,Brook’s Clinical Pediatric Endocrinology
,Brook’s Clinical Pediatric Endocrinology
Seventh Edition
Edited by
Mehul T. Dattani, MD FRCP FRCPCH
Professor and Head of Paediatric Endocrinology
Genetics and Genomic Medicine Programme
UCL Great Ormond Street Institute of Child Health
Great Ormond Street Hospital for Children NHS Foundation Trust
London, UK
Charles G. D. Brook, MA MD FRCP
Emeritus Professor of Paediatric Endocrinology
University College London
London, UK
,This edition first published 2020
© 2020 John Wiley & Sons Ltd
Edition History
Wiley‐Blackwell (6e, 2009)
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Library of Congress Cataloging‐in‐Publication Data
Names: Dattani, Mehul T., editor. | Brook, C. G. D. (Charles Groves Darville), editor.
Title: Brook’s clinical pediatric endocrinology / edited by Mehul T. Dattani, Charles G.D. Brook.
Other titles: Clinical pediatric endocrinology
Description: 7th edition. | Hoboken, NJ : Wiley-Blackwell, 2020. | Preceded
by Brook’s clinical pediatric endocrinology / edited by Charles G.D.
Brook, Peter E. Clayton, Rosalind S. Brown. 6th ed. 2009. | Includes
bibliographical references and index. |
Identifiers: LCCN 2019003272 (print) | LCCN 2019003907 (ebook) | ISBN 9781119152699 (Adobe PDF) |
ISBN 9781119152705 (ePub) | ISBN 9781119152682 (hardback)
Subjects: | MESH: Endocrine System Diseases | Adolescent | Child | Infant
Classification: LCC RJ418 (ebook) | LCC RJ418 (print) | NLM WS 335 | DDC 618.92/4–dc23
LC record available at https://lccn.loc.gov/2019003272
Cover Design: Wiley
Cover Image: © VikiVector/Getty Images
Set in 10/12pt Warnock by SPi Global, Pondicherry, India
10 9 8 7 6 5 4 3 2 1
, v
Contents
List of Contributors xix
Preface xxiii
About the Companion Website xxv
1 Genetics and Genomics 1
Anu Bashamboo and Ken McElreavey
Introduction 1
Basic Concepts in Human Genetics and Genomics 1
Genes and Chromosomes 1
Regulation of Gene Expression 4
RNA Editing 4
Classes of RNA Molecules and their Functions 4
MicroRNAs, Small Interfering RNAs, and Piwi‐interacting RNAs 5
LncRNAs 6
Other Small ncRNA Classes 7
Gene Mutations and Inheritance 7
Classes of Gene Mutations 7
Patient and Family History 8
Mendelian Inheritance Patterns 8
Non‐Mendelian Inheritance Patterns 9
Common Disorders with Complex Inheritance Patterns 10
Uniparental Disomy 11
Penetrance and Expressivity 11
Human Populations and Genetic Variation 12
Overview of Human Genetic Variation 12
Allele Frequencies Differ in Different Populations 12
Copy Number Variation (CNV) 13
Epigenetics 14
Epigenetic Mechanisms 14
Genomic Imprinting 14
Transgenerational and Multigenerational Epigenetic Inheritance 15
Advances in Genomic Analysis 15
Familial Linkage Analysis and GWAS Studies 15
Advances in Nucleic Acid Sequencing 16
NGS Protocols 17
Whole Genome (WGS) and Whole Exome Sequencing (WES) 17
Establishing Variant Causality 19
Dissecting Pathogenic from Non‐Pathogenic Variants 19
Genome Editing as a Powerful Tool for Establishing Causality 22
,vi Contents
he Age of Precision Medicine
T 24
Clinical Guidelines 24
Acknowledgments 25
Glossary of Terms 25
Further Reading 29
2 Measuring Hormones 31
Gerhard Binder
Introduction 31
Hormone Assays 31
Assay Validity 33
Technical Pitfalls when Measuring Hormones 36
Clinical Assay Validity 38
Stimulation Tests, Suppression Tests and Profiles 42
Optimal Clinical Use of Hormone Tests 44
Acknowledgements 44
References 44
3 Fetal Endocrinology 47
Harshini Katugampola, Evelien F. Gevers, and Mehul T. Dattani
Introduction 48
Transplacental Passage of Hormones 48
Development of Fetal Endocrine Systems 50
Pituitary Development 50
Adrenal Development 55
Thyroid Development 62
Gonadal Development 66
Disorders of Sex Development (see Chapter 4) 69
Development of the Fetal Autonomic Nervous System 69
Development of the Endocrine Pancreas 71
Development of Pancreatic Endocrine Function 73
