Dennis M. Styne Pediatric Endocrinology · To my loving wife Donna and my amazing children Rachel,...

Pediatric Endocrinology

123

A Clinical Handbook

Dennis M. Styne

Dennis M. Styne


A Clinical Handbook

ISBN 978-3-319-18370-1 ISBN 978-3-319-18371-8 (eBook) DOI 10.1007/978-3-319-18371-8

Library of Congress Control Number: 2015940868

© Springer International Publishing Switzerland 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.

Printed on acid-free paper

This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG Switzerland

Dennis M. Styne Pediatrics University of CaliforniaDavis School of Medicine Sacramento , CA , USA

To my loving wife Donna and my amazing children Rachel, Jonathan, Juliana, and Aaron, my wonderful son-in-law Michael, and my beautiful grandchildren Cooper and Samara all of whom immeasurably enrich my life.

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This book is written for practitioners ranging from students to residents, fam-ily physicians, and pediatricians puzzling over the approach to a child who seems to have an endocrine disorder in order to help readers evaluate and treat the more straightforward pediatric endocrine issues. The information in the text might prepare a provider for a meeting with parents of a child with an endocrine condition in order to improve communication or alternatively might provide the facts that will allow the practitioner to avoid an unneces-sary consultation. The chapters begin with the basic physiologic processes and concepts of endocrinology before putting this knowledge into action by addressing the major signs and symptoms and the diagnosis and management of pediatric endocrine disorders. This work is provided for anyone who wishes to have a consultation with a pediatric endocrinologist in absentia still realizing that an actual person-to-person consultation sets the gold standard. There are a multitude of more complex issues within pediatric endocrinology that cannot be mastered without adequate experience; managing a baby with ambiguous genitalia is only one example of the issues that are introduced in this text to allow the reader to understand the basics, but this small volume cannot possibly cover the complexities in their entirety. This volume is not meant to replace the outstanding larger and more detailed texts, manuscripts, and websites to which I refer the reader in the “suggested reading” section at the conclusion of each chapter. The concepts covered are designed to address in varying detail the subjects in the fi rst ten headings in the content outline of the Sub-board of Pediatric Endocrinology of The American Board of Pediatrics dealing with clinical conditions. However, there is no claim that this book will give the reader the expertise of a pediatric endocrinologist; for that a 3-year fellowship is only the fi rst step!

Sacramento, CA, USA Dennis M. Styne

Pref ace

ix

I am indebted to my colleagues in the fi eld of pediatric endocrinology across the world whose wisdom in print and in words I value and have tried to refl ect in this book. This text grew out of my teaching and clinical experiences and I am grateful to the innumerable students, house offi cers, and postgraduate practitioners I have encountered in the last 45 years that I have pursued this fi eld. Presentations to them helped me organize my thoughts and their probing questions led me to look at the issues in new ways. I am grateful to my fi rst teachers of this fi eld, Melvin M. Grumbach, Felix Conte, and the late Selna Kaplan, at the University of California San Francisco. They deserve much of the credit for my accomplishments as they started me in this wonderful fi eld. I am indebted to my coworkers at the University of California Davis School of Medicine, Drs. Nicole Glaser, Lindsey Albrecht, Abigail Fruzza, and Yvonne Lee: they have daily imparted their wisdom to me. My clinical team that provide outstanding care every day, especially to our numerous patients with diabetes mellitus, include Sultanna Iden, RN, CDE; Erin Conboy-Heiser, RN, CDE; Alexander Nella, RD, CDE; Dayna Green-Burgeson, RD, CDE; Vincent Fong, LCSW; and Breanne Harris, BS Diabetes Concierge. Edna Gun Utter, our AA (administrative assistant), helped me organize and for-mat this volume expertly. The supportive staff at Springer including Richard Lansing and Joseph Quatela gave indispensable editorial help. I acknowledge Dr. Edward Steinberg who provided initial support in my redirection into pediatric obesity and continues to provide constant wisdom. I am deeply indebted to the Yocha Dehe Wintun Nation who have endowed my faculty position and unwaveringly supported my work in pediatric endocrinology and health disparities over the last 15 years.

Acknowledgements

xi

Contents

1 Introduction to Pediatric Endocrinology: The Endocrine System .................................................................. 1 Suggested Readings ........................................................................ 10

2 The Evaluation of a Child or Adolescent with Possible Endocrine Disease .................................................. 11 The Medical History ....................................................................... 11 Physical Examination ...................................................................... 13

3 Disorders of the Hypothalamic–Pituitary Axis .......................... 17 Physiology ....................................................................................... 17 Pathology ........................................................................................ 19 Central Nervous System Tumors .................................................... 19

Craniopharyngioma ..................................................................... 20 Germinomas ................................................................................ 21

Pituitary Adenomas ......................................................................... 22 Other Central Nervous System Disorders ....................................... 23

Langerhans Cell Histiocytosis .................................................... 23 Postinfectious Infl ammatory Lesions of the Central Nervous System, Vascular Abnormalities, and Head Trauma ........................................................................ 23

Irradiation of the Central Nervous System ..................................... 24 Developmental Defects of the Midline ........................................... 24

Septo-Optic and Optic Dysplasia ................................................ 24 The Solitary Median Maxillary Incisor Syndrome ..................... 25

Idiopathic Hypopituitary Dwarfi sm ................................................ 25 Suggested Readings ........................................................................ 27

4 The Posterior Pituitary Gland and Disorders of Vasopressin Metabolism ........................................................... 29 Normal Vasopressin Physiology ..................................................... 29 Diabetes Insipidus ........................................................................... 33

Central Diabetes Insipidus .......................................................... 33 Nephrogenic Diabetes Insipidus ................................................. 35 Clinical Features of Diabetes Insipidus ...................................... 36

xii

Diagnosis of Diabetes Insipidus .................................................. 36 Treatment of Central Diabetes Insipidus .................................... 39 Treatment of Nephrogenic Diabetes Insipidus ............................ 41

The Syndrome of Inappropriate Secretion of Antidiuretic Hormone ................................................................. 41 Nephrogenic Syndrome of Inappropriate Antidiuresis ................... 42 Other Causes of Hyponatremia ....................................................... 43 The Treatment of Syndrome of Inappropriate Secretion of Antidiuretic Hormone ................................................. 43 The Triphasic Response After Surgery for Craniopharyngioma ................................................................... 44 Suggested Readings ........................................................................ 45

5 Disorders of Growth ..................................................................... 47 Measurement of Growth ................................................................. 47 Endocrine Factors in Postnatal Growth .......................................... 58

Growth Hormone ........................................................................ 58 Insulin-Like Growth Factor or IGF ............................................. 62 Epidermal Growth Factor ............................................................ 66 Erythropoietin ............................................................................. 66 Oncogenes ................................................................................... 66

Dental Development ....................................................................... 67 Abnormalities of Growth ................................................................ 67

Short Stature ................................................................................ 67 Growth and Attention-Defi cit Disorder ...................................... 73 Tall Stature .................................................................................. 86

Suggested Readings ........................................................................ 89

6 Disorders of the Thyroid Gland ................................................... 91 Normal Thyroid Physiology and Anatomy ..................................... 91 Fetal Thyroid Development in the Newborn .................................. 95 Laboratory Evaluation..................................................................... 97 Imaging of Thyroid ......................................................................... 98 Disorders of the Thyroid Gland ...................................................... 99

Goiter .......................................................................................... 99 Hypothyroidism .............................................................................. 101

Congenital Hypothyroidism (CH) ............................................... 101Acquired Hypothyroidism .......................................................... 108 Thyroid Hormone Overdose ....................................................... 117 Neoplasms ................................................................................... 117 Painful Thyroid Glands ............................................................... 120

Further Reading .............................................................................. 120

7 Disorders of Calcium Metabolism and Bone .............................. 123 Calcium Metabolism ....................................................................... 123

Storage and Absorption of Calcium ............................................ 123 The Calcium-Sensing Receptor .................................................. 124 Phosphate .................................................................................... 124 Magnesium .................................................................................. 125 Parathyroid Hormone and Parathyroid Hormone-Related Protein ........................................................... 126

Contents

xiii

Vitamin D and Its Metabolites .................................................... 127 Calcitonin .................................................................................... 129 Alkaline Phosphatase .................................................................. 129

Hypocalcemia ................................................................................. 130 Hypocalcemia in the Infant ......................................................... 130 Hypocalcemia in the Child and Adolescent ................................ 133 Diagnosis of Hypocalcemia ........................................................ 139 Normal Bone Growth .................................................................. 139 Vitamin D and Calcium Defi ciency ............................................ 140 Rickets ......................................................................................... 141

Hypercalcemia ................................................................................ 147 Primary Hyperparathyroidism .................................................... 149 Familial Hypocalciuric Hypercalcemia ...................................... 149 Miscellaneous Causes ................................................................. 150 Treatment of Hypercalcemia ....................................................... 152 Evaluation of Hypercalcemia ...................................................... 152 Aluminum Toxicity ..................................................................... 156


8 Disorders of Sexual Differentiation ............................................. 159 Normal Sexual Differentiation ........................................................ 159

Genotype ..................................................................................... 159 Gonadal Sex ................................................................................ 161 Phenotypic Sex ............................................................................ 162 Social Gender .............................................................................. 165

Disorders of Sexual Differentiation ................................................ 166 46, XX DSD: Conditions Causing Genetic Females to Become Virilized (Previously Called Female Pseudohermaphroditism) ................................................ 166 46, XY DSD: Disorders Causing Inadequate Virilization of a Genetic Male (Previously Called Male Pseudohermaphroditism) ................................................... 175 Gonadal DSD .............................................................................. 179 Endocrine Disruptors .................................................................. 180

The Diagnosis and Treatment of Ambiguous Genitalia .................. 180 Treatment ........................................................................................ 184 The Decision of Sex of Rearing ...................................................... 184 Multidisciplinary Team Management ............................................. 186

Youth with Gender Dysphoria .................................................... 186 Suggested Readings ........................................................................ 186

9 Disorders of Puberty ..................................................................... 189 Normal Pubertal Development ........................................................ 189

Physical Development ................................................................. 189 Age at Onset of Puberty .............................................................. 191 Ages of Pubertal Stages and Duration ........................................ 193 Skeletal Development and Bone Mineral Density ...................... 193

The Endocrine Changes of Puberty ................................................ 193 Gonadarche ................................................................................. 195

Contents

xiv

Spermarche ................................................................................. 200 Adrenarche .................................................................................. 200 Pediatric Sex Steroid and Gonadotropin\ Assays ........................ 200 Ovulation and Menarche ............................................................. 201 Miscellaneous Metabolic Changes ............................................. 202

Abnormalities of Puberty ................................................................ 202 Delayed Puberty .......................................................................... 202 Sexual Precocity .......................................................................... 217

Endocrine Disruption in Puberty .................................................... 224 Variations of Early Pubertal Development .................................. 224 Macroorchidism .......................................................................... 225 Differential Diagnosis of Precocious Puberty ............................. 225 Treatment of Precocious Puberty ................................................ 226

Polycystic Ovarian Syndrome ......................................................... 229 Suggested Readings ........................................................................ 230

10 Disorders of the Adrenal Gland ................................................... 233 Normal Adrenal Gland Physiology ................................................. 233 Measurement of Steroids ................................................................ 239 Disorders of the Adrenal Cortex ..................................................... 240

Hypoadrenal States ..................................................................... 240 Aldosterone Insuffi ciency or Resistance ..................................... 248 Adrenal Calcifi cations ................................................................. 248 Hyperadrenal States .................................................................... 249 Hypertension due to Adrenal Disease ......................................... 256

Adrenal Medulla ............................................................................. 257 Normal Physiology ..................................................................... 257 Disorders of the Adrenal Medulla ............................................... 258

Suggested Reading .......................................................................... 261

11 Diabetes Mellitus ........................................................................... 263 Insulin Biosynthesis and Action ..................................................... 265 Glucagon ......................................................................................... 266 Other GI Hormones ......................................................................... 267 Diabetes Mellitus ............................................................................ 270 Type 1 Diabetes Mellitus ................................................................ 270

Clinical Presentation of Diabetes Mellitus ................................. 272 Dietary Management ................................................................... 280 Preparation for Discharge ........................................................... 280 Home Measurement by Glucometer ........................................... 281 Subcutaneous Insulin Management ............................................ 282 Glycosylated Hemoglobin or Hemoglobin A1c ........................... 287 The Honeymoon Period .............................................................. 288 Sick Day Management ................................................................ 288 Hypoglycemia ............................................................................. 289 Somogyi Phenomenon ................................................................ 290 Dawn Phenomenon ..................................................................... 291 Surgery and Diabetes .................................................................. 291

Contents

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Diabetes Team Management ........................................................... 291 Iatrogenic or Other Acquired Forms of Diabetes Mellitus Type 1 ........................................................ 293

