Brook's Clinical Pediatric Endocrinology -  - ebook

Brook's Clinical Pediatric Endocrinology ebook

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The seventh edition of Brook's Clinical Pediatric Endocrinology has been compiled by an experienced editorial team and internationally renowned contributors; it presents basic science and clinical management of endocrine disorders for all involved in the care of children and adolescents. It provides treatments for a variety of hormonal diseases, including diabetes and hypoglycaemia, growth problems, thyroid disease and disorders of puberty, sexual differentiation, calcium metabolism, steroid metabolism and hypopituitarism.

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Table of Contents

Cover

List of Contributors

Preface

Acknowledgement

About the Companion Website

1 Genetics and Genomics

Introduction

Basic Concepts in Human Genetics and Genomics

Classes of RNA Molecules and their Functions

Gene Mutations and Inheritance

Human Populations and Genetic Variation

Epigenetics

Advances in Genomic Analysis

Establishing Variant Causality

The Age of Precision Medicine

Clinical Guidelines

Acknowledgments

Glossary of Terms

Further Reading

2 Measuring Hormones

Introduction

Hormone Assays

Assay Validity

Technical Pitfalls When Measuring Hormones

Clinical Assay Validity

Stimulation Tests, Suppression Tests and Profiles

Optimal Clinical Use of Hormone Tests

Acknowledgements

References

3 Fetal Endocrinology

Introduction

Transplacental Passage of Hormones

Development of Fetal Endocrine Systems

Neutralization of Hormone Activity in the Fetus

Plasticity of Fetal Endocrine Systems

Fetal Adaptations for Transition to Extrauterine Life

Frontiers in Fetal and Neonatal Endocrinology

References

4 Disorders of Sex Development

Normal Sex Development

Terminology

Causes of DSD

Impaired Gonadal Development

Disturbances of Testicular Hormone Production or Action

Virilization of an XX Individual

Management of DSD

Clinical Management

Other Examples of XY DSD

Future Perspectives

References

Weblinks

5 Disorders of Hypothalamo‐Pituitary Axis

Introduction

The Hypothalamo‐Pituitary Neuroendocrine Axis

Hypothalamo‐Pituitary Development

Congenital Disorders of Hypothalamo‐Pituitary Development

Acquired Disorders of Hypothalamo‐Pituitary Dysfunction

Investigation of Hypopituitarism

Management of Hypopituitarism

Conclusion

References

6 Disorders of Growth

Normal Growth

Short Stature

Acquired GH Deficiency

Syndromes Associated With Short Stature

Microcephalic Osteodysplastic Primordial Dwarfism Type II

Idiopathic Short Stature

Skeletal Dysplasias

Skeletal Dysplasia Classification

Tall Stature

References

7 Puberty and Its Disorders

Normal Puberty

Precocious Puberty

Delayed Puberty

Conclusions

References

8 The Thyroid Gland

Section 1: Development of the Thyroid Axis

Section 2: Clinical Thyroid Disorders

Section 3: Diagnostic Pitfalls

References

Weblinks

9 The Adrenal Cortex and Its Disorders

Introduction

Development, Function and Regulation of the Adrenal Gland

Adrenal Insufficiency (AI)

Adrenal Excess

Education, Support and Long‐Term Care

References

10 The Parathyroid and Disorders of Calcium and Bone Metabolism

Introduction

Physiology of Calcium and Bone Metabolism

Physiology of Bone Metabolism

Interactions between Calciotropic Agents

Fetal and Neonatal Calcium Metabolism

Post‐Neonatal Calcium, Phosphate and Magnesium Metabolism and the Calcium Cascade

Clinical Conditions

Hypocalcaemia

Hypercalcaemia

Disorders of Bone Metabolism

Inherited Inflammatory Diseases of Bone

Drugs Used in the Treatment of Disorders of Calcium and Bone Metabolism

Summary

References

Weblinks

11 Polyglandular Autoimmune Syndromes

Introduction

Autoimmune Polyendocrinopathy Syndrome Type 1 (APS1)

Autoimmune Polyendocrinopathy Syndrome Type 2 and Associated Disorders

Conclusion

References

12 Endocrine Neoplasia

Thyroid Neoplasia: Nodules and Cancer

Paragangliomas and Phaeochromocytomas

Adrenocortical Cancers

Tumours of the Ovary

Tumours of the Testes

References

13 Endocrine Late Effects of Cancer Treatments

Prevalence and Risk Factors for Endocrine Late Effects

Diagnosis and Management of Common Endocrine Late Effects

Summary

References

Weblinks

14 Disorders of Water Balance

Regulation of Water Balance

Diabetes Insipidus (DI)

