac rhythm disturbances and electrocardiographic (ECG) abnormalities (e.g., U waves, ST segment abnormalities, prolongation of QT interval) are common (70). TPP typically occurs in the early morning hours, following a day of strenuous exercise. Other apparent precipitating factors include high carbohydrate intake, trauma, infection, menses, emotional stress, and alcohol ingestion (59, 71). The frequency of attacks is variable, and individual episodes typically last from 3 to 36 h. Laboratory evaluation during episodes reveals biochemical evidence of thyrotoxicosis (e.g., elevated serum levels of total and free thyroid hormones with suppressed TSH), and, in the vast majority of cases, significant hypokalemia.

375

Body stores of potassium are normal, and hypokalemia is the result of intracellular shifts of potassium. Neuromuscular symptoms appear to resolve as potassium moves back out of the cells and may be hastened with supplemental potassium administration. Although the severity of muscle weakness/paralysis tends to reflect the degree of hypokalemia, episodes have occurred in a few patients with normal potassium levels (68, 71). Although the exact mechanisms responsible for this disorder remain unclear, patients experience TPP only while they are thyrotoxic. Thyrotoxicosis alters plasma membrane permeability to sodium and potassium, a function linked to Na⫹-K⫹ ATPase activity. Thyrotoxicosis also enhances tissue responsiveness to ␤-adrenergic stimulation and this further increases Na⫹-K⫹ ATPase activity. Na⫹-K⫹ ATPase is also activated by insulin, and this may explain the relationship between attacks and large carbohydrate loads. In addition, a defect in the muscles themselves has been proposed, since they fail to respond to direct electrical stimulation during the period of paralysis (72). Medical management includes hospital admission for the acute paralysis, cardiac monitoring, and close observation of serum potassium levels. Potassium supplements should be used to correct hypokalemia, and antithyroid therapy should be started. Episodes of TPP always cease once thyrotoxicosis is corrected, and permanent treatment for the overactive thyroid is imperative. While awaiting normalization of thyroid status, patients should avoid precipitating factors such as strenuous exercise and high carbohydrate intake. ␤-Adrenergic-blocking agents and pharmacological glucocorticoid therapy can be useful adjunctive treatments for TPP (67, 68).

III.

AUTONOMOUS THYROID NODULE

The autonomously functioning thyroid nodule is a discrete thyroid nodule that functions independently of normal pituitary control. The pathogenesis has not yet been established in all cases, but recent evidence suggests that somatic mutations of the ␣-subunit of G-protein (Gs␣; see below) and the third intracellular loop of the TSH receptor are probably responsible for the development of some cases (73, 74). In both situations, the mutations result in constitutive activation of adenylyl cyclase and unregulated production of cAMP. The unregulated cAMP production is responsible for the subsequent tissue hyperplasia and hyperthyroidism. This disorder predominantly occurs in adults, is rare during childhood, but has been reported in a child as young as 22 months (75). Most children with a thyroid nodule come to the attention of a physician because of a mass in the region of the thyroid gland. The majority of patients with autonomous thyroid nodules are clinically euthyroid, and in contrast to adults, clinical hyperthyroidism occurs very rarely in children. Autonomously functioning nodules that cause hyperthyroidism are almost in-

376

variably benign adenomas (toxic adenoma), but very rarely hyperthyroidism caused by hyperfunctioning papillary or follicular carcinoma has been reported (76). In these cases, the patients usually have extensive metastatic disease and the diagnosis of carcinoma has been established prior to onset of hyperthyroidism. The hyperthyroidism of the McCune-Albright syndrome (MAS) is also associated with single or multiple hyperfunctioning adenomatous nodules. This syndrome is characterized by polyostotic fibrous dysplasia, multiple cafe´-au-lait spots, and endocrine hyperfunction. The most common endocrinopathy is isosexual precocious puberty, but hyperthyroidism, acromegaly, Cushing syndrome, and hyperparathyroidism have been reported (77). In contrast to polyostotic fibrous dysplasia and precocious puberty that occur more commonly in girls with the syndrome, hyperthyroidism occurs with equal frequency in boys and girls. The age of onset of hyperthyroidism tends to be between 3 and 12 years (78), which is somewhat younger than the usual age of onset of hyperthyroidism caused by hyperfunctioning nodules in other individuals. The hyperthyroidism is clearly due to autonomous function of the thyroid gland; basal TSH levels are suppressed and the TSH response to TRH is blunted, thyroid-stimulating antibodies are undetectable, and T3 treatment fails to suppress radioactive iodide uptake by the thyroid. Current evidence indicates that the receptors for each of the hormones (i.e., LH, FSH, TSH, growth-hormonereleasing hormone [GHRH], adrenocorticotropic hormone [ACTH], and parathyroid hormone [PTH]) that might otherwise be implicated in the observed endocrinopathies of MAS are all coupled to G-proteins. The G-proteins are hetereotrimers composed of an ␣-subunit and a tightly coupled ␤␥-dimer (79). The ␣-subunit contains the guanine-nucleotide-binding site and has intrinsic GTPase activity. In the normal situation, the binding of one of these stimulatory hormones to its receptor facilitates the exchange of GTP for GDP in the guanine-nucleotide-binding site of the ␣-subunit (Gs␣). This results in the release of the G-protein from the receptor and its dissociation into free Gs␣-GTP and free ␤␥-dimer. Free Gs␣-GTP stimulates adenylyl cyclase activity, with the subsequent production of intracellular cAMP. After a preset time, the intrinsic GTPase of Gs␣ hydrolyses GTP to GDP, and the Gs␣-GDP reassociates with the ␤␥-dimer. The G-protein is thus returned to its inactive state and can now reassociate with its receptor and participate in another cycle (79). Recent studies have identified mutations in the Gs␣ gene in endocrine organs, bone, and skin from patients with MAS (79–81). These mutations involve the amino acid residue Arg201 that is critical for the intrinsic GTPase activity of Gs␣. Therefore, certain substitution mutations involving this amino acid residue result in the constitutive activation of adenylyl cyclase and unregulated production of intracellular cAMP. In some cases, the mutation has been

Dallas and Foley

found in abnormal sections of tissue but not in histologically normal sections from the same tissue (79). This observation would tend to explain the development of hyperfunctioning nodules within the thyroid gland. The amount of thyroid hormone that an autonomously functioning nodule produces appears to be related to its size. In adults with single autonomous nodules, hyperthyroidism usually occurs only when the nodule measures more than 2.5–3 cm in diameter (82). Both T4 and T3 can be produced in excess, but an elevated serum T3 level is frequently the only biochemical abnormality. In some patients, the T3 level may be elevated enough to inhibit the TSH response to TRH, but not enough to cause clinical hyperthyroidism (83). A radionuclide image, preferably using [123I]-iodine, should be included in the evaluation of the hyperthyroid child with a thyroid nodule. The radioiodine image allows one to study both trapping and organification by the nodule. Technetium images only demonstrate trapping by the nodule, and images are not always identical to those obtained with iodine. The diagnosis of a hyperfunctioning or ‘‘hot’’ nodule is established when the image reveals increased accumulation of the radioisotope in the nodule and decreased or absent uptake in the surrounding thyroid tissues. Surgical removal is the preferred method of treatment for the toxic thyroid nodule and usually is accomplished by partial thyroidectomy. Significant surgical complications are not expected, and postoperative hypothyroidism seldom occurs. With complete surgical removal of the autonomous nodule, hyperthyroidism should not recur postoperatively. Since the hyperthyroidism produced by the autonomous nodule is usually mild, a long preoperative preparation with antithyroid drugs is seldom necessary. Propranolol may be used to decrease the symptoms of hyperthyroidism. The administration of iodides is not indicated in the preoperative treatment of the autonomous nodule. Percutaneous intranodular ethanol injection under ultrasound guidance has been employed for the ablation of autonomous thyroid nodules (84). This approach appears to be safe and effective in adults and may prove to be a practical alternative to surgical treatment in children.

IV.

FAMILIAL NONAUTOIMMUNE HYPERTHYROIDISM

Familial nonautoimmune hyperthyroidism (FNH) is a rare condition that clinically can be confused with Graves’ disease. It has been estimated that FNH (also referred to as nonautoimmune hereditary hyperthyroidism) may account for 2–5% of all cases of diffuse hyperthyroidism (85). The disorder occurs because of a germline mutation in the TSH receptor gene. These so-called gain of function mutations result in the constitutive activation of the TSH receptor–G protein–effector system complex that ulti-

Hyperthyroidism

mately leads to increased thyroid follicular cell growth and function. The first family recognized to have this disorder was described in 1982 (86); as of this writing, approximately 10 kindreds with FNH have been identified (87, 88). Except for amino acid 281 (Ser281) in the extracellular domain, all the other identified mutation sites are located in transmembrane domains 1, 2, 3, 5, 6, and 7 of the TSH receptor (87). The disease is transmitted in an autosomal dominant fashion. Therefore, unlike in Graves’ disease, males and females can be affected equally. In described families, hyperthyroid individuals are spread over three to four generations. The onset of clinical hyperthyroidism is highly variable, with some patients presenting before the age of 1 year and others presenting in adolescence or early adulthood. However, clinically asymptomatic individuals can exhibit suppressed serum TSH levels for years prior to the clinical appearance of goiter or thyrotoxicosis (85). In affected individuals, both thyroid gland size and structure tend to change over time. In the youngest patients, the gland tends to be normal to slightly enlarged. In older patients, the thyroid is symmetrically enlarged and bruits may be audible over the lobes. Eventually, the diffusely enlarged gland may evolve into a multinodular goiter (85). Although eye signs of thyrotoxicosis (e.g., stare, lid lag, widened palpebral fissures, mild proptosis) may be present, infiltrative ophthalmopathy has not been observed in FNH. Laboratory evaluation reveals elevated serum levels of both total and free thyroid hormones and suppressed TSH. TSH receptor antibodies are not present. In general, serum antibodies to thyroid peroxidase and thyroglobulin also are not present, but these autoantibodies have been detected in a few patients with confirmed FNH (88). In the research setting, DNA from peripheral blood leukocytes can be used to sequence the TSH receptor gene for identification of point mutations associated with FNH. The recognition of FNH is of great importance for its management. The diagnosis should be considered in cases of apparent Graves’ disease when extrathyroidal signs and thyroid antibodies are absent and in patients with an extensive family history of hyperthyroidism. As in Graves’ disease, antithyroid drug therapy can control the hyperthyroidism; but, due to the persistent functional effects of the TSH receptor mutation, remission does not occur. While subtotal thyroidectomy may restore euthyroidism in some patients (87), significant regrowth of thyroid tissue may likewise occur with subsequent recurrence of clinical hyperthyroidism (85). Therefore, total ablation of the gland, either surgically or with radioiodine, should be considered in patients with FNH. Regular systematic screening for either clinical symptoms or early biochemical evidence of hyperthyroidism (i.e., suppressed serum TSH levels) should be undertaken to identify other affected family members. In addition, genetic counseling should be offered to affected families.

377

V.

TSH-INDUCED HYPERTHYROIDISM

Hyperthyroidism from increased TSH secretion can occur as the result of either a TSH-secreting pituitary adenoma or selective pituitary resistance to thyroid hormone. Although both are rare, each has been reported in childhood and adolescence (89). Unlike Graves’ disease, the gender ratio in patients with TSH-induced hyperthyroidism is 1: 1. Most cases of TSH-producing pituitary adenoma occur sporadically, but familial cases have been reported (90). Pituitary resistance to thyroid hormone appears to be familial with an autosomal dominant pattern of inheritance (89). The cause of pituitary resistance to thyroid hormone has not been established for all cases, but most represent forms of the syndrome of generalized resistance to thyroid hormone (GRTH; see below) (91, 92). The syndrome of GRTH is caused by a mutation in TR␤, one of the thyroid hormone receptor genes (92). Approximately 60 different mutations have been identified in patients from over 100 families (92). Although the reasons remain unclear, affected members within a family can exhibit different degrees of resistance to thyroid hormone, and various tissues (e.g., heart, liver, bone, and pituitary) can be affected to a greater or lesser degree (92, 93). Therefore, the pituitary gland in such individuals would be relatively more resistant to thyroid hormones than other tissues in the body. Pituitary thyrotroph resistance in these individuals is selective for thyroid hormones, since there is normal inhibition of pituitary TSH secretion by glucocorticoids and dopaminergic agents (89). Criteria essential for the diagnosis of this disorder include evidence of increased peripheral metabolism, diffuse thyromegaly, elevated free thyroid hormone levels, and inappropriately elevated serum levels of TSH (90). Although the TSH level may not be elevated above the normal range, it is always detectable, even in highly sensitive and specific immunoassays. In all other causes of hyperthyroidism, sensitive immunoassays will reveal very suppressed or undetectable serum levels of TSH. The clinical presentation is often very similar to Graves’ disease, and a high degree of suspicion is needed to make the diagnosis. The patient with pituitary adenoma, however, may present with visual complaints due to compression of optic nerve tracts by the adenoma. Increased pituitary secretion of growth hormone and prolactin has also been reported in patients with TSH-secreting tumors (90). Once the diagnosis of TSH-induced hyperthyroidism has been established, the clinician needs to determine if the increased TSH secretion results from a pituitary tumor or from pituitary resistance to thyroid hormone in order to determine the proper course of therapy. The TRH and T3 suppression tests may help differentiate these two disorders. In general, serum TSH levels do not increase in response to TRH when a pituitary tumor is the cause of hyperthyroidism. In contrast, the TSH response to TRH tends to be normal or exaggerated in pituitary resistance

378

to thyroid hormone (89). Pharmacological dosages of T3 cause significant TSH suppression in patients with pituitary resistance but fail to reduce TSH levels in patients with TSH-secreting pituitary adenomas. Determination of serum levels of the free ␣-subunit of the glycoproteins, including TSH, also can aid in differentiating these conditions; patients with TSH-secreting pituitary tumors generally have elevated (greater than 1) molar ␣-subunit/TSH ratios. This ratio tends to be less than 1 in patients with pituitary resistance to thyroid hormone (90). The measured ␣-subunit is usually expressed in ng/ml, whereas TSH is usually expressed in ␮U/ml. In order to determine the molar ␣-subunit/TSH ratio, one assumes a molecular weight for TSH of 28,000 D, a molecular weight for ␣-subunit of 13,600 D, and a specific activity for human TSH of 5 ␮U/ng (94). This results in a conversion factor of (28,000/13,600)/0.2 or approximately 10 (95). Therefore, [␣-subunit (ng/ml)/TSH (␮U/ ml)] ⫻ 10 = molar ␣-subunit/TSH ratio. CT scan and MRI studies of the pituitary region also can help to establish the diagnosis and to guide treatment. Treatment for TSH-secreting adenomas consists of selective adenonectomy or radiotherapy, or a combination of the two (93, 96). In the past, a brief course of antithyroid drugs was used to render the patient euthyroid prior to surgery. More recently, the somatostatin analog, octreotide, has proven useful in the management of TSH-producing pituitary tumors (93, 96). This drug normalizes thyroid hormone levels in most patients and causes a decrease in tumor size in some. However, because of tachyphylaxis, octreotide cannot be considered definitive treatment. The current approach to managing the TSHproducing pituitary tumor consists of achieving a euthyroid state with octreotide, followed by surgical resection of the tumor. Treatment of patients with pituitary resistance to thyroid hormone is more difficult. Ideally, treatment should be aimed at reducing TSH secretion by the pituitary. A number of agents including L-T3, D-T4, bromocryptine, and triiodothyroacetic acid (Triac) have been advocated (90, 93, 97–99). To date, each agent has been used in a limited number of patients, and the overall efficacy of each has not been determined. Octreotide has not been useful in the long-term treatment of these patients (93). Atenolol, a ␤-adrenergic-blocking agent that does not impair the peripheral conversion of T4 to T3, can be used to decrease the symptoms of hyperthyroidism (100). Although antithyroid drugs will reduce serum thyroid hormone levels, they will also increase TSH secretion and goiter size. Since prolonged TSH hypersecretion may lead to thyrotroph hyperplasia and potentially to the development of a TSH-secreting pituitary adenoma (101), prolonged treatment with antithyroid drugs is discouraged. Likewise, subtotal thyroidectomy and radioiodine therapy should not be used in patients with pituitary resistance to thyroid hormone.

Dallas and Foley

VI.

SUBACUTE AND HASHIMOTO’S THYROIDITIS

Subacute or granulomatous thyroiditis is a self-limited, presumably viral, inflammation of the thyroid gland. This entity is rarely seen in children, occurring more frequently between the third and fifth decades of life. Mild symptoms of thyrotoxicosis may occur, but they are often overshadowed by malaise, fever, and tenderness of the thyroid gland. The erythrocyte sedimentation rate is consistently elevated. Thyroid antibodies are usually negative early in the disease, but titers may rise transiently to abnormal levels during recovery. The thyrotoxic phase of this disease probably results from destruction of thyroid follicular cells with release of large amounts of preformed thyroid hormones. The toxic thyroiditis of Hashimoto’s disease occurs early in the course of chronic lymphocytic thyroiditis and probably results from extensive autoimmune destruction of thyroid follicular cells. The child may present with mild symptoms of thyrotoxicosis and a slightly enlarged, sometimes tender, thyroid gland. Thyroid antibodies are usually positive. Laboratory evaluation of both disorders reveals elevated serum T4, free T4, and T3 levels and undetectable TSH levels. The TSH response to TRH is either blunted or absent. The radioiodine uptake is typically low or absent during the thyrotoxic phase of these disorders and helps to differentiate toxic thyroiditis from Graves’ disease. Treatment of these disorders is symptomatic. Antithyroid drugs are not indicated in the treatment, but propranolol can be used to relieve the symptoms of thyrotoxicosis in both. The pain and tenderness of the thyroid gland may be relieved by therapeutic dosages of salicylates, but on occasion glucocorticoids may be required. These disorders have been discussed in detail in Chapters 15 and 17.

VII.

EXOGENOUS THYROID HORMONE

Thyrotoxicosis may result from the ingestion, usually chronic, of excessive quantities of thyroid hormone preparations (102). The term thyrotoxicosis factitia has been used to describe this situation. In children and adolescents, this ingestion may be surreptitious, iatrogenic, or accidental. Although therapeutic thyroid hormone preparations are the most obvious source, the clinician should keep in mind that ground meats and diet pills have reportedly been contaminated with large amounts of thyroid hormones and implicated in some patients with thyrotoxicosis factitia (102). Although acute accidental or intentional overdoses of thyroid hormones can produce marked elevations in serum T4 levels, the majority of children who take as much as 5–10 mg L-T4 in a single dose have few or no symptoms of thyrotoxicosis (103). When symptoms of thyrotoxicosis

Hyperthyroidism

occur in these cases, they are usually mild and consist of fever, tachycardia, irritability, vomiting, diarrhea, and hyperactive behavior. Although more serious reactions such as seizures have been reported, these occur very infrequently and several hours to days after the acute overdose (104). When preparations containing significant levels of T3 have been ingested, the onset of symptoms is within 6–12 h. The onset of symptoms following acute ingestion of L-T4 is generally within 12–48 h, but may be as late as 7–10 days after ingestion. The delayed onset of symptoms may be explained by the conversion of T4 to its biologically more active metabolite, T3. Serum levels of T4 and/or T3 following acute ingestion correlate poorly with development of toxicity (105). Because the majority of these cases are relatively benign and symptoms are absent or delayed, initial therapy should be limited to gastric decontamination with syrup of ipecac followed by activated charcoal and/or a cathartic (106). Some authorities also recommend cholestyramine as an initial adjunctive therapy because this agent binds thyroid hormones and reduces their enterohepatic circulation (105). Patients who have ingested thyroid hormone accidentally can then be evaluated closely at home pending the onset of symptoms. As in other accidental poisonings, the parents should be counseled on child safety measures. Only when symptoms occur should hospitalization or further treatment be considered. Propranolol is helpful in controlling tachycardia as well as improving symptoms of nervousness, diaphoresis, or tremor. Acetaminophen may be useful for control of fever. In the rare situation when a massive ingestion results in a life-threatening situation, exchange transfusion has been shown to reduce serum thyroid hormone concentrations effectively (105). Psychiatric evaluation may be indicated for patients with acute intentional overdoses. Chronic ingestion of thyroid hormone preparations can produce symptoms similar to hyperthyroidism of thyroid origin. However, thyromegaly is not present unless the patient also has a coincident thyroid disease such as Hashimoto’s thyroiditis. Likewise, infiltrative ophthalmopathy is absent; however, as in other causes of thyrotoxicosis, lid lag and stare may be present. The diagnosis of this disorder is not difficult if the clinician is able to obtain a history of thyroid hormone ingestion. However, this history may be difficult to obtain, especially in cases of surreptitious ingestion. Nevertheless, the clinician should still be able to diagnose this disorder using a limited number of tests. Thyroid function test results will depend on the type of preparation responsible for the thyrotoxicosis. If the preparation is composed mainly of T4, the patient will have elevated serum T4 and free T4 levels. If the preparation is T3 or has a high T3 /T4 ratio, the patient will have a low to normal serum T4 level. In both cases the serum T3 level is elevated. The radioiodine uptake is low to reflect the suppression of thyroid gland activity induced by exogenous thyroid hormone. Unlike all other causes of thyrotoxicosis, the plasma thyroglob-

379

ulin level in this disorder is undetectable or extremely low. Therefore, the plasma thyroglobulin level may be extremely helpful in differentiating this disorder from other causes of thyrotoxicosis. Treatment of thyrotoxicosis resulting from chronic ingestion of thyroid hormone preparations should be guided by the circumstances surrounding ingestion. For example, patients receiving excessive replacement for treatment of hypothyroidism should have their dosage reduced. The patient who is taking thyroid hormone surreptitiously should be advised to discontinue the medication; in some cases, psychotherapy may be necessary.

VIII.

EUTHYROID HYPERTHYROXINEMIA

The term euthyroid hyperthyroxinemia is used to describe the various conditions in which the serum T4 level, either total or free, is elevated in the absence of thyrotoxicosis. The causes are listed in Table 3 and can be classified into four major categories: increased T4 binding by serum proteins, generalized resistance to thyroid hormones, impaired peripheral conversion of T4 to T3, and changes in thyroid stimulation associated with psychiatric illness. Alterations in any of the serum thyroid hormonebinding proteins can produce elevations of the total T4 level, but the free T4 level remains normal. Increased thyroxine-binding globulin (TBG) concentration results from a variety of causes (Table 4) and produces concurrent elevations of the serum total T4 and T3 levels. Familial dysalbuminemic hyperthyroxinemia (FDH) is due to the presence of significant amounts of serum albumin with an unusually high affinity for T4. Since this albumin typically binds T3 only weakly, the serum T3 level remains normal. FDH is inherited in an autosomal dominant fashion and is expressed equally in males and females. Increased serum concentration or binding affinity of thyroxine-binding

Table 3 Conditions Causing Hyperthyroxinemia in the Absence of Thyrotoxicosis Increased T4-binding by serum proteins Increased concentration of TBG Familial dysalbuminemic hyperthyroxinemia Increased T4-binding by transthyretin Anti-T4 antibodies Generalized (pituitary and peripheral tissues) resistance to thyroid hormone Impaired conversion of T4 to T3 Pathophysiological conditions (e.g., type I deiodinase deficiency and certain nonthyroidal illnesses) Pharmacological agents (e.g., amiodarone, propranolol, heparin, iodine contrast agents, amphetamines, Lthyroxine) Changes in thyroid stimulation associated with psychiatric illness

380

Dallas and Foley Table 4 Factors Associated with Increased TBG Concentration Pregnancy Neonatal state Estrogens Oral contraceptives Acute intermittent porphyria Infectious and chronic active hepatitis Perphenazine Genetic determination

prealbumin (TBPA) or transthyretin can produce elevated serum total T4 levels but, as in FDH, the serum T3 level remains normal. The presence of endogenous antibodies directed against T4 can produce either true or spurious elevations in serum total T4 levels. The serum free T4 level is normal in the disorders of protein binding when it is determined by equilibrium dialysis or the two-step coated tube method. Determination of the free T4 by an analog-based free T4 method gives falsely high results in patients with FDH and endogenous anti-T4 antibodies. This occurs because the variant albumin or anti-T4 antibody in the serum readily binds the analog tracer used in these competitive immunoassays, and, thereby decreases the amount of tracer available to compete for the assay antibody. The low binding of tracer by the assay antibody gives the false impression of a high free T4 concentration. The FT4 index, as usually calculated from the resin T3 uptake test, accurately reflects the FT4 level only when increased T4 binding is due to TBG excess. T4 and T3 share the same binding site on TBG. When the concentration of TBG is increased, the available binding sites for both T4 and T3 are increased. The resin T3 uptake is inversely proportional to the number of available binding sites for T3; that is, when the available serum binding sites for T3 are increased, the resin T3 uptake is decreased. The FT4 index, when calculated as the product of the T4 and the resin T3 uptake, is usually normal in TBG excess because the elevated T4 is offset by the decreased resin T3 uptake. However, when increased serum T4 binding results because of FDH or increased T4-binding by TBPA or antiT4 antibodies, the resin T3 uptake remains normal because none of these proteins binds significant amounts of T3. Consequently, the FT4 index values are spuriously elevated. Therefore, one should always consider the possibility of an abnormal T4-binding protein when serum T3 and resin T3 uptake results are normal in the face of an elevated serum T4 level. It should be emphasized that patients with elevated serum T4 levels resulting from abnormal serum binding proteins are euthyroid; no antithyroid treatment is indicated. Generalized (pituitary and peripheral tissues) resistance to thyroid hormone (GRTH) is a rare disorder char-

acterized by thyromegaly, elevated serum total and free T4 and T3 levels, a preserved TSH response to TRH, and absence of the usual symptoms and signs of thyrotoxicosis. Although this syndrome is probably congenital, it is rarely diagnosed at birth and more often recognized during childhood and adult life (107). In the majority of affected individuals, it is inherited in an autosomal dominant fashion, but recessive transmission has also been reported (107). The male to female ratio in GRTH is close to 1. The tissue resistance to thyroid hormones is selective, and studies have shown that the pituitary thyrotrophs and peripheral tissue fibroblasts respond normally to dopaminergic drugs and/or glucocorticoids (108, 109). Pituitary secretion of TSH is responsible for thyromegaly, increased thyroid gland activity, and excessive thyroid hormone synthesis and secretion seen in this syndrome. Although the serum TSH level may not always be elevated, it is always detectable; administration of TRH produces a further increase in TSH levels. On the other hand, administration of supraphysiological dosages of exogenous T3 suppresses pituitary secretion of TSH in virtually all affected patients. The syndrome of GRTH results from mutations in one of the thyroid hormone receptor genes (92). Two thyroid hormone receptor genes, TR␤ and TR␣, are located on chromosomes 3 and 17, respectively (92). By alternative splicing of primary transcripts, these two genes code for four main isoforms of the thyroid hormone receptor (TR␣-1 and c-erbA ␣-2; TR␤-1 and TR␤-2). With the exception of the c-erbA ␣-2 isoform, each of these proteins has both T3-binding and DNA-binding domains and functions as a thyroid hormone receptor (92). All molecular genetic studies on patients with GRTH have revealed mutations in the T3-binding domain of the TR␤ gene. About 60 different mutations in TR␤ have now been identified in patients from over 100 families; the mutations consist of single amino acid substitutions at a single codon, single amino acid deletions, frameshift mutations, or truncations due to premature termination of translation from a mutation-generated stop codon (92). These mutations result in thyroid hormone receptors with defective T3 binding. In some cases, the same mutations have been described in different families. The clinical phenotype can vary among the families that have the same mutation and also within a family. This suggests that there may be other genetic modifiers that determine the clinical phenotype (92). Patients who inherit this disorder in an autosomal recessive fashion have mutations in both alleles of the TR␤ gene. On the other hand, patients who inherit GRTH in an autosomal dominant fashion have a wild-type allele, as well as a mutant allele for the receptor. These mutations are dominant negative in that the mutant receptors inhibit the function of the normal ␤-receptor (from wild-type allele) and the normal ␣-receptor (92). Recently, families with GRTH have been identified that have neither TR␤ nor TR␣ mutations (110). It has been proposed that ab-

Hyperthyroidism

normal intracellular thyroid hormone transport, mutations in thyroid hormone receptor cofactors, or dysregulation of cofactor expression may be responsible for the GRTH phenotype in these families. Thus far, no defects have been identified in any of the several thyroid hormone cofactor genes that have been studied in these patients (111). To date, no germline TR␣-1 mutants have been described in humans (92). It is possible that TR␣-1 mutations are either lethal in utero, silent, and/or extremely rare. Despite the elevated levels of circulating thyroid hormones, most patients with GRTH are clinically euthyroid. Although symptoms and signs of hypo- or hyperthyroidism are generally absent, a few patients have been reported with retarded bone age, mental retardation, stunted growth, and hearing defects (112). Persistent tachycardia, tremor, anxiety, and hyperactivity have likewise been observed in some patients (113). These findings suggest that the degree of resistance to thyroid hormone may not be the same in all tissues. The diagnosis of GRTH requires elevated serum levels of T4 and free T4. Serum T3 and reverse T3 levels are also elevated. The TBG level is normal and the resin T3 uptake is elevated. As mentioned above, serum TSH is always detectable, and the TSH response is either normal or exaggerated (89). The radioiodine uptake is increased. Laboratory tests of metabolic status such as basal metabolic rate, serum cholesterol and triglycerides, and carotene are usually normal. Most patients with GRTH require no treatment, but resistance to thyroid hormone may vary from tissue to tissue. Some patients may benefit from treatment with pharmacological dosages of T4 or T3; this is especially true in cases where the peripheral tissues are more resistant than the pituitary thyrotrophs. Affected children should be monitored closely for growth deceleration, delayed bone maturation, and impaired mental development. Thyroid hormone treatment should be instituted as necessary. Any therapeutic maneuvers that may reduce the elevated circulating thyroid hormone levels are contraindicated in patients with GRTH and should be avoided. Peripheral conversion of T4 to T3 occurs through the activity of 5⬘-deiodinase. A variety of pathophysiological conditions and pharmacological agents have been associated with impaired T4 to T3 conversion. The clinical syndrome of type I iodothyronine-deiodinase deficiency has been reported but appears to be extremely rare (114). The reported patient was clinically euthyroid and had elevated serum levels of T4 and reverse T3, along with normal serum T3 and TSH levels (115). Alterations in serum thyroid hormone levels often accompany nonthyroidal illnesses. Although the T4 level is typically low or normal, on occasion it may be elevated. The euthyroid sick or nonthyroidal illness syndrome is discussed in Chapter 15. Various drugs have been found to cause an elevation of serum T4 levels in adults, but the majority of these agents are not commonly used in chil-

381

dren and adolescents. Examples include amiodarone, propranolol, heparin, oral cholecystographic agents, and amphetamines. Elevated serum T4 levels are sometimes seen in clinically euthyroid children who are receiving replacement or suppressive therapy with L-T4. In these children the serum T3 level is normal. The mechanism responsible for normal T3 levels despite increased T4 concentrations has not been completely defined, but may be explained by the fact that 5⬘-deiodinase activity in peripheral tissues appears to be autoregulated by the levels of circulating T4. Thus, as the serum T4 concentration increases from low to elevated levels, the peripheral generation of T3 from T4 decreases, as reflected in the steady decline in the serum T3/T4 ratio (102). Therefore, in patients receiving L-T4 therapy, the serum T3 level is better than the serum T4 level as an indicator of metabolic status. Mild elevations in serum T4 levels are observed in about 20% of patients hospitalized for acute psychiatric disorders (116). This situation is most commonly observed in patients with mania, schizophrenia, and other major affective disorders, but is also occasionally seen in patients with alcoholism or personality disorder. Both total and free T4 levels are elevated, and, in an occasional patient, serum T3 is also mildly elevated (116). The serum TSH is usually normal to mildly increased at baseline, and this finding helps to differentiate this condition from the most common forms of thyrotoxicosis. Often, the TSH response to TRH is blunted. These biochemical findings do not appear to represent thyrotoxicosis, and they usually resolve spontaneously within a few weeks without specific therapy. It has been proposed that a decrease in central nervous system (CNS) dopaminergic inhibition results in activation of the hypothalamic–pituitary axis with enhanced TSH secretion and consequent elevations in serum T4 levels (117).

IX.

T3 AND T4 TOXICOSIS

Increased serum concentrations of both T4 and T3 are observed in the majority of children presenting with hyperthyroidism. However, some thyrotoxic children may present with an increased serum T3 concentration but a normal or occasionally low serum T4 concentration (i.e., T3 toxicosis), while others may present with an elevated serum T4 concentration and a normal or slightly decreased T3 level (i.e., T4 toxicosis). Just as in the usual presentation of thyrotoxicosis, the serum TSH level is suppressed in both these situations. T3 toxicosis can occur in the course of any disorder that causes hyperthyroidism. Most patients have elevations in both total and free T3 concentrations, but some will present with elevated free T3 levels while total T3 levels are still within the normal range (118, 119). During childhood, T3 toxicosis is most often encountered early in the course of either initial or relapsing Graves’ disease or

382

Dallas and Foley

in association with an autonomous nodule. In these situations, T3 toxicosis reflects a predominant hypersecretion of T3 by the thyroid gland, rather than an increase in the peripheral conversion of T4 to T3 (120). If left untreated, some patients with T3 toxicosis due to true hyperthyroidism, over time, will develop elevated serum concentrations of both T3 and T4. T3 toxicosis is also seen in thyrotoxicosis factitia related to ingestion of liothyronine (L-T3). T4 toxicosis occurs in two circumstances: iodine-induced thyrotoxicosis and thyrotoxicosis accompanied by severe intercurrent illness. With iodine-induced thyrotoxicosis, about one-third of patients have elevated serum T4 but normal serum T3 levels, and the remainder have proportionate elevations of serum T3 and T4 levels (120). In severe illness, peripheral conversion of T4 to T3 is impaired because of marked reductions in 5⬘-deiodinase activity. This accounts for the normal or low serum T3 levels in the presence of abnormally elevated serum T4 levels. Furthermore, serum reverse T3 (rT3) levels are also increased because of the impaired 5⬘-deiodinase activity. With resolution of the intercurrent illness, 5⬘-deiodinase activity normalizes with subsequent declines in serum rT3 levels and increases of serum T3 levels into the thyrotoxic range. On a clinical level, T4 toxicosis of this type needs to be differentiated from the low serum T3/elevated serum T4 levels occasionally observed in the euthyroid sick syndrome. The serum TSH level will be suppressed in T4 toxicosis, and it may also be very low or suppressed in the euthyroid sick syndrome. Therefore, serum TSH measurement may not be helpful initially in differentiating between these two conditions.

X.

GRAVES’ OPHTHALMOPATHY

Ophthalmic abnormalities are clinically evident in over half of the children and adolescents with Graves’ disease. In most of these patients, the signs and symptoms are relatively mild and include lid lag, lid retraction, stare, proptosis, conjunctival injection, chemosis, and periorbital and eyelid edema. Less commonly, patients may complain of eye discomfort, pain, or diplopia. Severe ophthalmopathy, associated with marked chemosis, severe proptosis, periorbital ecchymosis, corneal ulceration, eye muscle paralysis, and optic atrophy, is extremely rare during childhood and adolescence. The clinical onset of eye disease usually coincides with that of thyroid dysfunction, but it can precede or follow it by several months to years (121). Lid lag, lid retraction, and stare most commonly result directly from thyrotoxicosis with enhanced sympathetic stimulation of Mu¨ller’s muscle of the upper lid. These features can be found in patients with thyrotoxicosis of any cause and generally improve with normalization of thyroid hormone levels. The other signs and symptoms, however, are characteristic of Graves’ ophthal-

mopathy and can be explained by the mechanical effects of an increase in tissue volume within the bony orbit. Histological examination reveals accumulation of glycosaminoglycans (GAGs) in the connective tissue components of the orbital fat and muscles, as well as lymphocytic infiltration of the orbital tissues. The GAGs are hydrophilic macromolecules produced by orbital fibroblasts, and their accumulation results in enlargement of the extraocular muscles and surrounding fat (122). Enlargement of these tissues within the fixed space of the bony orbit leads to forward displacement of the globe (proptosis or exophthalmos). Chemosis and periorbital edema result from decreased venous drainage from the orbit and intraorbital inflammation. Extraocular muscle dysfunction results from accumulation of GAGs, edema, inflammation, and fibrosis of the endomysial connective tissues investing the muscle fibers (122). Although information regarding its pathogenesis is limited, Graves’ ophthalmopathy (GO) is generally considered to represent an organ-specific autoimmune disorder. Current evidence supports the contention that orbital fibroblasts are the primary targets of the autoimmune attack (123). However, the nature of the autoimmune reaction is unclear, and a target orbital autoantigen has not been conclusively identified. The close association of GO with autoimmune thyroid disease strongly suggests that the orbital antigen(s) may share unique structural characteristics with antigens of the thyroid gland. Recent studies support that two such candidate antigens, the TSH receptor (124) and thyroglobulin (125), are present in orbital tissues from patients with GO. Therefore, it is possible that either of these two proteins could be the primary target antigen in GO, thus providing a common link between the thyroid and eye diseases. Because the TSH receptor is the primary target antigen in Graves’ hyperthyroidism, most investigators currently consider it to be the leading candidate target antigen in GO. Several human and animal studies have provided compelling, although not yet definitive, evidence (reviewed in 123, 126) to support this role for the TSH receptor in GO. However, more studies are needed to determine which, if either, of these two proteins is the target autoantigen in GO. Thus far, thyroid peroxidase has not been detected in orbital tissues (121). Cell-mediated immunity appears to play a major role in the pathogenesis of GO. The extraocular muscles and orbital connective tissues are infiltrated by lymphocytes and macrophages. The lymphocytes are predominantly CD4⫹ and CD8⫹ T cells with a few B cells. Regardless of the target antigen that causes the lymphocytic infiltration, the proximal events in the pathogenesis of GO appear to be cytokine-mediated activation of orbital fibroblasts, secretion of GAGs by these cells, and ultimately, fibrosis. Immunohistochemical studies have demonstrated the presence of the cytokines, interferon-gamma (IFN-␥), tumor necrosis factor-␣ (TNF-␣), and interleukin-1␣ (IL1␣), in the cytoplasm of orbital-infiltrating mononuclear

Hyperthyroidism

cells and in adjacent orbital connective tissue from patients with early active GO (127). These findings support that T cells and antigen-presenting cells within these tissues are activated. Because transplacental passage of maternal thyroid-stimulating antibodies does not appear to cause infiltrative ophthalmopathy in neonates, and the presence of antibodies to orbital antigens is inconsistently related to eye disease, humoral autoimmunity appears to play at most a secondary role in the pathogenesis of GO (11). Because ophthalmopathy is relatively mild and selflimited in the vast majority of affected children and adolescents, specific treatment is usually not necessary. In general, eye findings improve in association with control of the hyperthyroidism. Occasionally, local measures may be used to treat symptoms. For example, eye drop or ointment preparations containing methylcellulose may be necessary to prevent corneal drying. Sleeping with the head elevated may help to reduce chemosis and periorbital edema. Other forms of treatment, such as oral corticosteroids, orbital irradiation, and surgical decompression, are rarely indicated in children and should be reserved for those with severe ophthalmopathy.

XI.

LABORATORY EVALUATION

The laboratory evaluation of thyrotoxicosis should be guided by the patient’s clinical presentation as determined by the medical history and physical examination. In all causes of thyrotoxicosis, except for TSH-induced hyperthyroidism, the serum TSH level will be undetectable or very suppressed using modern second- or third- generation TSH assays. For the child or adolescent presenting with obvious signs and symptoms of Graves’ disease, including a soft, diffusely enlarged, smooth goiter and proptosis, only a few laboratory tests are needed. In addition to the undetectable serum TSH, an elevated free T4 (or free T4 index) and the presence of TSHrAb (either TBII or TSI) substantiate the clinical diagnosis. When antithyroid drugs are selected as therapy, a baseline complete blood cell count with differential white blood count should be obtained: leukopenia occurs in untreated thyrotoxicosis and granulocytopenia is an occasional toxic reaction to antithyroid drugs. In less severe presentations, however, further laboratory tests may be necessary. Serum T3 levels will be elevated in nearly all patients with Graves’ disease. Measurement of serum total and/or free T3 levels can be useful in the occasional patient with early Graves’ disease who presents with an undetectable TSH but a normal serum free T4 level. For the patient who presents with symptoms of thyrotoxicosis and a firm, mildly tender, asymmetric goiter, the radioiodine uptake (RAI-U; Table 5) can differentiate Graves’ disease from either the toxic thyroiditis of Hashimoto’s disease or subacute thyroiditis (128, 129). Fur-

383 Table 5 Classification of Thyrotoxicosis by Radioiodine Uptake (RAI-U) RAI-U usually elevated: Graves’ disease Toxic adenoma Toxic multinodular goiter Familial nonautoimmune hyperthyroidism TSH-induced hyperthyroidism Trophoblastic disease RAI-U typically low: Subacute thyroiditis Toxic thyroiditis of Hashimoto’s disease Thyrotoxicosis factitia Iodine-induced hyperthyroidism Metastatic thyroid carcinoma

thermore, the RAI-U also can help to differentiate Graves’ disease from thyrotoxicosis factitia. Graves’ disease is the most common cause of thyrotoxicosis during pregnancy (4). However in the pregnant adolescent with mild symptoms of thyrotoxicosis and a normal to slightly enlarged thyroid gland, the possibility of hCG-mediated hyperthyroidism should be considered. Biochemical and clinical hyperthyroidism can occur when serum hCG levels exceed 100,000–300,000 IU/l (4). TSHrAb and autoantibodies to thyroglobulin and/or thyroid peroxidase are present in the majority of patients with Graves’ disease and reflect the autoimmune nature of the disorder. However, none of these autoantibodies is specific to Graves’ disease. Although almost all hyperthyroid patients with serum TSHrAb will have Graves’ disease, these antibodies also can be detected in patients with Hashimoto’s thyroiditis (27, 46, 47) and in patients with subacute thyroiditis (130). Thyroglobulin and/or thyroid peroxidase antibodies are present in the majority of patients with Hashimoto’s thyroiditis (131) and have been reported in several patients with subacute thyroiditis (130, 132) and a few patients with familial nonautoimmune hyperthyroidism (88). Therefore, by themselves, none of these antibodies should be considered as absolute proof of Graves’ disease in patients with thyrotoxicosis. Several studies have suggested that the recently cloned and characterized Na⫹/I⫺ symporter (NIS) may represent an important autoantigen in Graves’ disease (133). Although earlier studies (based on relatively small sample sizes) suggested that NIS autoantibodies might be present in up to 60–80% of Graves’ sera (133), a more recent study evaluating 177 Graves’ sera found these antibodies in only 5–10% of the samples (134). Furthermore, NIS antibodies also are present in 15–20% of sera from patients with Hashimoto’s thyroiditis (133, 134). At present, the functional roles, if any, that these antibodies play in either Graves’ disease or Hashimoto’s disease remain unclear. Although assays are not yet available for

384

Dallas and Foley

routine clinical use, based on current data, the measurement of NIS antibodies does not appear to offer any additional diagnostic benefit for patients with Graves’ disease. More detailed discussions of clinical features and laboratory studies that can be used to evaluate patients with other causes of thyrotoxicosis and to differentiate these disorders from Graves’ disease are presented in the appropriate subsections of this chapter.

XII. A.

Table 6

Toxic Side Effects of Antithyroid Drug Therapy

Elevated liver enzymes Granulocytopenia Dermatitis, urticaria Arthralgia, arthritis Lupus-like syndrome Lymphadenopathy Peripheral neuritis Fever Hepatitis

Nausea, abdominal discomfort Edema Conjunctivitis Thrombocytopenia Hypoprothrombinemia Toxic psychosis Sensorineural hearing loss Loss of taste sensation Disseminated intravascular coagulation

PROGNOSIS AND TREATMENT Introduction and Overview

The clinical course of Graves’ disease is variable and unpredictable. However, the hyperthyroidism in untreated Graves’ disease usually persists and progresses unless the thyroid gland has limited responsiveness as a result of coexisting chronic lymphocytic thyroiditis. Therefore, therapeutic intervention is recommended for all patients with active Graves’ disease. Despite recent advances in our knowledge of the TSH receptor and TSHrAbs, none of the currently available treatments is specifically directed against the underlying immunological abnormality that causes Graves’ disease. The three acceptable methods of therapy (antithyroid drugs, radioiodine ablation, and subtotal/total thyroidectomy) merely interrupt the disease process at the level of the thyroid gland, although treatment with thioureas has been reported to reduce levels of TSHrAb (135). The treatment of Graves’ disease in children and adolescents remains controversial. Although all three therapeutic modalities represent effective treatments for Graves’ hyperthyroidism, each has specific advantages and disadvantages that should be addressed when individual treatment plans are developed for affected individuals. The antithyroid drugs are generally well tolerated, their inhibitory effects on the thyroid are completely reversible, and some patients treated with them will achieve longterm or permanent remission (136). Therefore, antithyroid drug treatment will allow some children to avoid surgery or exposure to radioiodine. However, antithyroid drugs usually take 4–8 weeks initially to control hyperthyroidism, and a treatment period of several years is typically required to achieve a long-term remission. During this prolonged treatment period, noncompliance and drug toxicity (Table 6) can complicate patient management. Furthermore, relapse of hyperthyroidism frequently occurs following discontinuation of therapy (136). As yet, no reliable clinical, biochemical, immunological or genetic factors have been identified that allow absolute prediction of those patients likely to do well, or poorly, in achieving long-term remission with antithyroid drug therapy (137). Radioiodine (RAI) represents the easiest form of treatment, and the majority of patients can be successfully treated with a single oral dose (136). However, RAI ther-

apy is absolutely contraindicated during pregnancy and breastfeeding (137). Although hospitalization is not required, patients receiving RAI are usually advised to limit close contact with others and properly dispose of their urine for several days following treatment. RAI therapy is also slow to control hyperthyroidism; it usually takes 6–18 weeks to have its full effects on the thyroid. Some patients may require multiple doses of RAI to treat their disease adequately. Although RAI is generally well tolerated, radiation thyroiditis may occur. This is characterized by a transient increase in serum thyroid hormone levels with, occasionally, a worsening of hyperthyroid symptoms and thyroid gland tenderness. With ablative dosages, the thyroid gland will shrink and hypothyroidism will occur in the majority of patients. In rare cases parathyroid dysfunction may develop after RAI therapy (138). Concerns regarding the potential long-term carcinogenic and genetic risks of RAI in children/adolescents continue to linger (136). Surgical therapy represents the most rapidly effective form of treatment. Following at least 10–14 days of preoperative preparation with antithyroid drugs, stable iodine (e.g., SSKI or Lugol’s solution), and ␤-adrenergic blockers, either subtotal or total thyroidectomy can be performed. Both are complicated procedures, and the longterm cure rates and the incidence of complications depend in large part on the skill and experience of the surgeon. Due to the continued reliance on antithyroid drugs and the increasing acceptance of RAI as primary therapies for juvenile Graves’ disease, clinicians now infrequently recommend surgery for children with Graves’ disease. However, clinical indications for surgical therapy still exist. These include the patient with a very large goiter; the patient who fails to respond to medical treatment and refuses RAI; the very young patient (i.e., 25% of normal children (76). Trousseau’s sign is evoked by a sphygmomanometer cuff on the upper arm when inflated to above the systolic pressure for up to 3 min. The sensory and motor manifestations of tetany develop to a typical carpal spasm within 2 min. In the mildest cases the patient can overcome the spasm. In the severest, not even the examiner can overcome it. Only the severe grade of the sign is abnormal with certainty, since the milder grade occurs in a small percentage of normal subjects. The sign depends on induction of ischemia of the ulnar nerve. c. Seizures. Seizures resembling epilepsy occur. These are of two distinct types. First, as hypocalcemia lowers the threshold for pre-existing subclinical epilepsy, epileptic seizures of any type may occur (78). The other type consists of generalized tetany followed by prolonged tonic spasms. It may be preceded by the sensory symptoms of tetany. During the seizure there may be tongue biting, loss of consciousness, incontinence, and postictal confusion. Hypocalcemia is frequently associated with characteristic changes in the EEG (79); in severe hypocalcemia irregular, sharp spike-and-wave patterns may

432

Perheentupa

appear. These changes may not disappear for some days after restoration of normocalcemia, and abnormal background activity may continue for several weeks. 2.

Other

a. Basal Ganglion Calcification and Extrapyramidal Signs. In patients with HP or, especially, PHP untreated for many years, small irregular calcifications may be seen in the basal ganglia in skull radiographs, and particularly on computed tomographic scans (80). These lesions may cause various extrapyramidal signs, including choreoathetosis, dystonic spasms, and classic parkinsonism. b. Papilledema and Raised Intracranial Pressure. In longstanding untreated HP there may be swelling of the optic discs. This may occur within as little as 2 weeks after the onset of HP as seen following thyroid surgery. It is moderate in degree (70%) component. In 23 of 24 patients serum PTH levels were inappropriately low or undetectable, but in one levels were high as measured by N-terminal assay but undetectable by carboxyterminal assay (217). No PTG was found at the one autopsy that has been reported (217). Other frequent features are macrocephaly, absent diploid space in calvarium, delayed closure of the anterior fontanelle, dysmorphic face, and eye abnormalities (microphthalmia, hyperopia, papillary pseudoedema) (217–220). Micro-orchidism is com-

442

Perheentupa

mon, with suspected subfertility. The short stature was short-limbed in three families and proportional in the others.

D.

Other Syndromes

Among 212 cases collected from literature of the KearnsSayre syndrome associated with a distinct defect of the mitochondrial genome, 14 had HP. Four of these patients were hypomagnesemic, five had hypogonadism, four had diabetes mellitus, and two had hypothyroidism. These associated endocrinopathies were not more prevalent than in the non-HP patients (221). Two brothers have been described with a probable Xlinked recessive syndrome with congenital lymphedema of all limbs and pulmonary lymphangiectasia, HP, nephropathy, dysmorphism (medial flare of eyebrows, broad nasal bridge with lateral displacement of the inner canthi, hypertrichosis of the face and forehead, short nail beds, brachydactyly, and an increased carrying angle), prolapsing mitral valve, and brachytelephalangy. One of them had cataracts and the other dry itchy skin (222). In one family six members in three generations had autosomal dominant HP associated with short stature and premature osteoarthritis; in at least two of them HP appeared in childhood (223). Single cases with HP have been observed in association with the Dubowitz syndrome (MIM 223370; 224, 225), Hallermann-Streif syndrome (226, 227), Mulibrey nanism (MIM 253250; 228), and Silver-Russel syndrome (MIM 180860; 229).

E.

Other Congenital Isolated PTH Deficiency

Isolated PTG hypoplasia (also termed transient congenital HP or transient congenital PTG dysplasia; 230, 231) may become manifest as late neonatal tetany, or may not appear until the age of several weeks. Calcemia is then usually normalized within weeks or months. However, these patients may have permanent latent HP. Tetany may recur during a hypocalcemic stress, and permanent HP may occur after several years (161, 224, 232, 233).

XIII.

TRANSIENT HYPOPARATHYROIDISM

HP limited to the neonatal period is discussed in Chapter 21.

A.

not be predicted from total Ca. As a group, these 26 patients were more critically ill than the rest; 17 had inappropriately low plasma PTH level (234). No information was given on magnesemia, although hypomagnesemia is very common in critically ill patients (236). According to others, hypocalcemia in critically ill children was often associated with hypercalcitoninemia (237) or hypermagnesemia (238). These dysmineralemias seem to predict high mortality (234, 238) and their correction may improve the outcome. Children with severe burns may develop hypocalcemia, Mg depletion, HP, and renal resistance to PTH infusion. Fourteen sequentially recruited children with a burn of at least 40% of total body surface area were given a urinary Mg retention test a median of 20 days after the burn. Seven of them remained Mg depleted, which was not attributable to the burn size or to time from burn to study, or combined enteral and parenteral Mg intake. Both the Mg-depleted and the nondepleted group had low intact serum PTH levels in relation to serum Ca2⫹ concentration, indicating persistent HP. Thus, not the Mg depletion but rather a reduced set point for Ca suppression of PTH secretion was concluded to be the chief cause of the persistent HP (239). In an experiment, sheep were subjected to a 40% total body surface area burn or sham burn receiving anesthesia and fluid resuscitation only. The burned sheep were hypocalcemic and hypomagnesemic compared with the sham-burned controls. In their PTGs and kidneys the CaR mRNA was increased by 50% with a corresponding increase in the intensity of CaR immunoreactivity associated with the cell surface in the PTGs. These findings are consistent with upregulation of the parathyroid CaR and a related decrease in the set point for Ca suppression of PTH secretion that may contribute to the reported postburn HP and hypocalcemia (240).

B.

Maternal Hyperparathyroidism

HP is common in infants born to hyperparathyroid mothers; the maternal disease is often undiagnosed. Symptoms usually appear within the first 2 weeks, but may be delayed (241). Complete recovery is the rule, but the condition may be prolonged, and even permanent (242). It is presumed that this HP develops because of suppression of the fetal PTG by fetal hypercalcemia maintained by excessive placental transfer of Ca from the hypercalcemic mother.

Critical Illness

Hypocalcemia is frequently associated with critical illness in children (153–155), and some of these children have PTH deficiency (234, 235). Of 145 patients admitted to a pediatric intensive care unit (53 after major surgery, 92 for acute medical problems) 71 had subnormal total serum Ca. Subnormal serum Ca2⫹ was observed in 26 of them; but many others presumably had it because Ca2⫹ could

C.

Magnesium Depletion

HP is a frequent manifestation of Mg depletion. The mechanism involves impaired secretion of PTH (243, 244), target cell resistance to PTH, and independent disturbance of the blood–bone equilibrium. Mg depletion may be due to an inborn error of metabolism, a specific defect in the intestinal absorption of Mg, called primary

Hypoparathyroidism and Mineral Homeostasis

congenital hypomagnesemia (MIM 248250; 245, 246). It usually manifests as tetany at the age of 1–4 months. Serum Mg levels are 0.2 defined as hypercalciuria. Urinary calcium excretion is relatively high in infancy. Thus, urinary calcium/creatinine ratios are higher than in older children and range between 0.2 and 0.7 (71, 72). If suspected, hyperparathyroidism should be confirmed by measurement of circulating PTH levels. If PTH levels are normal when measured using two-site intact PTH assays, measurement of PTH levels by midmolecule should also be performed when the diagnosis remains a possibility.

X.

473

IIa (84, 85), which is associated with medullary carcinoma of the thyroid and pheochromocytoma. Hyperparathyroidism typically presents during adulthood, although cases have been reported in children. MEN IIb (MEN III) is not associated with primary hyperparathyroidism, although both MEN IIa and MEN IIb are caused by mutations in different domains of the rearranged during transfection (RET) proto-oncogene (86, 87). Radiation exposure may be associated with the development of hyperparathyroidism. An increased incidence of hyperparathyroidism has been reported in adult survivors of the Hiroshima atomic blast (88). It has been suggested that the incidence of hyperparathyroidism is greater three decades after head and neck radiotherapy (89, 90). Hyperparathyroidism has also been reported in a few patients treated with radioiodine for Graves’ disease (91, 92), however, with no greater frequency than that observed in the normal population (93). Primary hyperparathyroidism has been described in one infant with congenital hypothyroidism (76). Carcinoma of the parathyroid glands can present with biochemical features similar to those of primary hyperparathyroidism. Although there are very few reports of parathyroid carcinoma in children (94), parathyroid carcinoma has been reported in adolescents with familial hyperparathyroidism (95, 96).

PRIMARY HYPERPARATHYROIDISM

Fewer than 100 cases of isolated primary hyperparathyroidism have been reported in children (73–78). Both parathyroid adenomas and multiglandular hyperplasia have been described. It is postulated that primary hyperparathyroidism in children represents early presentation of the sporadic form of hyperparathyroidism that typically affects adults. No clear pattern of inheritance is generally found; although several kindreds have been reported in whom primary hyperparathyroidism affects several generations (79). Hypercalcemia is usually not an indication for a parathyroidectomy in FHH, when one mutant copy of the CaSR is present. However, severe neonatal hyperparathyroidism occurs within FHH kindreds in individuals homozygous for mutations of the CaSR (22, 80, 81). In affected individuals, severe hyperparathyroidism presents within the first few days of life, with serum calcium levels as high as 15–30 mg/dl. The serum phosphate level is usually low, and the serum PTH level is elevated. Nephrocalcinosis may be present, reflecting intrauterine hypercalcemia. This is a life-threatening condition that requires emergency extirpation of the parathyroid glands. Hyperparathyroidism may also be a feature of the inherited multiple endocrine neoplasia syndromes, MEN I and MEN II, which are autosomal dominant disorders (82, 83). Hyperparathyroidism is the most common presenting feature of MEN I (97% of cases), which is also associated with tumors of the pancreas (40%) and pituitary (20%). Hyperparathyroidism may occur in 20% of cases of MEN

XI.

SECONDARY AND TERTIARY HYPERPARATHYROIDISM

Secondary and tertiary hyperparathyroidism are often seen in hypocalcemic and/or hyperphosphatemic states, such as vitamin D deficiency. An appropriate response to hypocalcemia (secondary hyperparathyroidism) may evolve into autonomous PTH secretion (tertiary hyperparathyroidism) following prolonged hypocalcemic stimulation of parathyroid gland activity. In the newborn period secondary hyperparathyroidism may be seen in children born to hypocalcemic mothers. This typically resolves within several months of birth (97, 98). We have cared for infants with transient hyperparathyroidism whose mothers did not have hypocalcemia; hypercalcemia resolved by 3 months of age. Secondary hyperparathyroidism is a classic feature of moderate to severe vitamin D-deficient rickets. Diffuse parathyroid hyperplasia has been described in these patients (99) and progression to tertiary hyperparathyroidism may occur in the setting of chronic disease. Efforts should be taken place to prevent this progression since severe parathyroid hyperplasia may not be reversible and surgical extirpation of the parathyroid glands required (61). Chronic elevation of serum phosphate levels may be the most common cause of secondary hyperparathyroidism in children. The inability of the kidneys to excrete phosphate accounts for this phenomena (100, 101). This scenario is especially troublesome for a skeletal system

474

Rivkees and Carpenter

already at risk for metabolic bone disease. Thus, parathyroid function should be routinely monitored during chronic renal failure, and parathyroidectomy is needed in the setting of irreversible hyperparathyroidism (101–103). The regulation of parathyroid hormone secretion in X-linked hypophosphatemic rickets (XLH) is complex. Although earlier descriptions of the disorder suggest that circulating levels of PTH are normal prior to the initiation of therapy (104), we have found that many patients with XLH have elevated PTH levels prior to treatment. The recent demonstration that PHEX (the mutated gene in XLH) is expressed in parathyroid glands (105) raises the possibility that disordered regulation of PTH secretion may be part of the XLH phenotype. Phosphate therapy exacerbates the propensity of the parathyroid glands to secrete PTH in patients with XLH, even in the absence of hyperphosphatemia or hypocalcemia. Furthermore, this secondary hyperparathyroidism is a very frequent feature of phosphate-treated patients and may evolve into tertiary hyperparathyroidism. Hyperparathyroidism in XLH is seen more commonly when dosages of phosphate exceed 4 g/day elemental phosphorus (there are about 0.25 g of elemental phosphorus per g of phosphate). Secondary hyperparathyroidism also occurs when lower dosages of phosphorous are used without sufficient calcitriol (61, 106). Thus, phosphate should not be used as solitary treatment of XLH. Routine measurement of PTH levels in individuals with XLH is an important aspect of disease management, and is critical for making appropriate dosage adjustments in a timely manner. Adjunctive therapy with 24,25 dihydroxyvitamin D also mitigates secondary hyperparathyroidism in XLH and improves skeletal mineralization (27). Thus, improvement in parathyroid status may improve the long-term skeletal outcome of the disease.

XII.

COMPLICATIONS OF HYPERPARATHYROIDISM AND HYPERCALCEMIA

The adverse effects of hyperparathyroidism are related to excessive bone resorption and hypercalcemia. Excessive PTH activity leads to loss of skeletal mineral content, microarchitectural defects, and osteopenia (107). In adults with hyperparathyroidism, demineralization may be recognized on standard radiographs (56). Dual-energy x-ray absorptiometry is a much more sensitive means of detecting these changes (108). Hyperparathyroidism affects the kidneys in several ways. Hypercalcemia can directly reduce the glomerular filtration rate. Longstanding hypercalcemia may lead to deposition of calcium in the tubules, especially during hyperphosphatemia, resulting in nephrocalcinosis (109, 110). Nephrocalcinosis can be detected by ultrasound, which should be performed in individuals with hyperparathyroidism (111). Nephrolithiasis is well described in adults

with hyperparathyroidism (56), yet is unusual in children with hyperparathyroidism. Calcium levels in excess of 15 mg/dl also may result in polyuria secondary to nephrogenic diabetes insipidus. Hypercalcemia also affects other systems. Hypercalcemia may induce increased cardiovascular tone and hypertension (112). High calcium levels may lead to heart block and shortening of the ST segment (112). The central nervous system is also sensitive to the effects of calcium at high levels (113). Impaired mentation and convulsions may occur at levels above 15 mg/dl (113). Muscle weakness and hyporeflexia may occur (114). Gastric ulcers and constipation may reflect hypercalcemia (115). Anorexia may attend hypercalcemia. Patients are at increased risk for pancreatitis (116, 117). We have recently cared for a child who presented with recurrent pancreatitis associated with hypercalcemia (11–12 mg/dl) secondary to a parathyroid adenoma.

XIII.

TREATMENT OF HYPERPARATHYROIDISM AND HYPERCALCEMIA

Acute therapy of hypercalcemia is indicated for symptomatic individuals or when the total calcium exceeds 13 mg/dl (56, 118, 119). Treatment with intravenous saline (3000 ml/m2/day; 200–400 ml/kg/day) and furosemide (1 mg/kg every 4–6 h) lowers calcium levels within hours (120). After correction of acute hypercalcemia, a highsodium diet promotes continued renal calcium excretion. Oral furosemide therapy (1–2 mg/kg/day divided in two or three divided doses) may be of benefit. Adjunctive therapy with prednisone is usually not effective management of hypercalcemia due to hyperparathyroidism (44). Calcitonin may initially lower serum calcium levels, but patients often become refractory to the medication after several dosages. Bisphosphonates, which inhibit bone resorption, can be used to manage severe hypercalcemia over the short term, but are not recommended as a definitive treatment. Oral or intravenous phosphate therapy can lower circulating calcium levels (56), but leads to precipitation of calcium and phosphate salts in the vascular system and kidneys and is no longer recommended. Calciomimetic agents that act to inhibit PTH secretion by activating CaSR hold promise as a therapy for parathyroid hyperplasia (121). They are not yet available for widespread clinical use to treat hypercalcemia of any cause. Selective ablation of parathyroid glands by embolization has been shown to be effective only for some ectopic parathyroid glands (122). Surgery is the definitive cure for hyperparathyroidism. If isolated adenomas are detected, these should be removed. In the setting of multigland parathyroid hyperplasia, our usual approach is to remove three and one-half or four glands. In adults, treatment of the asymptomatic

Hyperparathyroidism in Children

patient with hyperparathyroidism has been the subject of debate (123, 124). Surgery is recommended for asymptomatic individuals with evidence of demineralization, nephrolithiasis, or nephrocalcinosis (118, 119, 123, 124). However, observation may be recommended for individuals without evidence of complications, as long as renal function, bone density, and gastrointestinal status is assessed regularly (118, 119, 123, 125, 126). Prolonged observation is generally not recommended for children with hyperparathyroidism. Given the longevity of the course in children, progressive skeletal mineral loss, and potential consequences of exposure of the kidneys to long-term hypercalcemia, we choose prompt surgery for patients in this age group. Preoperative localization of hyperactive parathyroid tissue is a challenging undertaking (118, 119). High-resolution ultrasonography, computed axial tomography, magnetic resonance imaging, and radionuclide scanning have been used to localize parathyroid tissue (127–130). Increasingly we are impressed with the ability of highresolution Doppler ultrasound to localize parathyroid adenomas. Arteriography and selective venous sampling have been used to localize abnormal parathyroid tissue (131), but successes with this technique are highly variable. Rapid PTH assays in the intraoperative setting are a new and important means for localizing hyperfunctioning parathyroid tissue (132, 133). The surgeon is able to monitor acutely the effects of gland removal and can be reassured regarding the removal of the abnormal tissue. After removal of the pathological parathyroid gland(s), PTH levels will promptly fall. If PTH levels do not fall after a gland is removed, additional parathyroid tissue must be identified and resected.

XIV.

MANAGEMENT AFTER PARATHYROIDECTOMY

After successful resection of hyperactive parathyroid tissue, serum calcium levels may rapidly fall. Intraoperatively, a Chevostek’s sign may be elicited by tapping over the facial nerve in the temporal–mandibular region in hypocalcemic patients. Laryngospasm may occur. Management of postoperative hypocalcemia may require intravenous infusions of calcium if symptoms are present or hypocalcemia is severe. Our usual goal is to maintain serum calcium in the lower range of normal using 30–50 mg/kg/day elemental calcium. When a subtotal parathyroidectomy is performed, the remaining parathyroid tissue that was previously suppressed by hypercalcemia will become functional within 30 h after surgery (134). Thus, calcium levels usually stabilize within 48 h after surgery. If hypocalcemia persists beyond the second postoperative day, oral calcitriol therapy should be started (0.025–0.5 ␮g twice per day). This potent vitamin D metabolite has a rapid onset of action and increases intestinal

475

calcium absorption. The dosage may be advanced until serum calcium levels stabilize. When serum calcium levels are stable and intravenous therapy is no longer needed, the calcitriol dosage can be gradually reduced. Adequate dietary calcium must also be provided for calcitriol to increase calcium levels. Thus, oral calcium supplementation is useful in this setting, since few children and adolescents have adequate dietary calcium intake. We provide up to 1g elemental calcium per day, divided in three doses. Care should also be taken to avoid hypercalcemia during vitamin D therapy, because single episodes of hypercalcemia can induce permanent renal damage in children. If the serum magnesium concentration is low (0.02), it was possible to stop intravenous therapy within a few weeks.

XV.

SUMMARY

Childhood primary hyperparathyroidism is a rare disorder that may present in an extremely severe form in neonates, sporadically in children, or as part of MEN syndromes. Secondary and tertiary hyperparathyroidism may occur in children with chronic hypocalcemia such as in vitamin D deficiency, or in renal disease, accompanied by hyperphosphatemia. Another condition that results in secondary hyperparathyroidism is X-linked hypophosphatemic rickets. The constellation of hypercalcemia, hypophospha-

476

Rivkees and Carpenter

temia, and renal phosphate wasting suggests PTH excess. By measuring PTH levels, hyperparathyroidism can be diagnosed, but requires careful differentiation from FHH. Long-term hyperparathyroidism is likely to lead to skeletal demineralization and renal damage. Thus, surgery is usually indicated for pediatric patients with hyperparathyroidism rather than observation. Children with demineralization and bone disease may be at risk for hungry bone syndrome postoperatively. The child with significant chronic hypocalcemia following parathyroidectomy is best managed with calcitriol and provision of adequate oral calcium.

16.

17.

18.

19.

REFERENCES 1. 2. 3. 4. 5.

6.

7.

8. 9.

10.

11. 12. 13. 14. 15.

Wolfe HJ. The anatomy of the parathyroids. In: DeGroot LJ, ed. Endocrinology. Philadelphia: WB Saunders, 1989: 844–847. Dekker A, Dunsford HA, Geyer SJ. The normal parathyroid gland at autopsy: the significance of stromal fat in adult patients. J Pathol 1979; 128:127–132. Christie AC. The parathyroid oxyphil cells. J Clin Pathol 1967; 20:591–602. Moore KL. The Developing Human. Philadelphia: WB Saunders, 1973. Spiegel AM, Marx SJ, Doppman JL, et al. Intrathyroidal parathyroid adenoma or hyperplasia. An occasionally overlooked cause of surgical failure in primary hyperparathyroidism. JAMA 1975; 234:1029–33. Chisaka O, Capecchi MR. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature 1991; 350:473– 479. Levy-Mozziconacci A, Lacombe D, Leheup B, Wernert F, Rouault F, Philip N. [Microdeletion of the chromosome 22q11 in children: apropos of a series of 49 patients]. Arch Pediatr 1996; 3:761–768. Trump D, Dixon PH, Mumm S, et al. Localisation of X linked recessive idiopathic hypoparathyroidism to a 1.5 Mb region on Xq26-q27. J Med Genet 1998; 35:905–909. Thakker RV, Davies KE, Whyte MP, Wooding C, O’Riordan JL. Mapping the gene causing X-linked recessive idiopathic hypoparathyroidism to Xq26-Xq27 by linkage studies. J Clin Invest 1990; 86:40–45. Tengan CH, Kiyomoto BH, Rocha MS, Tavares VL, Gabbai AA, Moraes CT. Mitochondrial encephalomyopathy and hypoparathyroidism associated with a duplication and a deletion of mitochondrial deoxyribonucleic acid. J Clin Endocrinol Metab 1998; 83:125–129. Burton PB, Moniz C, Quirke P, et al. Parathyroid hormone-related peptide: expression in fetal and neonatal development. J Pathol 1992; 167:291–296. Naylor SL, Sakaguchi AY, Szoka P, et al. Human parathyroid hormone gene (PTH) is on short arm of chromosome 11. Somatic Cell Genet 1983; 9:609–616. Vasicek TJ, McDevitt BE, Freeman MW, et al. Nucleotide sequence of the human parathyroid hormone gene. Proc Natl Acad Sci USA 1983; 80:2127–2131. Naveh-Many T. Post-transcriptional regulation of the parathyroid hormone gene by calcium and phosphate. Curr Opin Nephrol Hypertens 1999; 8:415–419. Silver J, Naveh-Many T. Regulation of parathyroid hor-

20.

21.

22. 23. 24.

25. 26.

27.

28. 29. 30. 31. 32. 33. 34.

mone synthesis and secretion. Semin Nephrol 1994; 14: 175–194. Orloff JJ, Reddy D, de Papp AE, Yang KH, Soifer NE, Stewart AF. Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions. Endocr Rev 1994; 15:40–60. Brown EM, Pollak M, Hebert SC. Sensing of extracellular Ca2⫹ by parathyroid and kidney cells: cloning and characterization of an extracellular Ca(2⫹)-sensing receptor. Am J Kidney Dis 1995; 25:506–513. Brown EM, Wilson RE, Thatcher JG, Marynick SP. Abnormal calcium-regulated PTH release in normal parathyroid tissue from patients with adenoma. Am J Med 1981; 71:565–570. Nussbaum SR, Potts JT, Jr. Immunoassays for parathyroid hormone 1–84 in the diagnosis of hyperparathyroidism. J Bone Miner Res 1991; 6 Suppl 2:S43–50; discussion S61. Brown EM, Pollak M, Chou YH, Seidman CE, Seidman JG, Hebert SC. Cloning and functional characterization of extracellular Ca(2⫹)-sensing receptors from parathyroid and kidney. Bone 1995; 17:7S-11S. Yamaguchi T, Chattopadhyay N, Brown EM. G proteincoupled extracellular Ca2⫹ (Ca2⫹o)-sensing receptor (CaR): roles in cell signaling and control of diverse cellular functions. Adv Pharmacol 2000; 47:209–253. Pollak MR, Seidman CE, Brown EM. Three inherited disorders of calcium sensing. Medicine (Baltimore) 1996; 75:115–123. Anast CS, Mohs JM, Kaplan SL, Burns TW. Magnesium, vitamin D, and parathyroid hormone. Lancet 1973; 1: 1389–1390. Sherwood LM, Mayer GP, Ramberg CF Jr, Kronfeld DS, Aurbach GD, Potts JT Jr. Regulation of parathyroid hormone secretion: proportional control by calcium, lack of effect of phosphate. Endocrinology 1968; 83:1043–1051. Rodriguez M, Almaden Y, Hernandez A, Torres A. Effect of phosphate on the parathyroid gland: direct and indirect? Curr Opin Nephrol Hypertens 1996; 5:321–328. Silver J, Yalcindag C, Sela-Brown A, Kilav R, NavehMany T. Regulation of the parathyroid hormone gene by vitamin D, calcium and phosphate. Kidney Int Suppl 1999; 73:S2–7. Carpenter TO, Keller M, Schwartz D, et al. 24,25 Dihydroxyvitamin D supplementation corrects hyperparathyroidism and improves skeletal abnormalities in X-linked hypophosphatemic rickets—a clinical research center study. J Clin Endocrinol Metab 1996; 81:2381–2388. Endres DB, Villanueva R, Sharp CF Jr, Singer FR. Measurement of parathyroid hormone. Endocrinol Metab Clin North Am 1989; 18:611–629. Woodhead JS. The measurement of circulating parathyroid hormone. Clin Biochem 1990; 23:17–21. Marcus R. Laboratory diagnosis of primary hyperparathyroidism. Endocrinol Metab Clin North Am 1989; 18:647– 658. Thode J. Ionized calcium and cyclic AMP in plasma and urine. Biochemical evaluation in calcium metabolic disease. Scand J Clin Lab Invest Suppl 1990; 197:1–45. Cooper KL. Radiology of metabolic bone disease. Endocrinol Metab Clin North Am 1989; 18:955–976. McAfee JG. Radionuclide imaging in metabolic and systemic skeletal diseases. Semin Nucl Med 1987; 17:334– 349. Segre GV, Abou-Samra AB, Juppner H, et al. Character-

Hyperparathyroidism in Children

35. 36.

37.

38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49.

50. 51.

52.

53.

ization of cloned PTH/PTHrP receptors. J Endocrinol Invest 1992; 15:11–17. Juppner H. Receptors for parathyroid hormone and parathyroid hormone-related peptide: exploration of their biological importance. Bone 1999; 25:87–90. Schipani E, Langman C, Hunzelman J, et al. A novel parathyroid hormone (PTH)/PTH-related peptide receptor mutation in Jansen’s metaphyseal chondrodysplasia. J Clin Endocrinol Metab 1999; 84:3052–3057. Karaplis AC, He B, Nguyen MT, et al. Inactivating mutation in the human parathyroid hormone receptor type 1 gene in Blomstrand chondrodysplasia. Endocrinology 1998; 139:5255–5258. Neer R. Calcium and phosphate homeostasis. In: DeGroot LJ, ed. Endocrinology. Philadelphia: WB Saunders, 1989: 927–953. Aurbach GD, Heath DA. Parathyroid hormone and calcitonin regulation of renal function. Kidney Int 1974; 6: 331–345. Bringhurst FR. Calcium and phosphate distribution, turnover, and metabolic actions. In: DeGroot LJ, ed. Endocrinology. Philadelphia: WB Saunders, 1989:805–843. Peacock M, Nordin BE. Tubular reabsorption of calcium in normal and hypercalciuric subjects. J Clin Pathol 1968; 21:353–358. Nordin BE, Hodgkinson A, Peacock M. The measurement and the meaning of urinary calcium. Clin Orthop 1967; 52:293–322. Nordin BE, Bulusu L. Plasma-phosphate and tubular reabsorption of phosphate. Lancet 1970; 2:212. Coe FL, Canterbury JM, Firpo JJ, Reiss E. Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest 1973; 52:134–142. Coe FL, Firpo JJ, Jr. Evidence for mild reversible hyperparathyroidism in distal renal tubular acidosis. Arch Intern Med 1975; 135:1485–1489. Welsh J, Weaver V, Simboli-Campbell M. Regulation of renal 25(OH)D3 1 alpha-hydroxylase: signal transduction pathways. Biochem Cell Biol 1991; 69:768–770. Suda T, Shinki T, Kurokawa K. The mechanisms of regulation of vitamin D metabolism in the kidney. Curr Opin Nephrol Hypertens 1994; 3:59–64. Langman CB. New developments in calcium and vitamin D metabolism. Curr Opin Pediatr 2000; 12:135–139. Norimatsu H, Yamamoto T, Ozawa H, Talmage RV. Changes in calcium phosphate on bone surfaces and in lining cells after the administration of parathyroid hormone or calcitonin. Clin Orthop 1982:271–278. Filvaroff E, Derynck R. Bone remodelling: a signalling system for osteoclast regulation. Curr Biol 1998; 8: R679–682. Norimatsu H, Wiel CJ, Talmage RV. Morphological support of a role for cells lining bone surfaces in maintenance of plasma calcium concentration. Clin Orthop 1979:254– 262. Ishii H, Wada M, Furuya Y, Nagano N, Nemeth EF, Fox J. Daily intermittent decreases in serum levels of parathyroid hormone have an anabolic-like action on the bones of uremic rats with low-turnover bone and osteomalacia. Bone 2000; 26:175–182. Brommage R, Hotchkiss CE, Lees CJ, Stancill MW, Hock JM, Jerome CP. Daily treatment with human recombinant parathyroid hormone-(1–34), LY333334, for 1 year increases bone mass in ovariectomized monkeys. J Clin Endocrinol Metab 1999; 84:3757–3763.

477 54.

55. 56. 57.

58. 59. 60.

61.

62. 63. 64. 65.

66.

67. 68. 69. 70.

71. 72. 73.

Mayer GP, Habener JF, Potts JT Jr. Parathyroid hormone secretion in vivo. Demonstration of a calcium-independent nonsuppressible component of secretion. J Clin Invest 1976; 57:678–683. Hellman P, Carling T, Rask L, Akerstrom G. Pathophysiology of primary hyperparathyroidism [in process citation]. Histol Histopathol 2000; 15:619–627. Habener JF, Potts JT. Primary hyperparathyroidism. In: DeGroot LJ, ed. Endocrinology. Philadelphia: WB Saunders, 1989:954–966. Arnold A, Staunton CE, Kim HG, Gaz RD, Kronenberg HM. Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. N Engl J Med 1988; 318: 658–662. Mallya SM, Arnold A. Cyclin D1 in parathyroid disease. Front Biosci 2000; 5:D367–371. Cryns VL, Thor A, Xu HJ, et al. Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med 1994; 330:757–761. Karges W, Jostarndt K, Maier S, et al. Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region. J Endocrinol 2000; 166:1–9. Rivkees SA, el-Hajj-Fuleihan G, Brown EM, Crawford JD. Tertiary hyperparathyroidism during high phosphate therapy of familial hypophosphatemic rickets. J Clin Endocrinol Metab 1992; 75:1514–1518. Rodd C, Goodyer P. Hypercalcemia of the newborn: etiology, evaluation, and management. Pediatr Nephrol 1999; 13:542–547. Jones KL. Williams syndrome: an historical perspective of its evolution, natural history, and etiology. Am J Med Genet Suppl 1990; 6:89–96. Meng X, Lu X, Morris CA, Keating MT. A novel human gene FKBP6 is deleted in Williams syndrome. Genomics 1998; 52:130–137. Marx SJ, Spiegel AM, Brown EM, et al. Circulating parathyroid hormone activity: familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. J Clin Endocrinol Metab 1978; 47:1190–1197. Marx SJ, Stock JL, Attie MF, et al. Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration. Ann Intern Med 1980; 92:351–356. Brown EM. Mutations in the calcium-sensing receptor and their clinical implications. Horm Res 1997; 48:199– 208. Jacobus CH, Holick MF, Shao Q, et al. Hypervitaminosis D associated with drinking milk. N Engl J Med 1992; 326:1173–1177. Holick MF, Shao Q, Liu WW, Chen TC. The vitamin D content of fortified milk and infant formula. N Engl J Med 1992; 326:1178–1181. Siperstein AE, Shen W, Chan AK, Duh QY, Clark OH. Normocalcemic hyperparathyroidism. Biochemical and symptom profiles before and after surgery. Arch Surg 1992; 127:1157–1166; discussion 1161–1163. Simeckova A, Zamrazil V, Cerovska J. Calciuria, magnesiuria and creatininuria—relation to age. Physiol Res 1998; 47:35–40. Sargent JD, Stukel TA, Kresel J, Klein RZ. Normal values for random urinary calcium to creatinine ratios in infancy. J Pediatr 1993; 123:393–397. Steendijk R. Metabolic bone disease in children. Clin Orthop 1971; 77:247–275.