Neonatal Diabetes ........................................................................... 297 Transient Neonatal Diabetes Mellitus ......................................... 297 Permanent Neonatal Diabetes Mellitus ....................................... 298

Type 2 Diabetes Mellitus ................................................................ 298 Wolfram Syndrome ..................................................................... 301 Maturity-Onset Diabetes of the Young or Monogenic Diabetes ............................................................... 301 Mitochondrial Disease and Diabetes .......................................... 301 Nonketotic Hyperosmotic Coma ................................................. 302

Summary ......................................................................................... 303 Suggested Readings ........................................................................ 303

12 Hypoglycemia ................................................................................ 305 Normal Carbohydrate Metabolism ................................................. 305

Glucose Regulatory Factors ........................................................ 306 Transition of the Fetus to Neonatal Life ..................................... 309

Hypoglycemia ................................................................................. 309 Hypoglycemia in the Newborn ................................................... 310 Hypoglycemia in Older Children ................................................ 316 Diagnosis of Hypoglycemia ........................................................ 319 Treatment of Hypoglycemia ....................................................... 322


13 Obesity ........................................................................................... 325 Defi nition ........................................................................................ 325 Etiology of Obesity ......................................................................... 329

Genetic Factors and the CNS Control of Appetite ...................... 329 Dietary Intake .............................................................................. 331 Energy Expenditure..................................................................... 336 Gut Microbiome .......................................................................... 336 Epigenetics .................................................................................. 336 The Obesogenic Environment ..................................................... 337 Endocrine Causes ........................................................................ 338 Iatrogenic Causes ........................................................................ 339

Comorbidities of Childhood and Adolescent Obesity .................... 339 Psychological Conditions............................................................ 340 Type 2 Diabetes ........................................................................... 340 The Metabolic Syndrome and Insulin Resistance ....................... 340 Polycystic Ovarian Syndrome ..................................................... 342 Hyperlipidemia and Risk for Cardiovascular Disease ................ 342 Hypertension ............................................................................... 347 Liver Disease ............................................................................... 349 Obstructive Sleep Apnea ............................................................. 350 Dermal Findings .......................................................................... 351 Orthopedic Conditions ................................................................ 351 Increased Growth and Advanced Skeletal Development ............ 351

Contents

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Earlier Puberty ............................................................................ 351 Enuresis ....................................................................................... 351 Cholelithiasis............................................................................... 351 Asthma ........................................................................................ 351 Pseudotumor Cerebri .................................................................. 351 Psoriasis ...................................................................................... 352

Laboratory Evaluation of Childhood Obesity ................................. 352 Treatment .................................................................................... 352 Lifestyle Modifi cation ................................................................. 353 Medication .................................................................................. 355 Surgery ........................................................................................ 356 Prevention ................................................................................... 357 Encourage Parental Modeling ..................................................... 357 Expose Children to Healthy Food in a Young Age ..................... 357 Encourage Breast-Feeding .......................................................... 357 Decrease or Eliminate the Intake of Sugar Sweetened Beverages and Limit the Intake of Juice ..................................... 358 Increase Public Safety ................................................................. 358 Modify the Diet ........................................................................... 358 Decrease Sedentary Time ............................................................ 358


14 Pediatric Endocrine Emergencies ................................................ 363 Acute Adrenal Insuffi ciency ........................................................... 363 Diabetic Ketoacidosis ..................................................................... 365 Hypocalcemia ................................................................................. 366 Hypercalcemia ................................................................................ 368 Hyperthyroidism in the Neonate ..................................................... 370 Thyroid Storm in Children and Adolescents .................................. 370 Hypoglycemia ................................................................................. 371 Hyponatremia/Hyperkalemia Due to Adrenal Insuffi ciency .......... 373 Hyponatremia Resulting from Syndrome of Inappropriate Secretion of Antidiuretic Hormone ...................... 374 Hypernatremia Due to Diabetes Insipidus ...................................... 374 Hypertension Due to Pheochromocytoma ...................................... 375 Suggested Reading .......................................................................... 375

15 Medications for Pediatric Endocrinology ................................... 377 Calcitonin, Human .......................................................................... 377 Calcitriol (1,25-Dihydroxycholecalciferol) .................................... 377 Calcium ........................................................................................... 377

Calcium Carbonate, Oral ............................................................ 377 Calcium Citrate, Oral .................................................................. 378 Calcium Glubionate, Oral ........................................................... 378 Calcium Gluconate IV ................................................................ 378 Hypocalcemia ............................................................................. 378 Calcium Lactate, Oral ................................................................. 378

DDAVP ........................................................................................... 378 Ergocalciferol (Vitamin D2) ........................................................... 378

Dietary Supplementation ............................................................ 379 Vitamin D Defi ciency.................................................................. 379

Contents

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Nutritional Rickets ...................................................................... 379 Vitamin D-Resistant Rickets ....................................................... 379 Vitamin D-Dependent Rickets .................................................... 379 Hypoparathyroidism or Pseudohypoparathyroidism .................. 379 Estrogen ...................................................................................... 379

Fludrocortisone Acetate (Florinef) ................................................. 379 Glucagon HCl ............................................................................. 379

Glucocorticoid Preparations ............................................................ 379 Growth Hormone Secretagogue Testing ......................................... 379 Hydrochlorothiazide ....................................................................... 380 Insulin Preparations ........................................................................ 380 Thyroxine (Levo) ............................................................................ 380 Magnesium Sulfate ......................................................................... 380

Hypomagnesemia or Hypocalcemia ........................................... 380 Daily Maintenance ...................................................................... 381

Mannitol (5, 10, 15, 20, 25 %) ........................................................ 381 Medroxyprogesterone Acetate .................................................... 381

Metformin ....................................................................................... 381 Mecasermin (rhIGF-1) .................................................................... 381 Methimazole ................................................................................... 381

Hyperthyroidism ......................................................................... 381 Nitroprusside ............................................................................... 381

Pamidronate .................................................................................... 381 Hypercalcemia ............................................................................ 381 Osteogenesis Imperfecta ............................................................. 382

Phosphate Supplements .................................................................. 382 Maintenance/Replacement .......................................................... 382

Potassium Iodide ............................................................................. 382 Potassium Supplements .................................................................. 382

Hypokalemia ............................................................................... 382 Monitor Serum K Closely and Watch EKG at All Times ............... 382 Propranolol ...................................................................................... 382

Hypertension ............................................................................... 382 Sodium Bicarbonate ........................................................................ 383Somatropin (Growth Hormone) ...................................................... 383

Growth Hormone Defi ciency ...................................................... 383 Noonan’s Syndrome .................................................................... 383 Prader-Willi Syndrome ............................................................... 383 SGA ............................................................................................. 383 SHOX Defi ciency ........................................................................ 383 Turner Syndrome ........................................................................ 383

Spironolactone ................................................................................ 383 Diuretic ....................................................................................... 383 Primary Aldosteronism ............................................................... 383 Hirsutism or Acne in Women...................................................... 383

Testosterone .................................................................................... 384 Vasopressin ..................................................................................... 384

Diabetes Insipidus ....................................................................... 384 Subcutaneous/Intramuscular ....................................................... 384


Contents

xviii

16 Laboratory Values for Pediatric Endocrinology ........................ 385 Adrenocorticotropic Hormone (ACTH) Quest ............................... 385

Adrenal Antibody Screen with Refl ex Titer QUEST .................. 386 Albumin (Microalbumin), 24-h Urine Quest .................................. 386 Albumin Serum Quest ..................................................................... 386 Aldosterone, 24-h Urine Quest ....................................................... 386 Aldosterone Serum, LC/MS/MS Quest .......................................... 387 Alkaline Phosphatase, Serum Quest ............................................... 387 Alkaline Phosphatase, Bone- Specifi c Labcorp ............................... 387 Androstenedione LC/MS/MS Quest ............................................... 388 Angiotensin II Quest ....................................................................... 388 Anti-Mullerian Hormone (AMH) Quest ......................................... 389 Arginine Vasopressin Quest ............................................................ 389 Congenital Adrenal Hyperplasia 21-Hydroxylase Defi ciency Common and Rare Mutations Quest ............................ 389 C Peptide, Serum Quest .................................................................. 389 Calcitonin Quest .............................................................................. 390 Calcium, 24-h Urine Quest ............................................................. 390 Calcium Ionized, Serum Quest ....................................................... 390 Calcium, Serum Quest .................................................................... 391 Carnitine, Serum Quest ................................................................... 391 Carotene Quest ................................................................................ 391 Catecholamines, Fractionated, 24-h Urine Quest ........................... 391 Catecholamines, Fractionated, Plasma Quest ................................. 392 Catecholamines, Fractionated, Random Urine Quest ..................... 393 Corticosterone LC/MS/MS Quest ................................................... 394 Corticotropin-Releasing Hormone (Mainly Use for Ectopic Production of CRH) Quest ........................................... 395 Cortisol-Binding Globulin (Transcortin) Quest .............................. 395 Cortisol Urinary Free 24-h Quest ................................................... 395 Cortisol-Free Serum Quest ............................................................. 395

Cortisol, Salivary......................................................................... 396 Cortisol Serum Total LC/MS/MS Esoterix ..................................... 396 Creatinine 24-h Urine Quest ........................................................... 397 Creatinine Random Urine Quest ..................................................... 397 Creatinine Clearance Quest ............................................................. 397 Creatinine Serum Quest .................................................................. 398 DHEA Serum Quest Esoterix ......................................................... 398 DHEA Sulfate, Serum Esoterix ...................................................... 399 Deoxycorticosterone (DOC), Serum Esoterix ................................ 399 11-Deoxycortisol (Compound S) Corticosterone, Serum Esoterix ................................................................................ 400 Dihydrotestosterone Esoterix .......................................................... 400 Dihydrotestosterone, Free, Serum Quest ........................................ 401 Estradiol, Serum Esoterix ............................................................... 401 Estrone, Serum Esoterix .................................................................. 402 Follicle-Stimulating Hormone, Third Generation, Serum Esoterix ................................................................................ 402

Contents

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Fructosamine, Serum Quest ............................................................ 403 Gastrin Serum Quest ....................................................................... 403 Glucagon Quest ............................................................................... 404 Glucose, Serum ............................................................................... 404 Glutamic Acid Decarboxylase-65 Autoantibodies Quest ............... 404 Glycated Albumin Quest ................................................................. 404

1,5-Anhydroglucitol Esoterix ..................................................... 405 Growth Hormone, Serum Esoterix.................................................. 405 Growth Hormone Antibody Quest .................................................. 405 Growth Hormone-Binding Protein (GHBP) Esoterix ..................... 405 Growth Hormone-Releasing Hormone Quest ................................. 406 Hemoglobin A1C, Blood Quest ........................................................ 406 Homovanillic Acid, 24-h Urine Quest ............................................ 406 17-Hydroxycorticosteroids, 24-h Urine Quest ................................ 407 18-Hydroxycorticosterone, Serum Esoterix.................................... 407 5-Hydroxyindoleacetic Acid (5-HIAA), 24-h Urine Quest ..................................................................................... 408 5-Hydroxyindoleacetic Acid (5-HIAA), Random Urine Quest ....................................................................... 408 17-Hydroxypregnenolone, Serum Esoterix .................................... 408 17-Hydroxyprogesterone (17OHP), Serum Esoterix ...................... 409 Insulin-Like Growth Factor 1 (IGF-1) (Previously Called Somatomedin C) Esoterix .................................................... 410 IGF-2 Esoterix ................................................................................ 411 IGF-Binding Protein-1 (IGFBP-1) Quest ....................................... 411 IGF-Binding Protein-2 (IGFBP-2) Quest ....................................... 411 IGF-Binding Protein-3 (IGFBP-3) Esoterix ................................... 412

Inhibin B Quest ........................................................................... 412 Insulin Antibodies, Highly Sensitive Quest .................................... 413 Insulin, Free Quest .......................................................................... 413 Insulin, Serum Quest ....................................................................... 413 Islet Cell Antibody Quest ................................................................ 413 Leptin, Serum Quest ....................................................................... 413 Luteinizing Hormone (LH), Third- Generation Serum Esoterix ................................................................................ 414 Metanephrine and VMA, Fractionated 24-h Urine Quest .............. 414 Metanephrine, Fractionated Random Urine Quest ......................... 415 Metanephrine, Fractionate Free Plasma Quest ............................... 416 Microalbumin .................................................................................. 416 Osmolality, Random Urine Quest ................................................... 416 Osmolality, Serum Quest ................................................................ 416 Osteocalcin, Serum Quest ............................................................... 416

Pancreatic Polypeptide Quest ..................................................... 417 Parathyroid Hormone Antibody, Serum Quest ............................... 417 Parathyroid Hormone (PTH), Intact, Serum Quest ......................... 417 Parathyroid Hormone and Related Protein (PTH-RP) Quest.......... 418 Pregnenolone, Serum Esoterix ........................................................ 418