Central Diabetes Insipidus and Adipsia

Primary Polydipsia

Nephrogenic Diabetes Insipidus

The Syndrome of Inappropriate Antidiuretic Hormone Secretion

Management of Central Diabetes Insipidus

Treatment of Nephrogenic Diabetes Insipidus

Treatment of Inappropriate Antidiuretic Hormone Secretion

Challenges

Conclusions

Clinical Guidelines

References

15 Diabetes Mellitus

Type 1 Diabetes

Type 2 Diabetes

Cystic Fibrosis‐Related Diabetes

Monogenic Forms of Diabetes

Rare Forms of Diabetes

Living with Diabetes

References

16 Disorders Associated with Hypoglycaemia in Children

Introduction

Physiology of Blood Glucose Control

Role of Gut Hormones in Glucose Homeostasis

Metabolic Adaptation to Birth

Metabolic Adaptation to Feeding and Fasting

The Regulation of Insulin Secretion and Role of K

ATP

Channels

Definition of Hypoglycaemia

Aetiology and Clinical Approach to Hypoglycaemia

Investigations for Hypoglycaemia

Emergency Management of Hypoglycaemia

Causes of Hypoglycaemia

References

17 Obesity

Introduction

Definitions, Differential Diagnosis, Assessments and Measurements

Aetiology of Obesity

Common or Multifactorial Obesity and Fetal Programming

Neurobiology of Satiety and Hunger

Hedonistic Signals and Addiction

Behaviour, Hypothalamus and Obesogenic Environment

Biology of Adipose Tissue and Adipocytes

Microbiota

Endocrinology of Obesity

Epigenetics

Social Inheritance

Sociodemographics

Nutrition and Malnutrition

Physical Activity

Sedentary Behaviour

Endocrine‐Disrupting Chemicals and Toxicology

Media Use

Cultural Aspects

Evolution

Epidemiology

Developed Countries

Developing Countries

Co‐Morbidities and Consequences

Social Participation

Mortality

Health Economics

Treatments

Microbiota

Urban Living

Advertising Industries

Conclusions

Further Reading

Weblinks

18 Genetic Obesity Syndromes

Introduction

Genetic Contributors to Obesity: The Evidence

Genetic Obesity Syndromes: An Overview

Obesity with Developmental Delay

Obesity Without Development Delay

Conclusions

References

Weblinks

19 Endocrine Care During Adolescence into Young Adulthood

Introduction

Adolescence and Young Adulthood

Exploratory and Health‐Related Behaviours

Addressing Adherence

Young People with Endocrine Conditions

Conclusion

References

Index

End User License Agreement

List of Tables

Chapter 1

Table 1.1 Commonly used databases in human genetic and genomic analysis.

Table 1.2 Characteristics of the three major classes of small RNAs involved in p...

Table 1.3 Types of inheritance and their associated family history.

Table 1.4 Different NGS protocols aimed at addressing specific biological questi...

Table 1.5 Commonly used variant‐level prediction tools to understand the potenti...

Table 1.6 Commonly used gene‐level tools to determine the degree to which a gene...

Chapter 2

Table 2.1 Immunoassay acronyms and their meaning.

Table 2.2 A 2 × 2 table displaying the possible outcomes of a diagnostic test.

Table 2.3 The formulas defining the major parameters of test validity.

Table 2.4 Major pre‐analytic steps and options.

Table 2.5 Recall rate, positive predictive value and prevalence of the newborn s...

Chapter 3

Table 3.1 The fetal endocrine milieu.

Table 3.2 Comparison of murine and human phenotypes in hypothalamo‐pituitary dev...

Table 3.3 Comparison of murine and human phenotypes in adrenal development.

Table 3.4 Neutralization of hormone actions in the fetus.

Chapter 4

Table 4.1 Biological classification of DSD.

Table 4.2 Newborn problems or situations in childhood that merit workup for DSD....

Table 4.3 Investigating an infant with a suspected DSD.

Table 4.4 Adapted checklist for assessing if an adolescent or young adult with D...

Chapter 5

Table 5.1 Hormone secreted by the anterior and posterior lobes of the pituita...

Table 5.2 Genetic disorders of hypothalamo‐pituitary development resulting in...

Table 5.3 Genetic disorders of hypothalamo‐pituitary development resulting in...