478 74. 75.

76. 77. 78.

79. 80. 81.

82. 83. 84.

85. 86. 87. 88. 89.

90.

91. 92.

93.

Rivkees and Carpenter Girard RM, Belanger A, Hazel B. Primary hyperparathyroidism in children. Can J Surg 1982; 25:11–13. Allen DB, Friedman AL, Hendricks SA. Asymptomatic primary hyperparathyroidism in children. Newer methods of preoperative diagnosis. Am J Dis Child 1986; 140: 819–821. Holcomb GWd, Perloff LJ. Primary hyperparathyroidism in a hypothyroid child. Surgery 1990; 108:588–592. Ross AJD. Parathyroid surgery in children. Prog Pediatr Surg 1991; 26:48–59. Damiani D, Aguiar CH, Bueno VS, et al. Primary hyperparathyroidism in children: patient report and review of the literature. J Pediatr Endocrinol Metab 1998; 11:83– 86. Marx SJ, Powell D, Shimkin PM, et al. Familial hyperparathyroidism. Mild hypercalcemia in at least nine members of a kindred. Ann Intern Med 1973; 78:371–377. Blair JW, Carachi R. Neonatal primary hyperparathyroidism—a case report and review of the literature. Eur J Pediatr Surg 1991; 1:110–114. Cole DE, Janicic N, Salisbury SR, Hendy GN. Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor gene [published erratum appears in Am J Med Genet 1997 Oct 17;72(2):251–252]. Am J Med Genet 1997; 71:202–210. Kraimps JL, Duh QY, Demeure M, Clark OH. Hyperparathyroidism in multiple endocrine neoplasia syndrome. Surgery 1992; 112:1080–6; discussion 1086–1088. Phay JE, Moley JF, Lairmore TC. Multiple endocrine neoplasias. Semin Surg Oncol 2000; 18:324–332. Benson L, Rastad J, Ljunghall S, Rudberg C, Akerstrom G. Parathyroid hormone release in vitro in hyperparathyroidism associated with multiple endocrine neoplasia type 1. Acta Endocrinol (Copenh) 1987; 114:12–17. Benson L, Ljunghall S, Akerstrom G, Oberg K. Hyperparathyroidism presenting as the first lesion in multiple endocrine neoplasia type 1. Am J Med 1987; 82:731–737. Komminoth P. Multiple endocrine neoplasia type 1 and 2: from morphology to molecular pathology 1997. Verh Dtsch Ges Pathol 1997; 81:125–138. Eng C. RET proto-oncogene in the development of human cancer. J Clin Oncol 1999; 17:380–393. Fujiwara S, Sposto R, Ezaki H, et al. Hyperparathyroidism among atomic bomb survivors in Hiroshima. Radiat Res 1992; 130:372–378. Tezelman S, Rodriguez JM, Shen W, Siperstein AE, Duh QY, Clark OH. Primary hyperparathyroidism in patients who have received radiation therapy and in patients who have not received radiation therapy. J Am Coll Surg 1995; 180:81–87. Schneider AB, Gierlowski TC, Shore-Freedman E, Stovall M, Ron E, Lubin J. Dose–response relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab 1995; 80:254–257. Esselstyn CB, Jr., Schumacher OP, Eversman J, Sheeler L, Levy WJ. Hyperparathyroidism after radioactive iodine therapy for Graves disease. Surgery 1982; 92:811–813. Kawamura J, Tobisu K, Sanada S, et al. [Hyperparathyroidism after radioactive iodine therapy for Graves’ disease: a case report]. Hinyokika Kiyo 1983; 29:1513– 1519. Bondeson AG, Bondeson L, Thompson NW. Hyperparathyroidism after treatment with radioactive iodine: not only a coincidence? Surgery 1989; 106:1025–1027.

94. 95. 96. 97. 98.

99. 100. 101. 102.

103. 104. 105. 106.

107.

108. 109.

110. 111. 112. 113. 114.

Wang CA, Gaz RD. Natural history of parathyroid carcinoma. Diagnosis, treatment, and results. Am J Surg 1985; 149:522–527. McHenry CR, Rosen IB, Walfish PG, Cooter N. Parathyroid crisis of unusual features in a child. Cancer 1993; 71:1923–1927. Mallette LE, Bilezikian JP, Ketcham AS, Aurbach GD. Parathyroid carcinoma in familial hyperparathyroidism. Am J Med 1974; 57:642–648. Goldberg E, Winter ST, Better OS, Berger A. Transient neonatal hyperparathyroidism associated with maternal hypoparathyroidism. Isr J Med Sci 1976; 12:199–201. Ghirri P, Bottone U, Coccoli L, et al. Symptomatic hypercalcemia in the first months of life: calcium-regulating hormones and treatment. J Endocrinol Invest 1999; 22: 349–353. Steendijk R. Vitamin D and the pathogenesis of rickets and osteomalacia. Folia Med Neerl 1968; 11:178–186. Pletka PG, Strom TB, Hampers CL, et al. Secondary hyperparathyroidism in human kidney transplant recipients. Nephron 1976; 17:371–381. Hanley DA, Sherwood LM. Secondary hyperparathyroidism in chronic renal failure. Pathophysiology and treatment. Med Clin North Am 1978; 62:1319–1339. Sanchez CP, Salusky IB, Kuizon BD, Abdella P, Juppner H, Goodman WG. Growth of long bones in renal failure: roles of hyperparathyroidism, growth hormone and calcitriol. Kidney Int 1998; 54:1879–1887. Koch Nogueira PC, David L, Cochat P. Evolution of secondary hyperparathyroidism after renal transplantation. Pediatr Nephrol 2000; 14:342–346. Arnaud C, Glorieux F, Scriver C. Serum parathyroid hormone in X-linked hypophosphatemia. Science 1971; 173: 845–847. Rowe PS. The PEX gene: its role in X-linked rickets, osteomalacia, and bone mineral metabolism. Exp Nephrol 1997; 5:355–363. Glorieux FH, Marie PJ, Pettifor JM, Delvin EE. Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets. N Engl J Med 1980; 303:1023–1031. Nakaoka D, Sugimoto T, Kobayashi T, Yamaguchi T, Kobayashi A, Chihara K. Prediction of bone mass change after parathyroidectomy in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2000; 85:1901– 1907. Adami S, Braga V, Squaranti R, Rossini M, Gatti D, Zamberlan N. Bone measurements in asymptomatic primary hyperparathyroidism. Bone 1998; 22:565–570. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy. A case–control study. Ann Surg 1995; 222:402–412; discussion 412–414. Deaconson TF, Wilson SD, Lemann J Jr. The effect of parathyroidectomy on the recurrence of nephrolithiasis. Surgery 1987; 102:910–913. Verge CF, Lam A, Simpson JM, Cowell CT, Howard NJ, Silink M. Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med 1991; 325:1843–1848. Klein I, Ojamaa K. Clinical review 36: Cardiovascular manifestations of endocrine disease. J Clin Endocrinol Metab 1992; 75:339–342. Petersen P. Psychiatric disorders in primary hyperparathyroidism. J Clin Endocrinol Metab 1968; 28:1491–1495. Patten BM, Bilezikian JP, Mallette LE, Prince A, Engel

Hyperparathyroidism in Children

115. 116. 117. 118.

119.

120. 121. 122. 123. 124.

125.

126.

WK, Aurbach GD. Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med 1974; 80:182–193. Barreras RF. Calcium and gastric secretion. Gastroenterology 1973; 64:1168–1184. Bess MA, Edis AJ, van Heerden JA. Hyperparathyroidism and pancreatitis. Chance or a causal association? JAMA 1980; 243:246–247. Sitges-Serra A, Alonso M, de Lecea C, Gores PF, Sutherland DE. Pancreatitis and hyperparathyroidism. Br J Surg 1988; 75:158–160. Proceedings of the NIH Consensus Development Conference on diagnosis and management of asymptomatic primary hyperparathyroidism. Bethesda, Maryland, October 29–31, 1990. J Bone Miner Res 1991; 6 Suppl 2:S1–166. NIH conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Intern Med 1991; 114: 593–597. Watson L. Diagnosis and treatment of hypercalcaemia. Br Med J 1972; 2:150–152. Coburn JW, Elangovan L, Goodman WG, Frazao JM. Calcium-sensing receptor and calcimimetic agents. Kidney Int Suppl 1999; 73:S52–58. Doppman JL, Marx SJ, Spiegel AM, et al. Treatment of hyperparathyroidism by percutaneous embolization of a mediastinal adenoma. Radiology 1975; 115:37–42. Potts JT, Jr. Clinical Review 9: Management of asymptomatic hyperparathyroidism. J Clin Endocrinol Metab 1990; 70:1489–1493. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999; 341:1249–1255. Silverberg SJ, Bilezikian JP, Bone HG, Talpos GB, Horwitz MJ, Stewart AF. Therapeutic controversies in primary hyperparathyroidism. J Clin Endocrinol Metab 1999; 84:2275–2285. Sosa JA, Powe NR, Levine MA, Udelsman R, Zeiger

479

127. 128.

129. 130.

131.

132.

133.

134. 135.

MA. Profile of a clinical practice: thresholds for surgery and surgical outcomes for patients with primary hyperparathyroidism: a national survey of endocrine surgeons. J Clin Endocrinol Metab 1998; 83:2658–2665. Barraclough BM, Barraclough BH. Ultrasound of the thyroid and parathyroid glands. World J Surg 2000; 24:158– 165. Zwas ST, Czerniak A, Boruchowsky S, Avigad I, Wolfstein I. Preoperative parathyroid localization by superimposed iodine-131 toluidine blue and technetium-99m pertechnetate imaging. J Nucl Med 1987; 28:298–307. Gotway MB, Higgins CB. MR imaging of the thyroid and parathyroid glands. Magn Reson Imaging Clin North Am 2000; 8:163–182. Hiromatsu Y, Ishibashi M, Nishida H, Okuda S, Miyake I. Technetium-99m tetrofosmin parathyroid imaging in patients with primary hyperparathyroidism. Intern Med 2000; 39:101–106. Reitz RE, Pollard JJ, Wang CA, et al. Localization of parathyroid adenomas by selective venous catheterization and radioimmunoassay. N Engl J Med 1969; 281:348– 351. Wilkinson RH, Jr., Leight GS, Jr., Garner SC, BorgesNeto S. Complementary nature of radiotracer parathyroid imaging and intraoperative parathyroid hormone assays in the surgical management of primary hyperparathyroid disease: case report and review. Clin Nucl Med 2000; 25: 173–178. Garner SC, Leight GS Jr. Initial experience with intraoperative PTH determinations in the surgical management of 130 consecutive cases of primary hyperparathyroidism. Surgery 1999; 126:1132–1138. Brasier AR, Wang CA, Nussbaum SR. Recovery of parathyroid hormone secretion after parathyroid adenomectomy. J Clin Endocrinol Metab 1988; 66:495–500. Brasier AR, Nussbaum SR. Hungry bone syndrome: clinical and biochemical predictors of its occurrence after parathyroid surgery. Am J Med 1988; 84:654–660.

21 Neonatal Calcium and Phosphorus Disorders Winston W. K. Koo Wayne State University, Detroit, Michigan, U.S.A.

I.

may be diminished end-organ responsiveness to hormonal regulation of Ca and P homeostasis at least during the first days after birth, although the functional capacity of the gut and kidney for Ca and P absorption and retention improves rapidly within days after birth. These issues are exaggerated in infants with heritable disorders of mineral metabolism such as extracellular calcium-sensing receptor mutations, and in infants experiencing adverse prenatal event such as maternal diabetes, intrapartum problems such as perinatal asphyxia, or postpartum complications such as multiple immature organ function with premature birth. In any case, it is important to review the physiology and molecular basis of mineral metabolism to allow a better understanding of the pathophysiology of clinical disorder. This in turn allows a more rational approach in the management of the neonate to minimize iatrogenic causes and the adverse impact of disorders of mineral homeostasis.

INTRODUCTION

The maintenance of calcium (Ca) and phosphorus (P) homeostasis requires a complex interaction of hormonal and nonhormonal factors; adequate functioning of various body systems, in particular, the renal, gastrointestinal, and skeletal systems; and adequate dietary intake. From a clinical perspective, this is reflected in the maintenance of circulating concentrations of Ca and P in the normal range and integrity of the skeleton. In the circulation, the amount of Ca and P constitutes less than 1% of the total body content; however, disturbances in serum concentrations of Ca and P are associated with disturbances of physiological function manifested by numerous clinical symptoms and signs. The skeleton, in contrast, is the major reservoir for Ca (the most abundant mineral in the body) and for P, which together with Ca forms the major inorganic constituent of bone. At all ages, 99% of total body Ca is in the skeleton as is about 89% of the total body P. Thus, the skeleton has the dual function of providing both structural and mechanical support and being a reservoir for mineral homeostasis. Disturbances in Ca and P homeostasis result in osteopenia and rickets in infants and children, and osteomalacia and osteoporosis in adults. Mechanisms to maintain Ca and P homeostasis in the neonate are the same as for children and adults. However, the newborn infant has a number of unique challenges to maintain Ca and P homeostasis during adaptation to extrauterine life and to continue the rapid rate of growth. These include an abrupt discontinuation of high rate of intrauterine accretion of Ca (>120 mg/kg/day) and P (>70 mg/kg/day) during the third trimester, a smaller skeletal reservoir available for mineral homeostasis, high requirement for Ca and P for the most rapid period of postnatal growth with an average gain in length of >25 cm during the first year, and delay in establishment of adequate nutrient intake for at least a few days after birth. There also

II.

MAINTENANCE OF CALCIUM AND PHOSPHORUS HOMEOSTASIS

A.

Circulating Calcium Concentrations

Serum Ca is found in three forms: approximately 40% is bound predominantly to albumin, approximately 10% is chelated and complexed to small molecules, and approximately 50% is ionized; complexed and ionized Ca are ultrafiltrable. Fetal circulating calcium concentrations as reflected in cord sera are higher than maternal concentrations and are indicative of active placental transfer. Cord serum total calcium concentrations (tCa) increase with increasing gestational age. Serum tCa may be as high as 3 mmol/l (conversion 1 mmol/l = 4 mg/dl) in cord blood from infants born at term, and they are significantly higher than paired material values at delivery (1–4). Serum tCa reaches a nadir during the first 2 days after birth (5–8); thereafter, it increases and stabilizes generally above 2.0 481

482

mmol/l (8 mg/dl). In infants exclusively fed human milk, the mean serum tCa increases from 2.3 to 2.7 mmol/l (9.2 to 10.8 mg/dl) over the first 6 months postnatally (9). Serum tCa in infants and children generally remains slightly higher than adult values (9–11). Normally, serum tCa in children and adults remains stable, with a diurnal range of fourfold reduction, from 31% to 7%, in frequency of LJM over this 20 year period, with a marked decrease in the proportion having moderate or severe LJM (9% vs. 35%). This reduction in the prevalence and severity of LJM was considered to be most likely the result of improved glucose control during this era (109). These study results are pertinent to the question of the importance of prepubertal duration and control of diabetes for the development of long-term microvascular complications. Even for the youngest age group studied or those with the shortest duration of diabetes, there was a marked decrease in the prevalence of LJM between the two eras, suggesting that improved control from the first years of childhood diabetes will reduce long-term complication risks. c. Skin. Necrobiosis lipoidica diabeticorum is a rarely seen pretibial lesion characterized by round or oval indurated plaques, with central atrophy and eventual ulceration. Unless they become infected, the lesions are painless. The relationship to diabetes control is uncertain, but there is an association with smoking, proteinuria, and retinopathy (110). Because these lesions do not heal well, trauma should be avoided and infection vigorously treated.

Diabetes in Child and Adolescent

621

Figure 2 Actuarial analysis of risk for development of microvascular complications with and without limited joint mobility, based on longitudinal study of 169 patients with diabetes duration ⱖ4.5 years followed from before the development of LJM or microvascular disease. (From Ref. 97.)

Lipoatrophy, seen as indentation or atrophy of the subcutaneous tissue resulting from insulin injection, has become uncommon with the generalized use of recombinant-derived human insulin. It is presumed that the impurities in animal extract insulin or the foreign nature of that insulin led to the problem. It was thought to be immune mediated, frequently following dermatomes and occurring symmetrically, distal from the actual injection sites. The lesions tended to resolve after a few years and were thought to be IgE mediated. Mild atrophy is still seen occasionally with the contemporary insulin, affecting ⬃3% of patients 1–19 years old in one study (111). Giving insulin injections around the edges of the atrophic area may be helpful. Lipohypertrophy, which always occurs at the site of injection, is a local reaction to repeated injection trauma, usually from inadequate site rotation, with scarring and decreased sensitivity to pain. The lesion can occur quite early, however, and may not be abolished by site rotation (112). Unlike lipoatrophy, lipohypertrophy continues to be frequent with improved insulin forms, present to some degree in as many as half of patients under 20 years of age (112). Both lipoatrophy and lipohypertrophy are associated with greater insulin antibody concentrations (111). The cosmetic effect is problematic, but most important is the possibility of varying absorption of insulin from areas of hypertrophy, resulting in erratic glycemic control.

2. Cataracts Cataracts occur rarely during recovery from ketoacidosis, typically in the newly diagnosed patient; they usually disappear rapidly but may persist and require surgical removal (113). In contrast to these sugar cataracts, subcapsular juvenile cataracts, associated with chronic hyperglycemia and caused by sorbitol accumulation, do not regress and always require removal. 3.

Growth Failure and Delayed Sexual Maturation Insulin has important influence on normal growth and development, largely through effects on anabolism and the growth hormone–insulin-like growth factor I (GH–IGF1) axis. Before the contemporary era of self blood glucose monitoring and more physiological insulin administration, modest growth retardation and delayed puberty were frequently seen in the pediatric diabetes clinic. Nonetheless, despite the generally nonphysiological traditional means of treating diabetes, most children with diabetes did not have serious growth or maturational delay problems. In twin pairs discordant for diabetes, the development of diabetes before the onset of puberty was associated with invariably shorter stature than that of the nonaffected twin (114). More contemporary studies demonstrate normal timing of puberty, with reduced growth and adult height even with modern therapeutic regimens, although these deviations are not substantial (115, 116).

622

Analyzing the stature of 142 patients with diabetes onset at least 2 years before puberty and with duration longer than 3 years, which provided sufficient time for a growth-inhibiting effect, Rosenbloom et al. in 1982 (117) found that 37% of 68 patients without LJM were below the 25th percentile of NCHS data. The 74 with LJM had four times the proportion with stature below the 25th percentile for age (77%), with no difference between the 31 with mild changes (involving one or two interphalangeal joints, one large joint, or only the metacarpophalangeal joints bilaterally) and those with more severe limitation (n = 43). When a similar group of children was examined in 1998, using the same criteria, only 22% of the 157 without LJM were below the contemporary NCHS 25th percentile and only 33% of the 18 with LJM were (118). Thus, contemporary diabetes control methods were resulting in improved growth along with the reduction in frequency of LJM. It will be recalled that the initial patients described with severe LJM had growth failure and delayed puberty (95, 96). Insulin deficiency is associated with manifold changes in the GH-IGF-I axis. Deficiency of portal insulin delivery to the liver results in reduced circulating GHbinding protein, the extracellular domain of the cell surface receptor for GH, with GH resistance and diminished IGF-I production (119, 120). The deficiency in insulin also results in decreased production of IGF binding protein-3 (IGFBP-3), which is the principal binding protein for circulating IGF-I, and increased production of IGFBP1 and IGFBP-2 (121). These latter BPs, unlike IGFBP-3, do not deliver their bound IGF-I to tissues. Furthermore, there is increased proteolysis of IGFBP-3, decreasing its viability in the circulation. In addition to the GH resistance, reflected in the lower concentrations of circulating GHBP, there may be postreceptor defects in GH action mediated by the insulin deficiency as well. Diminished circulating total and free IGF-I levels are associated with GH hypersecretion because of the absence of negative feedback from IGF-I. This hypersomatotropism increases glycemia and decreases insulin sensitivity, but is reversible with adequate insulin replacement (122). Growth failure and maturational delay with hepatomegaly and abdominal distention in insulin-treated children was first described by Mauriac in 1930 (123). The regression of hepatomegaly in 13 such patients, following transfer from regular insulin to protamine zinc insulin, was noted in 1936 (124). Hepatomegaly was apparently a common complication in children in the era when only short-acting insulin was available and aglycosuria was the objective. This was exemplified in a series from the Joslin Clinic in the late 1930s, of 60 youngsters with hepatomegaly, growth failure, delayed sexual maturation, and severe uncontrollable diabetes with frequent hypoglycemia and ketoacidosis (125). Improvement was associated with the change to long-acting protamine zinc insulin. There appear to be two forms of the Mauriac syndrome. In one form there is associated cushingoid obesity

Rosenbloom and Silverstein

and documented wide fluctuation between hyper- and hypoglycemia. This is suggestive of a pattern of over- and underinsulinization, which would be expected with treatment using only soluble insulin, with secondary hyperadrenalism. Periods of overinsulinization would appear to be essential for the development of obesity in this form of the syndrome, and for the induction of hyperadrenalism. In addition to the Joslin series, an impressive North American case was reported in 1962 of a 13.5-year-old girl with extremes of blood glucose from 1 to 29 mmol/ l, hypertension, edema, hepatomegaly, marked growth failure, sexual immaturity, cushingoid obesity, retarded bone age, hyperlipidemia, and osteoporosis. When her insulin dosage was reduced from 65 units a day (40 NPH/ 25 soluble) to 20 NPH daily, she had complete clearing of the abnormalities, catch-up growth, and sexual maturation (126). More recent reports are of patients with Mauriac syndrome who are not obese and without a history of alternating hypoglycemia and ketoacidosis; these patients are unmistakably inadequately insulinized continuously (127–129). Associated autoimmune problems that can result in growth failure include hypothyroidism and celiac disease. Approximately 20% of girls and 15% of boys with type 1 diabetes have evidence of autoimmune thyroid disease, determined by the presence of thyroid autoantibodies (130). Such autoantibodies should be tested for in all youngsters with type 1 diabetes. Those with positive results should have an annual determination of thyroid-stimulating hormone (TSH) level. Celiac disease has been described in 5–8% of children with type 1 diabetes; tissue transglutaminase antibodies should be sought in children with growth failure without obvious cause, even in the absence of diarrhea (131). Eating disorders are more common in children with diabetes than in the general population and should be considered in the assessment of any child who is not gaining weight or growing normally. Adolescent girls with diabetes are 2.4 times more likely than those without diabetes to have clinical eating disorders and 1.9 times more likely to have a subclinical eating disorder. Mean HbA1c levels were higher in adolescents with diabetes who had an eating disorder than in those who did not (132). 4.

Microvascular Complications

a. Pathogenesis. The hallmark of microvascular disease is thickened capillary basement membrane with alterations in membrane permeability and occlusion of small blood vessels. Several theories explain these findings. Protein glycation. It has been well documented that improved glycemic control is associated with decrease in microvascular disease and its progression (84). This suggests that excess glucose per se has deleterious effects on tissues. Some of these effects appear to be through binding to collagen by posttranslational nonenzymatic means.

Diabetes in Child and Adolescent

The amidori glycation products undergo slow (nonenzymatic) chemical rearrangements to form irreversible AGE. These AGE accumulate in the extracellular matrix and vascular intracellular proteins to cause structural tissue alterations with progressive occlusion of blood vessels. This glycation may alter the charge of the proteoglycan component of the basement membrane, resulting in leakage of negatively charged proteins from the plasma. The pores in glomeruli may also undergo alterations in size, resulting in protein leakage. The increased basement membrane thickening found in microvascular disease may be due to this glycation process, with accumulation of proteins that are not degradable. The nonenzymatic glycation of hemoglobin is an example of protein glycation and has been used as an indicator of glycemic control since the late 1970s. Amidori products may be involved in induction of strand breakage in DNA by interfering with gene transcription. This may explain the hyperglycemic memory observed in the EDIC study 4 years after the conclusion of the Diabetes Control and Complication Trials (DCCT). Although the mean HbA1c levels 4 years after conclusion of the DCCT were similar between the former intensive and former conventional groups (8.38% vs 8.45%), the rate of worsening of retinopathy by three steps or more was lower in the former intensive therapy group than in the former conventional group (84). The prevalence of micro-albuminuria (defined below) was 13.6% for the former conventional treatment group compared to 8.1% in the former intensive treatment group at study closeout; 9.9% of the former conventional group had albuminuria at years 3 and 4 compared to only 1.3% of patients in the former intensive group. Polyol pathway. Sorbitol (glucose alcohol) is formed enzymatically from glucose by the enzyme aldose reductase. The higher the blood sugar concentration, the more the sorbitol accumulation in a number of tissues, including lens and nerve. This influx of glucose into the polyol pathway is associated with decreased myoinositol uptake and decreased sodium/potassium/ATPase activity. These changes have been related to increased permeability and increased pressure and leakage in blood vessels, which may be related to the increased release of vasoconstrictive prostaglandins and decreased release of nitric oxide that mediates endothelium relaxation. The overall effect of these metabolic abnormalities is decreased vessel wall elasticity and microvascular hypertension (133). Abnormalities in the coagulation system. Elevated fibinogen levels and other antithrombotic factors may result in increased platelet stickiness. Increased prostaglandin metabolism increases coagulopathy, resulting in increased red blood cell aggregation and blockage of small capillaries (134). b. Nephropathy. Micro-albuminuria, defined as urinary albumin excretion rates of 20–200 ␮g/min or 30– 300 mg/24 h, is predictive of renal and cardiovascular

623

disease (135). Concentration above 300 mg/g is considered overt diabetic nephropathy. HbA1c levels, albumin excretion rate, low-density lipoprotein cholesterol, and body mass index were risk factors for the development of micro-albuminuria in 12.6% of 1134 men and women with type 1 diabetes aged 15–60 years during 7 years of follow-up in the EURO DIAB Prospective Complications Study (136). The prevalence and progression of micro-albuminuria and of clinical proteinuria were studied in 361 children with type 1 diabetes over the course of 12 years, with the conclusion that micro-albuminuria was rare before adolescence. The incidence of micro-albuminuria, however, increased between the ages of 10 and 18 years with 30.9% of males and 40.4% of females having one or more episodes of micro-albuminuria (137). A study of 101 normal albuminuric children and adolescents with diabetes found that 11% developed persistent micro-albuminuria during 8 years of follow-up. The odds ratio for the occurrence of micro-albuminuria with elevated vascular endothelial growth factor serum levels was 4.1, indicating that persistently increased serum levels of vascular endothelial growth factor may help to identify patients who are predisposed to persistent albuminuria (138). In Denmark, high HbA1c and high baseline albumin excretion rates predicted the development of persistent albuminuria over 6 years in 12.8% of 339 children and adolescents with type 1 diabetes (139). These results showed a higher incidence than in a large American cross-sectional survey of 702 children and adolescents with an average diabetes duration of 7.6 years. In this study, albumin excretion rate ⱖ15 ␮g/min measured on at least two of three urine collections was defined as micro-albuminuria, which increased from 5.1% to 11.6% after 10 years of diabetes duration and completion of puberty. Maternal hypertension was a significant risk factor, but patients’ BP was not, and HbA1c had a borderline effect (140). These findings contrast with other studies in which there is strong association between progression of micro-albuminuria and HbA1c values. A 4 year follow-up of 279 patients with type 1 diabetes found that the rate of progression was 1.3:100 person years in those with HbA1c levels 10%. The risk of progression rose steeply between HbA1c values of 7.5 and 8.5%, emphasizing the importance of improved glycemic control, especially of maintaining HbA1c values below 8.5% (141). The Pittsburgh Epidemiology of Diabetes Complications (EDC) study is an observational prospective study of 589 patients with onset of type 1 diabetes before the age of 17 years. Baseline low-density lipoprotein (LDL) levels ⱖ130, triglycerides ⱖ150, systolic blood pressure ⱖ130, and diastolic blood pressure ⱖ85 conferred relative

624

risks of 2.2, 3.2, 2.3, and 2.5, respectively, for developing nephropathy over 10 years (142). Homocysteine elevation has been considered a risk factor for premature cardiovascular disease. Young patients with type 1 diabetes diagnosed before the age of 12 years and with duration of disease longer than 7 years who had albumin excretion rates >70 ␮g/min had elevated homocysteine levels, indicating an association of diabetic nephropathy with premature cardiovascular disease (143). Annual testing of the urine for albumin is recommended for children from puberty and with 3–5 years of diabetes. The most convenient way to assess albuminuria is with the urinary albumin/creatinine ratio obtained on a spot urine sample. Micro-albuminuria in a single specimen may not indicate fixed disease. It is important to repeat the test on at least one other occasion in a random urine sample. A timed 12 h or 24 h urine specimen is preferable. It is also important to differentiate orthostatic proteinuria from that due to diabetic renal disease. With orthostatic proteinuria, a first void morning urine should not contain abnormal concentration of albumin, whereas a late afternoon urine often will. The DCCT demonstrated that micro-albuminuria and overt nephropathy can be delayed or prevented by intensive diabetes treatment (84). However, the United Kingdom Prospective Diabetes Study (UKPDS) and other studies have shown that blood pressure control is as important as glycemic control in prevention of nephropathy and in decreasing the rate of decline of glomerular filtration rate (GFR) in established disease (144). ACE inhibitors decrease albumin excretion rate in patients with hypertension as well as in nonhypertensive patients (145). Children and adolescents with micro-albuminuria have higher blood pressures than those with normal albuminuria (146–150). Because of this increased risk for development of nephropathy, it is essential to pay close attention to maintaining blood pressure at normal or near normal values. The treatment of choice for nephropathy has been ACE inhibition, which is effective whether or not the patient has hypertension. In addition to their antihypertensive effects, ACE inhibitors increase afferent vessel dilatation, thereby decreasing elevated intraglomerular pressure, a hallmark of diabetic nephropathy. The role of low-protein diets in treatment of micro-albuminuria has been debated for several years; there are no long-term studies in children. Studies in adults have shown that protein restriction slows the rate of decline of glomerular filtration rate (151). The albumin excretion rate has been decreased in adults with micro-albuminuria with the low protein diet (152). A low-protein diet of 0.8 g/kg body weight may be helpful in decreasing albuminuria and slowing the decline in renal function (153). Thus, high protein intake should be avoided in children with microalbuminuria. Because of the importance of adequate dietary protein in the growing child, however, protein restriction below 15% of total daily calories is not justified.

Rosenbloom and Silverstein

Adolescents should be counseled to avoid smoking: nicotine has profound vasoconstrictive effects that have been associated with progression of nephropathy in adults with type 1 diabetes (154). c. Retinopathy. Retinopathy is the most common microvascular disease in children and adolescents with type 1 diabetes. It is broadly defined to include background retinopathy, with the presence of microaneurysms only or microaneurysms and occasional dot blot hemorrhages, and proliferative retinopathy, with growth of new vessels, glia, and fibrous tissue. Fluorescein angiography is used to document severity of retinopathy by showing areas of retinal ischemia, proliferation of new blood vessels, and permeability of the retinal vessels. At diabetes diagnosis, there is increased blood flow through the retina. Early on, poor metabolic control may be associated with leakage of injected fluorescein in the vitreous (155, 156), with reversal by improved metabolic control. Anatomical disease begins as background nonproliferative changes within the retina resulting from increased vascular permeability and capillary and arteriolar occlusion. The increased permeability results in edema and the formation of hard exudates, whereas the occlusion results in formation of microaneurysms, hemorrhages, soft exudates, and capillary dropout. The growth of new blood vessels, glia, and fibrous tissue in front of the retina can result in vitreous hemorrhage and retinal detachment from shrinkage of the proliferating tissue. Although retinopathy has been reported to be present at onset of diabetes (105), it usually is not recognized before 5–10 years’ duration. By that time, 20–30% of patients will have background retinopathy, 30–50% after 10–15 years diabetes duration, and 70–80% after 15 years. The progression to blindness is not uniform and varies between 20 and 55% in different series (157). Diabetes accounts for 10–20% of all cases of blindness in adults (158). The incidence of retinopathy in 764 patients >15 years of age in the EURO DIAB prospective complications study was 56% after 7 years of follow-up. Risk factors for development of retinopathy included albumin excretion rate, cholesterol, triglycerides, and waist-to-hip ratio. In contrast to other studies, there was no association between retinopathy and blood pressure, cardiovascular disease, or smoking in this study (159). In a cross-sectional study of 725 African–Americans in New Jersey, 3% had macular edema and 20.6% had retinal hard exudates. The severity of retinopathy correlated with the presence of proteinuria, higher LDL cholesterol levels, systolic hypertension, poor glycemic control, and longer duration of disease. Hyperglycemia was strongly associated with retinopathy. Those patients whose HbA1c values were in the highest quartile were three times more likely to have retinopathy than those in the lowest quartile. Patients with renal disease were three times more likely to have retinopathy and 10 times more

Diabetes in Child and Adolescent

likely to have proliferative retinopathy than those without renal disease. Patients in the highest quartile of systolic blood pressure were three times more likely to have proliferative retinopathy than patients in the lowest quartile (160, 161). The Pittsburgh EDC found that systolic BP ⱖ120 mmHg conferred a relative risk (RR) of 1.6 for the development of proliferative retinopathy and RR was 2.7 if systolic BP ⱖ130; diastolic BP >79 mmHg conferred RR of 1.8, if ⱖ85 RR was 2.4, and if ⱖ90 mmHg, the relative risk of proliferative retinopathy was 4.6 in this population (142). Thus, it is important to maintain blood pressure near normal, because systolic blood pressures above 120 mmHg conferred increased risk of proliferative retinopathy. Homocysteine concentrations, which, as noted above, are elevated with cardiovascular disease, were higher in adolescents with proliferative retinopathy, further indicating a link between presence of microvascular complications and later onset of macrovascular disease (143). Because retinopathy is rare before puberty, it is recommended that children begin regular ophthalmological evaluation at the age of 9–10 years and following 3–5 years of diabetes. Once criteria for ophthalmological evaluation have been met, all children with diabetes should be evaluated by an ophthalmologist with serial fundus photographs at annual intervals and photocoagulation performed with the development of proliferative retinopathy. ACE inhibitors have been shown to slow the progression of retinopathy in patients with and without hypertension; thus, the presence of retinopathy is an indication for initiation of such therapy (162, 163). The use of retinal photocoagulation has markedly improved the prognosis for vision in patients with proliferative retinopathy (164, 165). Although the mechanism of action is uncertain, it is thought that the photocoagulation destroys ischemic retinal tissue, thus removing the stimulus for neovascularization. Laser therapy is also used for macular edema by destroying leaking microaneurysms and dilated capillaries. In cases of proliferative retinopathy, panretinal photocoagulation will destroy retinal tissue outside the macula and optic nerve so that the remaining retina is not ischemic and will, therefore, not produce the growth factors that result in proliferative diabetic retinopathy. The panretinal photocoagulation has the adverse effects of compromising color discrimination, visual fields, and night vision. In the case of vitreous hemorrhage or detached retina, vitrectomy can be used to remove the blood from the vitreous or to reattach a retina in the process of detaching. d. Neuropathy. Although symptomatic neuropathy is uncommonly seen in children and adolescents with diabetes, findings of sensory and autonomic motor nerve impairment can be demonstrated in young people. Peripheral neuropathy, including motor and sensory disturbances, as well as autonomic neuropathies, including gas-

625

trointestinal, cardiovascular, vasomotor instability, and hypoglycemia unawareness, have been described in childhood and adolescence. The pathogenesis of neuropathy in diabetes is likely multifactorial. The aldose reductase system is present in the lens and peripheral nerves and is responsible for metabolism of glucose to sorbitol. High glucose levels will accelerate the synthesis of sorbitol, which is not freely difusible. The sorbitol thus remains as an osmolar force within the nerve, causing swelling and possible destruction. Myoinositol, a component of neuronal cell membranes, and therefore involved in the control of neural transmission, has been found to be decreased in animals and humans with diabetes. In addition, the basement membrane of the Schwann’s cell is thickened and the vasa nervorum has capillary and arteriolar wall thickening by basement membrane accumulation, as part of the generalized microvascular disease of diabetes. Biopsy of affected nerves has shown numerous thrombosed vessels, axonal loss, and a characteristic segmental demyelination. Peripheral neuropathy. Clinical symptoms of peripheral neuropathy include numbness and paresthesias, especially pain and burning in the lower extremities, which is much worse at night. Usually a decrease in vibratory sense is the first clinical sign of neuropathy, followed by loss of ankle jerks and later by loss of pin prick sensation in a stocking distribution (166). These symptoms are commonly accompanied by anorexia with early satiety and postprandial vomiting due to gastroparesis from autonomic neuropathy. It is possible that undernutrition contributes to the neuropathy (167). The Pittsburgh EDC study found that 3% of 65 children under 18 years of age had neuropathy based on history and physical examination (168). Subclinical neuropathy, assessed by decreased motor nerve conduction velocities and sensory changes, is much more common, however, occurring in as many as 50–72% of adolescents (169). Neuropathy has been correlated with hyperlipidemia and smoking (168) and with LJM (106), but no relationship has been demonstrated between the presence of motor or sensory nerve conduction abnormalities and micro-albuminuria or retinopathy (170, 171). A recent study of 339 patients who were followed for 6 years found that neuropathy, determined by decreased vibration perception threshold, occurred in 62.5% of patients. Risk markers were male gender, age, and increased albumin excretion rate (140). The Pittsburgh EDC study found the relative risk of developing peripheral neuropathy to be 2.2 if LDL cholesterol was >129 mg/dl and 1.5 if LDL cholesterol was >99 mg/dl. Triglyceride levels >140 mg/dl likewise conferred a 1.5 relative risk. Systolic blood pressure >130 mmHg was associated with a relative risk of 4.0 and diastolic blood pressure >85 mmHg with a 2.0 relative risk. Glycemic control was not evaluated in this report (142). Improved metabolic control may result in resolution of sensory and motor nerve velocities as well as the sen-

626

sory and gastrointestinal symptoms. The DCCT showed that intensive diabetes therapy decreased clinical neuropathy by 60% (172). Peripheral motor and sensory nerve conduction velocities were significantly faster after 5 years of intensive therapy than after conventional treatment in the adolescent cohort (84). Autonomic neuropathy. Autonomic neuropathy most commonly results in gastroparesis, cardiovascular reflex loss, and hypoglycemic unawareness. Diabetic gastroparesis is associated with decreased gastric motility and delayed emptying time. Affected patients often complain of bloating and feelings of satiety following intake of small amounts of food and they often have anorexia and weight loss. There are some reports of resolution of gastroparesis with improved metabolic control (173, 174). Diagnosis can be made using technetium-coated egg in a gastric-emptying study. Use of metoclopramide or erythromycin may result in increased motility with resolution of symptoms. Diabetic diarrhea is watery, most frequent at night or following meals, and can result in fecal incontinence (175). Autonomic neuropathy of the cardiovascular system results in persistent tachycardia with a fixed heart rate in response to standing, Valsalva maneuver, and inspiration. Because of this, there is an inability to increase cardiac output resulting in hypotension with standing or exercise, and hypersensitivity to catecholamines. Patients with this neuropathy will frequently have a lower blood pressure when sitting or standing than when supine. Loss of awareness of hypoglycemia is the loss of the catecholamine-induced symptoms of sweating, tachycardia, nausea, sense of fear, and tremulousness that normally accompany severe drops in the blood glucose level. 5. Macrovascular Disease and Hyperlipidemia Diabetes mellitus is a strong risk factor for cardiovascular disease, conferring a two- to fourfold increased risk (176– 178). Risk factors that independently increase cardiovascular risk in people with diabetes include smoking, hypertension, dyslipidemia (179), renal dysfunction (179), and hyperglycemia (180–184). The Pathological Determinants of Atherosclerosis in Youth (PDAY) study of more than 3000 people who died between the ages of 15 and 34 evaluated risk factors for coronary heart disease by correlating pathological findings of fatty streaks and lipid-laden plaques to blood lipid values, smoking, hypertension, and tendency towards diabetes. There was a strong association of extent of disease with smoking, as measured by serum thiocyanate concentrations. All the aortas and about half of the right coronary arteries in the 15–19 year age group already had lesions. On average, 7% of the aortas and 12% of the right coronary arteries had raised lesions or advanced lesions of atherosclerosis at the young age of 15–19 years. The percentage of intimal surface involved with lesions in both the aorta and right coronary artery was positively associated with very-

Rosenbloom and Silverstein

low-density lipoproteins (VLDL) and LDL cholesterol, with a 5% increase in surface involvement with each 1 standard deviation increase of LDL and VLDL cholesterol levels. Conversely, a 1 standard deviation increase in HDL was associated with a 3% decrease in intimal surface involvement. HbA1c concentration was associated with more extensive and more advanced atherosclerosis in the aorta and right coronary artery, primarily in people between the ages of 25 and 34 years of age. The prevalence of raised lesions involving 5% or more of the intimal surface was twice as great in both the aorta and right coronary artery of people with hypertension throughout the entire 15–34 year age span (185). The Bogalusa heart study reported a study of 43 people aged 2–39 years who died from accidents or homicide and in whom premortem data were available. Half of the children 2–15 years of age had fatty streak lesions in the coronary arteries and 8% had fibrous plaques in their coronary arteries. These atherosclerotic lesions correlated with body mass index (BMI), systolic and diastolic blood pressure, total and LDL cholesterol, and triglycerides (186). It is thus important to address each of the risk factors for cardiovascular disease in order to decrease the risk of cardiovascular disease early in children with type 1 diabetes because the atherosclerosic process is already present in childhood. The increased cardiovascular risk in type 1 diabetes may be due to a number of factors, including endothelial dysfunction and increased arterial stiffness (187), and loss of endothelial integrity. Cardiomyopathy, consisting of interstitial fibrosis, has been described in adults with type 1 diabetes but is rare in children. The heart is subject to both microvascular disease, with microaneurysms and thickened capillary basement membrane, and macrovascular disease, with accelerated atherosclerosis. Recent studies have found higher levels of endothelin-1 (an indicator of endothelial damage) in patients with diabetes and hyperlipidemia than in controls; those patients with diabetes who had vascular complications had significantly higher endothelin-1 levels than did patients without complications. The patients with diabetes complications also had significantly higher apolipoprotein B levels than did healthy controls. Patients without microvascular or macrovascular disease had levels similar to those of controls. Thus, it is possible that the susceptibility to the development of atherosclerosis might be attributed to the relationship between elevated lipid levels and endothelin-1 (188). The Heart Outcome Prevention Evaluation (HOPE) study was a cohort study of 5545 individuals aged 55 years or more with a history of cardiovascular disease or with diabetes mellitus and at least one cardiovascular risk factor. Of the 3498 subjects in the latter category, microalbuminuria increased the relative risk of major cardiovascular events (relative risk 1.83), all-cause death (relative risk 2.09), and hospitalization for congestive heart

Diabetes in Child and Adolescent

failure (relative risk 3.23). Any degree of albuminuria was a risk factor for cardiovascular disease, the risk increasing with the albumin/creatinine ratio. The use of the ACE inhibitor ramipril resulted in significant risk reduction of 25% for myocardial infarction, 37% for cardiovascular deaths, 33% for stroke, and 24% for all causes of mortality. ACE inhibition also reduced the risk of overt nephropathy by 22% and dialysis by 15%. Ramipril not only works by decreasing blood pressure but it also has antithrombotic effects, reducing collagen-induced platelet aggregation by 18% and ADP-induced platelet aggregation by 39% (189). In addition, ACE inhibitors have effects on endothelium and fibrinolysis that are beneficial in preventing plaque rupture and subsequent thrombosis, which are two key events in the acute formation and progression of atherosclerotic disease (190). Similar to the findings of the UKPDS in adults with type 2 diabetes, the Pittsburgh EDC found a strong correlation between lipid levels and risk of cardiovascular disease in their 10 year study of patients with diabetes diagnosis in adolescence or earlier. They showed a relative risk of 2.3 for LDL cholesterol levels ⱖ130 mg/dl, and a relative risk of 1.8 for patients whose LDL levels were ⱖ100 mg/dl compared to those whose levels are lower. Triglycerides also conferred risk for cardiovascular disease with the relative risk being 2.5 for triglyceride levels ⱖ90 mg/dl and 3.3 if the levels were ⱖ150 mg/dl. Systolic blood pressure conferred additional risk with levels of ⱖ110 mmHg conferring a relative risk of 1.8, 120– 129 mmHg, 2.5, and ⱖ130 mmHg 5.6. Any diastolic blood pressure >80 conferred additional risks but the relative risk was extremely high, 4.2, with diastolic blood pressures ⱖ90 (142). The recommended treatment for adults with diabetes is to intervene when LDL cholesterol is >100 mg/dl and triglycerides >140 mg/dl. The data indicating that fatty streaks and atherosclerotic plaques are present during childhood indicate that the process begins early and, therefore, intervention should also begin early. Initial efforts at improving metabolic control with recommendations for diet and exercise should be initiated when lipid levels exceed target. If, after 3 months, fasting lipid profiles are not decreasing, pharmacological therapy should be considered. In our practice we have used HMG Co-A inhibitors (statins) with good success and few adverse reactions. Triglycerides, too, should be vigorously treated. In some patients optimal blood glucose levels will not be achieved despite intensive attempts to maximize glycemic control, resulting in isolated hypertriglyceridemia. In those instances, agents targeted at lowering triglyceride levels, such as gemfibrizol, should be considered. 6. Hypertension The UKPDS showed that above a baseline systolic blood pressure of 110 mmHg, the higher the blood pressure, the

627

greater the risk of cardiovascular disease (191). The Hypertension Optimal Therapy (HOT) study compared the outcomes of maintaining diastolic blood pressure to goals of ⱕ90 mmHg, ⱕ85 mmHg, or ⱕ80 mmHg. In the 15,001 patients with diabetes mellitus at baseline, the rate of major cardiovascular events, defined as myocardial infarction, stroke, or death due to any cardiovascular event, revealed that the group randomized to maintain a diastolic blood pressure ⱕ80 mmHg had half the risk of major cardiovascular events compared to the group randomized to a blood pressure ⱕ90 mmHg. This differs from the results seen in the group without diabetes, in which the risk reduction was only 10% for the lower compared to the higher blood pressure readings (192), indicating that diabetes conferred an additional risk for cardiovascular disease. These studies have led to the recommendations that hypertension should be treated to maintain a blood pressure of 130/80 mmHg or less and, as albumin excretion rate is an additional risk factor for cardiovascular disease (>20 mg/min, 30 mg/day, or 30 mg/g creatinine), blood pressure should be treated to a level of 120/75 mmHg or below in those with elevated albumin excretion rates (193).

IV. A.

TYPE 2 DIABETES Epidemiology

The definitions of incidence, prevalence, frequency, and epidemic have been provided in the preceding section on epidemiology of type 1 diabetes. Beginning around 1990, pediatric endocrinologists, who had been aware for decades of a small proportion of their diabetes patients having type 2 disease (194), noticed a sharp increase in the numbers of such patients (195). This was predominantly, but not exclusively, in the African–American and Hispanic– American population, and Native American youth were reported to have a 1% prevalence of type 2 diabetes as early as 1979 (196). There seems little argument that type 2 diabetes in children and adolescents has become an epidemic. The first recognition of a substantial prevalence was among Pima Indian 15–24-year-olds, 9:1000 (0.9%) having diabetes associated with obesity and long-term complications (196). This was in a population in which 50% of adults have type 2 diabetes. Half of these youngsters had ketoacidosis. By the 1990s, 5% of 15–19-year-olds and 2.2% of 10–14-year-olds (previously 0%) had type 2 diabetes (197). Among First Nations children and youth in Canada, the frequency of type 2 diabetes is comparable to that of type 1 diabetes in the white population (198). A study in Cincinnati reviewed 1027 consecutive records of children 0–19 years old diagnosed with diabetes and found that the proportion diagnosed as having type 2 increased from 2–4% between 1982 and 1992, to

628

16% in 1994 (199). It is interesting that this percentage was stable for over 20 years, Knowles having reported that approximately 3.5% of patients in this clinic had type 2 disease in 1971 (194). Thirty-three percent of those in the 10–19 year age group newly diagnosed in 1994 had type 2 disease. The estimated age-specific incidence for the community was 7.2:100,000, which is approximately half the incidence rate for type 1 diabetes in childhood, and a 10-fold increase from 1982 (30). In this study and also in a study from Arkansas, African–Americans accounted for 70–75% of the individuals with type 2 diabetes (200). It is estimated that one-third of Mexican– Americans with diabetes in southern California and over two-thirds of those in south Texas have type 2 disease (201, 202). In Native North Americans four to six times as many females as males are affected, but among African–American and Mexican–American groups with type 2 diabetes, sex ratio has been far less skewed. It varies from 1.7 females for every male among African–Americans to nearly 1:1 among Mexican–Americans (203). A study of 682 5–19-year-olds diagnosed between January 1, 1994, and December 31, 1998, at the three University-based diabetes centers in Florida found that 14% of the patients had type 2 disease. While 47% of type 1 patients were female, 63% of type 2 patients were. In contrast to the studies from Arkansas and Cincinnati, African–Americans were only 46% of those with type 2 diabetes while 22% were Hispanic, and the rest non-Hispanic whites. The risk for type 2 diabetes was three times greater for African–American youngsters and 3.5 times greater for Hispanics than for whites. During the initial year of the study, 8.7% of newly diagnosed patients were eventually classified as having type 2 disease, whereas in the last year of the study 19% were thus classified. This indicates a twofold increase in the proportion of new diabetes patients in this age group having type 2 disease over the relatively brief period of 5 years (28). The recognition of an epidemic of type 2 diabetes is not unique to North America. Libyan Arabs are reported to have an age-specific incidence for the 15–19-year-old group of 6:100,000, increasing to 26:100,000 for the 20– 24 year age group. Overall, this represents greater than twice the incidence for type 1 diabetes in males and over four times the incidence of type 1 diabetes in females (204). Among Hong Kong Chinese, type 2 diabetes accounts for >90% of young-onset diabetes and is strongly familial and associated with obesity (205). As with the Chinese, the Japanese have a very low incidence of type 1 diabetes. Annual urine testing for glucose of schoolchildren in the Tokyo area has been carried out since 1975, followed by oral glucose tolerance testing for those with glucosuria. In the 12–15 year age group, there has been a doubling of incidence of type 2 diabetes from 7.2 to 13.9:100,000 paralleling increasing obesity rates (206). Other reports indicate that obese youth who are Bangla-

Rosenbloom and Silverstein

deshi (207), Australian aborigines (208), New Zealand Maoris (209), or East Indians or Arabs living in the United Kingdom (210) are also being observed with type 2 diabetes. Five obese adolescents aged 13–15 years with type 2 diabetes are the first white youngsters reported from England, and this problem is expected to be more prevalent with the epidemic of childhood obesity in that country (211). A constant in the emergence of type 2 diabetes in young patients has been the association with obesity and increasing rates of that seminal condition. The U.S. National Health and Nutrition Examination Survey conducted between 1988 and 1994 found that 20% of children 12–17 years of age had BMIs above the 85th percentile for age (the definition of overweight), and that, depending on ethnicity, 8–17% were obese with a BMI >95th percentile. Not only was there a doubling of the frequency of childhood obesity since 1980 but the severity of obesity was also greater (212). In a 20-year biracial community-based study in Louisiana (the Bogalusa heart study) of 11,564 5–24-yearolds from 1973 to 1994, there was a mean weight increase of 0.2 kg/year along with increased skinfold thickness. Overweight as defined above increased from 15 to 30%, and obesity from 5 to 11% in 5–14-year-olds and increased 5–15% in 15–17-year-olds. The increases in the second 10 years of the study were 50% greater than those in the first 10 years (213). In the National Longitudinal Survey of Youth, a prospective cohort study of 8270 children aged 4–12 years, there was a significant increase in overweight and obesity between 1986 and 1998. The prevalence rates in 1998 for overweight were 38% for African–Americans and Hispanics, and 26% for whites, while 22% of African–Americans and Hispanics and 12% of whites were obese (214). The epidemic of obesity is also international. Similar trends to those in the United States have been reported for Japan (206) and the United Kingdom (215). In Russia, 6% of ⬃7000 6–18-year-olds examined in 1992 were obese and 10% were overweight, using US BMI reference data (216). In China, 3.6% of ⬃3000 6–18-year-olds examined in 1993 were obese and another 3.4% overweight (216). In 1996, in the United Kingdom, 22% of 6-yearolds were overweight, and 10% were obese; by age 15, 31% were overweight and 17% obese. Numerous studies in Europe have indicated that the highest rates of childhood obesity occur in Eastern European countries, particularly Hungary, and in the southern European countries of Italy, Spain, and Greece (217).

B.

Etiology

The recent increase in type 2 diabetes prevalence in young patients has been so rapid that it must be explained by changes in the environment, most obviously increasing obesity rates (218, 219). Nonetheless, not all or even a majority of obese youngsters develop type 2 diabetes, em-

Diabetes in Child and Adolescent

629

phasizing the importance of genetic factors. The thrifty genotype hypothesis, advanced nearly 40 years ago and recently updated (220, 221), explains the insulin resistance and relative beta-cell insufficiency associated with the development of obesity and type 2 diabetes as an adaptation for conserving energy and surviving famine. Until the modern era of continuous feasting, such a genotype would have had great survival advantage. Numerous studies have demonstrated either insulin resistance preceding the development of type 2 diabetes or that limited pancreatic beta-cell capability to respond to the increased insulin requirements associated with obesity is the basic lesion (222–228). Insulin resistance can be defined as the impaired ability to respond to physiological effects of insulin on glucose, lipid, and protein metabolism. Normal glycemic control requires the sensing of glucose concentration by the beta cells, the synthesis and release of insulin, binding of insulin to its receptors, and postreceptor insulin activation. This results in increased glucose uptake by muscles, fat, and liver tissue with decreased glucose production by the liver. In type 2 diabetes, there is peripheral insulin resistance in muscle and fat tissue, together with decreased pancreatic insulin secretion, and increased hepatic glucose output (Fig. 3). Note that both insulin resistance and impaired beta-cell function are required for the development of type 2 diabetes in this model (229). 1. Role of Fetal and Childhood Nutrition The association of lower birth weight, smaller head circumference, and thinness at birth with impaired glucose tolerance or type 2 diabetes and insulin resistance in adults has suggested in utero programming that limited ␤-cell capacity and induced insulin resistance in peripheral tissues (230, 231). The maternal undernutrition that led to low birth weight was thought to impair development of the endocrine pancreas. The effect of fetal undernutrition on adult glucose tolerance has been confirmed in large

Figure 3

studies in Sweden and the United States (232, 233). Glucose intolerance was also found in adults who were the offspring of mothers who had starved during the last trimester of pregnancy during the Dutch famine of World War II (234). Low birth weight has also been associated with increased cortisol axis activity in adults. South African nonobese 20-year-olds who had been underweight for gestational age had greater plasma cortisol response to adrenocorticotropin (ACTH), higher blood pressure, and impaired glucose tolerance compared to normal-birthweight controls (235). Three studies of young subjects from high-risk populations are consistent with reports of the effect of fetal nutrition on the risk for insulin resistance syndrome (type 2 diabetes, hypertension, hyperlipidemia) in adulthood. Current weight correlated with birth weight among 3061 Pima Indians aged 5–29 years, and 2 h glucose concentrations had a U-shaped relationship with birth weight in those >10 years old, regardless of current weight. Thus, higher blood glucose levels occurred in those with greater than normal and less than normal birth weight, unrelated to their current weight. The 2272 subjects without diabetes had negative correlations between birth weight and insulin concentrations at baseline and at 2 h, and insulin resistance. These findings supported the hypothesis of a survival advantage for insulin resistance in low-birthweight babies (236). In a study of 477 8-year-old Indian children, insulin resistance variables and plasma total and LDL cholesterol concentrations were strongly related to current weight. Lower birth weight was associated with elevated systolic BP, fasting plasma insulin and 32–33 split proinsulin concentrations, plasma lipids, glucose and insulin concentrations 30 min after glucose, and calculated insulin resistance. Children who had low birth weight but high fat mass at 8 years had the highest risk of insulin resistance syndrome variables and hyperlipidemia (237). Low-birthweight white and African–American children (n = 139)

Development of type 2 diabetes. (Adapted from Ref. 229.)

630

were studied when they were aged 4–14 years. There were significant differences between the two races in the effect of low birth weight on visceral fat mass as measured by DEXA and CT, fasting insulin, acute insulin response and beta cell function, and HDL cholesterol concentrations, indicative of the genetic differences suggested by the thrifty genotype hypothesis (238). The thrifty phenotype hypothesis has emerged from these studies indicating an effect of fetal nutrition on later glucose tolerance and other manifestations of insulin sensitivity. This hypothesis states that poor nutrition in fetal and early infant life would be detrimental to the development and function of the ␤-cells and insulin-sensitive tissues, primarily muscle, leading to insulin resistance. With obesity in later life, type 2 diabetes would develop. These findings could also be interpreted as a reflection of the thrifty genotype: that defective insulin action in utero results in decreased fetal growth and obesity-induced impaired glucose tolerance in later childhood or adulthood (26). Genetic factors affecting birthweight and glucose metabolism are of interest in this regard. The polymorphism of the variable number of tandem repeats (VNTR) locus of the insulin chain is associated with decreased body length, weight, and head circumference at birth (239). Decreased birthweight has been associated with heterozygosity for a mutation in the glucokinase gene (240). Finally, the glucose transporter 4 (GLUT4) expression is impaired in young adults with insulin resistance who were undernourished in utero (241). 2. Maternal Diabetes The influence of the diabetic intrauterine environment on the risk of type 2 diabetes in children was first appreciated from studies in the Pima Indian population. The prevalence of diabetes in the offspring of Pima women with diabetes during pregnancy is significantly greater than in nondiabetic mothers or those who develop diabetes after delivery (242). In another population, fetal ␤-cell function was assessed in 88 pregnancies with pregestational or gestational diabetes by measuring amniotic fluid insulin (AFI) concentration at 32–38 weeks’ gestation. The offspring had oral glucose tolerance testing done annually from 18 months of age. Only 1 of 27 adolescents with normal AFI had impaired glucose tolerance, in contrast to one-third of those with elevated AFI (243). These studies suggest a generation-to-generation accumulation of risk for type 2 diabetes that further increases the public health concern about the epidemic of this disease in young persons (244). 3. Role of Puberty In all reports of type 2 diabetes in childhood, the mean age at diagnosis is ⬃13.5 years, corresponding to the time of peak adolescent growth and development (198–203). Puberty is associated with relative insulin resistance, re-

Rosenbloom and Silverstein

flected in a two- to threefold increase in the peak insulin response to oral or intravenous glucose (245). Insulin-mediated glucose disposal is a mean 30% lower in adolescents than in prepubertal children or young adults (246). The physiological insulin resistance of puberty is of no consequence in the presence of adequate beta-cell function. The cause of this physiological resistance is likely to be increased activity of the GH-IGF axis, which is transitory and coincides with the physiological insulin resistance of adolescence (8). 4. Role of Obesity The insulin resistance associated with obesity is the fundamental problem in type 2 diabetes in children and adolescents, as it is in adults. Total obesity accounts for approximately 55% of the variance in insulin sensitivity (246). That obese children have hyperinsulinism has been known for over 30 years (247, 248). Obese children have ⬃40% lower insulin-stimulated glucose metabolism than nonobese children (246). African–American 5–10-yearolds, especially girls, have reduced insulin sensitivity in proportion to increases in blood pressure, triglycerides, subcutaneous fat, percentage of total body fat, and stage of sexual maturation (249). The amount of visceral fat in obese adolescents correlates directly with basal and glucose-stimulated insulinemia and inversely with insulin sensitivity (250). Insulin-stimulated glucose metabolism and fasting insulinemia decrease with increasing BMI (246). Glucose tolerance testing was carried out in 720 Pima Indians aged 10–39 years, including 325 who had been exclusively bottlefed as infants, 144 who were exclusively breastfed, and the rest who had been partially breastfed for the first 2 months of life. Those exclusively breastfed had significantly lower rates of type 2 diabetes than those exclusively bottlefed for each age decade, with an odds ratio for type 2 diabetes in exclusively breastfed individuals of 0.41 (251). Prolonged breastfeeding has been noted in a large study of nearly 10,000 5–6-year-old German children to markedly reduce the risk of overweight; 3.8% of those exclusively breastfed for 2 months were overweight vs. 0.8% of those breastfed for longer than 12 months (252). Lower insulin responses occur in breastfed versus bottlefed infants and breastfed infants have lower energy and protein intake. Association has been made between early high protein intake and later obesity. Breastfeeding results in a more appropriate caloric intake at a critical stage in development, whereas bottlefeeding is more likely to be associated with overfeeding and obesity. The typical overweight of the bottlefed infant may contribute to insulin resistance and obesity in adolescence and young adulthood. 5.

Polycystic Ovarian Syndrome and Premature Adrenarche There is increasing recognition of polycystic ovarian syndrome (PCOS) in the adolescent population (253). Girls

Diabetes in Child and Adolescent

with PCOS are reported to have ⬃40% reduction in insulin-stimulated glucose disposal compared to nonhyperandrogenic control subjects (254, 255). Premature adrenarche, which has been thought to be a benign condition, is now recognized as a risk factor for ovarian hyperandrogenism and PCOS (256). Affected children are also more likely to have been born small for gestational age, indicating another aspect of the association of insulin resistance and intrauterine undernutrition (257, 258). 6. Racial and Familial Influences A racial difference in the insulin responses to various stimuli parallels the ethnic/racial differential in type 2 diabetes frequency. Greater insulin responses to oral glucose are seen in African–American (AA) children and adolescents than in European–American (EA) children after adjustments are made for weight, age, ponderal (obesity) index, and pubertal stage. This is indicative of compensated insulin resistance in the AA youngsters (259, 260). Both prepubertal and pubertal AA children have higher fasting and stimulated insulin concentrations during glucose clamp studies than do EA youngsters (261). Lipolysis is also significantly less in AA children than in EA children, suggesting an energy conservation phenotype that would have survival value in times of famine but be detrimental with excess nutrition (thrifty genotype) (262). Prepubertal children who have a family history of type 2 diabetes have lower insulin-stimulated glucose disposal and nonoxidative glucose disposal than do those without such a family history, indicating that family history of type 2 diabetes is a risk factor for insulin resistance in children, as in adults (263). 7. Genetic Considerations The evidence that type 2 diabetes is a genetic disease includes the family clustering and segregation analyses that indicate that siblings of affected individuals have 3.5 times the general population risk of developing type 2 diabetes; studies of monozygotic twins that indicate a concordance of 80–100%, greater than twice the concordance in dizygotic twins and in monozygotic twins for type 1 diabetes; and the previously noted variations in insulin sensitivity and frequency of type 2 diabetes by ethnic origin (264). With rare exceptions, type 2 diabetes in children and adolescents, as in adults, is polygenic. The rare monogenic (autosomal dominant and mitochondrial) forms, however, provide insights for the study of typical type 2 disease (265). Autosomal dominant forms include MODY and ADM. Molecular defects in 6 genes have been identified in families with MODY, affecting hepatocyte nuclear factors, glucokinase, and insulin promoter factor-1. Over 200 different mutations have been described. A glucokinase mutation has been identified in 1 of 10 ADM families studied as well (9).

631

In mitochondrial forms, disease transmission is exclusively from the mother because mitochondria are inherited via the cytoplasm of the ovum. The diabetes is usually indistinguishable from typical type 2 diabetes. In addition to the diabetes, affected individuals may also have sensorineural hearing loss, cardiomyopathy, optic neuropathy, myopathy, encephalopathy, lactic acidosis, strokelike syndrome, or epilepsy (10–12). The identification of type 2 diabetes susceptibility genes involves choosing between two general approaches: the candidate gene approach and the genome scan approach. In the candidate gene approach, there is a problem identifying or choosing an appropriate candidate, or the candidate may be unknown at the time of the study, as was the case with the MODY genes. In the genome scan approach, the entire genome is examined for linkages within families or associations within populations. In these analyses, microsatellites are particularly useful and microassays of mRNA are able to identify gene patterns that are over- or underexpressed in specific disease states. Figure 4 illustrates possible candidate genes in the beta cell–target cell interaction. More than 20 loci have been linked to or associated with type 2 diabetes in adults, the most important being NIDDM1, described among Mexican–American sibships in Starr County Texas. This county, which is 97% Mexican–American, has the highest disease-specific diabetes mortality in Texas. The gene pool is 31% Native American. Some 474 autosomal markers and 16 X-linked markers were examined in 170 affected sibships involving 300 affected siblings and 78 unaffected siblings. Identified as linked to type 2 diabetes was the NIDDM1 site on chromosome 2, accounting for ⬃30% of family clustering. This was equal in importance, therefore, to the linkage with HLA in type 1 diabetes (267). This linkage was not identified in other populations, including non-Hispanic white, Japanese, French, Sardinian, and Finnish (264). The Calpain gene in the NIDDM1 region of chromosome 2 was subsequently found to be associated with type 2 diabetes in several of these populations, linked to different loci (268). Calpains are calcium-activated neutral proteases ubiquitously expressed from fetal life through adulthood, which function in signaling, proliferation, differentiation, and insulin-induced downregulation of IRS-1. Multiple polymorphisms of the gene encoding Calpain-10, encoded by the CAPN10 gene within the NIDDM1 region, have been found to be associated with type 2 diabetes. The highest-risk combination of polymorphisms give odds ratios of 2.8–3.6 in Mexican–Americans, 2.6 in Finns, and 5.0 in Germans (268). Nondiabetic Pima Indians who are homozygous for a common polymorphism of CAPN10 have reduced insulin-mediated glucose turnover as the result of decreased glucose oxidation rates (269). Figure 5 summarizes the factors that have been discussed in the development of type 2 diabetes.

632

Rosenbloom and Silverstein

Figure 4 Beta-cell candidate genes in diabetes mellitus include GLUT2 (glucose transporter 2), which is responsible for the facilitative uptake of glucose by beta-cells; glucokinase (GCK), which is the beta-cell glucose sensor; mitochondrial genes that provide power to the beta cell (an increased ratio of ATP to ADP ⫹ Pi[(ATP)]/[(ADP) ⫹ (Pi)]; the ATP-sensitive potassium (K⬘) channel (sulfonylurea receptor [SUR]); GLP-1 R (the beta-cell glucagen-like peptide-1 receptor) that responds to GLP from the gastrointestinal tract; insulin; PCII (prohormone convertase II, an example of an insulin-processing protein); and amylin, which is cosecreted with insulin. At the target cell (muscle, fat, or liver), candidate genes include the insulin receptor; intracellular proteins that are phosphorylated (insulin receptor substrate-1 [IRS1]); GLUT1; hexokinase II, which catalyzes the conversion of glucose to glucose-6-phosphate; glycogen synthase (GYS), which regulates glycogen production; and the regulatory subunit of phosphorylase (PHOSP) that regulates glycogen breakdown. GLUT4 is also a candidate gene, but GLUT4 is expressed only in muscle and fat tissues and is not expressed in the liver. (From Ref. 266.)

C.

Clinical Features

The most striking difference between type 1 and type 2 diabetes is that in type 2 diabetes hyperglycemia/diabetes is one of many manifestations of the insulin resistance syndrome (diabesity syndrome, syndrome X, or the metabolic syndrome) (see Fig. 6). Common type 1 diabetes is, on the other hand, until the development of long-term complications, a unitary hormone deficiency state (although other autoimmune mediated deficiencies, such as thyroid, may develop). Insulin resistance is a pathogenic factor in the devel-

opment of a broad spectrum of clinical conditions. These include hypertension, atherosclerosis, dyslipidemia, decreased fibrinolytic activity, impaired glucose tolerance type 2 diabetes, acanthosis nigricans, hyperuricemia, polycystic ovary disease, and obesity, which is the core abnormality (270). In addition to the metabolic effects related to insulin resistance, obesity has deleterious associations in childhood and adolescence that increase morbidity and contribute to cardiovascular risk. This increased risk has been documented to be the result of the persistence of obesity into adulthood, rather than specific effects during child-

Diabetes in Child and Adolescent

633

Figure 5

Factors in the development of type 2 diabetes.

hood (271, 272). Childhood obesity has been associated with elevated C-reactive protein and white blood cell counts, which are inflammatory indicators implicated in adult cardiovascular disease (273), proteinuria and focal segmental glomerular sclerosis (274), obstructive sleep apnea and other respiratory problems (275), hepatic steatosis (276), and orthopedic problems (275). Lipoprotein abnormalities noted in type 2 diabetes include hypertriglyceridemia, elevated VLDL, elevated LDL-cholesterol, elevated lipoprotein (a), decreased highdensity lipoprotein (HDL) cholesterol, increased small dense LDL particles, decreased lipoprotein lipase activity, increased lipoprotein glycation, and increased lipoprotein oxidation. The mechanism for this hyperlipidemia pattern is as follows. Fat cells, which are sensitive to insulin, store triglyceride and suppress hormone-sensitive lipase, the enzyme that breaks down triglycerides to release free fatty acids. Insulin also provides glucose to the fat cells for forming glycerol, the triglyceride backbone. With insulin resistance, there is abnormal breakdown of triglyceride and release of free fatty acids and glycerol, the latter contributing to gluconeogenesis. The free fatty acids cause insulin resistance in muscle tissue. In the liver, they are

Figure 6 Insulin resistance: associated conditions. (Adapted from Consensus Development Conference of the American Diabetes Association, Diabetes Care, 1997.)

reconverted to triglyceride, driving the production of LDL, which is the lipoprotein carrier of triglycerides, and the other dyslipidemic changes follow. The hyperinsulinemia of the insulin resistance state further drives the synthesis of fatty acids from glucose in the liver (277). In adults there is a strong association between the level of hyperglycemia and risk factors for macrovascular disease. Dyslipidemia is one of several factors that accelerate atherosclerosis in type 2 diabetes. Additional factors described include oxidative stress, glycation of numerous vascular proteins, defective endothelium-dependent vasodilatation, and abnormalities of platelet function and coagulation (increased fibrinogen, increased plasminogen activator inhibitor-1, decreased antithrombin III and other anticoagulant and proteins, elevated factors VII and VIII, elevated vascular adhesion molecule 1, increased platelet adhesiveness and aggregation, decreased platelet nitric oxide [NO] production [NO mediates vasodilatation], decreased platelet prostacyclin production, and glycation of platelet proteins) (278). Hypertension is estimated to account for 35–75% of diabetes complications involving both the microvasculature and macrovasculature (279). Diabetes or impaired glucose tolerance doubles the risk of developing hypertension (280). There is emerging evidence of a genetic predisposition to hypertension and type 2 diabetes related to the angiotensin-converting enzyme genotype (281). The hypertension in type 2 diabetes is due to volume expansion and increased vascular resistance, with reduced NOmediated vasodilatation and increased activity of the renin–angiotensin system (278). Acanthosis nigricans (AN) is an indicator of insulin resistance, prominent in genetic insulin resistance syndromes not associated with obesity. The frequency of AN in obese adolescents varies greatly by ethnicity: ⬃90% in Native Americans, ⬃50% in African–Americans, ⬃15% in Hispanic–Americans, and 85th percentile for age and sex (Figs. 17 and 27 in Chapter 43), weight for height >85th percentile, or weight >120% of ideal for height). Additionally, they should have two other risk factors, which were considered to be: family history of type 2 diabetes in first or second degree relatives; being of Amer-

ican Indian, African-American, Hispanic, or Asian/Pacific Islander race/ethnicity; and signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, PCOS). It was recommended that testing begin at age 10 or at the onset of puberty if puberty occurs at a younger age and that repeat testing be done every two years, with fasting plasma glucose as the preferred test. These criteria were not evidence based, which is why the consensus panel provided the disclaimer that clinical judgment should be used to test for diabetes in highrisk patients who do not meet these criteria. One might also take issue with the suggestion to use fasting plasma glucose. This was considered preferable because of its lower cost and greater convenience: 2 h plasma glucose increases earlier in the course of the development of type 2 diabetes, making it a more sensitive measure. Fasting hyperglycemia is an advanced stage of type 2 diabetes, and therefore highly specific but relatively insensitive as a testing method. Random plasma glucose concentration can be measured in those who have taken food shortly before testing, with a glucose concentration ⱖ7.8 mmol/ L (140 mg/dL) serving as an indication for further testing. The need for primary prevention efforts in childhood has been the subject of wide publicity for the past several years, with recognition of the epidemic of obesity (286– 291). Obesity is associated with diminished school performance due to sleep apnea, torpor associated with physical inactivity, and social stigmatization. Secondary prevention of obesity is rarely successful beyond the short term. Intervention in adult populations indicates the enormous difficulty in altering lifestyle and dietary habits. The challenge for the pediatrician and society is to counter eating and entertainment trends that provide popular social outlets and are highly attractive, heavily promoted, and readily available. Financially stressed school systems often sabotage community efforts by providing fast food concessions and soft drink and snack vending machines in exchange for financial support from the vendors. Food service in middle and high schools typically includes high-fat, high-calorie foods such as pizza and french fries. There are inadequate opportunities for noncompetitive sports permitting participation of all youngsters, such as aerobics and dance, and there has been a sharp reduction in compulsory physical education programs. For some minority youngsters, there is the additional problem of a lack of safe environments in which to be physically active, and lack of funding for afterschool programs. Finally, school curricula have not effectively incorporated healthy lifestyle training. A number of school-based and community-based programs have been developed targeting high-risk populations (290–295). School-based programs attempt to modify the food provided in school meals, incorporate healthy lifestyle training into classroom education, and create a school environment that promotes physical activity. Pre-

Diabetes in Child and Adolescent

school and kindergarten through sixth grade programs encourage family involvement; high-school-based programs focus on social networks and peer pressure in an effort to promote behavior change and reduce risk factors. Shortterm behavioral change has occurred with these programs, but longer-term studies are needed to determine whether these changes persist and reduce the risk for type 2 diabetes. Before the contemporary epidemic of type 2 diabetes, we had noted the occasional obese African–American teenager attending our diabetes adventure camp program and rapidly becoming normoglycemic with vigorous exercise, permitting withdrawal of insulin. This phenomenon has been documented in 1 week summer camp programs for North American Indian youth with type 2 diabetes, who are able to achieve normoglycemia after 5 days of increased physical activity. Unfortunately, the behaviors of camp are not maintained, and most of the youngsters return to poor glycemic control at home (292, 296). Programs are in place that emphasize nutrition and exercise in schools, including those on Indian reservations throughout the United States, but their effectiveness has yet to be documented (294, 297). The health-care system is increasing its appreciation of the magnitude of the obesity/type 2 diabetes problem. All who have contact with at-risk families need to emphasize the importance of intervention. Parent training by pediatricians, WIC and county health-department nurses, and other health personnel should continue to promote prolonged breastfeeding, which, in addition to its other many benefits, reduces the risk of obesity in childhood (251, 252). Parents also need to know that a fat baby is not a more healthy baby: candy, potato chips, and other foods with high caloric density and low nutritional value should not be used as rewards. Because children with normal-weight parents have a much lower risk of overweight (30 kg/m2, with elevated fasting insulin concentrations (>15 uU/ml), a family history of type 2 diabetes, and normal fasting glucose and HbA1c were randomized to receive metformin 500 mg twice daily or placebo for 6 months. Controls had an increase in BMI of 0.23 SD and metformin-treated subjects a decrease of 0.12 SD, a significant difference. There was also a significant decrease in fasting glucose concentrations and insulin levels in metformin-treated youngsters compared with controls. Transient abdominal discomfort or diarrhea occurred in 40% of those taking metformin (306). In adults, lifestyle intervention was more effective than metformin in preventing progression from impaired glucose tolerance to type 2 diabetes (302). There are limited data and no guidelines for surgical treatment of obesity in children and adolescents. A report in 1975 indicated a median weight loss of ⬃25% 3 years after gastric bypass or gastroplasty in 18 morbidly obese adolescents (307). A report 5 years later of 30 patients 30 kg weight loss. Incisional hernia, gallstones, or small bowel obstruction required surgery in four of the individuals. Medical complications included mild iron deficiency anemia and transient folate deficiency (309).

E.

Treatment

1. Challenges The treatment challenges of type 2 diabetes in children and adolescents differ greatly from those of type 1 diabetes, due largely to the nature of the disease and those most likely affected. While type 1 diabetes is distributed throughout the population, type 2 diabetes disproportionately affects families with fewer resources, paralleling the distribution of obesity in the population. Whereas type 1 diabetes occurs throughout childhood, usually during the time when parental influence predominates, type 2 diabetes affects mostly those in adolescence or beyond, when peer influence is most important. There is also a large difference in family experience, with only ⬃5% of families with a child with type 1 diabetes having affected family members; 90% or more of youth with type 2 diabetes have family experience. These family members have typically failed to control their weight and glycemia, developing complications and creating an aura of despair and futility. Treatment priorities are also different between type 1 and type 2 diabetes. Extensive lifestyle modification, beyond insulin administration and glucose monitoring, is only required by those patients with type 1 disease who are overweight and inactive. However, the emphasis is on lifestyle modification in all those with type 2 diabetes and secondarily on glucose monitoring and hypoglycemic medication. Finally, technological innovation has revolutionized management of type 1 diabetes with improved insulin purity and delivery, self blood glucose monitoring, and the development of insulin analogs, with an artificial pancreas on the horizon and the likelihood that there will be islet cell replacement. Technological advances have, however, been the underlying cause of the problem of type 2 diabetes, with advances in home entertainment systems, labor-saving devices, and transportation, and food preparation making calorically dense food increasingly available, desirable, and inexpensive. 2. Treatment Goals The goals of treatment are to promote weight loss, normalize glycemia and HbA1c, control or prevent hyperten-

sion and hyperlipidemia, reduce acanthosis nigricans, and increase exercise capability. Treatment is more important than might be indicated by the level of glycemia in some patients, because of the multitude of cardiovascular risk factors associated with insulin resistance. Just as in adults with newly diagnosed type 2 diabetes, young patients may already have evidence of complications, reflecting a prolonged period of impaired glucose tolerance. Among 100 Pima Indian children and adolescents with type 2 diabetes, 7% had high cholesterol (ⱖ200 mg/dl), 18% had hypertension (BP ⱖ140/90, now considered far too high a cut off), and 22% had micro-albuminuria (albumin/creatinine ⱖ30) at the time of diagnosis. Ten years later, while still in their 20s, they had mean HbA1c of 12% indicative of poor control, 60% had micro-albuminuria, and 17% had macro-albuminuria (albumin/creatinine ⱖ300) (310). Japanese investigators have described a high risk of renal failure in those who develop diabetes under 30 years of age (311). Reduction in the risk of complications may require more stringent glycemic control in the insulin resistance state of type 2 diabetes than is required in type 1 diabetes, with diligent attention to comorbidities. In the UKPDS there was a 25% decrease in the risk of microvascular complications when the average HbA1c decreased from 7.9 to 7.0% (312). Reduction in BP to below 144/82 resulted in a more dramatic decrease of 37% in the risk for microvascular disease, 44% decrease in stroke occurrence, and 36% decrease in heart failure (313). 3. Changing Behavior The behavioral changes and motivation required are so extensive that the treatment team requires a psychologist or social worker. One of the simplest changes to make is to eliminate the frequent consumption of high-calorie soft drinks, sweetened tea, and juices, substituting water, diet soft drinks, and artificial sweeteners for tea or Kool-Aid (314). Daily exercise should be documented in an attempt to break the vicious cycle of increased weight producing increased torpor, resulting in decreased activity and increased weight. As noted above, the most effective single method for doing this is turning off the television. A relatively small reduction in weight, accomplished by an increase in activity, can restore euglycemia and decrease hyperinsulinemia, as in the camp experience. The stages of change are outlined in Table 5 (315). 4. Hypoglycemic Agents Pharmacological therapy can decrease insulin resistance, increase insulin secretion, slow postprandial glucose absorption, or, in the case of insulin injection, supplement inadequate secretion of insulin (Table 6). a. Biguanides. The biguanides act on insulin receptors in the liver to reduce hepatic glucose production and in muscle and fat tissue to enhance insulin-stimulated glucose uptake. They have an anorexic effect that can pro-

Diabetes in Child and Adolescent Table 5

637

Stages of Change

Concept 1. Precontemplation

2. Contemplation

3. Preparation

4. Action

5. Maintenance

Definition

Application

Unaware of problem; has no intention of changing in the near future (next 6 months) and may deny need for change. ‘‘Everyone in our family is big.’’ Thinking about change, in the near future; knows there is an issue but is not ready to change; there may be intent to change in the next 6 months. ‘‘I’ve heard that some overweight kids are getting diabetes. But I don’t think I can handle going on a diet.’’ Making a plan to change; knows what s/he wants to do; is seeking more information, planning, even starting to change; may tell family and friends; there is an intent to change in the near future. ‘‘I found out that if I lose some weight, this smudge on my neck will fade. I’ve taked to my Mom about it . . .’’ Implementation of specific action plans; making changes in the environment to support the change. Relapse is normal. This stage may last as long as 6 months. ‘‘I’m walking three times a week for half an hour. I’ve quit drinking sodas . . .’’ Continuation of desirable actions; or repeating periodic recommended step(s); may last 6 months to 5 years; some add a sixth stage, termination; ‘‘I lost 10 pounds. The smudge on my neck went away. I am going to keep on walking and eating better.’’