Contents

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Progesterone, Serum Esoterix ......................................................... 418 Progesterone, Free, HPLC-MS/MS ................................................ 419Proinsulin, Serum Quest ................................................................. 419 Prolactin, Serum Quest ................................................................... 420 Renin Activity (PRA), Plasma Esoterix .......................................... 420 Sex Hormone-Binding Globulin (SHBG) Esoterix ........................ 420 Somatostatin Quest ......................................................................... 421 T3 (Triiodothyronine), Free, Nondialysis Quest.............................. 421 T3 (Triiodothyronine), Free, Dialysis Esoterix................................ 422 T3 (Triiodothyronine), Reverse Esoterix ......................................... 422 T3 (Triiodothyronine), Total, Radioimmunoassay Esoterix ............ 422 T4 (Thyroxine), Free, Direct Dialysis Serum Quest ........................ 423 T4 (Thyroxine), Free, Nondialysis, Serum Esoterix ........................ 423 T4 (Thyroxine), Total, Serum Quest ................................................ 424 Testosterone, Total, Serum Esoterix ............................................... 424 Testosterone Free, Serum or Plasma Esoterix ................................. 425

Testosterone Saliva Esoterix ....................................................... 426 Testosterone Bioavailable Esoterix ................................................. 426 Thyroglobulin Antibody, Serum Quest ........................................... 427 Thyroid Peroxidase Antibody (Anti-TPO), Serum Quest ............... 427 Thyroid-Stimulating Hormone (TSH), Serum Quest ...................... 427 Thyroid-Stimulating Immunoglobulin (TSI) Quest ........................ 428 TSH Receptor Antibody (TRAb) Esoterix. .................................... 428 Thyroxine-Binding Protein/Globulin (TBG), Serum Quest ........... 428 Vanillylmandelic Acid (VMA), Random Urine Quest ................... 429 Vanillylmandelic Acid (VMA), 24-h Urine Quest .......................... 429 Vitamin D, 1,25-Dihydroxy, Serum Esoterix .................................. 429 Vitamin D, 25-Hydroxy, Serum or Plasma Esoterix ....................... 430 S.I. Unit Conversion Table from Esoterix/Labcorp ........................ 431 Suggested Reading .......................................................................... 434

Laboratory values from ............................................................... 434

Index ....................................................................................................... 435

Contents

1© Springer International Publishing Switzerland 2016 D.M. Styne, Pediatric Endocrinology, DOI 10.1007/978-3-319-18371-8_1

Introduction to Pediatric Endocrinology: The Endocrine System

1

The endocrine system regulates reproduction, growth and development, homeostasis of the organism (or maintenance of the internal envi-ronment), and the production, storage, and utili-zation of energy. The endocrine system was originally understood to regulate metabolism by biochemical messengers or hormones that were released from specialized organs (glands) into the general circulation so that they could act at a distance. Thus, hormones were classically defi ned as circulating messengers, with the loca-tion of their action far from the site of secretion, endocrine action. Hormone action also may be paracrine (acting on adjacent neighboring cells to the cell of origin of the hormone by diffusion), autocrine (acting on the cell of origin of the hor-mone itself by diffusion), or intracrine (acting on the cell of origin without actually being secreted); often agents acting in these ways are called fac-tors rather than hormones. Indeed, these factors (e.g., growth factors) may be produced in most cells of the body rather than discrete endocrine glands (Fig. 1.1 ). The effects of hormones and factors may be generally considered to be directed toward the processes of cell differentia-tion, cell growth, and metabolism of the cell and the organism.

In the past, some of the endocrine glands appeared to be controlled by the pituitary gland, which was therefore considered to be “the master gland.” The discovery of the hypophysiotropic hormones of the hypothalamus and their role in the control of pituitary secretion made it clear

that a higher level of control of these functions exists. Now it is recognized that various regions of the brain regulate the hypothalamus with complex interconnections in the central nervous system. Many of the hormones of the pituitary–hypothalamic axis or molecules that share much of their structure and function are also found in the gastrointestinal tract and other tissues throughout the body, as well as the placenta. Overlap occurs between the control of the endo-crine system and the nervous system; hormone secretion can be regulated by nerve cells, and endocrine agents can serve as neural messengers. Further, the endocrine system is regulated by fac-tors important in the immune system (e.g., cyto-kines interact with the secretion of glucocorticoids, which then exert an infl uence on infl ammation). An entire system of regulation, rather than the simplistic view of the endocrine system, best describes the control of metabolism.

Many hormones are regulated in a feedback loop, so that the production of a hormone is controlled by its effect; for example, the corticotro pin-releasing factor (CRF) stimulates the adrenocorti cotropic hormone (ACTH) to produce cortisol, which in turn feeds back to suppress CRF and ACTH production so that equilibrium is reached and serum cortisol and ACTH remain in the normal range (Fig. 1.2 , Table 1.1 ). The set point of the equilibrium may change with development; in prepuberty, small amounts of sex steroids strongly suppress gonadotropin secretion, but during pubertal

2

development, the sensitivity of this feedback loop decreases. Thus increased sex steroid production that brings about the ensuing physical changes of puberty occurs because these pubertal levels of sex steroids can no longer suppress gonadotropin secretion, as would occur at a similar level of sex steroid secretion in the prepubertal state.

A clinician may deduce the level of an endo-crine defect in the system by measuring the con-centrations of hormones in serum or plasma at various steps of the process (e.g., a low serum cortisol and high adrenocortical-stimulating hor-mone (ACTH) indicates a primary defect at the level of the adrenal gland, whereas a low serum cortisol along with a low ACTH indicates a disor-der of the pituitary gland or the hypothalamus (Table 1.1 )). Positive feedback loops occur as well; the midcycle LH peak which triggers ovula-tion occurs due to positive estrogen feedback on higher CNS centers. In most cases, it is not suf-fi cient to obtain a single hormone measurement

without considering its controlling factors or the effects it exerts.

Endocrine disorders may manifest in several ways:

1. By excess hormone effect (e.g., in Cushing syn-drome, an excess of glucocorticoid is present; e.g., if the excess is secondary to auto nomous glucocorticoid secretion by a target organ (cor-tisol secretion by the adrenal gland), the trophic hormone ACTH will be suppressed).

2. By defi cient hormone: e.g., in glucocorticoid defi ciency, inadequate cortisol is present; if the defi ciency is at the target organ (the adre-nal gland), the trophic hormone (ACTH) will be elevated.

3. By an abnormal response of end organ to a hormone: e.g., in pseudohypoparathyroidism, resistance to parathyroid hormone (PTH) occurs, and so PTH is elevated, but the para-thyroid hormone exerts no effects.

Fig. 1.1 Endocrine, paracrine, autocrine, and intracrine effects. Endocrine effects occur when a hormone is secreted by a cell into the bloodstream to be carried a dis-tance until it leaves the bloodstream to interact with the cellular receptor, in this case a peptide cellular membrane receptor, to exert intracellular activity. Paracrine effects occur when a cell secretes a substance to cause biologi-cal effects on a neighboring cell, in this case via a pep-tide cellular membrane receptor, without entering the bloodstream. Autocrine effects occur when the cell secretes a substance to cause biological effects on the

cell of origin, in this case via a peptide cellular membrane receptor, without entering the bloodstream nor necessarily affecting nearby cells. Intracrine effects occur when a substance acts within the cell in which it was produced without crossing the cell membrane, in this case via an intracellular receptor. Endocrine effects are measured by assays on blood samples, but paracrine and autocrine effects cannot be directly measured by assaying blood samples. In fact, the results of blood sample analyses only provide a refl ection of what might be going on locally

1 Introduction to Pediatric Endocrinology: The Endocrine System

3

Fig. 1.2 Logic of evaluation of hypothalamic–pituitary feedback loops using the hypothalamic–pituitary–adrenal axis as an example. ( a ) The normal situation where the target gland (adrenal gland) regulates the stimulatory hor-mone by negative feedback inhibition. ( b ) Primary defect due to failure of the target gland and decrease in its secre-tion of hormone: the stimulatory hormone (ACTH)

increases due to absence of negative feedback inhibition. ( c ) Decreased or “hypo” situation whereby the stimula-tory hormone is absent and the target gland’s hormone product falls. In the hypothalamic–pituitary–target gland axis, this would be a secondary (ACTH secretory defect illustrated here) or tertiary (CRF secretory defect not illustrated in the fi gure) defect

Glomerulosa

Fasciculata

Reticularis

Medulla

Aldosterone Cortisol Androgens Catecholamines

Third ventricle Hypothalamus

CRF secreting cells

Neuroendocrine

a

cell nuclei

Superiorhypophyseal

artery

Long portalvessels

Stalk

Inferiorhypophysealartery

Posteriorpituitary

Short portalvessel

Hormonesecretion

ACTH

Adrenocorticotrophs

Anteriorpituitary

Secreting cells

4. By gland enlargement that may cause effects as a result of size rather than function; with a large nonfunctioning pituitary adenoma, abnormal visual fi elds and other neurological signs and symptoms will result, and pituitary endocrine cells may cease to function, even though no hormone is produced by the tumor itself.

Tumors of other nonendocrine organs also may produce hormones as with the ectopic

production of ACTH from an oat cell carcinoma of the lung in adults. Endocrine disorders may be revealed by the response of various organs to an excess or defi ciency of various hormones well before the size of the endocrine tumor makes it apparent (adrenal carcinoma may cause viriliza-tion before it exerts a mass effect).

Hormones have various molecular structures. Thus there are peptide (e.g., TRF), glycoprotein (LH), monoamine (epinephrine), amino acid


4

Glomerulosa

Fasciculata

Reticularis

Medulla



CRF secreting cells

Neuroendocrinecell nuclei

Superiorhypophyseal

artery

Long portalvessels

Stalk


Posteriorpituitary

Short portalvessel

Hormonesecretion

ACTH

Adrenocorticotrophs

Anteriorpituitary

Secreting cells

b

Fig. 1.2 (continued)

derivative (thyroxine), steroid (testosterone), and lipid (prostaglandin) structures of hormones. Different structures of hormones necessitate different receptors. Receptors are then linked to intracellular processes that bring about the (in normal situation) desirable effects. Some hor-mones exert a limited effect on a single organ (GnRH) or a few organs, and others have wide-spread effects (thyroxine). Some hormones are stored in their gland of origin (peptide hormones), while others have limited storage and must be synthesized to exert effects (steroids). Many hor-mones circulate in a protein-bound state that acts as a reservoir for future use or limits biological effect (SHBG for sex steroids or growth hor-mone- binding protein for growth hormone).

Peptide hormones are produced by various endocrine organs or in an ectopic manner by the cells of certain neoplasms. Peptide hormones act through specifi c cell membrane receptors; the receptors consist of an extracellular domain, which directly interacts with the ligand hormone, a transmembrane domain that connects actions outside the cell with the actions destined to occur within the cell, and the intracellular domain that contains the cellular constituents that cause vari-ous biological actions (Fig. 1.3 ). These internal cellular actions include phosphorylation of pep-tides or proteins and the generation of other mol-ecules that cause a cascade of events, ultimately leading to the metabolic action expected by the presence of the hormone on the receptor (Fig. 1.3 ).