Table 5.4 Pituitary phenotypes in murine models with spontaneous or induced d...

Table 5.5 Symptoms and signs in patients with congenital hypopituitarism.

Table 5.6

HESX1

mutations and their associated phenotypes.

Table 5.7

OTX2

mutations and their associated phenotypes.

Table 5.8 SOX3 dosage changes and their associated phenotypes.

Table 5.9 Genetic forms of isolated GH deficiency (IGHD).

Table 5.10 Common acquired causes of hypothalamo‐pituitary dysfunction.

Table 5.11 The differential diagnosis of pediatric suprasellar masses by neur...

Table 5.12 Common symptoms and signs at presentation of craniopharyngioma ran...

Table 5.13 Causes of hypophysitis.

Table 5.14 Known reported causative agents of CNS infection‐related hypopitui...

Table 5.15 Primary and secondary causes of haemochromatosis.

Table 5.16 Investigation and management of hypo‐ and hyperpituitarism: for su...

Chapter 6

Table 6.1 Clinical features of Turner syndrome.

Table 6.2 Clinical features of Noonan syndrome.

Table 6.3 Groups of conditions organized according to their molecular basis.

Table 6.4 Groups of conditions organized according to their clinical presentatio...

Table 6.5 Scoring system to aid in selection for genetic analysis of

SHOX

in pat...

Table 6.6 Aetiology of tall stature.

Table 6.7 Criteria for diagnosis of Marfan syndrome.

Table 6.8 Systemic scoring system.

Chapter 7

Table 7.1 Details of the Tanner stages of puberty.

Table 7.2 Serum gonadotrophins, gonadal and adrenal steroids in stages of pubert...

Table 7.3 Pubertal stages (according to Tanner) with respective testis volumes a...

Table 7.4 Clinical characteristics of the various forms of central precocious pu...

Table 7.5 Clinical characteristics of the various forms of peripheral precocious...

Table 7.6 When should suspected precocious puberty be explored?

Table 7.7 Differentiation between true precocious puberty and slowly progressive...

Table 7.8 Differential diagnoses of self‐limited delayed puberty.

Table 7.9 Syndromes associated with hypogonadotropic hypogonadism.

Table 7.10 Genetic causes of hypogonadotropic hypogonadism and associated featur...

Table 7.11 Upper limits for creatinine‐corrected urinary gonadotropin concentrat...

Table 7.12 Medications used for the treatment of self‐limited delay of puberty a...

Table 7.13 Medications used for the treatment of self‐limited delay of puberty a...

Chapter 8

Table 8.1 A summary of the genetic defects implicated in congenital hypothyroidi...

Table 8.2 A summary of causes of elevated T4 and/or T3 with suppressed or unsupp...

Chapter 9

Table 9.1 Key factors and enzymes involved in adrenal steroidogenesis.

Table 9.2 Potency of selected therapeutic steroids compared with cortisol based ...

Table 9.3 Causes of adrenal insufficiency.

Table 9.4 Monogenic causes of primary adrenal insufficiency.

Table 9.5 The Prader classification system for the appearance of external genita...

Table 9.6 A selection of the most common

CYP21A2

mutations found in 21‐OHD.

Table 9.7 Causes of glucocorticoid, mineralocorticoid and adrenal hormone excess...

Table 9.8 Clinical features of Cushing disease in children and young people comp...

Table 9.9 Selected websites for support groups and medical resources.

Chapter 10

Table 10.1 Investigation of disorders of calcium and bone metabolism.

Table 10.2 Hypocalcaemic disorders associated with genetic abnormalities. These ...

Table 10.3 Distal renal tubular acidosis and miscellaneous renal tubular disorde...

Table 10.4 Hypercalcaemic disorders associated with genetic abnormalities. The m...

Table 10.5 Genetic classification of osteogenesis imperfecta. The metabolic abno...

Table 10.6 Genetic disorders of altered bone mass. The metabolic abnormalities, ...

Table 10.7 Biochemical changes observed in disorders associated with hypocalcaem...

Chapter 11

Table 11.1 Frequencies of the major and main minor components of APS1.

Table 11.2 Rarer minor manifestations having reported association with APS1 [...

Table 11.3 The identified autoantigens in APS1 for the commoner disease componen...

Table 11.4 Investigations recommended in the routine follow‐up of APS1 patients ...

Table 11.5 Classification of APS3.

Table 11.6 Minor manifestations frequently associated with APS2.

Chapter 12

Table 12.1 Thyroid cancer TNM staging.