Development of the Parathyroid/Calcitonin System 75
Endocrine Regulation of Fetal Growth 78
Neutralization of Hormone Activity in the Fetus 82
Limitation of Hormone Secretion 82
Production of Inactive Hormone Metabolites 83
Delayed Expression or Neutralization of Receptor Response 83
Plasticity of Fetal Endocrine Systems 84
Fetal Adaptations for Transition to Extrauterine Life 85
Cortisol 86
Catecholamines 87
Thermogenesis 87
Calcium Homeostasis 87
Glucose Homeostasis 88
Other Endocrine Adaptations 88
Frontiers in Fetal and Neonatal Endocrinology 89
References 90
4 Disorders of Sex Development 105
Martine Cools and Birgit Köhler
ormal Sex Development
N 105
Terminology 106
Causes of DSD 107
, Contents vii
Impaired Gonadal Development 108
XY Individuals 108
XX individuals 111
Numerical Abnormalities of the Sex Chromosomes 112
Disturbances of Testicular Hormone Production or Action 113
Impaired Biosynthesis 113
Impaired Testosterone Action 114
Virilization of an XX Individual 116
Management of DSD 118
Initial Evaluation and Diagnostic Approach 118
Examination 119
Hormonal Workup 119
Genetic Tests 121
Sex Assignment, Gender Development, Early Genital Surgery and
Disclosure of the Condition 121
Clinical Management 122
Gonadal Tumour Risk and Indications for Gonadectomy 123
Information and Support for Parents Having a Baby with DSD 124
Information and Support for Children and Adolescents 124
Transition 124
Adult Outcome 125
Other Examples of XY DSD 126
Hypospadias 126
Cryptorchidism 126
Persistent Müllerian Duct Syndrome 126
Future Perspectives 127
References 127
Weblinks 131
5 Disorders of Hypothalamo‐Pituitary Axis 133
Hoong‐Wei Gan, Kyriaki‐Sandy Alatzoglou, and Mehul T. Dattani
Introduction 133
The Hypothalamo‐Pituitary Neuroendocrine Axis 134
Hypothalamo‐Pituitary Development 134
Hypothalamo‐Pituitary Organogenesis 135
Cell Differentiation, Organization and Plasticity in the
Anterior Pituitary 136
Early Developmental Genes and Transcription Factors 137
Terminal Cell Differentiation 143
Congenital Disorders of Hypothalamo‐Pituitary Development 144
Combined Pituitary Hormone Deficiencies (CPHD) 144
Isolated Pituitary Hormone Deficiencies 152
Acquired Disorders of Hypothalamo‐Pituitary Dysfunction 155
Central Nervous System (CNS) Tumours 155
Infiltrative and Inflammatory Disorders 166
Traumatic Brain Injury 168
CNS Infection 169
Haemochromatosis 170
Psychosocial Deprivation 171
Investigation of Hypopituitarism 172
Management of Hypopituitarism 173
Conclusion 174
References 174
,viii Contents
6 Disorders of Growth 199
P.G. Murray and P.E. Clayton
Normal Growth 200
Physiology of Growth 201
Short Stature 205
Aetiology of Growth Impairment 205
Growth Hormone Deficiency 205
Biochemical Evaluation of Suspected GH Deficiency 206
Neuroimaging 208
Genetic Studies 208
Management of Growth Hormone Deficiency 208
Safety of Growth Hormone Treatment 210
Reassessment of the GH‐IGF Axis at End of Growth 210
Monogenic Disorders Causing Growth Hormone Deficiency 211
Acquired GH Deficiency 211
Tumours Affecting the Hypothalamo–Pituitary Axis 211
Radiotherapy 212
Langerhans Cell Histiocytosis 213
Trauma 213
Hypophysitis 213
Disorders of GH Action and GH Sensitivity (Primary IGF‐I Deficiency) 213
Bioinactive GH 213
Laron Syndrome 214
STAT5B Deficiency 214
Acid‐Labile Subunit (ALS) Deficiency 214
IGF‐I Gene Deletions and Bioinactive IGF‐I 215
Recombinant Human IGF‐I Therapy 215
Disorders of IGF‐I Resistance 216
Growth Disorders not Related to the GH‐IGF Axis 216
The Short Small‐for‐Gestational‐Age Child 216
Management of Child Born SGA 217
Turner Syndrome 217
Syndromes Associated With Short Stature 219
Prader–Willi Syndrome 219
Noonan Syndrome and Associated Disorders 220
Primordial Growth Disorders 220
Silver–Russell Syndrome 220
3‐M Syndrome 223
Mulibrey Nanism 223
SHORT Syndrome 223
Floating–Harbor Syndrome 223