5

Table 1.1 The differential diagnosis of primary versus secondary or tertiary endocrine disease or autonomous function

Trophic hormone secretion (e.g., ACTH)

Target organ hormone secretion (e.g., adrenal gland) Condition Example

Normal Normal Normal

Low High Autonomous function of target gland

Adrenal adenoma (see Fig. 10.6 )

High High Target gland is stimulated by hypothalamic–pituitary axis

Cushing disease caused by pituitary microadenoma (see Fig. 10.5 )

Low Low Secondary or tertiary failure of target gland

ACTH defi ciency (see Fig. 1.2c )

High Low Primary failure of target gland

Addison’s disease (see Fig. 1.2b )

Glomerulosa

Fasciculata

Reticularis

Medulla



CRF secreting cells

Neuroendocrinecell nuclei

Superiorhypophyseal

artery

Long portalvessels

Stalk


Posteriorpituitary

Short portalvessel

Hormonesecretion

ACTH

Adrenocorticotrophs

Secreting cells

Anteriorpituitary

c

Fig. 1.2 (continued)


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G protein-coupled receptors (including ACTH, vasopressin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), TSH, gonadotropin-releasing hormone (GnRH), thyroid- releasing factor (TRF), growth hormone- releasing factor (GHRH), CRF, somatotropin- releasing inhibiting factor (SRIF or SS), glucagon, PTH receptors)

have seven transmembrane domains and a G protein complex that regulates the second mes-sengers such as calcium and cyclic adenosine monophosphate (AMP). Cytokine receptors for GH, prolactin, and leptin consist of extracel-lular, transmembrane, and cytoplasmic domains (Fig. 1.3 ). The extra membrane domain may

IR

IRS1 Shc

Cellmembrane

IRS1 Shc IRS Shc

p85p110P13K GRB2

Akt

p85p110

Akt

P13K GRB2

JAK2

STAT5MAPK

cascadeMAPK

cascade

NUCLEUS

IGF-1

SOCS

Cell proliferationand growth

Protein synthesisglycogen synthesis +

inhibition ofgluconeogenesis

inhibition of lipolysisregulation ofcell survival

IGF1R GHR

Insulin IGF-1 GH

Fig. 1.3 Schematic structure of cell-surface heterodi-meric insulin/insulin-like growth factor 1 (IGF-1) recep-tor and GH receptor (GHR) on an exemplary cell surface. The insulin receptor is a heterodimer composed of two α- and two β-subunits. The type 1 IGF receptor has a similar structure to the insulin receptor. Both have similar cellular responses to the ligand binding to the receptor, more the insulin sequence favors the IRS-1 to Akt pathway while the IGF-1 receptor proceeds through the MAPK pathway. In a situation in which there is excess insulin, such as found in the infant of a diabetic mother, insulin can cross- react with the IGF-1 receptor leading to increased growth. Conversely, IGF-1 can interact with the insulin receptor, causing insulin effects including hypoglycemia. Two independent GH receptor (GHR) molecules must interact with one molecule of GH to cause intracellular activities. This leads to the recruitment of Janus kinase 2 (JAK2), which phosphorylates the GHR, which provides a dock-ing site for STAT (signal transducer and activator of tran-scription). STAT is then phosphorylated and migrates uncoupled to the nucleus, where it regulates transcription

through binding elements of target genes. SOCS (suppressor of cytokine signaling) provides a localized feedback loop in which the consequences of GH binding to its receptor can be regulated. IGF-1 also provides a localized feed-back loop. The amino acid sequence of the extramem-brane portion of the GH receptor is cleaved from the GHR and becomes the circulating GH-binding protein (GHBP) which thereby refl ects the abundance of GHRs. Abbreviations: IGF-1 – insulin-like growth factor 1, GH – growth hormone, IR – insulin receptor, IGF-1R – insulin-like growth factor 1 receptor, GHR – growth hormone receptor, IRS-1 – insulin receptor substrate 1, Shc – Shc protein, GRB2 – growth factor receptor-bound protein 2, PI3K – phosphatidylinositol 3-kinase, Akt – Akt protein, JAK2 – Janus kinase 2, STAT5 – signal transducer and activator of transcription 5, SOCS – suppressor of cyto-kine signaling (Modifi ed from Trobec K, von Haehling S, Anker SD, Lainscak M. Growth hormone, insulin-like growth factor 1, and insulin signaling-a pharmacological target in body wasting and cachexia. J Cachexia Sarcopenia Muscle. 2011 Dec;2(4):191–200)


7

refl ect the structure of circulating binding pro-teins; e.g., the extracellular domain of the growth hormone receptor (GHR) bears the same amino acid sequence as a circulating growth hormone- binding protein (GHBP) with which GH circu-lates. The cytokine receptors must dimerize (two receptor molecules must join) to trigger a meta-bolic effect. The intracellular domain causes phosphorylation of tyrosine molecules (JAK2 kinases), which then phosphorylate signal trans-ducers, and activators of transcription (signal transducer and activator of transcription; STAT), which then travel to the nucleus to regulate deoxy-ribonucleic acid (DNA) action.

Peptide hormone receptor number and avidity may be regulated by hormones; continuous rather than episodic exposure to GnRH downregulates GnRH-receptor number as well as receptor activ-ity on pituitary gonadotropes. This phenomenon is utilized in treatment with super- active gonado-tropin-releasing hormone agonists. Mutations of

receptors may cause disease by rendering the receptor inoperative, or alternatively, the receptor may be stimulated without the presence of the hormone in constitutive activation. The G protein complex may be abnormal in certain diseases; e.g., McCune–Albright syndrome is associated with constitutive activation of G stimulatory pro-tein in affected cells. A constitutively active mutation in the seven- transmembrane domain may be present, as occurs in familial germ cell and Leydig cell maturation. Alternatively, dimer-ization may fail to occur in some cases of GH insensitivity.

The family of insulin receptors includes the insulin and insulin-like growth factor (IGF)-1 receptors (Fig. 1.4 ). These are heterodimeric, consisting of two α- and two β-chains. When the appropriate hormone binds to the extracellular domain, the conformation is altered, and phos-phorylation of tyrosine occurs in the intracellular portion. Through a cascade of effects involving

Peptide hormone

G-protein

Peptidehormonereceptor

Adenyl cyclase(inactive)

Phosphorylatedmolecules

active adenyl cyclase

ATP cAMP

A AA ACAT CAT CAT CAT

PKA (active) PKA (inactive)

�

�s

�s�s

�

Fig. 1.4 The binding of a peptide hormone to its cell mem-brane receptor, triggering intracellular events which elicit a response. Note the seven-transmembrane structure of the G-protein-coupled peptide hormone receptor (GPCR) which in this case is a receptor for glucagon used as an example for the general class of membrane-bound recep-tors. When the ligand attaches to its receptor, the GPRC undergoes a conformational change leading to activation of the associated heterotrimeric G protein compound by exchanging its bound GDP for GTP which then associates

with a specifi c G protein subunit, in this case, a Gs-alpha protein subunit, which converts inactive adenyl cyclase to the active form which in turn catalyzes the conversion of ATP into cyclic adenosine monophosphate (cAMP). cAMP then activates protein kinase A (PKA) by binding to the regulatory subunits of PKA (noted by an A). The regulatory subunits then dissociate from PKA and the remaining cata-lytic subunits in turn phosphorylate other proteins. Various effects can occur in the system based upon the G protein involved. Adapted from biochemistrypage.org, 2015


8

insulin-receptor substrates (IRSs), activation of mitogenesis and proliferation as well as effects on carbohydrate metabolism occur. Insulin and IGF-1 have differing effects on cell growth and metabolism, and while each molecule has greater effect on its own specifi c receptor, insulin can bind to the IGF-1 receptor, and IGF-1 can bind to the IR exerting effects characteristic of the other molecule. In states of elevated insulin such as in the infant of a diabetic mother, interaction of the insulin with a receptor similar to the insulin receptor, in this case the IGF-1 receptor, occurs stimulating growth.

Steroid hormones circulate noncovalently bound to various binding proteins. Steroid hor-mones exert their effects by diffusion through the

cell wall into the cytoplasm. Specifi c cytoplasmic steroid receptors bind to the steroid molecule, and the hormone–receptor complex translocates to the nucleus (Fig. 1.5 ). The steroid receptor then binds to DNA hormone response elements to produce the synthesis of messenger RNA (mRNA) which leads to translation of the mRNA on ribosomes and the production of proteins or peptides predicted by the steroid hormone that result in changes in cell function.

Thyroid hormone receptors are similar to steroid receptors in structure and function and are members of the steroid hormone superfamily. The receptors are present either as monomers (TR), heterodimers with retinoid X receptor (TR/RXR), or homodimers (TR/TR). TR/RXR

Nuclearmembrane

Steroid hormone

Cytoplasm

Plasmamembrane

Receptorprotein

Receptor−hormonecomplex

Hormoneresponseelements

Nucleus

DNA

mRNA

New protein

The unbound steroid hormonediffuses through the plasmamembrane

The steroid hormone binds toits receptor and enters thenucleus

The steroid hormone−receptorcomplex binds to a specificDNA sequence, the hormoneresponse element

Transcription of the gene tomRNA results from the bindingof the complex to the DNA

Specific protein synthesisresults are determined by themRNA

Cellmembrane

Fig. 1.5 Molecular pathway of steroid hormone action. The steroid circulates with a binding protein, from which it dissociates to pass through the cell membrane and reach the cytoplasm. The receptor is complexed with heat shock proteins (not shown), which dissociate, allowing the ste-roid to bind to the receptor. Once bound to the steroid, the steroid receptor is activated and is transported into the nucleus. The steroid receptor complex changes conforma-tion, allowing it to bind to the hormone response elements

(HREs), or receptor sites, of DNA causing the subsequent transcription of DNA into mRNA and translation of the mRNA into proteins which exert their subsequent effects. Similar mechanisms are employed by members of the thy-roid receptor ( TR ) gene family, though most of the latter are concentrated in the nuclear compartment and are not associated with the heat shock protein (HSP) complex prior to binding with the ligand. Adapted from Studyblue.com, 2015


9

heterodimers are the most transcriptionally active complex. In the absence of hormones, TR exists in a complex with corepressor proteins binding to hormone response elements (HREs) in DNA in an inactive state. Binding of thyroid hormone results in a conformational change in TR which displaces corepressors from the receptor/DNA complex while adding coactivator proteins to the complex. Once the DNA/TR/thyroid hormone/coactivator complex is formed, RNA polymerase transcribes DNA into mRNA which leads to translation of the mRNA on ribosomes and the production of proteins or peptides predicted by the hormone that result in changes in cell function.

Because of the feedback loops, interpretation of serum hormone levels must be related to their controlling factors; a given value of PTH may be normal in a eucalcemic patient, but the same value may be inadequate in a hypocalcemic patient with partial hypoparathyroidism, and this same value of parathyroid hormone may be excessive in a hypercalcemic patient who might have hyperparathyroidism. Thus a single endo-crine test may be inadequate to evaluate anoma-lies of a feedback loop.

A diurnal rhythm of hormone secretion occurs in some systems (e.g., serum ACTH increases in the early morning hours, followed by an increase in serum cortisol and by a decrease in both during the afternoon and evening). If the rhythm is dis-turbed, the amount of hormone present will vary from the normal pattern, and disease might occur; if the normal decrease of cortisol does not occur in the evening, Cushing syndrome might result, sim-ply because the p.m. cortisol values match the a.m. values and total daily cortisol secretion is exces-sive. Thus, although there is little increase in serum cortisol values above normal a.m. values, a great increase in cortisol effect occurs in such patients affected by Cushing disease.

Knowing the basic functions of hormones and their interactions lends logic to the evaluation of patients with endocrine diseases. This volume attempts to emphasize such a systematic evalua-tion of endocrine disease. The chapters are based on organ systems and begin with a brief explana-tion of the basic physiology at work.

Many of the conditions in this book are caused by gene mutations. If there is a genetic link for a given condition, a reference to the Online Mendelian Inheritance in Man (OMIM) is placed after the fi rst mention of the condition. Further information can be found on the OMIM website, http://www.ncbi.nlm.nih.gov/Omim/ . (OMIM can also be found under a pulldown menu tab entry on the PubMed site).

The format is as follows as described verbatim on the OMIM website:

Each OMIM entry is given a unique six-digit number as summarized below:

1----- (100000-) 2----- (200000-) Autosomal loci or phenotypes (entries created before May 15, 1994)

3----- (300000-) X-linked loci or phenotypes 4----- (400000-) Y-linked loci or phenotypes 5----- (500000-) Mitochondrial loci or phenotypes 6----- (600000-) Autosomal loci or phenotypes

(entries created after May 15, 1994)

Allelic variants are designated by the MIM number of the entry, followed by a decimal point and a unique 4-digit variant number. For exam-ple, allelic variants in the factor IX gene (300746) are numbered 300746.0001 through 300746.0101.

The symbols preceding a MIM number represent:

An asterisk (*) before an entry number indi-cates a gene.

A number symbol (#) before an entry number indicates that it is a descriptive entry, usually of a phenotype, and does not represent a unique locus. The reason for the use of the number symbol is given in the fi rst paragraph of the entry. Discussion of any gene(s) related to the pheno-type resides in another entry(ies) as described in the fi rst paragraph.

A plus sign (+) before an entry number indicates that the entry contains the description of a gene of known sequence and a phenotype.

A percent sign (%) before an entry number indi-cates that the entry describes a confi rmed Mendelian phenotype or phenotypic locus for which the underlying molecular basis is not known.

Suggested Readings

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10

No symbol before an entry number generally indicates a description of a phenotype for which the Mendelian basis, although suspected, has not been clearly established or that the separateness of this phenotype from that in another entry is unclear.

A caret (^) before an entry number means the entry no longer exists because it was removed from the database or moved to another entry as indicated.

*, The gene location is reliably matched with the clinical situation.

#, Two or more genes can cause the phenotype. Lack of either symbol, no mode of inheritance

has been proven . The website often has a link to photographs

demonstrating any dysmorphic characteristics of a condition. This source is frequently updated with clinical and basic information on the sub-jects referenced. There is a useful clinical synop-sis of many conditions that are listed. The reader may benefi t from frequently accessing this resource or the associated GeneTests website. It will be apparent if an entry has that many of the entries have been recently updated with new ref-erences and new information as indicated by a date noted at the bottom of the entry; other entries may still await such updates and may date from several years earlier.