Table 12.2 Familial syndromes presenting with PHEOs/PGLs and their characteristi...

Table 12.3 Medications and conditions that can interfere with catecholamine meas...

Table 12.4 Drugs potentially affecting metaiodobenzylguanidine (MIBG) uptake....

Table 12.5 Signs and symptoms of adrenocortical tumours in 58 children.

Table 12.6 Staging of adrenocortical tumours.

Table 12.7 Staging of pediatric ovarian germ cell tumours according to the Ameri...

Table 12.8 FIGO staging system for primary ovarian carcinoma.

Table 12.9 Comparison of ovarian SCST subtypes [31].

Table 12.10 Classification of prepubertal testicular tumours.

Table 12.11 Staging of pediatric testicular germ cell tumours according to the A...

Chapter 13

Table 13.1 Endocrine late effects of cancer treatments: hypothalamo–pituitary dy...

Table 13.2 Endocrine late effects of cancer treatments: common primary thyroid, ...

Table 13.3 Chemotherapy agents associated with potential gonadal toxicity.

Chapter 14

Table 14.1 Regulation of vasopressin secretion.

Table 14.2 Aetiologies of diabetes insipidus.

Table 14.3 Neuroradiological protocol in CDI.

Chapter 15

Table 15.1 Defined susceptibility loci for T1DM.

Table 15.2 Sensitivity of the major islet autoantibodies for the diagnosis of ne...

Table 15.3 Primary prevention trials in T1DM.

Table 15.4 Recombinant and analogue human insulin preparations widely used in ch...

Table 15.5 Guide to initial insulin pump rate settings in children and adolescen...

Table 15.6 Appropriate responses for adjustment of insulin and intake of carbohy...

Table 15.7 Outline of the mini‐dose glucagon protocol [116, 154, 155].

Table 15.8 Guidelines for T1DM management with exercise.

Table 15.9 Metabolic guidelines stipulated in the 2104 Guidelines of the Interna...

Table 15.10 Glucose concentrations and physiologic responses [271, 272].

Table 15.11 Common genetic loci associated with T2DM risk [405].

Table 15.12 Genes predisposing to T2DM.

Table 15.13 ADA Criteria for testing for T2DM or prediabetes in asymptomatic chi...

Table 15.14 Non‐insulin medications used in the treatment of T2DM in adults.

Table 15.15 Co‐morbidities and complications in youth with T2DM diabetes mellitu...

Table 15.16 Results of oral glucose tolerance testing with categories of dysglyc...

Table 15.17 Classification of maturity onset diabetes of the young (MODY).

Table 15.18 Monogenic subtypes of neonatal and infancy‐onset diabetes mellitus....

Chapter 16

Table 16.1 Causes of hypoglycaemia.

Table 16.2 Investigations in hypoglycaemia of unknown cause, the ‘hypoglycaemia ...

Table 16.3 More detailed investigations (depending on the suspected cause).

Table 16.4 Syndromes associated with hyperinsulinaemic hypoglycaemia [86–91].

Table 16.5 Genetic aetiology of CHI.

Table 16.6 Biochemical markers that help in the diagnosis of HH (when blood gluc...

Table 16.7 Summary of treatment for HH patients [92, 106, 107].

Table 16.8 Drugs used for medical therapy of hyperinsulinaemic hypoglycaemia ...

Chapter 17

Table 17.1 Factors that contribute to the development of obesity and may constit...

Table 17.2 Disorders that can present with obesity in childhood – differential d...

Table 17.3 Genetic syndromes that may be associated with childhood obesity.

Table 17.4 Co‐morbidity of obesity in childhood and adolescence.

Table 17.5 Hypothetical mechanisms of how obesity might affect onset and tempo o...

Table 17.6 Drugs that could potentially be used in obesity management in childre...

Table 17.7 Preventive strategies targeting overweight and obese children and ado...

Table 17.8 Unresolved questions in obesity research.

Table 17.10 Summary of multiple determinants of childhood overweight and obesity...

Chapter 19

Table 19.1 Biopsychosocial development through adolescence.

Table 19.2 HEEADSSS assessment for young people in endocrine clinics.

List of Illustrations

Chapter 1

Figure 1.1 Example of a typical mammalian gene structure. A typical gene has...

Figure 1.2 Symbols commonly used for creating pedigree charts.

Figure 1.3 Sequencing by synthesis (e.g. Illumina). (a) Randomly fragmented ...

Figure 1.4 Example of NGS exome sequence read alignment data visualized usin...