Increase awareness of need for change, personalize information on risks, benefits Motivate, encourage to make specific plans

mote weight loss. As noted above, metformin has also been used for this purpose. It has also been used to reduce acanthosis and ovarian hyperandrogenism. Long-term use is associated with a 1–2% reduction in HbA1c, but a high rate of side effects, including transient abdominal pain, diarrhea, and nausea, limits compliance in adolescents (316). Metformin must not be given to patients with renal

Table 6

Assist with feedback, problem solving, social support, reinforcement

Assist in coping, reminders, finding alternatives, avoiding relapses (as apply)

impairment or who have hepatic disease, cardiac or respiratory insufficiency, or who are undergoing radiographic contrast studies, because of the risk of lactic acidosis. Metformin is the only oral hypoglycemic agent for which there are available pediatric data. Eighty previously untreated patients age 8–16 years were randomized to receive metformin or placebo in a multicenter study. Dosage

Effects of Drug Action in Diabetes

Drug type Biguanides (metformin) Sulfonylureas Metiglinide (repaglinide) Glucosidase inhibitors (acarbose, miglitol) Thiazolidinediones (rosi-, pioglitazone) Insulin a

Assist in developing concrete action plans, setting gradual goals

BG = blood glucose.

Effect on BGa

Risk of low BGa

Weight increase

Lipid decrease

↓ Hepatic glucose output ↑ Hepatic insulin sensitivity ↑ Insulin secretion and sensitivity Short-term ↑ insulin secretion

⫹⫹

0

0

⫹

⫹⫹ ⫹⫹

⫹ ⫹

⫹ ⫹

0 0

Slow hydrolysis and absorption of complex CH0 ↑ Insulin sensitivity in muscle and fat tissue ↓ Hepatic glucose output ↓ Hepatic glucose output; overcomes insulin resistance

⫹

0

0

⫹

⫹⫹

0

⫹/⫺

⫹

⫹⫹⫹

⫹

⫹⫹

⫹

Action

638

began at 500 mg twice daily and increased to 2000 mg/ day over 2 weeks. Rescue criteria resulted in few placebo cases remaining by 16 weeks of the study. At 4 months or longer, the mean fasting glucose change from baseline was a decrease of 44 mg/dl with metformin and an increase of 20 mg/dl with placebo. The adjusted mean HbA1c with metformin was 7.5% and with placebo 8.6%. With metformin, there was no weight gain, and modest decrease in some patients, and lipid profiles improved. No serious adverse events were recorded (317). When metformin is not being effective, it is important to take an in-depth history of medication intake, including refill history from the pharmacy, which may demonstrate that the medication is not being taken. Metformin may normalize ovulatory abnormalities in girls with PCOS or ovarian hyperandrogenism, increasing their pregnancy risk. b. Sulfonylurea and Metiglinide/Repaglinide. This group of drugs increases insulin secretion and is thus most useful when there is residual beta-cell function. The sulfonylureas bind to specific receptors on the K⫹/ATP channel complex, while metiglinide and repaglinide bind to a separate site on the complex (Fig. 7). Activating ATP or binding by these drugs causes K⫹ channels to close, with resultant membrane depolarization, allowing calcium influx and insulin release. ATP-binding sites equilibrate rapidly; sulfonylurea sites do so slowly with prolongation of binding, which explains the sustained effects of traditional sulfonylureas. Metiglinide has an intermediate equilibration and binding duration, explaining its use for more rapid stimulation of insulin secretion and need for premeal dosing (318). The major adverse effects of the sulfonylureas have been hypoglycemia, which, as noted above, can be prolonged, and weight gain, which is particularly troublesome for adolescent patients. c. Glucosidase Inhibitors. Alpha-glucosidase inhibitors such as acarbose and miglitol reduce the absorption of carbohydrates in the upper small intestine by the inhibition of oligosaccharide breakdown, delaying absorption in the lower small intestine. This results in reduction in postprandial glycemia. Long-term use of glucosidase inhibitors is associated with a reduction in HbA1c of 0.5– 1% (319). Flatulence associated with the use of these agents makes them unacceptable to young patients. d. Thiazolidinediones. These drugs act directly on muscle, adipose tissue, and liver to increase insulin sensitivity, and are, therefore, considered specific agents for the manifold problems of the insulin sensitivity syndrome. They bind to nuclear proteins, activating peroxisome proliferator activator receptors (PPAR), which are orphan steroid receptors particularly abundant in adipocytes, thus increasing formation of proteins involved in the nuclearbased actions of insulin. These include cell growth, adipose cell differentiation, regulation of insulin receptor activity, and glucose transport into cells. Long-term treatment with thiazolidinediones has been associated with a

Rosenbloom and Silverstein

reduction in HbA1c of 0.5–1.3% (320). Side effects have included edema, weight gain, and anemia. The original member of this group of drugs, troglitazone, was associated with liver enzyme elevations in ⬃1% of those taking the drug, with mortality in some who had existing liver problems. For these reasons it was withdrawn from the market. The newer thiazolidinediones, rosiglitazone and pioglitazone, have not been shown to have significant hepatotoxicity. The binding of thiazolidinediones to PPAR␥ receptors is ubiquitous and includes arterial walls that contain muscle, affecting the growth of muscle cells and their migration in response to growth factors (321). These drugs also improve lipid profiles, decreasing LDL-cholesterol and triglycerides, while increasing HDL-cholesterol. These effects on vascular muscle and lipids could be important for the reduction of macrovascular disease associated with type 2 diabetes (322). Although studies are in progress, there is no published data yet on the use of rosiglitazone and pioglitazone in children. e. Insulin. The development of type 2 diabetes is an indicator of limited beta-cell function, estimated to be ⬃50% by the time of diagnosis in adults, most of whom will be insulin-requiring by 6 or 7 years later (323). Despite the insulin resistance, relatively low dosages of supplemental insulin (a few units) may be sufficient to maintain euglycemia. The newly available long-acting insulin analog without peak effects, insulin glargine, may be especially useful for type 2 diabetes in combination with premeal megilitinide, particularly in individuals unwilling to take metformin. Hypoglycemia has not been a common side effect of insulin in type 2 diabetes, but weight gain is an important adverse effect. All patients with type 2 diabetes eventually require treatment with insulin because of continuing loss of beta-cell function. f. Treatment Recommendations. Treatment decisions are based on symptoms, severity of hyperglycemia, the presence or absence of ketosis/ketoacidosis (DKA), or dehydration. Dehydration signs may be less obvious in the obese. Symptomatic youngsters with type 2 diabetes, in addition to frequently having ketoacidosis at onset, are at particular risk for the hyperglycemic hyperosmolar state (HHS) which carries a high mortality (324). Acute management of DKA is discussed in Chapter 27. A treatment decision tree for outpatient management is given in Figure 8 (328). Metformin should be the first oral agent used, because it is associated with HbA1c reductions similar to those resulting from use of sulfonylureas, without the risk of hypoglycemia and without weight gain. Furthermore, there may be greater effect on reducing LDL cholesterol and triglyceride levels. If there is failure of monotherapy using metformin over 3–6 months, sulfonylurea, metiglinide, or insulin can be added. Thiazolidinediones may

Diabetes in Child and Adolescent

Figure 7

639

Insulin secretory control mechanism affected by sulfonylurea and metiglinide.

be used in older adolescents. Combination formulations may result in better compliance. It is important to counsel adolescents with type 2 diabetes about sexuality and pregnancy, and provide contraceptive advice, as necessary. Metformin and thiazolidinediones may restore normal periods (326), and none of these oral agents should be used during pregnancy. Although routine self-monitoring of blood glucose may not be needed as frequently as with type 1 diabetes, frequent monitoring is needed during periods of acute illness, during dosage adjustment, or with symptoms that indicate hyper- or hypoglycemia. It is also necessary to monitor for asymptomatic hypoglycemia in individuals who are taking insulin or sulfonylureas. The frequency of routine self-monitoring of blood glucose needs to be individualized, but should include a combination of fasting and postprandial measurements. Assessments of HbA1c concentration should be done at least twice a year and, if metabolic control is unsatisfactory and requires treatment adjustment, every 3 months. The involvement of a dietitian with skill in the management of nutritional problems in children with diabetes is essential. Dietary recommendations need to be culturally appropriate, sensitive to family style and resources, and understood by all caregivers. g. Treating Comorbidities. Hypertension is an independent risk factor for the development of albuminuria, retinopathy, and cardiovascular disease in type 2 diabetes in adults. Its importance is emphasized by the experience of the UKPDS, in which hypertension control was more important than blood glucose control in reducing the risk of cardiovascular disease (313). Blood pressure should be measured at diagnosis and at least quarterly and compared to standards appropriate for age and height percentiles, as

noted in the tables in Chapter 38 (327). Elevations must be treated aggressively if there is persistent elevation above the usual percentile for the child or above the 90th percentile for either systolic or diastolic pressure. Angiotensin-converting enzyme inhibitors (ACEI) are the initial drug of choice. As with type 1 diabetes, many physicians use ACEI prophylactically. Lipid levels and urine albumin excretion should be measured shortly after diagnosis and annually, or more often if there is abnormality and if treatment effects need monitoring. Exercise, weight loss, and glycemic control may be sufficient to correct hyperlipidemia. Dietary recommendations should be for the reduced-fat diet consistent with step 1 American Heart Association guidelines. Lipid-lowering medications should be added if lipid levels do not normalize after 2–3 months of dietary and diabetes control efforts. HMG CoA reductase inhibitors (statins) are the most commonly used lipid-lowering agents in children; they are contraindicated in pregnancy or if there is risk of pregnancy (328). Unlike the recommendations for type 1 diabetes, in which is recommended that regular monitoring for complications not begin until adolescence and several years of diabetes, monitoring lipids and urinary albumin excretion, and examining the retina in those with type 2 diabetes, should begin at the time of diagnosis (8).

V.

OTHER TYPES OF DIABETES

A.

Cystic-Fibrosis-Related Diabetes

Cystic-fibrosis-related diabetes (CFRD) occurs in a substantial percentage of patients with CF and impaired glucose tolerance can be seen in most adolescents, which is

640

Rosenbloom and Silverstein

Figure 8

Treatment decision tree for outpatient management of type 2 diabetes.

the result of progressive pancreatic damage (329). Earlier reports suggested a prevalence of 2.5–7.6% in North America (330–332), but more recent reports indicate prevalences of 10–15% for overt diabetes (333–337). These rates continue to increase with the increase in longevity of patients with CF. Pancreatic involvement beginning in utero progresses throughout life (338, 339). It eventually results in impaired insulin secretion in the vast majority of CF patients who have pancreatic exocrine deficiency, even in the presence of normal glucose tolerance (332, 340–343). The development of CFRD is considered an indicator of deterioration in the clinical state (330, 344, 345). Decrease in pulmonary function has been noted 2–4 years before the onset of CFRD, with improvement with insulin therapy (346). The course of CFRD is complicated by the need for high caloric intake to counter malabsorption and catabolism, the intermittent use of glucocorticoids, and re-

current infection. The diabetes has features of type 1 and type 2 disease, with insulin dependency and resistance (15, 335, 347, 348). A recent report noted impaired glucose tolerance in 20% of 18 children with cystic fibrosis aged 9.5–15 years who were studied for the relationship of insulin secretion, IGF axis, and growth. However, impaired insulin secretion was present in 65% and was related to poor linear growth. It was considered that the increased demands for insulin during the pubertal growth period could indicate the need for treatment of growing children before the appearance of overt diabetes (349).

B.

Infantile Diabetes

1. Transient Diabetes of the Newborn This rare condition occurs from the first few hours to 6 weeks of life in small for gestational age infants who ap-

Diabetes in Child and Adolescent

pear hyperalert with marked subcutaneous wasting (350). Onset is sudden, with severe dehydration in the absence of vomiting or diarrhea. Histological appearance of the pancreas has been reported as normal (351, 352), showing decrease in islet cells (353, 354) or increased numbers of islets (355). Approximately one-third of reported patients have a family history of type 1 diabetes (350) and have siblings who have been reported with transient diabetes of the newborn (356–358). Insulin may be required for a few days to a few months. Some infants may have permanent diabetes and a number have been reported to develop diabetes 8–20 years later (359–363). 2. Pancreatic Dysgenesis/Agenesis Infants with transient diabetes who subsequently develop permanent diabetes (358–363) are thought to have dysgenesis of the pancreas. In one of these patients, no evidence of islet cell or other organ-specific autoimmunity was detected (361). Only a few patients with severe pancreatic dysgenesis or agenesis have been reported, with permanent neonatal diabetes. Some have not survived, particularly those with associated anomalies such as gallbladder achalasia, diaphragmatic hernia, and cardiac defects (364, 365). Several infants without associated anomalies have survived, including siblings from our clinic, both with onset at 4 months of age, who are now in their mid-30s and have long-term complications (366–368). Such patients have exocrine and endocrine deficiency.

REFERENCES 1. 2. 3. 4.

5. 6. 7.

8.

Rosenbloom AL, Ongley JP. Who provides what services to children in private medical practice? Am J Dis Child 1974; 127:357–361. Wilkins L. The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, 3rd edition. Springfield IL: Charles C. Thomas, 1965:542. Rosenbloom AL, Deeb LC, Allen L, Pollock BH. Characteristics of pediatric endocrinology practice: a workforce study. Endocrinologist 1998; 8:213–218. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2001; 24:S5–20. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979; 28:1039–1057. Winter WE, Maclaren NK, Riley WJ, et al. Maturity-onset diabetes of youth in black Americans. N Engl J Med 1987; 316:285–291. Banerji MA, Chaiken RL, Juey H, Tuomi T, Norin AJ, Mackay IR, Rowley MJ, Zimmet PZ, Lebovitz HE. GAD antibody negative NIDDM in adult with black subjects with diabetic ketoacidosis and increased frequency of human leukocyte antigen DR3 and DR4: Flatbush diabetes. Diabetes 1994; 43:741–745. American Diabetes Association. Type 2 diabetes in children and adolescents: consensus conference report. Diabetes Care 2000; 23:381–389.

641 9. 10.

11.

12.

13. 14.

15. 16.

17.

18. 19. 20. 21.

22.

23.

24.

25. 26.

Winter WE. Molecular and biochemical analysis of the MODY syndromes. Pediatr Diabetes 2000; 1:88–117. Reardon W, Ross RJM, Sweeney MG, Luxon LM, Pembrey ME, Harding AE, Trembath RC. Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 1992; 340:1376–1379. van den Ouwenland JMW, Lemkes HHPJ, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PAA, van de Kamp JJ, Maassen JA. Mutation in mitochondrial tRNA (Leu(URR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nature Genet 1992; 1:368–371. Kadowaki T, Kadowaki H, Mori Y, Tobe K, Sakuta R, Suzuki Y, Tanabe Y, Sakura H, Awata T, Goto Y, et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 1994; 330:962– 968. Taylor SI. Lilly Lecture: molecular mechanisms of insulin resistance: lessons from patients with mutations in the insulin-receptor gene. Diabetes 1992; 41:1473–1490. Rosenbloom AL, Goldstein S, Yip CC. Normal insulin binding to cultured fibroblasts from patients with lipoatrophic diabetes. J Clin Endocrinol Metab 1977; 44:803– 806. Moran A, Doherty L, Wang X, Thomas W. Abnormal glucose metabolism in cystic fibrosis J Pediatr 1998; 133: 10–17. Berelowitz M, Eugene HG. Non-insulin-dependent diabetes mellitus secondary to other endocrine disorders. In: LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes Mellitus. New York: Lippincott-Raven, 1996:496–502. Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, Price DA. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth hormone treatment. Lancet 2000; 355:610–613. Rosenbloom AL. Hot topic. Fetal growth, adrenocortical function, and the risk for type 2 diabetes. Pediatr Diabetes 2000; 1:150–154. Pandit MK, Burke J, Gustafson AB, Minocha A, Peiris AN. Drug-induced disorders of glucose tolerance. Ann Intern Med 1993; 118:529–540. O’Byrne S, Feely J. Effects of drugs on glucose tolerance in non-insulin-dependent diabetes (parts I and II). Drugs 1990; 40:203–219. Bouchard P, Sai P, Reach G, Caubarrere I, Ganeval D, Assan R. Diabetes mellitus following pentamidine-induced hypoglycemia in humans. Diabetes 1982; 31:40– 45. Assan R, Perronne C, Assan D, Chotard L, Mayaud C, Matheron S, Zucman D. Pentamidine-induced derangements of glucose homeostasis. Diabetes Care 1995; 18: 47–55. Gallanosa AG, Spyker DA, Curnow RT. Diabetes mellitus associated with autonomic and peripheral neuropathy after Vacor poisoning: a review. Clin Toxicol 1981; 18: 441–449. Esposti MD, Ngo A, Myers MA. Inhibition of mitochondrial complex I may account for IDDM induced by intoxication with rodenticide Vacor. Diabetes 1996; 45: 1531–1534. Forrest, JA, Menser MA, Burgess JA. High frequency of diabetes mellitus in young patients with congenital rubella. Lancet 1971; 2:332–334. Rosenbloom AL. Type 2 diabetes in children. American

642

27.

28.

29. 30.

31. 32.

33.

34.

35.

36.

37. 38.

39. 40.

41. 42.

Rosenbloom and Silverstein Association for Clinical Chemistry. Diagn Endocrinol Immunol Metabol 2000; 18:143–153. Hathout EH, Thomas W, El-Shahawy, Nabab F, Mace JW. Diabetic autoimmune markers in children and adolescents with type 2 diabetes. Pediatrics 2001 http://www. pediatrics.org/cgi/content/full/107/6/e102. Macaluso CJ, Bauer UE, Deeb LC, Malone JI, Chaudhari M, Silverstein J, Eidson M, Arbelaez AM, Goldberg RB, Gaughan-Bailey B, Brooks RG, Rosenbloom AL. Type 2 diabetes mellitus among Florida children, 1994 through 1998. Public Health Rep (in press). Fletcher RH, Fletcher SW, Wagner EH. Clinical Epidemiology, The Essentials. 2nd ed. Baltimore: Williams & Wilkins, 1988. Sekikawa A, LaPorte RE. Epidemiology of insulin-dependent diabetes mellitus. In Alberti KGMM, Zimmet P, DeFronzo RA, eds. International Textbook of Diabetes Mellitus. 2nd ed, vol 1. West Sussex, UK: John Wiley & Sons, 1997:89–96. LaPorte RE, Tuomilehto J, King H. WHO Multinational Project for Childhood Diabetes. Diabetes Care 1990; 13: 1062–1068. Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J, for the Diabetes Mondiale (DiaMond) Project Group. Incidence of childhood type 1 diabetes worldwide. Diabetes Care 2000; 23:1516–1526. LaPorte RE, Matsushima M, Chang Y-F. Prevalence and incidence of insulin-dependent diabetes. In National Diabetes Data Group, eds. Diabetes in America, 2nd ed. Washington, DC: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, NIH Publication No. 95-1468, 1995:37–46. Mimura G. Present status and future view of the genetics of diabetes in Japan. In Mimura G, Baba S, Goto W, Kobberling J, eds. Clinical Genetics of Diabetes Mellitus, International Congress Series 597. Amsterdam: Excerpta Medica, 1982:13–18. Kitagawa T, Fujita H, Hibi I, et al. A comparative study of the epidemiology of IDDM between Japan, Norway, Israel and the United States. Acta Paediatr Jpn 1984; 26: 275–281. Siemaitycki J, Colle E, Campbell S, Dewar R, Aubert D, Bellmonte, M. Incidence of IDDM in Montreal by ethnic group and by social class and comparisons with ethnic groups living elsewhere. Diabetes 1988; 37:1096–1112. Burden AC, Burden ML, Williams ER, et al. Evidence of frequent epidemics of childhood diabetes. Diabetes 1991; 40:373A. Karvonen M, Tuomilehto J, Libman I, LaPorte R for the World Health Organization DiaMond Project Group. A review of the recent epidemiological data on the worldwide incidence of type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1993; 36:83–892. Diabetes Epidemiology Research International Group. Secular trends in incidence of childhood IDDM in 10 countries. Diabetes 1990; 39:858–864. Dahlquist G, Blom L, Holmgren G, Hagglof B, Larson Y, Sterky G, Wall S. The epidemiology of diabetes in Swedish children 0–14 years—a six-year prospective study. Diabetologia 1985; 28:802–808. Joner G, Sovik O. Incidence, age at onset and seasonal variation of diabetes mellitus in Norwegian children. Acta Paediatr Scand 1981; 70:329–325. Tull ES, Roseman JM, Christian CLE. Epidemiology of childhood IDDM in U.S. Virgin Islands from 1979 to 1998. Diabetes Care 1991; 14:558–564.

43.

44.

45.

46. 47.

48.

49.

50.

51.

52. 53.

54.

55.

56.

57. 58.

Zhao HX, Stenhouse E, Soper C, Hughes P, Sanderson E, Baumer JH, Demaine AG, Millward BA. Incidence of childhood-onset type 1 diabetes mellitus in Devon and Cornwall, England, 1975–1996. Diabet Med 1999; 16: 1030–1035. Fleegler FM, Rogers KD, Drash A, Rosenbloom AL, Travis LM, Court JM. Age, sex, and season of onset of childhood diabetes in different geographic areas. Pediatrics 1979; 63:374–379. Karvonen M, Tuomilehto J, Virtala E, Pitkaniemi J, Feunanen A, Tuomilehto-Wolf E, Akerblom KA for the Childhood Diabetes in Finland (DiMe) Study Group. Seasonality in the clinical onset of insulin-dependent diabetes mellitus in Finnish children. Am J Epidemiol 1996; 143: 167–176. Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes. N Engl J Med 1994; 331:1428– 1436. Maclaren NK, Lan M, Coutant R, et al. Only multiple autoantibodies to islet cells (ICA), insulin, GAD65, IA-2 and IA-2␤ predict immune mediated (type 1) diabetes in relatives. J Autoimmun 1999; 12:279–287. Bingley PJ, Christie MR, Bonifacio E, et al. Combined analysis of autoantibodies improves prediction of IDDM in islet sell antibody-positive relatives. Diabetes 1994; 43: 1304–1310. Kulmala P, Savola K, Peterson JS, and the Childhood Diabetes in Finland (DiMe) Study Group. Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes. J Clin Invest 1998; 101:327–336. Krischer JP, Schatz D, Riley WJ, Spillar RP, Silverstein JH, Schwartz S, Malone J, Shah S, Vadheim CM, Rotter JI, Quatrin T, Maclaren NK. Insulin and islet cell autoantibodies as time dependent co-variates in the development of insulin dependent diabetes: a prospective study in relatives. J Clin Endocrinol Metab 1993; 77:743–749. Riley WJ, Maclaren NK, Krischer JP, Spillar RP, Silverstein JH, Schatz D, Shah S, Vadheim CM, Rotter JI. A prospective study of the development of diabetes in relatives of patients with insulin dependent diabetes. N Engl J Med 1990; 323:1167–1172. DPT-1 Study Group. The Diabetes Prevention Trial Type 1 Diabetes (DPT-1). Diabetes 1994; 43(Suppl)159A. Bougneres PF, Carel JC, Castano L, et al. Factors associated with early remission of type 1 diabetes in children treated with cyclosporine. N Engl J Med 1988; 318:663– 670. Lipton R, LaPorte RE, Becker DJ, et al. Cyclosporin therapy for prevention and cure of IDDM. Epidemiologic perspective of benefits and risks. Diabetes Care 1990; 13: 776–74. Silverstein J, Maclaren N, Riley W, Spillar R, Radjenovic D, Johnson S. Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N Engl J Med 1988; 319:599–604. Shah SC, Malone JI, Simpson NE. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N Engl J Med 1989; 320:550– 554. Keller RJ, Eisenbarth GS, Jackson RA. Insulin prophylaxis in individuals at high risk of type 1 diabetes. Lancet 1993; 341:927–928. Diabetes Prevention Trial—Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002; 346:1685–1691.

Diabetes in Child and Adolescent 59. 60. 61. 62.

63. 64.

65.

66. 67.

68. 69. 70. 71. 72.

73. 74.

75.

76.

77.

Pozzilli P, Andreani D. The potential role of Nicotinamide in the secondary prevention of IDDM. Diabetes Metab Rev 1993; 9:219–230. Kolb H, Burkert V. Nicotinamide in type 1 diabetes. DiabetesCare 1999; 22:B16–B20. Elliott RB, Chase HP. Prevention or delay to type 1 (insulin-dependent) diabetes mellitus in children using nicotinamide. Diabetologia 1991; 34:362–365. Elliott R, Pilcher C, Fergusson D, Stewart A. A population based strategy to prevent insulin-dependent diabetes using nicotinamide. J Pediatr Endocrinol Metab 1996; 9: 501–509. Rosenbloom AL, Schatz DA, Krischer JP, et al. Therapeutic controversy. Prevention and treatment of diabetes in children. J. Clin Endocrinol Metab 2000; 85:494–508. Lampeter EF, Klinghammer A, Scherbaum WA, et al. The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. DENIS group. Diabetes 1998; 47:980–994. Green A, Patterson CC, EURO DIAB TIGER Study Group. Trends in the incidence of childhood-onset diabetes in Europe 1989–98 Diabetologia 2001; 44(Suppl 3): B3–B8. Karvonen M, Pitkaniemi J, Tuomilehto J. The onset age of type 1 diabetes in Finnish children has become younger. Diabetes Care 1999; 22:1066–1070. Gardner SG, Bingley PJ, Sawtell PA, Weeks S, Gale EAM. Rising incidence of insulin dependent diabetes in children aged under 5 years in the Oxford region. Br Med J 1997; 315:713–717. Hyppo¨nen E, La¨a¨ra¨ E, Reunanen A, Ja¨rvelin M-R, Virtanen S. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358:1500–1503. Schein PS, Alberti KG, Williamson DH. Effects of streptozotocin on carbohydrate and lipid metabolism in the rat. Endocrinology 1971; 89:827–834. Banerjee S. Effect of certain substances of the prevention of diabetogenic action of alloxan. Science 1947;128–130. Pont A, Rubino JM, Bishop D. Diabetes mellitus and neuropathy following Vacor ingestion in man. Arch Intern Med 1979; 139:185–187. McKinney PA, Okasha M, Parslow RC, Law GR, Gurney KA, Williams R, Bodansky HJ. Early social mixing and childhood type 1 diabetes mellitus: a case–control study in Yorkshire, UK. Diabet Med 2000; 17:236–242. Karjalainen J, Martin JM, Knip M, et al. A bovine serum albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med 1992; 327:302–307. Norris JM, Beaty B, Klingensmith G, Hoffman MN, Yu L, Chase HP, Erlich HA, Hamman RF, Eisenbarth GS, Rewers M. Lack of association between early exposure to cow’s milk protein and beta-cell autoimmunity: Diabetes Autoimmunity Study in the Young. JAMA 1996; 276:609–614. Papaccio G, Ammendola E, Pisanti FA. Nicotinamide decreases MHC class II but not MHC class I expression and increases intercellular adhesion molecule-1 structures in non-obese diabetic mouse pancreas. J Endocrinol 1999; 160:389–400. Hyoty H, Hiltunen M, Knip M, Laakkonen M, Vahasalo P, Karjalainen J, Koskela P, Roivainen M, Leinikki P, Hovi T, Akerblom HK. A prospective study of the role of coxsackie B and other enteroviral infections in the pathogenesis of IDDM. Diabetes 1995; 44:652–657. Dahlquist GG, Ivarsson S, Lindberg B, Forsgren M. Ma-

643

78. 79.

80.

81. 82. 83.

84.

85.

86.

87. 88. 89.

90.

91.

92.

ternal enteroviral infection during pregnancy as a risk factor for childhood IDDM. Diabetes 1995; 44:408–413. Uriarte A, Cabrera E, Ventura R, Vargas J. Islet cell antibodies and ECHO-4 virus infection. Diabetologia 1987; 30:590A. Honeyman MC, Coulson BS, Stone NL, Gellert SA, Goldwater PN, Steele CE, Couper JJ, Tait BD, Colman PG, Harrison LC. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 2000; 49:1219– 1324. Helmke K, Otten A, Willems WR, Brockhaus R, MuellerEckhardt G, Stief T, Bertrams J, Wolf H, Federlin K. Islet cell antibodies and the development of diabetes mellitus in relation to mumps infection and mumps vaccination. Diabetologia 1986; 29:30–33. Silverstein JH, Rosenbloom AL. New developments in type 1 (insulin-dependent) diabetes. Clin Pediatr 2000; 39:257–266. Malone JI, Hellrung JM, Malphus EW, Rosenbloom AL, Grgic A, Weber FT. Good diabetic control—a study in mass delusion. J Pediatr 1976; 88:943–947. Rosenbloom AL, Silverstein JH, Riley WJ, Malone JI, Lezotte DC, McCallum M, Maclaren NK, Neufeld M. Total glycosylated hemoglobin estimation in the management of children and youth with diabetes. Bull Int Study Group Diabetes Child Adolesc 1980; 4:24–25. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) Research Group. Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT). J Pediatr 2001; 139:804–812. Rosenbloom AL, Lezotte DC, Weber FT, Gudat J, Heller DR, Weber ML, Klein S, Kennedy BB. Diminution of bone mass in childhood diabetes. Diabetes 1977; 26: 1052–1055. Ponder SW, McCormick DP, Fawcett HD, Tran AD, Oglesby GW, Brouhard BH, Travis LB. Bone mineral density of the lumbar vertebrae in children and adolescents with insulin-dependent diabetes mellitus. J Pediatr 1992; 120:541–545. Roe TF, Mora S, Costin G, Kaufman F, Carlson ME, Gilsanz V. Vertebral bone density in insulin-dependent diabetic children. Metabolism 1991; 40:967–971. De Schepper J, Smitz J, Rosseneu S, Bollen P, Louis O. Lumbar spine bone mineral density in diabetic children with recent onset. Horm Res 1998; 50:193–196. Rozadilla A, Nolla JM, Montana E, Fiter J, Gomez-Vaquero C, Sorler J, Roig-Escofet D. Bone mineral density in patients with type 1 diabetes mellitus. Joint Bone Spine 2000; 67:215–218. Gunczler P, Lanes R, Paz-Martinez V, Martins R, Esaa S, Colmenares V, Weisinger JR. Decreased lumbar spine bone mass and global turnover in children and adolescents with insulin-dependent diabetes mellitus followed longitudinally. J Pediatr Endocrinol Metab 1998; 11:413– 419. Gunczler P, Lanes R, Paoli M, Martinis R, Villaroel O, Weisinger JR. Decreased bone mineral density and bone formation markers shortly after diagnosis of clinical type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2001; 14: 525–528. Malone JI, Lowitt S, Duncan JA, Shah S, Vargas A, Root A. Hypercalciuria, hyperphosphaturia, and growth retar-

644

93.

94. 95. 96.

97.

98. 99.

100. 101. 102.

103. 104.

105.

106.

107.

108.

109.

110.

Rosenbloom and Silverstein dation in children with diabetes mellitus. Pediatrics 1986; 78:298–304. Thalassinor NC, Hadjiyauni P, Tzanela M, Akvizaki C, Philokiprou D. Calcium metabolism and diabetes mellitus: effect of improved blood glucose control. Diabet Med 1993; 10:341–344. Heath H, Melton LJ, Chic GP. Diabetes mellitus and risk of skeletal fracture. N Engl J Med 1980; 303:567–570. Rosenbloom AL, Frias JL. Diabetes mellitus, short stature and joint stiffness—a new syndrome. Clin Res 1974; 22: 92A. Grgic A, Rosenbloom AL, Weber FT, Giordano B, Malone JI, Shuster JJ. Joint contracture—common manifestation of childhood diabetes mellitus. J Pediatr 1976; 88: 584–588. Rosenbloom AL, Silverstein JH, Lezotte DC, Richardson K, McCallum M. Limited joint mobility in childhood diabetes mellitus indicates increased risk for microvascular disease. N Engl J Med 1981; 305:191–194. Salzarulo HH, Taylor LA. Diabetic ‘‘stiff joint syndrome’’ as a cause of difficult endotracheal intubation. Anesthesiology 1986; 64:366–368. Schnapf BM, Banks R, Silverstein JH, Rosenbloom AL, Chesrown S, Loughlin G. Pulmonary function in insulin dependent diabetes mellitus with limited joint mobility. Am Rev Respir Dis 1984; 130:930–932. Hanna W, Friesen D, Bombardier C, Gladman D, Hanna A. Pathological features of diabetic thick skin. J Am Acad Dermatol 1987; 16:546–553. Rosenbloom AL, Williams J, Linda SB. Quantitative assessment of limited joint mobility (LJM) in diabetes from radiographs. J Pediatr Endocrinol 1991; 4:243–247. Rosenbloom AL, Silverstein JH, Lezotte DC, Riley WJ, Maclaren NK. Limited joint mobility in diabetes mellitus of childhood: natural history and relationship to growth impairment. J Pediatr 1982; 101:874–878. Kohn RR, Schnider SL. Glucosylation of a of human collagen. Diabetes 1982; 31(suppl 3):47–51. Monnier VM, Vishwanath V, Frank KE, Elmets CA, Dauchot P, Kohn RR. The relation between complications of type 1 diabetes mellitus and collagen-linked fluorescence. N Engl J Med 1986; 314:403–408. Rosenbloom AL, Malone JI, Yucha J, Van Cader TC. Limited joint mobility and diabetic retinopathy demonstrated by fluorescein angiography. Eur J Pediatr 1984; 141:163–164. Starkman HS, Gleason RE, Rand LI, Miller DE, Soeldner J. Limited joint mobility (LJM) of the hand in patients with diabetes mellitus: relation to chronic complications. Ann Rheum Dis 1986; 45:130–135. Silverstein JH, Fennell R, Donnelly W, Banks R, Stratton R, Spillar R, Rosenbloom AL. Correlates of biopsy-studied nephropathy in young patients with insulin-dependent diabetes mellitus. J Pediatr 1985; 106:196–201. Silverstein JH, Gordon G, Pollock BH, Rosenbloom AL. Long term glycemic control influences the development of limited joint mobility in type 1 diabetes. J Pediatr 1998; 132:944–947. Infante J, Rosenbloom AL, Silverstein JH, Garzarella L, Pollack BH. Changes in frequency and severity of limited joint mobility in children with type 1 diabetes mellitus between 1976–78 and 1998. J Pediatr 2001; 138:33–37. Kelly WF, Nicholas J, Adams J, Mahmood R. Necrobiosis lipoidica diabeticorum: association with background retinopathy, smoking, and proteinuria. A case control study. Diabet Med 1993; 10:725–728.

111.

112. 113.

114. 115.

116.

117.

118.

119.

120.

121.

122.

123.

124. 125. 126. 127. 128.

Raile K, Noelle V, Landgraf R, Schwarz HP. Insulin antibodies are associated with lipoatrophy but also with lipohypertrophy in children and adolescents with type I diabetes. Exp Clin Endocrinol Diabetes 2001; 109:393– 396. Roper NA, Bilous RW. Resolution of lipohypertrophy following change of short-acting insulin to insulin lispro (Humalog). Diabet Med 1998; 15:1063–1064. Muritano ML, La Roche GR, Stevens JL, Gloor BRD, Schoenle EJ. Acute cataracts in newly diagnosed IDDM in five children and adolescents. Diabetes Care 1995; 18: 1395–1396. Tattersall RB, Pyke DA. Growth in diabetic children: studies in identical twins. Lancet 1973; 2:1105–1109. Holl RW, Heinze E, Seifert M, Grabert M, Teller WM. Longitudinal analysis of somatic development in pediatric patients with IDDM: genetic influences on weight. Diabetologia 1994; 37:925–929. Salerno M, Argenziano A, Di Maio S, Gasparini N, Formicola S, De Filippo G, Tenore A. Pubertal growth, sexual maturation, and final height in children with IDDM. Diabetes Care 1997; 20:721–724. Rosenbloom AL, Silverstein JH, Lezotte DC, Riley WJ, Maclaren NK. Limited joint mobility in diabetes mellitus of childhood: natural history and relationship to growth impairment. J Pediatr 1982; 101:874–878. Infante JR, Rosenbloom AL, Silverstein JH, Garzarella L, Pollack BH. Limited joint mobility (LJM) and stature in childhood type 1 diabetes (DM1): improved methods of control are making a difference. Proceedings, Endocrinology Society 81st Annual Meeting. San Diego, CA, 1999. Menon RK, Arslanian S, May B, Cutfield WS, Sperling MA. Diminished growth hormone binding protein in children with insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1992; 74:934–938. Massa G, Dooms L, Bouillon R, Vanderschueren-Lodeweyckz. Serum levels of growth hormone binding protein and insulin like growth factor I in children and adolescents with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1993; 36:239–243. Munoz MT, Barrior, Pozo J, Argente J. Insulin like growth factor I, its binding proteins 1 and 3, and growth hormone binding protein in children and adolescents with insulin-dependent diabetes mellitus: clinical implications. Pediatr Res 1996; 39:992–998. Bereket A, Lang CH, Wilson TA. Alterations in the growth hormone insulin like growth factor axis in insulindependent diabetes mellitus. Horm Metab Res 1999; 31: 172–181. Mauriac P. Gros ventre, he´patome´galie, troubles de croissance chez les enfants diabe´tiques traite´s depuis plusiers anne´e par l’insuline. Gaz Hebd Med Bordeaux 1930; 26:402–410. Rosenbloom AL, Clarke DW. Excessive insulin treatment and the Somogyi effect. In Pickup J, ed. Difficult Diabetes. Oxford: Blackwell, 1985: 103–131. Marble A, White P, Bogan I, Smith R. Enlargement of the liver in diabetic children: I. Its incidence etiology and nature. Arch Intern Med 1938; 62:740–750. Lasalle R, Chicoine L. Le syndrome de Mauriac: une observation clinique. Union Med Can 1962; 91:963–968. Lee RG, Bode HH. Stunted growth and hepatomegaly in diabetes mellitus. J Pediatr 1977; 91:82–84. Dorchy H, van Vliet G, Toussaint D, Ketelbant-Balasse

Diabetes in Child and Adolescent

129. 130.

131.

132.

133.

134.

135. 136.

137.

138.

139.

140.

141.

142.

143.

P, Loeb H. Mauriac syndrome: three cases with retinal angiofluorescein study. Diabete Metab 1979; 5:195–200. Winter R, Phillips L, Green O, Traisman H. Somatomedin activity in the Mauriac syndrome. J Pediatr 1980; 97: 589–600. Riley WJ, Maclaren NK, Lezotte DC, Spillar RP, Rosenbloom AL. Thyroid autoimmunity in insulin-dependent diabetes mellitus. The case for routine screening. J Pediatr 1981; 98:350–354. Aktay AN, Lee PC, Kumar V, Parton E, Wyatt DT, Werlin SL. The prevalence and clinical characteristics of celiac disease in juvenile diabetes in Wisconsin. J Pediatr Gastroenterol Nutr 2001; 33:462–465. Affenito SG, Adams CH. Are eating disorders more prevalent in females with type 1 diabetes mellitus when the impact of insulin omission is considered? Nutr Rev 2001; 59:179–182. Greene DA, Lattimer SA, Simon AAF. Sorbitol, inositides and sodium potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 1987; 316:599– 606. Lee P, Jenkins P, Bourke C, et al. Prothrombotic and antithrombotic factors are elevated in patients with type 1 diabetes complicated by microalbuminuria. Diabet Med 1993; 10:122–128. Viberti GC, Hill RD, Jarret TRJ, et al. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1982; 1:1430–1432. Chaturvedi N, Bandinelli S, Mangill R, Penno G, Rottiers RE, Fuller JH. Microalbuminuria in type 1 diabetes: rates, risk factors and glycemic threshold. Kidney Int 2001; 60: 219–227. Twyman S, Rowe D, Mansell P, Schapira D, Betts P, Leatherdale B. Longitudinal study of urinary albumin excretion in young diabetic patients—Wessex Diabetic Nephropathy Project. Diabet Med 2001; 18:402–408. Santilli F, Spagnoli A, Mohn A, Tumini S, Verrotti A, Cipollone F, Mezzetti A, Chiarelli F. Increased vascular endothelial growth factor serum concentrations may help to identify patients with onset of type 1 diabetes during childhood at risk for developing persistent microalbuminuria. J Clin Endocrinol Metab 2001; 86:3871– 3876. Olsen BS, Sjolie A, Hougaard P, Johannesen J, BorchJohnsen K, Marinelli K, Thorsteinsson B, Pramming S, Mortensen HB. A 6-year nationwide cohort study of glycaemic control in young people with type 1 diabetes. Risk markers for the development of retinopathy, nephropathy and neuropathy. Danish Study Group of Diabetes in Childhood. J Diabetes Complications 2000; 14:295–300. Levy-Marchal C, Sahler C, Cahane M, Czernichow P. Risk factors for microalbuminuria in children and adolescents with type 1 diabetes. J Pediatr Endocrinol Metab 2000; 13:613–620. Warram JH, Scott LJ, Hanna LS, et al. Progression of microalbuminuria to proteinuria in type 1 diabetes: nonlinear relationship with hyperglycemia. Diabetes 2000; 49:94–100. Orchard TJ, Forrest KYZ, Kuller LH, Becker DJ. Lipid and blood pressure treatment goals for type 1 diabetes: 10-year incidence data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 2001; 24:1053–1059. Chiarelli F, Pomilio M, Mohn A, et al. Homocysteine levels during fasting and after methionine loading in ad-

645

144. 145.

146. 147.

148.

149. 150.

151. 152.

153. 154. 155. 156. 157. 158. 159.

160. 161. 162.

olescents with diabetic retinopathy and nephropathy. J Pediatr 2000; 137:386–392. UKPDS Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 1998; 317:703–713. Mathiesen ER, Hommel E, Giese J, Parving HH. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. Br Med J 1991; 303:81–87. Dahlquist G, Rudberg S. The prevalence of microalbuminuria in diabetic children and adolescents and its relation to puberty. Acta Pediatr Scand 1987; 76:795–800. Joner G, Brinchmann-Hansen O, Torres CG, Hanssen KF. A nationwide cross-sectional study of retinopathy and microalbuminuria in young Norwegian type 1 (insulin dependent) diabetic patients. Diabetologia 1992; 35:1049– 1054. Mortensen HB, Marinelli K, Norgaard K, et al. A nationwide cross-sectional study of urinary albumin excretion rate, arterial blood pressure and blood glucose control in Danish children with type 1 diabetes mellitus. Diabet Med 1990; 7:887–897. Davies AG, Price DA, Poslethwaite RJ, Addison GM, Burn JL, Fielding BA. Renal function in diabetes mellitus. Arch Dis Child 1985; 60:299–304. Mathiesen ER, Ronn B, Jensen T, Storm B, Deckert T. Relationship between blood pressure and urinary albumin excretion in development of microalbuminuria. Diabetes 1990; 39:245–249. Walker C, Dodds RA, Murrells TJ, et al. Restriction of dietary protein in progression of renal failure in diabetic nephropathy. Lancet 1989; 2:1411–1444. Dullart RP, Beusekump BJ, Meijer S, et al. Long term effects of protein restricted diet on albuminuria and renal function in IDDM patients without clinical nephropathy and hypertension. Diabetes Care 1993; 16:483–492. Morgensen CE. The kidney and diabetes: how to control renal and related cardiovascular complications. Am J Kidney Dis 2001; 37(Suppl 2):S2–S6. Sawicki PT, Didjurgeit U, Muhlha¨user I, et al. Smoking is associated with progression of diabetic nephropathy. Diabetes Care 1994; 17:126–131. Kohner E, et al. The retinal blood flow in diabetes. Diabetologia 1975; 2:27–33. Cunha-Vaz JG, et al. Early breakdown of the blood–retinal barrier in diabetes. Br J Ophthalmol 1975; 59:649– 656. Keen H. Chronic complications of diabetes mellitus In: Galloway JP, Patvin JH, Shuman CR, eds. Diabetes Mellitus. Indianapolis: Eli Lilly, 1988:178–305. Will JC, Geiss LSM, Wetterhall SF. Diabetic retinopathy. N Engl J Med 1990; 323:613. Chaturvedi N, Sjoelie AK, Porta M, Aldington SJ, Fuller JH, Songini M, Kohner EM. Markers of insulin resistance are strong risk factors for retinopathy incidence in type 1 diabetes. Diabetes Care 2001; 24:284–289. Roy MS. Diabetic retinopathy in African American with type 1 diabetes: New Jersey 725: II. Risk factors. Arch Ophthalmol 2000; 118:105–115. Roy MS, Klein R. Macular edema and retinal hard exudates in African Americans with type 1 diabetes: the New Jersey 725. Arch Ophthalmol 2001; 119:251–259. Chaturvedi N, Sjolie AK, Stephenson JM. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID study group

646

163. 164. 165. 166. 167.

168.

169.

170.

171.

172.

173. 174.

175. 176. 177.

178.

179.

180.

Rosenbloom and Silverstein EURO DIAB controlled trial of lisinopril in insulin dependent diabetes mellitus. Lancet 1998; 351:28–31. Neely KA, Quillen DA, Schachatap, et al. Diabetic retinopathy. Med Clin North Am 1998; 82:847–87637. The Diabetic Retinopathy Study Research Group. Photocoagulation of proliferative diabetic retinopathy. Trans Am Acad Ophthalmol Ontolaryngol 1978; 85:82–106. Elfervig LS, Elfervig JL. Proliferative diabetic retinopathy. Insight 2001; 26:88–91. Bell DHS, Ward J. Peripheral and cranial neuropathies in diabetes. In Davidson JD, ed. Clinical diabetes mellitus. 3rd ed. New York: Thieme, 2000:621–635. White NH, et al. Reversal of neuropathic and gastrointestinal complications relate to diabetes mellitus in adolescents with improved metabolic control. J Pediatr 1981; 99:41–45. Maser RE, Steenkiste R, Dorman JS, et al. Epidemiological correlates of diabetic neuropathy: report from Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes 1989; 38:1456–1461. Ka¨a¨r ML, Saukkonen AL, Pitka¨nen, Akerblom HK. Peripheral neuropathy in diabetic children and adolescents. A cross-sectional study. Acta Paediatr Scand 1983; 73: 373–378. Dorchy H, Noel P, Kruger M, et al. Peroneal motor nerve conduction velocity in diabetic children and adolescents. Relationship to metabolic control, HLA-DR antigens, retinopathy and EEG. Eur J Pediatr 1985; 44:310–315. Becker DJ, Greene DA, Aono SA, et al. Assessment of subclinical autonomic and peripheral neuropathy in childhood insulin-dependent diabetes mellitus. Pediatr Adolesc Endocrinol 1988; 17:173–178. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993; 329:977–986. Reid B, DiLorenzo C, Trains L, et al. Diabetic gastroparesis due to postprandial antral hypomobility in childhood. Pediatrics 1992; 90:43–46. White N, Waltman S, Krupi T, et al. Reversal of neuropathic and gastrointestinal complications related to diabetes mellitus in adolescents with improved metabolic control. J Pediatr 1981; 99:41–45. Reid B, DiLorenzo C, Trains L, et al. Diabetic gastroparesis due to postprandial antral hypomobility in childhood. Pediatrics 1992; 90:43–46. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979; 241:2035– 2038. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16:434–444. Goldbourt U, Yaari S, Medalie JH. Factors predictive of long-term coronary heart disease mortality among 10059 male Israeli civil servants and municipal employees. Cardiology 1993; 82:100–121. Mudrikova T, Gmitrov J, Tkac I, Gonsorcik J, Szakacs M. Cardiovascular risk factors as predictors of mortality in type II diabetic patients. Wien Klin Wochenschr 1999; 111:66–69. Turner RC, Millns H, Neil HAW, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). Br Med J 1998; 16:823–828.

181.

182. 183. 184. 185.

186.

187.

188.

189.

190.

191.

192.

193. 194. 195. 196. 197.

Wei M, Gaskill SP, Haffner SM, Stern NP. Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality: the San Antonio Heart Study. Diabetes Care 1998; 21:1167–1172. Moss DR Klein BEK, Meuer SM. The association of glycemia and cause-specific mortality in a diabetic population. Arch Intern Med 1994; 154:2473–2479. Anderson DKG, Svardsudd K. Long-term glycemic control relates to mortality in type II diabetes. Diabetes Care 1995; 18:1534–1543. Kuusisto J, Mykkanen L, Pyorala K, Lasko M. NIDDM and its metabolic control predic coronary heart disease in elderly subjects. Diabetes 1994; 43:960–967. Malcom GT, Oalmann MC, Strong JP. Risk factors for atherosclerosis in young subjects: The PDAY Study— Pathobiological Determinants of Atherosclerosis in Youth. Ann NY Acad Sci 1997; 817:179–188. Berenson GS, Srinivasan SR, Bao W, Newman WP, Tracy RE, Wattigney WA. The Bogalusa Heart Study association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med 1998; 338:1650–1656. Wilkinson IB, MacCallum H, Rooijmans DF, Murray GD, Cockcroft JR, McKnight JA, Webb DJ. Increased augmentation index and systolic stress in type 1 diabetes mellitus. Q J Med 2000; 93:441–448. Sarman B, Farkas K, Toth M, Somogyi A, Tulassay Z. Circulating plasma endothelin-1, plasma lipids and complications in Type 1 diabetes mellitus. Diabetes Nutr Metab 2000; 13:142–148. Gerstein HC, Mann JF, Yi Z, Zinman B, Dinneen SF, Hoogwef B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 2001; 286:421–426. Skowasch D, Lentini S, Andrie R, Jabs A, Bauriedel G. Verminderte Plattchenaggregation bei ACE-Hemmertherapie. Ergebnisse einer Pilotstudie. [Decreased platelet aggregation during angiotensin-converting enzyme inhibitor therapy. Results of a pilot study.] Dtsch Med Wochenschr 2001; 126:707–711. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with microvascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. Br Med J 2000; 321:394– 395. Hansson L, Zanchetti A, Carruthers SG, Dahlo¨f B, Elmfeldt D, Julius S, Me´nard J, Rahn KH, Wedel H, Westerling S for the HOT Study Group: effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet 1998; 351:1755–1762. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1997; 157:2413–2446. Knowles HC. Diabetes mellitus in childhood and adolescence. Med Clin North Am 1971; 55:975–987. Rosenbloom AL, Joe JR, Young RS, Winter WE. The emerging epidemic of type 2 diabetes mellitus in youth. Diabetes Care 1999; 22:345–354. Savage PJ, Bennett PH, Senter RG, Miller M. High prevalence of diabetes in young Pima Indians. Diabetes 1979; 28:937–942. Dabelea D, Hanson RL, Bennett PH, Roumain J, Knowler WC, Pettitt DJ. Increasing prevalence of type 2 diabetes

Diabetes in Child and Adolescent

198. 199. 200. 201. 202. 203.

204.

205.

206.

207.

208.

209. 210. 211. 212. 213.

214. 215. 216.

in American Indian children. Diabetologia 1998; 41:904– 910. Dean HJ. NIDDM-Y in First Nation children in Canada. Clin Pediatr 1998; 39:89–96. Pinhas-Hamiel O, Dolan LM, Daniels SR, et al. Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. J Pediatr 1996; 128:608–615. Pihoker C, Scott CR, Lensing SY, et al. Non-insulin dependent diabetes mellitus in African-American youths of Arkansas. Clin Pediatr 1998; 37:97–102. Glaser NS, Jones KL. Non-insulin-dependent diabetes mellitus in Mexican-American children. West J Med 1998; 168:11–16. Neufeld ND, Raffal LF, Landon C, Chen Y-DI, Vadheim CM. Early presentation of type 2 diabetes in MexicanAmerican youth. Diabetes Care 1998; 21:80–86. Fagot-Campagna A, Pettitt DJ, Engelgau MM, Burrows MT, Geiss LS, Valdez R, Beckles GLA, Saaddine J, Gregg EW, Villiamson DF, Narayan KMV. Type 2 diabetes among North American children and adolescents: an epidemiological review and a public health perspective. J Pediatr 2000; 136:664–72. Kadiki OA, Reddy MR, Marzouk AA. Incidence of insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes (NIDDM) (0–34 years at onset) in Benghazi, Libya. Diabetes Res Clin Pract 1996; 32:165–173. Chan JCN, Cheung CK, Swaminathan R, et al. Obesity, albuminuria, and hypertension among Hong Kong Chinese with non-insulin-dependent diabetes mellitus (NIDDM). Postgrad Med J 1993; 69:204–210. Kitagawa T, Owada M, Urakami T, Yamauchi K. Increased incidence of non-insulin dependent diabetes mellitus among Japanese schoolchildren correlates with an increased intake of animal protein and fat. Clin Pediatr 1998; 37:111–115. Sayeed MA, Hussain MZ, Banu A, Rumi MAK, Azad Khan AK. Prevalence of diabetes in a suburban population of Bangladesh. Diabetes Res Clin Pract 1997; 34: 149–155. Braun B, Zimmerman MB, Kretchmer N, Spargo RM, Smith RM, Gracey M. Risk factors for diabetes and cardiovascular disease in young Australian aborigines. A 5year follow-up study. Diabetes Care 1996; 19:472–479. McGrath NM, Parker GN, Dawson P. Early presentation of type 2 diabetes mellitus in young New Zealand Maori. Diabetes Res Clin Pract 1999; 43:205–209. Ehtisham S, Barrett TG, Shawl NJ. Type 2 diabetes mellitus in UK children—an emerging problem. Diabetic Med 2000; 17:867–871. Drake AJ, Smith A, Betts PR, Crowne EC, Shield JP. Type 2 diabetes in obese white children. Arch Dis Child 2002; 86:207–208. Troiano RP, Flegal KM. Overweight children and adolescents: description, epidemiology, and demographics. Pediatrics 1998; 101(suppl):497–504. Freedman DS, Srinivasan SR, Valdez RA, Williamson DF, Berenson GS. Secular increases in relative weight and obesity among children over two decades: the Bogalusa Heart Study. Pediatrics 1997; 99:420–426. Strauss RS, Pollack HA. Epidemic increase in childhood overweight, 1986–1998. JAMA 2001; 286:2845–2848. Reilly JJ, Dorosty AR. Epidemic of obesity in UK children. Lancet 1999; 354:1874–1875. Wang Y. Cross-national comparison of childhood obesity: the epidemic and the relationship between obesity and

647

217. 218. 219. 220. 221. 222.

223.

224.

225.

226.

227.

228.

229. 230. 231. 232.

233. 234. 235.

socioeconomic status. Int J Epidemiol 2001; 30:1129– 1136. Livingstone B. Epidemiology of childhood obesity in Europe. Eur J Pediatr 2000; 159(suppl 1):S14–S34. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002; 346:591–602. Blair SN, Nichaman MZ. The public health problem of increasing prevalence rates of obesity and what should be done about it. Mayo Clin Proc 2002; 77:109–113. Neel JV. Diabetes mellitus: a ‘‘thrifty’’ genotype rendered detrimental by ‘‘progress’’? Am J Hum Genet 1962; 14: 353–362. Lev-Ran A. Thrifty genotype: how applicable is it to obesity and type 2 diabetes? Diabetes Rev 1999; 7:1–22. Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of noninsulin-dependent diabetes mellitus: prospective studies of Pima Indians. N Engl J Med 1993; 329:1988–1992. Haffner SM, Stern MP, Dunn J, et al. Diminished insulin sensitivity and increased insulin response in non-obese, non-diabetic Mexican Americans. Metabolism 1990; 39: 842–847. Haffner SM, Miettinen H, Stern MP. Insulin secretion and resistance in non-diabetic Mexican Americans and nonHispanic whites with a parental history of diabetes. J Clin Endocrinol Metab 1996; 81:1846–1851. Groop L, Forsblom C, Lehtovirta M, Tuomi T, Karanko S, Nisse´n M, Ehrnstro˜m B-O, Forse´n B, Isomaa B, Snickers B, Taskinen N-R. Metabolic consequences of a family history of NIDDM (the Botnia Study): evidence for sex specific parental effects. Diabetes 1996; 45:1585–1593. Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25 year follow-up study. Lancet 1992; 340:925– 929. Pigon J, Giacca A, Ostenson C-G, Lam L, Vranic M, Efendi S. Normal hepatic insulin sensitivity in lean, mild non-insulin-dependent diabetic patients. J Clin Endocrinol Metab 1996; 81:3702–3708. O’Rahilly S, Turner RC, Matthew D. Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med 1988; 318:1225– 30. AR Saltiel, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1994; 45:1661–1669. Philipps K, Barker DJP. Fetal growth and impaired glucose tolerance in men and women. Diabetologia 1993; 36: 225–228. Philips DIW, Barker DJP, Hales CN, et al. Thinness at birth and insulin resistance in adult life. Diabetologia 1994; 37:150–154. Lithell HO, McKeigue PM, Gerglund L, et al. Relation at birth to non-insulin-dependent diabetes and insulin concentrations in men aged 50–60 years. Br Med J 1996; 312:406–410. Curhan GC, Willett WC, Rimm EB, et al. Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation 1996; 94:3246–3250. Ravelli AC, van der Meulen JH, Michels RP, et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet 1998; 351:173–177. Levitt NS, Lambert EV, Woods D, et al. Impaired glucose tolerance and elevated blood pressure in low birth weight,

648

236. 237.

238. 239.

240.

241.

242. 243.

244. 245.

246. 247. 248. 249.

250. 251.

252. 253.

Rosenbloom and Silverstein nonobese, young South African adults:early programming of cortisol axis. J Clin Endocrinol Metab 2000; 85:4611– 4618. Dabelea D, Pettitt DJ, Hanson RL, et al. Birthweight, type 2 diabetes, and insulin resistance in Pima Indian children and young adults. Diabetes Care 1999; 22:944–950. Bavdekar A, Yajnik CS, Fall CHD, et al. Insulin resistance syndrome in 8-year old Indian children. Small at birth, big at 8 years, or both? Diabetes 1999; 48:2422– 2429. Li C, Johnson MS, Goran MI. Effects of low birth weight on insulin resistance syndrome in Caucasian and AfricanAmerican children. Diabetes Care 2001; 24:2035–2042. Dunger DB, Ong KK, Huxtable SJ, Sherriff A, Woods KA, Ahmed ML, Golding J, Pembrey ME, Ring S, Bennett ST, Todd JA. Association of the INS VNTR with size at birth. ALSPAC study team. Avon longitudinal study of pregnancy and childhood. Nat Genet 1998; 19:98–100. Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S. Mutations in the glucokinase gene of the fetus result in reduced birthweight. Nat Genet 1998; 268– 270. Jaquet D, Vidal H, Hankard R, Czernichow P, Levy-Marchal C. Impaired regulation of glucose transporter 4 gene expression in insulin resistance associated with in utero undernutrition. J Clin Endocrinol Metab 2001; 86:3266– 3271. Pettitt DJ, Aleck KA, Baird HR, et al. Congenital susceptibility to NIDDM: role of intrauterine environment. Diabetes 1988; 37:622–628. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism. Diabetes Care 1995; 18:611–617. Dabelea D, Knowler WC, Pettitt DJ. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. J Matern Fetal Med 2000; 9:83–88. Rosenbloom AL, Wheeler L, Bianchi R, et al. Age adjusted analysis of insulin responses during normal and abnormal oral glucose tolerance tests in children and adolescents. Diabetes 1975; 24:820–828. Caprio S, Tamborlane WV. Metabolic impact of obesity in childhood. Endocrinol Metab Clin North Am 1999; 28: 731–747. Drash AM. Relationship between diabetes mellitus and obesity in the child. Metabolism 1973; 22:337–344. Martin MM, Martin AL. Obesity, hyperinsulinism, and diabetes mellitus in childhood. J Pediatr 1973; 192–201. Young-Hyman D, Schlundt DG, Herman L, DeLuca F, Counts D. Evaluation of the insulin resistance syndrome and 5- to 10-year old overweight/obesity African-American children. Diabetes Care 2001; 24:1359–1364. Caprio S. Relationship between abdominal visceral fat and metabolic risk factors in obese adolescents. Am J Hum Biol 1999; 11:259–266. Pettitt DJ, Forman MR, Hanson RL, Knowler WC, Bennett PH. Breastfeeding and incidence of non-insulin-dependent diabetes mellitus in Pima Indians. Lancet 1997; 350:166–168. Von Kries R, Koletzko R, Sauerwald T, et al. Breast feeding and obesity: cross-sectional study. Br Med J 1999; 319:147–150. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syn-

254. 255.

256.

257.

258.

259. 260.

261. 262.

263.

264. 265. 266.

267.

268. 269.

270. 271.

drome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999; 84:165–169. Lewy V, Danadian K, Arslanian SA. Early metabolic abnormalities in adolescents with polycystic ovarian syndrome (PCOS). Pediatr Res 1999; 45:93A. Lewy V, Danadian K, Arslanian SA. Roles of insulin resistance and B-cell dysfunction in the pathogenesis of glucose intolerance in adolescents with polycystic ovary syndrome. Diabetes 1999; 48:A292. Banerjee S, Raghavan S, Wasserman EJ, et al. Hormonal findings in African-American and Caribbean Hispanic girls with premature adrenarche: implications for polycystic ovarian syndrome. Pediatrics 1998; 102:E36. Vuguin P, Linder B, Rosenfeld RG, et al. The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African American and Caribbean Hispanic girls with premature adrenarche. J Clin Endocrinol Metab 1999; 84:2037–2042. Iban˜ez L, Potau N, Marcos MV, deZegher F. Exaggerated adrenarche and hyperinsulinism in adolescent girls born small for gestational age. J Clin Endocrinol Metab 1999; 84:4739–4741. Svec F, Nastasi K, Hilton C, et al. Black-white contrasts and insulin levels during pubertal development: the Bogalusa Heart Study. Diabetes 1992; 41:313–317. Jiang X, Srinivasan SR, Radhakrishnamurthy B, et al. Racial (black–white) differences in insulin secretion and clearance in adolescents: the Bogalusa heart study. Pediatrics 1996; 97:357–360. Arslanian S. Insulin secretion and sensitivity in healthy African-American vs. American-white children. Clin Pediatr 1998; 37:81–88. Danadian K, Lewy V, Janosky JJ, Arslanian S. Lipolysis in African–American children: is it a metabolic risk factor predisposing to obesity? J Clin Endocrinol Metab 2001; 86:3022–3026. Danadian K, Balasekaran G, Lewy V, et al. Insulin sensitivity in African-American children with and without a family history of type 2 diabetes. Diabetes Care 1999; 22:1325–1329. Lindgren CM, Hirschhorn JN. The genetics of type 2 diabetes. Endocrinologist 2001; 11:178–187. Rosenbloom AL, Joe JR, Young RS, Winter WE. The emerging epidemic of type 2 diabetes mellitus in youth. Diabetes Care 1999; 22:345–354. Rosenbloom AL, House DV, Winter WE. Non-insulin dependent diabetes mellitus (NIDDM) in minority youth: research priorities and needs. Clin Pediatr 1998; 37:143– 152. Hanis CL, Boerwinkle E, Chakraborty R, et al. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 1996; 13:161–6. Horikawa Y, Oda N, Cox NJ, et al. Genetic variation in the gene encoding calpain-IO is associated with type 2 diabetes mellitus. Nat Genet 2000; 26:163–75. Baier LJ, Permana PA, Yang X, et al. A calpain 10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 2000; 106: R69–R73. American Diabetes Association Consensus Development Conference On Insulin Resistance. Diabetes Care 1998; 21:310–314. Steinberger J, Moran A, Hong C-P, Jacobs DR, Sinaiko AR. Adiposity in childhood predicts obesity and insulin

Diabetes in Child and Adolescent

272.

273. 274. 275.

276. 277. 278. 279.

280.

281.

282.

283.

284. 285. 286. 287. 288. 289. 290. 291.

resistance in young adulthood. J Pediatr 2001; 138:469– 473. Freedman DS, Khan LK, Dietz WH, Srinivasan SR, Berenson GS. Relationship of childhood obesity to coronary heart disease risk factors in adulthood: the Bogalusa heart study. Pediatrics 2001; 108:712–718. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Low-grade systemic inflammation in overweight children. Pediatrics 2001; 107:e13. Adelman RD, Restaino IG, Alon US, Blowey DL. Proteinuria and focal segmental glomerulosclerosis in severely obese adolescents. J Pediatr 2001; 138:481–485. Smith JC, Field C, Braden DS, Gaymes CH, Kastner J. Coexisting health problems in obese children and adolescents that might require special treatment considerations. Clin Pediatr 1999; 38:305–307. Strauss RS, Barlow SE, Dietz WH. Prevalence of abnormal serum amrinotransferase values in overweight and obese adolescents. J Pediatr 2000; 136:727–733. Goldberg IJ. Diabetic dyslipidemia: causes and consequences. J Clin Endocrinol Metab 2001; 86:965–971. Kirpichnikov D, Sowers JR. Diabetes mellitus and diabetes-associated vascular disease. Trends Endocrinol Metab 2001; 12:225–230. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy has risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Community Study. N Engl J Med 2000; 342:905–912. Salomaa VV, Strandberg TE, Vanhanen H, Naukkarinen V, Sarna S, Miettinen TA. Glucose tolerance and blood pressure: long-term follow-up in middle-age men. Br Med J 1991; 302:493–496. Wierzbicki AS, Nimmo L, Feher MD, Cox A, Foxton J, Lant AF. Association of angiotensin-converting enzyme DD genotype with hypertension in diabetes. J Hum Hypertens 1995; 9:671–673. Stuart CA, Gilkison CR, Smith MM, Bosma AM, Keenan BS, Nagamani M. Acanthosis nigricans as a risk factor for non-insulin dependent diabetes mellitus. Clin Pediatr 1998; 37:73–79. Nguyen TT, Keil MF, Russell DL, et al. Relation of acanthosis nigricans to hyperinsulinemia and insulin sensitivity in overweight African-American and white children. J Pediatr 2001; 138:474–480. Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 2002; 346:802–810. Sackett DL, Holland WW. Controversy in detection of disease. Lancet 1965; 2:357–359. Sokol RJ. The chronic disease of childhood obesity: the sleeping giant has awakened. J Pediatr 2000; 136:711– 713. Tersbakovec AM, Watson MH, Wenner WJ, Marx AL. Insurance reimbursement for treatment of obesity in children. J Pediatr 1999; 134:573–578. Zwiaur KFM. Prevention and treatment of overweight and obesity in children and adolescents. Eur J Pediatr 2000; 159(suppl 1):S56–S68. Segel DG, Sanchez JC. Childhood obesity in the year 2001. Endocrinologist 2001; 11:296–306. Trevino RP, Pugh JA, Hernadez AE, Menchaca VD, Ramirez RR, Mendoza M. Bienestar: a diabetes risk factor prevention program. J School Health 1998; 68:62–66. Epstein LH, Myers MD, Raynor HA, Saelens BE. Treatment of pediatric obesity. Pediatrics 1998; 101:554–570.

649 292. 293. 294.

295.

296. 297.

298.

299. 300.

301.

302.

303. 304.

305.

306.

307. 308. 309.

Cook VV, Hurley JS. Prevention of type 2 diabetes in childhood. Clin Pediatr 1998; 37:123–129. Teufel NI, Ritenbaugh CK. Development of a primary prevention program: insight gained in the Zuni Diabetes Prevention Program. Clin Pediatr 1998; 37:131–141. Gortmaker SL, Cheung LWY, Peterson KE, Chomitz G, Cradle JH, Dart H, Fox MK, Bullock RB, Sobol AM, Colditz G, Field AE, Laird N. Impact of a school-based interdisciplinary intervention on diet and physical activity among urban primary school children. Arch Pediatr Adolesc Med 1999; 153:975–983. Macaulay AC, Paradis G, Potvin L, et al. The Kahnawake Schools Diabetes Prevention Project: intervention, evaluation and baseline results of a diabetes primary prevention program with a native community in Canada. Prev Med 1997; 26:779–790. Dean HJ. NIDDM-Y in the first nation children in Canada. Clin Pediatr 1998; 39:89–96. Perry CL, Stone EJ, Parcel GS, et al. School-based cardiovascular health promotion: the child and adolescents trial for cardiovascular health (CATCH). J School Health 1998; 68:406–413. Levine MD, Ringham RM, Kalarchian MA, Wisniewski L, Marcus MD. Is family based behavioral weight control appropriate for severe pediatric obesity? Int J Eat Disord 2001; 30:318–328. Robinson TM. Reducing children’s television viewing to prevent obesity. A randomized controlled trial. JAMA 1999; 282:1561–1567. Swinburn BA, Metcalf PA, Ley SJ. Long-term (five-year) effects of a reduced fat diet intervention in individuals with glucose intolerance. Diabetes Care 2001; 24:619– 624. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344:1343–1350. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393– 403. Jeffrey RW. Community programs for obesity prevention: the Minnesota Heart Health Program. Obesity Res 1995; 3(suppl 2):283S–288S. Epstein LH, Valoski AM, Kalarchian MA, McCurley J. Do children lose and maintain weight easier than adults: a comparison of child and parent weight changes from six months to ten years. Obesity Res 1995; 3:411–417. Joe JR. Perceptions of diabetes by Indian adolescents. In: Joe JR, Young RS, eds. Diabetes as a Disease of Civilization: the Impact of Culture Change on Indigenous Peoples. Berlin: Mouton de Gruyter, 1994:329–356. Freemark M, Bursey D. The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics 2001;107. http://www.pediatrics. org/cgi/content/full/107/4/e55. Soper RT, Mason EE, Printen KJ, Ellweger H. Gastric bypass for morbid obesity in children and adolescents. J Pediatr Surg 1976; 10:51–58. Anderson AE, Soper RT, Scott DH. Gastric bypass for morbid obesity in children and adolescents. J Pediatr Surg 1980; 15:876–881. Strauss RS, Bradley LJ, Brolin RE. Gastric bypass surgery and adolescents with morbid obesity. J Pediatr 2001; 138:499–504.

650 310.

311.

312.

313. 314.

315.

316.

317.

318. 319.

320. 321. 322. 323.

324. 325. 326.

327.

Rosenbloom and Silverstein Fagot-Compagna A, Knowler WC, Pettitt DJ. Type 2 diabetes in Pima Indian Children: Cardiovascular risk factors at diagnosis and 10 years later. Diabetes 1998; (suppl 1):A155. Yokoyama H, Okudaira M, Otani T, et al. High incidence of diabetic nephropathy in early-onset Japanese NIDDM patients. Risk analysis. Diabetes Care 1998; 21:1080– 1085. UKPDS Group: Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837–853. UKPDS Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 1998; 317:703–713. Ludwig DS, Peterson KE, Gortmaker SL. Relation between consumption of sugar sweetened drinks and childhood obesity: a prospective observational analysis. Lancet 2001; 357:505–508. Kids, teens, and type 2 diabetes: what you need to know. An essential reference for school nurses. University of Texas Health Science Center at San Antonio: Department of Pediatrics; and The Children’s Center At the Texas Diabetes Institute, 2000. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin dependent diabetes mellitus. The multicenter metformin study group. N Engl J Med 1995; 333:541–549. Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2002; 25:89–94. Lebovitz HE. Insulin secretagogues, old and new. Diabetes Rev 1999; 7:139–152. Chiasson J, Josse R, Hunt J, Palmason C, Rodger NW, Ross SA, Ryan EA, Tan MH, Wolever TM. The efficacy of acarbose in the treatment of patients with non-insulindependent diabetes mellitus. A multicenter controlled clinical trial. Ann Intern Med 1994; 121:928–935. Schwartz S, Raskin P, Fonseca V, Graveline JF. Effect of troglitazone a in insulin treated patients with type 2 diabetes. N Engl J Med 1998; 338:861–866. Law RE, Goetze S, Xi X-P, et al. Expression and function of PPAR␥ rat and human vascular smooth muscle cells. Circulation 2000; 101:1311–1318. Olefsky JM, Saltiel AR. PPAR␥ and the treatment of insulin resistance. Trends Endocrinol Metab 2000; 11:362– 367 . UKPDS Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837–853. Morales A, Rosenbloom AL. Death at the onset of type 2 diabetes (T2DM) in African-American youth. Pediatr Res 2002; 51:124A. Silverstein JH, Rosenbloom AL. Treatment of type 2 diabetes in children and adolescents. J Pediatr Endocrinol Metab 2000; 13(suppl 6):1403–1409. Azziz R, Ehrmann RS, Legro RS, et al. Troglitazone improves a ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double-blind, placebo-controlled trial. J. Clin Endocrinol Metab 2001; 86:1626–1632. National Heart, Long, and Blood Institute. Report of the second task force on blood pressure control in children —1987. J Pediatr 1987; 79:1–25.

328.

329. 330. 331. 332. 333.

334. 335.

336.

337.

338. 339.

340. 341. 342.

343.

344.

Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pederson TR, Kjekshus J, Pyarola K, for the Scandinavian Simvastatin Survival Study Group. Reduced coronary events in Simvastatin treated patients with coronary heart disease and diabetes or impaired fasting glucose levels. Arch Intern Med 1999; 59:2661–2667. Handwerger S, Roth J, Gorden P, Di SantAgnese P, Carpenter D, Peter G. Glucose intolerance in cystic fibrosis. N Engl J Med 1969; 56:451–461. Finkelstein SM, Wielinski CL, Elliott GR, Warwick WJ, Barbosa J, Wu SC, Klein DJ. Diabetes mellitus associated with cystic fibrosis. J Pediatr 1998; 56:373–377. FitzSimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr 1993; 122:1–9. Rodman HM, Doershuk CJ, Roland JM. The interaction of 2 diseases: diabetes mellitus and cystic fibrosis. Medicine (Baltimore) 1986; 65:389–397. Lanng S, Thorsteinsson B, Nerup J, Koch C. Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Paediatrica 1994; 56: 849–853. Hayes F, OBrien A, Fitzgerald MX, McKenna MJ. Diabetes mellitus in an adult cystic fibrosis population. Irish Med J 1995; 56:102–104. Yung B, Kemp M, Hooper J, Hodson ME. Diagnosis of cystic fibrosis related diabetes: a selective approach in performing the oral glucose tolerance test based on a combination of clinical and biochemical criteria. Thorax 1999; 56:40–43. Cotellessa M, Minicucci L, Diana MC, et al. Phenotype/ genotype correlation and cystic fibrosis related diabetes mellitus (Italian Multicenter Study). J Pediatr Endocrinol Metabol 2000; 56:1087–1093. Milla CE, Warwick WJ, Moran A. Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med 2000; 56:891–895. Kopito L, Shwachman H, Vawter G, Edlow J. The pancreas in cystic fibrosis: chemical composition and comparative morphology. Pediatr Res 1976; 56:742–749. Ornoy A, Arnon J, Katznelson D, Granat M, Caspi B, Chemke J. Pathological confirmation of cystic fibrosis in the fetus following prenatal diagnosis. Am J Med Genet 1987; 56:935–947. Lippe B, Sperling M, Dooley R. Pancreatic alpha and beta cell functions in cystic fibrosis. J Pediatr 1977; 56:751– 755. Moran A, Diem P, Klein D, Levitt M, Robertson RP. Pancreatic endocrine function in cystic fibrosis. J Pediatr 1991; 56:715–723. Arrigo T, Cucinotta D, Conti Nibali S, Di Cesare E, Di Benedetto A, Magazzu G, De Luca F. Longitudinal evaluation of glucose tolerance and insulin secretion in nondiabetic children and adolescents with cystic fibrosis: results of a two-year follow-up. Acta Paediatr 1993; 56: 249–253. Cucinotta D, De Luca F, Gigante A, Arrigo A, Di Benedetto A, Tedeschi A, Lombardo F, Romano G, Sferlazzas C. No changes of insulin sensitivity in cystic fibrosis patients with different degrees of glucose tolerance: an epidemiological and longitudinal study. Eur J Endocrinol 1994; 56:253–258. Lanng S, Thorsteinsson B, Nerup J, Koch C. Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis. Eur J Pediatr 1992; 56:684– 687.

Diabetes in Child and Adolescent 345.

346.

347.

348. 349.

350. 351. 352.

353. 354. 355. 356. 357.

Hardin DS, Stratton R, Kramer JC, Reyes de la Rocha S, Govaerts K, Wilson DP. Growth hormone improves weight velocity and height velocity in prepubertal children with cystic fibrosis. Horm Metab Res 1998; 56:636–641. Lanng S, Thorsteinsson B, Lund Andersen C, Nerup J, Schiotz PO, Koch C. Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complications. Acta Paediatr 1994; 56:72–77. Austin A, Kalhan SC, Orenstein D, Nixon P, Arslanian S. Roles of insulin resistance and beta cell dysfunction in the pathogenesis of glucose intolerance in cystic fibrosis. J Clin Endocrinol Metab 1994; 56:80–85. Hardin DS, Sy JP. Effects of growth hormone treatment in children with cystic fibrosis: the National Cooperative Growth Study experience. J Pediatr 1997; 56:S65–S69. Ripa P, Robertson I, Cowley D, Harris M, Masters IB, Cotterill AM. The relationship between insulin secretion, the insulin like growth factor access and growth in children with cystic fibrosis. Clin Endocrinol 2002; 56:383–389. Gentz JCH, Cornblath M. Transient diabetes of the newborn. Adv Pediatr 1969; 16:345. Hickish G. Neonatal diabetes. Br Med J 1956; 1:95–96. Dourov M, Buyl-Strouvens ML. Age´ne´sie du pancre´as. Observation anatomoctinique d’un cas de diabe`te sucre´, avec ste´atorrhe´e et hypotrophie, chez un nouveau-ne´. Arch Franc Pe´diatr 1969; 26:641–650. Lewis E, Eisenberg H. Diabetes mellitus neonatorum. Am J Dis Child 1935; 49:408–410. Tidd JT, Stanage WF. Congenital diabetes mellitus. S D J Med 1965; 18:15–19. Osboume GR. Congenital diabetes. Arch Dis Child 1965; 40:332. Ferguson AW, Milner RDG, Naidu SH. Transient neonatal diabetes rnellitus in three successive male siblings. Arch Dis Child 1971; 46:724–729. McGill JJ, Roberton DM. A new type of transient diabetes mellitus of infancy? Arch Dis Child 1986; 61:334–336.