It is important to remember that many of the autosomal-dominant conditions in OMIM may actually arise de novo rather than in an inherited pattern.

Two other websites are listed below for genetic information. GeneReviews is a peer-reviewed

website which addresses various genetic syn-dromes, some of which are listed in this book. The GeneTests website lists genetic clinics and locations, and genetic tests can be obtained from research labs or commercial laboratories.

Suggested Readings

Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD). World Wide Web URL: http://omim.org/ https://www.genet-ests.org/

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1116/

Kublaoui B, Levine MA. Chapter 3—Receptor transduc-tion pathways mediating hormone action. In: Pediatric Endocrinology (Fourth Edition). Sperling MA editor. 2014: 34–89.

Menon RK, et al. Chapter 2—Molecular endocrinology and endocrine genetics. In: Pediatric Endocrinology (Fourth Edition). Sperling MA, editor, 2014:9–33.

Habener JF. Mechanism of action of hormones that act on nuclear receptors. In: Williams textbook of endocri-nology. Kronenberg HM, Mel. Med S, Larsen PR, Polonsky KS, editors. Elsevier/Saunders 2011.

Spiegel AM, Carter-Su C, Taylor SI, Kulkarni RN. Mechanism of action of hormones that act at the cell surface. In: Williams textbook of endocrinology. Kronenberg HM, Mel. Med S, Larsen PR, Polonsky KS, editors, Elsevier/Saunders. 2011.

Gardner DG, Anderson M, Nissenson RA. Hormones and Hormone Action. In: Greenspan’s Basic & Clinical Endo crinology (9th edition). Gardner DG, Shoback DM, Greenspac FS, editors. New York: McGraw-Hill Medical, 2011.


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The Evaluation of a Child or Adolescent with Possible Endocrine Disease

As in all disciplines, the history and physical examination are crucial in determining a course of evaluation. A standard pediatric history and physical examination will serve the evaluator well, but in a few areas, increased attention is required. The type of problem under consider-ation may change the direction of questioning and evaluation. The following general approach is discussed in more detail in the following chap-ters regarding specifi c disorders, but this outline is meant to direct the initial evaluation.

The Medical History

In many cases, the diagnosis is apparent from the medical history (Table 2.1 ). In general, the parents will be the sources of information, but in most cases, it will be useful to obtain previous medical records, often from several sources because of the recent tendency of transferring care of a child if the child moves to new locations or has a manda-tory change of insurance. Modern electronic medical records have menus for medical, surgi-cal, family, and birth histories, which should be carefully fi lled out once and easily accessed in future visits for reference or updating.

All aspects of the pregnancy history may be of importance. This includes medical complica-tions, nutritional status, toxic or medication exposures (smoking, infections, medications), gestational age, complications or diffi culties of delivery, and Apgar scores.

Medical history must aim to uncover any possible chronic disorders that might have con-tributed to the disease under evaluation or might complicate the treatment. Many chronic disor-ders may decrease growth rate; it might be said that almost every page of a pediatric textbook has a reason for impaired growth. If no previous height measurements are available, a history of changes in shoe or clothing size can be of value to determine whether the child is growing ade-quately, although follow-up measurements over a period of at least 3 months (and longer if possi-ble, as accuracy increases with the length of time of follow-up) are necessary for diagnosis. In older girls, or younger ones if the issue requires it, a menstrual history is necessary; age of menarche (onset), regularity, and amount of fl ow and dis-comfort are important. Inquire about abnormal patterns of urination or defecation.

The interview to obtain a medication history must often be specifi c, as many do not consider vitamins or “natural substances” as medicine, although excessive vitamins might be the very cause of a disorder (e.g., hypervitaminosis D). In addition, medications found around the house may be of importance; did the child get into the oral contraceptives or hormone replacement therapy used by another member of the family? Lotions, creams, and hair treatments may contain hor-mones; tea tree oil may cause feminizing effects while testosterone gel can be transferred from the intended recipient to children by touch or by the use of a common towel. Diet and nutritional

2

12

Table 2.1 Medical history for pediatric endocrinology

Chief complaint

History of present illness

Birth history and prenatal history

Gestational age

Complications of pregnancy

Toxic exposures

Maternal accidents

Medication taken including vitamins and “natural” treatments

Substances used, including cigarettes

Were ultrasounds obtained, and was the growth normal?

Was fetal motion normal?

Newborn period

Method of delivery

Complications of delivery

Orientation of delivery

Apgar scores

Birth weight % related to gestational age

Developmental assessment

Use of oxygen or other types of support or treatment

Hypoglycemia; documented by blood sugar value or inferred by activity or behavior?

Development

Age of milestones: sitting, cruising, walking; speaking words, sentences. Perform a developmental test if problems are noted

Family history

Direct questions are often necessary, as family might not volunteer information to general questions. Refer to chapters for associated conditions of importance

Note full siblings, half siblings, stepparents, or biologic parent relationships

Construct a family tree if possible

Were there any miscarriages?

Age and percentile of height and weight of siblings

Height and weight of parents; approximate weight, if obesity is noted, is important

Ethnicity of parents

Area where parents spent their childhood, especially if there is a possibility of famine, war, or refugee status in their history

Is there consanguinity?

Age of menarche in mother and sisters if old enough

Age father stopped growing or started to shave and the same information from brothers, if old enough

History of disease similar to patient or otherwise of importance in related individuals

Ask about early deaths due to heart disease or strokes specifi cally in all conditions under evaluation

Social: who lives at home, what is their relationship, how do they interact, and are there adequate funds for the child’s benefi t especially for nutrition?

Diet: is there adequate food and of a healthful quality? Is there any aversion to eating, is there lack of satiety, or is there an unusual diet? In evaluation of obesity, much more detail of diet composition and a dietician consultation are important

Surgical procedures

Allergies

Accidents, especially to the head

(continued)

2 The Evaluation of a Child or Adolescent with Possible Endocrine Disease

13

patterns are of general importance but also may contribute to the etiology of a condition. Signifi cant levels of estrogen or other substances might be found in a noncommercial source of beef.

Educational achievement, ability, and history are important. In addition, it is important to deter-mine if of psychological problems if related to the condition the child is manifesting (e.g., severe short stature or precocious puberty)?

Family history is of great importance in the evaluation. Family history of chronic disease, including neurologic or endocrine conditions, is determined, and the construction of a family tree is helpful. In many cases, the questions must be direct, such as, “Has anyone in the family had thy-roid disease?” rather than a general query since many feel that once treated, there is no disease; asking if someone in the family has hypertension may elicit “no” as an answer; asking whether some of the family members take medication for hyper-tension might be returned with the statement “I do but it is all under control now.” Because par-ents of pediatric patients are young and subject to developing new medical conditions (such as type 2 diabetes, hypertension, or dyslipidemia) which are of importance in the evaluation of the child, family medical history must be obtained repeat-edly at subsequent visits. Did the parents immi-grate from a developing country or live an underprivileged life to account for their own his-tory or stature, if abnormal? Was the child adopted, or should another biologic parent who is no longer in the house be included in the history? If an autosomal recessive defect is suspected,

determine whether consanguinity is present. Are there relatives who died young without diagno-ses? Indeed in this era of obesity, all cardiac events or strokes at a young age (various defi nitions are used for “young,” but one suggested is the occur-rence of an event before age 50 years in men and before age 60 years in women) must be noted. Even though it may be an endocrine visit, queries about dyslipidemia or hypertension are important in this age of obesity. The examiner must ask the age of menarche in the mother or of the growth spurt or age at fi rst shaving in the father (a father will rarely recall his age of onset of puberty!).

Interfamilial interactions can be observed dur-ing the interview process to evaluate the possibil-ity of psychosocial dwarfi sm or other psychosocial complications.

A history of surgery, allergies, and accidents to the central nervous system (CNS) or other important areas is pertinent.

Physical Examination

Physical examination must be complete (Table 2.2 ). Accurate determination and plotting of height (in centimeters) as described in Chap. 5 , weight (in kilograms), and body mass index (BMI) must accompany the determination of vital signs (see Chap. 13 for details). An infant should have weight and height interpreted in terms of gestational age (by using intrauterine growth charts; see Chap. 5 ).

A patient who has stature below the third per-centile for height according to the Centers for

Table 2.1 (continued)

Medications taken, including vitamins or “natural substances.” Direct questions are often necessary, as family might not volunteer information to general questions such as, “Does the child take any medications?” Does anyone have high blood pressure may be answered negatively until you fi nd that the individual is taking medications to make the blood pressure normal!

School history: grade level, grades obtained, any changes, interrelationships with schoolmates, teasing or bullying interactions?

Educational achievement in patient and in siblings and parents

Review of systems in general and directed specifi cally to the issues under consideration

Areas of concern will vary with the disease under consideration, so check the appropriate chapters to determine specifi c symptoms and signs of importance

In most situations today, ask about amount of television viewing or screen time per day, amount of activity, sports or other forms of exercise, and especially do so in children with obesity


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Table 2.2 Physical examination for pediatric endocrinology

All vital signs will vary with the age of the child, so refer to the Harriet Lane Manual or other sources for standards for age

Pulse

Blood pressure (interpret in terms of blood pressure for height, and make sure there is an adequate-sized cuff; see Chap. 13 )

Respiratory rate

Temperature if pertinent to disease under consideration or intercurrent illness

Infant length, measured as described in Chap. 5 , performed by two adults

After age 2 years, measure height in centimeters on a stadiometer without shoes on; repeat 2 or 3 times if stature is the main complaint, and make sure measurements are consistent and repeatable within 0.3 cm

Weight in kilograms in light or no clothes

Calculated body mass index (BMI) (kg/m 2 ) interpreted on chart for sex and age

Upper/Lower-segment ratio as necessary (especially in boys with disorders of puberty) (see Chap. 5 )

Arm span as necessary (especially in chondrodystrophies or abnormalities of puberty) (see Chap. 5 )

HEENT (head, eyes, ears, nose, throat)

Look for midline defects, including cleft palate or lip

Observe for signs of syndromes

Cataracts or colobomas?

Development and status of dentition for age. Single central maxillary incisor as a midline defect that might relate to hypopituitarism?

Acne or comedones?

Beard?

Voice change?

Neck

Motion

Goiter? Measure width and height of thyroid lobes, and estimate thickness (e.g., 25 % or 50 % greater than normal) Nodules? Bruits?

Acanthosis nigricans at back of neck?

Lungs: customary pediatric examination

Heart: customary pediatric examination

Abdomen: customary pediatric examination

Axillary hair or odor; enlarging axillary sweat glands?

Breast stage in girls (see Chap. 9 )

Stage of pubic hair (see Chap. 9 )

Stage of genital development in boys (see Chap. 9 )

Extremities: customary pediatric examination unless chondrodystrophy is suspected, and then note ratio of proximal to distal portions of extremities. Look for Madelung deformity in short stature (see Chaps. 5 and 9 ). Note motion of joints and back. Evaluate upper-to-lower segment ratio. Observe for contractures or subtle signs of cerebral palsy.

Scoliosis evaluation

Skin

Café-au-lait spots (number, type, shape, and size), subcutaneous calcifi cations, acanthosis nigricans

Neurologic: customary pediatric examination with special attention to the CNS in most cases

Cranial nerves: signs of central nervous system (CNS) disease, optic disk development, visual fi elds, and, in delay of puberty, sense of smell

Chvostek or Trousseau signs

Tremor

Deep tendon refl exes: customary pediatric examination but look for delayed relaxation of ankle refl exes

2 The Evaluation of a Child or Adolescent with Possible Endocrine Disease

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Disease Control (CDC) or WHO charts, who is growing at a rate less than the fi fth percentile for height velocity for age, or is below the third per-centile for corrected mid parental height is wor-thy of evaluation; a combination of two or more of these characteristics warrants increased concern. Determination of arm span and upper-to- lower segment ratio is useful in the evaluation of short stature (e.g., to indicate hypochondroplasia or achondrop lasia or other abnormalities of dispro-portionate growth) or of delay in puberty (e.g., to look for the long arms and lower upper-to-lower segment ratio of hypogonadism known as eunuchoid proportions). The arm span is mea-sured with the patient standing with the back to the wall with arms spread horizontally and is the distance from one outstretched middle fi ngertip to the other. The lower segment is measured from the top of the symphysis pubis to the fl oor, whereas the upper segment is calculated by sub-tracting the lower segment from the height of the child. The upper-to-lower segment ratio varies with age (Fig. 5.7 ). A decreased upper-to-lower segment ratio is found in Klinefelter syndrome, and an increased ratio is found in untreated hypo-thyroidism, among other possibilities.