Figure 1.5 An example of a Clinical Actionability Evaluation scheme for eith...

Figure 1.6 Overview of the main CRISPR/Cas9 system and experimental approach...

Chapter 2

Figure 2.1 The principle of the competitive immunoassay. The hormone in the ...

Figure 2.2 The principle of the non‐competitive two‐site immunoassay. The ho...

Figure 2.3 Schema of gas chromatography–mass spectrometry (GC–MS)..

Figure 2.4 Historical bioassay of growth hormone. Hypophysectomized female r...

Figure 2.5 Youden plot for external quality control. The Youden plot is a gr...

Figure 2.6 Control chart for internal quality control. Three quality control...

Figure 2.7 Interference by bridging antibodies. Heterophilic antibodies are ...

Figure 2.8 The ‘hook effect’. A very high amount of hormone exceeding the hi...

Figure 2.9 Positive and negative test outcome – the ideal and the reality. T...

Figure 2.10 Post‐test probabilities are dependent on pretest probabilities o...

Figure 2.11 Receiver‐operating‐characteristic (ROC) plot analysis. ROC analy...

Figure 2.12 Non‐parametric distribution of the hormone. The calculation of s...

Chapter 3

Figure 3.1 Placental neutralization of hormone activity during maternal–feta...

Figure 3.2 Transcription factors and signalling molecules involved in anteri...

Figure 3.3 Patterns of change of fetal plasma human placental lactogen (hPL)...

Figure 3.4 Hemi cross section of a 5‐week human embryo showing the locations...

Figure 3.5 Patterns of change of fetal plasma adrenocorticotropic hormone (A...

Figure 3.6 Approach to a neonate presenting with signs and symptoms of adren...

Figure 3.7 Patterns of change of fetal plasma thyroid‐stimulating hormone (T...

Figure 3.8 Illustration of the homeobox genes that program development of th...

Figure 3.9 Patterns of change of plasma concentrations of human chorionic go...

Figure 3.10 Summary of the molecular and cellular events of gonadal differen...

Figure 3.11 Expression of main transcription factors during pancreatic embry...

Figure 3.12 Proposed actions of parathyroid hormone (PTH), PTH‐related prote...

Figure 3.13 Actions of cortisol and catecholamines during fetal adaptation t...

Chapter 4

Figure 4.1 Schematic representation of the fundamental components of sex dev...

Figure 4.2 Events temporally related to sex differentiation in the male fetu...

Figure 4.3 Schematic representation of the principal morphologic and functio...

Figure 4.4 Examples of gonadal differentiation patterns, illustrating the va...

Figure 4.5 Pathways of testosterone synthesis in the human testis. The domin...

Figure 4.6 The classic pathway of steroidogenesis leading to dihydrotestoste...

Figure 4.7 A schematic diagram of androgen action in a target cell. Circulat...

Figure 4.8 The feto‐placental‐maternal steroid unit. The androgen substrate ...

Chapter 5

Figure 5.1 T

1

‐weighted sagittal MRI image illustrating the anatomical relati...

Figure 5.2 Relationship between pituitary hormones, their hypothalamic stimu...

Figure 5.3 Rodent pituitary development indicating the four main stages by d...

Figure 5.4 Schematic representation of the developmental cascade of transcri...

Figure 5.5 MR imaging of a 9‐year‐old boy with a 13‐base‐pair deletion in

PR

...

Figure 5.6 MR imaging of a patient with septo‐optic dysplasia demonstrating ...

Figure 5.7 Sagittal MRI with dedicated pituitary views demonstrating the pre...

Figure 5.8 Serial T

1

‐weighted MRI images with gadolinium contrast of a patie...

Figure 5.9 Suggested algorithm for differentiating between central DI, cereb...

Figure 5.10 Suggested algorithm for genetic screening of pituitary adenomas....

Chapter 6

Figure 6.1 The infancy, childhood, puberty model of growth.

Figure 6.2 Central and peripheral components that regulate the GH axis. NPY,...

Figure 6.3 GH signal transduction. Binding of GH to two dimerised GH recepto...

Figure 6.4 IGF‐I signal transduction. Binding of IGF‐I to the IGF‐1R leads t...

Figure 6.5 The RAS/MAPK pathway. The pathway is activated by binding of a li...

Figure 6.6 Flow chart for investigation and diagnosis of SRS. *Studies have ...

Chapter 7

Figure 7.1 Schematic of the hypothalamic–pituitary–gonadal axis. WAT, white ...