651 358. 359. 360. 361.

362. 363. 364.

365.

366. 367.

368.

Coffey JD, Killelea DE. Transient neonatal diabetes mellitus in half-sisters: a sequel. Am J Dis Child 1982; 136: 66–727. Campbell IW, Fraser DM, Duncan LJP, Keay AJ. Permanent insulin-dependent diabetes rnellitus after congenital temporary diabetes mellitus. Br Med J 1978; 2:174. Geffner ME, Clare-Salzler M, Kaufman DL, et al. Permanent diabetes developing after transient neonatal diabetes. Lancet 1993; 341:1095. Gottschalk ME, Schatz DA, Clare-Salzler M, et al. Permanent diabetes without serologic evidence of autoimmunity after transient neonatal diabetes. Diabetes Care 1992; 15:1273–1276. Weimerskirch D, Klein DJ. Recurrence of insulin-dependent diabetes mellitus after transient neonatal diabetes: a report of two cases. J Pediatr 1993; 122:598–600. Edidin DV. Permanent diabetes developing after transient neonatal diabetes. Lancet 1993; 341:1095. To¨pke B, Menzel K. Die Pankreasagenesie des Neugeborenen; ein seltenes, klinisch aber charakteristisches Krankheitsbild. Acta Paediatr Acad Sci Hung 1976; 17: 147–51. Wo¨ckel W, Scheibner K. Aplasie des Pankreas mit Diabetes mellitus, intrahepatische Gallengangsaplasie und weitere Missbildungen bei einem hypotrophen Neugeborenen. Zentralbl Pathot Anat 1977; 121:186–194. Howard CP, Go VLW, Infante AJ, et al. Long-term survival in a case of functional pancreatic agenesis. J Pediatr 1980; 97:786–789. Winter WE, Maclaren NK, Riley WR, Toskes PP, Andres J, Rosenbloom A. Congenital pancreatic hypoplasia: a syndrome of exocrine and endocrine insufficiency. J Pediatr 1986; 109:465–468. Wright NM, Metzger DL, Clarke WL. Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from pancreatic agenesis. Am J Dis Child 1993; 147:607–608.

26 Management of the Child with Diabetes Oscar Escobar, Dorothy J. Becker, and Allan L. Drash University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

I.

lead to improved purification techniques, which helped to circumvent initial problems with nonpurified pancreas extracts such as local and generalized reactions and immunemediated inactivation of insulin through antibody production. Years of research and sophistication of molecular engineering have lead to the production of human insulin through recombinant DNA technology and the design of insulin analogs with particular pharmacokinetic profiles that allow extrarapid or retarded insulin action of injected insulin.

INTRODUCTION

Three distinct aspects of diabetes management have occupied the minds of physicians and researchers for decades: the control of the disease, its prevention, and its cure. Simultaneous with significant advancements in the control of the metabolic disturbances of diabetes and its complications, immense efforts have recently been carried out through large-scale clinical trials to find a strategy to prevent the disease in susceptible individuals, and, through arduous bench, animal, and clinical research, to find a definitive cure. These latter two objectives have been elusive, but as more people and resources are committed to this endeavor their attainment looks closer. Since the first recognition of diabetes as a clinical entity, utmost attention has been paid to its control. Initial efforts were directed toward amelioration of the symptoms of polyuria and polydipsia, which would lead to severe cachectic states and eventually to death within weeks or months. Severe dietary restriction, especially in the intake of sugars and other carbohydrates, high-fat diets, and even complete starvation were the only available strategies to achieve that goal before the discovery of insulin. This therapeutic approach did not prevent death as an almost immediate outcome of the disease and, surely enough, contributed to the progression through the final stages of the disease. The discovery of insulin by Banting and Best in 1922 divided the history of diabetes in two. When injections of pancreas extracts started to be used as management for this disease, the expectations of the outcome changed drastically. Survival beyond the first months after diagnosis was now possible, starvation was not necessary, and patients could recover from their initial cachexia. Progressive refinement by the pharmaceutical industry

II.

METABOLIC DISTURBANCES AS A CONSEQUENCE OF INSULIN DEFICIENCY

The hormone insulin has pervasive effects on overall energy homeostasis. Although diabetes mellitus is usually considered a disease of carbohydrate metabolism, in fact, equally serious alterations are present in the area of lipid and protein metabolism. The actions of insulin referable to carbohydrate metabolism are multifold. Insulin promotes the translocation of glucose from the intravascular space to the intracellular space by activation of insulin receptors that promote glucose transport. Intracellularly, insulin promotes the utilization of glucose as a direct energy source, or storage of glucose as glycogen (primarily in the liver, muscle and kidney), or converted into lipids with accumulation within the cell via the lipid synthesis pathway. Insulin also inhibits the release of glucose from the liver, promoting hepatic glucose storage. The actions of insulin on lipid metabolism include the transfer of socalled excess dietary carbohydrate calories into the lipid synthesis and storage pool and the inhibition of lipid mobilization from adipose tissue stores. Insulin has both di653

654

Escobar et al.

rect and indirect effects on protein metabolism. The insulin molecule, apparently through specialized cell membrane receptors, works in a coordinated fashion with pituitary growth hormone to stimulate amino acid uptake into cells and promote cell growth and multiplication. Insulin promotes glycolysis and inhibits gluconeogenesis indirectly. Insulin release is stimulated by dietary intake (glucose, amino acids and, to a much lesser extent, fats and ketones). The body energy metabolism is under the direct control of insulin during the prandial and immediate postprandial periods, whereas it is probably under the control of glucagon and epinephrine in the distal postprandial periods, growth hormone and cortisol being added during intervals of fasting. The overall effect in the normal healthy individual is very narrow variations in the concentration of all nutrients throughout the course of each day, despite feasting and fasting cycles. These well-regulated nutrient concentrations include glucose, amino acids, triglyceride, cholesterol, ketone bodies, and a number of energy intermediates such as lactate, pyruvate, and glycerol. The extremes of both hyper- and hypoglycemia are avoided, as are significant variations in lipid and protein concentration. The deficiency of insulin results in a reversal of all these normal patterns. Hyperglycemia results as a consequence of impaired peripheral glucose uptake and increased hepatic glucose production, from an increased rate of both glycogenolysis and gluconeogenesis. Hyperlipidemia results from a marked increase in the mobilization of preformed fat in adipose tissues, and ketonuria results if this process continues unabated, without intervention of insulin therapy. The concentration of several counterregulatory hormones is increased, including growth hormone, adrenocorticotropic hormone (corticotropin), cortisol, glucagon, and, in extreme stress, the catecholamines. Insulin deficiency and counterregulatory hormone excess combine to complicate the metabolic picture further, exacerbating hyperglycemia, hyperlipidemia, and ketogenesis. This leads to an increased rate of proteolysis and gluconeogenesis, placing the individual in negative nitrogen balance (1, 2). Acidosis, which is an additional complicating factor, ensues as the result of direct and indirect effect of insulin deficiency. Increased serum ketone concentration is the main cause of acidosis in insulin deficiency. Two additional sources of acidosis in the individual with moderate to severe fluid deficit are build-up of excretable organic acids resulting from decreased renal clearance and accumulation of lactic acid resulting from anaerobic metabolism of peripheral tissues.

III.

MANAGEMENT

We are currently in the midst of changes in the strategies, techniques and objectives of diabetes management. There are continual improvements in techniques used for short-

and intermediate-term assessment of metabolic control using capillary blood glucose monitoring and measurements of glycosylated proteins, particularly glycosylated hemoglobin, as well as attempts to standardize their laboratory measurements. The widespread utilization of these monitoring techniques has provided the patient and the therapeutic team with quantitative means of assessing metabolic status over time. There have been also advancements in other areas, since the improvement in the purification of pork insulin and the introduction of human insulin produced by DNA technology. More recently, beef insulin has been taken off the US market and there is widespread use of insulin analogs. The latter may allow much more precise tailoring of an individual patient’s insulin therapeutic needs based on the individual’s lifestyle (3, 4). An improvement of insulin infusion devices, both external and implanted, also provides the potential for more physiological insulin delivery (5). Ultrasound-enhanced transdermal delivery of insulin and oral insulin therapy is appearing as a possible way to treat diabetic patients. Trials of inhaled insulin are currently underway (6–10). With these methodological advances has come an increasing interest in attempting to normalize energy metabolism, with the anticipation that this will eliminate or reduce the serious vascular complications of diabetes. This increasingly popular therapeutic movement has been improperly referred to as intensive insulin therapy rather than the more appropriate intensive diabetes therapy (11). Unfortunately, many, both physicians and patients have concluded that the way to improve diabetes management is simply to give insulin more often. This is a serious misconception. Intensive diabetes therapy also includes the need for intensive blood glucose monitoring and close attention to the patient’s dietary regimen. Successful therapeutic management of the child and adolescent with diabetes mellitus requires a highly integrated four-pronged approach: insulin administration, dietary management, physical activity, and education and emotional support (12–15).

IV.

INSULIN THERAPY

A.

Insulin Requirements

Initial insulin requirements are approximately 1.0 unit/kg/ day. A partial remission, referred to as the honeymoon period, is identified as a decline in insulin requirement below 0.5 units/kg/day associated with very good metabolic control as measured by near-normal glycosylated hemoglobin levels. This occurs in more than 65% of all newly diagnosed patients during the first several weeks after diagnosis, with the nadir in insulin requirement reached on average between 12 and 16 weeks after diagnosis. During this period, insulin doses must be carefully adjusted downward to prevent hypoglycemia. In some cases the evening dose can be entirely eliminated.

Management of Diabetes

This is particularly true in children under 6 years of age. We believe that the duration of this remission period is usually longer than experienced in the past and in some cases may last longer than 2 years before increasing insulin needs are again expressed. The maintenance of some residual C-peptide secretion by intensive therapy must be a goal of treatment in view of the beneficial effects on the prevention of microvascular complications seen in the Diabetes Control and Complications Trial (DCCT) (16). Eventually, in all patients, insulin requirements begin to climb after the nadir of remission and generally plateau at about 0.8 units/kg/day in the preadolescent and somewhat above 1.0 units/kg/day in the adolescent. Pubertal development is associated with increased insulin requirements secondary to insulin resistance induced by changes in the hormonal millieu. It is not infrequent to find adolescent patients who require 1.5–1.8 units/kg/day to maintain target hemoglobin A1c (HbA1c) levels (17).

B.

Available Insulin Preparations and Insulin Management Strategies

The last 20 years have witnessed major changes in all aspects of insulin treatment. Improvement in manufacturing techniques has resulted in a remarkably increased purity of commercially available insulin preparations. Mixed beef and pork insulin, formerly the standard of therapy, has been removed from the marketplace for the most part. Highly purified pork insulin is currently available in some but not all countries. Human insulins produced by recombinant DNA technologies are the most frequently available choices. New synthetic insulin analogs have been engineered to provide either extra-rapid action or prolonged, peakless pharmacokinetics. Human insulin has been thought to have both theoretical and practical advantages and has been the insulin of choice. Two issues have raised concern about this apparently reasonable conclusion. Several investigators, particularly Europeans, have reported that severe hypoglycemia, usually without typical hypoglycemic symptoms, is far more common in patients treated with human insulin preparations. This suggests that there is something uniquely different about the body’s response to human insulin that increases the likelihood of hypoglycemia. The controversy remains unresolved, with most studies not supportive of a uniquely dangerous hypoglycemic potential for human insulin (18, 19). The second issue has to do with the time course of human insulin. It relates to our own experience and decision to prefer pork insulin, especially in children under 10 years of age. All the human insulin preparations appear to have a quicker onset time and a shorter duration of effect than the comparable pork insulin preparations (20). Diabetes in very young children can be controlled using a split-dose regimen of NPH insulin plus lispro or regular insulin given before breakfast and before the evening meal using pork NPH. When using this schedule with human insulin, the shorter time course

655

of human NPH, particularly overnight, did not provide adequate glucose control. Raising the dosage increased the likelihood of nocturnal hypoglycemia. If a two injection/ day regimen is used, we recommend highly purified pork NPH insulin, which provides better and more prolonged coverage especially through the night. Insulin antibody formation is the same whether pure pork or human insulins are used. Although we still support the use of pork insulin, we have recently faced the problem of decreased availability of these preparations. For this reason and where flexibility of schedule is needed, we recommend using alternative insulin injection regimens that circumvent the problem of poor overnight coverage. One such regimen involves the administration of human NPH insulin before breakfast and before the bedtime snack. We have found human ultralente insulin useful only in the context of a four shot/day regimen when it can provide basal coverage, but with significant variation in its effect. The use in the near future of long-acting insulin analogs may provide another strategy to avoid this problem, as discussed below. A fast-acting insulin analog is also given before breakfast and before dinner and, if necessary, with a bedtime snack. Regular insulin was, until not too long ago, the only fast-acting insulin available. The introduction of insulin lispro, an extra-rapid acting insulin analog, in the last decade has broadened the repertoire of therapeutic options. Insulin lispro is synthetically produced by recombinant DNA technology, introducing a reversal of the natural occurring sequence of proline and lysine in positions B-28 and B-29, respectively to LysB28, ProB29. It is highly homologous with human insulin, yet it does not self-associate into dimers as does human insulin. The stabilized hexamer complexes of insulin lispro immediately dissociate into monomeric subunits upon injection into the subcutaneous tissue. This characteristic confers on insulin lispro at least three differences compared to human regular insulin: the action starts earlier (10–15 min), the peak insulin concentration in plasma is higher (more than double), and the duration of action is shorter (less than 4 h). A similar pharmacokinetic profile is found in insulin aspart, another analog also produced by recombinant DNA technology substituting proline in position B28 with Aspartate (21–23). These rapid analogs provide a more precise action profile at mealtimes. Our current practice in the treatment of the great majority of school-age patients involves three insulin shots: human or pork NPH plus insulin lispro before breakfast, insulin lispro before supper, and human or pork NPH insulin before bedtime snack. Variations in this basic regimen are designed depending on the need. They include, but are not limited to, substitution of regular insulin for insulin lispro; the use of an insulin injection (either regular or lispro) before lunch or lispro before an afternoon snack; and the use of fast-acting insulin in conjunction with the bedtime dose of NPH insulin, depending on the blood glucose and the size of the snack. Advan-

656

Escobar et al.

tages of these short-acting analogs include lower postprandial blood glucose levels, less hypoglycemia, and thus better hypoglycemia awareness and counterregulation in response to low blood sugar levels. An additional advantage in pediatric patients, especially infants, is that medication can be given after eating due to these agents’ rapid initiation of action. This allows dosing adjustments depending on the food intake, which in infants is very frequently unpredictable. More recently, long-acting insulin analogs have been synthesized with the idea of providing peakless basal insulin concentrations. Also produced by recombinant DNA technology, these analogs are designed to have a longer period of action by changing their isoelectric point (i.e., insulin glargine) or by promoting their binding to serum proteins such as albumin (fatty acid acylated insulins) (21). Insulin glargine has already been approved by the Food and Drug Administration (FDA) and became available a few months before completion of this chapter. Two arginine molecules are added at the C-terminus of the Bchain. With these two extra positive charges, the isoelectric point changes and creates a molecule that is soluble at a more acidic pH and less soluble at the physiological pH of subcutaneous tissue. Another modification of the molecule, a substitution of Asparagine in position 21 of the A-chain by Glycine, is intended to protect it from deamidation and dimerization that would otherwise occur in the acidic solution in which it is formulated. The acidity of its formulation (pH 4.0) allows insulin glargine to remain soluble. Once injected in the subcutaneous tissue, the solution is neutralized and forms microprecipitates from which insulin glargine is slowly released, providing virtually no peak concentrations and duration of action for at least 24 h (24). Disadvantages of this type of insulin include the fact that it cannot be mixed with any other type of insulin. Therefore, two separate injections must be given when the action of a rapid action insulin is needed at the same time. The acidic pH of the preparation seems to be responsible for a burning sensation at the injection site for some patients. Large multicenter trials of the effectiveness of these newer analogs in the pediatric population are soon to be initiated in the United States. It should be possible in the near future to tailor the individual patient’s insulin management carefully to his or her lifestyle and changing requirements. The availability of this new family of synthetic insulins will make the demise of animal insulin less painful for all of us. Premixed insulins, such as 70/30 or 75/25 H are used only in patients with compliance problems because of the inablity to adjust doses according to planned food intake, meal plans, or ambient blood sugar levels.

C.

Insulin Dosage Adjustments

By applying glucose goals derived from self-monitoring of blood glucose, insulin adjustments are made as necessary to attempt continually to bring the patient’s glucose

variation into the target range. Diet and exercise alterations are also considered and applied as necessary. We use a 10% rule for insulin changes: By summing the total insulin dose and dividing by 10, one obtains the number of units of insulin that is generally safe to increase or decrease in a patient who requires change. However, a maximum increase is 6 units (total insulin dose of 60 units). If the patient’s blood glucose levels are generally high throughout, then the distribution of the increase follows the current distribution: usually two-thirds added to the morning and one-third to the evening dosage. On the other hand, if the patient is persistently out of range at a particular time, for example before dinner, then the dose modification applies only to the morning or lunch-time insulin and the amount is determined by calculating 10% of the morning dose. The distribution between NPH insulin and regular insulin or insulin lispro depends upon both the pre- and postprandial blood glucose levels. In the asymptomatic patient, we prefer to make insulin adjustments relatively slowly, after 3–5 days on a particular dose. On the other hand, if the patient is symptomatic and/or ketonuric, one must be more aggressive in moving toward a more acceptable blood glucose excursion. Most patients are provided with insulin scales for their shortacting insulin doses that can be used in anticipation of planned activity, food intake, and to correct current hyperglycemia.

V.

INTENSIVE DIABETES THERAPY

There has been a gradual movement toward intensification of diabetes management, climaxed by the results of the DCCT. The term ‘‘intensive insulin therapy’’ has unfortunately become embedded in our terminology and to the uninitiated may be interpreted to mean that overall diabetes management can be improved simply by increasing the frequency of insulin administration. The proper message, of course, is that improved results are accomplished in the great majority of patients only with intensification of all aspects of management. The therapeutic set of the diabetes team, with full cooperation of the patient and family, is directed toward achieving either optimal management utilizing whatever resources are available or something less. The concept of conventional vs. intensive management must be set aside. We must undertake to do the very best we can with each patient, understanding that there are major differences in resources and abilities as well as many barriers to the achievement of metabolic near-normality (25–28). Intensive diabetes therapy almost always includes frequent insulin injections or continuous insulin infusion.

A.

Continuous Subcutaneous Insulin Therapy

In the early days of insulin pumps in the 1980s, we developed extensive pump experience with our adolescent patients. Their initial metabolic response was gratifying in

Management of Diabetes

terms of decreasing glycosylated hemoglobin and blood glucoses. As we evaluated these patients over time, however, the enthusiasm for living with a pump declined and their compliance with the intensive therapeutic regimen diminished. Thus, the early successes were lost. At that time we concluded that the rigors of insulin pump therapy with the available pumps were such that few children or adolescents would adapt successfully to it. We essentially discontinued pump use in our general clinic population (29). More recently, however, advances in delivery systems have made pump therapy much easier for the patient, with more reliable insulin delivery and less complications. The potential for success with pump therapy has been demonstrated in carefully selected patients who are either very mature and have made a clear commitment to improved health or have very dedicated families. Determining patient eligibility for continuous subcutaneous insulin infusion (CSII) therapy has been a subject of controversy. Among the factors involved are the age of the patient, the degree of prior glycemic control and multiple psychological, familial, cultural, and socioeconomic issues. The American Diabetes Association suggests four basic conditions that should be met by the patient to increase the chances of obtaining benefit from CSII: motivation, willingness to work in conjunction with the health care team, demonstrated understanding of the technical aspects of correct use of the pump, and ability to obtain and interpret data to make decisions regarding pump programming (30, 31). Patient’s age and the degree of prior glycemic control are major factors accounting for the heterogeneity of eligibility criteria for CSII in different centers. Some centers have been more liberal with the use of insulin pumps in younger patients including young children and even infants, while others prefer to reserve this mode of therapy for older children, adolescents, and young adults capable of independent decision-making. The involvement of parents or caregivers is a sine qua non in the former group. The parental share of responsibility approaches 100% in the youngest patients, and should decrease in the older ones, although at least a certain degree of supervision continues to be highly recommended in the latter. Improvement of glycemic control achieved by adolescent patients with the participation of their parents or responsible adults decreases significantly when these patients are left on their own (32). This most probably reflects a decrease in the frequency of blood glucose monitoring and/or failure to give premeal insulin boluses. Poor judgment at the time of deciding on pump programming and bolus calculation according to the blood sugar level, the food to be eaten, and the amount of exercise predicted for the next minutes or hours would be additional concerns in some adolescents managed through CSII without parental involvement. Our most recent experience with CSII (33) showed that metabolic control improved in patients switched from multiple daily insulin injections (MDI) to CSII as mani-

657

fested by a decrease of 0.5% of HbA1c at 3 and 6 months after initiation. HbA1c levels at 9 and 12 months after initiation of CSII were not significantly different from baseline. A similar difference in Hb1Ac levels was observed between patients managed with MDI and those receiving CSII during the same observation period, with lower HbA1c levels in the latter. The patients who had worsening of their diabetic control when switched to CSII were older than the patients whose condition improved. They also had higher baseline levels of HbA1c. We found that the patients more likely to experience improved metabolic control are those with better control to begin with than patients in poorer control who are older adolescents and whose condition tends to worsen. A beneficial effect of CSII found by us and others is the reduction in the frequency of severe hypoglycemia. We have not seen an increase in body weight in patients managed with CSII, as would be expected according to the results of DCCT. Despite the lack of improvement in metabolic control in older adolescents with poorer control, reduction in the frequency of DKA has been reported (34). Approximately one-third of DCCT’s intensively managed patients were using an insulin infusion device. The general experience did not clearly document a benefit of either pump or MDI therapy. Since then, uncontrolled studies have suggested improved glycemic control and less hypoglycemia in children and adolescents in CSII (35), although similar results are not universally reported (36). Our own experience suggests that CSII does not improve glycemic control in those with high HbA1cs but can improve quality of life. The biggest risk is exaggerated expectations of pump therapy.

VI.

SOMOGYI EFFECT AND DAWN PHENOMENON

A very common management problem is illustrated by the child whose fasting blood glucose levels are consistently elevated. The usual strategy is to increase the evening NPH insulin until these levels are satisfactory. The common complication of this technique is that nocturnal hypoglycemia may be induced, leading to the Somogyi reaction and rebound hyperglycemia the next morning. This is particularly true with human insulin because of its shorter duration time. This hypoglycemia is masked by counterregulation or waning of insulin action. If fasting glucose levels are high, with NPH given at bedtime the addition of lispro at this time may be beneficial. In essentially all patients, excluding some toddlers, a minimum program of three injections per day program is needed. This is due to the need to continue covering the postprandial glucose rise after dinner with regular insulin or insulin lispro and administration of lispro as late as possible. This change has been frequently successful and surprisingly well accepted by most patients and parents (37, 38).

658

Escobar et al.

Elevated plasma glucose concentrations in the morning (after 5 am), without preceding hypoglycemia characterize the so-called dawn phenomenon. This occurs as a result of increased insulin requirements in the early morning, which could be related to either increased insulin clearance or decreased insulin action. An earlymorning surge of growth hormone, one of the insulincounterregulatory hormones, has been hypothesized as a causal factor. Whether long-acting insulin analogs are able to avoid this morning rise in blood glucose levels as a result of the dawn phenomenon in children and adolescents remains to be demonstrated in larger-scale pediatric trials. The once-popular concept of the Somogyi effect is unlikely to explain early-morning hyperglycemia, although counterregulation can account for past hypoglycemic euglycemia. Rebound hyperglycemia probably only occurs after active food therapy of low blood sugar (although this is not well reported in children).

VII.

DIETARY MANAGEMENT

As stated above, the nutritional component is one of the cornerstones of diabetes management. Recommendations on nutritional intervention in diabetes have changed over the years. Before the discovery of insulin, the concept of dietary management relied on severe restriction of caloric intake leading to starvation diets. This was followed by low-carbohydrate–high-fat diets and, most recently, higher-carbohydrate–lower-fat diets (see Table 1). Our own recommendations since the early 1970s have been 50–55% carbohydrate, 15–20% protein, and 30% fat with limitation of saturated fat and cholesterol to 150 kb and contains 17 exons. TPO functions to oxidize iodide and to organify iodine covalently bound to thyroglobulin tyrosine residues, forming monoiodothyronine (MIT) and diiodothyronine (DIT). TPO is next responsible for the coupling reaction forming triiodothyronine and tetraiodothyronine. The catalytic domain of TPO is oriented toward the colloid space where organification of iodide and iodination of thyroglobulin occur. On the immediate extracellular N-terminal portion of TPO, an epidermal growth factor precursor-like domain and complement protein C4b-like domain are recognized. TPO demonstrates extensive homology with myeloperoxidase, an autoantigen in some forms of systemic vasculitis (219). The TMA autoantibody reacts with TPO in its native conformation (220). Antibodies to TPO (e.g., TPOAb) are more sensitive for the detection of AITD; however, because such TPOAbs are more common in the general pop-

Winter

ulation than TMA, TPOAb may be less specific than TMA. This may lead to improvements in the TMA assay but this is still somewhat controversial (221). Autoantibodies to thyroglobulin (e.g., TGA) are not as common as TMA/TPOAb in all forms of AITD and CLT. Thyroglobulin is a 2748 amino acid, 330 kD homodimeric glycosylated iodoprotein that can represent 75% of the total protein content of the thyroid gland. There are multiple regions of repeated structure within the protein. The coding portion of the thyroglobulin gene covers >250 kb of DNA and 42 exons. The gene is located on chromosome 8q24. Synthesized by thyroid follicular cells, thyroglobulin is secreted into the lumen of the thyroid follicle forming the colloid, where it becomes the substrate for thyroid hormone synthesis. Two new autoantigens have been recognized in AITD: megalin (GP330) and the thyroid Na⫹/I⫺ symporter. Megalin is a multiligand receptor found on the apical surface of selected epithelial cells including the thyroid gland. Antibodies to megalin were found in 50% of subjects with autoimmune thyroiditis and 10% of Graves’ disease subjects (222). Megalin is also referred to as a polyspecific receptor protein. Na⫹/I⫺ symporter is not believed to be a major thyroid autoantigen because autoantibodies to the symporter are found in only 10% of subjects with Hashimoto’s thyroiditis and 20% of Graves’ disease subjects (223). In children, TMA correlates best with the presence of CLT; virtually 100% of children with CLT will have TMA, albeit some also have TGA (224,225). About 2% of the general childhood population have at least one antithyroid autoantibody. Thyroid autoimmunity is also highly associated with gastric parietal cell autoimmunity: approximately 25% of TMA-positive patients also have gastric parietal cell autoantibodies (PCA). About 25% of PCA-positive patients likewise also have TMA, indicating an underlying genetic predisposition to both thyroid and gastric (thyrogastric) autoimmunities in such patients (226). The histological correlate of PCA is chronic lymphocytic gastritis that can cause achlorhydria, iron deficiency, and intrinsic factor deficiency. Long-term deficiency of intrinsic factor can cause cobalamine deficiency and pernicious anemia. A major target autoantigen in atrophic gastritis is the H⫹/K⫹ ATPase pump. Both the 95 kDa alpha subunit and 60–90 kDa beta subunits of the gastric H⫹/K⫹ ATPase pump (proton pump) are targeted (227,228). Thyrogastric autoimmunities appear to be frequently inherited as an autosomal dominant trait with increased expression in female patients. Unlike type 1 diabetes, CLT and thyrogastric autoimmunities are not inherited in association with particular parental HLA haplotypes (229). HLA does appear to modulate (230) the clinical expression of the disease: DR4 and/or DR5 are associated with CLT and pernicious anemia in population studies and DR3 is associated with Graves’ disease. A model can be created

Autoimmune Endocrinopathies

in which a non-HLA gene provides the predominant susceptibility to AITD that, in the presence of DR4 or DR5, stimulates a Th1-mediated antithyroid attack presenting as autoimmune thyroiditis, whereas the presence of DR3 stimulates a Th2-mediated antithyroid attack presenting as Graves’ disease. Genetics does play a major role in the pathogenesis of CLT in studies of adults. No data in children have been reported. In a study of 2945 female Danish twin pairs, concordance for autoimmune hypothyroidism was 55% in monozygotic twins and 0% in dizygotic twins (231). Concordance in TPOAb and/or TGA positive results was 80% in monozygotic twins and 40% in dizygotic twins. Besides the genetic influence of HLA, association studies strongly suggest that the cytotoxic T-lymphocyte-associated serine esterase-4 (CTLA-4) gene located on chromosome 2q33, or genes closely linked to CTLA-4, influence the development of AITD including Graves’ disease and Hashimoto’s thyroiditis (232). CTLA-4 is expressed on the surface of activated T cells. Interaction of CTLA-4 with B7 from antigen-presenting cells provides a suppressive influence to downregulate activated T cells. Therefore failure to turn off activated T cells could theoretically lead to autoimmunity. Kotsa et al. showed that microsatellite-defined CTLA-4 allele 106 was increased in autoimmune hypothyroidism (233). Donner et al. from Germany demonstrated that the alanine CTLA-4 leader sequence polymorphism (threonine/alanine) at amino acid 17 was more frequent in Hashimoto’s thyroiditis (22%) than controls (15%) (234). One year later these investigators described that a ⫺318 cytosine/thymine promoter variant associated with AITD (both Graves’ and Hashimoto’s thyroiditis) was linked to an exon 1 polymorphism (235). However, by itself, Hashimoto’s thyroiditis was not significantly associated with a promoter polymorphism. Thymine in the promoter was linked to adenine in exon 1 of the CTLA4 gene. In contrast to these German data, researchers from the United Kingdom did not find evidence for genetic association of the ⫺318 polymorphism with Graves’ disease, autoimmune hypothyroidism, or systemic lupus erythematosus (236). It is controversial whether CTLA-4 plays a role in the association of AITD and type 1 diabetes. Djilali-Saia et al. (237) found no influence for CTLA-4 on the association of type 1 diabetes and AITD. While the CTLA-4 codon 17 A/G polymorphism was associated with autoimmune hypothyroidism, the polymorphism was no more strongly associated with type 1 diabetes plus AITD than Graves’ disease or Hashimoto’s thyroiditis alone. On the other hand in Japanese type 1 diabetes subjects under age 30 years (238), the G-variant of the Thr17Ala CTLA-4 exon polymorphism was more common in type 1 diabetes subjects than controls (39% vs. 28%) and was more common in type 1 diabetes subjects with AITD (54%) than either of the other groups. The authors point out that while there are no data to suggest that the Thr17Ala polymorphism influences the func-

699

tion of CTLA-4, this polymorphism may be linked to an AT microsatellite polymorphism that could affect mRNA stability. A new locus on chromosome 13 termed Hashimoto’s thyroiditis locus-1 (HD-1) was detected in linkage studies in 1999 (239). This locus was uniquely linked to Hashimoto’s thyroiditis and did not show linkage to Graves’ disease. In a subset of the families studied, a locus on chromosome 12 was linked to Hashimoto’s thyroiditis. One locus on chromosome 6 (AITD locus-1 [AITD-1]) was linked to both Hashimoto’s thyroiditis and Graves’ disease. This locus was close to, but distinct from, the HLA complex. As opposed to the above population association studies, using family-based linkage studies many candidate gene loci have been excluded as affecting AITD including CTLA-4, the T-cell receptor V␣ and V␤ complexes, the Ig heavy chain locus (240), the estrogen receptor alpha gene, and the aromatase gene (241). The Graves’ disease1 locus (GD-1) on chromosome 14 is also not linked to Hashimoto’s thyroiditis (242) nor is the TSH receptor gene associated with AITD (243). Thus the current state of the genetics of CLT can be summarized as follows. In families, AITD including CLT, atrophic thyroiditis, or Graves’ disease appears to be inherited as a dominant trait. HLA DR4 and/or DR5 are associated with an increased risk for CLT. Loci on chromosomes 2 (CTLA-4) and 13 also influence the development of CLT. Non-MHC regions on chromosome 6 and chromosome 12 deserve further study. 2.

Effects of AITD on the Fetus and Newborn: Congenital Hypothyroidism and Transient Hyperthyrotropinemia Women with CLT do not have a significantly increased risk of bearing a infant with congenital hypothyroidism because TMA, TPOAb, and TGA that do cross the placenta are not pathogenic. This has been known for over 20 years (244). However, if the mother has antagonistic TSH receptor autoantibodies, transient congenital hypothyroidism or transient hyperthyrotropinemia can result (245). In one study, 15 of 34 women giving birth to children with congenital hypothyroidism had evidence of TSH receptor antagonist autoantibodies (246). Variable neonatal thyroid function can be observed in babies born to mothers with AITD, ranging from hypothyroidism to hyperthyroidism depending upon the mix and titer of agonist vs. antagonist TSH receptor autoantibodies (247). A report of familial nongoitrous congenital hypothyroidism due to maternal AITD was reported as early as 1960 (248). In a North American study, TSH receptor-blocking autoantibodies accounted for 2% of infants with congenital hypothyroidism identified in a T4 screening program and overall affected 1:180,000 newborns (249). Thyrotropin-binding inhibitory immunoglobulins have been identified in infant and maternal sera (250).

700

Finding thyroid-binding inhibitory immunoglobulins in mothers of infants with congenital hypothyroidism suggests that the hypothyroidism will be transient. However, thyroid replacement therapy in such infants should be continued until age 3 or 4 years when a trial without hormone replacement can be carried out to confirm or deny that the hypothyroidism is persistent (251). 3. Postpartum Thyroiditis With an increasing frequency of adolescent girls becoming mothers (intended or unintended teenage pregnancy), pediatricians and pediatric endocrinologists must be aware of postpartum thyroiditis that occurs in 5–10% of women following delivery (252). Postpartum thyroiditis is a variant of autoimmune thyroiditis: following delivery, mothers can express any one of several possible clinical courses including hypothyroidism (3–6 months following delivery; ⬃40% of cases of postpartum thyroiditis), hyperthyroidism (⬃35% of cases), or hyperthyroidism followed by hypothyroidism (⬃25% of cases) (253,254). In many cases, euthyroidism supervenes by 12 months postpartum yet there is an high risk of hypothyroidism in the long term (255). After 3–5 years, up to 25% of such women can develop hypothyroidism. About one-third of women with postpartum hyperthyroidism appear to have Graves’ disease (256). Postpartum thyroiditis recurs very commonly in subsequent pregnancies. An increased rate of miscarriage in women with thyroid autoantibodies has been suggested (257). Postpartum thyroiditis may represent a rebound of thyroid autoimmunity following delivery with release of the general immunosuppressive state imposed on the immune system by pregnancy (258). Effervescence of autoimmune disease following parturition is also seen in women with other autoimmune diseases such as Graves’ disease and systemic lupus erythematosus. Women who are positive for thyroid autoantibodies in the first trimester have a 33–50% risk of experiencing postpartum thyroiditis. Women with type 1 diabetes are at threefold higher risk for postpartum thyroiditis than women in the general population (259). During episodes of hypothyroidism, thyroid hormone replacement in postpartum thyroiditis is appropriate to restore the euthyroid state. Thyroid hormone can be discontinued at ⬃9 months to observe whether the euthyroid state has recurred. During a phase of hyperthyroidism, if symptoms are mild, no therapy is indicated because thyrotoxicosis rarely lasts more than 1–2 months. Similar to hashitoxicosis, postpartum thyrotoxicosis is usually the consequence of thyroid gland destruction and release of thyroid hormone; thus antithyroid drugs such as propylthiouracil or methimazole are not indicated. Radioactive iodine uptake in a hyperthyroid stage of postpartum thyroiditis is not elevated unless true Graves’ disease is present. If therapy is required for thyrotoxicosis, a betablocker such as propranolol can be used but the drug’s

Winter

dosage should be tapered once the destructive phase of postpartum thyroiditis remits.

B.

Graves’ Disease

Graves’ disease is the result of thyroid-stimulating autoantibodies (TSAb) that mimic the action of TSH by binding to and activating the TSH receptor (260). These immunoglobulins, upon binding to TSH receptors on the surface of thyroid epithelial follicular cells, stimulate cyclic AMP production, and thus lead to excessive thyroid hormone production and clinical hyperthyroidism (261). Some TSAbs may also activate phospholipase A2 and these autoantibodies may be particularly goitrogenic. The TSH receptor is the major thyroid autoantigen in Graves’ disease. As opposed to CLT, in which thyroid gland destruction is mediated by a CD4 Th1-mediated cell-mediated response, Graves’ disease results from a CD4 Th2 response against the TSH receptor (262). Covering 60 kb, the 10 exon TSH receptor gene is located on chromosome 14q31 (263). Smaller mRNA transcripts can be observed, but the major mRNA is 4.3 kb. Prior to glycosylation, the TSH receptor apoprotein core weighs 84.5 kDa and ⬃100 kDa after glycosylation. The first nine exons encode the N-terminal extracellular domain of 398 amino acids. Six N-glycosylation sites are identified in the extracellular domain. TSH binds to this region of the TSHR. Encoded by a single large exon (exon 10), the 346 amino acid carboxyl half of the receptor contains the seven hydrophobic transmembrane segments that are connected by three extra- and three intracellular loops and the cytoplasmic tail of the TSHR. This portion of the TSHR demonstrates homology with other G protein-coupled receptors and activates the Gs protein complex upon TSH binding to the extracellular domain. The TSH receptor is a member of the superfamily of G-protein-coupled receptors. Other members of this receptor superfamily include the ACTH receptor, ␣-adrenergic and ␤-adrenergic catecholamine receptors, luteinizing hormone (LH) receptor, follicle-stimulating hormone (FSH) receptor, human chorionic gonadotropin (hCG) receptor, glucagon receptor, parathyroid hormone (PTH) receptor, and somatostatin receptor. TSH receptor autoantibodies bind to the extracellular domain of the receptor as expected (264). TSAbs were first described in the McKenzie mouse assay system as long-acting thyroid stimulator (LATS) (265). LATS was observed as delayed, but prolonged, thyroid gland stimulation after the injection of human immunoglobulin into mice. In some patients with low levels of LATS a substance that blocked LATS absorption by thyroid cells was termed LATS protector (LATS-P) (266). LATS-P corresponds more closely to human-specific LATS. In commercial radioimmunoassays to measure TRAbs, either thyrotrophin-binding inhibitory immunoglobulins (TBII) or thyroid-stimulating immunoglobulins (TSI) can be determined (267). TBII detect autoantibodies that can bind to the TSH receptor by the ability of human

Autoimmune Endocrinopathies

serum to compete with radioactively labeled TSH for binding to the TSH receptor. TBII titers are higher when more [125I]TSH binding is inhibited. The TBII assay does not differentiate agonistic autoantibodies as seen in Graves’ disease from antagonistic autoantibodies as observed in many cases of atrophic thyroiditis and some cases of Hashimoto’s thyroiditis. On the other hand, the TSI assay detects antibodies with stimulatory effects on the TSH receptor as seen in Graves’ disease. The TSI assay is typically negative in cases of autoimmune thyroiditis. The action of TSIs can be measured as the production and release of cAMP or thyroid hormone from slices of thyroid glands or cultured thyroid cells such as the FRTL-5 thyrocyte line. The titer of TSIs does not correlate with the severity of Graves’ disease. Being IgG autoantibodies, TRAbs can cross the placenta. In about 1% of pregnancies in which the mother presently has Graves’ disease or had Graves’ disease in the past, TRAbs with agonistic activity against the TSH receptor produce fetal and neonatal hyperthyroidism. In cases of maternal Graves’ disease, some experts have suggested that testing for TRAbs should be undertaken in the third trimester of pregnancy to assess the risk of neonatal Graves’ disease. If the TRAb titer is high, there is an increased risk of fetal and neonatal hyperthyroidism. Cord blood testing for TRAbs is another approach if maternal testing has not been pursued previously. TRAbs may be persistent even if the mother has had a thyroidectomy for treatment of Graves’ disease or is spontaneously euthyroid. The clinical appearance of neonatal hyperthyroidism may be delayed for 3–10 days if the mother was treated with the antithyroid drugs propylthiouracil or methimazole. Because TRAbs can represent a mixture of agonistic (e.g., TSIs) and antagonistic TSH receptor autoantibodies, the clinical course in the neonate born to a woman with Graves’ disease can be variable. If there is sustained fetal tachycardia, treatment of fetal hyperthyroidism with maternal administration of propylthiouracil and concurrent T4 can be considered because of the increased risk of poor fetal outcome (268). TMA/TPOAb and/or TGA are found in the sera of a large percentage of patients with Graves’ disease. These autoantibodies, therefore, do not differentiate CLT from Graves’ disease. In patients with sustained hyperthyroidism, and exophthalmos and/or pretibial myxedema, who are positive for TMA/TPOAb and/or TGA, the diagnosis of Graves’ disease is appropriate. However with positive TMA/TPOAb and/or TGA, if the patient is predominantly clinically euthyroid with goiter or hypothyroid and an episode of hyperthyroidism lasted only 2 months or less, the appropriate diagnosis is CLT with temporary hashitoxicosis from transient accelerated thyroid gland destruction. The radioactive iodine uptake in Graves’ disease is elevated; the radioactive iodine uptake in hashitoxicosis is not elevated.

701

In terms of genetic susceptibility to Graves’ disease, it has already been mentioned that AITD, including Graves’ disease, is often inherited in an apparent autosomal dominant mode within affected families (269). Firstdegree family members of individuals with Graves’ disease display a high frequency of thyroid autoantibodies and AITD as well as GPCA, pernicious anemia, islet autoantibodies, and type 1 diabetes (270). Graves’ disease is associated with HLA-DR3 (271), but, within families, inheritance of AITD is not linked to the inheritance of specific HLA haplotypes (272). In the HLA-DQ region, Graves’ disease is associated with DQA1*0501 (273). Recently the HLA DRB3*020/DQA1*0501 haplotype has been associated with Graves’ disease in African–Americans (274). In the mid-1990s, CTLA-4 polymorphisms on chromosome 2q33 were implicated in influencing genetic susceptibility to Graves’ disease (275). Researchers studied a CTLA-4 gene (AT)n microsatellite polymorphism within the 3⬘ untranslated region of exon 3. The relative risk for Graves’ disease with the 106-base pair allele was 2.82. Two years later the CTLA-4 exon 1, 49 A/G polymorphism interchanging alanine for threonine was associated with Graves’ disease (276). Graves’ disease patients show more alanine alleles than controls (73% vs. 58%). The CTLA-4 A/G polymorphism was substantiated in a new data set from the United Kingdom in 1999 (277). These investigators also found preferential transmission of the A allele to offspring with Graves’ disease. Researchers from the University of Newcastle-upon-Tyne calculated that 50% of inherited susceptibility to Graves’ disease was provided by the CTLA-4 and MHC regions (278). Loci on chromosomes 14q31 (termed GD-1 [242, 279]), 12q (IFN-␥ [280]), 6 (TAP1 and TAP2 [281]), 20q11.2 (termed GD-2 [282,283]) and the X chromosome (termed GD-3 [279]), IL-4 promoter (chromosome 5q31.1 [284]), vitamin D receptor (285) and chromosome 18q21 (286) have subsequently been linked to or associated with Graves’ disease. Loci shown not be associated with Graves include the TSH receptor (287,288),TNF receptor 2 (chromosome 1p36.3-p36.2 [289]), IL-1␣, IL-1␤, IL-1 receptor antagonist, IL-1 receptor, IL-4 receptor, IL-6, IL10, and TGF-␤ (284,290). Although the MHC and CTLA4 loci appear to have the greatest influence on the development of Graves’ disease, many other loci are under investigation on multiple chromosomes (291). Exophthalmos in Graves’ disease and other thyroid disorders is also believed to be immunologically mediated (292). The spectrum of such associations is termed thyroid-associated ophthalmopathy (TAO). Clinically euthyroid patients presenting with exophthalmos often have TMA, TGA, and LATS-P (293). Even without frank exophthalmos, 68% of patients with Graves’ disease have abnormally increased intraocular pressure on upward gaze (294). Since part of the thyroid’s lymphatic drainage traverses the retro-orbital space, it has been postulated that

702

Winter

thyroid antigens such as thyroglobulin might attach to the eye muscles and cause tissue damage as immune complexes are formed between thyroglobulin and antithyroglobulin autoantibodies. An exophthalmos-stimulating autoantibody has been described. Antibody to a soluble eye-muscle antigen has also been demonstrated. A older hypothesis that is again gaining favor proposes that growth of retro-orbital tissues in autoimmune exophthalmos is due to TSH receptors on fat cells and muscle cells that are affected by thyroid-stimulating immunoglobulins. The nature of the orbital antigens is unresolved and controversial, revolving around discussions of the TSH receptor, a 64 kD autoantigen (295), a 72 kD heat shock protein (296), and the G2s gene product (297). Regarding the causes of ophthalmopathy associated with Graves’ disease, there is evidence for both CD4 Th1 and CD4 Th2 subset involvement (298). Various therapies for extreme exophthalmos that threaten vision include prednisone, orbital irradiation, surgical decompression, and newer uses of immunomodulatory agents such as nicotinamide (299).

V.

AUTOIMMUNE ADDISON’S DISEASE

Addison’s disease is manifested as glucocorticoid and mineralocorticoid deficiency. Second only to iatrogenic adrenal cortical suppression from exogenous glucocorticoid administration, autoimmune adrenalitis with lymphocytic infiltration of the adrenal cortex is the most common cause of Addison’s disease. In the era before antibiotics were available, tuberculosis was the most common cause of adrenal failure. Complement-fixation testing using saline extracts of adrenal tissue was the first methodology employed to detect adrenal autoantibodies (300). Shortly thereafter, indirect immunofluorescence using cryocut sections of unfixed human adrenal cortical tissue became the method of choice for the detection of adrenal autoantibodies. Cytoplasmic fluorescence of the adrenal cortical cells demonstrates that adrenal cytoplasmic autoantibodies are present in the serum being tested (301). All layers of the adrenal cortex often fluoresce, whereas the medulla rarely fluoresces (302). The adrenal cortical cytoplasmic autoantigens were localized to the microsomes of the adrenal cortical cells by examination of ultracentrifuged adrenal fractions (303). A peroxidase-labeled protein A technique has been also been developed to detect adrenal autoantibodies (304). However, the results of such autoantibody testing were not identical to those using indirect immunofluorescence. Adrenal cytoplasmic autoantibodies are detected in up to 75–80% of new-onset subjects with Addison’s disease (305). Autoantibodies to the surface of human or murine adrenocortical cells can be detected in some patients by indirect immunofluorescence. In one study, 24 of 28 individuals (86%) with Addison’s disease displayed auto-

antibodies to the adrenal cell surface (306). Cytoplasmic and surface autoantibodies are strongly correlated. Because of the difficulty and expense of obtaining isolated viable adrenal cortical cells, such tests for surface autoantibodies are relegated to research laboratories and have been replaced by the enzyme autoantibody immunoassays discussed below. In the 1990s, with the molecular cloning of the adrenal steroidogenic enzymes, various immunoassays were developed to detect autoantibodies directed against these enzymes. The adrenal enzymes 17-alpha-hydroxylase (307), 21-hydroxylase (308,309), and the side chain cleavage enzyme P450scc have been shown to be autoantigens targeted in individuals with adrenalitis. The P450scc enzyme autoantibody is identified in sera from patients with autoimmune polyglandular syndrome type 1 but not in patients with isolated autoimmune Addison’s disease (310). The 21-hydroxylase autoantibodies are believed to be most clearly associated with Addison’s disease and adrenal cytoplasmic autoantibodies (311). Germane to 21hydroxylase as a major autoantigen in Addison’s disease is that in-vitro-demonstrated suppression of in-vivo 21hydroxylase activity does not advance progression to adrenal failure (312). This illustrates that while adrenal autoantibodies are plentiful in autoimmune Addison’s disease, these autoantibodies are not pathogenic. Similarly to the natural history of type 1 diabetes, the development of Addison’s disease passes through various sequential, cumulative stages: elevated renin and normal to low aldosterone, deficient cortisol response to ACTH injection, elevated basal ACTH concentrations, and deficient basal aldosterone and cortisol secretion (313). Similarly to the predictive function of islet autoantibodies for the development of type 1 diabetes, autoantibodies directed against the adrenal cortical cytoplasm or steroidogenic enzymes precede the first appearance of the clinical manifestations of Addison’s disease (314). Adrenal cytoplasmic autoantibodies are predictive of the development of Addison’s disease in children and, to a lesser degree, in adults (315). Complement-fixing adrenal cytoplasmic autoantibodies may be more strongly associated with progression to adrenal failure than those that do not fix complement (316). This likely reflects the fact that complement-fixing autoantibodies are higher-titer autoantibodies. This certainly appears to the case for ‘‘non-complement-fixing’’ ICA vs. ‘‘complement-fixing’’ ICA: higher-titer ICA more strongly predict the development of type 1 diabetes in nondiabetic individuals. Addison’s disease occurs in less than 3 years in up to 50% of initially asymptomatic adrenal cytoplasmic autoantibody-positive individuals. In adrenal cytoplasmic autoantibody-positive children, 9 of 10 developed Addison’s disease during follow-up of up to 10 years. The nonaddisonian child, nevertheless, still had laboratory evidence of adrenal insufficiency (317). The relationship between increased titers of adrenal autoantibodies (both cytoplasmic and 21-hydroxylase au-

Autoimmune Endocrinopathies

toantibodies) and more severe degrees of impaired adrenocortical function and increased risk of progression to Addison’s disease has been recognized (318). In the natural history of the development of Addison’s disease, adrenal autoantibody concentrations were reported to rise until the development of clinical disease, when autoantibody reactivity waned. Excluding autoimmune polyglandular syndrome 1, isolated autoimmune Addison’s disease and autoimmune Addison’s disease associated with autoimmune polyglandular syndrome 2 has been associated with HLA-B8 and HLA-DR3. These associations are no stronger than the HLA associations discussed for AITD and are considerably weaker than the HLA associations described for type 1 diabetes. Adrenalitis commonly occurs with other autoimmune diseases (autoimmune polyglandular syndrome types 1 and 2 [319]) and Addison’s disease by itself or as part of autoimmune polyglandular syndrome 2 has also been associated with HLA-DR4 in addition to HLA-DR3. Therefore, the genetic basis for type 1 diabetes and Addison’s disease is, in part, similarly linked to an HLAassociated gene or genes. Polymorphisms of the CTLA-4 gene at the 49 A/G site were associated with Addison’s disease in subjects with the HLA-DQA1*0501 allele (320). In studies of the (AT)n microsatellite within exon 3, the 106 base pair allele was more common in English patients with Addison’s disease than controls but no difference was observed in Norwegians, Finns, or Estonians (321). In 2000, a study from the United Kingdom demonstrated an association between the G allele of the CTLA-4 A/G polymorphism in isolated Addison’s disease as well as Addison’s disease that was part of autoimmune polyglandular syndrome type 2 (322).

VI.

ACQUIRED PRIMARY GONADAL FAILURE

In patients with hypergonadotropic hypogonadism, the presence of serum steroidal cell autoantibodies (SCA) detected by indirect immunofluorescence supports the diagnosis of an autoimmune cause for primary gonadal failure (323). SCA were described using indirect immunofluorescence as early as 1968 (324). In patients of either gender, such autoantibodies react with steroid hormoneproducing cells in the theca interna/granulosa layer of graafian follicles, cells of the corpus luteum, the placental syncytiotrophoblast, Leydig’s cells of the testes, and cells of the normal adrenal cortex. If SCA are present, an independent determination about the presence of adrenal cytoplasmic autoantibodies cannot be made. Premature menopause, male climacteric, or infertility are clinical manifestations of gonaditis (325). Gonaditis is seen more often in female patients and is usually recognized in association with autoimmune polyglandular syndrome type 1 but can occur in autoimmune polyglandular

703

syndrome type 2. Approximately 1:4 women with autoimmune Addison’s disease will exhibit amenorrhea and 10% will develop premature ovarian failure (326). In the absence of associated autoimmune disorders, SCA specifically against the ovary can be rare (327). On the other hand, Fenichel et al. (328) observed gonadal autoantibodies in ⬃60% of cases of idiopathic premature ovarian failure. SCA frequently predict later ovarian failure. Over 12 years of follow-up, ovarian failure occurred in 100% of SCA-positive women with autoimmune polyglandular syndrome type 1 (329). Autoantibodies directed against steroidogenic enzymes in cases of gonaditis should not be surprising given the embryological commonality of the adrenal cortex and gonads. However, in the absence of associated adrenal autoimmunity, autoantibodies to P450scc 17-hydroxylase and 21-hydroxylase are uncommon (330,331), while autoantibodies to 3␤-hydroxysteroid dehydrogenase have been reported in at least one study (332). Autoantibodies to 3␤-hydroxysteroid dehydrogenase in women with premature ovarian failure have been associated with DQB1 alleles with aspartic acid at position 57 (333). This might be somewhat surprising since non-aspartic-acid residue 57 DQB1 alleles increase risk for type 1 diabetes.

VII.

IDIOPATHIC HYPOPARATHYROIDISM

Idiopathic (presumed autoimmune) hypoparathyroidism in children is often seen in association with mucocutaneous candidiasis or autoimmune Addison’s disease as part of autoimmune polyglandular syndrome type 1 (334). Lymphocytic infiltration of the parathyroid glands is observed in cases of idiopathic hypoparathyroidism, especially if associated with autoimmune polyglandular syndrome type 1. This attests to the autoimmune nature of so-called idiopathic hypoparathyroidism in at least some patients. There is continued controversy about whether parathyroid autoantibodies can be detected by indirect immunofluorescence (335,336). Parathyroid autoantibodies detected by indirect immunofluorescence can be preabsorbed with human mitochondria, indicating that such parathyroid autoantibodies are not tissue-specific (337). Using Western blotting, autoantibodies to the extracellular domain of the calcium receptor in patients with hypoparathyroidism have been reported (338). However this finding has yet to be substantiated by other research laboratories. Autoantibodies cytotoxic for cultured bovine parathyroid cells in subjects with hypoparathyroidism have been described (339). Finally autoantibodies to circulating parathyroid hormone (340,341) and the renal tubular parathyroid hormone receptor (342) have been observed in adults but have not so far been described in children. In the absence of recognized causes of hypoparathyroidism (eg., postparathyroidectomy or DiGeorge syndrome), and in the absence of candidiasis and Addison’s

704

Winter

disease (or adrenal autoantibodies), it is presently not possible to confirm the diagnosis of idiopathic hypoparathyroidism as autoimmune in etiology because of the lack of confirmed autoantibodies to the parathyroid gland that can be easily measured (see Chapter 19).

VIII.

HYPOPHYSITIS AND AUTOIMMUNE DISEASE OF THE PITUITARY

In rare cases of hypopituitarism in which mass lesions of the pituitary were suspected, histological examination of surgical specimens has revealed hypophysitis (343). Such idiopathic lymphocytic hypophysitis is believed to be autoimmune in etiology. In some patients with type 1 diabetes, as well as their immediate relatives, autoantibodies reactive with prolactin and growth-hormone-secreting cells have been visualized by indirect immunofluorescence (344). No associations between such autoantibodies and clinical disease were recognized in these individuals. By Western blotting, pituitary autoantigens of 40 kDa and 49 kDa have been identified, although expression of these proteins was not restricted to the pituitary (345). For the 49 kDA autoantibody, positive sera were most common in subjects with lymphocytic hypophysitis (70%) with lower frequencies in subjects with Addison’s disease (42%), thyroid autoimmunity (15%), rheumatoid arthritis (13%), and normal subjects (10%). In a group of Swedish patients with hypopituitarism, 28% had 49 kDa autoantibodies (346). Cases of lymphocytic hypophysitis continue to be reported (347) and definitely occur in children (348). However idiopathic hypopituitarism in children is believed generally to be rarely caused by autoimmunity (349).

IX.

AUTOIMMUNE DIABETES INSIPIDUS

In some patients with idiopathic diabetes insipidus (DI), autoantibodies to the antidiuretic-hormone-producing cells of the hypothalamus have been recognized (350). Problematic is the need for fresh human hypothalamus as substrate for indirect immunofluorescence. DI-associated hypothalamic (vasopressin-cell) autoantibodies are not removed by preabsorption with vasopressin, oxytocin, neurophysin I, or neurophysin II (351). Up to one-third of children with otherwise idiopathic DI may have an autoimmune process responsible for their condition. An adult has been reported with scleroderma and DI (352). Suspected autoimmune DI has also been observed in cases of autoimmune polyglandular syndrome type 1 (353) and other autoimmune conditions (354–356). Adolescents with autoimmune DI and hypophysitis have been reported (357,358). Most cases of hypophysitis do not involve the posterior pituitary. DI-associated hypothalamic (vasopressin-cell) autoantibodies can precede the development of DI and appear to be predictive of the development of DI in initially unaffected subjects (359,360).

X.

ASSOCIATED NONENDOCRINE AUTOIMMUNE DISEASES

A.

Chronic Lymphocytic Gastritis Producing Atrophic Change

Gastritis has been classified as type A gastritis with sparing of the antrum, evidence of autoimmunity to the gastric parietal cells, destruction of the parietal cells and hypergastrinemia; or as type B gastritis due to Helicobacter pylori infection with involvement of the antrum and hypogastrinemia (361). Autoimmune atrophic gastritis (type A gastritis) due to chronic lymphocytic infiltration of the gastric fundus, as noted previously, is commonly associated with thyroiditis and type 1 diabetes (362–364). In this process the gastric parietal cells in the fundus and body of the stomach are destroyed along with their ability to secrete hydrochloric acid and intrinsic factor. Achlorhydria can be frequently found; however, intrinsic factor secretion is usually preserved except in cases of longstanding gastric autoimmunity. With prolonged deficiency of intrinsic factor, pernicious anemia manifested as a megaloblastic anemia and neuropathy may occur during mid to late life. Autoantibodies to the cytoplasm of the gastric parietal cell (PCA) and autoantibodies that block vitamin B12 binding to intrinsic factor (IF-blocking autoantibodies), or block the absorption of the IF–vitamin B12 complex, are markers for chronic lymphocytic gastritis. PCA are assayed by indirect immunofluorescence using stomach fundus as substrate. As noted previously, the target autoantigen in chronic lymphocytic gastritis is the H⫹/K⫹ ATPase pump. An ELISA methodology for the detection of H⫹/K⫹ ATPase pump autoantibodies has been described (365). Gastric parietal cell autoantibodies often appear early in the course of the disease, are associated with achlorhydria, and are absent in about half the patients by the time pernicious anemia is clinically apparent. Intrinsic factor autoantibodies can appear late in the course of disease, often close to the onset of pernicious anemia and thereafter.

B.

Chronic Hepatitis

In the absence of a previous hepatitis B or hepatitis C infection, chronic hepatitis may result from an autoimmune process. Chronic autoimmune hepatitis is observed frequently in autoimmune polyglandular syndrome type 1. The presence of autoantibodies to smooth muscle (SMA; ⬃50% prevalence), mitochondria (antimitochondrial antibodies [AMA]; ⬃15% prevalence) and liver–kidney– mitochondrion-1 [LKM1]) can serve as markers for autoimmune hepatitis (366). Although nonspecific, antinuclear antibodies (ANA) can also be observed in ⬃80% of cases of autoimmune hepatitis.

Autoimmune Endocrinopathies

Nine different mitochondrial antigens have been described termed M1 through M9. The E2 subunit of the pyruvate dehydrogenase complex (the M2 AMA antigen), the asialoglycoprotein receptor (367), cytochrome P450, UDP-glucuronosyl-transferases (368), and F-actin (the SMA autoantigen) are autoantigens described in chronic hepatitis.

C.

Celiac Disease

Celiac disease (also known as celiac sprue or gluten-induced enteropathy) is characterized by gluten intolerance, abnormal small bowel histological changes, and malabsorption. IgA autoantibodies against gliadin, reticulin, and endomysium have been described in subjects with celiac disease, but the major autoantigen appears to be the enzyme transglutaminase (369). Individuals with transglutaminase autoantibodies (370) should undergo periodic small bowel biopsy. If the histological findings of celiac disease are identified, wheat and wheat products should be eliminated from the diet. Transglutaminase autoantibodies have been detected in ⬃10% of subjects with type 1 diabetes.

XI.

AUTOIMMUNE DISEASE ASSOCIATIONS

The concurrence of multiple autoimmune endocrinopathies (with or without other nonendocrine autoimmune diseases) is common. Two consistent associations have been classified into the autoimmune polyglandular syndromes (APS) (371,372) (Table 10). Almost every disease combination (Table 11) has been noted clinically.

A.

APS-1

In APS-1, the primary diseases usually present clinically in the order listed in Table 10. If a component disease is skipped, it usually does not present later. Malabsorption, early-onset pernicious anemia, alopecia, vitiligo, primary

Table 10 Type 1

2

Autoimmune Polyglandular Syndromes Diagnostic criteria

At least two of the following: Mucocutaneous candidiasis Hypoparathyroidism Addison’s disease or adrenal autoantibodies Addison’s disease (or adrenal autoantibodies) plus Autoimmune thyroid disease (Schmidt syndrome) Insulin dependent diabetes, or Autoimmune thyroid disease and insulin-dependent diabetes (Carpenter syndrome)

705 Table 11

Autoimmune Polyglandular Syndromes Diabetes

Adrenalitis/Addison’s disease Hypoparathyroidism Mucocutaneous candidiasis Dental enamel hypoplasia/nail dystrophy AITD Type 1 diabetes Gonaditis Hypophysitis Autoimmune hepatitis Vitiligo/alopecia Dermatitis herpetiformis Fat malabsorption IgA deficiency Celiac disease Autoimmune pernicious anemia Pure red cell aplasia Immune thrombocytopenic purpura Progressive myopathy Myasthenia gravis Stiff man syndrome Parkinson’s disease

Type 1

Type 2

⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹ ⫹ ⫹⫹ ⫺ ⫹⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫺ ⫺ ⫺

⫹⫹⫹ ⫺ ⫺ ⫺ ⫹⫹⫹ ⫹⫹⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫺ ⫹ ⫺ ⫹ ⫹ ⫹

⫺, unobserved or rare; ⫹, observed; ⫹⫹, common; ⫹⫹⫹, pathognomonic.

hypogonadism, and chronic active hepatitis may frequently accompany APS-1. AITD and/or type 1 diabetes are infrequently encountered. Another term used for APS1 is autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), emphasizing that selective immunoendocrinopathies are associated with candidiasis and ectodermal problems. APS-1 can be identified in siblings although most cases are sporadic. The greatest recent development in the genetics of autoimmune endocrine disease was the identification of a single gene locus termed the autoimmune regular (AIRE) that is responsible for APS-1 (373) [located on chromosome 21 (374)]. Homozygosity or compound heterozygosity for AIRE mutations produces APS1 in an autosomal recessive pattern of inheritance (375). The predicted protein sequence of AIRE suggests that AIRE functions as a transcription factor (376).

B.

APS-2

APS-2 was first described by Schmidt (Schmidt syndrome: Addison’s disease plus chronic lymphocytic thyroiditis) and later as Carpenter syndrome (Schmidt syndrome plus type 1 diabetes). Unlike APS-1, which presents in childhood, APS-2 can occur at any age, but occurs more commonly in midlife and shows a female

706 Table 12

Winter Autoimmune Endocrinopathy Associations

A. Type 1 diabetes

B. Genetic syndromes (Down, Turner, Klinefelter)

C. Congenital infections (rubella)

Autoimmune thyroid disease Chronic lymphocytic thyroiditis Graves’ disease Pernicious anemia Addison’s disease Type 1 diabetes Autoimmune thyroid disease Chronic lymphocytic thyroiditis Graves’ disease Pernicious anemia Type 1 diabetes Chronic lymphocytic thyroiditis

predominance (2:1) in contrast to APS-1 in which the gender ratio is unbiased. APS-2 is strongly associated with HLA-DR3 and DR4 and may share certain common genetic origins with type 1 diabetes (377). However, when subjects with type 1 diabetes are excluded from the APS2–HLA analysis, the strong HLA association disappears.

Table 13

C.

Other Autoimmune Endocrinopathy Associations

The association of type 1 diabetes with thyrogastric autoimmunity is of great clinical importance (378) (Table 12). Approximately 20% of patients with type 1 diabetes have TMA, and 9% have PCA. These autoantibodies are usually present at the time of diagnosis of type 1 diabetes. Of type 1 diabetes patients with TMA, almost one-half will eventually manifest thyroid dysfunction. Of these, 80% develop primary hypothyroidism, while the remaining 20% will manifest Graves’ disease. Hyperthyroidism may precede the clinical onset of type 1 diabetes. In childhood, frank pernicious anemia is unusual in type 1 diabetes patients with PCA; however, achlorhydria is commonly associated with the PCA autoantibody. Adrenal cytoplasmic autoantibodies are present in 2% of type 1 diabetes patients and are most commonly associated with TMA and PCA (APS-2). Six percent of children and young adults with type 1 diabetes and TMA have adrenal cytoplasmic autoantibodies. Approximately one-half of patients with adrenal cytoplasmic autoantibodies will show evidence of chemical hypoadrenocorticalism (i.e., raised basal renin/ACTH levels) while 20% will have more overt features of adrenocortical insufficiency when

Clinically Useful Tests for the Diagnosis of Autoimmune Endocrinopathies and Related Diseases

Disease Type 1 diabetes

Chronic lymphocytic thyroiditis

Graves’ disease

Addison’s disease Primary gonadal failure

Associated nonendocrine diseases Chronic lymphocytic gastritis/ pernicious anemia Chronic active hepatitis Celiac disease Vitiligo

Autoantibody

Technique

ICA: Islet cell cytoplasmic autoantibody IAA: Insulin autoantibody GADA: GAD autoantibody IA-2A: IA-2 autoantibody TMA: Thyroid microsomal autoantibody TPOAb: thyroperoxidase autoantibody TGA: Thyroglobulin autoantibody TMA, TPOAb, TGA TBII: Thyrotropin-binding inhibitory immunoglobulin TSI: Thyroid-stimulating immunoglobulin ACA: Adrenal cytoplasmic autoantibody 21-hydroxylase autoantibody SCA: Steroidal cell autoantibody 3␤-hydroxysteroid dehydrogenase autoantibody

IFL (unfixed blood group O pancreas) RBA RBA RBA HA, IFL, RIA, CF, latex agglutination RIA or immunochemiluminometric assay HA, IFL, RIA, CF, latex agglutination See above Radioreceptor assay

PCA: Gastric parietal cell autoantibody IFAb: Intrinsic factor blocking autoantibody SMA: Smooth muscle autoantibody Mitochondrial autoantibody Transglutaminase autoantibody Melanocyte or tyrosinase autoantibody

In vitro bioassay, RIA IFL RBA IFL RBA

IFL RIA IFL IFL ELISA IFL WB

CF, complement fixation; ELISA, enzyme-linked immunosorbent assay; HA, hemagglutination; IFL, indirect immunofluorescence; RBA, radiobinding assay; RIA, radioimmunoassay; WB, Western blot.

Autoimmune Endocrinopathies

707

studied (379). At least 1:6 such patients will ultimately develop clinical Addison disease, giving an overall prevalence of Addison disease in type 1 diabetes patients of 0.33% (1:300). In many genetic syndromes, especially those with chromosomal abnormalities (i.e., Down, Turner, and Klinefelter syndromes), increased frequencies of autoimmune endocrinopathies (especially thyrogastric autoimmunity and type 1 diabetes) are recognized. In patients with congenital infections such as rubella, the frequencies of AITD and type 1 diabetes are increased. Undoubtedly new autoimmune polyendocrinopathies will continue to be described in the future such as the triple H syndrome (dysfunction of the hippocampus [impaired anterograde memory], hair follicle [alopecia areata], and hypothalamic–pituitary–adrenal axis from isolated ACTH deficiency) (380). Table 13 outlines a variety of tests available for autoantibody detection. Those in bold are often of greatest potential value to the clinician. A positive autoantibody result in an unaffected individual can predict the later development of autoimmune disease. In an affected individual, a positive autoantibody result can demonstrate that

Table 14

XII.

CLINICAL APPROACH TO THE AUTOIMMUNE ENDOCRINOPATHIES AND RELATED DISEASES

In general, whenever one autoimmune disease is suspected or diagnosed, a search for other autoimmune diseases should be launched guided by knowledge of the common associations noted previously (381,382). Any patient with TMA/TPOAb should be studied for PCA and vice versa. Any patient with TMA/TPOAb and/or PCA should be evaluated for adrenocortical cytoplasmic or 21-hydroxylase autoantibodies, especially if type 1 diabetes is present. Because of the high frequency of CLT and atrophic gastritis in patients with type 1 diabetes, all type 1 diabetes patients should be screened

Clinical Evaluation of Individuals Positive for Various Autoantibodies

Condition/autoantibody(s) ICA, GADA, IA-2A and/or IAAa

TMA, TPOAb, and/or TGA Adrenal cytoplasmic autoantibody (or) 21hydroxylase autoantibody Steroidal cell autoantibody (or) 3␤-hydroxysteroid dehydrogenase autoantibody Gastric parietal cell autoantibody

Smooth muscle autoantibody (or) mitochondrial autoantibody Transglutaminase autoantibodies Autoimmune polyglandular syndrome type 1 without apparent hypoparathyroidism Autoimmune polyglandular syndrome type 1 without apparent hypoadrenalism Mucocutaneous candidiasis and/or isolated hypoparathyroidism a

the disease in question has an autoimmune cause. A clinical approach to the testing of clinically unaffected yet autoantibody-positive individuals is presented in Table 14 (see below). Again, prediction and prevention studies concerning type 1 diabetes should only be carried out in a research setting.

For research purposes only.

Yearly clinical evaluation/measurement Frequently sampled intravenous glucose tolerance test: if first-phase insulin response is repeatedly 100 and 1000 ␮M) (89,90). Mild hyperlactacidemia and hypocalcemia, probably due to parathyroid hormone (PTH) resistance, are common (37,96). Amylase and lipase are increased if pancreatitis is present (91–93). Blood glucose levels are usually low, but in some patients they may be high, even before IV fluids have been started (100,101). This is particularly frequent in patients with ketolysis defects (i.e., 2-methyl-acetoacetyl-CoA thiolase, succinyl-acetoacetate-CoA-transferase deficiencies), who can present with hyperglycemia and ketosis resembling an episode of diabetic ketoacidosis (52). In contrast, patients with 3-OH 3-methyl glutaryl-CoA lyase deficiency, a defect affecting leucine catabolism and ketone bodies synthesis, present with metabolic acidosis (characteristic of OA) and hypoketotic hypoglycemia (characteristic of fatty acid oxidation defects) (51–52). 2. Late-Onset Form In the intermittent, late-onset form, patients present with recurrent attacks of coma or lethargy with ataxia or dystonia. Acute hemiplegia, hemianopsia, and cerebellar hemorrhage have also been described (36–37). Increased protein intake or endogenous catabolism, due to an intercurrent illness, may trigger these crisis. The first attack may present at several months or years of age, or even in adolescence or adulthood, and has frequently been pre-

793

ceded by episodes of dehydration, anorexia, vomiting, failure to thrive, hypotonia, developmental delay, and/or other symptoms (37,102,103). Between attacks, clinical and laboratory evaluations may appear normal. However, the laboratory profile obtained during the attacks is similar to that described for the severe neonatal form, with the exception of hyperammonemia, which is less frequent (37). 3. Chronic Form The chronic progressive form is characterized by persistent anorexia, failure to thrive, and vomiting. These symptoms are frequently attributed to gastrointestinal problems. Renal Fanconi syndrome or osteoporosis may develop. Hypotonia and muscle weakness can be present, mimicking congenital or metabolic myopathies. Developmental delay, progressive mental retardation, self-mutilation, and seizures sometimes accompany the above-mentioned symptoms (1,36,37,104).

C.

Diagnosis

The most important test is the analysis of UOA performed by gas chromatography and mass spectrometry (GC/MS). Diagnostic possibilities of this test greatly increase if the urine is collected during the acute episode, when the characteristic profile for each OA is most likely to be found (45,105). In an acutely sick patient, the laboratory performing the test must be alerted so that the result can be available as soon as possible. Typical UOA profiles show elevated excretion of 3-OH-isovaleric acid and isovalerylglycine in IVA; and 3-OH-propionic acid, 3-hydroxyvaleric acid, methylcitrate, tiglylglycine and propionylglycine in PA. In MMA, there is a large increase of methylmalonic acid, with or without mild elevation of some of the propionate metabolites (37,45). Ketone bodies (3-OH-butyrate and acetoacetate) may be increased in decompensated patients with any of the above-mentioned OA. Another reliable and fast methodology for the diagnosis of several OA is the analysis of AC by tandem mass spectrometry (TMS). This methodology is highly sensitive and can be performed in blood spots on filter paper (Guthrie card), plasma, urine, or cerebrospinal fluid (CSF) (106–107). AC analysis allows the diagnosis of more than 20 different diseases (OA, fatty acid oxidation defects, and aminoacidopathies) and is being used not only for the diagnosis of symptomatic patients but also for mass newborn screening (108–110). Abnormal profiles can even be obtained from cord blood in asymptomatic newborns (111–112). A typical AC profile shows a large increase of isovalerylcarnitine in IVA. However, other AC species, such as pivaloylcarnitine and 2-methylbutyrylcarnitine, have the same molecular weight and should be considered when the profile is being interpreted (53,113). In PA and MMA there is a large increase of propionylcarnitine. A slight increase of methylmalonylcarnitine is also usually

Organic Acidemias Enzyme deficiency

Acetyl CoA carboxylase Malonyl-CoA decarboxylase

Glutaric aciduria type I L-2-Hydroxyglutaric aciduria

Glutaryl-CoA dehydrogenase ?

Organic acidemias with primary CNS involvement

— Malonic aciduria

Isovaleric aciduria Isovaleryl-CoA dehydrogenase 3-Methyl crotonylglycinuria 3-Methyl crotonyl-CoA carboxylase 3-Methyl glutaconic aciduria type I 3-Methyl glutaconyl CoA hydratase 3-OH 3-methyl glutaric aciduria 3-OH 3-methyl glutaryl-CoA lyase 2-Methyl butyrylglycinuria 2-methylbutyryl-CoA-dehydrogenase/ short-branched-chain acyl-CoA dehydrogenase 2-methyl-3-hydroxybutyric aciduria 2-methyl-3-hydroxybutyryl-CoA dehydrogenase 2-Methyl acetoacetic aciduria 2-methyl acetoacetyl-CoA thiolase (Bketo-thiolase) — Succynyl-CoA: 3-ketoacid CoA transferase — Isobutyryl-CoA dehydrogenase 3-OH-isobutyric aciduria 3-OH isobutyryl-CoA deacilase 3-OH-isobutyric aciduria 3-OH isobutyric-acid dehydrogenase (?) 3-OH-isobutyric aciduria Methylmalonate semialdehyde dehydrogenase Propionic aciduria Propionyl-CoA carboxylase Methylmalonic aciduria Methylmalonyl-CoA mutase (mut⫹/ mut⫺) Methylmalonic aciduria Cobalamin defect B: adenosyltransferase deficiency Methylmalonic aciduria Cobalamin defect A: Reductase deficiency Methylmalonic aciduria Cobalamin defects C, D and F

Organic acidemias due to defects in branched-chain aminoacids

Common name

Table 4

Lys, Try Lys, Try

63–65

62–64

62–64

38,41,44,67 38,42,68,69

37 Secondary FAO inhibition. 36,37,66 Combined malonic/methylmalonic aciduria

Methylmalonic aciduria without homocystinuria Methylmalonic aciduria without homocystinuria Homocystinuria and methylmalonic aciduria

AdoCbl. synthesis defect. Val, Ileu, Met, Treo, OCFA, Ch. AdoCbl. Synthesis. Val, Ileu, Met, Treo, OCFA, Ch. AdoCbl and MetCbl synthesis. Val, Ileu, Met, Treo, OCFA, Ch. Leu, Ileu Leu, Ileu

37,48,49,60 37,61,62

56 36,37,57,58 36,37,57 36,37,57,59

Val Val Val Val. (B-ala, L-alloisoleucine) a

52

Ketolysis, Leu

Val, Ileu, Met, Treo, OCFA, Ch. Val, Ileu, Met, Treo, OCFA, Ch.

52

Ketolysis, Ileu

36,37,46 36,37,47–49 36,37,50 51,52 53,54

References

55

b

a

Comments

Ileu, 2-methyl fatty acids.

Leu Leu Leu Leu, ketone bodies synthesis Ileu

Pathway involved

794 Abdenur

Unknown Normal 3-methyl glutaconyl CoA hydratase activity Normal malonyl-CoA decarboxylase activity

3-Methyl glutaconic aciduria, type III and IV

Malonic aciduria

Unknown

Unknown

Synthesis of phospholipids (?)

Tyrosine, homogentisic acid Gamma glutamyl cycle Cholesterol and non sterol isoprenes Unknown

Oxalate Oxalate Glycerol

Unknown Lys,Try Glu, GABA N-acetyl-aspartic acid

50,84

81–83

75 76 77–80

73 73 74

Found in Costeff syndrome, 37,50 Pearson syndrome, ATPase syntase deficiency, and others 37,85

Differential diagnosis with SCAD and mild MAD

Peroxisomal defect Peroxisomal defect X-linked.

Neurotransmitter defect

43,70 71 39 40,72

Val, valine; Ileu, isoleucine; Met, methionine; Treo, treonine; Lys, lysine; Try, tryptophan; Glu, glutamic acid; GABA, 4-aminobutyric acid; FA, fatty acids; OCFA, odd-chain fatty acids; Ch, cholesterol (side-chain); AdoCbl, adenosylcobalamin; MetCbl, methylcobalamin; FAO, fatty acid oxidation; SCAD, short-chain acyl-CoA dehydrogenase deficiency; MAD, multiple acyl-CoA dehydrogenase deficiency. a 3-Methyl crotonyl-CoA carboxylase, propionyl-CoA carboxylase and pyruvate carboxylase (see prymary lactic acidemias) are impared in holocarboxylase syntethase and biotinidase deficiency (48,49,86). b Impaired protein and fatty acid metabolism.

Alkaptonuria Pyroglutamic aciduria Mevalonic aciduria/hyper-IgD and periodic fever syndrome Encephalopathy, petechiae, and Unknown ethylmalonic aciduria syndrome 3-Methyl glutaconic aciduria type Acyltransferase deficiency (?) II Barth syndrome: X-linked Normal 3-methyl glutaconyl CoA hydracardiomyopathy and neutropenia tase activity.

Alanine/glyoxylate aminotransferase D-Glyceric dehydrogenase Glycerol kinase (isolated or as a contiguous gene defect) Homogentisic acid oxidase Glutathione synthetase Mevalonate kinase

Dehydrogenase (?) 2-Ketoadipic dehydrogenase Succinic semialdehyde dehydrogenase Aspartoacylase deficiency

Hyperoxaluria type I Hyperoxaluria type II Glyceroluria

Miscellaneous organic acidemias

D-2-Hydroxyglutaric aciduria 2-Ketoadipic aciduria 4-OH butyric aciduria N-acetylaspartic aciduria

Emergencies of Inborn Metabolic Diseases 795

796

Abdenur

present in the latter. It is important to consider that the increase in diagnostic AC species is limited in patients with severe carnitine deficiencies. Acylglycines by GC/MS stable isotope dilution or TMS may also be used for diagnosis (53,105,113a). Quantitative AA usually show a nonspecific elevation of glycine. Glutamine is also elevated, reflecting the hyperammonemia usually seen in these patients, with the exception of PA (113b,113c). Total and free carnitine levels are low, with elevation of the acylcarnitine/free carnitine ratio (37).