If a problem of growth or pubertal progression is under evaluation, one must consider whether a low body weight is the source of the problem. If nutrition is suboptimal, usually the problem is not endocrine in origin, and other causes must be considered. Alternatively, if the child is starting puberty early or progressing too fast, is excess weight the cause? Every child must have a BMI calculated and interpreted on a chart. Body mass index charts are found at www.CDC.com; low BMI for age might indicate malnutrition due to chronic disease, whereas elevated BMI for age might indicate rapid growth due to obesity.

The general appearance of the child may fur-nish a clue as to the chronicity of the problem and its emotional effects. Levels of energy and activ-ity are important. Suspicion of a syndrome must be clarifi ed by the examination. The head, eyes, ears, nose, and throat (HEENT) examination may

point to a midline defect, syndrome, or neuro-logic condition. Is there a goiter or nodule of the thyroid gland? Cardiac, pulmonary, and abdomi-nal examinations must be thorough but do not differ appreciably from those in a general pediat-ric examination. Skin examination might reveal café-au-lait spots or subcutaneous calcifi cations. The extremities may appear to be curved or abnormal or an abnormality of gait may be noted, as an indication of rickets. Neurologic examina-tion is essential in many disorders considered in the book. Signs of dysfunction might suggest a neoplasm or a congenital defect associated with an endocrine condition.

In almost all conditions, it is important to determine the stage of pubertal development. This must be done with care and consideration, as the patient, especially in the teenage years, may be embarrassed; if the patient refuses and the caregiver cannot achieve acquiescence, this por-tion of the examination may have to be omitted on this visit, as it should not be done by force. Even with cooperation, a nonrelated adult chaper-one should be in the room during the examina-tion. Determination of stage of breast and pubic hair growth is performed in girls and genitalia and pubic hair (as well as beard) in boys, accord-ing to standard rating techniques (see Chap. 9 ). If a child refuses the exam, pictures as in Figs. 9.1 , 9.2 , and 9.3 may be presented to the patient to ask which fi gure they think they look most like their stage of development; this is not as accurate as a detailed exam, but it may be all it is possible. In addition, the development of axillary odor or hair, the presence of comedones or acne, and the maturation of facial features are noted in all; if the child refuses genital examination, at least this other information is helpful. The appearance of abnormal distribution or amount of facial or body hair may be an indication of a problem.

Often when no other diagnosis is found in the general clinician’s offi ce, an endocrine disorder is considered and referral made. The results are often disappointing as not every obscure symp-tom or fi nding can be related to endocrinology!


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Disorders of the Hypothalamic–Pituitary Axis

The hypothalamic–pituitary axis might be considered as a translator of the action of higher central nervous system activity into endocrine secretion. In many cases, hypopituitarism is the term used to describe a defect in the secretion of pituitary hormones, but in fact, the condition may be a hypothalamic problem; growth hormone defi -ciency most often is caused by the lack of growth hormone-releasing factor from the hypothalamus rather than a defect in the growth hormone- secreting cells of the pituitary gland. Thus, hypopi-tuitarism is a vague term although it is in frequent use.

Physiology

The hypothalamus is located in the forebrain below the thalamus, hence the name. Under the infl uence of higher central nervous system centers the hypothalamus exerts endocrine effects either directly, in the production and release of vasopres-sin and oxytocin from the posterior pituitary, or indirectly, through the release of hypothalamic-releasing or inhibiting factors, small peptides pro-duced in minute quantities, which reach the anterior pituitary gland from the median eminence of the hypothalamus through the hypophysiotro-

pic, or hypothalamic–pituitary, portal vessels to regulate anterior pituitary hormone secretion (Fig. 3.1 ). Thus, disorders of any of these intercon-nected regions, the CNS, the hypothalamus, or the pituitary gland, can cause endocrine disease.

A sequence of homeodomain proteins and transcription factors cause primordial cells to develop into the characteristic cells of the ante-rior pituitary gland, the gonadotroph, the thyro-troph, the lactotroph, the somatotroph, and the corticotroph. Mutations in several of these, PROP 1, PIT 1, LHX3, LHX4, HESX1, and TPIT lead to hypopituitarism with a varying array of pituitary hormone defects depending on the mutation. There are commercial tests available to screen for these mutations.

The pituitary gland receives arterial blood from the superior hypophyseal artery which gives rise to the capillary bed that bathes the endocrine cells of the median eminence of the hypothalamus and into which they release their trophic hormones. These capillaries form the long hypo physiotropic, or hypothalamic–pituitary, portal system which carries the hypothalamic trophic factors to ensure that they reach the cells of the anterior pituitary gland to stimulate the secretion of their pituitary hormones. There is a second short portal system which connects the posterior and anterior pituitary glands as well. A second capillary bed drains the pituitary secretions into the venous system.

The hypothalamic factors are peptides—the shortest, TRF, composed of three amino acids—that regulate anterior pituitary function. These

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(A more detailed discussion of specifi c hormones is found in the chapters related to their functions (e.g., growth hor-mone (GH) is presented in Chap. 5 ))

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peptides are growth hormone-releasing factor (GRF) which stimulates the release of growth hormone (GH), gonadotropin-releasing hormone (GnRH) which stimulates the release of the gonadotropins (luteinizing hormone (LH) and follicle- stimulating hormone (FSH)), thyrotropin-releasing factor (TRF) which stimulates the release of thyrotropin (TSH), and prolactin, corti-cotropin-releasing factor (CRF) which stimulates the release of adrenocorticotropin (ACTH) and vasopressin, and prolactin inhibitory factor (PIF or dopamine) which suppresses the release of pro-lactin. Somatostatin (SRIF) has many functions throughout the body including the gastrointestinal (GI) tract, but for the purposes of this discussion, somatostatin suppresses growth hormone secre-tion as well as TSH and prolactin secretion. The glycoprotein hormones LH, FSH, TSH, and hCG are heterodimers composed of an alpha and a beta subunit. The alpha subunit is common for all of these hormones, but the beta subunits confers specifi city on each hormone.

Prolactin and growth hormone share some structural homology to human placenta lactogen and derive from a common gene of origin.

Prolactin is released in a pulsatile manner and increases during stress. Dopamine is secreted by tuberoinfundibular dopamine (TIDA) neurons of the arcuate nucleus and exerts inhibitory effect on the D2 receptors of lactotrophs, causing suppres-sion of prolactin secretion, and also on the D2 receptors of the thyrotroph, causing suppression of TSH secretion. Estrogen exerts a stimulatory effect on prolactin secretion, and pregnancy is a period of increased prolactin secretion. Prolactin is high in the neonatal period and then reaches a plateau in childhood only to decrease during male puberty. Prolactin remains stable during female puberty. Like growth hormone, prolactin exerts its effects by binding to a cytokine-like receptor on the cell membrane. Prolactin’s most notable endo-crine effect relates to the production of breast milk but it exerts many other effects on the immune sys-tem, cell cycle, growth differentiating and anti-apop-tosis, hematopoiesis and angiogenesis, and blood clotting.

After secretion into the peripheral circulation, the pituitary hormones exert their effects on target glands and organs specifi c for that pituitary hormone. Target endocrine glands in most cases

Hypothalmichormone

Effect

Pituitary hormone

GRF

+

GH

SRIF or SS

–

Target organ Many tissues, including the liver,

produce IGF-1

GnRH

+

LH⁄FSH

Gonads:testosterone

or estradiol

TRF

+

TSH and Prl

Thyroid gland:T4 and T3

CRF

+

ACTH

Adrenal gland:Cortisol

(and DHEAS)

PIF

–

Prolactin

Mammary gland in females

and mammary gland in femalesacting through

prolactin

Fig. 3.1 The hypothalamic factors, the pituitary hormones that they control, and the target organs of the pituitary hormones

3 Disorders of the Hypothalamic–Pituitary Axis

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produce their own hormones that provide feed-back to suppress their controlling hypothalamic and pituitary hormones in turn (e.g., cortisol from the adrenal gland provides negative feedback inhi bition to the hypothalamic–pituitary system to suppress hypothalamic corticotropin-releasing hormone that stimulates pituitary adrenocortico-tropin that in turn stimulates the release of adrenal cortisol). Prolactin is the only pituitary hormone that is mainly suppressed by a hypothalamic fac-tor, prolactin inhibitory factor (dopamine) and GABA (although centrally administered GABA may also stimulate prolactin secretion), whereas all other pituitary hormones are mainly stimulated by hypothala mic factors (it is true that GH is sup-pressed by the somatotropin release-inhibiting factor (SRIF), but it is also stimulated by the growth hormone- releasing factor (GRF)). Thus hypothalamic disease may lead to a decrease in secretion of most pituitary hormones and an increase in prolactin secretion, whereas a pituitary gland disorder may cause a decrease in prolactin secretion as well as a decrease in other pituitary hormones, a useful diagnostic feature.

The hypothalamus contains the terminal of the axons of vasopressin-secreting neurons while also serving as a location through which other vaso-pressin-secreting axons pass on their way to their own axon terminal in the posterior pituitary gland. Thus hypothalamic damage will cause diabetes insipidus, whereas the result of pituitary stalk sec-tion is variable, depending on the level of lesion. If a pituitary stalk section or disorder is high on the pituitary stalk, all vasopressin- secreting neurons may be affected, and the result is diabetes insipi-dus, whereas if the pituitary stalk section is low, some vasopressin- secreting neurons may survive intact, and vasopressin secretion and action are still possible, so that diabetes insipidus may not develop or may only be transient (Chap. 4 , Fig. 4.4 ).

Oxytocin is produced in the hypothalamus and transported by neurophysin 1 to and stored in the posterior pituitary. Oxytocin is released with dila-tion of the uterus and cervix and plays a role in nor-mal parturition; exogenous oxytocin is invoked to promote the delivery of the baby in certain circum-stances. Oxytocin plays a role in maternal bonding with a newborn baby and plays a role in lactation after stimulation of the nipples by suckling.

Pathology

Disorders of the hypothalamus or pituitary gland affect endocrine function, but disorders else-where in the CNS or radiation therapy to the CNS for other conditions may also cause signifi cant endocrine effects. Although destructive lesions of the hypothalamic–pituitary axis usually decrease endocrine activity (e.g., hypogonado-tropic hypogonadism), depending on location, some diseases of the hypothalamic–pituitary axis may instead cause increased function (e.g., pre-cocious puberty). Alternatively, functioning lesions may cause endocrine effects because of their secretions rather than exerting effects due to destruction of tissue by their size or location (e.g., pinealomas secrete the human chorionic gonadotropin (hCG) and cause precocious puberty in boys, while nonfunctioning adenomas of the pituitary gland destroy cell structure and can cause decreased pituitary secretion).

Specifi c terminology relates to the level of the endocrine lesion. A disorder of the target gland (e.g., thyroid, adrenal gland) is considered a pri-mary disease. A lesion of the pituitary gland is considered a secondary defect, and a lesion of the hypothalamus is a tertiary condition (see Chap. 1 , Fig. 1.2 ).

Central Nervous System Tumors

Most CNS tumors affecting the hypothalamic–pituitary axis will cause multiple pituitary defects. A hypothalamic tumor may, for example, be detected by the presence of galactorrhea, due to increased prolactin secretion from the pituitary gland in the absence of prolactin inhibitory factor from the hypothalamus, occurring along with defi ciencies of other pituitary hormones. However, in hypothalamic disease, GH is most often affected, and GH defi ciency is the most common outcome. GH defi ciency may at fi rst appear to be an isolated fi nding until more careful endocrine evaluation reveals other pituitary defects.

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hypothalamic–pituitary defi ciencies without contributing history (e.g., surgery or trauma to the area) may very well indicate the development of a CNS tumor, especially if anterior and poste-rior defi ciencies occur together. In contrast, congenital defects of hypothalamic–pituitary hormones appear at or soon after birth, so that early onset of combined posterior and anterior defi ciencies may cause signifi cant effects but do not necessarily refl ect the development of a tumor. Nonetheless, a magnetic resonance imag-ing (MRI) evaluation of a child with onset of hypopituitarism of any age is indicated to deter-mine whether a defi nable anatomic defect is causing the condition.

Craniopharyngioma

Craniopharyngioma is a rare embryonic malfor-mation of nonglial origin in childhood (0.5–2.0 new cases/million population/year or 1.2–4 % of pediatric intracranial tumors) but is a more common CNS neoplasm in pediatrics. It is the most common brain tumor associated with hypothalamic–pituitary dysfunction and sexual infantilism and comprises 80–90 % of neo-plasms found in the pituitary and up to 15 % of all intracranial tumors in childhood. Symptoms usually arise before the age of 20 years with a peak incidence between the ages of 6 and 14 years with about 30–50 % occurring in the pediatric age range. Harvey Cushing introduced the term “craniopharyngioma” and said that they were “the most formidable of intracranial tumors.”