IMAGe Syndrome 224
Bloom Syndrome 224
Microcephalic Osteodysplastic Primordial Dwarfism Type II 224
Seckel Syndrome 224
Meier–Gorlin Syndrome 224
Nijmegen Breakage Syndrome 224
Fanconi Anaemia 224
Idiopathic Short Stature 225
Treatment of ISS 226
Skeletal Dysplasias 227
Skeletal Dysplasia Classification 227
Achondroplasia 228
Hypochondroplasia 228
, Contents ix
Leri–Weill Dyschondrosteosis and SHOX Deficiency 229
Tall Stature 229
Familial Tall Stature, Constitutional Tall Stature and Obesity 230
Precocious Puberty 230
GH Excess 230
Syndromes Associated with Tall Stature 231
Management of Tall Stature 232
References 233
7 Puberty and Its Disorders 235
Sasha R. Howard, Nicolas de Roux, Juliane Leger, Jean‐Claude Carel, and Leo Dunkel
Normal Puberty 235
Introduction 235
Physical Changes that Occur During Puberty 236
Timing of Puberty and Relationship with Linear Growth 239
The Hypothalamic–Pituitary–Gonadal Axis 245
The Reactivation of the Gonadotropic Axis at Puberty 253
Precocious Puberty 256
Introduction 256
Aetiologies of Premature Sexual Development 256
Consequences of Precocious Puberty 259
Evaluation of the Child with Premature Sexual Development 259
Management 264
Delayed Puberty 265
Definition 265
Differential Diagnosis 265
Assessment 275
Management 278
Conclusions 283
References 284
8 The Thyroid Gland 289
Catherine Peters and Nadia Schoenmakers
Section 1: Development of the Thyroid Axis 289
Thyroid Gland Development 289
Molecular Control of Thyroid Development 290
Thyroid Hormone Biosynthesis 290
The Hypothalamic–Pituitary–Thyroid Axis 292
Negative Regulation of Thyroid Hormone Synthesis 292
Thyroid Hormone Transport 293
Thyroid Hormone Transport Proteins 293
Thyroid Hormone Metabolism 293
Thyroid Hormone Action 294
Positive Regulation of Genes by Thyroid Hormone 296
Negative Regulation of Genes by Thyroid Hormone 296
Thyroid Hormone Receptor Function 296
Thyroid Hormone Effects on Target Tissues 296
Thyroid Hormone Effects on the Gut 297
Maturation of Thyroid Hormone Development 298
Section 2: Clinical Thyroid Disorders 301
Congenital Hypothyroidism 301
Prematurity 308
Drugs/Iatrogenic 308
Fetal and Neonatal Goitre 308
, x Contents
Congenital Hyperthyroidism 308
TSH Receptor Mutation 309
McCune–Albright Syndrome 309
Acquired Thyroid Disorders 309
Hashimoto’s Thyroiditis 310
Graves’ Disease 311
Thyroid Storm 313
Thyrotoxic Periodic Paralysis 313
Other Forms of Thyroiditis 314
Subacute (De Quervain’s) Thyroiditis 314
Euthyroid Goitre 314
Thyroid Nodule 314
Iodine Status 314
Section 3: Diagnostic Pitfalls 315
Normal Thyroid Hormone with Elevated TSH 315
Reduced Thyroid Hormones Without TSH Elevation 315
Elevated Thyroid Hormones and Unsuppressed TSH 315
Defective TH Action – Resistance to Thyroid Hormone (RTH) 317
Defective TH Metabolism – SECISBP2 318
Defective Thyroid Hormone Transport – MCT8 319
Familial Dysalbuminaemic Hyperthyroxinaemia (FDH) 319
References 320
Weblinks 334
9 The Adrenal Cortex and Its Disorders 335
Claire R. Hughes, Elim Man, and John C. Achermann
Introduction 335
Development, Function and Regulation of the Adrenal Gland 336
History of Adrenal Medicine 336
Development and Anatomy of the Adrenal Gland 336
Steroidogenesis 339
Dynamic Regulation of Steroidogenesis 346
Steroid Hormone Actions 350
Adrenal Insufficiency (AI) 353
Overview of AI 353
Presentation of AI 355
Diagnosing AI and its Causes 358
Treatment of AI 367
Secondary AI 370
Causes of Primary AI (Excluding CAH) 372
Congenital Adrenal Hyperplasia (CAH) 381
Adrenal Excess 393
Glucocorticoid Excess (Cushing Syndrome) 393
Mineralocorticoid Excess 399
Androgen Excess 400
Education, Support and Long‐Term Care 401
Education 401
Support Organizations 403
Transition and Long‐Term Care 404
References 405
10 The Parathyroid and Disorders of Calcium and Bone Metabolism 409
Jeremy Allgrove and Moira Cheung
Introduction 409