D.

Treatment: The Acute Episode

Rapid recognition and treatment of the acute metabolic decompensation in patients with OA can be life-saving. Treatment should provide supportive therapy, promote anabolism, and remove the offending toxins and should be carried out in specialized centers (37,114).

Figure 2 Metabolic pathway of the branched-chain amino acid catabolism and related compounds. Numbers denote sites of the known enzymatic blocks. 1, Branched-chain-oxoacid dehydrogenase; 2, Isovaleryl-CoA dehydrogenase; 3, 3-Methylcrotonyl-CoA-carboxylase; 4, 3-MethylglutaconylCoA-hydratase; 5, 3-OH 3-methyl glutaryl-CoA lyase; 6, 2methylbutyryl-CoA-dehydrogenase; 7, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase; 8, 2-methyl acetoacetyl-CoA thiolase (B-keto-thiolase); 9, Isobutyryl-CoA-dehydrogenase; 10, 3-OH isobutyryl-CoA deacilase; 11, 3-OH isobutyric-acid dehydrogenase; 12, Methylmalonate semialdehyde dehydrogenase; 13, Succynyl-CoA: 3-ketoacid CoA transferase; 14, Acetyl CoA carboxylase (cytosolic); 15, Malonyl-CoA decarboxylase; 16, Propionyl-CoA carboxylase; 17, Methylmalonyl-CoA mutase, cobalamin defects A, B, C, D, and F; 18, 3-OH-butyric-acid dehydrogenase; 19, 3-OH 3-methyl glutaryl-CoA synthase. (Adapted from Ref. 37.)

1. Supportive Therapy The treatment will depend on the patient’s clinical condition. A central line to ensure IV access and an arterial line for blood pressure monitoring and frequent blood drawing should be placed. Assisted ventilation, inotropics, albumin, and/or blood products are frequently needed. Acutely ill patients with OA are usually dehydrated due to poor intake, vomiting, hyperventilation, and increased urinary losses. After fluid resuscitation is provided, IV hydration should be aimed at correcting dehydration over a period of 48 h. Rapid rehydration should be avoided due to the risk of cerebral edema. If pH is less than 7.20, metabolic acidosis should be only partially corrected with sodium bicarbonate at an initial dosage of 1– 3 mEq/kg, repeated as needed. Overcorrection of the metabolic acidosis should be avoided, since this can increase cerebral edema. In severely acidotic patients sodium overload can be prevented by giving 30–50% of the sodium requirements as sodium bicarbonate instead of sodium chloride. Blood gases, electrolytes, BUN, glucose, calcium, ammonium, and urine ketones should be monitored every 2–4 h. Initial potassium levels are usually normal or high in acutely ill patients, but these levels might be artificially increased due to the acidosis. In fact, potassium requirements are elevated due to the usual history of vomiting that precedes the admission and to the treatment with a high GIR and insulin (see below). Liver function tests, creatinine, amylase, and lipase levels should be checked initially and repeated as needed. Acute pancreatitis should be treated when present (91–93). Cultures should be obtained and antibiotics started. Staphylococcal and Candida infections should be considered in the differential diagnosis, and complete blood count (CBC) and platelet count should be evaluated daily.

Emergencies of Inborn Metabolic Diseases

2. Anabolism It has been shown that endogenous production is an important source of abnormal metabolites in nonacutely ill patients with OA. This production is probably due to protein turnover (115,116) and is increased by fatty acid breakdown and intestinal production of propionate in patients with PA and MMA (87,88). These endogenous sources of toxic metabolites become even more important in severely ill patients and treatment should be aggressive to decrease their production (37). Oral intake is usually not possible and IV nutrition should be used to promote anabolism. Initially, this goal can be partially achieved by giving a high GIR to provide at least 8–10 mg/kg/min (Table 2). It is important to note that even with such a GIR, caloric intake is not sufficient to cover the patient’s needs (Table 3), which are increased during the decompensation (117). Patients with OA can develop hyperglycemia and glycosuria, even with low GIR. We have documented an inadequate insulin response to hyperglycemia during the acute decompensation (118), which may or not be associated with pancreatitis (91). If hyperglycemia develops, insulin should be used (37,119). The requirements vary depending on the severity of the patient’s condition and the GIR. In our experience, in a severely ill patient receiving a GIR of 8–10 mg/kg/min, a dosage of 0.10– 0.15 U/kg/h is enough to control hyperglycemia, but it is advisable to start with a lower dosage (0.05 U/Kg/h) and to adjust it according to blood sugar levels. Insulin requirements decrease when acidosis improves. Plasma ammonia levels decrease in parallel with those of the organic acids (90). Once acidosis has been corrected and ammonia and transaminase levels are close to normal, fats can be added to the treatment. If amylase and lipase levels are high or oral intake is not possible, IV lipids (Intralipid) should be used, starting at 0.5 g/kg/ day and increasing gradually to 2 g/kg/day. When the oral route can not be used for more than 48 h, total parenteral nutrition (TPN) should be considered. TPN has been successfully used in chronic and acutely ill patients with OA and allows an effective anabolism that cannot be achieved with glucose and lipids alone (119,120). An ideal IV amino acid mixture should contain lower concentration of those AAs that are precursors of the increased organic acid (i.e., leucine in IVA). Such preparations are not available in the majority of the medical centers. As an alternative, any available amino acid solution can be used cautiously. We start with an amount that provides 30–50% of the recommended intake of the AA involved in the metabolic block. This amount can be increased gradually depending on the results of blood gases, ammonium, and serum AA. Levels of the abnormal metabolites in urine (UOA) or blood (acylcarnitines) should also be evaluated to monitor the response to treatment. With a high caloric supply from carbohydrates and fat, an IV amino acid dosage of 1–1.5 g/kg/day can be achieved, but special mixtures, deprived of the offending amino acids, might be required to supply

797

more protein. As patient improves, the oral/NG tube route can be restarted (see section on long-term treatment). 3. Detoxification In IVA and MMA, the organic acids are effectively excreted through the urine. Therefore, detoxification procedures should be indicated only in those severely ill patients who do not respond rapidly to treatment in spite of maintaining a good urinary output (37,114). In contrast, urinary excretion of propionic acid is poor, therefore detoxifying procedures should be considered early in the treatment in patients with PA (37,121). The most effective detoxification method is hemodialysis, which allows a high clearance of organic acids, amino acids and ammonium. Hemofiltration, peritoneal dialysis, or blood exchange transfusions can be used when the former is not available. Continuous venovenous hemofiltration is well tolerated by newborns or infants and allows rapid toxin removal (114). Peritoneal dialysis is available in most centers and is more effective in newborns than children. The dialysate should be warmed and buffered with bicarbonate. Hypertonic solutions can be used when overhydration is present. In those circumstances, hyperglycemia can develop and insulin might be needed. To treat the hyperammonemia, sodium benzoate (250 mg/kg/day) can be used alone, or in conjunction with any of the above-mentioned detoxification procedures (37,122). The amount of sodium provided through this source should be accounted for when the daily sodium requirements are calculated (see section on treatment of urea cycle defects). Intravenous carnitine is another resource for toxin removal. This therapy will correct the decreased levels of free carnitine, provide enough substrate for the synthesis of nontoxic acylcarnitine compounds (i.e., isovalerylcarnitine, propionylcarnitine, etc.) that are excreted through the urine, and restore the intramitochondrial levels of CoA (36,37). After obtaining a sample for basal levels, a dosage of 100–400 mg/kg/day (divided every 4–6 h) should be given. The highest dosage should be used in newly diagnosed patients who may have severe carnitine depletion. In patients with IVA, treatment with L-glycine increases the conversion of isovaleryl-CoA to the nontoxic compound isovalerylglycine, which is excreted through the urine (36,123). Oral or nasogastric-tube supplementation of L-glycine (250–600 mg/kg/day, divided in four to eight doses) prepared in a 100 mg/ml water solution should be given during the acute episode (36,37). Another potential resource for toxin removal is the administration of cofactors: biotin (10–20 mg/day) in PA and hydroxycobalamin (1–2 mg/day IM) in MMA (37). However, patients with severe neonatal presentation rarely respond to vitamin treatment. Clinical improvement correlates with correction of the metabolic acidosis, hyperammonemia, and ketonuria. Patients with MMA may develop persistent lactic acidemia due to chronic glutathione deficiency,

798

Abdenur

which can be corrected with high dosages of vitamin C (2 g/day) (124). Lactic acidosis secondary to thiamine deficiency has been described in PA patients (125).

E.

Long-Term Management

When the patient’s condition allows for it, PO or NG feedings can be started. Natural protein is restricted to meet the recommended amounts of the AAs involved in the metabolic block, and can be initially provided with an infant formula. Total protein requirements for age and gender are achieved by adding special formulas devoid of the offending amino acids (36,37). Recent studies suggest that energy requirements might be normal or even low in OA patients out of crisis (126). However, energy intake should be adequate to meet the patient’s needs for normal growth, to maintain anabolism when poor appetite is present, and also should cover the increased requirements during intercurrent illnesses (37). Caloric requirements can be met with the use of protein-free powders (i.e., Prophree, Ross Laboratories; 80056, Mead Johnson; Duocal, SHS). As an alternative, carbohydrate supplements or oil (except for olive oil in PA and MMA patients) can be added to the formula when these products are not available. Osmolarity of the final preparation should be considered to prevent diarrhea. Long fasting periods should be avoided (115) and dietary treatment should meet all the requirements for micronutrients and minerals. Iron and calcium supplements are frequently needed. Oral carnitine (in IVA, PA, and MMA) and/or glycine (for IVA) supplementation should be maintained, and vitamin therapy should only continue if a positive response has been documented. Metronidazole has been shown to be effective in decreasing the production of propionate by the gut flora (37,88,127). Recommended dosage is 10–20 mg/kg/day. Due to the possible side effects of metronidazole (leukopenia, peripheral neuropathy, and pseudomembranous colitis), it has been recommended to restrict its use to 10 consecutive days every month (37). We have not seen adverse effects after using the drug at 10 mg/kg/day daily for prolonged periods of time. The long-term prognosis varies depending upon the particular OA, age at onset, response to vitamin therapy, and residual enzyme activity. Several mutations have been found (128–130), and clear genotype/phenotype has been described for a particular group of MMA patients (131). Family compliance, psychological adjustment, and education are important for successful treatment. Nasogastric or gastrostomy feedings are usually needed and frequent hospitalizations are common in the most severe cases. Guidelines should be given to parents and primary physicians for special situations such as intercurrent illnesses, immunizations, anesthesia, or surgery (37,132, 133). Reported long-term outcome has varied from a normal development to different degrees of neurological in-

volvement, including mental retardation and movement disorders (134–140). Other long-term complications, including poor growth, malnutrition, cutaneous lesions (141), deficiency of trace elements (142), and osteoporosis can be prevented if good metabolic control and proper nutritional treatment can be achieved. Cardiomyopathy has been reported in some patients with OA (37,56,143). Tubular dysfunction and progressive renal insufficiency are common in MMA patients (37,144–148). It is not clear if these long-term manifestations can be prevented with optimum metabolic control. Kidney transplantation or combined kidney and liver transplantation have been performed in several patients with MMA. In general, better metabolic control and higher protein tolerance were obtained, but decompensations, mental deterioration, or acute basal ganglia lesions could not be prevented with these treatments (149,151). Similar experience has been reported for PA patients undergoing liver transplant (140,152). Early diagnosis and intensive treatment are key factors in improving long-term prognosis (36,37). Therefore, the availability of newborn screening with tandem mass spectrometry opens a new chapter for the outcome of these diseases (108–111).

IV.

FATTY ACID OXIDATION DEFECTS

A.

Pathophysiology: Mitochondrial Fatty Acid Oxidation

Mitochondrial fatty acid oxidation (FAO) disorders are a relatively new group of IMD of increasing relevance. Understanding the FAO process is essential to interpret the pathophysiology of these diseases and to develop adequate strategies for treatment. FAO is the major source of energy for skeletal muscle and the heart, while liver oxidizes fatty acids (FA) primarily during fasting (153,154). The FAO process begins when triglycerides, stored in adipose tissue, are broken down to glycerol and fatty acids, mainly long-chain. The latter are transported in blood bound to albumin and enter liver cells through a specific transport system (155). Carnitine, an important metabolite in fatty acid oxidation, is transported into the tissues by a plasma membrane carnitine transporter (CT) specific for kidney, muscle, and heart (153,154). Once inside the cell, FFA of carbon length 18 or shorter are oxidized in the mitochondria, while longer-chain fats are metabolized in the peroxisomes (156). Fatty acids are activated to their corresponding acyl-CoA by specific acyl-CoA synthetases. The resulting acyl-CoAs enter the mitochondria in different ways, depending on their chain length. Short- (4–6 carbons) and medium-chain (6–10 carbons) acyl-CoAs directly enter the mitochondrial matrix. In contrast, longchain acyl-CoAs (12–18 carbons) enter the mitochondria through a complex active transport system (Fig. 3). Initially, long chain acyl-CoAs are conjugated to carnitine

Emergencies of Inborn Metabolic Diseases

by carnitine palmitoyl transferase I (CPT-I), located in the outer mitochondrial membrane. There are two tissue-specific isoforms of CPT-I, hepatic and muscular, but only patients with the hepatic form have been described so far (154). Long-chain acylcarnitines are carried through the intermembranous space by a carnitine–acylcarnitine translocase (translocase). Finally, another enzyme, carnitine palmitoyl-transferase II (CPT II), bound to the inner mitochondrial membrane, releases carnitine and longchain acyl-CoAs into the mitochondrial matrix (153,154). Carnitine is recycled and acyl-CoAs of all chain lengths undergo a series of cyclic enzymatic reactions (Fig. 3). The first step in the mitochondrial FAO of saturated straight-chain fats is a dehydrogenation of the acyl-CoA to enoyl-CoA. This reaction is catalyzed by four related enzymes, the acyl-CoA dehydrogenases (ACDs): very

799

long-, long-, medium-, and short-chain acyl-CoA dehydrogenases (VLCAD, LCAD, MCAD, and SCAD, respectively), which differ in their chain-length specificity (153,156). Nevertheless, there is some degree of overlap in their activity. Recent data suggest that the main enzyme involved with long straight-chain fatty acid metabolism is VLCAD and that LCAD may play a role in the metabolism of branched-chain fatty acids (157). All dehydrogenases have flavin adenine dinucleotide (FAD) bound at the active site. Electrons released during these reactions are channeled by the electron transfer flavoprotein (ETF), a mitochondrial matrix enzyme with ␣- and ␤-subunits, and the ETF-ubiquinone oxidoreductase (ETF-QO), a component of the inner mitochondrial membrane that feeds the electrons into the respiratory chain via ubiquinone (156,158). ETF and ETF-QO defects impair not only

Figure 3 Enzymes and transporter proteins involved in mitochondrial oxidation of saturated straight-chain fatty acids. CT, carnitine transporter; FATP, fatty acid transport proteins; AS, acyl-CoA synthetase(s); CPT I, carnitine palmitoyltransferase I; TR, carnitine-acylcarnitine translocase; CPT II, carnitine palmitoyltransferase II; ETF, electron transfer flavoprotein; ETF-QO, ETF-ubiquinone-oxidoreductase; 1, very long-chain acyl-CoA-dehydrogenase; 2, medium-chain acyl-CoA-dehydrogenase; 3, short-chain acyl-CoA-dehydrogenase; 4, mitochondrial trifunctional protein (MTP): 4a, long-chain-enoyl-CoA-hydratase; 4b, long-chain 3-hydroxy-acyl-CoA-dehydrogenase; 4c, long-chain-ketoacyl-CoA thiolase; 5, short-chain-enoyl-CoA-hydratase (crotonase); 6, short-chain 3-hydroxy-acyl-CoA-dehydrogenase; 7, medium-chain 3-ketoacyl-CoA thiolase; 8, hydroxymethylglutaril-CoA-sinthetase; 9, hydroxymethylglutaril-CoA-lyase (enzyme involved in ketogenesis and leucine metabolism);10, 3-OHbutyric-acid dehydrogenase. CoA, Coenzyme A; CoASH, free CoA; FAD, flavin adenine dinucleotide; FADH, reduced form of FAD.

800

Abdenur

the dehydrogenases involved in fatty acid oxidation but also those involved in the metabolism of branched-chain aminoacids (valine, isoleucine, and leucine), lysine, hydroxylysine, tryptophan, and sarcosine. In the second step of FAO, the enoyl-CoAs produced by the ACDs are hydrated to hydroxyacyl-CoAs by an enoyl-CoA-hydratase. Then, the hydroxyacyl-CoAs undergo dehydrogenation to ketoacyl-CoAs by a hydroxyacyl-CoA dehydrogenase and finally there is a cleavage of the thioester bond by an acyl-CoA ketothiolase (Fig. 3). This process completes one turn of the FAO cycle and results in the release of acetyl-CoA and a new acyl-CoA molecule that is two carbons shorter (153,156). The exact mechanism of the last three steps varies for substrates of different chain length. For long-chain acyl-CoA substrates the reactions are carried by a mitochondrial trifunctional protein (MTP) with enoyl-CoA-hydratase, hydroxyacylCoA dehydrogenase, and ketoacyl-CoA thiolase activities (159,160). This protein is an octamer composed of four ␣- and four ␤-subunits. The ␣-subunits contain the longchain 3-enoyl-CoaA hydratase activity and the long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) activities; the ␤ subunit has the long-chain 3-ketoacyl-CoA thiolase activity (161). Biochemical studies have identified two groups of LCHAD-deficient patients. The first, and most common, has an isolated LCHAD deficiency due to mutations in the LCHAD coding region of the ␣-subunit gene. Activities of the other two enzymes of the trifunctional protein are preserved in these patients. In the second group all three enzyme activities are deficient (162). For shorterchain fatty acids, individual enzymes, each one with a single activity, have been identified: short-chain-enoylCoA-hydratase (crotonase), short-chain 3-hydroxyacylCoA dehydrogenase (SCHAD), and medium-chain 3-ketoacyl-CoA thiolase (153,156). The acetyl-CoA moieties produced during the FAO are used as a source of energy through the tricarboxylic acid cycle. Under fasting conditions, acetyl-CoA moieties produced in the liver become the substrate for the synthesis of ketone bodies that are used as fuel by several tissues, including the brain. Two enzymes are involved in ketone bodies synthesis: hydroxymethylglutaryl-CoA-synthase and hydroxymethylglutaryl-CoA lyase (Fig. 3) (52,163). The latter is also the final enzyme of leucine catabolic pathway.

B.

Clinical Presentation

Several enzymatic defects in FAO and ketogenesis have been found in humans, all inherited as autosomic recessive diseases. These defects have become one of the most important group of IMD, due to the number of patients and the severe outcome. In a series of 107 patients, Saudubray et al. found that 50 patients and 47 siblings died, 30% within the first week and 60% before age 1 year (164).

1. Main Clinical Features The most common diseases are MCAD, LCHAD, and MAD deficiencies, but it is possible that many patients with long-chain fatty acid oxidation defects still die without recognition of their underlying disease. Table 5 summarizes the known defects in saturated straight-chain fatty acid metabolism found in humans and their most distinctive features. Clinical presentation in patients with FAO defects ranges from completely asymptomatic to severe malformations or unexplained sudden death in infancy or adulthood. As expected by the important role of FAO in liver, heart, and muscle the main clinical presentation of FAO defects is dominated by symptoms related to these organs. Neurological symptoms are also common during the acute crisis and they might be in part related to hypoglycemia and impaired ketogenesis. Neonatal presentations, including malformations, lethargy, hypotonia, heart-beat abnormalities, liver involvement, or sudden death, were thought to be limited to CPT-II, translocase, and MAD deficiencies (158, 164,182) but neonatal cases of MCAD, LCHAD, and VLCAD deficiencies have also been reported (164, 183,184). In classic cases, patients with FAO defects appear normal until the first episode of metabolic decompensation occurs in infancy or early childhood. A history of a dead sibling is common (164). The metabolic crisis is characterized by vomiting, followed by lethargy, hypotonia, and slight liver enlargement. Respiratory distress due to cardiac insufficiency and/or metabolic acidosis can be present. A prolonged period of fasting, and/or hypercatabolism can trigger the episode. Symptoms are usually erroneously attributed to an intercurrent illness or cyclic vomiting syndrome (153,164). Patients can recover from the initial crisis, and repeat another episode, remaining asymptomatic in between. Liver insufficiency can be severe, leading to a Reye-like syndrome, complicated by hypothermia and gastrointestinal bleeding (185). Cholestasis has also been reported in patients with LCHAD deficiency (164,175,186). Cardiac involvement is characterized by hypertrophic or, less commonly, dilated cardiomyopathy. Severe arrhythmia (ventricular and supraventricular tachycardia, ventricular fibrillation), conduction defects (bundle branch block, atrioventricular (AV) block, sinus node dysfunction), and cardiac insufficiency can be found in neonates, especially in those with CPT-II, translocase, and LCHAD deficiencies (154,164,170,182), which are diseases in which there is an accumulation of long-chain-acyl-CoAs and long-chain acylcarnitines. Heart-beat disorders have not been observed in CT, CPT-I, or MCAD deficiencies. Pericardial effusion and endocardial fibroelastosis have been described (187). Symptoms of skeletal muscle involvement have been described for the majority of the FAO defects, and they are especially common in patients with CPT II-adult type-, LCHAD and mild MAD deficiencies. Usual mani-

Yes Yes

Defects in plasmatic membrane transport Carnitine transporter (CT) Fatty acid transport protein (FATP)

No No

No No

Yes Yes

Yes

Yes Yes

Yes

No No

Yes

Yes No

Yes

Yes

No

Yes No

Heart

Abnormalities related to liver, muscle, and heart involvement are described in the text. a Enzyme involved in ketogenesis and leucine catabolism.

Yes Yes

Ketone body synthesis Hydroxymethylglutaril-CoA-synthetase (HMG-S) Hydroxymethylglutaril-CoA-lyasea (HMG-L)

Yes

Yes

Yes Yes

Yes Yes

Yes Yes

Yes Yes

Yes

No Yes

Yes Yes Yes

Yes

Yes

Electron transfer Multiple acyl-CoA-dehydrogenase (MAD) Electron transfer flavoprotein (ETF) ETF-ubiquinone-oxidoreductase (ETF-QO)

Long-chain 3-hydroxy-acyl-CoA-dehydrogenase (LCHAD) Mitochondrial trifunctional protein (MTP) Short-chain 3-hydroxy-acyl-CoA-dehydrogenase (SCHAD) Medium-chain 3-ketoacyl-CoA thiolase deficiency (MCKAT)

Mitochondrial beta oxidation Very long-chain acyl-CoA-dehydrogenase (VLCAD) Medium-chain acyl-CoA-dehydrogenase (MCAD) Short-chain acyl-CoA-dehydrogenase (SCAD)

No Yes

Yes Yes No

Yes

Yes

Carnitine-acylcarnitine translocase (translocase) Carnitine palmitoyltransferase II (CPT-II) Neonatal

Infantile Late onset (most frequent)

Yes

Yes

No

Yes No

Muscle

Carnitine palmitoyltransferase I (CPT-I)

Defects in mitochondrial transport

Liver

Main organ involved

Defects in Mitochondrial Oxidation of Saturated Straight-Chain Fatty Acids

Known enzyme deficiencies in humans

Table 5

Few patients reported (163,181). Hypoketotic hypoglycemia and severe metabolic acidosis. (51,52,163).

Great phenotypic variation from severe neonatal form with malformations to progressive muscle weaknes with lipidic myopathy (158).

Few cases reported. More severe than LCHAD deficiency (177). Few cases reported. Variable phenotype. Ketonuria, muscle and liver isoforms (?) (178). Few patients known. Typical organic acid profile (179,180).

Most frequent FAO defect. Reye-like episodes. Sudden death (172). Variable phenotype. Ophthalmoplegia, myopathy, metabolic acidosis (173,174). Retinitis pigmentosa, peripheral neuropathy (175,176).

Neonatal and infantile presentation. Arrhythmias (171).

Severe neonatal presentation. Renal and brain abnormalities reported (168,169). Less frequent (169,170). Most common cause of rhabdomyolysis and myoglobinuria (169).

Plasma carnitine elevated or normal. Renal tubular acidosis reported (166). Neonatal presentation. Heart beat abnormalities. Hyperammonemia (167).

Very low plasma carnitine levels (165). Severe episodic liver failure. Two patients reported (155).

Distinctive features

Emergencies of Inborn Metabolic Diseases 801

802

festations are hypotonia and/or progressive proximal weakness. Acute episodes of muscle pain or cramps, fatigue, and/or exercise intolerance with rhabdomyolysis can appear in response to stress, prolonged exercise, or cold, and can produce acute renal failure. Muscle involvement has not been associated to CPT-I deficiency (154,164,188). Malformations are mainly associated with MAD deficiency, but have also been described in CPT-II deficiency. Most common dysmorphic features are a high forehead, wide-spaced eyes, and low-set ears, resembling a Zellweger syndrome. Renal dysplasia (polycystic kidneys) and brain malformations have also been reported (153,158,164). Retinitis pigmentosa and peripheral neuropathy have been found in patients with LCHAD deficiency. The former seems to be related to deficiency of docosahexaenoic acid (DHA). Endogenous synthesis of DHA may be impaired in LCHAD-deficient patients and a preliminary study treating these children with oral DHA has shown promising results (189). Mental retardation and/or other neurological sequelae are observed mostly in patients who had severe encephalopathy associated to Reye’s-like syndrome (164,185). Other manifestations, specific for a given defect, are outlined in Table 1. 2.

Maternal Complications During Pregnancy of Affected Fetuses The association between LCHAD deficiency in the fetus and maternal pre-eclampsia, the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) or acute fatty liver of pregnancy (AFLP) has been well documented (162,190 – 192). These complications have been reported in up to 79% of pregnancies with fetuses affected with LCHAD, while there were no complications if the fetus was heterozygous or normal. Ibdah et al. reported that the complications were related to the presence of the prevalent E474Q mutation on one or both alleles (homozygous or compound heterozygous) of the LCHAD-affected fetus (162,191). However, a recent report describes three families with trifunctional enzyme deficiency and maternal hepatic dysfunction in pregnancy not associated with the common E474Q mutation (193). Affected LCHAD patients show a higher incidence of prematurity, asphyxia, intrauterine growth retardation, and intrauterine death than their unaffected siblings (190). These findings highlight the importance of obtaining molecular diagnoses for patients and parents, and to provide adequate genetic counseling and molecular prenatal diagnosis when indicated (194). More recently, AFLP has also been reported in pregnancies with fetal CPT-1, MCAD, and SCAD deficiencies, raising the possibility of a common mechanism producing liver disease in mothers carrying fetuses affected with FAO defects (195 – 197).

Abdenur

3. Sudden Infant Death Many FAO defects have been associated with episodes of sudden, unexpected, infant death. Different studies analyzing postmortem specimens of liver, bile, cultured fibroblasts, or blood spots in filter paper have estimated that 2–5% of sudden infant death syndrome (SIDS) can be attributed to FAO defects (198–200). They include deficiencies of the carnitine transporter, translocase, VLCAD, LCHAD, MCAD, SCHAD, and MAD (171,198–204). The mechanism of sudden death in these patients is not clear, but acute arrhythmia may account for the unexpected deaths in children with abnormalities in long-chain fatty acid metabolism (182). Acylcarnitine analysis by tandem mass spectrometry in postmortem bile or in the newborn screening samples (Guthrie card) stored by state programs have significantly expanded the retrospective diagnosis of fatty acid oxidation disorders (200,204,205). With the availability of newborn screening by tandem mass spectrometry and early treatment, it is reasonable to expect that the number of patients who experience sudden death due to FAO defects will decrease significantly. Other metabolic diseases, not involving fatty acid metabolism, have also been found in children who experience sudden or unexpected death in infancy. Among others they include glutaric aciduria type I, myophosphorilase deficiency, lysinuric protein intolerance, and defects of the respiratory chain (1,200,206–209).

C.

Laboratory Abnormalities

The most common laboratory abnormality found during an acute episode is hypoglycemia. Ketone bodies can be detected in urine, but in smaller amounts than expected for the degree of hypoglycemia (hypoketotic hypoglycemia). Total nonesterified fatty acids (NEFA) are increased, and the NEFA to ketone body ratio is abnormally high (>3) when the sample is obtained before IV glucose is started (210). As an exception to the rule, patients with SCHAD deficiency may present with large amounts of ketones in urine (178). Elevated liver enzymes, mild hyperammonemia, and slight metabolic acidosis are common. Abnormal clotting factors are seldom observed. Very high levels of CK (several thousands) and aldolase reveal muscle involvement. Hyperuricemia appears to be a common finding in MCAD deficiency and mild elevation of lactic acid is present in LCHAD deficiency (175,211). Myoglobinuria can be present in any FAO defect affecting skeletal muscle, and is a common presentation in the adult form of CPT II deficiency (153,154,164). During the acute episode, a liver biopsy under light microscopy shows micro- and macrovesicular steatosis. These abnormalities usually lead to the diagnosis of Reye syndrome. However, the electron microscopy will lack the characteristic mitochondrial changes of Reye syndrome (188,212). Fibrosis and cirrhosis has been described in

Emergencies of Inborn Metabolic Diseases

liver biopsies of VLCAD and LCHAD deficiencies. Pathology of skeletal and cardiac muscle shows fatty infiltration (lipidic myopathy) (153,158,188).

D.

Diagnosis

Once the diagnosis of a FAO defect is suspected, samples should be immediately obtained for specialized metabolic studies. They must include blood spots in filter paper (Guthrie card), serum, and urine. Analysis of acylcarnitines (AC) by TMS in plasma or blood spots in filter paper have become the most important tool for diagnosis of FAO defects. This methodology is highly sensitive and abnormal profiles can be obtained even when samples are collected out of crisis. In rare cases an AC profile can be misread as normal when free carnitine levels are very low or when the sample is obtained out of crisis in nonfasting conditions. Typical AC profiles can be identified for CPTII/translocase, LCAD/VLCAD, MCAD, SCAD, LCHAD, and MAD as well as for HMG-CoA-lyase deficiencies (106,107,213–215). In the transport defects of long-chain fatty acids and the carnitine uptake deficiency AC are uninformative; in CPT-I deficiency, low levels of all AC species (including acetylcarnitine), combined with high levels of free carnitine, are suggestive of the defect (216). AC have been reported as normal in children with SCHAD (203) and HMG-CoA-synthase deficiencies (217). AC analysis performed in the newborn screening card have allowed retrospective diagnosis in patients who died of MCAD, CPT II, VLCAD, translocase, and MAD deficiencies (111,169,185,202,204,218). Tandem mass spectrometry is also being employed by many screening programs around the world for the neonatal detection of FAO defects as well as other IMD (109–111,219,220). It is likely that early diagnosis and treatment will change the natural history of the disease for many patients (221). Urine OA profile is the second choice for the diagnosis of FAO defects. It is important that analysis and interpretation be performed in an experienced center. Several defects can be diagnosed if samples are obtained during the acute episode; they include HMG-CoA-lyase, MCAD, LCHAD, SCAD, MCKAT, SCHAD, and MAD. However, frequently the results may be suggestive of, but nonspecific for, an FAO defect or give a false-negative result when samples are collected after the patient has been started on supportive therapy (105,188,222). Therefore, patients with FAO defects can be misdiagnosed if only standard OA analysis is performed. Quantitative analysis of acylglycines by GC/MS stable isotope dilution or tandem mass spectrometry is an alternative method for diagnosis when acylcarnitines are not available and/or when UOA analysis gives a negative result (105,223). Carnitine levels are informative. Total and free carnitine levels are normal or high in CPT-I deficiency and extremely low in the CT defect. In all other FAO diseases, total and free carnitine are usually decreased, and the per-

803

centage of acylcarnitines is increased (164,188). Another method for the diagnosis of FAO defects is to measure the levels of individual free fatty acids in plasma by GC/ MS (224). This method is sensitive but time consuming. We have shown that in MCAD and MAD deficiencies, levels of individual fatty acids correlate well with those of the acylcarnitine of the same carbon length (221,225). However, short-chain-3-hydroxy fatty acids are not esterified with carnitine and therefore their measurement might be important for the diagnosis of SCHAD, when the acylcarnitine profile is noncontributory (226). In vitro flux studies with labeled fatty acids in lymphocytes of fibroblasts are another useful tool for diagnosis (227,228). Fasting or loading tests are less frequently needed and should only be performed in experienced centers if the above-mentioned specialized tests are not informative (164). Enzyme activity can be measured in the majority of these conditions in cultured fibroblasts, liver, and/or muscle. Tissue specificity is known for CT, and CPT-I, and has also been postulated for SCHAD, while HMG-CoA-synthase is only expressed in liver. Molecular studies are available for most of the FAO defects (229). Common mutations have been described in MCAD and LCHAD deficiencies. Several studies have shown that a missense mutation 985 A>G, accounts for the majority of the mutant alleles in MCAD deficiency, being more prevalent in northern Europeans (219,229– 231). In LCHAD deficiency, a common 1528 G>C mutation has been identified (175,229).

E.

Treatment: The Acute Episode

Acutely ill patients with suspected FAO defect should be treated in an experienced pediatric intensive care unit. Delay in proper treatment may result in death or permanent brain damage (164,188). 1. Supportive Therapy Intravenous hydration should be given cautiously because patients with hyperammonemia may have cerebral edema and patients with heart involvement may develop cardiac insufficiency. Intracranial pressure monitoring should be considered if brain swelling is suspected and mannitol can be used if needed. Clotting factors may be required in patients with severe liver dysfunction and H2 blockers should be given to prevent gastrointestinal bleeding. Salicylates and valproic acid are contraindicated due to their potential mitochondrial toxicity and should be investigated as a potential cause of the metabolic crisis (232). Epinephrine and glucagon have a lipolytic effect and therefore should be avoided. 2. Anabolism In order to suppress lipolysis, intravenous fluids should provide a glucose infusion rate of 10 mg/kg/min or more,

804

Abdenur

regardless of the blood sugar levels found on admission (164,188). If patients develop hyperglycemia, IV insulin can be given. Due to the required high glucose concentration in the IV fluids, a central line is needed. As an alternative, glucose (10% glucose polymers solution) can be provided via NG tube. In patients known to have longchain fatty acid defects, medium-chain triglycerides (1–3 grams/kg/day) can be added via NG tube as soon as the GI tract allows for it. 3. Detoxification Treatment with intravenous carnitine (100–200 mg/kg/ day) is life saving for the carnitine transport defect (CTD). There is general agreement to the use of carnitine (50– 100 mg/kg/day) in patients with short- and medium-chain defects (153,156,164). However, use of carnitine for defects involving long-chain fatty acids is still controversial, due to the possible role of long-chain acylcarnitines in the development of heart beat abnormalities (164). A recent study also shows that medium- and long-chain acylcarnitines suppress mitochondrial fatty acid transport through inhibition of translocase (233). A conservative approach is to start treatment with 50% of the usual dosage and adjust it to maintain free carnitine levels within normal limits. Riboflavin (100–200 mg/day) should be tried in patients with MAD and SCAD deficiencies, even though only a few patients with mild variants have been reported to respond to it (188).

F.

Long-Term Management

Carnitine is the only treatment needed for the CT deficiency. For all other FAO defects, the key to chronic treatment is to avoid prolonged fasting and to use a fat-restricted diet. Guidelines for treatment of the different conditions are outlined in Table 6. The formula to be used depends on the enzymatic defect. There is a rationale for the use of medium-chain triglycerides (MCT) in patients with impaired metabolism of long-chain fatty acids (FATP,

Table 6

CPT-I, translocase, CPT-II, VLCAD, LCHAD, MTP). In contrast, the use of MCT is contraindicated for patients with short- or medium-chain FAO defects as well as for MAD and defects in ketogenesis. Enough essential fatty acids (linoleic and ␣-linolenic) acids should be provided to avoid deficiencies. Dietary supplementation with DHA appears to be beneficial in LCHAD-deficient patients to prevent retinal damage (189). In addition to the low-fat diet, patients with MAD should also have a mild protein restriction. Patients HMG-CoA-lyase may likewise benefit from leucine restriction. Blood glucose, liver enzymes, uric acid, ammonia, and CK are late markers of a metabolic crisis (188) and cannot be used to monitor fasting tolerance or response to dietary changes. In contrast, acylcarnitines have been shown to be a sensitive marker. AC levels tend to increase rapidly during short fasting periods and reflect the accumulation of toxic metabolites (221,225). Treatment of infants and young children with severe enzyme deficiencies needs to be aggressive and may require frequent feedings during the day and overnight NG or G-tube feedings (164). In children over 2 years of age, the diet can be supplemented with uncooked cornstarch. In children with poor appetite who have severe enzyme deficiencies, cornstarch can be given at regular intervals throughout the 24 h, as used for patients with glycogen storage diseases. In less severely affected patients uncooked cornstarch (1–2 g/kg) can be used at bedtime only. We have documented the beneficial effect of uncooked cornstarch in decreasing abnormal metabolites in children with MCAD, MAD (221,225), and LCHAD deficiencies. As an alternative for young children whose amylase activity is deficient, we have successfully used cornstarch with exogenous amylase (221). Education and family compliance are essential to avoid life-threatening decompensations, which can occur very rapidly in young patients. Long-term prognosis varies according to the disease, residual enzyme activity, age at diagnosis, and long-term treatment. The mortality rate has been estimated at 25% for MCAD deficiency; the ma-

Guidelines for the Nutritional Treatment of Fatty Acid Oxidation Defects Metabolic abnormality

Calories Protein Fat MCT LCFA EFA CHO

Long-chain FAO

Medium- and short-chain FAO, HMG-CoA-synthase

Electron transfer (MAD), HMG-CoA-lyase

>20% RDA RDA 25–30% 15–20% (1–3 g/kg/d) ⫾10% 4% 60–65%

>20% RDA RDA 15–25% Contraindicated — 4% 60–75%

>20% RDA 7% 15–20% Contraindicated — 4% 73–78%

MCT, medium-chain triglycerides; LCFA, long-chain fatty acids; EFA, essential fatty acids; CHO, carbohydrates. Fat and CHO are expressed as % or total calories.

Emergencies of Inborn Metabolic Diseases

jority of these patients die in the initial episode (185,234). Long-term complications in MCAD deficiency include developmental delay, muscle weakness, failure to thrive, and cerebral palsy (172,185,234). To prevent the mortality and severe morbidity of MCAD, it would be mandatory to implement newborn screening programs (108,172,185, 219). Limited information is still available for the longterm prognosis of patients with other FAO defects, but it is likely that, as shown for MCAD deficiency, newborn screening may change the natural history of these diseases (221).

V.

PRIMARY LACTIC ACIDEMIAS

The primary lactic acidemias (PLA) are a group of IMD with variable clinical presentation, including life-threatening episodes of metabolic acidosis, and complex biochemical, enzymatic, and molecular diagnosis. They represent abnormalities in pyruvate metabolism that are recognized biochemically by its primary consequence, hyperlactacidemia, and clinically by symptoms reflecting energy deficiency (1,235). Pyruvic acid produced by the glycolytic pathway can follow different metabolic fates. To produce energy, pyruvate enters the mitochondria and undergoes aerobic catabolism via acetyl-CoA, the tricarboxylic acid cycle (TCA) and the respiratory chain (Fig. 4). During fasting periods, pyruvic acid can also be an intermediary substrate for gluconeogenesis, via oxaloacetic acid. A block in any of the many enzymatic steps involved in those pathways can increase pyruvic acid levels, with simultaneous elevation of lactic acid and alanine, and limit the production of energy or glucose synthesis. In general, the PLA can be classified into four groups: Defects in pyruvate dehydrogenase complex Defects in the TCA cycle Defects in gluconeogenesis Defects in oxidative phosphorylation (respiratory chain)

A.

Pathophysiology and Clinical Presentation

Correlation between symptoms and enzymatic block is difficult: one enzymatic defect can present with different phenotypes and different enzyme deficiencies can give a similar clinical presentation. A detailed description of each enzymatic defect is beyond the scope of this chapter, so we will mainly address those conditions that can present with severe hyperlactacidemia, requiring emergency treatment. 1. Pyruvate Dehydrogenase Complex Deficiency of pyruvate dehydrogenase complex (PDHC) is one of the most frequent causes of PLA. This thiaminedependent enzymatic complex is responsible for the decarboxylation of pyruvate to acetyl-CoA (Fig. 4) and is

805

made of four different components: E1-␣, E1-␤, E2, and E3. Two regulatory components at the E1 level are known: pyruvate dehydrogenase kinase and pyruvate dehydrogenase phosphatase, which inactivate and activate, respectively, the enzyme activity. An E3-binding protein (formerly called X-lipoate protein) is also part of the complex (235,236). Deficiencies in different components of the PDHC have been reported, but the most common is the deficiency of the E1-␣ subunit. Three different clinical presentations have been outlined. The most severe is neonatal, characterized by overwhelming lactic acidosis at birth. These children present soon after birth with poor feeding, hypotonia, lethargy, and respiratory distress. Mild dysmorphysm (frontal bossing, low nasal bridge, upturned nose, long philtrum) has been described, and death occurs within the first weeks of life (236,237). A less severe picture appears in infants and young children with hypotonia, developmental delay, and seizures. The third form presents with acute, intermittent episodes of ataxia, which can be triggered by a high-carbohydrate intake (235 – 237). The E1-␣ subunit is encoded by an X-linked gene. However, due to the important role of the PDHC in energy metabolism, males as well as females can be affected. Most defects of E1-␣ gene are de novo, with point mutations being more common in males and deletions or insertions in females (236,238). This information is extremely important for genetic counseling. Defects in the E2 component, the E3-binding protein, and the pyruvate dehydrogenase phosphatase, while rare, have been reported (236,239,240). Described phenotypes have ranged from severe mental retardation to Leigh syndrome and refractory lactic acidosis. The E3 component (dihydrolipoamide dehydrogenase) is common to three other enzymatic complexes: the ␣-ketoglutarate dehydrogenase (␣-KGD) (involved in TCA cycle), the branched-chain 2-ketoacid dehydrogenase (BCKD), which is the enzyme deficient in maple syrup urine disease (MSUD), and the glycine cleavage system (involved in glycine catabolism). Few patients with deficiency of the E3 component (lipoamide dehydrogenase) are known. Their clinical and biochemical presentation is variable, with a combination of the different manifestations of the PDHC, ␣-KGD, and BCKD deficiencies. Recurrent episodes of liver failure, cardiomyopathy and myoglobinuria have also been reported (235,236, 241–243). Progressive involvement of the basal ganglia and brainstem is frequent in PDHC-deficient patients, and can lead to nystagmus, dystonia, apnea, or sudden, unexpected death. Magnetic resonance imaging (MRI) findings in these patients are suggestive of subacute necrotizing encephalopathy (Leigh syndrome). However, it is important to note that Leigh syndrome has also been described in patients with pyruvate carboxylase, the TCA cycle, and respiratory chain deficiencies (see below) as well as in other inborn metabolic diseases (IMD) (1,244,245). Other

Figure 4 Pyruvate metabolism, the TCA cycle, and the respiratory chain. See explanation in the text. Enzymes: 1, lactate dehydrogenase; 2, pyruvate carboxylase; 3, pyruvate dehydrogenase complex; 4, ␣-ketoglutarate dehydrogenase; 5, fumarase. (From: D.C. De Vivo and S. Di Mauro. Disorders of pyruvate metabolism, the citric acid cycle and the respiratory chain. In: Inborn Metabolic Diseases. Diagnosis and management. J. Fernandes, JM Saudubray and Tada. Eds. Springer Verlag-1st Ed., 1990, pp. 127–160.)

806 Abdenur

Emergencies of Inborn Metabolic Diseases

frequent abnormalities of the CNS in PDHC deficiency are congenital malformations of the brain, including agenesis or hypoplasia of the corpus callosum (235–237). 2. Defects in the TCA Cycle The TCA cycle is responsible for the oxidative decarboxylation of citrate to oxaloacetate (Fig. 4). Several enzymes are involved, and defects in ␣-ketoglutarate dehydrogenase (␣-KGD), fumarase, and succinate dehydrogenase (SDH) have been characterized. Structure of ␣-KGD is similar to the PDHC and the BCKD, sharing with them the E3 component. Therefore the three enzymes can be affected in E3 deficiency (see section on PDHC deficiency above). A few patients with isolated ␣-KGD have also been reported. They present in infancy or early childhood with severe neurological involvement, including developmental delay, hypo- or hypertonia, and ataxia (235,246–248). Structural brain abnormalities can be present. Fumarase deficiency appears to be more common. Clinical presentation ranges from severe neurological involvement, seizures, and death in childhood to mild mental retardation and survival into adulthood (235,248– 250). Dysmorphic facial features and neonatal polycythemia have been recently reported (251). Structural brain malformations such as diffuse polymicrogyria, hypomyelination, agenesis of the corpus callosum, Leigh syndrome, decreased white matter, and cortical atrophy are common (250,251). A few patients with SDH are known. This TCA cycle enzyme is also part of complex II of the respiratory chain (succinate–ubiquinone oxidoreductase) and these patients’ clinical presentation resembles more a respiratory chain defect (see below) (235). A combined deficiency of SDH, aconitase, complex I and III has been reported (252). This defect is apparently caused by abnormalities in the iron–sulfur clusters common to these enzymes. 3. Defects in Gluconeogenesis Gluconeogenic defects involve deficiencies in the four regulatory enzymes of this pathway: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-diphosphatase, and glucose-6-phosphatase. Deficiency of the latter affects gluconeogenesis as well as glycogen degradation and is responsible for the glycogen storage disease type 1. In general, patients with gluconeogenic defects present not only lactic acidosis but also hypoglycemia and hepatomegaly. Pyruvate carboxylase (PC), a biotin-dependent enzyme responsible for the carboxylation of pyruvate to oxaloacetate (Fig. 4), plays an important role in gluconeogenesis, lipogenesis, and energy production. Decreased availability of oxaloacetate also impairs the synthesis of aspartate and glutamate with secondary abnormalities in the urea cycle and the synthesis of glutamine-derived neurotransmitters. Deficiency of the PC can be isolated or as a part of the biotinidase or ho-

807

locarboxylase synthetase deficiencies (see organic acidemias). Isolated PC deficiency has been described in about 40 patients. Three clinical presentations are differentiated. The most severe form presents in neonates with lactic acidosis, hypotonia, and seizures, progressing to coma and death in the first few months of life (235,236). A less severe phenotype, mainly described in North American Indians, presents in infancy with developmental delay, failure to thrive, and seizures, progressing to severe mental retardation. Mild hepatomegaly is present in both clinical presentations. Macrocephaly and brain abnormalities, including decreased myelination, ischemia-like lesions, cyst, periventricular leukomalacia, Leigh syndrome, subdural hematomas, and brain atrophy have been described (235,236,253,254). These abnormalities are thought to be related to the important role of PC in astrocyte metabolism. The third, less common, phenotype is characterized by episodic attacks of lactic acidosis with slight neurological involvement (235,236). Phosphoenolpyruvate carboxykinase (PEPCK) deficiency is very rare. Symptoms appear in the newborn period or early infancy and include failure to thrive, hypotonia, lethargy, and hepatomegaly. Renal tubular acidosis as well as skeletal and cardiac muscular involvement have been reported (235). Fructose-1,6-diphosphatase (FDP) deficient patients present in the newborn period with symptoms of hypoglycemia, hypotonia, and liver enlargement. Neurological involvement in these patients is only related to the hypoglycemic episodes (255). 4. Defects in Oxidative Phosphorylation The oxidative phosphorylation (OXPHOS) is a complex system that carries electrons through a series of reactions to generate ATP. Our understanding of this system has greatly increased in the last few years with significant advances in molecular genetics. The OXPHOS is composed of five different complexes (I, II, III, IV, and V), located in the inner mitochondrial membrane. Each complex has several protein components, some of them encoded by nuclear DNA (nDNA) and others by mitochondrial DNA (mtDNA) (256,257). The only exception is complex II, which has only nDNA-encoded proteins. Differentiation between abnormalities in the OXPHOS caused by defects in nDNA or mtDNA is important for prenatal diagnosis and genetic counseling: nDNA defects follow a mendelian inheritance, while mtDNA is maternally transmitted. The nuclear DNA is responsible for the synthesis of about 70 OXPHOS subunits, their transport into the mitochondria, and their proper processing and assembly (256). A great number of the nuclear genes, the majority of them still unidentified, are responsible for these processes. The mtDNA is a small circular molecule (16.5 kb) that encodes for 13 OXPHOS subunits together with ribosomal RNAs and the 22 mitochondrial transfer RNAs

808

necessary for mRNA expression (256,257). Each cell contains hundreds of mitochondria and thousands of mtDNA. In patients with mtDNA abnormalities, normal and abnormal mtDNA coexist in the same cells (heteroplasmy). During cell division, mitochondria are randomly distributed to the new cells (replicative segregation) and, as the cells divide, the relative proportions of normal and abnormal mtDNA change (256). These characteristics of the mtDNA have clinical implications. In the same patient some tissues/organs may or may not be affected depending on their proportion of normal and abnormal mtDNA. Furthermore, tissues that are not affected at one point may become affected when the number of abnormal mitochondria reaches a threshold for phenotypic expression. These facts explain why the same molecular defect can present with different phenotypes, which can also change over time (256–258). Clinical presentation of patients with OXPHOS diseases is extremely variable. Neonatal decompensation, with severe metabolic acidosis, is not frequent but has been described in fatal and benign infantile myopathy due to complex IV (COX deficiency) as well as in deficiencies of other complexes (257–260). These children present in the neonatal period with severe hypotonia, abnormal movements, poor sucking, lethargy, respiratory distress, and severe lactic acidosis. Ketosis is usually present. A picture resembling neonatal-onset diabetes mellitus, with hyperglycemia, ketosis, and hyperlactacidemia has been reported in patients with OXPHOS defects (261). Another severe neonatal presentation is seen in one of the variants of the mitochondrial DNA depletion syndrome (see below). These children develop severe liver failure, with hypoglycemia, lactic acidosis, and elevated liver enzymes within the first day of life. Liver histopathological examination reveals micronodular cirrhosis, cholestasis, microvesicular steatosis, and accumulation of iron. Electron microscopy shows abnormal proliferation of mitochondria. Less severe infantile forms of this syndrome have been reported in children with failure to thrive, vomiting, ypotonia, hypoglycemia, and progressive liver dysfunction (258,262–264). Because OXPHOS is present in all cells, patients with a subacute or chronic course can have different combinations of symptoms and signs. In general, an OXPHOS defect must be considered when there is an unexplained association of symptoms, with early onset and a rapidly progressive course involving seemingly unrelated organs (257,258). A list of the most frequent signs and symptoms is presented in Table 7. Patients with OXPHOS diseases are prone to multiorgan involvement; therefore abnormalities in tissues with high energy needs including muscle, liver, kidney, pancreas, bone marrow, heart, brain, retina, auditory nerve, and endocrine system should be searched for. In patients with CNS involvement MRI of the brain will provide useful information (Table 7) (265). Different combinations of symptoms and signs are possible, and classification of OXPHOS diseases has been difficult.

Abdenur Table 7 Most Frequent Findings Associated with OXPHOS Diseases Hypotonia Developmental delay Progressive encephalopathy, regression Seizures, myoclonus Strokelike episodes Recurrent ataxia Cortical blindness Brain abnormalities Absence of corpus callosum Porencephalic cysts Abnormal signaling of the basal ganglia Leukodystrophy Cortical atrophy/poliodystrophy Leigh’s disease Sudden infant death Muscle weakness, myopathy Myalgia, exercise intolerance, myoglobinuria Palpebral ptosis, progressive external ophthalmoplegia Cataracts, corneal opacities Retinitis pigmentosa Sensorineural hearing loss Cardiomyopathy (mainly hyperthrophic) Heart block (A-V, and others) Failure to thrive, intrauterine growth retardation Renal Fanconi’s syndrome Tubulointerstitial nephritis, renal failure Episodic vomiting Chronic diarrhea, villous atrophy Exocrine pancreatic dysfunction Liver failure Anemia (sideroblastic), myelodysplasia Diabetes mellitus Growth hormone deficiency Hypothyroidism, hypoparathyroidism Recurrent hypoglycemia Craniofacial dysmorphic features Hair abnormalities (dry, thick, brittle hair) Skin abnormalities (mottled pigmentation in exposed areas) Source: Refs. 256–258.

They have been categorized based on their molecular defect in mtDNA or nDNA. Known mtDNA abnormalities include point mutations, deletions, and duplications. In general, point mutations follow a pattern of maternal inheritance while deletions tend to be sporadic. Many of them correlate with well-defined syndromes, but significant overlapping and variation exist (Table 8). In the last few years, an increasing number of mutations in nuclear OXPHOS genes are being recognized. The most frequent inheritance in this group is autosomal recessive, but any mendelian pattern is possible. Some clinical entities are defined but their genes are still unidentified. They include, among others, the mtDNA depletion syndrome, hereditary spastic paraplegia, and the

Emergencies of Inborn Metabolic Diseases Table 8 Most Common Clinical Syndromes Associated with mtDNA Defects Mainly associated with mtDNA mutations Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (266) Myoclonic epilepsy and ragged-red fibers (HERRF) (267) Neuropathy, ataxia, and retinitis pigmentosa (NARP) (268) Leber’s hereditary optic neuropathy (LHON) (269) Diabetes mellitus and deafness (270) Mainly associated with mtDNA deletions/duplications Pearson syndrome:

Anemia (sideroblastic)/pancytopenia, exocrine pancreatic insufficiency, failure to thrive, liver dysfunction, myopathy, lactic acidosis (271,272) Kearns Sayre syndrome: Age before 20 years, progressive external ophthalmoplegia, retinitis pigmentosa, cerebellar ataxia, increased CSF protein, complete heart block, diabetes mellitus (273) Wolfram syndrome: Diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (274) Progressive external ophthalmoplegia (275) Source: Refs. 256–258.

myoneurogastrointestinal encephalopathy (MNGIE) (256, 258,264). Nuclear genes responsible for specific deficiencies of subunits in complex I (producing Leigh disease) and complex IV (citochrome oxidase deficiency) have been identified (256,259). More important, nuclear genes affecting the OXPHOS have been found to be the cause of Friedreich’s ataxia (276) and the Barth syndrome (277). It is likely that in the next few years more chronic diseases associated with nDNA defects affecting OXPHOS will be described.

B.

Diagnosis

Initial laboratory work-up for a patient with suspected PLA with an acute or chronic presentation is similar. In patients with intermittent symptoms, diagnostic possibilities increase when samples are obtained during the acute decompensation. Fasting blood levels for lactate (L), pyruvate (P), ammonia, and AAs and urine for organic acids should be obtained. Additional information can be obtained by measuring blood levels of 3-OH-butyrate (3OHB), acetoacetate (AcAc), total and free carnitine, and urine amino acids. Accurate measurement of L and P requires rapid and proper handling of the specimens. Arterial samples are preferred, and the use of a tourniquet should be avoided if venous samples are to be obtained.

809

In patients with acute decompensations, laboratory tests disclose severe metabolic acidosis, high anion gap, and markedly elevated lactic acid. The lactic/pyruvate (L/ P) molar ratio should be calculated (normally 10–20). A low to normal value suggests PDHC deficiency. By contrast, PC and respiratory chain defects (complex I, III, and IV) show elevated L/P ratios (278). Reduced 3OHB/AcAc ratio is seen in PC deficiency (235,278). Lactic acidosis due to poor perfusion, hypoxia, liver insufficiency, sepsis, or sedation with propofol (2,6-di-isopropylphenol) (Diprivan, Zeneca Pharma, Mississauga, ON, Canada) should be ruled-out (278,279). In general they do not present with ketosis. In patients with chronic disease, even slight elevations of lactate provide a clue for diagnosis. More severe biochemical abnormalities might only be present during attacks, which are usually triggered by intercurrent illnesses. In some patients increased lactic acid levels are only detected when they are measured 1–2 h after a regular or a high-carbohydrate meal. Elevated fasting levels of lactic acid that decrease after a high-CHO meal, with simultaneous increase in ketone bodies, are suggestive of PC deficiency (235). In patients with CNS involvement and normal lactic acid in blood, L and P levels have to be measured in cerebral spinal fluid. Hypoglycemia is associated with lactic acidemia during fasting in patients with gluconeogenic defects, while hyperglycemia can be found in OXPHOS and PDHC deficiencies (261,278). Mild hyperammonemia is present in neonates with PC and fumarase deficiencies and increased uric acid and hypophosphatemia are found in those with FDP deficiency. In the latter, provocative tests with fructose and glycerol, performed under close supervision, are useful for diagnosis. Glucose tolerance tests should be avoided because they can trigger an acute decompensation in PDHC-deficient patients. Urine organic acids analysis provides useful information in PLA patients, but, with the exception of the TCA cycle defects, cannot determine the site of the metabolic block. Usual findings are elevated lactic, pyruvic, and 2-hydroxybutyric acids. Elevation of TCA cycle intermediates (succinic, fumaric, malic, and ␣-ketoglutaric acids) might be present in patients with OXPHOS defects. Ketonuria suggests PC deficiency. However, increased ketones can also be found in patients with other PLA defects. Glycerol and glycerol-3-phosphate can be found in the urine of patients with FDP deficiency. A recent report suggests that glycerol intolerance syndrome might be indeed a partial FDP defect (280). ␣-Ketoglutaric and lactic acids are increased in ␣-keto glutarate dehydrogenase. However, abnormal excretion of the former could be intermittent (247). Increased ␣-ketoglutaric is also found in patients with glycogen storage disease type I. In patients with lipoamide dehydrogenase (E3 deficiency), the increased levels of lactic and ␣-keto glutaric acids are accompanied by metabolites of 2-hydroxy- and 2-ketoacids. Fumarase deficiency is characterized by increased fumaric

810

Abdenur

acid with different degrees of lactic, succinic, and ␣-ketoglutaric acids (235). Methylglutaconic acid has been reported in several patients with OXPHOS defects, as well as in other diseases (see section on organic acidemias) (278). Isolated elevations of lactic acid in urine can be found in patients with urinary infections due to E. cloacae (281) and in patients with short gut or blind loop syndrome, who excrete high amounts of D-lactic acid, which is undistinguishable from the L-isomer (282). Quantitative plasma AAs have similar limitations to UOA. A common finding for all PLA is an elevation of alanine, while elevated glutamate and glutamine may be present in patients with PDHC, ␣-KGD, and OXPHOS deficiencies (235, 278). Serum amino acids are characteristic in the neonatal form of PC deficiency, with increased elevation of alanine, proline, citrulline, and lysine and decreased levels of aspartate and glutamine (235,236,253,254). In the E3 subunit deficiency, mild elevations of branched-chain AAs and alanine are characteristic. A muscle biopsy is another important tool for the diagnosis of PLA, especially for OXPHOS diseases. Specimens should be obtained for light and electron microscopy and tissue should be immediately frozen for enzymatic studies. The specimens should be referred to an experienced laboratory. The presence of ragged red fibers (modified Gomori trichrome stain) are suggestive of an OXPHOS defect. Important information is also obtained from succinate dehydrogenase and cytochrome oxidase reactions, immunohistochemistry, mtDNA quantification, and electron microscopy (245,258,283). Enzymatic diagnosis for defects in pyruvate oxidation, the TCA cycle, and gluconeogenesis can be done in blood, fibroblasts, or other tissues (235,236). The reference laboratory should be contacted for the best specimen to be obtained for each particular enzyme. Enzyme activity for the respiratory chain is best measured in muscle. However, the assessment is complicated due to several factors, including different percentages of abnormal mtDNA and different isoforms of the same enzyme in different tissues (245,257,258). Point mutations in a tRNA of the mtDNA, or mtDNA depletion can affect the enzyme activity of several respiratory chain complexes. Secondary deficiencies of the respiratory chain due to defects in mitochondrial ␤-oxidation and other enzyme deficiencies are possible (257). In patients who die unexpectedly, enzymatic studies can be done on frozen samples (skeletal muscle, heart, liver, and brain) if they are obtained no more than 4 h postmortem. Molecular diagnosis for the majority of the enzymes described is available. Regarding the OXPHOS defects, the mutations or deletions should be searched for, according to the clinical presentation (245,256,258).

C.

Treatment: The Acute Episode

Treatment of acute neonatal lactic acidemia requires an intensive care unit. Sodium bicarbonate in large amounts

is usually required to control the metabolic acidosis. If hypernatremic metabolic acidosis develops, it should be treated with peritoneal or hemodialysis. Special solutions with sodium bicarbonate (instead of sodium chloride) and devoid of acetate or lactate should be used in those procedures. A high GIR can severely worsen the lactic acidemia in patients with PDHC deficiency. Therefore, initial intravenous fluids should provide a low GIR that can be increased according to clinical and biochemical response. A high GIR is indicated in patients with PC deficiency. After the appropriate samples for diagnosis have been obtained, treatment with one or several drugs can be started in patients with life-threatening lactic acidemia (Table 9). A wide range of dosages have been used. Assessment of the response to vitamin therapy is difficult and well-documented data are rare. The most commonly used are biotin, thiamine, riboflavin, and coenzyme-Q10. These compounds are cofactors involved in the different metabolic pathways. Vitamins C and K have been used as artificial electron acceptors (235,256,284). Dichloroacetate (DCA) stimulates the activity of the PDHC and is used, in dosages of 15–200 mg/kg/day in the treatment of PLA of unknown origin as well as in PDHC and complex I deficiencies (235,256,284). In patients with low carnitine levels, carnitine supplementation (50–100 mg/kg/ day) should be used to maintain normal free carnitine levels. A recent report documents a marked improvement of a cardiomyopathy following treatment with idebenone, a synthetic analog of coenzyme Q10 (285). Treatment with succinate, nicotinamide, corticosteroids, chloranphenicol, vitamin-E, methylene blue, and acetylcarnitine have been advocated for some conditions (256,284). When final diagnosis becomes available, an attempt to withdraw those vitamins not involved in the metabolic block should be done, one at a time, with careful monitoring of the clinical and biochemical response.

Table 9

Pharmacological Treatment for PLA

Agent Thiamine Lipoic acid Dichloroacetate Biotin Riboflavin Coenzyme-Q10 Idebenone Vitamin C Vitamin K3, menadione or K1, phylloquinone

Dosage (range)

Deficiency

500–2000 mg/day 200–300 mg/day 10–50 mg/kg/day 15–200 mg/kg/day 10–50 mg/day 50–300 mg/day 60–360 mg/day 30–90 mg/day 500–4000 mg/day 50–100 mg/day

PDHC OXPHOS PDHC PDHC, OXPHOS PC OXPHOS OXPHOS OXPHOS OXPHOS OXPHOS

Emergencies of Inborn Metabolic Diseases

D.

Long-Term Management

In patients with chronic disease it is advisable to add one drug or vitamin at a time, according to the suspected diagnosis, and maintain careful monitoring of the patient’s response. However well-documented long-term studies are difficult and, in general, prognosis is poor. In patients with PDHC deficiencies, thiamine (500–2000 mg/day), lipoic acid (which is bound to the E2 component), carnitine, and DCA have been tried with variable results (235,242). A high-fat (75–80%), low-CHO (5%) diet has been useful in some patients. The rationale is to provide alternative sources of Acetyl-CoA, not derived from pyruvate (235,284). However, a detailed study showed mild improvement in development but not change in long-term survival of these patients (286). In PDHC deficiency due to abnormalities in the E3 component, dietary treatment is more difficult because the affected enzymes impair protein, carbohydrate, and fat metabolism. Restriction of branched-chain amino acids (as in MSUD) is helpful to reduce blood levels of branched-chain AAs and their metabolites in urine (235). In patients with PC deficiency, treatment with biotin (10–50 mg/day) is indicated. Citrate and aspartate have also been tried in the treatment of this condition, with improvement in blood chemistry but poor long-term neurological outcome (254). A low-fat–high-CHO diet with frequent feeds is also indicated in patients with PC deficiency as well as in all the other gluconeogenic defects (235,284). Restriction of protein intake to reduce production of gluconeogenic substrates has also been proposed in PC deficiency. In patients with FDP deficiency, mild restriction of sucrose and fructose is indicated. Controlled exercise has been helpful in some patient with OXPHOS defects to enhance the aerobic capacity and decrease lactic acid levels (256). Liver transplantation has been performed in patients with hepatic respiratory chain disorders, but extrahepatic manifestations may appear later despite successful transplantation (287). Treatment with valproic acid and phenobarbital should be avoided because they inhibit the respiratory chain (257). Supportive treatment for the different manifestations of OXPHOS diseases (exocrine pancreatic deficiency, anemia, diabetes, renal Fanconi’s syndrome, etc.), as well as psychological support for patients and family should be provided.

VI. A.

MAPLE SYRUP URINE DISEASE Pathophysiology

Maple syrup urine disease (MSUD) is an autosomal recessive disease affecting the metabolism of the branchedchain amino acids (BCAA) leucine, isoleucine, and valine. BCAA play an important role in intermediate metabolism. They are substrates for gluconeogenesis and ketogenesis, and their end-catabolic product, acetyl-CoA, is a precursor for fatty acid and cholesterol synthesis. The defect in

811

MSUD is located in the branched-chain 2-ketoacid dehydrogenase complex (BCKD), which is made of four different components: E1-␣, E1-␤, E2, and E3 (288). The E1 component is thiamine dependent. BCKD deficiency results in the elevation of BCAA and their corresponding branched-chain 2-ketoacids (BCKA) 2-ketoisocaproic, 2keto-3-methylvaleric, and 2-ketoisovaleric. Accumulation of these compounds is responsible for the characteristic odor as well as the clinical course of the disease.

B.

Clinical and Laboratory Manifestations

Five phenotypes have been described, based on the clinical presentation and response to thiamine therapy: classic, intermediate, intermittent, thiamine-responsive, and E3(dihydrolipoamide dehydrogenase) deficient (288). The classic form is the most common. Children appear normal at birth, but between the first and the second week of life present with poor feedings, lethargy, dystonic posturing, seizures, and apneas. The characteristic maple syrup odor can easily be detected in urine. This intoxication-like encephalopathy resembles that of the organic acidemias. Biochemical abnormalities include ketoacidosis and hypoglycemia; hyperammonemia may be mild or absent (37,288). Diagnosis can be made by measurement of either plasma AAs or UOA. Typical findings in the former are elevated levels of BCAA, mainly leucine (1000–5000 ␮M/l), and the presence of L-alloisoleucine, which is a transamination product of the 2-keto-3-methylvaleric acid (105). Routine UOA analysis shows an elevation of branched-chain 2-OH-acids and BCKA. The latter are better detected when the sample is previously oximated. Ketone bodies are also usually present. The intermediate form of MSUD presents in infancy to young adulthood with neurological impairment, seizures, failure to thrive, and ataxia. Ketoacidosis is less severe and acute crisis may be absent. In these patients BCAA are always abnormal, with leucine levels ranging between 400 and 2000 ␮M/l (289). The intermittent form presents in children or adults with episodes of acute decompensation (ataxia, seizures, coma, and ketoacidosis) triggered by infections or high protein ingestion. Plasma leucine values are mildly elevated during the crisis, but they can be normal while compensated (288). The thiamine-responsive patients are a heterogeneous group. Their clinical presentation resembles that of patients with the intermediate form of the disease. Treatment with thiamine tends to normalize the BCAA levels, and some patients can be completely off diet. Thiamine dosages have ranged from 10 to 1000 mg/day and response was achieved days or weeks after starting the treatment (37,288,290). The E3 component of the BCKD is common to other three enzymatic complexes: pyruvate dehydrogenase complex (PDHC), ␣-ketoglutarate dehydrogenase (␣-KGD), and the glycine cleavage system (involved in glycine catabolism). Clinical presentation in these patients is varia-

812

Abdenur

ble, combining features of BCKD and primary lactic acidemias (see section on PDHC deficiency above). MSUD is transmitted as an autosomal recessive condition and has been diagnosed in all ethnic groups. The general incidence of the disease is estimated at 1:185,000, but the incidence is much higher for some inbred communities, such as the Mennonites (288). Mutations in the genes encoding for the different components of the BCKD have been identified. Different genotypes correlate with the severity of clinical presentation (288,289).

For children treated in specialized centers, survival is 100% (37,288). However, some degree of psychomotor impairment seems to be present, even in patients with early diagnosis and strict dietary treatment (294,297,298). Successful pregnancies have been reported in patients with intermediate MSUD who were evaluated with close monitoring (288).

ACKNOWLEDGMENTS Thanks to CVA, NA, and MA for their support.

C.

Treatment: The Acute Episode

Acute management of MSUD patients follows the same principles outlined for the treatment of organic acidemias (see section on organic acidemias above). Patients with MSUD usually require less bicarbonate than OA to correct the metabolic acidosis. High-energy nutrition alone is not sufficient to lower leucine levels rapidly (37). Therefore dialysis should be considered early in the treatment, especially in patients with acute and severe encephalopathy and/or with leucine levels above 1500 ␮Mol. Hemodialysis, hemofiltration, and continuous blood exchange transfusion, in this order, are the preferred methods for toxin removal (24,114,291). As in OA, pancreatitis and brain edema have been reported in acutely ill MSUD patients (37,292–294). The latter has been documented in CT and MR studies, which also showed dysmyelination of several areas of the brain in patients under poor metabolic control (295). Unlike in OA, secondary carnitine deficiency is not common in MSUD patients.

D.

Long-Term Management

Long-term treatment of UCD patients is also based on the same principles as the organic acidemias (see section on organic acidemias above). Because leucine is considered the most toxic of the BCAA, leucine requirements are followed to prescribe the diet. Occasionally, small amounts of valine and isoleucine need to be added to the diet because the tolerance for leucine is lower than of the other two BCAA. Administration of thiamine is indicated for thiamine-responsive patients. Prognosis of MSUD patients has dramatically improved due to the early diagnosis achieved through newborn screening programs (NBS), intensive treatment, and availability of special formulas. NBS programs are being performed using the traditional bacterial inhibition assay or new techniques such as TMS. The later is being used in many centers to detect not only MSUD but also many other IEM (109,110,296). We have detected abnormal levels of leucine ⫹ isoleucine and valine before 24 h of age in a patient with MSUD whose sibling had a classic form of the disease (111). These results suggest that TMS will lower the impact of early discharge on newborn screening.

REFERENCES 1.

2. 3. 4. 5.

6.

7. 8.

9.

10.

11. 12.

13. 14.

Saudubray JM, Ogier de Baulny H, Charpentier C. Clinical approach to inherited metabolic disorders. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases. 2nd eds. Berlin: Springer-Verlag, 2000:3–42. Scriver CR, Beaudet AL, Sly WS, Valle D. ed. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001. Fernandes J, Saudubray JM, van den Berghe G. ed. Inborn Metabolic Diseases. 2nd ed. Berlin: Springer-Verlag, 2000. Nyhan WL, Ozand PT, eds. Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001: 1909–1963. Leonard JV. Disorders of the urea cycle. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases. 2nd ed. Berlin: Springer-Verlag, 2000: 214–222. Butterworth RF. Effects of hyperammonemia on brain function. J Inherit Metab Dis 1998; 21 (Suppl 1) 1998: 6–20. Voorhies TM, Ehrlich ME, Duffy TE, Petito CK, Plum F. Acute hyperammonemia in the young primate: physiologic and neurophathologic correlates. Pediatr Res 1983; 17:971–975. Connelly A, Cross JH, Gadian DG, et al. Magnetic resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl transferase deficiency. Pediatr Res 1993; 33:77–81. Schubiger G, Bachmann C, Barben P, et al. N-acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxification. Eur J Pediatr 1991; 150:353–356. Christodolou J, Qureshi IA, McInnes RR, et al. Ornithine transcarbamylase deficiency presenting with stroke-like episodes. J Pediatr 1993; 122:423–427. Mattson LR, Lindor NM, Goldman DH, et al. Central pontine myelinolysis as a complication of partial ornithine carbamoyl transferase deficiency. Am J Med Genet 1995; 60:210–213. Rowe PC, Newman SL, Brusilow SW. Natural history of symptomatic partial ornithine transcarbamylase deficiency. N Engl J Med 1986; 314:541–47. Arn PH, Hauser ER, Thomas GH, et al. Hyperammonemia in women with a mutation at the ornithine trans-

Emergencies of Inborn Metabolic Diseases

15. 16.

17.

18.

18a.

19.

20.

21.

22.

23. 24.

25.

26.

27. 28.

29.

carbamylase locus. N Engl J Med 1990:322: 1652– 1655. Nyhan WL, Ozand PT, ed. Argininemia. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998: 194–198. Webster DR, Simmonds HA, Barry DMJ, Becroft DMO. Pyrimidine and purine metabolites in ornithine carbamoyl transferase deficiency. J Inherit Metab Dis 1981; 4:27–31. Hudak ML, Jones D, Brusilow S. Differentiation of transient hyperammonemia of the newborn and urea cycle enzyme defects by clinical presentation. J Pediatr 1985: 107:712–719. Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 1998;338:1352–1357. Tuchman, Lichtenstein GR, Rajagopal BS, et al. Hepatic glutamine synthetase deficiency in fatal hyperammonemia after lung transplantation. Ann Intern Med 1997; 127:446–449. Maestri NE, Lord CR Glynn M, et al. The phenotype of ostensibly healthy women who are carriers for ornithine transcarbamylase deficiency. Medicine 1998; 77:389– 397. Bonham JR, Guthrie P, Downing M, et al. The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease. J Inherit Metab Dis 1999; 22:174–184. Tuchman M, Morizono H, Rajagopal BS, et al. The biochemical and molecular spectrum of ornithine transcarbamylase deficiency. J Inherit Metab Dis 1998; 21(Suppl. 1):40–58. McCullogh BA, Yudkoff M, Batshaw ML, et al. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet 2000; 93:313–319. Hendricks KM. Estimation of energy needs. In: Hendricks KM, Walker WA, ed. Manual of Pediatric Nutrition. 2nd ed. Philadelphia: B.C. Decker, 1990:59–71. Rutledge SL, Havens PL, Haymond MW, et al. Neonatal hemodialysis: effective therapy for the encephalopathy of inborn errors of metabolism. J Pediatr 1990; 116:125– 128. Chen CY, Chen YC, Fang JT, Huang CC. Continuous arteriovenous hemodiafiltration in the acute treatment of hyperammonaemia due to ornithine transcarbamylase deficiency. Ren Fail 2000; 22:823–836. Donn SM, Schwartz RD, Thoene JG. Comparison of exchange transfusion, peritoneal dialysis and hemodialysis for the treatment of hyperammonemia in an anuric newborn infant. 1979; J Pediatr 95:67–70. Feillet F, Leonard JV. Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis 1998; 21(Suppl 1):101–111. Praphanphoj V, Boyadjiev SA, Waber LJ, et al. Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring in the treatment of severe hyperammonaemia. J Inherit Metab Dis 2000; 23:129– 136. Oechsner M, Steen C, Sturenburg HJ, Kohlschutter A. Hiperammonaemic encephalopathy after initiation of valproate theraphy in unrecognised ornithine transcarbamylase deficiency. J Neurol Neurosurg Psychiatry 1998; 64:680–682.

813 30. 31. 32. 33. 34.

35.

36.

37.

38.

39.

40. 41.

42.

43. 44.

45.

46. 47.

Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle dissorders in Japan. J Inherit Metab Dis 1998; 21(Suppl. 1):151–159. Saudubray JM, Touati G, Delonay P, et al. Liver transplantation in urea cycle disorders. Eur J Pediatr 1999; 158(Suppl. 2):S55–S59. Maestri NE, Hauser ER, Bartholomew D, Brusilow SW. Prospective treatment of urea cycle disorders. J Pediatr 1991; 119:923–928. Whitington PF, Alonso EM, Boyle JT, et al. Liver transplantation for the treatment of urea cycle disorders. J Inherit Metab Dis 1998; 21(Suppl. 1):112–118. Raper SE, Wilson JM, Yudkoff M, et al. Developing adenoviral-mediated in vitro gene therapy for ornithine transcarbamylase deficiency. J Inherit Metab Dis 1998; 21(Suppl 1):119–137. Lee B, Dennis JA, Healy PJ, et al. Hepatocyte gene therapy in a large animal: a neonatal bovine model of citrullinemia. Proc Natl Acad Sci USA 1999; 96:3981– 3986. Sweetman L, Williams JC. Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, ed. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2125–2164. Ogier de Baulny H, Saudubray JM. Branched-chain organic acidurias. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases. 2nd ed. Berlin: Springer-Verlag, 2000:195–212. Hoffmann GF. Disorders of Lysine catabolism and related cerebral organic-acid disorders. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases. 2nd ed. Berlin: Springer-Verlag, 2000:241– 254. Gibson KM, Hoffmann GF, Hodson AK, Bottiglieri T, Jacobs C. 4-Hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism. Neuropediatrics 1998; 29:14–22. Traeger EC, Rapin I. The clinical course of Canavan disease. Pediatr Neurol 1998; 18:207–212. Goodman SI, Frerman FE. Organic acidemias due to defects in Lysine oxidation: 2-ketoadipic acidemia and glutaric acidemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2195–2205. Barth PG, Hoffmann GF, Jaeken J, et al. L-2-hydroxyglutaric acidaemia: Clinical and biochemical findings in 12 patients and preliminary report on L-2-hydroxyacid dehydrogenase. J Inherit Metab Dis 1993;16:753–761. van der Knaap MS, Jacobs C, Hoffmann GF, et al. D-2hydroxyglutaric aciduria. Biochemical marker or clinical disease entity? Ann Neurol 1999; 45:111–119. Superti-Furga A, Hoffmann GF. Glutaric aciduria type 1 (glutaryl-CoA-dehydrogenase deficiency): advances and unanswered questions. Eur J Pediatr 1997; 156: 821– 828. Hoffmann GF. Organic acid analysis. In: Blau N, Duran M, Blaskovics ME, eds. Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1996:32–49. Nyhan WL, Ozand PT, eds. Isovaleric acidemia. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:41–45. Nyhan WL, Ozand PT, eds. 3-methylcrotonyl-CoA-carboxylase deficiency/3-methylcrotonylglycinuria. In: At-

814

48.

49.

50. 51.

52.

53.

54.

55.

56.

57. 58.

59.

60. 61.

62. 63.