Various theories of the embryologic origin of this nonglial intracranial tumor are current: one theory favors development from ectodermal rem-nants of Rathke’s pouch and another develop-ment from residual embryonic epithelium of the anterior pituitary gland and of the anterior infun-dibulum. Craniopharyngiomas may reside within or above the sella turcica, or, more rarely, they may be found in the nasopharynx or the third ventricle.

Craniopharyngioma appears to be a monoclonal tumor, and about 50 % have genetic abnormali-ties such as gains in activity at 1q, 12q, and 17q. About 70 % of cases of craniopharyngioma in childhood are the adamantinomatous type with cyst formation. These types have dysregulation of the Wnt signaling pathway and a mutation in the β-catenin gene (CTNNB1) in contrast to the papillary type of craniopharyngioma which has BRAF mutations and is more often found in adult patients.

CNS signs of craniopharyngiomas develop as the tumor encroaches on surrounding structures. Symptoms of craniopharyngioma include head-ache, visual disturbances, short stature, diabetes insipidus, vomiting, and weakness of one or more limbs. Visual defects including bilateral temporal fi eld defi cits due to impingement on the optic chi-asm), optic atrophy or papilledema, and signs of GH defi ciency, delayed puberty, and hypothy-roidism are features of craniopharyngiomas. Although most patients are shorter than the mean in height and have decreased height velocity at diagnosis, a long, indolent course is possible. Defi ciencies of gonadotropins, GH, thyrotropin (TSH), ACTH, and arginine vasopressin are com-mon. The serum concentration of prolactin may be decreased. The bone age reading may be delayed and is common and may point to the age of onset of tumor growth.

About 70 % of patients with a craniopharyn-gioma have suprasellar or intrasellar calcifi cation (found in fewer than 1 % of normal individuals) and an abnormal sella turcica, which are some-times found on radiographs taken for other indi-cations, including orthodontia. CT reveals fi ne calcifi cations that are not apparent on lateral skull radiographs. MRI scan before and after gadolin-ium is the diagnostic procedure of choice for sus-pected craniopharyngioma and can determine whether the tumor is cystic or solid and indicate the presence of hydrocephalus; if necessary, a CT scan can be used to search for calcifi cations. The new susceptibility weighted imaging (SWI) tech-nique allows MRIs to reveal calcifi cations where older techniques did not.


21

Smaller craniopharyngiomas, usually intrasellar, can be treated by transsphenoidal microsurgery, but larger or suprasellar masses which are more frequently found in childhood require craniot-omy, and the approach must be individualized. Shunting may be required for hydrocephalus prior to surgical treatment of the tumor. The reported post surgical 5-year overall survival is 88–94 %, the 10-year overall survival is 70–92 %, and the 20-year survival is 76 %. The combina-tion of limited tumor removal and radiation ther-apy leads to a satisfactory neurologic prognosis, better cognitive outcome, and better endocrine outcome compared with attempts at complete surgical extirpation. Fre quent and early tumor relapse after apparently complete resection and tumor progression after incomplete resection suggest the wisdom of radiation therapy after sur-gery. Alternative approaches include proton beam therapy, and, in mainly cystic craniopharyngioma cases, instillation of radioisotopes or sclerosing substances such as bleomycin or interferon-alpha is being investigated. Nonetheless, the preferred manner of treatment to retain the best quality of life is not yet established, but longitudinal studies such as the randomized multinational trial KRANIOPHARYNGEOM 2007 may answer this question. It is recommended that craniopha-ryngioma be considered a chronic disease requir-ing constant monitoring.

The hypothalamic syndrome is comprised of obesity; fatigue; behavioral changes; circadian rhythm irregularities; abnormal sleep patterns; dysregulation of body temperature, heart rate, and blood pressure, as well as abnormalities in thirst and is found in approximately one-third of patients at diagnosis in childhood. After surgery, these fi ndings may occur in 65–80 % of patients. Postoperative hyperphagia and obesity (e.g., BMI >5 SD above normal) can be striking and correlate with the magnitude of hypothalamic damage on cranial MRI. Injury to the hypo-thalamic ventromedial nuclei (associated with increased parasympathetic activity and hyperin-sulinemia) or to the paraventricular nuclei may cause these fi ndings, and suppression of the increased insulin secretion may be helpful with the use of octreotide. Short-term follow-up

studies demonstrate the efficacy of bariatric surgery in the management of obesity in affected patients. Hypothalamic-sparing surgery decreases the risk of postoperative hyperphagia and obe-sity. Aberrant sleep patterns and even narcolepsy and daytime somnolence may follow surgical treatment of craniopharyngiomas, with melato-nin improving sleep patterns in some. Although the endocrine complications are more manage-able, the combination of antidiuretic hormone insuffi ciency (i.e., diabetes insipidus) and impaired sense of thirst that arises after surgery in some patients remains a complex management problem.

A Rathke-cleft cyst is often discovered as an incidental fi nding on MRI, but it can produce symptoms and signs indistinguishable from those of a craniopharyngioma, such as precocious or delayed puberty. Surgical drainage and excision of the cyst wall are customary approaches.

Germinomas

Germinomas (i.e., pinealomas, ectopic pinealo-mas, atypical teratomas, or dysgerminomas) and other germ cell tumors of the CNS are the most common extrasellar tumors that arise in the suprasellar hypothalamic region and in the pineal region that commonly cause sexual infantilism. Germinomas constitute 66 % of all intracranial germ cell tumor (GCT) which comprise 3–11 % of pediatric brain tumors. About 84 % are found in the pineal and the neurohypophyseal regions. Peak incidences occur in the second decade and during infancy. They are found more often in males. Polydipsia and polyuria are the most com-mon symptoms, followed by visual diffi culties and abnormalities of growth and puberty or movement disorders. Diagnosis is often delayed for months to years because the fi ndings are sometimes attributed to psychiatric disorders. Defi ciencies of vasopressin and GH are most common, but other anterior pituitary hormone defi ciencies (including gonadotropin defi ciency) and elevated serum prolactin levels are also frequent. Determination of the concentration of hCG in spinal fl uid and in serum and assessment


22

of α-fetoprotein levels provide useful tumor markers in children and adolescents with germ cell tumors. Germ cell tumors in boys can cause isosexual GnRH-independent sexual precocity by secretion of hCG (see Chap. 9 ). Subependymal spread of germ cell tumors along the lining of the third ventricle is common, and seeding may involve the lower spinal cord and cauda equina. MRI with contrast enhancement is useful in the detection of isolated enlargement of the pituitary stalk, an early fi nding of germinomas that requires periodic MRI monitoring, especially in patients with diabetes insipidus. The size of the pituitary gland increases by 100 % between year 1 and year 15, but the pineal gland does not normally change in size after the fi rst year of life; any later enlargement indicates a mass lesion. Pineal cysts are a rare cause of central precocious puberty.

Irradiation is the preferred treatment for pure germ cell tumors such as germinomas; surgery is rarely indicated, except for biopsy to establish a tissue diagnosis. However, attempts to decrease the long-term morbidity of radiation therapy leads to consideration of chemotherapy. Chemotherapy alone is inadequate, but the combination of che-motherapy and radiation therapy can be success-ful, and both treatment methods are recommended for a mixed germ cell tumor. Because testicular germ cell tumors are occasionally found years after successful therapy for CNS germ cell tumors, long-term surveillance is indicated.

Hypothalamic and optic gliomas or astrocyto-mas, occurring as part of neurofi bromatosis (von Recklinghausen disease (*162200 NEURO-FIBROMATOSIS, TYPE I; NF1, due to muta-tions in the neurofi bromin gene)) or arising independently, can also cause sexual infantilism. Gliomas and meningiomas are the most common CNS tumors to develop in childhood cancer sur-vivors treated with CNS radiation, often in the young adult or even late teenage years.

Pituitary Adenomas

Only 2–6 % of all surgically treated pituitary tumors occur in childhood and adolescence, with about 1 in 1,000,000 children affected.

Most functional pituitary adenomas are ACTH secreting, with prolactinomas, GH secreting, or nonfunctioning adenomas occurring less com-monly. Most pituitary tumors are monoclonal lesions caused by mutations of guanine nucleotide- binding protein, GNAS; a transcript of the GNAS gene, Gs-alpha, encodes the alpha subunit of the stimulatory guanine nucleotide-binding protein (G protein). Gs-alpha is expressed biallelically in nearly all tissues and plays essen-tial roles in a multitude of physiologic processes. Adolescent onset of pituitary tumors may be the fi rst manifestation of multiple endocrine neopla-sia type I (see Chap. 10 ). Familial isolated pituitary adenoma (FIPA) (#102200 PITUITARY ADENOMA) is diagnosed in a family with a his-tory of pituitary adenomas including prolactino-mas. About 20 % of cases of FIPA have a germline mutation in aryl hydrocarbon receptor-interacting protein (AIP).

With more sensitive imaging techniques, the presence of a pituitary incidentaloma, a previously unsuspected pituitary lesion that is discovered on an imaging study performed for an unrelated reason, may be discovered. Evaluation of secretory activity of such a lesion, consideration of mass effects, and follow-up to monitor a change in size are important, but some lesions detected will not be related to the endocrine abnormality for which the imaging procedure was ordered.

The incidence of prolactinoma is low in child-hood, but one in fi ve presents in the 15–24-year age group. A case survey reported that 61 % of prolactinomas were macroadenomas (more often in boys; hypopituitarism and growth failure were common) and 39 % were microadenomas (more often in girls; delayed puberty was common). Delayed onset of puberty was rare, although pri-mary amenorrhea was the presenting symptom in more than 50 % of pubertal females. Presenting symptoms included oligomenorrhea and galac-torrhea in the girls and headache in the boys. Galactorrhea may be demonstrable only by man-ual manipulation of the nipples (blood samples for prolactin should be obtained before examina-tion or many hours later, because manipulation of the nipples raises prolactin levels). The degree of elevation of prolactin may indicate the size of the


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prolactinoma. Microadenomas may demonstrate prolactin levels over 100 ng/mL, while values over 500 ng/mL are suggestive of a macroprolac-tinoma. Certain medications will also raise pro-lactin to levels suggestive of an adenoma when in fact there is no adenoma; risperidone and meto-clopramide are two examples although there are many more psychiatric medications that can raise serum prolactin values.

Dopaminergic therapy is often successful in decreasing prolactin values. The dopamine agonist bromergocriptine may decrease serum prolactin concentrations and decrease tumor size, which is a useful approach before surgery of large macroprolactinomas is undertaken and when resection of the adenoma is incomplete. Pubertal progression and normal menstrual function in girls usually follow reduction of serum prolactin levels. Caberogline is a D2 receptor agonist that can be given 2 times per week (not approved for children). Pituitary apoplexy followed caberog-line treatment of a macroprolactinoma in a 16-year-old girl; this complication has been seen in adults treated with bromocriptine. Tricuspid regurgitation may occur as a cumu lative effect of treatment. Transsphenoidal res ection of microp-rolactinomas in children and adolescents is an effective treatment if medication is ineffective.

High serum levels of macroprolactin, a complex of immunoglobulin G and monomeric prolactin with little biologic activity in vivo, cross-react in commercial prolactin assays, leading to a fi nding of pseudohyperprolactinemia; high prolactin val-ues should be rechecked with subfractionation after polyethylene glycol precipitation to elucidate this potential confusion. When prolactin levels are truly quite high, the molecule may complex with IgG antibodies used in certain assays causing a “hook effect” leading to artifactually low prolactin levels when values actually are quite high. In this situation, a 1–100 dilution of serum before analy-sis is necessary. As prolactin rises in stress, an upset child may have a falsely elevated prolactin suggesting a disorder when there is none.

It is recommended that screening for multiple endocrine neoplasia type I (MENIN gene) and FIPA (AIP gene) occur in anyone with a pituitary adenoma under 21 years of age.

Other Central Nervous System Disorders

Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (604856 ICD+ LANGERHANS CELL HISTIOCYTOSIS) is a clonal proliferative disorder of Langerhans his-tiocytes or their precursors characterized by the infi ltration of the skin, viscera, and bone with lipid-laden histiocytic cells or foam cells. The cause is not clear, but there are features of a neo-plasm and features of a reactive immunologic dis-order. Diabetes insipidus, caused by infi ltration of the hypothalamus or the pituitary stalk, is the most common endocrine manifestation, with GH defi ciency and delayed puberty as possible out-comes. The lung, liver, and spleen may be involved with this infi ltration, and exophthalmos due to infi ltration of the orbit is seen. Other fi nd-ings include cyst-like areas in fl at and long bones of the skull, the ribs, the pelvis, and the scapula and the long bones of the arms and legs and in the dorsolumbar spine. The appearance of “Floating teeth” within rarefi ed bone of the mandible and absent or loose teeth are found. Mastoid or tem-poral bone involvement may lead to chronic otitis media. Treatment with glucocorticoids, antineo-plastic agents, and radiation therapy is promising in terms of survival, but more than 50 % of patients have late sequelae or disease progression. The natural waxing and waning course of this rare disease makes evaluation of therapy diffi cult and highlights the importance of national treatment protocols. Letterer–Siwe disease (%246400 ICD+LETTERER-SIWE DISEASE) has similar-ities to Langerhans' cell histiocytosis but may occur in an autosomal recessive pattern.