Abdenur las of metabolic diseases. 1st ed. London: Chapman & Hall Medical, 1998:53–56. Nyhan WL, Ozand PT, eds. Multiple carboxylase deficiency/holocarboxylase synthetase deficiency. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:27–32. Nyhan WL, Ozand PT, eds. Multiple carboxylase deficiency/biotinidase deficiency. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998: 33–40. Nyhan WL, Ozand PT, eds. 3-methylglutaconic aciduria. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:57–63. Nyhan WL, Ozand PT, ed. 3-hydroxy-3-methyl-glutarylCoA-lyase deficiency. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:253– 258. Morris AA. Disorders of ketogenesis and ketolysis. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases. 2nd ed. Berlin: Springer-Verlag, 2000:151–156. Gibson KM, Burlingame TG, Hogema B, et al. 2-methylbutyryl-CoA-dehydrogenase deficiency: a new inborn error of L-Isoleucine metabolism. Pediatr Res 2000; 47: 830–833. Andresen BS, Christensen E, Corydon TJ, et al. Isolated 2-methylbutyrylglycinuria caused by short/branchedchain acyl CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism. Am J Hum Genet 2000; 67: 1095–1103. Zschocke J, Ijlst L, Brand J, et al. 2-methyl-3-hydroxybutyryl-CoA-dehydrogenase deficiency: a novel neurodegenerative disorder. J Inherit Metab Dis 2000; 23: Suppl 1:109(A). Roe CR, Cederbaum SD, Roe DS, et al. Isolated isobutyryl-CoA-dehydrogenase deficiency: an unrecognized defect in human valine metabolism. Mol Gene Metab 1998; 65:264–271. Nyhan WL, Ozand PT, eds. 3-Hydroxyisobutyric aciduria. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:64–68. Brown GK, Hunt SM, Scholem R, et al. B-hydroxyisobutyril-CoA-deacylase deficiency: a defect in valine metabolism associated with physical malformations. Pediatrics 1982; 70:532. Chambliss KL, Gray RG, Rylance G, Pollit RJ, Gibson KM. Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency. J Inherit Metab Dis 2000; 23:497–504. Nyhan WL, Ozand PT, eds. Propionic acidemia. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:4–12. Fenton WA, Gravel RA, Rosenblatt DA. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2165–2194. Nyhan WL, Ozand PT, ed. Methylmalonic acidemia. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:13–23. Rosenblatt DS. Disorders of Cobalamin and folate transport and metabolism. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases. 2nd ed. Berlin: Springer-Verlag, 2000:283–300.

64.

65.

66.

67. 68. 69. 70. 71. 72. 73.

74.

75. 76.

77. 78. 79.

80.

81. 82.

Andersson HC, Shapira E. Biochemical and clinical response to hydroxycobalamin versus cyanocobalamin in patients with methylmalonic acidemia and homocystinuria (cblC). J Pediatr 1998; 132:121–124. Nyhan WL, Ozand PT, eds. Methylmalonic aciduria and homocystinuria/Cobalamin C and D disease. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998: 24–26. Bennet MJ, Harthcock PA, Boriack RL, Cohen JC. Impaired fatty acid oxidation (FAO) in malonyl-CoA decarboxylase (MCD) deficiency. J Inherit Metab Dis 2000; 23:Suppl 1:99(A). Nyhan WL, Ozand PT, eds. Glutaric aciduria (type I). In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:46–52. Nyhan WL, Ozand PT, eds. L-2-hydroxyglutaric aciduria. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:76–78. Topcu M, Coskun T, Saatci I, et al. L-2-hydroxyglutaric aciduria: report of 18 turkish patients. J Inherit Metab Dis 2000; 23:Suppl 1:104(A). Nyhan WL, Ozand PT, eds. D-2-hydroxyglutaric aciduria. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:73–75. Nyhan WL, Ozand PT, eds. 2-Oxoadipic aciduria. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:79–81. Nyhan WL, Ozand PT, eds. Canavan disease/aspartoacylase deficiency. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:637–642. Danpure C. Primary hyperoxaluria. In: Scriver CR, Beaudet AL, Sly WS, Valle D, ed. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:3323–3370. McCabe E. Disorders of glycerol metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, ed. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:3323–3370. Nyhan WL, Ozand PT, eds. Alkaptonuria. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:104–108. Glutathione synthetase deficiency and other disorders of the ␥-glutamyl cycle. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:3323–3370. Nyhan WL, Ozand PT, eds. Mevalonic aciduria. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:510–514. Houten SM, Wanders RJ, Waterham HR. Biochemical and genetic aspects of mevalonate kinase and its deficiency. Biochem Biophys Acta 2000; 1529:19–32. Houten SM, Frenkel J, Kuis L, et al. Molecular basis of classical mevalonic aciduria and the hyperimmunoglobulinaemia D and periodic fever syndrome: high frequency of 3 mutations in the mevalonate kinase gene. J Inherit Metab Dis 2000; 24: 367–370. Di Rocco N, Caruso U, Waterham HR, et al. Mevalonate kinase deficiency in a child with periodic fever without hyperimmunoglobulin D. J Inherit Metab Dis 2000; 23: Suppl 1:109(A). Burlina AB, Dionici-Vici C, Bennett MJ, et al. A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts. J Pediatr 1994; 124:79–86. Garcia Silva MT, Ribes A, Campos Y, et al. Syndrome

Emergencies of Inborn Metabolic Diseases

83. 84.

85.

86.

87. 88. 89. 90.

91. 92. 93. 94. 95. 96. 97.

98. 99.

100. 101.

of encephalopathy, petechiae and ethylmalonic aciduria. Pediatr Neurol 1997; 17:165–170. Nyhan WL, Ozand PT, eds. Ethylmalonic aciduria. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:646–650. Vreken P, Valianpour F, Grivell LA, Nijtmans, LG, Wanders RJA, Barth PG. Abnormal cardiolipin and phosphatidylglycerol remodeling in Barth syndrome. J Inher Metab Dis 2000; 23:Suppl.1: 150(A). Nyhan WL, Ozand PT, eds. Malonic aciduria with normal malonil-CoA-decarboxylase. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:69–72. Wolf B. Disorders of biotin metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, ed. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:3935–3964. Thompson GN, Walter JH, Bresson JL, et al. Sources of propionate in inborn errors of metabolism. Metabolism 1990; 11:1133–1137. Leonard JV. Stable isotope studies in propionic and methylmalonic acidaemia. Eur J Pediatr 1996; 156[suppl 1]: S67–S69. Coude FX, Sweetman L, Nyhan WL. Inhibition by propionyl-coenzyme A of N-Acetyglutamate synthtase in rat liver mitochondria. J Clin Invest 1979:1544–1551. Coude FX, Ogier H, Grimber G, Parvy P, Dinh DP, Charpentier C, Saudubray JM. Correlation between blood ammonia concentration and organic acid accumulation in isovaleric and propionic acidemia. Pediatrics 1982; 69:115–117. Khaler SG, Sherwood WG, Woolf D, et al. Pancreatitis in patients with organic acidemias. J Pediatr 1994; 124: 239–243. Fiumara A, Barone R, Nigro F, Ribes A, Pavone L. Pancreatitis in organic acidemias. J Pediatr 1995; 126:852. Burlina AB, Dionisi-Vici, Piovan S, et al. Acute pancreatitis in propionic acidemia. J Inher Metab Dis 1995; 18: 169–172. Al essa M, Rahbeeni Z, Jumaah S, et al. Infectious complications of propionic acidemia in Saudi Arabia. Clin Genet 1998; 54:90–94. Koopman RJJ, Happle R. Cutaneous manifestations of methylmalonic acidemia. Arch Dermatol Res 1990; 282: 272–273. Griffin TA, Hostoffer RW, Tserng KY, et al. Parathyroid resistance and B cell lymphopenia in propionic acidemia. Acta Paediatr 1996; 85:875–878. Heidenreich R, Natowicz M, Hainline B, Berman P, Kelley R, Hillman R, Berry GT. Acute extrapyramidal syndrome in methylmalonic acidemia: ‘‘metabolic stroke’’ involving the globus pallidus. J Pediatr 1988; 113:1022– 1027. Haas RH, Marsden DL, Capistrano-Estrada S, et al. Acute basal ganglia infarction in propionic acidemia. J Child Neurol 1995; 10:18–22. Bergman AJ, Van der Knaap MS, Smeitink JA, et al. Magnetic resonance imaging and spectroscopy of the brain in propionic acidemia: clinical and biochemical considerations. J Pediatr 1996; 129:758–760. Boeckx RL, Hicks JM. Methylmalonic acidemia with the unusual complication of severe hyperglycemia. Clin Chem 1982; 28:1801–1803. Attia N, Sakati N, al Ashawal A, et al. Isovaleric acidemia appearing as diabetic ketoacidosis. J Inherit Metab Dis 1996; 19:85–86.

815 102. 103.

104. 105. 106.

107.

108. 109.

110. 111.

112.

113.

113a.

113b.

113c. 114.

115.

Shapira SK, Ledley FD, Rosenblatt DS, Levy HL. Ketoacidotic crisis as a presentation of mild methylmalonic acidemia. J Pediatr 1991; 119:80–84. Sethi KD, Ray R, Roesel RA, Carter AL, Gallagher BB, Loring DW, Hommes FA. Adult onset chorea and dementia with propionic acidemia. Neurology 1989; 39: 1343–1345. Nyhan WL, Bay C, Beyer EW, Mazi M. Neurologic nonmetabolic presentation of propionic acidemia. Arch Neurol 1999; 56:1143–1147. Rinaldo P. Laboratory diagnosis of inborn errors of metabolism. In: Suchy FJ, ed. Liver disease in children. 1st ed. St. Louis: Mosby, 1994:295–308. Rashed MS, Bucknall MP, Little D, et al. Screening blood spots for inborn errors of metabolism by electrospray tandem mass spectrometry with a microplate batch process and a computer algorithm for automated flagging of abnormal profiles. Clin Chem 1997; 43:1129– 1141. Vreken P, van Lint AEM, Bootsma AH, et al. Quantitative plasma acylcarnitine analysis using electrospray tandem mass spectrometry for the diagnosis of organic acidemias and fatty acid oxidation defects. J Inherit Metab Dis 1999; 22:302–306. Levy HL. Newborn screening by tandem mass spectrometry: a new era. Clin Chem 1998; 44: 2401–2402. Naylor EW, Chace DH. Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and aminoacid metabolism. J Child Neurol 1999; 14(Suppl 1):S4–S8. Rashed MS, Rahbeeni Z, Ozand P. Application of electrospray tandem mass spectrometry to neonatal screening. Semin Perinatol 1999; 23:183–193. Abdenur JE, Chamoles NA, Schenone AB, et al. Supplemental newborn screening of aminoacids (AA) and acylcarnitines by electrospray tandem mass spectrometry: experience in Argentina (abstr.). J Inherit Metab Dis 2000; 23:Suppl. 1:13. Patterson AL, Pourfarzam M, Henderson MJ. The utility of cord blood analysis in the diagnosis of organic acidemias (abstr.). J Inherit Metab Dis 2000; 23:Suppl. 1:84. Abdenur JE, Chamoles NA, Schenone AB, et al. Diagnosis of isovaleric acidemia by tandem mass spectrometry: false positive result due to pivaloylcarnitine in a newborn screening programme. J Inherit Metab Dis 1998; 21:624–630. Bonafe L, Troxler H, Kuster T, et al. Evaluation of urinary acylglycines by electrospray tandem mass spectrometry in mitochondrial energy metabolism defects and organic acidurias. Mol Genet Metab 2000; 69:302– 311. Tuchman M, Yudkoff M. Blood levels of ammonia and nitorgen scavenging aminoacids in patients with inherited hyperammonemia. Mol Genet Metab 1999; 66:10– 15. Ierardi-Curto L, Kaplan S, Saitta S, et al. The glutamine paradox in a neonate with propionic acidemia and severe hyperammonaemia. J Inherit Metab Dis 2000; 23:85–86. Ogier de Baulny H, Saudubray JM. Emergency treatments. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases. 2nd ed. Berlin: Springer-Verlag, 2000:53–61. Thompson GN, Chalmers RA. Increased urinary metabolite excretion during fasting in disorders of propionate metabolism. Pediatr Res 1990; 27:413–416.

816 116. 117. 118. 119.

120. 121. 122.

123.

124.

125. 126. 127. 128.

129.

130.

131.

132.

133. 134.

Abdenur Millington DS, Roe ChR, Maltby DA, Inoue F. Endogenous catabolism is the major source of toxic metabolites in isovaleric acidemia. J Pediatr 1987; 110:56–60. Bodamer OAF, Hoffman GF, Visser GH, et al. Assessment of energy expenditure in metabolic disorders. Eur J Pediatr 1997; 156(Suppl 1):S24–S28. Abdenur J, Greene C. Unpublished observation, 1992. Kalloghlian A, Gleispach H, Ozand PT. A patient with propionic acidemia managed with continuous insulin infusion and total parenteral nutrition. J Child Neurol 1992; 7(Suppl):S88–S91. Khaler SG, Millington DS, Cederbaum SD, et al. Parenteral nutrition in propionic and methylmalonic acidemia. J Pediatr 1989; 115:235–241. Roth B, Younossi A, Skopnik H, Leonard JV, Lehnert W. Haemodialysis for metabolic decompensation in propionic acidemia. J Inherit Metab Dis 1987; 10:147–151. Praphanphoj V, Brusilow S, Hamosh A, Geraghty MT. The use of intravenous sodium benzoate and sodium phenylacetate in propionic acidemia with hyperammonemia. J Inherit Metab Dis 2000; 23:Suppl. 1:91(A). Fries MH, Rinaldo P, Schmidt-Sommerfeld E, et al. Isovaleric acidemia: response to a leucine load after three weeks of supplementation with glycine, L-carnitine, and combined glycine-carnitine therapy. J Pediatr 1996; 129: 449–452. Tracy E, Arbour L, Chessex P, et al. Glutathione deficiency as a complication of methylmalonic acidemia: response to high doses of ascorbate. J Pediatr 1996; 129: 445–448. Matern D, Seydewitz HH, Lehnert W, et al. Primary treatment of propionic acidemia complicated by thiamine deficiency. J Pediatr 1996; 129:758–760. Feillet F, Bodamer OA, Dixon M, et al. Resting energy expenditure in disorders of propionate metabolism. J Pediatr 2000; 136:659–663. Thompson GN, Chalmers RA, Walter JH, et al. The use of metronidazole in management of methylmalonic and propionic acidemias. Eur J Pediatr 1990; 149:792–796. Vockley J, Rogan PK, Anderson BD, et al. Exon skipping in IVD RNA processing in isovaleric acidemia caused by point mutations in the coding region of the IVD gene. Am J Hum Genet 2000; 66:356–367. Ugarte M, Perez Cerda C, Rodriguez Pombo P, et al. Overview of mutations in the PCCA and PCCB genes causing propionic acidemia. Hum Mutat 1999; 14: 275– 282. Fuchshuber A, Mucha B, Baumgartner ER, et al. Mut0 methylmalonic acidemia: eleven novel mutations of the methylmalonyl CoA mutase including a deletion-insertion. Hum Mutat 2000; 16:179. Crane AM, Martin LS, Valle D, Ledley FD. Phenotype of disease in three patients with identical mutations in methylmalonyl CoA mutase. Hum Genet 1992; 89:259– 264. Weinberg GL, Laurito CE, Geldner P, et al. Malignant ventricular disrythmias in a patient with isovaleric acidemia receiving general and local anesthesia for suction lipectomy. J Clin Anesth 1997; 9:668–670. Harker HE, Emhardt JD, Hainline BE. Propionic acidemia in a four-month-old male: a case study and anesthetic implications. Anesth Analg 2000; 91:309–311. North KN, Korson MS, Gopal YR, et al. Neonatal onset propionic acidemia: neurologic and developmental profiles and implications for management. J Pediatr 1995; 126:916–922.

135. 136.

137. 138. 139. 140. 141. 142.

143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153.

154. 155.

van der Meer SB, Poggi F, Spada M, et al. Clinical outcome and long term management of 17 patients with propionic acidemia. J Pediatr 1996; 155:205–210. van der Meer SB, Poggi F, Spada M, et al. Clinical outcome of long term management of patients with vitamin B-12 unresponsive methylmalonic acidemia. J Pediatr 1994; 125:903–908. Varvogli L, Repetto GM, Waisbren SE, Levy HL. High cognitive outcome in an adolescent with mut- methylmalonic acidemia. Am J Med Genet 2000; 96:192–195. Anderson HC, Marble M, Shapira E. Long-term outcome in treated combined methylmalonic acidemia and homocystinemia. Genet Med 1999; 1:146–150. Nicolaides P, Leonard JV, Surtees R. Neurological outcome of methylmalonic acidemia. Arch Dis Child 1998; 78:508–512. Saudubray JM, Touati P, Delonlay P, et al. Liver transplantation in propionic acidaemia. Eur J Pediatr 1999; 158[suppl 2]:S65–S69. De Raeve L, Meirleir L, Ramet J, Vandenplas Y, Gerlo E. Acrodermatitis enteropathica-like cutaneous lesions in organic aciduria. J Pediatr 1994; 124:416–420. Yannicelli S, Hambidge KM, Picciano MF. Decreased selenium intake and low plasma selenium concentrations leading to clinical symptoms in a child with propionic acidemia. J Inher Metab Dis 1992; 15:261–268. Massoud AF, Leonard JV. Cardiomyopathy in propionic acidaemia. Eur J Pediatr 1993; 152:441–445. D’angio CT, Dilon MJ, Leonard JV. Renal tubular dysfunction in methylmalonic acidemia. Eur J Pediatr 1991; 150:259–263. Dudley J, Allen J, Tizard J, McGraw M. Benign methylmalonic acidemia in a sibship with distal renal tubular acidosis. Pediatr Nephrol 1998; 12:564–566. Rutledge SL, Geraghty M, Mroczek E, et al. Tubulointerstitial nephritis in methylmalonic acidemia. Pediatr Nephrol 1993; 7:81–82. Baumgartner ER, Viardot, et al. Long term follow-up of 77 patients with isolated methylmalonic acidemia. J Inher Metab Dis 1995:138–142. Dechaux M, Touati G, Vargas Poussou R, et al. Renal function in children with methylmalonic acidaemia. J Inher Metab Dis 2000; 23:Suppl. 1:97(A). van’t Hoff WG, Dixon M, Taylor J, et al. Combined liver–kidney transplantation for methylmalonic acidemia. 1998; J Pediatr 132:1043–1044. van’t Hoff WG, McKiernan PJ, Surtees RAH, Leonard JV. Liver transplantation for methylmalonic acidemia. 1999; Eur J Pediatr 1999; 158[suppl 2]:S70–S74. Packman S, Rosenthal P, Weisiger K, et al. Liver transplantation in Cbl B methylmalonic acidemia. J Inherit Metab Dis 2000; 23:Suppl. 1:95(A). Yorifuji T, Muroi J, Uematsu A, et al. Living-related liver transplantation for neonatal-onset propionic acidemia. J Pediatr 2000; 137:572–574. Roe CR, Ding J. Mitochondrial fatty acid oxidation disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2297– 3327. Brivet M, Boutron A, Slama A, et al. Defects in activation and transport of fatty acids. J Inher Metab Dis 1999; 22:428–441. Al Odaib A, Shneider AL, Bennet M, et al. A defect in the transport of long-chin fatty acids associated with acute liver failure. N Engl J Med 1998; 339:1752–1757.

Emergencies of Inborn Metabolic Diseases 156. 157.

158.

159.

160.

161.

162. 163.

164. 165.

166. 167.

168.

169. 170.

171.

Wanders RJA, Vreken P, den Boer MEJ, et al. Disorders of mitochondrial fatty acyl-CoA B-oxidation. J Inher Metab Dis 1999; 2:442–487. Wanders RJ, Denis S, Ruiter JP, Ijlst L, Dacremont G. 2,6-Dimethylheptanoyl-CoA is a specific substrate for long-chain acyl-CoA dehydrogenase (LCAD): evidence for a major role of LCAD in branched-chain fatty acid oxidation. Biochem Biophys Acta 1998; 1393:35–40. Frerman FE, Goodman SI. Defects of electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: Glutaric acidemia type II. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2357–2366. Uchida Y, Izai K, Orii T, Hashimoto T. Novel fatty acid B-oxidation enzymes in rat liver mitochondria. II. Purification and properties of enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase/3-keto-acyl-CoA thiolase trifunctional protein. J Biol Chem 1992;267:1034–1041. Carpenter K, Pollit RJ, Middleton B. Human liver longchain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane bound beta oxidation enzyme of mitochondria. Biochem Biophys Res Commun 1992; 183:443–448. Ushikubo S, Ayoama T, Kamijo T, et al. Molecular characterization of mitochondrial trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both ␣- and ␤-subunits. Am J Hum Genet 1996; 58:979–988. Ibdah JA, Yang Z, Bennet M. Liver disease in pregnancy and fetal fatty acid oxidation defects. Mol Genet Metab 2000; 71:182–189. Mitchell GA, Fukao T. Inborn errors of ketone body metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2327– 2356. Saudubray JM, Martin D, de Lonlay P, et al. Recognition and management of fatty acid oxidation defects: a series of 107 patients. J Inherit Metab Dis 1999; 22:488–502. Stanley CA, De Leeuw S, Coates P, et al. Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann Neurol 1991; 30: 709–716. Olpin SE, Allen J, Bonham JR, et al. Features of palmitoyltransferase type I deficiency. J Inherit Metab Dis 2001; 24:3542. Lopriore E, Gemke RJ, Verhoeven NM, et al. Carnitineacylcarnitine translocase deficiency: phenotype, residual enzyme activity and outcome. Eur J Pediatr 2001; 160: 101–104. North K, Hoppel CL, De Girolami U, et al. Lethal neonatal deficiency of carnitine palmitoyl transferase II associated with dysgenesis of the brain and kidneys. J Pediatr 1995; 127:414–420. Bonnefont JP, Demaugre F, Prip-Buus C, et al. Carnitine palmitoyltransferase deficiencies. Mol Genet Metab 1999; 68:424–440. Vianney-Saban C, Stremler N, Paul O, et al. Infantile form of carnitine palmitoyltransferase type II deficiency in a girl with rapid fatal onset. J Inher Metab Dis 1995; 18:362–363. Mathur A, Sims HF, Gopalakrishnan D, et al. Molecular heterogeneity in very-long-chain Acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation 1999; 99:1337–1343.

817 172. 173. 174.

175.

176.

177.

178.

179.

180. 181.

182.

183.

184.

185. 186.

187. 188.

Wilson CJ, Champion MP, Collins JE, et al. Outcome of medium chain acyl-CoA dehydrogenase deficiency after diagnosis. Arch Dis Child 1999; 80:459–462. Bhala A, Willi S, Rinaldo P, et al. Clinical and biochemical characterization of short-chain acyl-CoA dehydrogenase deficiency. J Pediatr 1995; 126:910–915. Tein I, Haslam RH, Rhead W, et al. Short chain acylCoA-dehydrogenase deficiency. A cause of ophthalmoplegia and multicore myopathy. Neurology 1999; 52: 366–372. Tyni T, Palotie A, Viinikka L, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with the G1528 mutation: clinical presentation of thirteen patients. J Pediatr 1997; 130:67–76. Gillingham M, Van Calcar S, Ney D, et al. Dietary management of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). A case report and survey. J Inherit Metab Dis 1999; 22:123–131. Ibdah JA, Tein I, Dionisi-Vici C, et al. Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggest a novel genotype-phenotype correlation. J Clin Invest 1998; 102:1193–1199. Bennett MJ, Spotswood SD, Ross KF, et al. Fatal shortchain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency: clinical, biochemical and pathological studies on three subjects with this recently identified disorder of mitochondrila beta oxidation. Pediatr Dev Pathol 1999; 2:337–345. Kamijo T, Indo Y, Souri M, et al. Medium chain 3-ketoacyl-coenzyme A thiolase deficiency: a new disorder of mitochondrial fatty acid B-oxidation. Pediatr Res 1997; 42: 569–576. Rinaldo P, Raymond K, Al-odaib A, et al. Clinical and biochemical features of fatty acid oxidation disorders. Curr Opin Pediatr 1998; 10:615–621. Mitchell G, Bouchard L, Robert MF, et al. Mitochondrial 3-hydroxy-3-methyl-glutaryl-CoA synthase deficiency. Clinical course and description of causal mutations in the two known patients. J Inherit Metab Dis 2000; 23[Suppl. 1]:108(A). Bonnet D, Martin D, Lonlay P, et al. Arrhytmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children. Circulation 1999; 100: 2248–2255. Christodolou J, Hoarse J, Hammond J, et al. Neonatal onset of medium-chain-acyl-Coenzyme A dehydrogenase deficiency with confusing biochemical features. J Pediatr 1995; 126:65–68. Thiel C, Baudach S, Schnackenberg U, Vreken P, Wanders R. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: neonatal manifestation at the first day of life presenting with tachipnoea. J Inherit Metab Dis 1999; 22:839–840. Iafolla AK, Thompson RJ, Roe CR. Medium-chain acylcoenzyme A dehydrogenase deficiency: clinical course in 120 affected children. J Pediatr 1994; 124:409–415. Ibdah JA, Dasouki MJ, Strauss AW. Long-chain 3hydroxyacyl-CoA dehydrogenase deficiency: variable expressivity of maternal illness during pregnancy and unusual presentation with infantile cholestasis and hypocalcemia. J Inherit Metab Dis 1999; 22:811–814. Tripp M, Katcher M, Peters HA, et al. Systemic carnitine deficiency presenting as familial endocardial fibroelastosis. N Engl J Med 305:385–390. Stanley CA. Disorders of fatty acid oxidation. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn

818

189.

190.

191. 192. 193.

194. 195.

196.

197. 198.

199.

200.

201. 202. 203.

204.

205.

Abdenur Metabolic Diseases. 2nd ed. Berlin: Springer-Verlag, 2000:140–149. Harding CO, Gillingham MB, van Calcar SC, et al. Docosahexaenoic acid and retinal function in children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 1999; 2:276–280. Tyni T, Ekholm E, Pihko H. Pregnancy complications are frequent in long-chain-3hydroxyacyl-coenzyme A dehydrogenase deficiency. Am J Obstet Gynaecol 1998; 178:603–608. Ibdah JA, Bennett MJ, Rinaldo, et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med 1999; 340:1723–1731. Treem WR. Pregnancy and liver disease. Beta oxidation defects. Clin Liver Dis 1999; 3:50–67. Chakrapani A, Olpin S, Cleary M, et al. Trifunctional protein deficiency: three families with significant maternal hepatic dysfunction in pregnancy not associated with E474Q mutation. J Inher Metab Dis 2000; 23:826–834. Ibdah JA, Zhao Y, Viola J, et al. Molecular prenatal diagnosis in families with fetal mitochondrial trifunctional protein mutations. J Pediatr 2001; 138:396–399. Innes AM, Seargeant LE, Balachandra K, et al. Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy. Pediatr Res 2000; 47:43– 45. Nelson J, Lewis B, Walters B. The HELLP syndrome associated with fetal medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 2000; 23:518– 519. Matern D, Hart P, Murtha AP, et al. Acute fatty liver of pregnancy associated with short-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr 2001; 138:585–588. Boles RG, Buck EA, Blitzer MG, et al. Retrospective biochemical screening of fatty acid oxidation disorders in post mortem liver of 418 cases of sudden death in the firs year of life. J Pediatr 1998; 132:924–933. Lundemose JB, Kolvraa S, Gregersen N, et al. Fatty acid oxidation disorders as primary cause of sudden and unexpected death in infants and young children: an investigation performed on cultured fibroblasts from 79 children who died aged between 0–4 years. Mol Pathol 1997; 50:212–217. Rashed MS, Ozand PT, Bennet MJ, et al. Inborn errors of metabolism diagnosed in sudden death cases by acylcarnitine analysis of postmortem bile. Clin Chem 1995; 41:1109–1114. Rinaldo P, Stanley CA, Hsu BY, et al. Sudden neonatal death in carnitine transporter deficiency. J Pediatr 1997; 131:304–305. Nuoffer JM, de Lonlay P, Costa C, et al. Familial neonatal SIDS revealing carnitine-acylcarnitine translocase deficiency. Eur J Pediatr 2000; 159:82–85. Treacy E, Lambert D, Barnes R, et al. Short-chain hydroxyacyl-CoA dehydrogenase deficiency presenting as unexpected infant death: a family study. J Pediatr 2000; 137:257–259. Poplawski NK, Ranieri E, Harrison JR, Fletcher JM. Multiple acyl-CoA-dehydrogenase deficiency: diagnosis by acylcarnitine analysis of a 12 year old newborn screening card. J Pediatr 1999, 134:764–766. Rinaldo P, Yoon HR, Yu C, et al. Sudden and unexpected neonatal death: a protocol for the postmortem diagnosis of fatty acid oxidation disorders. Semin Perinatol 1999; 23:204–210.

206. 207. 208.

209.

210. 211. 212.

213.

214.

215.

216.

217.

218.

219.

220.

221.

222.

El-schahawi M, Bruno C, Tsujino S, et al. Sudden infant death syndrome (SIDS) in a family with myophosphorilase deficiency. Neuromusc Disord 1997 7:81–3. de Klerk JB, Duran M, Huijmans JG, Mancini GM. Sudden infant death and lysinuric protein intolerance. Eur J Pediatr 1996; 155:256–257. Pastores GM, Santorelli FM, Shanske S, et al. Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G). Am J Med Genet 1994; 50:265–71. Dionisi-Vici C, Seneca S, Zeviani M, et al. Fulminant Leigh syndrome and sudden unexpected death in a family with the T9176C mutation of the mitochondrial ATPase 6 gene. J Inher Metab Dis 1998: 21:2–8. Treem WR. Inborn defects in mitochondrial fatty acid oxidation. In: Suchy FJ, ed. Liver disease in children. 1st ed. St. Louis: Mosby, 1994:852–887. Davidson-Mundt A, Luder A, Greene C. Hyperuricemia in medium-chain-acyl-coenzyme-A dehydrogenase deficiency. J Pediatr 1992; 120:444–446. Treem WR, Witzleben CA, Picoli DA, et al. Mediumchain and long-chain acyl CoA dehydrogenase deficiency: clinical, pathologic and ultrastructural differentiation from Reye’s syndrome. Hepatology 1986; 6: 1270–1278. Millington DS, Terada, Chase DH, et al. The role of tandem masss spectrometry in the diagnosis of fatty acid oxidation disorders. In Coates PM, Tanaka K, eds. New Developments in Fatty Acid Oxidation. Progress in Clinical and Biochemical Research. New York: Wiley-Liss, 1992:339–354. van Hove JLK, Zhang W, Kahler SG, et al. Mediumchain acyl-CoA-dehydrogenase deficiency: diagnosis by acylcarntine analysis in blood. Am J Hum Genet 1993; 52:958–966. van Hove, Kahler SG, Feezor, et al. Acylcarnitines in plasma and blood spots of patients with long-chain 3hydroxyacyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 2000; 23:571–582. Sim KG, Wiley V, Wilken B. Carnitine palmitoyltransferase I deficiency in neonates identified by dried blood spot free carnitine and acylcarnitine profile. J Inherit Metab Dis 2001; 24:51–59. Zschocke J, Hegardt FG, Casals N, et al. Clinical biochemical and molecular characterization of 3-hydroxy3-methylglutaryl-CoA synthase deficiency. J Inherit Metab Dis 2000; 23:Suppl. 1:107(A). Brivet M, Slama A, Millington DS, et al. Retrospective diagnosis of carnitine acylcarnitine translocase deficiency in the proband Guthrie card and enzymatic studies in parents. J Inherit Metab Dis 1996; 19:181–184. Ziadeh R, Hoffman EP, Finegold DN, et al. Mediumchain Acyl-CoA dehydrogenase deficiency in Pennsylvania: neonatal screening shows high incidence and unexpected mutation frequencies. Pediatr Res 1995; 37: 675–678. Wilcken B, Wiley V, Carpenter K. Two years of routine newborn screening by tandem mass spectrometry in New South Wales, Australia (abstr.). J Inherit Metab Dis 2000; 23:Suppl. 1:4. Abdenur JA, Chamoles NA, Schenone AB, et al. Multiple acyl-CoA-dehydrogenase deficiency: use of acylcarnitines and fatty acids to monitor the response to dietary treatment. Pediatr Res 2001; 50:61–66. Bennet MJ, Weinberger MJ, Sherwood WG, Burlina AB. Secondary 3-hydroxydicarboxylic aciduria mimicking

Emergencies of Inborn Metabolic Diseases

223.

224.

225.

226.

227.

228.

229. 230.

231.

232. 233.

234. 235.

236.

237.

238.

long-chain 3-hdroxyacyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 1994; 17:283–286. Bonafe L, Troxler H, Kuster T, et al. Evaluation of urinary acylglycines by electrospray tandem mass spectrometry in mitochondrial energy metabolism defects and organic acidurias. Mol Genet Metab 2000; 69:302– 311. Costa CG, Dorland L, Holwerda U, et al. Simultaneous analysis of plasma free fatty acids and their 3-hydroxy analogs in fatty acid ␤-oxidation disorders. Clin Chem 1998; 44:463–471. Abdenur JA, Chamoles NA, Specola N, Schenone AB, et al. MCAD deficiency: Acylcarnitines by tandem mass spectrometry (MS-MS) are useful to monitor dietary treatment. Adv Exp Med Biol 1999; 46:353–363. Jones PM, Burlina AB, Bennet MJ. Quantitative measurement of total and free 3-hydroxy fatty acids in serum or plasma samples: short-chain 3-hydroxy fatty acids are not esterified. J Inherit Metab Dis 2000; 23:745–750. Brivet M, Slama A, Saudubray JM, et al. Rapid diagnosis of long chain and medium chain fatty acid oxidation disorders using lymphocytes. Ann Clin Biochem 1995; 32:154–159. Shen JJ, Matern D, Millington D, et al. Acylcarnitines in fibroblasts of patients with long-chain 3-hydroxyacylCoA dehydrogenase deficiency and other fatty acid oxidation disorders. J Inherit Metab Dis 2000; 23:27–44. Gregersen N, Andresen BS, Bross P. Prevalent mutations in fatty acid oxidation disorders: diagnostic considerations. Eur J Pediatr 2000; 159[Supp. 3]:S213–218. Matsubara Y, Narisawa K, Tada K, et al. Prevalence of K329E mutation in medium chain acylCoA dehydrogenase gene determined from Guthrie cards. Lancet 1991; 338:552–553. Andresen BS, Bross P, Szabolcs U, et al. The molecular basis of medium-chain-acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there a correlation between genotype and phenotype? Hum Mol Genet 1997; 6:695–707. Njolstad PR, Skjeldal OH, Agsteribbe A, et al. Medium chain acyl-CoA dehydrogenase deficiency and fatal valproate toxicity. Pediatr Neurol 1997; 16:160–162. Baillet L, Mullur RS, Esser V, McGarry JD. Elucidation of the mechanism by which (⫹)-acylcarnitines inhibit mitochondrial fatty acid transport. J Biol Chem 2000; 275:36766–36768. Pollit, Leonard JV. Prospective surveillance study of medium chain acyl-CoA dehydrogenase deficiency in the UK. Arch Dis Child 1998; 79:116–119. Kerr DS, Wexler I, Zinn AB. Disorders of pyruvate metabolism and the tricarboxylic acid cycle. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases. 2nd ed. Berlin: Springer-Verlag, 2000: 126–138. Robinson BH. Lactic acidemia: Disorders of pyruvate carboxylase and pyruvate dehydrogenase. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2275–2295. Nyhan WL, Ozand PT, eds. Deficiency of pyruvate dehydrogenase complex. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:278– 284. Lissens W, De Meirleir L, Seneca S, et al. Mutations in the X-linked pyruvate dehydrogenase (E1) subunit gene

819

239.

240. 241.

242.

243. 244. 245. 246. 247. 248.

249.

250. 251. 252.

253.

254. 255. 256.

(PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat 2000; 15:209–219. Robinson BH, Mac Kay N, Petrova-Benedict R, et al. Defects in the E2 lipoyltransacetylase and the X-lipoyl containing component of the pyruvate dehydrogenase complex in patients with lactic acidemia. J Clin Invest 1990; 85:1821–1824. Ito M, Kobashi H, Naito E, et al. Decrease of pyruvate dehydrogenase phosphatase activity in patients with congenital lactic acidemia. Clin Chim Acta 1992; 209:1–7. Yoshida I, Sweetman L, Kulovich S, Nyhan WL, Robinson B. Effect of lipoic acid in a patient with defective activity of pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and branched-chain keto acid dehydrogenase. Pediatr Res 1990; 27:75–79. Elpeleg ON, Ruitenbeek W, Jakobs C, et al. Congenital lactic acidemia caused by lipoamide dehydrogenase deficiency with favorable outcome. J Pediatr 1995; 126: 72–74. Saada A, Aptowitzer I, Link E, Elpeleg ON. ATP synthesis in lipoamide dehydrogenase deficiency. Biochem Biophys Res Commun 2000; 16:382–386. Makino M, Horai S, Goto Y, Nonaka I. Mitochondrial DNA mutations in Leigh syndrome and their phylogenetic implications. J Hum Genet 2000; 45:69–75. DiMauro S, Bonilla E, De Vivo D. Does the patient have a mitochondrial encephalomyopathy? J Child Neurol 1999; 14(Suppl 1):S23–S35. Kohlschutter A, Behbehani A, Langenbeck U, et al. A familial progressive neurodegenerative disease with 2oxo-glutaric aciduria. Eur J Pediatr 1982; 138:32–37. Dunckelmann RJ, Ebinger F, Schulze A, et al. 2-ketoglutarate dehydrogenase deficiency with intermittent 2ketoglutaric aciduria. Neuropediatrics 2000; 31:35–38. Rustin P, Bourgeron T, Parfait B, et al. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim Biophys Acta 1997; 1361: 185–197. Bourgeron T, Chretien D, Poggi-bach J, et al. Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. J Clin Invest 1994:2514–2518. Coughlin EM, Christensen E, Kunz P, et al. Molecular analysis and prenatal diagnosis of human fumarase deficiency. Mol Genet Metab 1998; 63:254–262. Kerrigan JF, Aleck KA, Tarby TJ, et al. Fumaric aciduria: clinical and imaging features. Ann Neurol 2000; 47:583–588. Hall RE, Henriksson KG, Lewis SF, et al. Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron sulfur proteins. J Clin Invest 1993; 92:2660–2666. Brun N, Robitaille Y, Grignon A, et al. Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with acute neonatal form. Am J Med Genet 1999; 84:94–101. Ahmad A, Khaler S, Kishnani PS, et al. Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate. Am J Med Genet 1999; 87:331–338. Nyhan WL, Ozand PT, eds. Fructose 1,6-diphosphatase deficiency. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:273–277. Shoffner JM. Oxidative phosphorylation diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2367–2423.

820 257.

258.

259. 260.

261. 262.

263. 264. 265. 266.

267.

268.

269.

270. 271.

272. 273.

274.

Abdenur Munnich A. Defects of the respiratory chain. In: Fernandes J, Saudubray JM, van den Berghe G, eds. Inborn Metabolic Diseases. 2nd ed. Berlin: Springer-Verlag, 2000:158–168. Munnich A, Rotig A, Cormier-Daire V, Rustin P. Clinical presentation of respiratory chain deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2261–2274. Robinson BH. Human citochrome oxidase deficiency. Pediatr Res 2000; 48:581–585. Pastores GM, Santorelli FM, Shanske S, et al. Leigh syndrome and hypertrophic cardiomyopathy in a patient with a mitochondrial DNA point mutation (T8993G). Am J Med Genet 1994; 50:265–71. Munnich A, Rotig A, Chretien D, et al. Clinical presentation of mitochondrial disorders in childhood. J Inherit Metab Dis 1996; 19:521–527. Naviaux R. The mitochondrial DNA depletion syndromes. In: Nyhan WL, Ozand PT, eds. Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998: 314–320. Mazziota MRM, Ricci E, Bertini E, et al. Fatal infantile liver failure associated with mitochondrial DNA depletion. J Pediatr 1992; 121:896–901. Vu TH, Sciacco M, Tanji K, et al. Clinical manifestations of mitochondrial DNA depletion. Neurology 1998; 50:1783–1790. van der Knaap MS, Jakobs C, Valk J. Magnetic resonance imaging in lactic acidosis. J Inher Metab Dis 1996; 19:535–547. Nyhan WL, Ozand PT, eds. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:297–304. Nyhan WL, Ozand PT, eds. Myoclonic epilepsy and ragged red fibers (MERRF). In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998: 292–297. Nyhan WL, Ozand PT, eds. Neurodegeneration, ataxia and retinitis pigmentosa (NARP). In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:304–309. Wallace DC, Lott MT, Brown MD, Kerstann K. Mitochondria and neuro-ophthalmological diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001:2425–2512. Kadowaki T, Kadowaki H, Mori Y, et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 1994; 330:962–966. Rotig A, Bourgeron T, Chretien D, et al. Spectrum of mitochondrial DNA rearrangements in the Pearson marrow–pancreas syndrome. Hum Mol Genet 1995; 4: 1327–1331. Nyhan WL, Ozand PT, eds. Pearson syndrome. In: Atlas of Metabolic Diseases. 1st ed. London: Chapman & Hall Medical, 1998:309–313. Moraes CT, DiMauro S, Zeviani M, Lombes A, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 1989; 320:1293. Rotig A, Cormier V, Chatelain P, et al. Deletion of the mitochondrial genome in a case of early onset diabetes mellitus, optic atrophy and deafness (Wolfram syndrome). J Clin Invest 1993; 91:1095–1102.

275.

276.

277. 278.

279. 280.

281. 282. 283. 284. 285.

286.

287. 288.

289. 290. 291.

292.

293.

Zeviani M, Servidei S, Gellera C, et al. An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 1989; 339:309–313. Rotig A, De Lonlay P, Chretien D, et al. Frataxin expansion causes aconitase and mitochondrial iron-sulfur protein deficiency in Friedreich ataxia. Nat Genet 1997; 17:215. Bionne S, D’Adamo P, Maestrini E, et al. A novel Xlinked gene, G4.5 is responsible for Barth syndrome. Nat Genet 1996; 12:385. Poggi-Travert F, Martin D, Billette de Villemeur T, et al. Metabolic intermediates in lactic acidosis: compounds samples and interpretation. J Inherit Metab Dis 1996; 19: 478–488. Cray SH, Robinson B, Cox PN. Lactic acidemia and bradyarrhythmia in a child sedated with profolol. Crit Care Med 1998; 26:2087–2092. Beatty ME, Zhang YH, Mc Cabe ER, Steiner RD. Fructose-1-6-diphosphatase deficiency and glyceroluria: one possible etiology for GIS. Mol Genet Metab 2000; 69: 338–340. Rogers JG, Wilkinson RG, Skelton I, Danks DM. Tertiary lactic acidosis. J Pediatr 1981; 99: 272–273. Bongaerts G, Bakkeren J, Severijen R, et al. Lactobacilli and acidosis in children with short small bowel. J Pediatr Gastroenterol Nutr 2000; 30:288–293. Romero NB, Lombes A, Touati G, et al. Morphological studies of skeletal muscle in lactic acidosis. J Inher Metab Dis 1996; 19:528–534. Morris AAM, Leonard JV. The treatment of congenital lactic acidoses. J Inherit Metab Dis 1996; 19:573–580. Lerman-Sagie T, Rustin P, Lev D, et al. Dramatic improvement in mitochondrial cardiomyopathy following treatment with idebenone. J Inher Metab Dis 2001; 24: 28–34. Wexler ID, Hemalatha SG, McConnell J, et al. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology 1997; 49:1655–1661. Sokal EM, Sokol R, Cormier V, et al. Liver transplantation in mitochondrial respiratory chain disorders. Eur J Pediatr 1999; 158(Suppl 2):S81–S84. Chuang DT, Shih V. Maple syrup urine disease (branched-chain ketoaciduria. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGrawHill, 2001:1971–2005. Peinemann, Danner DJ. Maple syrup urine disease 1954 to 1993. J Inherit Metab Dis 1994; 17:3–15. Fernhoff P, Lubitz D, Danner DJ, et al. Thiamine responsive maple syrup urine disease. Pediatr Res 1985; 19:1011–1016. Jouvet P, Poggi F, Rabier D, et al. Continuous venovenous haemofiltration in the acute phase of neonatal maple syrup urine disease. J Inher Metab Dis 1997; 20: 463–472. Friedrich CA, Marble A, Maher J, et al. Successful control of branched-chain aminoacids in maple syrup urine disease using elemental aminoacids in total parenteral nutrition during acute pancreatitis. Am J Hum Genet 1992; 51:A350. Riviello JJ, Rezvani I, Digeorge AM, et al. Cerebral edema causing death in children with maple syrup urine disease. J Pediatr 1991; 119:42–47.

Emergencies of Inborn Metabolic Diseases 294.

295. 296.

Treacy E, Clow CL, Reade TR, et al. Maple syrup urine disease: interrelations between branched-chain aminooxo- and hydroxyacids; implications for treatment: associations with CNS dysmyelination. J Inherit Metab Dis 1992;15:121–135. Brismar J, Aqeel A, Brismar G, et al. Maple syrup urine disease: findings on CT and MRI scans of the brain in 10 infants. Am J Neuroradiol 1990; 11:1219. Chase DH, Hillman SL, Millington DS, et al. Rapid

821

297. 298.

diagnosis of MSUD in blood spots from newborns by tandem mass spectrometry. Clin Chem 1995; 41: 62–68. Nord A, van Doorninck WJ, Greene C. Developmental profile of patients with maple syrup urine disease. J Inherit Metab Dis 1991; 14:881–89. Hilliges C, Awiszus D, Wendel U. Intellectual performance of children with maple syrup urine disease. Eur J Pediatr 1993; 152:144–147.

34 Obesity in Children Ramin Alemzadeh Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.

Russell Rising and Maribel Cedillo EMTAC, Inc., Miami, Florida, U.S.A.

Fima Lifshitz Miami Children’s Hospital and University of Miami School of Medicine, Miami, Florida; State University of New York Health Science Center at Brooklyn, Brooklyn, New York; Pediatric Sunshine Academics; and Sansum Medical Research Institute, Santa Barbara, California, U.S.A.

I.

East. More worrisome is the fact that the body mass index (BMI) in adults is expected to almost double in most of the major market economies of the world by the year 2030 (8). France, the Netherlands, United Kingdom, and the United States also report increasing prevalence of obesity in children and adolescents. Data from 79 developing countries and a number of industrialized nations suggests that 22 million children under 5 years of age are overweight (>⫹2 standard deviations above National Child Health Survey (NCHS) reference median weight for height) (9). These increases in obesity may be partly due to the greater social economic status of the market economies (10). In the future, the prevalence of childhood obesity may be as much as the current rise in adult obesity, but the consequences may be more severe as the duration of obesity will be longer. It may therefore have a greater deleterious impact on health and the rate of morbidity and mortality than obesity starting in adulthood. Many children are at high risk of becoming overweight between the ages of 3 and 10 years. This is the time they begin school and socialization with other children. Furthermore, the risk of becoming an obese adult was 3–10 times greater if the child’s weight was greater than the 95th percentile for their age. Obese parents impose even a greater risk that their children will be overweight. There is a 75% chance that children aged 3–10 will be overweight if both parents were obese. This drops

PREVALENCE

Childhood obesity is one of the most complex and poorly understood clinical syndromes in pediatrics. Obesity is a common nutritional disorder among children and adolescents in the United States, with an estimated prevalence of 20% as compared to 30% in the adult population. A study in Europe found that 15 and 22% of adult men and women, respectively, were obese (1). Furthermore, 60 and 75% of men and women, respectively, in urban Samoa were obese (2). It is estimated that obesity affects 7% of the world’s adult population. The percentage of overweight children and adolescents has increased by almost 50% in the past two decades (3). This disturbing trend in childhood and adolescent obesity parallels a concurrent increase in prevalence of this disorder (4). It is estimated that 10–20% of obese infants will remain overweight (5). It has also been observed that about 40% of overweight children will continue to have increased weight during adolescence and 75–80% of obese adolescents become obese adults (6). Moreover, more than one-third of overweight children will eventually become obese adults (7). Obesity in children is expected to continue to increase into the 21st century. Obesity is present in every continent. This includes the established market economies including the economies of Europe, Latin America, the Caribbean, and the Middle

823

824

Alemzadeh et al.

to a 25–50% chance with just one obese parent. These statistics suggest that behavior modification or treatment intervention at an early age may be important for preventing future adolescent and adulthood obesity (11).

II.

MORBIDITY

Obesity in childhood is a major public health problem and is strongly linked to persistence into adulthood. This increases the obese individual’s risks for hypertension (12), hyperlipidemia (13), respiratory diseases (14), diabetes (15), orthopedic conditions (16, 17), psychosocial disorders (18), and social and economic consequences (19). The altered nutritional state in obesity results in many endocrine changes that disappear with weight loss. These include excess insulin secretion, insulin resistance, and alterations at the level of the hypothalamic pituitary gonadal and adrenal axis. Hyperinsulinemia of obesity is strongly linked with cardiovascular diseases, including type 2 diabetes mellitus, hyperlipidemia, and hypertension (20). Obesity is associated with hypertension in 10–30% of children (12) regardless of age, gender, and duration. Obese children and adolescents tend to have elevated levels of total serum cholesterol, triglycerides, and low-density lipoprotein, and decreased levels of high-density lipoproteins (12). They are also at increased risk for coronary heart disease as they grow into obese adults (21, 22). With few exceptions, the clinical features of cardiovascular heart disease are not apparent until the third or fourth decade of life. However, there is substantial evidence that the atherosclerotic process is initiated during childhood (23, 24). In a study by Must et al., long-term morbidity and mortality of overweight adolescents were examined (25). They demonstrated that obesity in adolescent subjects were associated with an increased risk of mortality from all causes and disease-specific mortality among men, but not among women. On the other hand, the risk of morbidity from coronary heart disease and atherosclerosis was increased in both men and women who had been obese in adolescence. This suggests that body weight reduction among the young may decrease the risks for many of the obesity-related health disorders. Increased cholesterol turnover and its concentration in the bile of obese individuals predispose them to a high incidence of steatohepatitis (26) and gallbladder disease (27). Indeed, gallstones (cholelithiasis) have been reported to be three times more common in morbidly obese people than in normal subjects. Gallstones may also result while the obese person is on a hypocaloric diet. This may be due to mobilization of adipose tissue cholesterol during weight loss (28). Furthermore, the risk of colorectal cancer and gout was increased among women who had been obese in adolescence. Finally, obesity in adolescence was a more significant predictor of these risks than being overweight in adulthood (29).

Syndrome X is a clinical quartet of hyperinsulinemia, hyperlipidemia, hypertension, and subsequent cardiovascular disease (30). It is believed that obesity is a component of this metabolic syndrome and has been described in obese children (31) and adolescents (32). In a more recent study, Chen et al. suggested that syndrome X is characterized by the linking of a metabolic entity (hyperinsulinemia/insulin resistance, hyperlipidemia, and obesity) to a hemodynamic factor (hypertension) through a shared correlation with hyperinsulinemia/insulin resistance. Clustering features of syndrome X are independent of gender and age in both black and white populations (33). Nonautoimmune forms of youth-onset diabetes are becoming increasingly prevalent as rates of obesity in children and adolescents accelerate (15). Many health professionals have recognized an emerging epidemic of type 2 diabetes mainly affecting minorities (34–36). Epidemiological data obtained from various centers suggest an almost fourfold increase in the prevalence of type 2 diabetes among minority groups such as Native, African, and Hispanic Americans aged 10–19 years over the past 10 years (15, 37). Increasing prevalence of type 2 diabetes in the youth is not limited to North America. For instance, among Japanese junior high school students, the incidence of type 2 diabetes is almost seven times that for type 1 diabetes (38). It is believed that the increasing incidence of type I diabetes is associated with changing food patterns and rising obesity rates among Japanese school children (39). Children have hyperinsulinism as a result of obesity, as do adults, and childhood obesity is commonly associated with impaired glucose tolerance (40). The stress of obesity and the increased demand for insulin during adolescence explain the predominantly pubertal and postpubertal onset of type 2 diabetes in obese children (41). Orthopedic complications of obesity are believed to be largely of mechanical nature. During childhood, slipped capital femoral epiphysis, Legg-Calve-Perthes disease, and genu valgum tend to be more common in obese subjects. Orthopedic disorders such as Blount’s disease (tibia vara) and slipped capital femoral epiphysis are frequently seen in obese adolescents (16, 17). Rapid weight gain or obesity during infancy and childhood tends to be a risk factor for frequent respiratory infections (14). The work of breathing is increased in obese individuals and larger body mass places increased demands for oxygen consumption and carbon dioxide elimination. Many obese subjects suffer from chronic hypoxemia secondary to ventilation–perfusion mismatch. This is characterized by increased ventilation of upper lobes and increased perfusion of the lower lobes. Insufficient elimination of carbon dioxide, in some obese subjects, leads to hypoventilation (pickwickian) syndrome (42), which is characterized by chronic hypoxemia and hypercapnia. These subjects have blunted respiratory drive to both hypoxemia and hypercapnia.

Obesity in Children

Sleep apnea is also seen in severe obesity and is characterized by cessation of air flow for 10 s or longer on 30 occasions during 7 h of sleep. Parents of obese children and adolescents usually report that their children snore loudly and sometimes appear to stop breathing. Sleep apnea is a major problem found to be associated with increased risk of traffic accidents (43). The apnea may be obstructive, central, or combined. In most patients, no anatomical abnormalities of the upper airway can contribute to the development of obstructive sleep apnea (OSA). It has been shown that the occurrence of OSA in obese subjects is related to the size of the region enclosed by the mandible (44, 45) and sites and sizes of fat deposits around the pharynx, as well as subjects’ weight. In patients with OSA, alveolar hypoventilation results from increased oxygen demand during the apneic episode. Coexistent cardipulmonary or neuromuscular disease in subjects with OSA can play a role in the development of alveolar hypoventilation. During the apneic episodes, the systemic blood pressure increases whereas the heart rate and cardiac output decrease. Apnea-associated cardiac arrhythmias have been frequently observed in patients with OSA and increases their risk for cardiovascular mortality (46). Relief of respiratory obstruction alleviates OSA. This may be accomplished by weight loss and continuous positive airway pressure (CPAP) during sleep. Obesity is also accompanied by advanced skeletal maturity (bone age) and early menarche (29). Amenorrhea, oligomenorrhea, and/or dysfunctional uterine bleeding are common among obese adolescent females. Some of these patients will also develop polycystic ovarian syndrome (47–49).

A.

Psychosocial Impact of Obesity

In addition to the medical complications associated with obesity, the juvenile-onset obese subject is also at risk for psychological morbidity (18). It has also been shown that obesity tends to confer disability greater than that associated with other forms of chronic illness (19). This disability seems to be linked to the public nature of obesity. Peer group discrimination is the factor that prompts parents to seek treatment in their obese child. Even young school-aged children have been observed to view their overweight classmates as less desirable playmates (50). Overweight children are frequently teased on the playground and usually excluded from games. Obese children are under considerable psychological stress and are generally viewed by society as clumsy, unattractive, and overindulgent. Overweight children as young as 5 years of age have been found to associate their obesity with lower body esteem and lower perceived cognitive ability. A parent’s concern about obesity and restriction of food were associated with negative self-evaluations among girls (51). In one study a mothers’ own dietary restraint and concern about their daughter’s obesity predicted child feeding

825

practices. This suggests that a mother’s control over her daughter’s feeding practices and concern about the child’s obesity may be an important, nonshared, environmental influence on the daughter’s eating habits and relative weight (52). Moreover, obese elementary school-aged girls were more likely to be dieting and express concern about their overweight than similarly aged boys (53). All of these results suggest that childhood obesity can occur early in a child’s life and has to be addressed by the whole family. Lowered self-image, heightened self-consciousness, and impaired social functioning have been noted in some individuals who either become or remain obese during adolescence (54). Studies of obese adolescents have demonstrated obsession with being overweight, passivity, and withdrawal from social contact (18). Some investigators have found similarities between the behavior of obese subjects and racial minorities expressing prejudice (55). In fact, it has been shown that the obese persons were less likely to get admitted to a college than their lean counterparts, although there were no significant differences in their application rates, academic standing, or economic background (56). Moreover, obese individuals are 20% less likely to marry and are of lower income status than normal-weight individuals with other chronic medical conditions.

B.

Economic Impact of Obesity

The increasing prevalence of obesity in adults is associated with rising health care costs. The cost of treating obesity-related illnesses to the economy of United States business sector has escalated in recent years. In one study employees of United States businesses between 25 and 64 years old were classified as nonobese (BMI < 25 kg), mildly obese (BMI 25–29), or moderately to severely obese (BMI > 29). The cost of obesity to the medical insurers of these businesses in 1994 was $12.7 billion, including $2.6 billion as a result of mild and $10.1 billion due to more severe obesity. Health insurance expenditures for treating obesity-related illnesses such as hypertension, type 2 diabetes, and coronary artery disease amounted to 43% of the total amount. The rest was the result of increased sick leave, and life and disability insurance payments. Overall, obesity was responsible for 5% of all health-related expenditures in the United States in 1994 (57). Other countries have seen similar obesity-related increases in health care costs in adults. For example, total obesity-related health care costs for Canada in 1997 was $1.8 billion or 2.4% of total health care expenditures. The major contributors were hypertension ($656.6 million), type 2 diabetes ($423.2 million), and coronary artery disease ($346.0 million). This represents a considerable amount of available health care dollars for treating obesity-related comorbidities in Canada (58).

826

Alemzadeh et al.

Health care cost can be tracked according to increases or decreases in a standard measure of obesity, such as the BMI. For example, health care costs for 5689 adults more than 40 years old, who were enrolled in a Minnesota health plan, were evaluated. Data were adjusted for age, race, gender, and chronic disease status. Physical activity was associated with 4.7% lower health care charges per active day per week while BMI was associated with 1.9% higher charges per BMI unit. Never-smokers with a BMI of 25 and who participated in physical activity 3 days per week had mean annual health care charges that were approximately 49% lower than physically inactive smokers with a BMI of 27.5. These data suggest that adverse health risks translate into significantly higher health care costs (59). The recent advent of specialized programs for treating childhood obesity limits the amount of data available to track specific costs. This is due to many of these programs either being supported by outside funding or to their operating costs being incorporated into adult obesity program budgets. However, managed care organizations are now beginning to offer benefits for the treatment of childhood obesity through better access to established community childhood obesity programs (60).

III.

SOCIAL OBESITY

People want to be thin. They like to be slim and trim and they fear being even a little bit overweight. This fear is present among all individuals, even those who are not overweight, but who want to be thinner (61, 62). The likes and dislikes of the population have changed. In the past, excess body fat was a symbol of wealth, power, and status. Now people do not like this type of appearance. Even children, by the time they reach the first grade, prefer other disabilities to obesity (63). The desire to be thin constitutes a problem that must be considered as a form of social obesity. This phenomenon often translates as a fear of obesity (61). The fear of obesity may lead people to both healthpromoting and health-compromising eating behaviors. Health promoting activities include exercising; eating fruits, vegetables, and reduced-fat food; limiting the amount of food eaten; and avoiding sweets and junk food. Health-compromising activities involve the use of diet pills, laxatives, or water pills; self-induced vomiting; skipping meals; dieting and fasting (64).

Birch explored 5-year-old girls’ ideas, concepts, and beliefs about dieting. They found that 34–64% of the girls had ideas about dieting and weight loss and understood the link between eating and body shape. Girls’ knowledge about how people diet is inappropriate. These included descriptions of modified eating behaviors, such as drinking diet shakes and sodas, eating more fruits and vegetables, and use of special diet foods and restrictive eating behaviors. Mothers seem to be modeling both health-promoting and health-compromising eating behaviors to their daughters. Girls whose mothers reported current or recent food restriction were more than twice as likely to have ideas about dieting (65). Another factor found to influence girls’ ideas, concepts, and beliefs about dieting is family history of overweight. The media was also mentioned by 55% of the children as a source of dieting ideas (66). Children not only diet, they also worry about their body appearance. More and more children are concerned about and dissatisfied with their body image. Studies have shown that 55% of girls and 35% of boys in grades 3–6 want to be thinner (66). The Children’s Version of the Eating Attitudes Test showed a negative correlation with children’s BMI (66). It was found that 4.8% of them had scores suggestive of anorexia nervosa. Stice et al. found that eating disturbances that emerged during childhood led to inhibited and secretive eating, overeating, and vomiting. Maternal body dissatisfaction, internalization of the thin ideal, dieting, bulimic symptoms, and maternal and paternal body mass prospectively predicted the emergence of childhood eating disturbances. Infant feeding behavior and body mass during the first month of life also predicted the emergence of eating disturbances (67). Parents who worry about their children becoming overweight may set the stage for a vicious cycle. Johnson and Birch found those parents who control what and how much their children eat may impede energy self-regulation and put these children at higher risk for overweight (68). These findings suggest that the optimal environment for children’s development of self-control of energy intake is that in which parents provide healthy food choices but allow children to assume control of how much they consume (68). The Framingham Children’s Study showed that children whose parents had high degrees of dietary control had greater increases in body fatness than did children whose parents had the lowest levels of dietary restraint and disinhibition (69).

B. A.

Children

Currently, a large portion of the population, including children, is attempting to lose weight. While children should be learning to enjoy food, it appears that they are dieting without supervision. Dieting in childhood is becoming a common habit. Very young children are reporting frequent dieting. A recent national survey found that 31% of fifth grade girls have dieted (64). Abramovitz and

Adolescents

There is a high prevalence of extreme measures taken by high school students throughout the country to avoid obesity (70–72). They often diet and have inappropriate eating habits and purging behaviors. Young persons, even when they are not overweight, diet to avoid obesity at a time when they are still growing and developing (73, 74). This can adversely affect their growth, resulting in nutritional dwarfing (75).

Obesity in Children

Neumark recently published results from a national survey examining weight-related behaviors among 6728 American adolescents in grades 5–12 (64). Almost half of the female population (45%) and 20% of male adolescents reported dieting. Older adolescent girls were significantly more likely to diet than younger ones. Dieting was reported by 31% of fifth graders and increased consistently to 62% among the 12th graders. The largest increase was among adolescent girls between the eighth (40%) and ninth (53%) grades. Thirteen percent of the girls and 7% of the boys reported disordered eating behaviors (64). In another study, Neumark studied 3832 adults and 459 adolescents from four regions of the United States for weight-control behaviors. Based on gender, weight-control behaviors were found in 56.7% of adult women, 50.3% of adult men, 44.0% of adolescent girls, and 36.8% of adolescent boys (76). Moses et al. showed that high school adolescents in an affluent suburban location were dieting at a very high rate. Forty-one percent of the adolescents were dieting on the day of the survey. Sixty-seven percent of all the adolescents had made on their own important dietary efforts during the past 4–8 weeks. Dieting occurred in normalweight and underweight students. About 30% of dieters were among the underweight and those of normal weight for height. However, the proportion of the overweight students who were dieting was relatively low: 50–60% (62). A distorted perception of ideal body weight (below appropriate body weight for height) is very prevalent among high school students. Adolescents often know what their ideal weight should be, but some prefer to be 10% less than their ideal weight for their height (62). Healthcompromising behaviors and the fear of obesity may have detrimental consequences in children. Inappropriate nutrient intake may lead to nutritional dwarfing, failure to thrive, and various other nutritional problems, as described in another chapter of this book and elsewhere (76).

C.

Dieting/Body Image Problem

It is important to pay close attention to the new classification scheme related to behavioral and mental health concerns for children and adolescents published in 1996 by the American Academy of Pediatrics. The Diagnostic and Statistical Manual for Primary Care (DSM-PC) is now paying attention to dieting/body image behaviors that were, in the past, not considered to be eating disorders. Older children and younger adolescents may exhibit behaviors that do not meet full DSM-IV criteria, yet still deserve attention. The two specific complexes in the DSM-PC related to eating disorders are: dieting/body image behaviors and purging/binge-eating behaviors (77). There are two levels of pathology for both of these behavior patterns that are not healthy, but do not fulfill DSM-IV criteria for an eating disorder. In DSM-PC, var-

827

iations constitute minor deviations from normal that still might be of concern for a parent or clinician (77). An adolescent with a dieting/body image problem will be one who exhibits voluntary food limitation in a pursuit of thinness. He or she experiences a systematic fear of gaining weight that extends beyond a simple dieting/body image variation. However, the intensity of the problem does not meet criteria for anorexia. An obese adolescent who exhibits dieting/body image behaviors and or purging/binge-eating behaviors has a more complicated problem which adds to the difficulties in treatment and long-term health.

IV.

GROWTH ASSESSMENT

The measurement of body weight, the parameter commonly used to assess adiposity, is not an optimal method to differentiate between being overweight and being obese. Indeed, individuals with larger than average body frames or excess muscle mass (athletes) may be mistakenly considered obese since they have excess body weight. Since they do not have excess body fat, they are not obese but their relative weight for height may be above 120%, which is a commonly used criterion of obesity in children. Age-specific growth charts (73) allow a more precise assessment of a child’s nutritional status. These charts help the clinician to evaluate a child’s weight and its relationship to height. They also provide a view of the previous growth patterns and thus establish the presence of obesity more accurately. However, weight and height nomograms also fail to take into account the frame size and body composition of the patient. The importance of growth charts in the evaluation of childhood obesity is illustrated in the example shown in Figure 1. Julie is a 5year-old girl with a pattern of morbid obesity. Review of her growth records revealed that Julie’s rate of weight gain became excessive after 3 months of age and progressed at an accelerated pace after 1 year of age. This coincided with acceleration of linear growth. The final point on Julie’s growth chart (weight: 50 kg; height: 116.5 cm) represents 249% of her ideal body weight for height. In contrast, in Figure 2 the growth chart of Michael with a pattern of constitutional overweight is shown. In this patient, body weight progression was constant throughout, being two major percentiles above that of height with an excess weight for height of 38% throughout his life span. These two types of growth patterns provide clear evidence of two distinct clinical patterns necessitating different approaches. In Julie’s case, all efforts need to be made to stop the disproportionate body weight accretion; in Michael’s case, caution must be exercised not to interfere with the balance and adjustment already achieved by the patient in maintaining body weight. In a survey of high school children, Moses et al. showed that constitutional patterns of overweight are encountered in about 25% of

828

Alemzadeh et al.

Figure 1 Growth pattern of a patient with severe obesity before and after treatment was initiated. Note that the patient was gaining excess weight for height that started after 3 months of age. Her BMI was 36.8 at the time of his first visit.

Figure 2 Growth pattern of a patient with constitutional overweight. Note that the patient’s weight was in excess for height but remained proportional throughout his life. His BMI at 10 years old was 24.

the students with excess body weight for height, remaining proportional throughout their school years (62). The morbid obesity pattern of growth is rare, observed in 0.8% of students. Therefore, the clinical assessment of an obese child must include measurements of height and weight progression for the proper assessment and recommendations for treatment.

grade III, >40 BMI. The BMI system of classification of obesity is important because it has been found that the risk for medical complications of obese patients increases at BMI levels above 25 (79). According to the National Center for Health Statistics’ Health and Nutrition Examination Survey (80), individuals with a BMI above 27 have a markedly increased risk for hypertension, hypercholesterolemia, and diabetes mellitus. In contrast, when the BMI index is less than 25, there are no apparent physical effects of obesity on the individual, although there may be social problems and psychological concerns with body appearance. However, the use of BMI has limited applications in the assessment of overweight children since its calculation is based primarily on a stable height, which is not applicable to growing children. Also, the BMI can underestimate the percentage of lean body mass

A.

BMI

Body mass index (BMI) is a widely used method to define the relationship between weight and height (78). The BMI is calculated as weight (kg)/height(m2) and provides a practical clinical tool for classification of individuals with normal and those with various degrees of obesity (grades I–III): grade I, BMI 25–29; grade II, BMI 30–40; and

Obesity in Children

since it does not account for variations in musculature; this could lead to classification of normal children as being overweight. Charts of BMI relative to age are used in many countries to determine childhood obesity. They are easy to use, nonintrusive, and have been validated against measures of body fat. Many countries, including the United States, use the 85th percentile for BMI to define children who are overweight and then above the 95th percentile for obesity in children. Furthermore, no differences in the relationship between BMI and age exist among boys and girls up to age 20 from the United States, United Kingdom, Japan, and Singapore (81). The stage of maturity may cause additional errors when BMI is used to determine obesity in children and adolescents from different ethnic groups (82). In spite of these ethnic differences, BMI correlates (>0.8) with body fat as determined by both skinfold thickness measurements and by densitometry (83). This suggests that BMI is a reasonable criterion for determining obesity in children and adolescents. There are several potential errors associated with BMI as an indicator of obesity in children. The increasing height in children from birth until adulthood may cause a difference in the weight-for-height relationship assumed in current BMI-for-age charts. Gender and age also affect body weight and height. Furthermore, puberty may introduce another change in the weight-for-height relationship. Ethnic origin and social class may also affect both body weight and height. However, in adults, these relations are simpler because adult height is assumed to be fixed. Therefore, body weight is adjusted for height only. Usually this adjustment takes the form of body weight/height2. However, this is not always the best adjustment depending on the age of the child. One study found that the power used to adjust height (Benn index) changed from 2.0 to 3.5 over the first 20 years of life in order to maintain the best relationship with skinfold thickness. The strongest relationships with skin-fold thickness were obtained in children between 9 and 10 years old. Using only a Benn index of 2.0 may introduce subtle errors in BMI when used in younger children. Taller children will tend to have greater BMIs than shorter children. However, trying to define which Benn index to use at certain ages will lead to more errors than if just one standard Benn index is used, such as the current Benn index of 2.0 (84).

B.

Key Indicators

In the United States, percentiles are the most commonly used method for clinical monitoring of individual growth. In 2000 the National Center for Health Statistics (NCHS) growth charts were revised. The revised growth charts will include growth curves for BMI and utilize newer mathematical methods for curve smoothing. New data from the third cycle of the National Health and Nutrition Examination Survey (NHANES III) showed increased prev-

829

alence of overweight in children. Currently being debated is whether it is appropriate to exclude the heavier NHANES III children in the revised growth reference data. For height and weight, percentiles increase monotonically with age. This should be preserved in any curvesmoothing process while still maintaining some variability. Methodologies for smoothing curves include cubic splines, kernel regression, locally weighted regression, and running medians. Locally weighted regression is currently being applied to the NCHS chart revisions. Revised NCHS growth charts for BMI may eliminate subtle errors in some of the percentiles currently used to define childhood obesity.

C.

Skinfolds

Skinfold thickness from several separate sites, including both trunk and extremities, provide a reliable estimate of obesity and regional fat distribution. The correlation of multiple skinfold measurements with total body adiposity is in the range of 0.7–0.8. One problem with skinfold measurements is that the equations used must be changed for age, gender, and ethnic background. Body fat increases with age, even through the sum of the skinfolds remains constant. This means that the fat deposition with age occurs in large part at sites other than subcutaneous ones (85). Also, triceps skinfold (TSF), which is typically the site of measurement, is often difficult to grasp and measurement reliability can be poor. It has been observed that there is a strong correlation between BMI and TSF among age- and gender-matched groups, suggesting that these measures are interchangeable for use in classification of individuals and in the evaluation of secular trends of obesity and super obesity (86).

D.

Body Fat

Several methods are available for the estimation of body fat content. These include methods that measure body density derived from its specific gravity, that is, the weight of body in and out of the water. This process makes it possible to fractionate the body into its fat and lean components, assuming a density for fat of 0.91 g/cm2. The technique remains basically a research method; however, bioelectrical impedance analysis (BIA) has been commonly used as a noninvasive and inexpensive method for estimation of body fat and lean mass (87). Bioelectrical impedance relies on the association between conductivity and tissue fluid and electrolyte content. It has proved to be fairly reliable in assessing total body water, but is less reliable in the estimation of body fat, especially in obese children (88, 89). Other noninvasive methods, such as the use of ultrasound waves applied to the skin, can provide a measure of fat depth. In a group of children, Czinner et al. demonstrated a significant correlation (r = 0.969) between the body adiposity (skin fold thickness) measured with ultrasound

830

Alemzadeh et al.

and calipers (90). However the data derived from ultrasound method were 15 – 25% lower than fat obtained by calipers. The authors concluded that the ultrasound-derived body fat estimates represented only the subcutaneous body fat and not the whole body adiposity (i.e., visceral fat). On the other hand, other studies have shown that sonography is a reliable tool in measuring small variations in quantities of intra-abdominal (visceral) fat and is superior to waist to hip ratio (WHR) in evaluating regional fat distribution and visceral adiposity (91). Dual energy x-ray absorptiometry (DEXA) has been used as a reliable method for estimating fat-free mass and body fat. It has a unique ability to provide precise measures of regional fat mass, lean mass, and bone mineral content (92, 93). The DEXA technique can also be utilized for the evaluation of fat distribution and its role in insulin resistance syndrome and cardiovascular risk factors (94). Computerized axial tomography (CT) scan and magnetic resonance imaging (MRI) can also be used to quantitate lean and fat tissue. They provide accurate anatomical details and can reliably measure total and regional body adiposity. Numerous studies have shown the feasibility of using CT scans to measure human adiposity (95). In a recent study, Ross et al. (96) demonstrated that MRI can provide a reliable measure of subcutaneous and visceral adipose tissue in obese subjects. A principal benefit of measuring adipose tissue by MRI or CT is the development of mathematical equations from external anthropometry that can predict MRI adipose tissue.

E.

Total Body Electrical Conductivity

Validation for the use of total body electrical conductivity (TOBEC) for body composition measurements in infants has allowed accurate determinations of fat-free mass and fat mass without the assumptions associated with other methods. This method is appealing due to its ease of use, lack of radiation exposure, and the fact that little subject cooperation is required. The entire procedure takes only 5 min and does not require that infants or young children be sedated. This method involves passing an individual through a large solenoidal coil driven by a 2.5 MHz oscillating radiofrequency that generates a magnetic field. Upon passage through the instrument, all electrolytes, with fat-free mass containing the majority, contribute to disruption of the magnetic field. The instrument registers the magnitude of the magnetic field disruption and provides a value referred to as the TOBEC number. The TOBEC number depends on the conductivity, the length and cross-sectional area of the conductor, as well as electrical and coil parameters. The TOBEC number equals the instrument constants multiplied by the length and volume of the conductor. The square root of the TOBEC number (SQRT TOBEC # ⫻ length) has been found to be directly correlated with fat-free mass and fat mass in Hanford piglets (97).

F.

Air Displacement Plethysmography

Until recently, there was no easy-to-use and accurate method to determine body composition in adults. The recent availability of the BodPod Body Composition System has allowed accurate determinations of body composition without the associated problems with hydrostatic weighting (98). The principle of the method is similar to hydrostatic weighting except that body volume is now obtained by air displacement. Subjects sit for 2 min in a 450 l chamber and a moving diaphragm determines the difference in air pressure between where the subject is sitting in the front chamber and a rear reference chamber. The pressure difference, along with the subject’s body weight, are used to calculate body volume. From these results, body density is calculated and any of the standard equations for calculating fat-free mass and fat mass can be used. The procedure is entirely safe and requires no special cooperation on the part of the subject. In a validation study with 68 subjects, no differences were found in fatfree mass and percentage body fat when determined by both the BodPod Body Composition System and hydrostatic weighting (99). Furthermore, the BodPod Body Composition System can accommodate adults up to 160 kg (350 lb). In children the BodPod Body Composition System may underestimate body fat. In one study body density was determined in 54 boys and girls from 10 to 18 years of age by both the BodPod Body Composition System and hydrostatic weighing. Body fat values calculated from both of these densities were compared to those determined by DEXA. Body fat calculated from both the Bodpod and DEXA were correlated; however, body fat estimates from the Bodpod were 2.9% lower than those derived from DEXA. This may be due to the significantly higher body density obtained from the Bodpod Body Composition System. These results suggest that body fat percentages in children derived from the Bodpod Body Composition System may not be as accurate (100).

G.

Fat Distribution

In recent years, several studies have revealed major morphological and metabolic features that differentiate upper from lower body obesity (101–103). In adults, body fat distribution is more important than percentage body fat in predicting morbidity. Adults with a preponderance of abdominal fat (‘‘android’’) have a higher frequency of hypertension, hyperinsulinernia, diabetes, and hyperlipidernia than equally obese individuals with predominantly pelvic (‘‘gynecoid’’) fat distribution. The distribution of body fat is assessed using WHR. Increasing WHR in excess of 0.8 has been accompanied by abnormalities in glucose, insulin, and lipoprotein homeostasis (104, 105). Thus, the evaluation of body fat distribution is an essential element in the assessment of obesity. However, it has been observed that WHR cannot predict visceral adiposity in

Obesity in Children

obese individuals (90, 93). On the other hand, using CT scan, MRI, or visceral-to-subcutaneous fat tissue ratio (VSR) has been shown to be a better index of regional fat distribution than WHR (106, 107). Furthermore, VSR correlates more closely with metabolic variables such as levels of serum lipids, insulin, and glucose than WHR. A WHR greater than 0.8 has been associated with hyperinsulinernia, insulin resistance, and future development of noninsulin-dependent diabetes mellitus (NIDDM) in adults. In Julie’s case (Fig. 1), the WHR was 0.96 with significant upper body adiposity, whereas Michael’s WHR was 0.76 with modest subcutaneous adiposity. The presence of upper body obesity in markedly obese children may be associated with development of acanthosis nigricans (brownish discoloration of skin) along the skin creases of posterior cervical, axillary, and other flexural areas.

V.

WHO IS AT RISK?

A.

Infants and Children

It has been shown that parental fatness is related to future obesity in their children. When both parents are overweight, about 80% of their children will be obese. When one parent is obese, this incidence decreases to 40%; and when both parents are lean, obesity prevalence drops to approximately 14% (107). However, the reasons for these associations are not clear since most of the studies fail to separate the genetic and environmental influences in a critical way. The susceptibility to obesity may begin at birth as a consequence of metabolic variations in energy expenditure. Roberts et al. (108) demonstrated that excessive weight gain among a group of infants born to obese mothers was accompanied by reduced level of physical energy expenditure (108). This was probably the result of infants mimicking the activity patterns of their moderately inactive parents or siblings. Furthermore, Ravussin et al. observed decreased levels of energy expenditure in obese compared to nonobese families (109). These findings are similar to another study in which energy intake at 6 months predicted body fatness by 1 year of age (110). In contrast, several studies have found that energy intake in infants less than 3 months old is not a determinant of body fatness by 2–3 years of age (111, 112). Later studies have verified that parental fatness is related to the incidence of their children becoming obese. Previous metabolic studies in infants cited above (109–112), which tried to identify alterations in metabolic rate that may contribute to future obesity, were inconclusive. Recent improvements in indirect calorimetry technology have enabled more accurate measurements of infant energy expenditure. The new Enhanced Metabolic Testing Activity Chamber (EMTAC) has been validated for accurate measurements of the components of energy

831

expenditure, such as resting and sleeping metabolic rates, along with physical activity, in infants from birth to 6 months old (113). Furthermore, during metabolic measurements in the EMTAC, parents have unrestricted access to their infants in a comfortable environment that is as close to normal as possible. This eliminates potential errors in energy expenditure due to stress caused by forced separation between parents and infants for long periods of time. With this new technology future metabolic studies in infants will be able to determine if changes in just one or more of the components of energy expenditure contribute to future childhood obesity. Some of the physiological components of obesity found in adults may apply to infants from the time of birth. For example, a change in the utilization of nutrients as determined by the RQ (114), a lower than average body temperature (115), and sleeping body core temperature (116) may contribute to additional positive energy balance, thus leading to body weight gain in infants. A recent study using microneurographic recordings of sympathetic nervous system activity found that lower sympathetic nervous system activity occurs in obese adults (117). However, no current studies have addressed any of these potential causes of childhood obesity. Weight gain and adiposity in infancy and early childhood are also influenced by several environmental factors (118). For instance, birth weight, duration of feeding, male gender, and age at the introduction of solid foods seem to affect significantly the rate of weight gain during the first year of life. Maternal weight only becomes a significant determinant for adiposity during the second year of life. The latter probably reflects the maternal environmental influences that may contribute significantly to the development of obesity since they determine child’s energy intake and expenditure (119). Vigorous feeding of infants and children may set the ground for the development of obesity (120, 121). Overweight children have been observed to eat more rapidly and chew their food less than those of normal weight (121). The influence of many environmental factors on the rate of weight gain, with or without a genetic susceptibility, has been evaluated by some investigators (122). Body adiposity and growth of newborns are influenced significantly by maternal weight and rate of weight gain during the prenatal period (123). It has long been observed that infants of diabetic mothers have increased body adiposity at birth and at 1 year of age (124). It has also been shown that macrosomic infants of mothers with gestational diabetes mellitus (GDM) have evidence of increasing body size and adiposity with increasing age and that maternal GDM and maternal prepregnant adiposity are significant predictors of their unique growth patterns (125). In a subsequent study, differences of up to 500 calories per day in energy expended as a result of spontaneous physical activity (i.e., fidgeting) were observed

832

Alemzadeh et al.

among obese children compared to normal-weight children (126). Differences in basal metabolic rate (BMR) and physical activity were found in 3–5-year-old offspring of obese parents. Basal metabolic rate of children with at least one obese parent was 10% lower than that of children with lean parents (127). Children of lean parents had about twice the energy expenditure for physical activities of children with at least one obese parent, suggesting that children of obese parents are less physically active.

B.

Teens

Obesity in teenagers is fast becoming a national concern. The latest results from NHANES III (1988–1994) found a high prevalence of adolescent obesity. Of 2850 children ages 12–18 years, 16% were overweight (85th percentile < BMI < 95th percentile), and 10% were obese (BMI > 95th percentile). However, a South Carolina Health Maintenance Organization (HMO) determined BMI in 30,445 children during the years 1995–1997 to determine the prevalence of childhood obesity in their members’ population (128). The criteria for overweight and obesity were similar to those mentioned for NHANES III. In this subject sample 35 and 34% of the boys and girls, respectively, aged 12–17 years, were overweight. This means that 1:3 children in this HMO was above normal weight. Furthermore, 19% of the boys and 18% of the girls in this population were obese. The prevalence of obesity in this adolescent population was greater than that obtained from NHANES III (128). These surveys suggest that more programs specific for treating obesity in teenagers may be necessary.

VI.

GENETICS

It has long been known that obesity runs in families. Obese parents impose even a greater risk that their children will be overweight. There is a 75% chance that children aged 3–10 will be overweight if both parents were obese. This drops to a 25–50% chance with just one obese parent. These statistics suggest that behavior modification or treatment intervention at an early age may be important for preventing future adolescent and adulthood obesity (11).

A.

Twin Studies

The role of genetic factors in obesity was evaluated by Stunkard et al., who demonstrated no relationship between the body fat indices of adoptive parents and their adoptive children (129). They showed that BMI of biological parents was more closely correlated with the weight status of their offspring although they did not live together. The importance of the genetic component was also confirmed by a more recent study involving monozygotic twins (130). The BMIs of identical twins reared apart compared with those reared together were essentially the same. Also,

the use of skinfolds as genetic markers in twins has been reported (131). With the use of correlation coefficients to estimate the heritability of skinfold thickness, it has been shown that there was a significant environmental component among children less than 10 years, whereas heritability estimated in twins more than 10 years of age was very high. In a recent study involving Swedish adult twins, Heitmann et al. (132) recently suggested that although food choices seemed to play a role in the frequency of consumption of various foods, genetics also influenced the preference for several foods. However, there was no evidence that the consumption frequency of any of the foods was differentially associated with expression of genes responsible for weight gain.

B.

Leptin

A major advance in understanding the pathogenesis of obesity is the discovery of the hormone leptin. It is produced by adipose tissue and has been found to modify feeding behavior in rodents by suppressing food intake and stimulating energy expenditure (133, 134). Leptin exerts its actions centrally on appetite and thermogenic control centers located in the hypothalamus. It is believed that obesity in humans is due to a desensitization of leptin reception within the hypothalamus, resulting in hyperphagia (133–135). Obese individuals have marked elevation of their plasma levels of leptin directly proportional to body fat mass (136). Sustained elevated levels of plasma leptin are proposed to uncouple leptin actions on its receptors in the hypothalamus, thereby attenuating signal transduction pathways that exert the effects of the hormone on satiety and energy expenditure (133, 137). Furthermore, leptin acts directly on receptors in pancreatic beta-cells to suppress insulin secretion in rodents (138– 140). Thus, some have proposed the existence of an adipoinsular axis in which insulin stimulates adipogenesis and leptin production, and leptin inhibits insulin secretion through its effect on beta-cell ATP-sensitive potassium channels (141). Seufert et al. recently proposed that in obese individuals leptin reception by beta cells is desensitized, similar to what is proposed to occur at the level of the hypothalamus (142). This desensitization of suppression of insulin secretion of beta cells contributes to the hyperinsulinemia of obesity. Hyperinsulinemia, in turn, leads to increased adipogenesis and insulin resistance, culminating in some individuals in the development of diabetes. The recent discovery of the obese (Lep) gene (143) has provided new insights into the regulation of energy metabolism in the body (Fig. 3). The Lep gene is specifically expressed in adipocytes (143, 144) and encodes a 167 amino-acid-secreted protein called leptin. The physiological importance of quantitative changes in leptin concentration indicates that regulation of the Lep gene is a critical control point (145–147). Leptin receptors have been found in several hypothalamic nuclei, including the

Obesity in Children

Figure 3

833

Schematic of the current view of the roles of leptin in energy homeostatsis.

arcuate nucleus, ventromedial, lateral, dorsomedial, and paraventricular hypothalamic nuclei (148). These hypothalamic nuclei express one or more neuropeptides and neurotransmitters that regulate food intake and/or body weight. Genetic data indicate that neuropeptide Y (NPY) and one or more of its receptors act in response to absent (and possibly low) leptin, whereas melanocyte-stimulating hormone (MSH), its receptor, the melanocortin-4 receptor, and possibly the agouti-related transcript (ART) are re-

quired for the response to an increased plasma leptin concentration (149). Neuropeptide Y is the most potent orexigenic agent known when administered intrathecally. Neuropeptide Y mRNA is increased in ob/ob mice and decreases after leptin treatment (150). Leptin also increases corticotropin-releasing hormone (CRH) gene expression and synthesis (151), which, in turn, inhibits food intake and increases energy expenditure (152). Conversely, food intake has effects on both the plasma leptin

834

concentration and Lep gene expression. Fasting decreases and refeeding increases Lep gene expression (153, 154) and the plasma leptin concentration (155). It is believed that decreased leptin expression per adipocyte could lead to obesity with normal (but inappropriately low) plasma leptin concentrations. This hypothesis is supported by the observation that ob/ob mice carrying a poorly expressed leptin transgene are obese, despite having relatively normal leptin levels (147). Similarly, 5– 10% of obese human subjects have relatively low levels of leptin, indicative of a reduced rate of leptin production in this subgroup (156). Low leptin levels also predispose preobese Pima Indians to weight gain (157). In almost all cases, obese subjects express at least some leptin, indicating that human Lep gene mutations are likely to be rare. Except for a few reported cases of Lep mutations in massively obese subjects (158, 159), researchers have not been able to demonstrate Lep mutations in most obese subjects (160). Although the Lep gene has been linked to severe obesity in some family studies, mutations in the leptin-coding sequence were not identified (161, 162). The molecular basis for this association is unknown but could be related to differences in the amount of expression of leptin mRNA. Loci on human chromosome 2 may be linked to leptin levels and, to a lesser extent, to BMI (163). These loci are near the gene for human proopiomelanocortin (POMC), which is a precursor of MSH. It has been shown that abnormal melanocortin signaling in yellow agouti (Ay ) or melanocortin-4-knockout mice leads to obesity and leptin resistance (164). A subset of neurons expresses both Lep receptor and POMC, and leptin modulates POMC gene expression (165). Krude et al. (166) recently described two red-haired subjects with severe obesity and adrenal insufficiency. It has also been shown that agonists of beta MSH and MSH decrease food intake and pretreatment of animals with a beta-MSH antagonist blunts the anorectic effect of injected leptin (167). Therefore, association of mutations in leptin and its receptor with massive obesity confirms its importance in regulating human body weight (168). However, these syndromes are rare. Changes in Lep gene expression have been shown to be associated with parallel changes in plasma insulin concentration (169). Since insulin itself has a stimulatory effect on Lep gene expression and leptin secretion (170), it is likely that feeding-induced changes in leptin concentrations are dependent on insulin. Furthermore, insulinemia has been shown to regulate plasma leptin and to be a determinant of its plasma concentration in normal-weight and obese human subjects (171). In fact, plasma leptin level in obese children and adults correlates not only with the degree of insulinemia but also with percentage of body fat (171), suggesting that human obesity is generally associated with an insensitivity to leptin. However, investigators have recently reported that inadequate insulin-induced leptin production in obese insulin-resistant subjects may contribute to the development of obesity (172).

Alemzadeh et al.

Lahlou et al. recently suggested that increased circulating leptin concentrations during the dynamic phase of childhood obesity are indicative of leptin resistance (173). They observed that leptin did not act as an appetite regulator in the obese children without a significant impact on basal energy expenditure. These investigators also showed that obese girls had higher leptin levels than boys. A comparable gender-related difference was found in nonobese children. This sexual dimorphism of circulating leptin levels could reflect a physiological role in the regulation of reproduction in humans. In mice, while the ob/ob males are normally fertile, administration of leptin to infertile female ob/ob mice is needed to restore fertility (174). It is therefore possible that leptin plays a role in the female gonadostat as a signaling hormone reflecting the amount of fat stores at the hypothalamic–pituitary level or directly at the ovarian level (175). It is likely that quantitative and possible functional changes in adipose tissue of girls entering puberty may physiologically increase leptin to levels that allow the hypothalamic–pituitary–gonadal axis to complete sexual maturation and prepare for pregnancy. The sexual dimorphism for circulating leptin levels observed in lean girls and boys is consistent with these metabolic considerations. Thus, the lack of premature puberty despite hyperleptinemia in massively obese girls could be taken as an additional index of central leptin resistance. Finally, leptin increases energy expenditure by direct effects on CNS and the peripheral tissues. Leptin infusion into the CNS increases sympathetic activity to brown adipose tissue, kidney, and adrenal gland (176). However, it is not yet known whether blockage of beta-adrenergic receptors attenuates leptin-induced weight loss. Thus the role of the sympathetic nervous system in mediating the weight-reducing effect of leptin is not yet established. Leptin also prevents reduced energy expenditure normally associated with decreased food intake (145). Administration of leptin also decreases blood glucose and insulin concentrations in ob/ob mice (177). Leptin induces depletion of triglyceride in adipose tissue and pancreas by increasing intracellular fatty acid oxidation and gene expression of the enzymes involved in fatty acid oxidation (178, 179). Leptin also increases the expression of uncoupling protein-2 (UCP-2) in adipose tissue and pancreas (179). Uncoupling proteins disrupt the mitochondrial proton gradient in brown fat (and possibly other tissues), resulting in the generation of heat rather than ATP. However, it has been suggested that leptin treatment does not cause a net increase in 24 h energy expenditure but instead blunts the decreased energy expenditure that generally accompanies food restriction (145). It is thus uncertain whether leptin increases energy expenditure or activates uncoupling protein. In summary, a complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level. Leptin and its receptors are integral components of this system. Although the entire

Obesity in Children

pathogenesis of human obesity is unknown, it is assumed to be, in part, the result of differences in leptin secretion and/or leptin sensitivity and its interaction with underlying genetic and environmental factors.

C.

Ghrelin

Ghrelin is an acylated peptide hormone recently purified from rat stomach. The hormone consists of 28 amino acids in which the serine-3 residue is n-octanolylated. It is primarily synthesized in the stomach but its principal site of action is growth hormone secretagogue receptors located on hypothalamic neurons and in the brainstem. Only two amino acids are not conserved between rat and human ghrelin. The main function of ghrelin is the regulation of pituitary growth hormone secretion independent of growth-hormone-releasing hormone and somatostatin. It has been suggested that ghrelin is an endocrine link between the stomach, hypothalamus, and pituitary. This may be important for the regulation of energy balance (180– 182). There may be different effects between rodents and humans in regard to the action of ghrelin. For example, peripheral daily administration of ghrelin to both rats and mice caused body weight gain by reducing fat utilization. Furthermore, intracerebroventricular administration of ghrelin in increasing amounts generated a dose-dependent increase in food intake and body weight gain. Through the measurement of 24 h energy expenditure in a rodent calorimeter, ghrelin was found to exhibit its effect by increasing carbohydrate and reducing fat utilization without any changes in food intake. This was determined from the RQ derived from the ratio of carbon dioxide production and oxygen consumption. This change in nutrient utilization resulted in an increased amount of body fat without any corresponding changes in fat-free mass or bone mineral content. Furthermore, no changes occurred in energy expenditure or physical activity (182). It was theorized that the concentration of serum ghrelin will be increased in obese humans. Furthermore, predominantly obese ethnic groups, such as the Pima Indians of Southern Arizona, would have the greatest plasma concentrations of ghrelin. In one study, 15 lean and obese white subjects and 15 lean and obese Pima Indian adults had plasma ghrelin, insulin, and leptin determined. In contrast to the hypothesis, both obese groups had significantly lower plasma ghrelin concentrations than the respective lean groups. Furthermore, plasma insulin and leptin concentrations were increased. Moreover, plasma ghrelin concentrations were negatively correlated with body weight, percentage body fat, as well as plasma leptin and insulin. These data suggest that plasma ghrelin is downregulated in obesity. This may result from increased concentrations of both leptin and insulin. These investigators further suggest that reduced plasma ghrelin concentrations may represent adaptation to a positive energy balance associated with obesity (183).

835

D.

Adipose Tissue Endocrine Functions

Adipose tissue is comprised of lipid-filled cells surrounded by a matrix of collagen fibers, vessels, fibroblasts, and immune cells. Its main function is the storage of triglycerides for times of energy deprivation. However, adipose tissue may be involved in other aspects of metabolism that may affect the onset of obesity. Adipose tissue metabolizes sex steroids and glucocorticoids. For example, 17 beta-hydroxysteroid oxidoreductase converts androstenedione to testosterone and estrone to estradiol. This may be important for fat distribution. Estrogens stimulate fat accumulation in the breast and subcutaneous tissue, while androgens promote central obesity. Alteration of these interconversions may predispose individuals to reproductive disorders and certain cancers (184, 185). Adipose tissue also produces and secretes certain inflammatory cytokines, for example tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). It has been suggested that both of these cytokines prevent obesity through inhibition of lipogenesis, increased lipolysis, and promotion of adipocyte death via apotosis. However, TNF-alpha has been found to be a mediator of insulin resistance in obesity (186, 187). C-reactive protein, stimulated by elevated IL-6, has been found to be correlated with obesity, insulin resistance, elevated THF-alpha, and endothelial dysfunction (188). Alteration of coagulation and complement factors may contribute to the obesity associated cardiovascular disease. Fibrinogen and plasma activator inhibitor type-1 (PAI-1) are altered in obesity and may be involved in cardiovascular disease. For example, high levels of PAI1 have been detected after myocardial infarction. Much of the PAI-1 is synthesized by adipose tissue and is increased in proportion to visceral adiposity. This may serve as a link between abdominal/central obesity and cardiovascular disease (189).

E.

Adiponectin

Plasma concentrations of adiponectin, a novel adiposespecific protein with putative antiathrogenic and anti-inflammatory effects, were recently found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular diseases conditions commonly associated with insulin resistance and hyperinsulinemia (190). It has also been shown that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than the degree of adiposity and glucose intolerance.

F.

Mutations

In monogenetic or dysmorphic forms of obesity, transmitted by both recessive and dominant modes of inheritance, there are also alterations in energy balance that result in obesity. Patients with Prader-Willi syndrome are

836

Alemzadeh et al.

characterized by hyperphagia, hypotonia, developmental delay, hypogonadism, and short stature (191). In these children, obesity may start during the first year of life and becomes prominent by the second year, which in the presence of hyperphagia can result in morbid obesity. It was previously suggested that a low metabolic rate caused the obesity in these children (192). However, it has been demonstrated that a lower energy requirement of these children is due to less fat-free mass and not to an unusually low metabolic rate (193). Translocation or deletion of chromosome 15 has been reported in about 50% of these patients (194). In contrast, Lawrence-Moon-Biedl syndrome is another dysmorphic form of obesity characterized by retinitis pigmentosa, hypogonadism, mental retardation, and polydactyly. It is inherited by an autosomal recessive gene (195). It is believed that excessive weight gain in these children is caused by disturbance of hypothalamic appetite center(s), which leads to increased food intake. Pseudohypoparathyroidism is also associated with obesity and short stature and is characterized by short fourth metacarpal, short thick neck, rounded facies, mental retardation, and hypocalcemia (196). It is commonly inherited as a sex-linked dominant trait and may be accompanied by hypothyroidism and gonadal failure. Other genetic syndromes that include obesity are Alstrom’s, Carpenters, and Cohen’s. The mechanisms of excess weight in these patients have not been elucidated as yet.

VII.

hepatic synthesis of cholesterol and tissue lipogenesis (205, 206). Increasing meal frequency, or nibbling has been shown to significantly lower serum cholesterol and insulin levels (207). This is thought to have a beneficial effect in decreasing triglyceride synthesis in adipose tissue through a reduction in postprandial glucose and insulin levels. However, this effect may be significantly minimized by a parallel reduction in the postprandial thermogenesis stimulated by insulin and glucose (208). The main determinant of BMR is fat-free mass (FFM) and the main determinant of energy expenditure is physical activity. It is believed that minor alterations in any of these could result in positive energy balance and lead to obesity over prolonged periods of time. For example, obligatory energy expenditure, reflected by a decreased resting metabolic rate, could be the consequence of an increased metabolic efficiency in obese persons. On the other hand, a reduced level of activity could also lead to an increased energy balance and weight gain. The resting energy expenditure and the baseline activity levels are thought to be genetically determined. In fact, studies among obese Pima Indians have demonstrated low BMR values and, therefore, enhanced metabolic efficiency of energy consumption among some families with obesity (209, 210). However, other studies demonstrated that BMR values, corrected for FFM, among obese subjects were relatively higher than those in nonobese subjects (211), suggesting that attainment of energy balance and weight maintenance in obese individuals requires a larger energy intake than in nonobese individuals.

ENERGY BALANCE

Obesity is a heterogenous group of disorders that can result from an energy imbalance over an extended period of time in which energy intake exceeds expenditure. It is superficially apparent that obese subjects ingest more food relative to their needs. However, caloric intakes have been reported to be comparable among overweight and normal weight adults (197), suggesting that obese subjects have ‘‘increased metabolic efficiency.’’ It has been shown that low total and resting energy expenditure are risk factors for long-term weight gain in infants (198) and adults (199), respectively. However, Dwyer et al. (200) showed that obese children might not eat more than their normal-weight peers and they may expend relatively fewer calories to maintain their body weight. This phenomenon has been referred as adaptation and results after frequent dieting efforts have taken place. This results in lower energy requirements due to loss of lean body mass (201). Repeated weight reduction attempts result in alterations in body composition and decreased fat-free mass. This leads to decreased metabolic demands and thus fewer calories needed to maintain weight (202). Reduced meal frequency, or gorging (i.e., one to two meals daily), has been associated with an increased risk of obesity (203, 204). This is also associated with high fasting serum lipid and insulin levels. Insulin stimulates

VIII.

PHYSICAL ACTIVITY

It is not clear whether inactivity is a cause or consequence of obesity. However, it is believed that a sedentary lifestyle increases the risk for obesity. Furthermore, low cardiorespiratory fitness is an independent predictor of cardiovascular heart disease in obese adult men. This is comparable to diabetes mellitus, high blood pressure, and smoking (212). Physical activity in children has declined over recent decades implying an increasingly sedentary lifestyle in Western industrialized countries. Reports have indicated that physical activity declines almost 50% during adolescence, with girls becoming increasingly more sedentary than boys (213). A recent observation is that this pattern is due to a gender dimorphism in the developmental changes in energy expenditure before adolescence, independent of body composition, with a conservation of energy use in girls achieved through an appreciable reduction in physical activity (214). Social and environmental influences are also believed to have major roles in the gender and developmental variation in physical activity (215). The role of physical energy expenditure in the development of obesity is not very clear. Obese individuals have often been described as sluggish or lazy. A study of

Obesity in Children

children and adolescents by Bullen et al. (216) indicated that obese youngsters were less active than their peers. However, an earlier study, which measured caloric expenditure by measuring oxygen consumption, found that obese individuals actually expended more calories through activity than did normal-weight individuals (217). Maffeis et al. (218) recently demonstrated that walking and running are energetically more expensive for obese children than for nonobese children. The estimates of energy requirements for children were derived in a time when more physical exertion was needed for daily living; therefore, energy requirements for children may be overestimated for today’s sedentary lifestyle. Prentice et al. (219) measured energy expenditure in children aged 0–3 years by the doubly labeled water method and found that energy needs were overestimated by 15% as originally recommended by the World Health Organization (WHO) (220). Goran et al. (221) likewise showed that energy requirements were 25% overestimated for 4–6-year-old children. Fontvieille et al. (222) found that energy requirements for 5–6-year-old children were overestimated by 24% in comparison to that calculated according to the WHO. The sedentary lifestyles of today’s children may easily account for consistent overestimates of childhood energy requirements. Indeed, children living a sedentary lifestyle with unlimited access to food are prone to consuming more energy than they expend, and therefore are at increased risk of obesity. Child obesity experts have suggested that the relationship between television and obesity may be the consequence of enhanced food consumption during viewing. This may be due to the influence of food advertisements (223, 224). Experimental studies have demonstrated that a causal relationship exists between specific televised messages and children’s eating behavior (225) and between television viewing and participation in sports (226). Earlier studies among children and adolescents found an association between hours of television viewing and the development of obesity (227). Indeed, this association was further supported by a recent observation that the levels of physical activity and hours of television viewing tend to have a strong relationship with body weight and degree of obesity among children (228). It is also possible that the way a child watches television and the content of the television programs may be more important than the number of viewing hours. However, it has been recently shown that television viewing has a fairly profound lowering effect on metabolic rate in both lean and obese individuals. This may be an important factor in susceptible children who are at risk for weight gain and potentially lead to obesity (224).

IX.

HYPERINSULINISM

Syndrome X is a clinical quartet of hyperinsulinemia, hyperlipidemia, hypertension, and subsequent cardiovascular

837

disease (30). It is believed that obesity is a component of this metabolic syndrome and has been described in obese children (31) and adolescents (32). In a more recent study Chen et al. suggested that syndrome X is characterized by the linking of a metabolic entity (hyperinsulinemia/insulin resistance, hyperlipidemia, and obesity) to a hemodynamic factor (hypertension) through a shared correlation with hyperinsulinemia/insulin resistance. Clustering features of syndrome X are independent of gender and age in both black and white populations (33). Hyperinsulinism and insulin resistance are characteristic features of obesity (229). It has been demonstrated that insulin secretion increases as the severity of obesity increases (210), and this increase in insulin secretion is accompanied by varying degrees of resistance to insulinmediated glucose uptake (230). Indeed, the observed abnormalities in glucose tolerance in some obese adolescents are consistent with the presence of hyperinsulinernia and insulin resistance. Occasionally, young patients with a strong positive family history of type 2 diabetes develop the disease. Also, insulin resistance may result in the development of acanthosis nigricans, a hyperpigmentation of skin, which is commonly seen in the back of the neck, axillae, and other flexural areas (71). Hyperinsulinernia is usually accompanied by hyperandrogenism, which leads to hirsutism. The presence of hyperinsulinemia favors the maintenance of the obese state by stimulating lipogenesis via activation of lipoprotein lipase and by inhibiting lipolysis. The hyperinsulinernia and insulin resistance are believed to cause preferential shunting of substrates to adipose tissue, with conversion of periadipocytes to adipocytes; this is associated with hyperplasia and hypertrophy of fat cells, inducing an unabated lipogenic state and obesity (231). It has also been shown that the lipogenic action of insulin occurs at a lower insulin concentration than its glycoregulatory action (232). Additionally, Le Stunff et al. (233) demonstrated that hyperinsulinernic obese children oxidized more fat and less glucose than their lean counterparts. This impairment of glucose metabolism may, in part, by caused by an excessive utilization of fatty substrate (234). This finding supports the concept of decreased glucose utilization and its shunting to fatty acid and triglycerides synthesis. The hyperinsulinernia of obesity is apparently due to a combination of increased pancreatic secretion and a reduction of in heptatic extraction (235). The extent of the changes in insulin level is correlated with increasing fat cell size and degree of obesity and is more prominent in individuals with central obesity (235, 236). The mechanisms for the enhanced insulin secretion are not well understood, but one explanation is that it is an adaptive response to the diminished insulin-binding sites (237). However, dysregulation of beta-cell function has been described in obese children in the absence of insulin resistance (233). Odeleye et al. (238) found high fasting in-

838

sulin levels in lean prepubertal Pima Indian children are predicative of the development of adolescent obesity (238). The observed metabolic alterations in the insulin-resistant state are predominant with regard to glucose metabolism, especially with respect to cellular glucose uptake and hepatic glucose production, whereas effects on amino acid metabolism and fat metabolism are less significant. These metabolic changes lead to blood glucose elevation (239) and enhanced fatty acid storage in adipose tissue. Kida et al. (240) demonstrated diminished insulin receptor binding in monocytes of obese children that inversely correlated with their degree of obesity. Both receptor and postreceptor binding defects appear to play a role in insulin resistance of obesity. However, it is not clear whether hyperinsulinemia-induced downregulation of insulin receptors and/or decreased receptor-induced hyperinsulinernia are the mechanisms for the observed alterations. These abnormalities correct towards normal range with weight loss. Other investigators have evaluated the rate of body fat distribution and altered fatty acid metabolism in insulin resistance and hyperinsulinemia of obesity. For instance, obese subjects with an abdominal fat distribution have reduced hepatic insulin binding (241, 242). A possible cellular mechanism may be the result of high physiological free fatty acid (FFA) concentrations. It has been suggested that the inhibitory effect of FFA is energy dependent and does not change the total cellular number of insulin receptors or their binding characteristics, indicating that the receptor internalization or recycling is influenced (243). Svedberg et al. (244) demonstrated that obesity with high ambient FFA levels influences internalization/recycling of hepatic insulin receptors, leading to reduced cell surface binding (244). An increased supply of FFAs to muscle has been suggested to restrain glucose transport and disposal through the inhibitory action of the products of FFA oxidation (citrate, acetyl-CoA, adenosine 5-triphospate, etc.). This is due to the FFA oxidation products’ influence on key enzymes of glucose metabolism (pyruvate dehydrogenase, phosphofructokinase, and hexokinase) (234). The observed substrate competition is suggested to impede insulin action on glucose metabolism through derangement in lipid metabolism (245, 246). In children, progressive augmentation of fat stores and lipid oxidation during the first years of obesity could therefore induce a progressive reduction in glucose oxidation and decreased insulin action (233). This suggests that the increase in lipid oxidation precedes the changes in glucose oxidation and insulin levels associated with long-duration obesity. Finally, elevated circulating levels of insulin due to insulin-producing tumor (insulinoma) or to excessive administration of insulin to an insulin-dependent diabetic patient can lead to obesity. These patients develop obesity, short stature, and hepatomegaly (Mauriac syndrome) (247).

Alemzadeh et al.

X.

HORMONAL ALTERATIONS

A.

Adrenals

Adrenal glucocorticoid production is enhanced in obese children (248). Obese children tend to maintain normal serum cortisol levels due to its increased urinary clearance and in direct proportion to an increase in lean body mass. Increased clearance of cortisol has a stimulatory effect on pituitary adrenocorticotrophic hormone (ACTH) release. Adrenocorticotrophic hormone stimulates increased production of adrenal sex steroids such as dehydroepiandrosterone and testosterone. Increased production of adrenal sex steroids leads to early adrenarche (pubarche) in obese children (248). The release of cortisol is maintained under a normal circadian rhythm. Furthermore, it is believed that elevated plasma cortisol in some obese individuals is related to the hyperinsulinernia of obesity and contributes to the characteristic body fat distribution and altered body composition (249). In obese children, serum levels of epinephrine and norepinephrine remain normal. Adrenal hypercorticolism has long been recognized in the differential diagnosis of pediatric obesity. Although some patients have a fat distribution suggestive of Cushing syndrome, the use of corticosteroid therapy for a variety of inflammatory and allergic conditions is also associated with the development of obesity. In this type of obesity the problem is transient and resolves once use of the drug is stopped. Cushing syndrome is a rare cause of obesity and these patients can be differentiated from those with exogenous obesity by the cessation of growth that accompanies excess cortisol.

B.

Growth

Obese children are commonly tall for their age. This is associated with advanced skeletal maturity and early onset of puberty as well as premature pubarche (248). The lean body mass is often increased in these children (250). Reduced serum concentrations of growth hormone (GH) are characteristically seen in obese individuals and have been attributed to diminished GH secretion as well as accelerated GH clearance (251). The concentrations of insulinlike growth factor (IGF)-1 tend to vary because, unlike insulin, it circulates bound to specific proteins such as IGF-binding proteins (IGFBPs) with variable affinities (252–254). Six IGFBPs have been structurally identified, but only IGFBP-1, -2, and -3 have been well characterized in humans (251). In contrast to the lack of diurnal variation of IGFBP-2 and IGFBP-3, circulating levels of IGFBP-1 vary widely throughout the day in an inverse relationship with changes in plasma insulin (255, 256). Acute and chronic elevations in plasma insulin lower IGFBP-1 by suppressing its production by the liver, which, in turn, increases the bioavailability of free IGF-1 (257, 258). The blunted growth hormone response in

Obesity in Children

obese subjects could be secondary to negative feedback inhibition by IGF-1 (259). However, other investigators have suggested that IGF-1 levels are maintained or even enhanced by the hyperinsulinemia of obesity (260). The metabolic syndrome induced by increased adiposity appears to have profound effects on the complex interplay among GH, IGF-1, and IGFBPs during puberty. However, the effect is an increase in the ratio of free to total IGF1 in obese subjects, which may help to explain the lack of alteration of the pubertal growth spurt in obese adolescents even in the presence of lower GH levels. On the other hand, GH deficiency or pituitary dwarfism is reported to result in a mild degree of obesity compared to other causes of weight gain. It is believed that weight gain in a growth-deficient child is caused by diminished energy expenditure. Indeed, it has been observed that GH stimulates the growth of muscle tissue and breakdown of fat tissue, therefore affecting body composition (261). There is a potential for reduced growth performance during obesity treatment. This may be due to the inherent reduction in nutrient intake associated with various obesity treatment programs. For example, a reduction in height velocity was found in children undergoing an energy-restrictive 6 month obesity treatment protocol. However, children undergoing a 12 month, less energy restrictive obesity treatment showed no reductions in height velocity. Furthermore, both groups had similar heights from baseline until 12 months, suggesting that the children undergoing the more restrictive 6 month protocol showed catch-up growth following treatment (262). The situation was not similar in regard to increases in fat-free mass. The more restrictive group had smaller increases in fat-free mass after 12 months than the 12 month treatment groups (263). A recent review of 10 year follow-up data in children found no significant changes in final height in regard to the amount of energy restriction during obesity treatment. Furthermore, multiple regression analysis found that childhood percentage of overweight did not contribute to predicting height change. However, a reduction in the percentile for height did occur in children from baseline to 10 years after treatment. The mean height of the children was over the 70th percentile for height prior to, and it decreased to just over the 50th percentile 10 years after, obesity treatment. These studies suggest that children participating in comprehensive obesity treatment programs, which include energy restriction, may attain an appropriate adult height and this will be similar to their parents (263). Children who diet without appropriate supervision do have growth failure (61).

C.

Prolactin

Basal prolactin levels are normal or slightly elevated in obese children. However, the prolactin response to provocative stimuli is often diminished (264). Donders et al. suggested that decreased serotonin in the brain was a potential mechanism for the blunted prolactin response. Oth-

839

ers have hypothesized that this may be due to a hypothalamic defect that contributes to the abnormal prolactin response and aberrant appetite regulation, especially when prolactin response does not return to normal with weight loss in the same obese patients.

D.

Thyroid

No evidence links thyroid dysfunction to exogenous obesity. Serum levels of thyroxine, free thyroxine, and thyroid-stimulating hormone (TSH) are normal in obese individuals. Hypothyroidism is not a common cause of obesity. Excessive weight gain, secondary to an underactive thyroid gland, is due to a combination of decreased metabolic rate and enhanced fluid retention (265). In children, hypothyroidism is associated with poor linear growth. Therefore, a normally growing but overweight child is not likely to be hypothyroid.

E.

Reproductive Hormones

Puberty may begin early in tall overweight children with advanced skeletal age. Kaplowitz et al. recently demonstrated that obesity is an important contributing factor to the earlier onset of puberty in girls (266). Pubertal elevations of follicular-stimulating hormone (FSH) have been observed in the 7–9-year-old girls, without any changes in luteinizing hormone (LH) levels (266). This is usually complicated by an adiposity-related decrease in circulating concentrations of sex hormone-binding globulin (SHBG). This results in a higher fraction of free or unbound serum sex steroids that are more bioactive than the ones in lean subjects (266). In general, the SHBG abnormalities correlate with the degree of obesity, which are reversed with weight loss (266). Low serum estradiol levels and elevated progesterone levels have been observed in young prepubertal and early pubertal obese girls compared to age-matched lean girls (266). The emergence of hyperandrogenism in pubertal girls may be associated with rapid weight gain, signs of hirsutism or virilism, and irregular menstrual periods (47). This is usually accompanied by hyperinsulinernia and insulin resistance with or without glucose intolerance. There is strong evidence that insulin exerts a regulatory effect on ovarian androgen synthesis (48). In fact, a positive correlation between the degrees of hyperinsulinemia and hyperandrogenism can be found in obese women (49). Since insulin is believed to effect its regulatory action through LH on ovarian function, some obese patients may also present with polycystic ovaries and abnormally elevated serum LH, low follicle-stimulating hormone (FSH), and high free testosterone levels. Obese adolescent boys appear to have an attenuated testicular response to human chorionic gonadotropin (HCG). This is probably an artifact of decreased/ro SHBG. Indeed, Glass et al. (235) demonstrated that despite a decrease in SHBG levels and increased percentage

840

Alemzadeh et al.

free testosterone, the free testosterone levels were normal. Serum dihydrotestosterone levels remain normal in obese subjects. Aromatization of androgens to estrogens by adipose tissue, in males, appears to be enhanced without any evidence of clinical feminization (235). However, free and total testosterone levels may be diminished in morbidly obese males. This is commonly associated with decreased gonadotropin levels, suggesting some degree of hypogonadotropic hypogonadism (158). These alterations in pituitary and gonadal hormones return to normal range with weight loss (159). Precocious puberty may lead to obesity. Children with precocious puberty prior to treatment show no differences in regard to lean or fat mass. However, during treatment with gonadotropin-releasing hormone (GnRH) over for several years, these children end up with a reduction of lean mass and increased fat mass. This may be due to a shortening of the prepubertal growing period and by the so-called menopausal effect of the treatment. After treatment these children end up with a greater amount of fat mass, which may lead to obesity (267, 268). In another study both boys and girls with precocious puberty had BMI scores above the 85th percentile prior to and during treatment with GnRH. After treatment the scores still remained above the 85th percentile, indicating obesity. These results suggest that children with precocious puberty are prone to obesity. Furthermore, treatment of precocious puberty with GnRH does not itself contribute to obesity.

XI.

HYPOTHALAMUS

Lesions of the ventromedial area of the hypothalamus (VMH) may result form inflammatory processes such as encephalitis, arachnoiditis, tuberculosis, or trauma, or malignancy (Fro¨hlich syndrome) (269, 270). Children with hypothalamic obesity may present with a history of foraging and stealing foods. They have a voracious appetite and may display frequent tantrums if food is denied. In children, craniopharyngioma is the most common CNS tumor that leads to hypothalamic and pituitary dysfunction (271). Hypothalamic obesity is often coupled with other hypothalamic–pituitary disturbances, which may exacerbate the obesity (e.g., growth hormone deficiency or hypothyroidism), but the obesity resists treatment with hormonal replacement (272, 273). It is believed that hypothalamic injury leads to alterations in the appetite center, which can cause hyperphagia and obesity (274). However, there is increasing evidence that the hyperinsulinemia seen in this disorder plays a role in the development of obesity. An animal model of VMH damage results in hyperphagia, obesity, hyperinsulinemia, and insulin resistance (275, 276). It is believed that VMH damage causes a disinhibition of vagal tone (277) at the pancreatic beta cell, which leads to insulin hypersecretion and resultant obesity (278). Lustig et al. (279) recently dem-

onstrated that children with hypothalamic obesity have excessive insulin secretion during a standard oral glucose tolerance test (279). They also observed that treatment of these children with octreotide, a long-acting somatostatin receptor agonist (280), attenuated hyperinsulinemia in these children and promoted weight loss. These investigators concluded that normalization of insulin secretion may be an effective therapeutic strategy in children with this syndrome. Alterations in dopamine systems and/or abnormalities of monamines can cause various types of hyperphagia (281). On the other hand, serotonin is believed to act as a satiety factor and an inhibitor of feeding reward in the hypothalamus (282). The role of other humoral signals in regulation of appetite and body adiposity has been extensively studied (283, 284). For instance, it has been thought that a number of gut hormones (i.e., cholecystokinin) feed back to appetite-controlling areas of the CNS in the regulation of meal size and frequency (284, 285). A study by Stromayer et al. (285) demonstrated that administration of a cholecystokinin (CCK) antagonist L364,718 resulted in increased daily food intake in lean but not obese Zucker rats. This is consistent with other observations that CCK decreases appetite, and that satiety deficit in obese rats contributes to overeating in these animals. The composition of food has been proposed to affect brain neurotransmitter metabolism in some individuals. For instance, individuals referred to as ‘‘carbohydrate cravers’’ have been described to binge on high-carbohydrate foods during the early evening and night (286). However, most individuals seem to prefer high-fat lowsugar foods because of their high palatability. Unfortunately, high-fat meals result in less intense satiety than high-carbohydrate meals of equal caloric value (287). Finally, mild obesity may occur in adolescent patients with Klinefelter (288) and Turner syndromes (289) with primary hypogondism. It is believed that hypogonadism results in excessive deposition of fat due to the deficiency of anabolic hormones, which are responsible for the growth of muscle. In Klinefelter syndrome, this effect is enhanced by the unopposed influence of estrogen, leading to further fat accumulation in the hips and buttocks to produce the characteristic eunuchoid appearance.

XII.

TREATMENT MODALITIES

The main goal of therapy should be to achieve the objective of lifelong weight control. Therefore, it is important to know the child’s pattern of growth and weight gain. In general, any therapeutic approach for childhood obesity should be designed to induce decreased energy intake and increase energy expenditure while maintaining normal growth. Intervention to induce weight loss must consider all of the factors believed to cause obesity and the treatment modalities that have been effective. Since most of our present experience in the treatment of obesity centers

Obesity in Children

on environmental and behavioral factors, these represent the primary areas of intervention. Genetic factors also play a very significant role in obesity and can help to identify the child at risk. This allows for early intervention in a child predisposed to obesity and is indicated before obesity reaches extreme proportions. Furthermore, any form of treatment for obesity should take into account potential underlying medical conditions (i.e., hypotonia) that may frustrate or render it ineffective. Therefore, the therapeutic plan should be individualized to reach its desired goal. There are some indications that successful treatment of pediatric obesity is possible. It has been reported by two studies that one-third of the children initially treated maintained their reduced weight after 5 and 10 years. Furthermore, preadolescent children showed better responses to initial treatment and maintenance of long-term weight loss (290). These studies are encouraging, but more research needs to be conducted to determine compliance with treatment and maintenance of weight loss into adulthood (290). A number of treatment modalities for childhood obesity exist. However, prior to initiation of any form of therapy, a comprehensive medical evaluation is indicated. This should comprise information on the rate of growth, developmental milestones, and family history. The latter is essential to identify those with parental obesity, hypertension, diabetes mellitus, hyperlipidemia, and thyroid dysfunction. Furthermore, the assessment should include nutritional, psychological, and physical fitness evaluations as well. Obese children are not overnourished in all aspects. Indeed, the reverse may be true as excess calorie intake increases other nutrient requirements that are not necessarily provided by the diet. For example, obesity is often associated with mineral and vitamin deficits (343). It has been reported that a subgroup of obese adolescents and adults (5–43%) engages in binge eating (291). Those who do are described as rigid dieters and under tremendous psychological stress. These individuals have a higher drop out rate from weight reduction programs than those who do not binge.

XIII. A.

DIETS Dietary Intake

The role of dietary intake in obesity remains controversial, although new data have shed more light on this problem. Obese patients often claim that they do not ingest excess food (292). These patients often seek medical evaluation for failure to lose weight despite a history of severe caloric restriction. There are no differences in resting energy expenditure nor in metabolic rates between diet-sensitive and diet-resistant obese individuals. However, differences in lean body mass account for the variations in weight reduction induced by dietary intake restrictions in obese individuals. They are frequently thought to be hyporme-

841

tabolic and are often treated with thyroid or other hormones to facilitate weight loss. This is neither safe nor necessary; moreover, the observed minus the total predicted energy expenditure vary in relation of weight progression (293). Patients who gain weight increase their metabolic rate whereas those who are on diets and are losing weight may reduce their energy expenditure by 10–20%. Thus the results of dietary efforts can only be successful if the reduced intakes are accompanied by increased energy expenditures to overcome the metabolic adaptations that occur with dieting. Obese individuals may reduce nutrient intake without weight loss. The possible explanations for this failure include an energy intake significantly higher than reported and a low total energy expenditure. A number of studies have demonstrated that obese individuals tend to underreport food intake compared to normal-weight subjects (294–296). Indeed, careful metabolic balance studies in some obese adults have shown a failure to lose weight despite self-reported low caloric intakes. This may be due to substantial misreporting of food intake and physical activity and not to an abnormality in thermogenesis (296). However, the problem is often confounded in the clinical setting by the difficulties in assessing food intake and food efficiency. A high susceptibility to obesity may also be the result of unlimited availability of palatable and high-calorie-density foods. Laboratory adult rats fed a ‘‘supermarket diet’’ consisting of high-carbohydrate/high-fat foods (i.e., chocolate chip cookies, marshmallows, peanut butter etc.), gained 2.5 times more weight than normal controls (297). In some animals, the weight gain was not reversed after the rat was switched back to chow. It is believed that supermarket diets increase the number and size of fat cells. Dietary composition and different rates of nutrient utilization of ingested diets can influence body weight maintenance. Using indirect calorimetric technique in nonobese males, Flatt et al. (298) demonstrated that under sedentary conditions, ingested carbohydrates are quickly metabolized while the rate of fat oxidation remains unchanged. Moreover, it has been suggested that the body tightly regulates carbohydrate balance for up to 36 h after ingestion and is not affected by alteration in the body’s fat balance (299). On the other hand, fat balance is believed to be regulated over a varying long term and it may take several days before the fat balance adjusts to new levels of fat ingestion. Thus, it is believed that excessive fat consumption over a long period of time will result in a positive fat balance and weight gain (300, 301). Therefore, a number of medical organizations including the American Heart Association (302) and the American Diabetes Association (303) currently recommend consumption of low-fat diets in the prevention and treatment of obesity. However, the relationship between the dietary fat and obesity has recently been questioned (304–306) since

842

both cross-sectional and longitudinal analyses have failed to show a consistent association between dietary fat and body fat (307, 308). Furthermore, recent studies indicate that weight loss on low-fat diets is usually modest and transient (304, 309). It is also noteworthy that the rate of obesity has continued to rise in the United States despite reported reduction in mean fat intake over the past 30 years, from 42% to about 34% of dietary calories (306, 307, 310, 311). Glycemic index (GI) is another dietary factor that may influence body weight. Glycemic index is a property of carbohydrate-containing food that describes the rise of blood glucose after a meal (312). The GI of a meal is determined mainly by the amount of carbohydrate content and by other dietary factors affecting food digestibility, gastrointestinal motility, or insulin secretion (including carbohydrate type, food structure, fiber, protein, and fat) (313–316). The average American diet contains starchy foods that are primarily refined grain products, cereals, and potatoes and have a high GI. In contrast, vegetables, legumes, and fruits have generally a low GI (317). It has been suggested that a potential adverse consequence of the decrease observed in mean fat intake in recent years is a concomitant increase in dietary GI. A reduction of dietary fat tends to cause a compensatory increase in sugar and starch intake (318–320). In fact, a rise in total carbohydrate consumption and GI of American diets, over the past 2 decades, has been reported (307, 318, 320). Since fat slows gastric emptying (315), carbohydrate absorption from low-fat meals may be accelerated. High-carbohydrate diets have been demonstrated to increase basal plasma insulin levels in animals and humans (321, 322). It has also been shown that marked obesity is associated with elevated basal plasma insulin secretory response to glucose and protein (323, 324). The hyperinsulinemia of obesity has been regarded as a compensatory adaptation to the peripheral insulin resistance characteristics of the obese state (325). Since the diets of moderately obese individuals are excessive in both total calories and in the quantity of carbohydrate ingested, the hyperinsulinemia of obesity may also be a consequence of these dietary factors rather than merely a secondary response to insulin resistance. Indeed, it has recently been shown that voluntary intake after a high-GI meal was 53% greater that after a medium-GI meal, and 81% greater than after a low-GI meal. In addition, compared with the lowGI meal, the high-GI meal resulted in higher serum insulin levels, plasma glucagon levels, postabsorptive plasma glucose, and serum fatty acids levels, along with an elevation in plasma epinephrine (326). It is, therefore, likely that the slower absorption of glucose after ingestion of highGI meals induces a sequence of hormonal and metabolic changes that promote excessive food intake in obese adolescents. Recently, Spieth et al. suggested that a lowglycemic-index diet in the treatment of childhood obesity resulted in greater weight loss than a standard reduced-fat

Alemzadeh et al.

diet (327). Long-term effects and safety of this diet needs to be evaluated in children. The traffic-light diet is another approach that may be suitable for preschool and preadolescent children. This consists of a 900–1300 kcal/day diet of ‘‘tagged’’ foods designed to meet the age recommendations for appropriate nutrient intake using the basic four food groups outlined in the food guide pyramid. These diet groups fit food into three categories: green foods (go) can be consumed in unlimited amounts; yellow foods (caution) have average nutritional values within their group, and red foods (stop) provide less nutrient density per calorie because of high fat or simple carbohydrate content (328, 329). Combined with a comprehensive treatment protocol, this diet has been found to reduce obesity and change eating habits in preadolescent children (329–332). Furthermore, weight loss up to 10 years has been maintained when the traffic light diet was combined with behavioral, exercise, and familial components of a comprehensive treatment program (333, 334).

B.

Very-Low-Calorie Diets

The national task force on the prevention and treatment of obesity published a report on the efficacy of very-lowcalorie diets on weight reduction (335). Although rapid weight loss could be achieved, the long-term evolution of obese patients on these diets was disappointing. Slowly but surely they regained their weight and by 1–5 years they were of the same weight as before the treatment, regardless of the diet given. There are few studies documenting the success of structured programs for treating childhood obesity that encompass just the use of very-low-calorie diets. Low-carbohydrate diets are usually high in protein and fat. They involve intake of large amounts of meat and restrict carbohydrate-containing foods such as fruits, vegetables, and grain products. The high intake of fat in such diets can increase the risk of coronary heart disease and other problems such as gallstones and high cholesterol. The body depends heavily on its fat stores for energy while on a low-carbohydrate diet. This can lead to ketosis. The rapid weight loss on these diets is composed of 60–70% water and the dieters often regain weight rapidly once normal eating is resumed (336, 337). Very-low-calorie restriction using a protein-sparing, modified fast (PSMF) diets (400– 800 kcal/day) is designed to produce rapid weight loss of up to 5 lb (2.3 kg per week), while preserving vital lean body mass. The protein is provided as lean meat or fish, or in a milk or egg-based liquid formula. It has been suggested that these diets spare body protein by decreasing insulin levels and enhancing fat breakdown (338), while inhibiting the release of amino acids from muscle (339). However, in the past several deaths have been associated with the use of these formulas (298). Moreover, these quick-fix weight-loss schemes may be unsafe for use in

Obesity in Children

children and do not promote healthy eating behavior for long-lasting weight control. Nutritionally balanced very-low-calorie diets, combined with exercise, may improve the outcomes in structured obesity treatment programs for children (340, 341). In one study obese adolescents entered a structured 10 week program that included exercise and behavior modification, along with a very-low-calorie diet. After 10 weeks BMI decreased from 33.8 to 29.6. Fat mass was reduced without decrements in both lean body mass or energy expenditure (342). In another study by the same investigators, 87 obese children from 7 to 17 years old participated in a year-long program similar to that described above. The results were the same and weight and body fat loss were maintained for 1 year. These results suggest that a multidisciplinary structured program to treating obese children that is maintained for long periods of time may yield positive results. However, it is important to reiterate that energy intake, not energy consumption or distribution of calories, determines weight loss (343). Therefore a balanced diet that provides a reduced intake is preferable because it achieves long-term weight control with healthier eating behaviors as described below.

C.

Food Management

Many special diets and dietary regimens have been used in the management of obesity. Diets are most likely to succeed if they are individualized according to current eating patterns, degree of motivation, intellect, amount of family support, and financial considerations. Therefore, a management approach to food intake is preferable to a diet prescription. A well-balanced calorie restrictive intake that provides all the necessary nutrients is the most effective and safest treatment for obesity. The reduction in caloric intake should be based on the weight history of the child in conjunction with usual calorie intake, body size, rate of growth, degree of adiposity, desired weight, and estimated daily activity level. As a general rule moderately obese children should be placed on an energy intake and exercise level that will slow weight gain in accordance with age and growth. In specific instances, to allow for parental or patient desires, it may be appropriate to design a nutrient intake to induce a slight weight loss. To accomplish this goal, it can be assumed that 1 lb of fat represents 3500 kcal. Initially a 10% calorie reduction in the usual nutrient intake is recommended. The food choices must be individualized to the taste and preferences of the family and the patient with the aim of meeting all the dietary goals and guidelines. This should be achieved gradually to ensure compliance while appropriate eating patterns are established. It is important to correct all potential nutritional deficits at the beginning of the treatment and to monitor any alteration that may develop throughout the follow-up period. Obese children are not overnourished in all aspects, just in energy. They often ingest inappropriate in-

843

takes, which may lead to essential nutritional deficits (343) or other alterations (i.e., hypertriglyceridemia). The following is an example of an initial approach to the treatment of an obese adolescent. A 14-year-old boy with a weight of 72 kg and a BMI 28 was examined because of obesity. The initial nutritional evaluation documented that he was ingesting the diet shown in Table 1. This diet is not unusual for an adolescent boy and is typical of this age group (344). Analysis of the diet reveals that he was ingesting 3200 kcal (44.5 kcal/kg/day), which is 128% of that recommended for his age. He was also ingesting 44% of the total calories from fat; 14.6% of the total calories from saturated fat and 723 mg cholesterol, all being very high. He also had a high sodium intake of 4739 mg, almost double than that recommended for his age. Although his intake was very inappropriate, treatment was started with a slight modification to improve compliance. By eliminating one doughnut and switching from regular soda to diet soda, his energy intake was reduced to the level necessary to avoid weight gain and maintain his current weight (38.5 kcal/kg/day). By simply eliminating those two items from the diet, there was a drop in calorie intake of 433 kcal/day. Of course, other inappropriate dietary habits were not corrected, although cholesterol intake dropped by 19 mg/day. Once the patient adjusts to these simple changes, further work will be necessary to improve upon the excess fat intake and reduce the amount of saturated fat from the diet. Patients who do not comply with simple measures might not necessarily learn to improve their nutritional habits for life.

Table 1 Typical Intake of an Adolescent Evaluated for Obesity Energy (kcal) Breakfast Two sausages and 2 eggs Coffee (1 cup) Whole milk (1 cup) Fruit juice (1 cup) Lunch McDonald’s Quarter Pounder French fries (10 stripes) Soda (1 can) Dinner Half chicken breast Baked potato (1) Salad with dressing (8 oz) Daily snack Donuts (2) Chocolate chip cookies (3) Ice cream (1 cup) Potato chips (10 pieces) Total

300 0 150 110 525 160 148 220 220 85 570 185 270 105 3207

844

Alemzadeh et al.

Another example is a 50 kg 5-year-old patient with a BMI of 37. The patient and the family were highly motivated to cease excess body weight gain and to improve upon the biochemical abnormalities detected in the work up (i.e., hyperinsulinemia). It has recently been demonstrated that hyperinsulinemia in obesity is more resistant to weight loss than normoinsulinernic obesity in children (41). Her caloric intake was reported to be 1400–1500 kcal/day. This level of caloric uptake was not excessive for maintenance of body weight (30 kcal/kg/day). However, it contained a high proportion of dietary fats. A realistic goal for her was set at 10% of body weight loss and then weight maintenance until her weight would catch up with her height and normalize the height-to-weight ratio. This was a long-term plan that would require a successful attempt at 3 years of body maintenance. Food management was initiated without reducing the total calories, since her total daily caloric intake did not appear to be excessive for weight. Instead, her food choices were modified to reduce the fat intake. She was placed on a 1500 kcal meal plan with decreased fat content (30%) while increasing complex carbohydrates. This included increasing vegetables in her diet and substituting low-calorie snacks for high-fat foods. She was given three meals and three snacks daily. It is well recognized that frequent meals are more effective for weight control than one large meal (345). Therefore, diets that consist of one or two large meals per day were discouraged. Day-to-day variations in caloric consumption are characteristic of normal eating patterns and thus they should be allowed as long as they are within an acceptable range. For example, it would be appropriate for Julie, on a 1500 kcal meal plan, to have a range of intakes from approximately 1200 to 1800 kcal/day. While assessment of the rate of weight loss and growth is important, periodic assessment of nutrient composition of the diet is essential. This is particularly important for such micronutrients as calcium, iron, magnesium, copper, zinc, folacin, and vitamins, since these are very likely to be deficient on a restricted dietary intake (345).

XIV.

completing a 10-week program that included resistance training combined with a low-calorie diet, behavior modification, aerobic and flexibility exercises. Furthermore, compliance with the exercise regimen was 100% (347). Physical activity has a significant influence on energy expenditure and the energy cost for most activities is generally greater for heavier people. There is also some evidence that increased activity in the obese individual may decrease appetite while increasing metabolic rate. Both obese and lean individuals experience a 19–30% decrease in resting metabolic rate within 24–48 h following caloric restriction (336). Thus caloric restriction without an increase in physical activity may not result in continued weight loss. Regular aeroboic exercise combined with energy restriction will result in greater reductions in body weight than dieting alone (301). Intermittent exercise and use of home exercise equipment are effective in inducing and maintaining weight loss (348). Individuals who used the equipment longer were those who lost more weight and sustained their weight loss for longer periods of time. The type of exercise is also important: long bouts of exercise of greater intensity were more beneficial. The benefits transcend those of body weight. The relationship between cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men was clear (212). Fitness is an independent predictor of health, comparable to diabetes mellitus, cholesterol levels, hypertension, and smoking. However, by simply engaging in leisure-time physical activity major benefits may be attained. This is often not achieved, since most persons trying to lose weight are not using a recommended combination of reducing calorie intake and engaging in leisure-time physical activity (150 minutes per week) (349). In the patients mentioned above on dietary treatment, if they added to their treatment regimen a habit of walking 20 min/day they would enhance their energy expenditure by 5.8 kcal/min. In other words, they would spend 116 kcal/day above the dietary restriction, therefore increasing weight loss and enhancing their health. The amount of energy necessary for various physical activities is shown in Table 2.

EXERCISE

Dietary management of childhood obesity should always be combined with an exercise program. However, exercise should be prescribed on an individual basis. An exercise program based upon the initial fitness level (346) with a slow progression of the intensity, frequency, and duration is required to achieve the goal of weight control. For instance, morbidly obese children may achieve maximal energy expenditure during a brisk walk, since prescriptions for more demanding physical activities like jogging are likely to be impossible at the start. Resistance training may also be a suitable component of a structured obesity treatment program. One study found that weight loss was maintained for up to 1 year in obese preadolescents after

XV.

FAMILY INVOLVEMENT

Supportive counseling and reinforcement can help set the goals for health professionals, patient, and parent, allowing for long-lasting results and avoidance of failure and frustration. Refusal to adhere to a weight-reduction plan may be due to lack of family support, insufficient motivation, or other psychological stresses. For instance, it has been demonstrated that children of married parents lose weight at higher rates than those of divorced parents (328). When a weight-reduction plan has been recommended, conflicts frequently arise between the patient and nondieting family members regarding the degree of dietary restriction and who is permitted to eat different foods.

Obesity in Children

845

Table 2 Energy Expenditure in Occupational, Recreational, and Sports Activities (kcal/min) for a 50 kg Individual Activity Basketball Cycling Leisure Racing Computer typing Dancing Ballroom Vigorous Eating (sitting) Football Gymnastics Swimming Backstroke Breast stroke Crawl, fast Crawl, slow Tennis Volleyball Fishing Gardening: Mowing Marching Running: 8 min/mile Sitting quietly Skiing (hard snow): Moderate speed Walking (comfortable pace) Fields and hillsides Grass track Writing (sitting)

Calories expended (50 kg/110 lb) 6.9 5.9 8.5 1.4 2.6 8.4 1.2 6.6 3.3 8.5 8.1 7.8 6.4 5.5 2.5 3.1 5.6 7.1 10.8 1.1 6.0 4.1 4.1 1.5

Energy expenditure is related to the size of the individual and should therefore be related to body weight. The usual dietary energy allowance for children 4–18 years varies between 34 and 82 kcal/kg/day. For competitive and long endurance exercises in children, energy expenditure should be increased by 17.6–52.8 kcal/kg/day above usual.

Dietary restriction should never be introduced in a punitive fashion. In some cases, the obese child and the entire family may adhere to a diet similar in composition if not quantity. Participation of the entire family should help minimize the feelings of isolation of the obese child. It has been shown that family involvement is essential for the success of any obesity treatment plan. Children whose families are involved in their treatment protocol lose more weight and maintain it for more prolonged periods that those whose families are not participatory (333). Eating patterns, food choices, and other behavioral factors of importance in obesity are family characteristics. Dietary management and physical exercise are essential components for the development of effective treatment. The area of greatest concern for psychologists is

how to get children to alter food intake and activity behaviors. Because the primary focus is on changing the child’s behavior, parenting skills represent an integral component of the intervention. Stimulus-control procedures in the behavioral control of overeating have led to the development of several behavioral techniques for the treatment of obesity which include self-monitoring of body weight and/or food intake, goal setting, reward and punishment, aversion therapy, social reinforcement, and stimulus control. Several of these modifications have been found to be effective with children (328–334). These interventions are based on the assumptions that the obese child is an overeater who is hypersensitive to food stimuli and can be trained to behave like a nonobese person and subsequently lose weight. Moreover, positive family support has been shown to improve the degree of immediate and long-term weight loss in children and adolescents (330–332). Any program designed specifically for treating obese children must include a group format with individualized counseling, parent participation, frequent sessions over a long period of time, appropriate exercise, and changes in the home environment to reinforce changes in the child’s lifestyle. The behavior modification sessions should include self-monitoring, goal setting and contracting, parenting skills training, skills for managing the high-risk situation, and skills for maintenance and relapse prevention (340).

XVI. A.

OTHER THERAPIES Drugs

Long-term use of medications to suppress appetite or antiobesity pills are not usually indicated in the treatment of pediatric obesity. Studies involving the use of anorectic drugs alone or in combination with behavior therapy have demonstrated that weight loss is no greater than when behavior therapy was used alone. When the drugs were stopped, the weight was regained more rapidly (338). Furthermore, the effectiveness of appetite-suppressant drugs (i.e., amphetamines) appears to decrease with time and there may be side effects. The addictive potential of amphetamines and the risk of depression associated with fenfluramine have resulted in the minimal use of these agents in children and adolescents. The use of serotonin agonists such as fluoxetine and fenfluramine in the short term has proven useful as an adjunct in weight-loss programs for children and adolescents (342, 350). These drugs seem to decrease appetite and carbohydrate craving. Although they are by no means the solution to weight loss, they may help individuals at the beginning of a weight loss program by suppressing appetite. They must be used with caution and for a very limited time (351). In fact, serious side effects such as pulmonary hypertension and valvular heart lesions have been associated with the use of fenfluramine

846

Alemzadeh et al.

and its derivative, dexfenfluramine, in combination with another appetite suppressant (i.e., phentermine) (352). Recently, a new selective serotonin reuptake inhibitor, sibutramine (Meridia), has been shown to be effective in weight reduction trials in obese adults without significant adverse effects. However, the safety and efficacy of this agent have yet to be evaluated in obese children and adolescents. Another potential antiobesity medication is metformin, an antihyperglycemic drug, that has been reported to enhance insulin sensitivity leading to reduced appetite and body weight in obese children and adults (353). Fremark et al. recently demonstrated that a 6 month trial of metformin treatment (500 mg twice daily) in a group of obese adolescents caused significant reductions in BMI, fasting glucose, and insulin compared to a placebo group (353). In a 2 month study, Metformin (850 mg twice daily) in a group of adolescents on a hypocaloric diet caused significant reductions in weight, fasting insulin, leptin, and lipids compared to a placebo group (354). The use of diazoxide, an inhibitor of glucose-mediated insulin secretion, in a group of hyperinsulinemic obese adults was recently shown to be effective in short-term weight reduction with few adverse effects (355). Daily subcutaneous administration of octreotide (somatostatin analogue), an inhibitor of pancreatic insulin secretion, to a group of children and adolescents with hypothalamic obesity secondary to cancer therapy likewise resulted in significant reduction in body weight over a 6 month period (279). The results of these studies imply that attenuation of hyperinsulinemia of obesity may be of therapeutic benefit in the management of this disorder. However, long-term efficacy and safety of these agents have yet to be evaluated in children.

B.

Fat and Sugar Substitutes

Bulking agents and nonprescription diet aids, such as methylcellulose and other noncaloric bulk materials, have also been used in experimental and clinical attempts to inhibit food intake. The rationale for the use of such agents is that they swell in the stomach and supposedly give a feeling of satiety. Indeed, several lines of evidence suggest that dietary fiber may play a key role in the regulation of circulating insulin levels. Dietary fiber reduces insulin secretion by slowing the rate of nutrient absorption following a meal (312, 313). In the experimental setting, insulin sensitivity increases (314) and body weight decreases (315) in animals fed high-fiber diets. In addition, a recent study revealed that fiber consumption predicted insulin levels, weight gain, and other cardiovascular heart disease (CVD) risk factors more strongly than total or saturated fat consumption. Therefore, high-fiber diets (10–15 g/day) may protect against obesity and CVD by lowering insulin levels (316). The use of inhibitors of digestive enzymes, such as intestinal lipase and disaccharidase, in obese and diabetic

adult patients has been shown to be beneficial for weight reduction and improved glycemic control (356, 357). For instance, a gastrointestinal lipase inhibitor (Orlistat) has been reported to be of potential benefit by reducing fat absorption from the intestinal tract in obese adults undergoing significant weight reduction (356). However, undesirable side effects such as diarrhea and flatulence were frequently observed in these patients. This was accompanied by reduction in the levels of fat-soluble vitamins A, D, and E, which can be prevented by multivitamin supplementation. The safety and efficacy of the latter have yet to be evaluated in pediatric patients. There are many misconceptions about the benefit of foods containing nonnutritive sweeteners. Currently, three nonnutritive sweeteners are approved for use in the United States: saccharin, aspartame, and acesulfame K. Other sweeteners include sorbitol, mannitol, and xylitol. Many obese individuals consume foods containing these sweeteners, thinking they are reducing their caloric intake. However, many of these foods either contain the same amount of or more calories than their regular sweetened counterparts. For example, dietetic chocolate contains 168 calories per 2 oz serving. Regular sweetened chocolate only contains 150 calories for a similar-sized serving (358). Therefore, without proper advice from a dietician, many obese individuals may be overconsuming calories by including dietetic foods in their diets. These foods also tend to be more expensive.

C.

Surgery

There are very few applications of surgical procedures in the management of pediatric obesity. Four types of surgical procedures have been used to change eating behavior: jejunoileal and gastric bypass, gastric plication, and jaw wiring. The jejunoileal bypass procedures are usually followed by a large weight loss. However, significant complications including diarrhea, vitamin D deficiency with osteomalacia, vitamin B12 and folate deficiencies, renal (oxalate) calculi, hyperuricemia, and liver disease follow these procedures (359). A second procedure is the gastric bypass, which appears to be effective in producing weight loss without serious late complications seen with the jejunoileal procedure (360). Gastric plication (gastroplasty), involving a stapling procedure, is also widely used. Following the gastric bypass or gastroplasty procedure, patients food intake is decreased by the sensation of fullness. They also show less anxiety, depression, irritability, and preoccupation with food during weight loss compared with their weight-reduction attempts before the surgical procedure (361). In controlled studies gastric bypass appears slightly more effective than gastroplasty. Although successful initially in almost all patients, the failure rate for both procedures is high (up to 50%) (362). These procedures should be considered carefully in a select group of adolescents with significant medical com-

Obesity in Children

plications who have been frequently unsuccessful in losing weight with other conventional therapies.

D.

New Therapies

The administration of exogenous leptin has been shown to result in loss of body fat in animals with elevated leptin levels (364), as well as in humans with leptin deficiency, by reducing food intake (365). Recently, Heymsfield et al. demonstrated that a 6 month administration of subcutaneous recombinant leptin in high dosages induced weight loss in some obese adults with elevated endogenous leptin concentrations who were maintained on a eucaloric diet (365). However, they suggested that additional research into the potential role for leptin and related hormones in the treatment of human obesity was needed; the medication is not the magic bullet for most obese patients.

E.

Kids Weight Down Program

A program specifically designed for treating childhood obesity must be the best approach to dealing with obesity in children. A Kids Weight Down Program may include staff consisting of a registered dietician, child psychologist, physician, and exercise physiologist. The program should require that parents participate in their child’s treatment. Treatment is begun after a preliminary physical exam and laboratory testing that includes a lipid profile. Treatment may consist of one or two sessions per week, for 10 weeks, for both children and parents. All medical assessments are repeated at the end of the treatment period to determine compliance and progress. The treatment regimen consists of a moderate weightreducing diet along with an exercise program. The recommended energy intake consists of a 10% reduction diet as the main dietary prescription, as described above. This dietary prescription should not depend on any fad diets or eliminate any ethnic or cultural foods normally consumed by the families. As part of the weekly sessions, the children must exercise twice a week under the supervision of an exercise physiologist. The child’s sessions must also include lessons and games to teach the importance of an appropriate nutritionally balanced diet for weight loss. The goal should be to make the sessions enjoyable for children as well as convey knowledge about the importance of losing excess body weight. The parents’ sessions consist of education about the importance of family participation in the child’s treatment. Each week parents may discuss problems/solutions associated with the progress of the child’s treatment. This should include some of the problems encountered in changing the family dynamics in order to foster a positive influence on the child’s treatment. Having parents’ sessions, separate from the children, enabled them to support one another and allow open discussion about the problems of treating an obese child. The program is usually successful for a short duration.

847

However, the importance of long-term follow-up and management can never be stressed enough. The unique program suggested above is costly because of the high demand for specialized personnel. Insurance companies usually do not provide any reimbursement for participation in such a program.

XVII.

YO-YO WEIGHT CYCLING

Weight cycling has a profound effect on body composition and its metabolic efficiency (366). Weight loss followed by regain results in loss from muscle, regained as fat; increased risk of heart disease; and frustration (201, 202). Chronic dieters learn to cope with dieting. They develop a very efficient metabolism and maintain their weight with fewer and fewer calories with each attempt to lose weight. There is loss of muscle mass as a result of body composition changes during weight cycling. The increased fat mass leads to elevation of basal insulin and lipoprotein lipase levels (367), resulting in more fat deposition. In addition to changes in the body composition, the patient becomes psychologically frustrated as he or she fails to achieve the desired weight loss. The outcome is a patient who ingests very few calories and yet cannot lose weight. Chronic dieters may also be increasing their risk for heart disease more than if excess weight remained at a stable level. Dieting leads to fat mobilization and during, the regaining phase, fat deposition in the arteries. The regained weight is more likely to be distributed in the upper body where it is potentially more harmful (96) and associated with a higher incidence of heart disease and glucose intolerance (104). Appropriate strategies to avoid weight cycling should be considered at the beginning of a child’s weight-reduction program. When a child is ready to participate in a weight reduction program, it should represent a serious commitment of all involved.

XVIII.

PREVENTION

The successful treatment of childhood and adolescent obesity is an effective approach to the prevention of severe adult disease. Long-term follow-up of children treated with diet, exercise, and behavior modification has shown significantly lower weights 5–10 years later than for children treated in other ways (332, 333, 368). However, not all obese children who were treated successfully initially were able to maintain their reduced relative body weight. Nevertheless, none of these studies has had similar design and/or control populations, making a critical comparison very difficult. In addition, the increasing prevalence of childhood and adolescent obesity suggests that even the most successful treatment may be of limited benefit if it relies on the traditional doctor/patient interaction model. Furthermore, the metabolic phenotype (i.e., hyperinsulinemia) and family history of type 2 diabetes (369), hypertension and/or hyperlipidemia, may play a major role

848

in a patient’s response to conventional weight management strategies. Therefore, development of effective methods for weight reduction should be continued and multidisciplinary research to identify factors that prevent relapses should be encouraged. Children should be encouraged to develop healthy eating habits and exercise patterns that prevent excessive weight gain. This is especially important for children in high-risk groups, for instance, with obese parents and those who are overweight by the time they enter school (370). Health professionals should inform parents of the potential risks and provide instructions on preventive measures at an early age. The introduction of a variety of nutritious foods to children’s diets will lead to the development of healthy eating practices in children and adolescents. These foods should include an assortment of fresh or frozen vegetables and legumes; dairy products; fresh fruits; breads (preferably whole grain); and pastas, rice, cereals, and other grain products. Sweets and other nutrient-poor foods should be allowed in limited amounts that do not interfere with the child’s consumption of basic foods. With relatively free access to these highly palatable choices (i.e., caloric-dense snacks), the chances of overeating are increased and may encourage the development of obesity in predisposed children. However, these changes have not been very successful in preventing the increase in obesity in children. Other lifestyle changes may be important in resolving this problem. A more appropriate approach should include reduction of sedentary activities such as television viewing and video game use. In a comprehensive study, 198 third and fourth grade students were organized into two groups. One group served as the control while the intervention group participated in a 6 month course geared toward reduction in television viewing, video tape, and game use. After completion of the course, the BMI of the intervention group was reduced from 18.8 to 18.1 kg/m2. Furthermore, triceps skinfold thickness, waist circumference, and waist-to-hip ratio showed similar positive changes. Moreover, children in the intervention group self-reported fewer hours watching television while consuming meals in front of the television. However, no changes were found between the two groups in regard to high-fat food intake, physical activity, and cardiorespiratory fitness. These results suggest that just reducing television viewing and video game use contribute to positive changes in obesity indices in children (371). Primary public health measures are critical to formulate a sound approach to the prevention of obesity in children. It is the responsibility of schools and government agencies, as well as food industries, to support measures that can improve the food habits and exercise patterns of children and adults. The schools should play an active role in providing healthy food choices in the cafeteria and provide appropriate exercise programs for normal-weight and obese children separate from competitive

Alemzadeh et al.

athletics. Government and local authorities can insist that schools implement and promote physical fitness programs and provide easy access to exercise facilities in the community. The media should assume a responsible position with regard to idealized concepts of beauty by appropriate programming and feeding of messages to children and to society at large.

XIX.

FINAL CONSIDERATIONS

Obesity and significant comorbidities are reaching epidemic proportions among children. A variety of genetic, environmental, and other factors account for the development of obesity. Understanding leptin’s role in regulating food intake and energy expenditure is an important discovery. It has been identified as a component of the pathophysiological alterations in this entity, including hyperinsulinemia and its complications. Inborn alterations of leptin have also been identified in individuals with severe morbid obesity. However, most obese populations exhibit various degrees of leptin desensitization. Early recognition of excessive weight gain in relation to linear growth is important and should be closely monitored by pediatricians and health care providers. The use of BMI percentiles may also help to identify children at risk and quantify the severity of obesity. Prevention is critical, since effective treatment of this disease is limited. Food management and increased physical activity must be encouraged, promoted, and prioritized to protect children. Dietary practices must foster moderation and variety, with a goal of setting the appropriate eating habits for life. Advocacy is needed to elicit insurance coverage of the disease.

ACKNOWLEDGMENT This work was supported in part by NIH grant (#1R41HD/ DK38180-01A2) and by Pediatric Sunshine Academics.

REFERENCES 1. 2. 3. 4.

5. 6.

Popkin BM. The nutrition transition in low-income countries: an emerging crisis. Nutr Rev 1994; 52:285–298. Hodge AM, Dowse GK, Zimmet PZ, Collins VR. Prevalence and secular trends in obesity in Pacific and Indian Ocean island populations. Obes Res 1995; 2:77S–87S. Troiano RP, Flegal KM. Overweight children and adolescents: description, epidemiology, and demographics. Pediatrics 1998; 101:497–504. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults: The National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA 1994; 272:205–211. Merritt RJ. Obesity. Curr Probl Pediatr 1982; 12:1–58. Stunkard A, Burt V. Obesity and the body image. II. Age at onset of disturbances in body image. Am J Psychiatry 1967; 123:1443–1447.

Obesity in Children 7. 8. 9. 10. 11. 12.

13.

14. 15. 16. 17. 18. 19.

20. 21.

22. 23. 24.

25.

26. 27.

Stark O, Atkins E, Wolff OH, Douglas JW. Longitudinal study of obesity in the National Survey of Health and Development. Br Med J (Clin Res Ed) 1981; 283:13–17. Kopelman. Obesity as a medical problem. Review. Nature 2000; 404:635–642. Daher M. World Health Report. J Med Liban 1998; 46: 212–217. Seidell JC. Obesity: a growing problem. Acta Paediatr 1999; 88:S46–S50. Gray GA. Contemporary Diagnosis and Management of Obesity. Newtown, PA: Handbooks in Health Care, 1998: 120. Williams DP, Going SB, Lohman TG, Harsha DW, Srinivasan SR, Webber LS, Berenson GS. Body fatness and risk for elevated blood pressure, total cholesterol, and serum lipoprotein ratios in children and adolescents. Am J Public Health 1992; 82:358–363. Vanhalla MJ, Vanhalla PT, Keinanen-Kiukaanniemi SM, Kumpusalo EA, Takala JK. Relative weight gain and obesity as a child predict metabolic syndrome as an adult. Int J Obes 1999; 23:656–659. Tracey VV, De NC, Harper JR. Obesity in respiratory infection in infants and young children. Br Med J 1971; 1:16–18. Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epidemic of type 2 diabetes in youth. Diabetes Care 1999; 22:345–354. Kelsey JL, Acheson RM, Keggi KJ. The body build of patients with slipped capital femoral epiphysis. Am J Dis Child 1972; 124:276–281. Kling TF Jr. Angular deformities of the lower limbs in children. Orthop Clin North Am 1987; 18:513–527. Wadden TA, Stunkard AJ. Psychopathology and obesity. Ann NY Acad Sci 1987; 499:55–65. Gortmaker SL, Must A, Perrin JM, Sobol AM, Dietz WH. Social and economic consequences of overweight in adolescence and young adulthood. N Engl J Med 1993; 329: 1008–1012. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37:1595–1607. Webber LS, Srinivasan SR, Wattigney WA, Berenson GS. Tracking of serum lipids and lipoproteins from childhood to adulthood: the Bogalusa heart study. Am J Epidemiol 1991; 133:884–899. Webber LS, Cresanta JL, Voors AW, Berenson GS. Tracking of cardiovascular disease risk factor variables in school-age children. J Chron Dis 1983; 36:647–660. Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis 1989(suppl 1)9:I19–I32. Berenson GS, Wattigney WA, Tracy RE, Newman WP 3rd, Srinivasan Dalferes ER Jr, Strong JP. Atherosclerosis of the aorta and coronary arteries and cardiovascular risk factors in persons aged 6 to 30 years and studied at necropsy (The Bogalusa Heart Study). Am J Cardiol 1992; 70:851–858. Must A, Jacques PF, Dallal GE, Bajema CJ, Dietz WH. Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935. N Engl J Med 1992; 327:1350–1355. Moran JR, Ghishan FK, Halter SA, Greene HL. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol 1983; 78:374–377. Bennion LJ, Knowler WC, Mott DM, Spagnola AM, Bennett PH. Development of lithogenic bile during puberty in Pima Indians. N Engl J Med 1979; 300:873–876.

849 28. 29. 30. 31. 32.

33.

34. 35. 36. 37.

38.

39.

40. 41. 42. 43.

44.

45.

46.

Liddle RA, Goldstein RB, Saxton J. Gallstone formation during weight-reduction dieting. Arch Intern Med 1989; 149:1750–1753. Dietz WH Jr. Obesity in infants, children and adolescents in the United States. I. Identification, natural history and aftereffects. Nutr Res 1981; 1:117–137. Williams B. Insulin resistance and syndrome X. Lancet 1994; 344:521–524. Arsalanian S, Suprasongsin C. Insulin sensitivity, lipids, and body composition in childhood: is ‘‘syndrome X’’ present? J Clin Endocrinol Metab 1996; 81:1058–1062. Steinberger J, Moorehead C, Katch V, Rochini AP. Relationship between insulin resistance and abnormal lipid profile in obese adolescents. J Pediatr 1995; 126:690– 695. Chen W, Srinivasan SR, Elkasababny A, Berenson GS. Cardivascular risk factor clustering features of insulin resistance syndrome (syndrome X) in a biracial (blackwhite) population of children, adolescents, and young adults. Am J Epidemiol 1999; 150:666–674. Glaser NS. Non-insulin-dependent diabetes mellitus in childhood and adolescence. Pediatr Clin North Am 1997; 44:307–337. Dean HE, Mundy RLL, Moffatt M. Non-insulin-dependent diabetes mellitus in Indian children in Mannitoba. Can Med Assoc J 1992; 147:52–57. Dean H. NIDDM-Y in First Nation children in Canada. Clin Pediatr (Phila) 1998; 37:89–96. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. Increased incidence of non-insulindependent diabetes mellitus among adolescents. J Pediatr 1996; 128:608–615. Kitagawa T, Owada M, Urakami T, Tajima N. Epidemiology of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in Japanese children. Diabetes Res Clin Pract 1994; 24(suppl)S7–S13. Kitagawa T, Owada M, Urakami T, Yamauchi K. Increased incidence of non-insulin-dependent diabetes mellitus among Japanese school children correlates with an increased intake of animal protein and fat. Clin Pediatr 1998; 37:111–115. Martin MM, Martin AL. Obesity; hyperinsulinism, and diabetes mellitus in childhood. J Pediatr 1973; 82:192– 201. Rosenbloom AL. Age-related plasma insulin response to glucose ingestion in children and adolescents. IRCS Metab Nutr: Pediatr 1974; 2:1210–1214. Mallory GB Jr, Fiser DH, Jackson R. Sleep-associated breathing disorders in morbidity obese children and adolescents. J Pediatr 1989; 115:892–897. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med 1999; 340:847–851. Shelton KE, Gay SB, Hollowell DE, Woodson H, Suratt PM. Mandible enclosure of upper airway and weight in obstructive sleep apnea. Am Rev Respir Dis 1993; 148: 195–200. Horner RL, Mohiaddin RH, Lowell DG, Shea SA, Burman ED, Longmore DB, Guz A. Sites and sizes of fat deposits around the pharynx in obese patients with obstructive sleep apnea and weight matched controls. Eur Respir J 1989; 2:613–622. Shepard JW Jr. Cardiopulmonary consequences of obstructive sleep apnea. Mayo Clin Proc 1990; 65:1250– 1259.

850 47.

48. 49. 50. 51. 52. 53. 54.

55. 56. 57. 58. 59. 60.

61. 62. 63. 64. 65. 66. 67. 68.