Postinfectious Infl ammatory Lesions of the Central Nervous System, Vascular Abnormalities, and Head Trauma

Postinfectious or other infl ammatory lesions of the CNS, granulomatous disease of the area and vascular abnormalities, and head trauma may

Other Central Nervous System Disorders

24

cause abnormal hypothalamic–pituitary function. Tuberculous or sarcoid granulomas of the CNS are associated with delayed puberty. The original case of adiposogenital dystrophy, or Fröhlich’s syndrome characterized by decreased growth and delayed puberty with obesity, is thought to have been caused by tuberculosis infection rather than a neoplasm.

Hydrocephalus may cause hypopituitarism, but precocious puberty also is a possible result, depending on the amount of pressure exerted on various central nervous system locations. Clinical fi ndings will include signs of increased intra-cranial pressure. When hydrocephalus or sub-arachnoid cysts, which can cause similar effects, are decompressed, pituitary abnormalities may improve.

Irradiation of the Central Nervous System

Radiation of the head for treatment of CNS tumors, leukemia, or neoplasms of the head and the face, in which the radiation fi eld involves the hypothalamus or pituitary fi eld, may result in the gradual onset of hypothalamic–pituitary failure over a period of months to a few years. This occurs mainly due to hypothalamic rather than pituitary damage by the radiation and is dose- dependent. This etiology comprises an growing group of patients with hypopituitarism because of the increasing success in radiation treatment of such neoplasms. GH defi ciency is the most com-mon hormone disorder resulting from radiation of the CNS, but gonadotropin defi ciency, hypo-thyroidism, and decreased bone density also occur. Self-reported fertility was reported to be lower in women who received CNS radiotherapy for acute lymphoblastic leukemia at about the time of menarche, although the average age of women in a long-term study was in the early 20s, and longer follow-up of fertility may change the results. Conversely, early or central precocious puberty may occur after radiation therapy for CNS lesions. The combination of GH defi ciency and precocious puberty is a possible outcome of

central nervous system radiation for a brain tumor and may be diffi cult to detect clinically, as the growth rate of the child is greater than that found in patients with GH defi ciency alone, because the sex steroid secretion increases growth rate during pubertal development (see Chaps. 5 and 9 ). Irradiation of the CNS in early life predisposes the patient to later onset of sec-ondary CNS tumors sometimes in just a few years after treatment of the fi rst tumor. Such patient must be monitored to determine what pituitary defects have developed so that it may be treated appropriately.

Developmental Defects of the Midline

Congenital defects of pituitary secretion also may result from anatomic malformations of the hypo-thalamus, from pituitary hypoplasia or aplasia, or from more subtle defects of hormone secretion. Congenital defects of the midline associated with hypopituitarism range from holoprosencephaly (cyclopia, cebocephaly, orbital hypo telorism) to single maxillary incisor and even to cleft palate (4 % of cases of cleft lip and/or palate are associ-ated with GH defi ciency, so that all growth failure in cleft palate should not necessarily be attributed to poor feeding or nutrition alone). Individuals with myelomeningocele (myelodysplasia) have an increased frequency of endocrine abnorma-lities, including hypothalamic hypothyroidism, hyperprolactinemia, and decreased gonadotropin concentrations, whereas some patients demon-strate central precocious puberty.

Septo-Optic and Optic Dysplasia

Septo-optic dysplasia (optic nerve hypoplasia, absent septum pellucidum, or variations of both caused by abnormal development of the prosencephalon) (# 182230. SEPTOOPTIC DYSPLASIA due to a mutation at 3p21.2-p21.1). The HESX1 homeobox gene or SOX2 (see below), SOX3, and OTX2 may be associated with


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25

signifi cant visual impairment which often leads to pendular nystagmus (to-and-fro nystagmus due to inability to focus on a target). Small, pale optic disks occur, but not the appearance of optic atrophy, which would suggest previous development of the optic nerves with subsequent deterioration due to acquired pathology.

A midline hypothalamic defect may lead to the combination of GH defi ciency and diabetes insipidus and may be associated with defi cient ACTH, TSH, and gonadotropin secretion as well. Short stature and delayed puberty may be the most obvious results, although true precocious puberty is an alternative outcome in rare cases of this midline defect. The septum pellucidum is absent in about 50 % of cases of optic hypoplasia or dysplasia, and this defect is readily demon-strable by CNS imaging techniques, most fre-quently by MRI.

The MRI fi ndings of congenital hypopituita-rism may include an ectopic posterior pituitary gland “hot spot” and the appearance of what appears to be a “pituitary stalk transection” and a hypoplastic pituitary gland due to the lack of hypothalamic stimulatory factors. In some patients, the neurohypophysis may appear absent because of a missing hot spot although physiologic changes in hydration may affect the hot spot, which represents vasopressin content, with no true anatomic defect. Abnor malities of the corpus callosum and cerebellum are com-mon on MRI. Four groups are described: those with normal MRI results, those with abnormali-ties of the septum pellucidum and with a normal hypothalamic–pituitary area, those with abnor-malities of the hypothalamic–pituitary area and a normal septum pellucidum, and those with abnormalities in both areas. No endocrine abnormalities were described in the fi rst group, but the others had progressively more endocrine abnormalities, with precocious puberty most common in the second group. Early diagnosis is important because of the risk of sudden death associated with adrenal insuffi ciency if ACTH is inadequate.

Delayed puberty is rarely described in dupli-cation of the hypophysis.

The Solitary Median Maxillary Incisor Syndrome

(#147250 SOLITARY MEDIAN MAXILLARY CENTRAL INCISOR; SMMCI) Solitary median maxillary incisor is associated with the eponymous midline defect and with a prominent midpalatal ridge (torus palatinus) and hypopituitarism. The defect in this autosomal dominant condition is in the sonic hedgehog gene (SHH) at gene map locus 7q3.

Idiopathic Hypopituitary Dwarfi sm

In addition to HESX1 homeobox mutations, auto-somal recessive mutations in homeobox genes encoding transcription factors involved in the early aspects of pituitary development lead to hypogonadotropic hypogonadism and other pitu-itary hormone defi ciencies (Table 3.1 ). PROP1 muta tions (#262600 PITUITARY HORMONE DEFICIENCY, COMBINED, 2; CPHD2) at gene map locus 5q35.3 cause GH and TSH defi ciency and produce delayed puberty or late onset of sec-ondary hypogonadism in adulthood and more rarely may also cause ACTH defi ciency. In one study of 73 patients with idiopathic multiple pitu-itary hormone defi ciencies, 35 had a mutation in PROP1. Homozygous Arg73Cys mutation of PROP1 allowed spontaneous puberty in 2 of 10 affected family members. ACTH defi ciency may develop later and is more rarely a feature of PROP1 defi ciency; patients must be monitored for this serious complication.

Mutations of POU1F1 (PIT *173110 POU DOMAIN, CLASS 1, TRANSCRIPTION FACTOR 1; POU1F1 at 3p11) cause defi ciency in GH, TSH, and prolactin.

Homozygous mutations occur in the LHX3 gene (#221750 PITUITARY HORMONE DEFICIENCY, COMBINED, 3; CPHD3) at gene map locus 9q34.3. The LHX3 gene encodes a member of the LIM class of homeodomain pro-teins, which are associated with multiple pituitary hormone defi ciencies, including LH and FSH, and often with severe restriction of head rotation. LH4 (#262700

Idiopathic Hypopituitary Dwarfi sm

26

Tab

le 3

.1

Gen

etic

for

ms

of m

ultip

le p

ituita

ry/h

ypot

hala

mic

hor

mon

e de

fi cie

ncie

s

Def

ect

Hor

mon

es d

efi c

ient

In

heri

tanc

e M

utat

ions

O

ther

fea

ture

s

POU

1F1

GH

, Prl

, TSH

A

uto-

rece

ssiv

e an

d au

toso

mal

do

min

ant

Mis

sens

e, n

onse

nse,

fr

ames

hift

, spl

icin

g Se

vere

impa

irm

ent o

f po

stna

tal g

row

th, v

aria

ble

pitu

itary

hyp

opla

sia

PRO

P1

GH

, Prl

, TSH

, LH

, FSH

, an

d A

CT

H d

evel

opin

g la

ter

in s

ome

Aut

o-re

cess

ive

Non

sens

e, f

ram

eshi

ft,

splic

ing

Tra

nsie

nt p

ituita

ry h

yper

plas

ia in

som

e

HE

X1

Any

or

all,

incl

udin

g va

sopr

essi

n A

uto-

rece

ssiv

e an

d au

toso

mal

do

min

ant

Mis

sens

e, f

ram

eshi

ft

Sept

o-op

tic d

yspl

asia

or

hypo

plas

ia

LIM

HO

ME

O B

OX

G

EN

E 3

; LIM

3 L

HX

3 G

H, P

rl, T

SH, L

H, F

SH,

and

AC

TH

in s

ome

Aut

o-re

cess

ive

Mis

sens

e, n

onse

nse,

fr

ames

hift

, spl

icin

g L

imite

d ne

ck r

otat

ion,

sho

rt c

ervi

cal s

pine

, se

nsor

ineu

ral d

eafn

ess

LIM

HO

ME

O B

OX

G

EN

E 4

; LIM

4 L

HX

4 G

H, P

rl, T

SH, L

H, F

SH,

and

AC

TH

A

utos

omal

dom

inan

t M

isse

nse,

fra

mes

hift

C

ereb

ella

r ab

norm

aliti

es, v

ery

smal

l sel

la tu

rcic

a in

som

e, a

bnor

mal

pet

rous

bon

e

SOX

2 L

H,F

SH, v

aria

ble

GH

A

utos

omal

dom

inan

t M

isse

nse,

non

sens

e,

fram

eshi

ft

Ano

phth

alm

ia/m

icro

phth

alm

ia, e

soph

agea

l at

resi

a, g

enita

l tra

ct a

bnor

mal

ities

, hyp

otha

lam

ic

ham

arto

ma,

sen

sori

neur

al h

eari

ng lo

ss, d

iple

gia

GL

I2

GH

, Prl

, TSH

, LH

, FSH

, an

d A

CT

H

Hap

loin

suffi

cie

ncy

Mis

sens

e, f

ram

eshi

ft

Hol

opro

senc

epha

ly, c

rani

ofac

ial a

bnor

mal

ities

, po

lyda

ctyl

y, p

artia

l age

nesi

s of

the

corp

us

callo

sum

FGF8

L

H, F

SH, a

nd v

asop

ress

in

Aut

o-re

cess

ive

and

auto

som

al

dom

inan

t M

isse

nse,

chr

omos

ome

dele

tion

Ano

smia

, hol

opro

senc

epha

ly, M

oebi

us

synd

rom

e, s

epto

-opt

ic d

yspl

asia

SOX

3 Is

olat

ed G

HD

or

GH

, Prl

, T

SH, L

H, F

SH, a

nd A

CT

H

X-l

inke

d V

aria

tions

in p

olya

lani

ne

trac

t len

gth,

chr

omos

ome

dupl

icat

ion

Men

tal r

etar

datio

n, in

fund

ibul

ar h

ypop

lasi

a,

ecto

pic

post

erio

r pi

tuita

ry, m

idlin

e ab

norm

aliti

es

OT

X2

Isol

ated

GH

D o

r G

H, P

rl,

TSH

, LH

, FSH

, and

AC

TH

A

utos

omal

dom

inan

t M

isse

nse,

non

sens

e,

mic

rode

letio

n A

noph

thal

mia

/mic

roph

thal

mia

, col

obom

a,

deve

lopm

enta

l del

ay

TB

X19

A

CT

H

Aut

osom

al r

eces

sive

M

isse

nse,

non

sens

e,

fram

eshi

ft, s

plic

ing

Neo

nata

l hyp

ogly

cem

ia, n

eona

tal c

hole

stat

ic

jaun

dice

GH

gro

wth

hor

mon

e, P

rl p

rola

ctin

, TSH

thyr

oid-

stim

ulat

ing

horm

one,

LH

lute

iniz

ing

horm

one,

FSH

fol

licle

-stim

ulat

ing

horm

one,

AC

TH

adr

enoc

ortic

otro

pic

horm

one


Dennis M. Styne Pediatric Endocrinology · To my loving wife Donna and my amazing children Rachel,...

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Transcript of Dennis M. Styne Pediatric Endocrinology · To my loving wife Donna and my amazing children Rachel,...