Alemzadeh et al. Ciampelii M, Fulghesu AM, Cucinelli F, Pavone V, Ronsisvalle E, Guido M, Caruso A, Lanzone A. Impact of insulin and body mass index on metabolic and endocrine variables in polycystic ovary syndrome. Metabolism 1999; 48:167–172. Pasquali R, Casimirri F. The impact of obesity on hyperandrogenism and polycystic ovary syndrome in premenopausal women. Clin Endocrinol (Oxf) 1993; 39:1–16. Singh KB, Mahajan DK, Wortsman J. Effects of obesity on the clinical and hormonal characteristics of the polycyctic ovary syndrome. J Reprod Med 1994; 39:805–808. Staffieri JR. A study of social stereotype of body image in children. J Pers Soc Psychol 1967; 7:101–104. Davison KK, Birch LL. Weight status, parent reaction, and self-concept in five-year-old girls. Pediatrics 2001; 107:46–53. Birch LL, Fisher JO. Mothers’ child-feeding practices influence daughters’ eating and weight. Am J Clin Nutr 2000; 71:1054–1061. Vander Wall JS, Thelen MH. Eating and body image concerns among obese and average weight children. Addit Behav 2000; 25:775–778. Stunkard A, Mendelson M. Obesity and the body image. 1. Characteristics of disturbances in the body image of some obese persons. Am J Psychiatry 1967; 123:1296– 1300. Monello LF, Mayer F. Obese adolescent girls: an unrecognized ‘‘minority’’ group? Am J Clin Nutr 1963; 13: 35–39. Canning H, Mayer J. Obesity: its possible effect on college acceptance. N Engl J Med 1996; 275:1172–1174. Thompson D, Edelsberg J, Kinsey KL, Oster G. Estimated economic costs of obestity to U.S. business. Am J Health Promot 1998; 13:120–127. Birmingham CL, Muller JL, Palepu A, Spinelli JJ, Anis AH. The cost of obesity in Canada. Can Med Assoc J 1999; 160:483–488. Pronk NP, Goodman MJ, O’Connor PJ, Martinson BC. Relationship between modifiable health risks and shortterm health care charges. JAMA 1999; 282:2235–2239. Pronk NP, Boucher J. Systems approach to childhood and adolescent obesity prevention and treatment in a managed care organization. Int J Obes Rel Metab Disord 1999; 2: S38–S42. Pugliese MT, Lifshitz F, Grad G, Fort P, Marks-Katz M. Fear of obesity: a cause of short stature and delayed puberty. N Engl J Med 1983; 309:513–518. Moses N, Banilvy M, Lifshitz F. Fear of obesity among adolescent girls. Pediatrics 1989; 83:33–398. Richardson SA, Goodman N, Hastorf H, et al. Cultural uniformity in reaction to physical disabilities. Am Sociol Rev 1961; 26:241–247. Neumark-Sztainer D, Hannan P. Weight-related behaviors among adolescent girls and boys: Results from a national survey. Arch Pediatr Adolesc Med 2000; 154:569–577. Abramovitz B, Birch L. Five-year-old girls’ ideas about dieting are predicted by their mothers’ dieting. J Am Diet Assoc 2000; 100:1157–1163. Schur E, Sanders M, Steiner H. Body dissatisfaction and dieting in young children. Int J Eat Disord 2000; 27:74– 82. Stice E, Agras W, Hammer L. Risk factors for the emergence of childhood eating disturbances: a five-year prospective study. Int J Eat Disord 1999; 25:375–387. Johnson S, Birch L. Parents’ and children’s adiposity and eating style. Pediatrics 1994; 94:653–661.

69.

70. 71. 72. 73. 74.

75. 76.

77. 78.

79. 80.

81. 82. 83. 84. 85.

86.

87.

88.

Hood MY, Moore LL, Sundarajan-Ramamurti A, Singer M, Cupples LA, Ellison RC. Parental eating attitudes and the development of obesity in children. The Framingham Children’s Study. Int J Obes 2000; 24:1319–1325. Lifshitz F. Fear of obesity in childhood. Ann NY Acad Sci 1993; 699:230–236. Flier JS. Metabolic importance of acanthosis nigricans. Arch Dermatol 1985; 121:193–194. Lifshitz F, Tarim O, Smith MM. Nutrition in adolescence. Review. Endocrinol Metab Clin North Am 1993; 22:673– 683. Hamill PV, Drizd TA, Johnson CL, Reed RB, Roche AF, Moore WM. Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 1979; 32:607–629. Pugliese M, Lifshitz F, Fort P, Recker B, Ginsberg L. Pituitary–hypothalamic response in adolescents with growth failure due to fear of obesity. J Am Coll Nutr 1987; 6:113–120. Lifshitz F, Moses N, Cervantes C, Ginsberg L. Nutritional dwarfing in adolescents. Semin Adolesc Med 1987; 3: 255–266. Neumark-Sztainer D, Rock CL, Thornquist MD, Cheskin LJ, Neuhouser ML, Barnett MJ. Weight-control behaviors among adults and adolescents: associations with dietary intake. Prev Med 2000; 5:381–391. Kreipe RE. Eating disorders in adolescents and older children. Pediatr Rev 1999; 12:410–421. Hammer LD, Kraemer HC, Wilson DM, Ritter PL, Dornbusch SM. Standardized percentile curves of body-mass index for children and adolescents. Am J Dis Child 1991; 145:259–263. Pi-Sunyer FX. Obesity. In: Shils ME, Young VR, eds. Modern Nutrition in Health and Disease. Philadelphia: Lea & Febiger, 1988:795–816. National Center for Health Statistics, U.S. Department of Health, Education and Welfare: NCHS growth curves for children: birth to 18 years. Series H, No. 165, DHEW Publication No. (PHS) 78-1650, 1977. Franklin MF. Comparison of weight and height relations in boys from 4 countries. Am J Clin Nutr 1999; 70:157S– 162S. Bellizzi MC, Dietz WH. Workshop on childhood obesity: summary of the discussion. Am J Clin Nutr 1999; 70: 173S–175S. Malina RM, Katzmarzyk PT. Validity of the body mass index as indicator of the risk and presence of overweight in adolescents. Am J Clin Nutr 1999; 70:131S–136S. Dietz WH, Bellizzi MC. Introduction: the use of body mass index to assess obesity in children. Am J Clin Nutr 1999; 70:123S–125S. Durnin JV, Womersley J. Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. Br J Nutr 1974; 32:77–97. Must A, Dallal GE, Dietz WH. Reference data for obesity: 85th and 95th percentiles of body mass index (wt/ht2) and triceps skinfold thickness. Am J Clin Nutr 1991; 53: 839–846. Guo SM, Roche AF, Houtkooper L. Fat-free mass in children and young adults predicted from bioelectric impedance and anthropometric variables. Am J Clin Nutr 1989; 50:435–443. Houtkooper LB, Going BS, Lohman TG, Roche AF, Van Loan M. Bioelectrical impedance estimation of fat-free mass in children and youth: a cross-validation study. J Appl Physiol 1992; 72:366–373.

Obesity in Children 89.

90. 91.

92.

93. 94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

Wells JC, Fuller NJ, Dewit O, Fewtrell MS, Elia M, Cole TJ. Four-component model of body composition in children: density and hydration of fat-free mass and comparison with simpler models. Am J Clin Nutr 1999; 69:904– 912. Czinner A, Varady M. Quantitative determination of fatty tissue on body surface in obese children by ultrasound method. Padiatr Padol 1992; 27:7–10. Armellini F, Zamboni M, Rigo L, Bergamo-Andreis IA, Robbi R, De Marchi M, Bosello O. Sonography detection of small intra-abdominal fat variations. Int J Obes 1991; 15:847–852. Ellis KJ. Measuring body fatness in children and young adults: comparison of bioelectric impedance analysis, total body electrical conductivity, and dual-energy X-ray absorptiometry. Int J Obes Rel Metab Disord 1996; 20: 866–873. Kohrt WM. Preliminary evidence that DEXA provides an accurate assessment of body composition. J Appl Physiol 1998; 84:372–377. Paradisi G, Smith L, Burtner C, Leaming R, Garvey WT, Hook G, Johnson A, Cronin J, Steinberg HO, Baron AD. Dual energy X-ray absorptiometry assessment of fat mass distribution and its association with the insulin resistance syndrome. Diabetes Care 1999; 22:1310–1317. Kvist H, Chowdhury B, Grangard U, Tylen U, Sjostrom L. Total and visceral adipose-tissue volumes derived from measurements with computed tomography in adult men and women: predictive equations. Am J Clin Nutr 1988; 48:1351–1361. Ross R, Shaw KD, Martel Y, de Guise J, Avruch L. Adipose tissue distribution measured by magnetic resonance imaging in obese women. Am J Clin Nutr 1993; 57:470– 475. Fiorotto ML, Cochran WJ, Klish WJ. Fat-free mass and total body water of infants estimated from total body electrical conductivity measurements. Pediatr Res 1987; 22: 417–421. Megan AM, Gomez TG, Bernauer EM, Mole PM. Evaluation of a new air displacement plethysomgraph for measuring human body composition. Med Sci Sport Exerc 1995; 27:1686–1691. de Ridder CM, de Boer RW, Seidell JC, Nieuwenhoff CM, Jeneson JA, Bakker CJ, Zonderland ML, Erich WB. Body fat distribution in pubertal girls quantified by magnetic resonance imaging. Int J Obes Relat Metab Disord 1992; 16:443–449. Lockner DW, Heyward VH, Baumgartner RN, Jenkins KA. Comparison of air-displacement plethysmography, hydrodensitometry, and dual X-ray absorptiometry for assessing body composition of children 10 to 18 years of age. Ann NY Acad Sci 2000; 904:72–78. Kissebah AH, Vydelingum N, Murray R, Evans DJ, Hartz AJ, Kalkhoff RK, Adams PW. Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 1982; 54:254–260. Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women. Metabolism 1984; 33:48–75. Kalkhoff RK, Hartz AH, Rupley D, Kissebah AH, Kelber S. Relationship of body fat distribution to blood pressure, carbohydrate tolerance, and plasma lipids in healthy obese women. J Lab Clin Med 1983; 102:621–627. Peiris AN, Hennes MI, Evans DJ, Wilson CR, Lee MB, Kissebah AH. Relationship of anthropometric measure-

851

105. 106.

107. 108. 109.

110.

111. 112. 113.

114.

115. 116.

117.

118. 119.

120.

121.

ments of body fat distribution to metabolic profile in premenopausal women. Acta Med Scand Suppl 1988; 723: 179–188. Peiris AN, Struve MF, Mueller RA, Lee MB, Kissebah AH. Glucose metabolism in obesity: influence of body fat distribution. J Clin Endocrinol Metab 1988; 67:760–767. Zamboni M, Armellini F, Milani MP, Todesco T, De Marchi M, Robbi R, Montresor G, Bergamo AI, Bosello O. Evaluation of regional body fat distribution: comparison between W/H ration and computed tomography in obese women. J Intern Med 1992; 232:341–347. Garn SM, Sullivan TV, Hawthorne VM. Fatness and obesity of the parents of obese individuals. Am J Clin Nutr 1989; 50:1308–1313. Roberts SB, Savage J, Coward WA, Chew B, Lucas A. Energy expenditure and intake in infants born to lean and overweight mothers. N Engl J Med 1988; 318:461–466. Ravussin E, Burnand B, Schutz Y, Jequier E. Twentyfour-hour energy expenditure and resting metabolic rate in obese, moderately obese, and control subjects. Am J Clin Nutr 1982; 35:566–573. Dewey KG, Heinig MJ, Nommsen LA, Peerson JM, Lonnerdal B. Breast-fed infants are leaner than formula-fed infants at 1 y of age: the DARLING study. Am J Clin Nutr 1993; 57:140–145. Wells JC, Stanley M, Laidlaw AS, Day JM, Davies PS. Energy intake in early infancy and childhood fatness. Int J Obes Rel Metab Disord 1998; 22:387–392. Davis PS, Wells JC, Fieldhouse CA, Day JM, Lucas A. Parental body composition and infant energy expenditure. Am J Clin Nutr 1995; 61:1026–1029. Cole CR, Rising R, Hakim A, Danon M, Mehta R, Choudhury S, Sundaresh M, Lifshitz F. Comprehensive assessment of the components of energy expenditure in infants using a new infant respiratory chamber. J Am Coll Nutr 1999; 18:233–241. Zurlo F, Lillioja S, Puente AED, Nyomba BL, Raz I, Saad FM, Swinburn BA, Knowler WC, Bogardus C, Ravussin E. Low ratio of fat to carbohydrate oxidation as a predictor of weight gain: study of 24-h RQ. Am J Physiol 1990; 259:E650–E657. Rising R, Keys A, Ravussin E, Bogardus C. Concomitant interindividual variation in the body temperature and metabolic rate. Am J Physiol 1992; 263:E730–E734. Rising R, Fontvieille AM, Larson DE, Spraul M, Bogardus C, Ravussin E. Racial difference in body core temperature between Pima Indian and Caucasian men. Int J Obes Rel Metab Disord 1995; 19:1–5. Spraul M, Ravussin E, Fontvieille AM, Rising R, Larson DE, Anderson EA. Reduced sympathetic nervous activity. A potential mechanism predisposing to body weight gain. J Clin Invest 1993; 92:1730–1735. Kramer MS, Barr RG, Leduc DG, Boisjoly C, McVeyWhite L, Pless IB. Determinants of weight and adiposity in the first year of life. J Pediatr 1985; 106:10–14. Cutting TM, Fisher JO, Grimm-Thomas K, Birch LL. Like mother, like daughter: familial patterns of overweight are mediated by mothers’ dietary disinhibition. Am J Clin Nutr 1999; 69:608–613. Drabmam RS, Cordua GD, Hammer D, Jarvie GJ, Horton W. Developmental trends in eating rates of normal and overweight preschool children. Child Dev 1979; 50:211– 216. Agras WS, Kraemer HC, Berkowitz RI, Korner AF, Hammer LD. Does a vigorous feeding style influence early development of adiposity? J Pediatr 1987; 110:799–804.

852 122. 123. 124.

125. 126.

127. 128.

129. 130. 131.

132. 133. 134. 135.

136. 137. 138.

139.

140. 141.

Alemzadeh et al. Hill JO, Peters JC. Environmental contributions to the obesity epidemic. Science 1998; 280:1371–1374. Udal JN, Harrison GG, Vaucher Y, Walson PD, Morrow G III. Interaction of maternal and neonatal obesity. Pediatrics 1978; 62:17–21. Vohr BR, McGarvey ST. Growth patterns of large-forgestational-age and appropriate-for-gestational-age infants of gestational diabetic mothers and control mothers at age 1 year. Diabetes Care 1997; 20:1066–1072. Vohr BR, McGarvey ST, Tucker R. Effects of maternal gestational diabetes on offspring adiposity at 4–7 years of age. Diabetes Care 1999; 22:1284–1291. Ravussin E, Lillioja S, Anderson TE, Christin L, Bogardus C. Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber. J Clin Invest 1986; 78:1568–1578. Griffiths M, Payne PR. Energy expenditure in small children of obese and nonobese parents. Nature 1976; 260: 698–700. Gauthier BM, Hickner JM, Ornstein S. High prevalence of overweight children and adolescents in the practice partner research network. Arch Pediatr Adolesc Med 2000; 154:625–628. Stunkard AJ, Srensen TI, Hanis C, Teasdale TW, Chakraborty R, Schull WJ, Schulsinger F. An adoption study of human obesity. N Engl J Med 1986; 314:193–198. Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who have been reared apart. N Engl J Med 1990; 322:1483–1487. Bray GA. The inheritance of corpulence. In: Cioffi LA, James WPT, Van Itallie TB, eds. The Body Weight Regulatory System: Normal and Disturbed Mechanisms. New York: Raven Press, 1981:61–64. Heitmann BL, Harris JR, Lissner L, Pedersen NL. Genetic effects on weight change and food intake in Swedish adult twins. Am J Clin Nutr 1999; 69:597–602. Flier JS. Leptin expression and action: new experimental paradigms. Proc Natl Acad Sci USA 1997; 94:4242– 4245. Flier JS. Clinical review 94: what’s in a name? In search of leptin’s physiologic role. J Clin Endocrinol Metab 1998; 83:1407–1413. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1995; 1:1311–1314. Smith SR. The endocrinology of obesity. Endocrinol Metab Clin North Am 1996; 25:921–942. Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1998; 1:619–625. Emilsson U, Liu YL, Cawthorne MA, Morton NM, Davenport M. Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 1997; 46:313–316. Fehmann HC, Bode HP, Ebert T, Karl A, Go¨ke B. Interaction of GLP-1 and leptin at rat pancreatic ␤-cells: effects on insulin secretion and signal transduction. Hormo Metab Res 1997; 29:572–576. Zhao AZ, Bornfeldt KE, Beavo JA. Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J Clin Invest 1998; 102:869–873. Kieffer TJ, Heller RS, Leech CA, Holz GG, Habener JF. Leptin suppression of insulin secretion by the activation of ATP-sensitive K⫹ channels in pancreatic beta cells. Diabetes 1997; 46:1087–1093.

142.

143. 144.

145.

146.

147. 148.

149. 150.

151. 152. 153.

154.

155. 156.

157.

158. 159.

Seufert J, Kieffer TJ, Leech CA, Holz GG, Moritz W, Ricordi C, Habener JF. Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implication for the development of adipogenic diabetes mellitus. J Clin Endocrinol Metab 1999; 84:670–676. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:425–432. Masuzaki H, Ogawa Y, Isse N, Satoh N, Okazaki T, Shigemoto M, Mori K, Tamura N, Hosoda K, Yoshimasa Y, et al. Human obese gene expression—adipocyte-specific expression and regional differences in the adipose tissue. Diabetes 1995; 44:855–858. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci USA 1997; 94:8878–8883. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382:250– 252. Ioffe E, Moon B, Connolly E, Friedman JM. Abnormal regulation of leptin gene in the pathogenesis of obesity. Proc Natl Acad Sci USA 1998; 95:11852–11857. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, Friedman JM. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci USA 1997; 94:7001–7005. Friedman JM. The alphabet of weight control. Nature 1997; 385:119–120. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A, et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 1995; 377:530–532. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest 1996; 98:1101–1106. Rothwell NJ. Central effects of CRF on metabolism and energy balance. Neurosci Biobehav Rev 1990; 14:263– 271. Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B, Auwerx J. Transient increase in obese gene expression after food intake or insulin administration. Nature 1995; 377:527–529. Zheng D, Jones JP, Usala SJ, Dohm GL. Differential expression of OB messenger RNA in rat adipose tissues in response to insulin. Biochem Biophys Res Commun 1996; 218:434–437. Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab 1996; 81:3419–3423. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334:292–295. Ravussin E, Pratley RE, Maffei M, Wang H, Friedman JM, Bennett PH, Bogardus C. Relatively low plasma leptin concentrations precede weight gain in Pima Indians. Nat Med 1997; 3:238–240. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998; 18:213–215. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte

Obesity in Children

160.

161.

162. 163.

164. 165.

166.

167.

168. 169.

170.

171. 172.

173.

174.

175.

JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998; 392:398–401. Maffei M, Stoffel M, Barone M, Moon B, Dammerman M, Ravussin E, Bogardus C, Ludwig DS, Flier JS, Talley M, et al. Absence of mutations in the human ob gene in obese/diabetic subjects. Diabetes 1996; 45:679–682. Clement K, Garner C, Hager J, Philippi A, LeDuc C, Carey A, Harris TJ, Jury C, Cardon LR, Basdevant A, Demenais F, Guy-Grand B, North M, Froguel P. Indication for linkage of the human OB gene region with extreme obesity. Diebetes 1996; 45:687–690. Reed DR, Ding Y, Xu W, Cather C, Green ED, Price RA. Extreme obesity may be linked to markers flanking the human OB gene. Diabetes 1996; 45:691–694. Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, Stern MP, MacCluer JW, Blangero J. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 1997; 15:273–276. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385:165–168. Hakansson ML, Brown H, Ghilardi N, Skoda RC, Meister B. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J Neurosci 1998; 18:559–572. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19:155–157. Satoh N, Ogawa Y, Katsuura G, Numata Y, Masuzaki H, Yoshimasa Y, Nakao K. Satiety effect and sympathetic activation of leptin are mediated by hypothalamic melanocortin system. Neurosci Lett 1998; 249:107–110. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395:763–770. Havel PJ, Kasim-Karakas S, Mueller W, Johnson PR, Gingerich RL, Stern JS. Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss. J Clin Endocrinol Metab 1996; 81: 4406–4413. Leroy P, Dessolin S, Villageois P, Moon BC, Friedman JM, Ailhaud G, Dani C. Expression of ob gene in adipose cells. Regulation by insulin. J Biol Chem 1996; 271: 2365–2368. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. Leptin: the tale of an obesity gene. Diabetes 1996; 45:1455–1462. Saad MF, Khan A, Sharma A, Michael R, Riad-Gabriel MG, Boyadjian R, Jinagouda SD, Steil GM, Kamdar V. Physiological insulinemia acutely modulates plasma leptin. Diabetes 1998; 47:544–549. Lahlou N, Landais P, De Boissieu D, Bougneres PF. Circulating leptin in normal children and during the dynamic phase of juvenile obesity: relation to body fatness, energy metabolism, caloric intake and sexual dimorphism. Diabetes 1997; 46:989–993. Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 1996; 318: 318–320. Cioffi JA, Shafer AW, Zupancic TJ, Smith-Gbur J, Mikhail A, Platika D, Snodgrass HR. Novel B219/OB recep-

853

176. 177.

178.

179.

180.

181. 182. 183. 184. 185. 186. 187.

188.

189.

190.

191.

192.

tor isoforms: possible role of leptin in hematopoiesis and reproduction. Nat Med 1996; 2:585–589. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest 1997; 100:270–278. Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, Prunkard DE, Porte D Jr, Woods SC, Seeley RJ, Weigle DS. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 1996; 45: 531–535. Chen G, Koyama K, Yuan X, Lee Y, Zhou YT, O’Doherty R, Newgard CB, Unger RH. Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad Sci USA 1996; 93:14795– 14799. Zhou YT, Shimabukuro M, Koyama K, Lee Y, Wang MY, Trieu F, Newgard CB, Unger RH. Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation. Proc Natl Acad Sci USA 1997; 94:6386–6390. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402(6762): 656–660. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S. A role for ghrelin in the central regulation of feeding. Nature 2001; 409:194–198. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407:908–913. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50:707–709. Siiteri PK. Adipose tissue as a source of hormones. Am J Clin Nutr 1987; 45:277S–282S. Bjorntorp P. The regulation of adipose tissue distribution in humans. Int J Obes Rel Metab Disord 1996; 20:291– 302. Sethi J, Hotamisligil GS. The role of TNFa in adipocyte metabolism. Semin Cell Dev Biol 1999; 10:19–29. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995; 95:2409–2415. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cystokines originating from adipose tissue? 1999; 19:972–978. Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. 1996; 2:800–803. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: Close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001; 86:1930–1935. Bray GA, Dahms WT, Swerdloff RS, Fiser RH, Atkinson RL, Carrel RE. The Prader-Willi syndrome: a study of 40 patients and a review of the literature. Medicine (Baltimore) 1983; 62:59–80. Widhalm K, Veitt V, Isigler K. Evidence for decreased energy expenditure in the Prader-Labhart-Willi syndrome: assessment by means of the Vienna calorimeter. Proc Int Cong Nutr 1981;

854 193. 194.

195. 196. 197. 198. 199.

200.

201. 202. 203. 204. 205.

206.

207.

208. 209.

210.

211.

Alemzadeh et al. Schoeller DA, Levitksy LL, Bandini LG, Dietz WW, Walczak A. Energy expenditure and body composition in Prader-Willi syndrome. Metabolism 1988; 37:115–120. Ledbetter DH, Riccardi VM, Airhart SD, Strobel RJ, Keenan BS, Crawford JD. Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N Engl J Med 1981; 304:325–329. Bauman ML, Hogan GR. Laurence-Moon-Biedl syndrome. Report of two unrelated children less than 3 years of age. Am J Dis Child 1973; 126:119–126. Spiegel AM. Pseudohypoparathyroidism. In: Scriver CR, Beadet AL, et al., eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, 1989:2013–2027. Maxfield E, Konishi F. Patterns of food intake and physical activity in obesity. J Am Diet Assoc 1966; 49:406– 408. Roberts SB, Savage J, Coward WA, Chew B, Lucas A. Energy expenditure and intake in infants born to lean and overweight mothers. N Engl J Med 1988; 318:461–466. Ravussin E, Lillioja S, Knowler WC, Christin L, Freymond D, Abbott WG, Boyce V, Howard BV, Bogardus C. Reduced rate of energy expenditure as a risk factor for body-weight gain. N Engl J Med 1988; 318:467–472. Dwyer JT, Feldman JJ, Mayer JK. Adolescent dieters: who are they? Physical characteristics, attitudes and dieting practices of adolescent girls. Am J Clin Nutr 1967; 20:1045–1056. Rossner S. Weight cycling a ‘‘new’’ risk factor? J Intern Med 1989; 226:209–211. Steen SN, Oppliger RA, Brownell KD. Metabolic effects of repeated weight loss and regain in adolescent wrestlers. JAMA 1988; 260:47–50. Bray GA. Lipogenesis in human adipose tissue: some effects of nibbling and gorging. J Clin Invest 1972; 51: 537–548. Fabry P, Tepperman J. Meal frequency a possible factor in human pathology. Am J Clin Nutr 1970; 23:1059– 1068. Dietschy JM, Brown MS. Effect of alterations of the specific activity of the intracellular acetyl CoA pool on apparent rates of hepatic cholesterogenesis. J Lipid Res 1974; 15:508–516. Lakshmanan MR, Nepokroeff CM, Ness GC, Dugan RE, Porter JW. Stimulation by insulin of rat liver b-hydroxyb-methylglutaryl coenzyme A reductase and cholesterolsynthesizing activities. Biochem Biophys Res Commun 1973; 50:704–710. Jenkins DJ, Wolever TM, Vuksan V, Brighenti F, Cunnane SC, Rao AV, Jenkins AL, Buckley G, Patten R, Singer W, et al. Nibbling verses gorging: metabolic advantages of increased meal frequency. N Engl J Med 1989; 321:929– 934. Acheson K, Jequier E, Wahren J. Influence of B-adrenergic blockade on glucose-induced thermogenesis in man. J Clin Invest 1983; 72:981–986. Odeleye OE, de Courten M, Pettitt DJ, Ravussin E. Fasting hyperinsulinemia is a predictor of increased body weight gain and obesity in Pima Indian children. Diabetes 1997; 46:1341–1345. Bogardus C, Lillioja S, Mott D, Reaven GR, Kashiwagi A, Foley FE. Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians. J Clin Invest 1984; 73:800–805. Bandini LG, Schoeller DA, Dietz WH. Energy expenditure in obese and nonobese adolescents. Pediatr Res 1990; 27:198–203.

212.

213. 214.

215.

216. 217. 218.

219.

220. 221. 222.

223. 224. 225. 226.

227. 228.

229. 230.

Wei M, Kampert JB, Barlow CE, Nichaman MZ, Gibbons LW, Paffenbarger RS Jr, Blair SN. Relationship between low cardiorespiratory fitness and mortality in normalweight, overweight, and obese men. JAMA 1999; 282: 1547–1553. Rowland TW. Exercise and Children’s Health. Champaign, IL: Human Kinetics Books, 1990:356. Goran MI, Gower BA, Nagy TR, Johnson RK. Developmental changes in energy expenditure and physical activity in children: evidence for a decline in physical activity in girls before puberty. Pediatrics 1998; 101:887– 891. Garcia AW, Broda MA, Frenn M, Coviak C, Pender NJ, Ronis DL. Gender and developmental differences in exercise beliefs among youth and prediction of their exercise behavior. J School Health 1995; 65:213–219. Bullen BA, Reed RB, Mayer J. Physical activity of obese and nonobese adolescent girls appraised by motion picture sampling. Am J Clin Nutr 1964; 14:211–223. Waxman M, Stunkard AJ. Caloric intake and expenditure of obese boys. J Pediatr 1980; 96:187–193. Maffeis C, Schutz Y, Schena F, Zaffanello M, Pinelli L. Energy expenditure during walking and running in obese and nonobese prepubertal children. J Pediatr 1993; 123: 193–1999. Prentice AM, Lucas A, Vasquez-Velaquez L, Davies PS, Whitehead RG. Are current dietary guidelines for young children a prescription for overfeeding? Lancet 1988; 2: 1066–1069. Energy and protein requirements. Report of a joint FAO/ WHO ad hoc expert committee. Rome, March 22 to April 2, 1971. FAO Nutr Meet Rep Ser 1973; (52):1–118. Goran MI, Carpenter WH, Poehlman ET. Total energy expenditure in 4-to-6-yr-old children. Am J Physiol 1993; 264:E706–E711. Fontvielle AM, Harper IT, Ferraro RT, Spraul M, Ravussin E. Daily energy expenditure by five-year-old children measured by doubly labeled water. J Pediatr 1993; 123: 200–207. Gorn GJ, Goldberg ME. Behavioral evidence for the effects of televised food messages on children. J Consumer Res 1982; 9:200–205. Klesges RC, Shelton ML, Klesges LM. Effects of television on metabolic rate: potential implications for childhood obesity. Pediatrics 1993; 91:281–286. Jeffrey DB, McLellarn RW, Fox DT. The development of children’s eating habits: the role of television commercials. Health Ed Q 1982; 9:174–189. Williams TM, Handford AG. Television and other leisure activities. In: Williams TM, ed. The Impact of Television: A Natural Experiment in Three Communities. Orlando, FL: Academic Press, 1986:143–213. Dietz WH Jr, Gortmaker SL. Do we fatten our children at the television set? Obesity and television viewing in children and adolescents. Pediatrics 1985; 75:807–812. Andersen RE, Crespo CJ, Bartlett SJ, Cheskin LJ, Pratt M. Relationship of physical activity and television watching with body weight and level of fatness among children: results from the Third National Health and Nutrition Examination Survey. JAMA 1998; 279:938–942. Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest 1988; 81:442–448. Kashiwagi A, Verso MA, Andrews J, Vasquez B, Reaven G, Foley FE. In vitro insulin resistance of human adipo-

Obesity in Children

231.

232. 233. 234.

235. 236. 237. 238.

239.

240.

241.

242.

243. 244.

245.

246.

247.

248.

cytes isolated from subjects with noninsulin-dependent diabetes mellitus. J Clin Invest 1983; 72:1246–1254. Caro JF, Dohm LG, Pories WJ, Sinha MK. Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and type II diabetes. Diabetes Metab Rev 1989; 5:665–689. Schade DS, Eaton RP. Dose response to insulin in man: differential effects on glucose and ketone body regulation. J Clin Endocrinol Metab 1977; 44:1038–1053. Le Stunff C, Bougneres PF. Time course of increased lipid and decreased glucose oxidation during early phase of childhood obesity. Diabetes 1993; 42:1010–1016. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbance of diabetes mellitus. Lancet 1963; 1:758–789. Glass AR. Endocrine aspects of obesity. Med Clin North Am 1989; 73:139–160. Rosenbaum M, Leibel RL. Pathophysiology of childhood obesity. Adv Pediatr 1988; 35:73–137. Olefsky JM. Decreased insulin binding to adipocytes and circulating monocytes from obese subjects. J Clin Invest 1976; 57:1165–1172. Odeleye OE, de Courten M, Pettitt DJ, Ravussin E. Fasting hyperinsulinemia is a predictor of increased body weight gain and obesity in Pima Indian children. Diabetes 1997; 46:1341–1345. DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 1989; 38: 387–395. Kida K, Wantabe N, Fujisawa Y, Goto Y, Matsuda H. The relation between glucose tolerance and insulin binding to circulating monocytes in obese children. Pediatrics 1982; 70:633–637. Rossell R, Gomis R, Casmitjana R, Segura R, Vilardell E, Rivera F. Reduced hepatic insulin extraction in obesity relationship with plasma insulin levels. J Clin Endocrinol Metab 1983; 56:608–611. Peiris AN, Mueller RA, Smith GA, Struve MF, Kissebah AH. Splanchnic insulin metabolism in obesity. Influence of body fat distribution. J Clin Invest 1986; 78:1648– 1657. Svedberg J, Bjorntorp, Smith U, Lonnroth P. Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes. Diabetes 1990; 39:570–574. Svedberg J, Bjorntorp P, Smith U, Lonnroth P. Effect of free fatty acids on insulin receptor binding and tyrosine kinase activity in hepatocytes isolated from lean and obese rats. Diabetes 1992; 41:294–298. Felber JP, Ferrannini E, Golay A, Meyer HU, Theibaud D, Curchod B, Maeder E, Jequier E, DeFronzo RA. Role of lipid oxidation in pathogenesis of insulin resistance of obesity and type II diabetes. Diabetes 1987; 36:1341– 1350. Lillioja S, Bogardus C, Mott DM, Kennedy AL, Knowler WC, Howard BV. Relationship between insulin-mediated glucose disposal and lipid metabolism in man. J Clin Invest 1985; 75:1106–1115. Daneman D, Drash AL, Lobes LA, Becker DJ, Baker LM, Travis LB. Progressive retinopathy with improved control in diabetic dwarfism (Mauriac’s syndrome). Diabetes Care 1981; 4:360–365. Jabbar M, Pugliese M, Fort P, Recker B, Lifshitz F. Excess weight and precocious pubarche in children: altera-

855

249.

250. 251.

252. 253.

254.

255.

256.

257.

258. 259.

260.

261.

262. 263. 264.

tions of adrenocortical hormones. J Am Coll Nutr 1991; 4:289–296. Freedman DS, Srinivasan SR, Burke GL, Shear CL, Smoak CG, Harsha DW, Webber LS, Berenson GS. Relation of body fat distribution to hyperinsulinemia in children and adolescents: the Bogalusa Heart Study. Am J Clin Nutr 1987; 46:403–410. Forbes GB. Influence of nutrition. In: Forbes GB, ed. Human Body Composition: Growth, Aging, Nutrition and Activity. New York: Springer-Verlag, 1987:209–247. Loche S, Cappa M, Borrelli P, Faedda A, Crino A, Cella SG, Corda R, Muller EE, Pintor C. Reduced growth hormone response to growth hormone-releasing hormone in children with simple obesity: evidence for somatomedinC mediated inhibition. Clin Endocrinol 1987; 27:145– 153. Leroith D. Insulin-like growth factors. N Engl J Med 1997; 336:633–637. Attia N, Tamborlane WV, Heptulla R, Maggs D, Grozman A, Sherwin RS, Caprio S. The metabolic syndrome and insulin-like growth factor I regulation in adolescent obesity. J Clin Endocrinol Metab 1998; 83:1467–1471. Minuto F, Barreca A, Del Monte P, Fortini P, Resentini M, Morabito F, Giordano G. Spontaneous growth hormone and somatomedin-C-insulin-like growth factor-I secretion in obese subjects during puberty. J Endocrinol Invest 1988; 11:489–494. Suikkari AM, Koivisto VA, Rutanen EM, Yki-Jarvinen H, Karonen SL, Seppala M. Insulin regulates the serum level of low molecular weight plasma insulin-like growth factor binding proteins. J Clin Endocrinol Metab 1988; 66: 266–271. Suikkari AM, Koivisto VA, Koistinen R, Seppala M, YkiJarvinen H. Dose-response characteristics for suppression of low molecular weight plasma insulin-like growth factor-binding protein by insulin. J Clin Endocrinol Metab 1989; 68:135–140. Holly JM, Smith CP, Dunger DB, Edge JA, Biddlecombe RA, Williams AJ, Howell R, Chard T, Savage MO, Rees LH, et al. Levels of the small insulin-like growth factorbinding protein are strongly related to those of insulin in prepubertal and pubertal children but only weakly so after puberty. J Endocrinol 1989; 121:383–387. Holly JMP. The physiological role of IGFBP-1. Acta Endocrinol (Copenh) 1991; 124:55–60. Rosskamp R, Becker M, Soetadji S. Circulating somatomedin-C levels and the effect of growth hormone and somatostation-like plasma levels of growth hormone and somatostation-like immunoreactivity in obese children. Eur J Pediatr 1987; 146:48–50. Kopeleman PG, Weaver JV, Noonan K. Abnormal hypothalamic function and altered insulin secretion and IGFBP-1 binding in obesity. Int J Obes 1990; 14:S75– S79. Novak LP, Hayles AB, Cloutier MD. Effect of HGH on body composition of hypopituitary dwarfs. Four-compartment analysis and composite body density. Mayo Clin Proc 1972; 47:241–246. Amador M, Ramos LT, Morono M, Hermelo MP. Growth rate reduction during energy restriction in obese adolescents. Exp Clin Endocrinol 1990; 96:73–82. Epstein LH, Valoski A, McCurley J. Effect of weight loss by obese children on long-term growth. Am J Dis Child 1993; 147:1076–1080. AvRuskin TW, Pillai S, Kasi K, Juan C, Kleinberg DL.

856

265. 266.

267.

268.

269.

270.

271. 272.

273. 274. 275. 276. 277.

278. 279.

280.

281.

Alemzadeh et al. Decreased prolactin secretion in childhood obesity. J Pediatr 1985; 106:373–378. Kyle LH, Ball MF, Doolan PD. Effect of thyroid hormone on body composition in myxedema and obesity. N Engl J Med 1966; 275:12–17. Kaplowitz PB, Slora EJ, Wasserman RC, Podlow SE, Herman-Giddens ME. Earlier onset of puberty in girls: Relation to increased body mass index and race. Pediatrics 2001; 108:347–353. Chiumello G, Brambilla P, Guarneri MP, Russo G, Manzoni P, Sgaramella P. Precocious puberty and body composition: effects of GnRH analog treatment. J Pediatr Endocrinol Metab 2000; 13:S791–S794. Palmert MR, Mansfield MJ, Crowley WF Jr, Crigler JF Jr, Crawford JD, Boepple PA. Is obesity an outcome of gonadotropin-releasing hormone agonist administration? Analysis of growth and body composition in 110 patients with central precocious puberty. J Clin Endocrinol Metab 1999; 12:4480–4488. Bray G, Gallagher TF Jr. Manifestations of hypothalamic obesity in man: a comprehensive investigation of eight patients and a review of the literature. Medicine (Baltimore) 1975; 54:301–330. Didi M, Didock E, Davies HA, Oligvy-Stuart AL, Wales JKH, Shalet SM. High incidence of obesity in young adults after treatment of acute lymphoblastic leukemia of childhood. J Pediatr 1995; 127:63–67. Stahnke N, Grubel G, Langestein I, Willig RP. Long-term follow-up of children with craniopharyngioma. Eur J Pediatr 1984; 142:179–185. Thomsett MJ, Conte FA, Kaplan SL, Grumbach MM. Endocrine and neurologic outcome in childhood craniopharyngioma: review of effect of treatment in 42 patients. J Pediatr 1980; 97:728–735. Sorva R. Children with craniopharyngioma: early growth failure and rapid postoperative weight gain. Acta Paediatr Scand 1988; 77:587–592. Sklar CA. Craniopharyngioma: endocrine sequalae of treatment. Pediatr Neurosurg 1994; 21:120–123. Jeanrenaud B. An hypothesis on the aetiology of obesity: dysfunction of the central nervous system as a primary cause. Diabetologia 1985; 28:502–513. Powley TL, Laughton W. Neural pathways involved in the hypothalamic integration of autonomic responses. Diabetologia 1981; 20:378–387. Ionescu E, Rohner-Jeanrenaud F, Berthoud HR, Jeanrenaud B. Increases in plasma insulin levels in response to electrical stimulation of the dorsal motor nucleus of the vagus nerve. Endocrinology 1983; 112:904–910. Rohner-Jeanrenaud F, Jeanrenaud B. Involvement of the cholinergic system in insulin and glucagon oversecretion of genetic preobesity. Endocrinology 1985; 116:830–834. Lustig RH, Rose SR, Burghen GA, Velasquez-Mieyer P, Broome DC, Smith K, Li H, Hudson M, Heideman RL, Kun LE. Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by somatostatin agonist. J Pediatr 1999; 135:162– 168. Koontz AJ, MacDonald LM, Schade DS. Octreotide: a long-acting inhibitor of endogenous hormone secretion for human metabolic investigations. Metabolism 1994; 43:24–31. Blundell JE. Impact of nutrition on the pharmacology of appetite. Some conceptual issues. Ann NY Acad Sci 1989; 575:163–170.

282. 283. 284. 285.

286. 287. 288. 289. 290.

291. 292. 293. 294.

295. 296.

297. 298.

299. 300. 301. 302.

Samanin R, Garattini S. Serotonin and the pharmacology of eating disorders. Ann NY Acad Sci 1989; 575:194– 208. Bray GA. Peptides affect the intake of specific nutrients and the sympathetic nervous system. Am J Clin Nutr 1992; 55:265S–271S. Woods SC, West DB, Stein LJ, McKay LD, Lotter EC, Porte SG, Kenney NJ, Porte D Jr. Peptides and the control of meal size. Diabetologia 1981; 20:S305–S313. Stromayer AJ, Greenberg D, Von Heynr, Dornstein L, Balkman C. Blockade of cholecystokinin (CCK) satiety in genetically obese Zucker rats (abstract). Soc Neurosci 1988; 14:1196. Wurtman JJ. Disorders of food intake. Excessive carbohydrate snack intake among a class of obese people. Ann NY Acad Sci 1987; 499:197–202. Drewnoswki A, Greenwood MR. Cream and sugar: human preferences for high-fat goods. Physiol Behav 1983; 30:629–633. Ratcliffe SG, Bancroft J, Axworthy D, McLaren W. Klinefelter’s syndrome in adolescence. Arch Dis Child 1982; 57:6–12. Polychronakos C, Letarte J, Collu R, Ducharme JR. Carbohydrate intolerance in children and adolescents with Turner syndrome. J Pediatr 1980; 96:1009–1014. Epstein LH, Valoski AM, Kalarchian MA, McCurley J. Do children lose and maintain weight easier than adults: a comparison of child and parent weight changes from six months to ten years. Obes Res 1995; 3:411–417. Lowe MR, Caputo GC. Binge eating in obesity. Toward the specification of predictors. Int J Eating Disord 1991; 10:49–55. Schoeller DA. How accurate is self-reported dietary energy intake? Nutr Rev 1990; 48:373–379. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med 1995; 332:621–628. Mertz W, Tsui JC, Judd JT, Reiser S, Hallfrisch J, Morris ER, Steele PD, Lashley E. What are people really eating? The relation between energy intake derived from estimated diet records and intake determined to maintain body weight. Am J Clin Nutr 1991; 54:291–295. Bandini LG, Schoeller DA, Cyr HN, Dietz WH. Validity of reported energy intake in obese and nonobese adolescents. Am J Clin Nutr 1990; 52:421–425. Lichtman SW, Pisarska K, Berman ER, Pestone M, Dowling H, Offenbacher E, Weisel H, Heshka S, Matthews DE, Heymsfield SB. Discrepancy between self-reported and actual caloric intake and exercise in obese subjects. N Engl J Med 1992; 327:1893–1898. Sclafani A, Springer D. Dietary obesity in adult rats: similarities in hypothalamic and human obesity syndromes. Physiol Behav 1976; 17:461–471. Flatt JP, Ravussin E, Acheson KJ, Jequier E. Effects of dietary fat on postprandial substrate oxidation and on carbohydrate and fat balances. J Clin Invest 1985; 76:1019– 1024. Schutz Y, Flatt JP, Jequier E. Failure of dietary fat intake to promote fat oxidation: a factor favoring the development of obesity. Am J Clin Nutr 1989; 50:307–314. Golay A, Bobbioni E. The role of dietary fat in obesity. Int J Obes Rel Metab Disord 1997; 21:S2–S11. Rolls BJ, Shide DJ. The influence of dietary fat on food intake and body weight. Nutr Rev 1992; 50:283–290. America Heart Association. Dietary guidelines for healthy American adults: a statement for health professionals

Obesity in Children

303. 304. 305.

306.

307. 308.

309. 310.

311. 312. 313. 314.

315.

316. 317. 318.

319. 320. 321. 322.

from the nutrition committee, American Heart Association. Circulation 1996; 94:1795–1800. American Diabetes Association. Nutrition recommendations and principles for people with diabetes mellitus. Diabetes Care 2000; 23:S43–S46. Katan MB, Grundy SM, Willett WC. Should a low-fat, high-carbohydrate diet be recommended for everyone? Beyond low-fat diets. N Engl J Med 1997; 337:563–566. Larson DE, Hunter GR, Williams MJ, Kekes-Szabo T, Nyikos I, Goran MI. Dietary fat in relation to body fat and intraabdominal adipose tissue: a cross-sectional analysis. Am J Clin Nutr 1996; 64:787–788. Allred JB. Too much of a good thing? An overemphasis on eating low-fat foods may be contributing to the alarming increase in overweight among US adults. J Am Diet Assoc 1995; 95:417–418. Nicklas TA. Dietary studies of children: The Bogalusa Heart Study experience. J Am Diet Assoc 1995; 95:1127– 1133. Kant AK, Graubard BI, Schatzkin A, Ballard-Barbash R. Proportions of energy intake from fat and subsequent weight change in the NHANES 1 epidemiologic followup study. Am J Clin Nutr 1995; 61:11–17. Lissner L, Heitman BL. Dietary fat and obesity: evidence from epidemiology. Eur J Clin Nutr 1995; 49:79–90. Lenfant C, Ernst N. Daily dietary fat and total energy intakes—Third National Health and Nutrition Examination Survey, phase 1, 1988–1991. MMWR 1994; 43:116– 117. Stephen AM, Wald NJ. Trends in individual consumption of dietary fat in the United States, 1920–1984. Am J Clin Nutr 1990; 52:457–469. Wolever TM, Jenkins DJ, Jenkins AL, Josse RG. The glycemic index: methodology and clinical implications. Am J Clin Nutr 1991; 54:846–854. Bjork I, Granfeldt Y, Liljeberg H, Tovar J, Asp N-G. Food properties affecting the digestion and absorption of carbohydrates. Am J Clin Nutr 1994; 59:699S–705S. Granfeldt Y, Hagander B, Bjork I. Metabolic responses to starch in oat and wheat products. On the importance of food structure, incomplete gelatinization or presence of viscous dietary fiber. Eur J Clin Nutr 1995; 49:189–199. Welch IM, Bruce C, Hill SE, Read NW. Duodenal and ileal lipid suppresses postprandial blood glucose and insulin responses in man: possible implications for dietary management of diabetes mellitus. Clin Sci 1987; 72:209– 216. Trout DL, Behall KM, Osilesi O. Prediction of glycemic index for starchy foods. 1993; 58:873–878. Foster-Powell K, Miller JB. International tables of glycemic index. Am J Clin Nutr 1995; 62:871S–890S. Stephen AM, Sieber GM, Gerster YA, Morgan DR. Intake of carbohydrate and its components—international comparisons, trends overtime, and effects of changing to lowfat diets. Am J Clin Nutr 1995; 62:851S–867S. Nicklas TA, Webber LS, Koschak ML, Berenson GS. Nutrient adequacy of low fat intakes for children: the Bogalusa Heart Study. Pediatrics 1992; 89:221–228. Popkin BM, Haines PS, Patterson RE. Dietary changes in older Americans 1977–1987. Am J Clin Nutr 1992; 55: 823–830. Grey NJ, Goldring S, Kipnis DM. The effect of fasting, diet, and actinomycin D on insulin secretion in the rat. J Clin Invest 1970; 49:881–889. Grey NJ, Kipnis DM. Effect of diet composition on the

857

323.

324. 325.

326. 327.

328. 329. 330.

331.

332. 333. 334. 335. 336.

337.

338.

339. 340. 341.

hyperinsulinemia of obesity. N Engl J Med 1971; 285: 827–831. Bagdade JD, Bierman EL, Porte D Jr. The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest 1967; 46:1549–1557. Floyd JC Jr, Fajans SS, Conn JW, Khoph RF, Rull J. Stimulation of insulin secretion by amino acids. J Clin Invest 1966; 1487–1502. Rabinowitz D, Zierler KL. Forearm metabolism in obesity and its response to intra-arterial insulin. Characterization of insulin resistance and evidence for adaptive hyperinsulinism. J Clin Invest 1962; 41:2173–2181. Ludwig DS, Majzoub JA, Al-Zahrani A, Dallal GE, Blanco I, Roberts SB. High glycemic index foods, overeating, and obesity. Pediatrics 1999; 103:E26. Spieth LE, Harnish JD, Lenders CM, Raezer LB, Pereira MA, Hangen SJ, Ludwig DS. A low-glycemic index diet in the treatment of pediatric obesity. Arch Pediatr Adolesc Med 2000; 154:947–951. Epstein LH, Valoski A, Koeske R, Wing RR. Familybased behavioral weight control in obese young children. J Am Diet Assoc 1986; 86:481–484. Valoski A, Epstein LH. Nutrient intake of obese children in a family-based behavioral weight control program. Int J Obes 1990; 14:667–677. Epstein LH, Wings RR, Steranchak L, Dickson B, Michelson J. Comparison of family based behavior modification and nutrition education for childhood obesity. J Pediatr Psychol 1980; 5:25–36. Epstein LH, Valoski AM, Vara LS, McCurley J, Wisniewski L, Kalarchian MA, Klein KR, Shrager LR. Effects of decreasing sedentary behavior and increasing activity on weight change in obese children. Health Psychol 1995; 14:109–115. Epstein LH, Valoski A, Wing RR, McCurley J. Ten-year follow-up of behavioral family-based treatment for obese children. JAMA 1990; 264:2519–2523. Epstein LH, Valoski AM, Wing RR, McCurley J. Ten year outcomes of behavioral family-based treatment for childhood obesity. Health Psychol 1994; 13:373–383. Sothern MS, von Almen TK, Schumacher HD, Suskind RM, Blecker U. A multidisciplinary approach to the treatment of childhood obesity. Del Med J 1999; 71:255–261. National Task Force on the Prevention and Treatment of Obesity, National Institutes of Health. Very low-calorie diets. JAMA Review 1993; 270:967–974. Andersen T, Backer OG, Stokholm KH, Quaade F. Randomized trial of diet and gastroplasty compared with diet alone in morbid obesity. N Engl J Med 1984; 310:352– 356. Wadden TA, Stunkard AJ. Controlled trial of very low calorie diet, behavior therapy, and their combination in the treatment of obesity. J Consult Clin Psychol 1986; 54: 482–488. Flatt JP, Blackburn GL. The metabolic fuel regulatory system: implications for protein-sparing therapies during caloric deprivation and disease. Am J Clin Nutr 1974; 27: 175–187. Sherwin RS, Hendler RG, Felig P. Effect of ketone infusion on amino acid and nitrogen metabolism in man. J Clin Invest 1975; 55:132–1390. Robinson TN. Behavioural treatment of childhood and adolescent obesity. Int J Obes Rel Metab Disord 1999; 2: S52–S57. Sothern MS, Loftin M, Suskind RM, Udall JN Jr, Blecker

858

342. 343.

344. 345. 346.

347.

348.

349.

350. 351.

352.

353.

354.

Alemzadeh et al. U. The impact of significant weight loss on resting energy expenditure in obese youth. J Invest Med 1999; 47:222– 226. Boeck MA. Safety and efficiency of fluoxetine in morbidly obese adolescent females. Int J Obes 1991; 15(suppl 3):60. Golay A, Allaz AF, Ybarra J, Bianchi P, Saraiva S, Mensi N, Gomis R, de Tonnac N. Similar weight loss with lowenergy food combining or balanced diets. Int J Obes Rel Metab Disord 2000; 24:492–496. Mahan K, Escott-Stump S. Krauses’s Food Nutrition and Diet Therapy. Philadelphia: WB Saunders, 1996:463– 469. Apfelbaum M, Bostarron J, Lacatis D. Effect of caloric restriction and excessive caloric intake on energy expenditure. Am J Clin Nutr 1971; 24:1405–1409. Hagan RD, Upton SJ, Wong L, Whittam J. The effects of aerobic conditioning and/or caloric restriction in overweight men and women. Med Sci Sports Exerc 1986; 18: 87–94. Sothern MS, Hunter S, Suskind RM, Brown R, Udall JN Jr, Blecker U. Motivating the obese child to move: the role of structured exercise in pediatric weight management. South Med J 1999; 92:577–584. Jakicic JM, Winters C, Lang W, Wing RR. Effects of intermittent exercise and use of home exercise equipment on adherence, weight loss, and fitness in overweight women: a randomized trial. JAMA 1999; 282:1554– 1560. Serdula MK, Mokdad AH, Williamson DF, Galuska DA, Mendlein JM, Heath GW. Prevalence of attempting weight loss and strategies for controlling weight. JAMA 1999; 282:1353–138. Selikowitz M, Sunman, Pendegast A, Wright S. Fenfluramine in Prader-Willi syndrome: a double blind, placebo controlled trail. Arch Dis Child 1990; 65:112–114. Oleandri SE, Maccario M, Rossetto R, Procopio M, Grottoli S, Avogadri E, Gauna C, Ganzaroli C, Ghigo E. Three-month treatment with metformin or dexfenfluramine does not modify the effects of diet on anthropometric and endocrine-metabolic parameters in abdominal obesity. J Endocrinol Invest 1999; 22:134–140. Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335:609–616. Freemark M, Bursey D. The effect of metformin on body mass index and glucose tolerance in obese adolescents and fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics 2001; 107:E55. Kay JP, Alemzadeh R, Langley G, D’Angelo L, Smith P, Holshouser S. Beneficial effects of Metformin in nor-

355.

356. 357. 358. 359. 360. 361. 362. 363. 364.

365.

366. 367. 368. 369.

370. 371.

moglycemic morbidly obese adolescents. Metabolism 2001; 50:1457–1461. Alemzadeh R, Langley G, Upchurch L, Smith P, Slonim AE. Beneficial effect of diazoxide in obese hyperinsulinemic adults. J Endocrinol Metab 1998; 83:1911– 1915. Matsuo T, Odaka H, Ikeda HE. Effect of an intestinal disccharidase inhibitor (AO-128) on obesity and diabetes. Am J Clin Nutr 1992; 55:314S–317S. James WP, Avenell A, Broom J, Whitehead J. A one-year trial to assess the value of orlistat in the management of obesity. Int J Obes Rel Metab Disord 1997; 21:S24–S30. Wunschel IM, Sheikholislam BM. Is there a role for dietetic foods in the management of diabetes and/or obesity? Diabetes Care 1978; 1:247–249. O’Leary JP. Gastrointestinal malabsorptive procedures. Am J Clin Nutr 1992; 55:567S–570S. Alden JF. Gastric and jejunoileal bypass: a comparison in the treatment of morbid obesity. Arch Surg 1997; 112: 799–806. Saltzstein EC, Gutmann MC. Gastric bypass for morbid obesity; preoperative and postoperative psychological evaluation of patients. Arch Surg 1980; 115:21–23. Freeman JB, Burchett H. Failure rate with gastric partitioning for morbid obesity. Am J Surg 1977; 112:799–806. Bray GA, Gray DS. Treatment of obesity: an overview. Diabetes Metab Rev 1988; 4:653–679. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269:540–543. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M. Recombinant leptin for weight loss in obese and lean adults. JAMA 1999; 282:1568–1575. Ravussin E, Burnand B, Schutz Y, Jequier E. Energy expenditure before and during energy restriction in obese patients. Am J Clin Nutr 1985; 41:753–759. Brownell KD, Greenwood MR, Stellar E, Sharager EE. The effects of repeated cycles of weight loss and regain in rats. Physiol Behav 1986; 38:459–464. Nuutienen O, Knip M. Long-term weight control in obese children: persistence of treatment outcome and metabolic changes. Int J Obes 1992; 16:279–287. Sigal RJ, El-Hashimy M, Martin BC, Soeldner JS, Krolowski AS, Wanam JH. Acute postchallenge hyperinsulinemia predicts weight gain. Diabetes 1997; 46:1025– 1029. Black O, James WPT, Besser CM. A report of the Royal College of Physicians. J R Coll Physicians Long 1983; 17:5–65. Robinson TN. Reducing children’s television viewing to prevent obesity: a randomized controlled trial. JAMA 1999; 282:1561–1567.

35 Hyperlipoproteinemias in Children and Adolescents Kurt Widhalm University of Vienna, Vienna, Austria

I.

particles are responsible for the transport of lipids after absorption from the gut to the liver and to the organs (Fig. 1). Figure 1 shows clearly that cholesterol and triglycerides are ingested into the gastrointestinal tract and are converted to chylomicrons. These triglyceride-rich particles are taken up by the liver by means of a specific apo E receptor and are secreted as very-low-density lipoproteins (VLDL) into the circulation. These particles are converted to the short-lived intermediate-density lipoproteins (IDL), which are formed into low-density lipoproteins (LDL), which are smaller, denser, and contain more cholesterol. These most atherogenic vehicles are taken up by the liver by means of LDL receptors and, to a smaller extent, by a nonreceptor pathway by the so-called scavenger cells. The smallest lipoproteins, high-density lipoproteins (HDL), are partly responsible for the transport of LDL back to the liver. The classification and composition of the various lipoproteins are shown in Table 1. In regard to the atherogeneity of the various plasma lipoproteins, there is enough evidence, both on a pathophysiological and on a epidemiological level, that the most pathogenic particles are LDL, and, to a lesser extent, VLDL. In contrast, HDL particles have a protective function against atherogenesis: subjects with high HDL levels are rarely affected with cardiovascular diseases. However, subjects with low levels are considered to be at higher risk, even if they have normal cholesterol concentrations. If total and LDL cholesterol levels are elevated, fatty streaks and fibrous plaques develop in nonhuman primates, mainly due to diets high in saturated fatty acids and cholesterol. In adults, but also in adolescents, the amount of saturated fat in the diet influences the concentration of serum cholesterol strongly. However, it seems very likely that genetic factors also are involved in the regulation of cholesterol metabolism, because there are

INTRODUCTION

A body of evidence now shows that elevated levels of plasma cholesterol, especially low-density lipoprotein (LDL) cholesterol, are associated with an increased probability of premature cardiovascular disease in the adult. This is particularly true for subjects with the most common familial hypercholesterolemia (a dominant disorder of the lipoprotein metabolism) who usually have a manifest atherosclerosis in the fourth to fifth decade. There is also no doubt that atherosclerosis starts in childhood and therefore preventive measures should be initiated as early as possible to prevent progression of the disease. Hyperlipoproteinemias are biochemical abnormalities in which one or more lipids/lipoproteins is either elevated or has an abnormal composition. It should be the goal of any pediatrician or general physician to detect these abnormalities during childhood in order to start as early as possible with preventive therapeutic measures. It is not well established that early reduction of atherogenic lipoproteins is associated with delayed development of atherosclerosis; however, many facts from adult studies support this theory very strongly. Nevertheless, the power of knowledge from intervention studies in adult population would not allow for randomized studies in the pediatric age group because of ethical concerns. In this chapter the main focus will be on the clinical aspects of diagnostic and therapeutic procedures for lipoprotein disorders in children.

II.

LIPOPROTEIN BACKGROUND AND BASICS

There is a strong relationship between the intake of fats, in particular saturated fats, and the development of premature cardiovascular diseases. One of the main mechanisms involved in that process is most probably the concentration and composition of plasma lipoproteins. These 859

860

Widhalm

Figure 1

Schematic pathway of lipids and lipoprotein.

considerable differences in the effect of diet on the levels of plasma lipoproteins. Intervention studies in adults have clearly shown that lowering blood cholesterol levels is associated with a reduction of coronary heart disease. This association has not yet been found in children; most probably it will be very difficult to carry out a study to establish a direct scientific evidence for this relation. Thus, several indirect data are available to support the hypothesis, which means that lowering of elevated plasma lipoproteins, mainly LDL cholesterol, is indicated even in the pediatric age group. First, there is clear evidence that early coronary atherosclerosis often begins in childhood and adolescence and is directly related to high serum total cholesterol, LDL cholesterol, VDL cholesterol, and low HDL levels. Second, children and adolescents from families with a higher incidence of premature coronary heart diseases often have elevated total cholesterol and LDL cholesterol levels. Third, there is a strong familial aggregation of total, LDL, and HDL cholesterol levels in children and their parents. Finally, among the genetically based disorders of lipoprotein metabolism, the most common are familial hypercholesterolemia and familial combined hyperlipidemia. In affected families premature cardiovascular diseases are much more frequently diagnosed than in families with desirable cholesterol concentrations. Lipoprotein disorders are therefore, from a preventive point of view, very important and can be diagnosed in

children. This should encourage the enforcement of therapeutic and preventive strategies for the whole family.

III.

DEFINITION OF HYPERLIPOPROTEINEMIA/ DYSLIPOPROTEINEMIA

The concentration mainly of total cholesterol and triglycerides in plasma or within the various lipoprotein particles is the basis of laboratory diagnosis of hyperlipidemia or hyperlipoproteinemia. Usually levels exceeding the 95th percentile or below the 5th percentile are considered abnormal. In most studies the Lipid Research Clinics Program (LRCP)-levels were used as reference guidelines for children and adults (Table 2). According to the Expert Panel on Blood Cholesterol Level in Children and Adolescents of the National Cholesterol Education Program and the American Academy of Pediatrics, children with a parental history of elevated total cholesterol levels (>240 mg/dl) should be tested for their cholesterol levels. Children with other risk factors or with incomplete family history should be screened by the pediatrician. Children with total cholesterol levels less than 170 mg/dl have optimal levels and do not require intervention. Children with cholesterol levels between 170 and 200 mg/dl should undergo another cholesterol measurement and the two values should be averaged. If this level is greater than 170 mg/dl, a lipid profile is recommended. On the other hand, this expert panel has recommended

Hyperlipoproteinemias Table 1

861

Lipoprotein Classification

Chylomicrons Density (g/ml) Diameter (nm) Origin Chol TG Phospholipids and proteins Very-low-density lipoprotein Density (g/ml) Diameter (nm) Origin Chol TG Phospholipids and proteins Intermediate-density lipoprotein Density (g/ml) Diameter (nm) Origin Chol TG Phospholipids and proteins Low-density lipoprotein Density (g/ml) Diameter (nm) Origin Chol TG Phospholipids and proteins High-density lipoprotein Density (g/ml) Diameter (nm) Origin Chol TG Phospholipids and proteins

0, 95 75–1200 Intestine 5 90 5 0, 95–1006 30–80 Liver 13 65 22 1006–1019 25–35 Liver, VLDL 35 40 25 1019–1063 18–25 Liver, VLDL, IDL 43 10 47 1063–121 5–12 Liver, intestine, other 18 2 80

that all children with a family history of premature coronary heart disease (before the age of 55 years in a parent or grandparent) should undergo a complete lipoprotein profile. Thus, the discriminating parameter is the LDL cholesterol concentration: if this is >130 mg/dl, it is considered to be elevated. Levels 190 mg/dl or >160 mg/dl) and a family history of cardiovascular diseases after a 3–6 month diet period, the administration of bile-acid resins seems to be indicated. These drugs, which are not absorbed from the gastrointestinal tract, are not very palatable and therefore only a few children and adolescents adhere to this type of drug treatment. Reported results range between 15 and 25% LDL cholesterol reduction. Even in children who were placed on these drugs from years, no impairment of growth or development has been observed. However, it

Hyperlipoproteinemias

would seem advantagous to add mainly fat-soluble vitamin supplements in order to ensure adequate vitamin nutrition. The use of the widely used statins (inhibitors of the 3-hydroxy-methylglutaryl-COA-reductase), which are the standard drugs for treatment of adults, is restricted to few trials. These drugs are not generally licensed for subjects under the age of 18 years. However, it has been shown very clearly that even their use over years is not associated with any adverse effects on growth, development, or other variables. Furthermore, no serious side effects have been reported, whereas the LDL cholesterol-lowering effects range between 20 and 35%. These drugs might be also the agents of choice in adolescents with markedly elevated LDL cholesterol levels, because there are no other regimens currently available or on the horizon for the near future. For patients with extremely high LDL cholesterol levels and those with homozygous forms of FH, repeated LDL apheresis can be effective treatment. In some patients liver transplantation and concomitant liver–heart transplantations have been performed to remove the organ responsible for the metabolic disorder. Gene therapy has been performed in some affected subjects; however, this type of treatment seems to be far from introduction into routine use. It has also not been possible so far to achieve longterm LDL cholesterol reductions.

863

very rarely in children. If it does, the association with overnutrition and obesity is not uncommon. In such cases reduction in energy intake is important, and the intake of saturated fats should be lowered as well. Excessive forms of hypertriglyceridemia (former type I or type V hyperlipidemia) are rare and characterized by markedly increased concentrations of triglycerides through the presence of chylomicrons. The lack of lipoprotein-lipase or the activating enzyme (Apo C-II) is responsible for this disorder. Patients with this disorder often have triglyceride levels of 1000 mg/dl and even higher, which causes a milky plasma. The risk for atherosclerosis is relatively low; however, in some cases pancreatitis can occur as a complication. In some patients a strongly fat-restricted diet can achieve marked reduction of triglycerides, but in many of the affected subjects a sustained lowering of triglycerides cannot be attained. Diets containing MCT are not really established, whereas some attempts with fish oil (w-3fatty acids) have been made. Drugs are not indicated for treatment of patients.

REFERENCES 1. 2.

VI.

FAMILIAL COMBINED HYPERLIPIDEMIA

This type of lipoprotein disorder is relatively common (3– 5:1,000) and is inherited as an autosomal dominant trait. In affected families different types of hyperlipidemias can be observed. One-third of the subjects present with hypercholesterolemia, one third with isolated hypertriglyceridemia, and one third have both elevated cholesterol and triglyceride levels. Patients with this disorder usually have LDL particles that are enriched with Apo B, thus estimation of Apo B might differentiate between FCH and the familial hypertriglyceridemia. Subjects with FCH have an increased risk for cardiovascular diseases; however, the risk seems to be lower than in patients with FH. Treatment consists of institution of a classic low-fat (saturated fats ↓, monounsaturated fats ↑, low cholesterol) diet; in some patients drugs are necessary, in which cases statins and fibrates are commonly used. There are very few reports detailing pediatric patients. Even the diagnosis is not very easy in this age group, because the lipid and lipoprotein pattern is not fully developed, as in adults.

3. 4. 5. 6.

7.

8. 9. 10.

VII.

HYPERTRIGLYCERIDEMIA/ CHYLOMICRONEMIA SYNDROME

Familial hypertriglyceridemia, which is characterized by an increased concentration of VLDL particles, presents

11.

PDAY Research Group: Natural history of aortic and coronary atherosclerotic lesions in Youth. Findings from the PDAY Study. Atheroscler Thromb 1993; 13:1291–1298. Strong JP, Malcolm GT, McMahan CA, et al. Prevalence and extent of atherosclerosis in adolescents and young adults. Implications for Prevention from the Pathobiological Determinants of atherosclerosis in Youth Study. JAMA 199; 281:727–735. American Academy of Pediatrics. Committee on Nutrition. Cholesterol in childhood. Pediatrics 1998; 101:141–147. Hooper L, Summerbell CD, Higgins JPT, et al. Dietary fat intake and prevention of cardiovascular disease: systematic review. Br Med J 2001; 322:757–763. Kwiterovich PO Jr. Identification and treatment of heterozygous familial hypercholesterolemia in children and adolescents. Am J Cardiol 1993; 72:30B–37B. Williams RR, Hunt SC, Schumacher C, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 1993; 72:171–176. Assouline L, Levy E, Feoli-Fonseca JC, et al: Familial hypercholesterolemia: molecular, biochemical, and clinical characterization of a French-Canadian Pediatric Population. Pediatrics 1995; 96:239–246. Griffin TC, Christoffer KK, Brians HJ, et al. Family history evaluation as a predictive screen for childhood hypercholesterolemia. Pediatrics 1989; 884:365–373. Nissen HK, Guldberg P, Hansen AB, et al. Clinically applicable mutation screening in familial hypercholesterolemia. Human Mutat 1996; 8:168–177. Tonstad S. A rational approach to treating hypercholesterolemia in children. Drug Safety 1997; 16:330–341. Widhalm K, Brazda G, Schneider B, et al. Effect of soy protein diet versus standard low fat, low cholesterol diet on lipid and lipoprotein levels in children with familial or polygenic hypercholesterolemia. J Pediatr 1993; 123:30– 34.

864 12.

13.

Widhalm Stein EA,, Illingworth DR, Kwiterovich PO Jr, et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia. A randomized controlled trial. JAMA 1999; 281:137–144. The Writing Group for the DISC collaborative Research Group. Efficacy and safety of lowering dietary intake of fat cholesterol in children with elevated low-density lipoprotein cholesterol. JAMA 1995; 273:1429–1435.

14.

15.

Widhalm K, Koch S, Pakosta R, et al. Serum lipids, lipoproteins and apolipoproteins in children with and without family history of premature coronary heart disease. J Am Coll Nutr 1992; 11:32s–35s. Cortner JA, Coates PM, Liacomas CA, et al. Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management. J Pediatr 1993; 123:177– 184.

36 Endocrine Disorders After Cancer Therapy Raphae¨l Rappaport and Elisabeth Thibaud Hoˆpital Necker–Enfants Malades, Paris, France

I.

endocrinology and oncology clinic. Most treatment protocols combine chemotherapy and irradiation, but chemotherapy is becoming an important and sometimes exclusive form of treatment for many conditions. It is therefore important to consider the detailed structure of a given treatment for each child, focusing on the location of the radiation fields causing direct damage to endocrine glands or to the skeleton, and on the use of cytotoxic chemotherapy that could be responsible for direct damage to the gonads (Table 1). In general, the time at which the late endocrine effects may occur is variable.

INTRODUCTION

Advances in the treatment of malignant diseases have resulted in a dramatic fall in mortality rates for most of them, which means that an increasing number of survivors may have to cope with the late effects of cancer treatment. The protocols used include surgery, tumor-targeted radiotherapy, chemotherapy, and total-body irradiation and/or intensive chemotherapy followed by bone marrow transplantation. There has now been a sufficient follow-up interval for most conditions and for the current therapeutic regimens, so that most children can be followed with a prospective view of most potential complications. Appropriate therapeutic decisions can therefore be taken to avoid or minimize severe complications such as dwarfism or abnormal pubertal development. Although the primary goal is still to cure the malignant disease, knowledge of the side effects of treatment should contribute to the choice of any new therapeutic protocol. According to the British National Registry of Childhood Tumors, acute leukemias, mostly lymphoblastic leukemias occurring in early childhood, account for one-third of all registrations. Lymphomas, most frequently nonHodgkin’s type, account for a further 10% with a higher incidence in late childhood. Brain and spinal tumors make up 25% of all tumors, and retinoblastoma, which is often bilateral and familial, is a major condition requiring cranial irradiation in infants. Most of these tumors require high dosages of radiation, which severely damage the hypothalamus and pituitary gland. The remaining childhood cancers include gonadal, bone and soft tissue sarcomas, and embryonal tumors, such as Wilms’ tumors and neuroblastoma (1). Because most children with malignant diseases are treated according to nationally or internationally driven protocols in pediatric oncology centers, it has now become clear that the most constructive evaluation and follow-up of survivors might be undertaken by a combined

II.

GROWTH

Growth depends on growth hormone secretion and the timing of puberty but also on a number of factors unrelated to pituitary deficiency, such as chemotherapy, associated acute and chronic disease effects, and exposure of cartilage plates to irradiation, as seen in children with spinal or total-body irradiation. Spontaneous growth after cranial irradiation is shown in Figure 1.

A.

After High-Dosage Cranial Irradiation

Radiation doses in excess of 3000 cGy reduce final height in most children. The height loss is progressive, reaching about 1 standard deviation (SD) before puberty and 2 SD at final height. Growth retardation develops more rapidly, within 2 years, in patients given 4500 cGy or more. Bone age is delayed, and typical features of GH deficiency may appear in prepubertal patients (2).

B.

After Low-Dosage Cranial Irradiation

Variable patterns of growth have been reported. Typically, there is a moderate height reduction during the acute phase of the disease and the associated induction chemotherapy. This is followed by a subnormal or normal 865

866

Rappaport and Thibaud

Table 1 Targets Critical to Growth According to Irradiation Protocols

Growth hormonea Sex steroidsb Thyroid hormoneb Skeleton

Cranial

Craniospinal

Total body

⫹⫹ ⫹ ⫹

⫹⫹ ⫹ ⫹⫹ ⫹⫹

⫹ ⫹ ⫹⫹ ⫹

a

Hypothalamic and pituitary defect. Primary and/or secondary defects according to radiation protocols.

b

growth rate until puberty. An additional height loss of 1 SD may occur during puberty (2). A few patients have shown normal growth after irradiation, despite a GH deficiency (3). The overall mean loss in adult height in patients treated with cranial doses of 1800–2400 cGy varies from 0.9 to 1.4 SD (4–6). Final short stature is more likely to occur after intensive induction chemotherapy in children irradiated at a younger age, if puberty began earlier, and in patients with familial short stature. Because GH deficiency remains the prime candidate as a cause of growth retardation, all children should be tested for GH secretion before and at onset of puberty if they demonstrate a significant decrease in linear growth. This issue is even more critical in patients, most frequently girls, presenting with sexual precocity. These irradiated patients are prone to obesity in the long-term with increased circulating leptin levels independent of GH status (7).

C.

After Spinal or Total-Body Irradiation

Some protocols include extensive skeletal irradiation, and these patients are exposed to more severe and early

growth retardation. One group of patients includes those given spinal irradiation (generally 2400 cGy) in addition to cranial irradiation for medulloblastoma. They may lose up to 2 SD of height within 2 years following irradiation and have a mean final height loss of 2–3 SD, with a short upper segment largely attributed to the lack of spinal growth (8, 9). Children irradiated before age 6 years are more severely affected. Some degree of reduced spinal growth and disproportion also occurs after whole-abdomen or, more rarely, after flank irradiation, as performed for abdominal malignancies, such as Wilms’ tumors (10). Total-body irradiation as conditioning for bone marrow transplantation is another therapy that leads to growth retardation unrelated to GH deficiency. It is increasingly used as the ultimate therapy in leukemia and in some nonmalignant diseases (11, 12). The outcome of growth in these patients depends on the radiation dosage and its fractionation (13). An immediate growth retardation is observed in patients given a single 1000 cGy dose. The more recent protocols with fractionated doses of 800–1000 cGy have little impact on short-term growth. Final height has been reported to decrease by 1 SD with diminished sitting height. GH deficiency was found in 30% of these patients, with some improvement in GH production over the years (14). Difference in treatment protocols may explain some discrepancy among reported data. Other factors such as prolonged corticosteroid therapy, renal failure, and chronic graft-vs.-host disease may also contribute to growth retardation. The frequency and severity of GH deficiency depend on the radiation protocols, and GH may not play a major role in the growth disturbance of these patients (13, 15–17). Growth retardation may be caused by several factors, the most important being direct skeletal irradiation, so that the contribution of GH deficiency to a decreased growth rate remains difficult to assess. In adult long-term survivors serum insulin-like growth factor 1 (IGF-1) values were only partly correlated with GH secretion. Normal IGF-1 levels were found in contrast with evidence of GH deficiency (18, 19) and could be explained by increased adiposity. Primary thyroid insufficiency occurs in most patients given total-body irradiation. Elevated plasma TSH appears within 2 years, but fewer than 10% of patients have overt hypothyroidism. Most boys and girls irradiated before puberty develop primary gonadal failure with elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Delayed or absence of sex steroid secretion then contributes to growth retardation at the age of puberty and requires replacement therapy.

D. Figure 1 Mean prepubertal height changes after cranial and craniospinal irradiation and final heights in patients treated for leukemia, head and neck tumors, or medulloblastoma. (From Ref. 61.)

After Chemotherapy

The effect of chemotherapy on growth is difficult to assess because many factors, such as differences among protocols, infection, poor nutrition, and the disease itself, may play a role. These patients do not develop GH deficiency after treatment by chemotherapy alone, but the moderate,

After Cancer Therapy

867

In contrast, gonadotropin deficiency may develop within a few years after high-dosage cranial radiation for tumors, as indicated by arrested puberty, primary amenorrhea in girls, and absence of LH and FSH response to an LH-releasing hormone (LHRH) stimulation test (28). Some girls suffer only from menstrual irregularities, and their impact on fertility has not been documented. Gonadotropin deficiency is usually associated with GH deficiency and moderate hyperprolactinemia, a combination indicating multiple hypothalamic pituitary deficiencies.

early growth retardation, as reported in children also irradiated for leukemia (20) or cranial tumors (9), may be related to the induction chemotherapy and caused by a transient insensitivity to growth hormone (21). However, a recent study showed that the final height of patients treated for leukemia with chemotherapy alone was normal (6). There may even be catch-up growth in immunodeficient growth-retarded children after preparative chemotherapy for bone marrow transplantation (13). Because some data still suggest that chemotherapy has a moderately detrimental effect on growth (5), follow-up of all patients remains necessary. However, growth is unlikely to be a critical issue in nonirradiated patients.

III.

IV.

The first case of induced hypopituitarism after cranial radiation for a tumor distant from the hypothalamic–pituitary region was reported in 1966 (29). Growth hormone deficiency is at present the most common pituitary defect occurring after radiation (Table 2). The hypothalamus is more radiosensitive than the pituitary gland, so that GH deficiency is probably caused by a dysfunction of GHreleasing hormone (LHRH) somatostatin control. This may explain the differences observed between spontaneous and pharmacologically stimulated GH secretion, as well as the persistence of normal GH responses to the GHRH stimulation test (31, 33). Experimental studies in monkeys (32) and the changes observed in the other anterior pituitary functions in adult patients (33) support such a hypothesis. The severity and frequency of pituitary defects vary according to the initial disease and its specific therapeutic regimens, but the radiation dosage effectively delivered to the hypothalamic–pituitary region defines the risk factor. It depends on the total dosage, the number of fractions, and the duration of treatment: a given dose delivered in a shorter time period is more likely to cause GH deficiency than one delivered over a long period (2, 34). Assessment of GH secretion requires a pharmacological GH stimulation test (35). If growth is retarded despite normal GH peak responses, it has been suggested that one

PUBERTY

A surprising finding is that children who have received cranial irradiation may present with early or true precocious puberty (22, 23). This is in contrast with the delayed puberty usually accompanying idiopathic GH deficiency. Early puberty occurred in girls after cranial irradiation for leukemia, and the children who had been irradiated when very young tended to have the earliest puberty (24, 25). This is an important consideration because of the risk of excessive bone maturation and early epiphyseal closure. It also tends to narrow the window of opportunity to treat with human growth hormone (hGH) before secretion of sex steroids. Puberty not only occurs earlier but it is shortened with early menarche (26). The final height loss may even be more severe if full-blown precocious puberty is associated with untreated GH deficiency. In patients with optic glioma presenting with precocious puberty at the time of irradiation, the persistence of a normal growth rate within 1 or 2 years after cranial radiation may be misinterpreted, and excessive progression of bone age will lead to early cessation of growth. Growth hormone testing is then necessary 1 year after irradiation to unmask any associated GH deficiency and allow GH therapy to begin (27).

Table 2

GROWTH HORMONE SECRETION

Endocrine Abnormalities After External Cranial Irradiation in Patients Evaluated at Least 4 Years After Irradiationa Frequency of cases with endocrine abnormality (%)

Cause Leukemia, 24 Gy Face and neck tumors, 25–45 Gy Medulloblastoma, 25–45 Gy Optic glioma, 45–55 Gy a

GH deficiency

Cases (n)

Complete

Partial

Thyroidb

ACTH

LHRHc

86 56 59 39

30 46 52 77

22 22 24 23

2 35 47 46

0 7 8 3

3 16 20 40

Expressed as percentage of affected cases in each patient group. GH deficiency; complete, after stimulation, GH peak