Figure 7.2 Tanner staging of puberty onset in boys and girls.

Figure 7.3 The distribution of pubertal timing in healthy boys (a) and girls...

Figure 7.4 Relationship between peak height velocity and pubertal developmen...

Figure 7.5 Relationship between peak height velocity and pubertal developmen...

Figure 7.6 Effects of oestrogen on growth. Oestrogens exert systemic effects...

Figure 7.7 Evolution of average menarcheal age (year) in the USA and Nordic ...

Figure 7.8 Possible roles in the hypothalamic–pituitary–ovarian axis of seve...

Figure 7.9 Factors that affect the migration of gonadotropin‐releasing hormo...

Figure 7.10 Mutations in single genes at many levels of the HPG axis can cau...

Figure 7.11 Genetic regulators in the trans‐synaptic and glial control of Gn...

Figure 7.12 The HPG axis during fetal and postnatal life. Circulating concen...

Figure 7.13 Inhibitory regulation of the hypothalamic–pituitary axis. This i...

Figure 7.14 Aetiologies of precocious puberty. (

See insert for colour repres

...

Figure 7.15 Flow chart for the evaluation of a patient with delayed puberty....

Chapter 8

Figure 8.1 A summary of the key steps in thyroid gland morphogenesis and the...

Figure 8.2 A summary of the key steps in thyroid hormone biosynthesis in the...

Figure 8.3 A panel of four illustrations: (a) The deiodination of thyroid ho...

Figure 8.4 Maturation of thyroid gland development and function during gesta...

Figure 8.5 Postnatal changes in the serum concentration of TSH, T4, T3 and r...

Figure 8.6 Postnatal changes in the serum T4, concentration in premature bab...

Figure 8.7 Graphical representation of changing thyroid hormone requirements...

Figure 8.8 Infant with severe untreated congenital hypothyroidism diagnosed ...

Figure 8.9 Ten‐year‐old female with severe primary hypothyroidism caused by ...

Chapter 9

Figure 9.1 Simplified overview of the hypothalamo–pituitary–adrenal axis sho...

Figure 9.2 Overview of human adrenal development. (a) Key events in adrenal ...

Figure 9.3 (a) Typical total combined adrenal weight in humans from early de...

Figure 9.4 (a) Cartoon showing the structure of the adult adrenal gland. (b)...

Figure 9.5 The chemical structures of cholesterol and three other important ...

Figure 9.6 Simplified overview of steroidogenesis in the adrenal gland and t...

Figure 9.7 The two electron transfer systems for haem‐containing cytochrome ...

Figure 9.8 The role of PAPSS2 and sulphotransferase in the conversion of DHE...

Figure 9.9 The cortisol to cortisone shuttle catalysed by the 11β‐hydroxyste...

Figure 9.10 Central regulation of ACTH synthesis and release. (a) The role o...

Figure 9.11 Representative profile showing the circadian variation in circul...

Figure 9.12 Overview of the renin–angiotensin system (RAAS) and regulation o...

Figure 9.13 Cartoon showing the classic cellular actions of cortisol on gene...

Figure 9.14 Typical normal ranges for aldosterone and plasma renin activity ...

Figure 9.15 (a) Typical ages at presentation of several of the more common o...

Figure 9.16 Common features of acute and chronic primary adrenal insufficien...

Figure 9.17 Clinical signs of hyperpigmentation associated with primary adre...

Figure 9.18 Cartoon showing the cellular function of several factors associa...

Figure 9.19 Cartoon showing selected pathogenic variants in the MC2R (ACTH r...

Figure 9.20 The biochemical consequences of 21‐hydroxylase (P450c21) deficie...

Figure 9.21 Prader staging of external genitalia in CAH.

Figure 9.22 Genomic locus on chromosome 6p21 containing

CYP21A2

(encoding 21...

Figure 9.23 Diagnostic value of 17‐hydroxyprogesterone (17‐OHP) in 21‐hydrox...

Figure 9.24 The balance of excess glucocorticoid treatment compared with ins...

Figure 9.25 Clinical features of childhood Cushing syndrome. (a) Typical gro...

Figure 9.26 Example of a medical alert card for individuals with adrenal ins...

Figure 9.27 Description of an emergency pack that can be carried by children...

Figure 9.28 Overview of an illness management flow sheet for patients with a...

Chapter 10

Figure 10.1 Schematic representation of divalent cation transport across gas...

Figure 10.2 Schematic representation of the sigmoidal relationship between i...

Figure 10.3 Simplified representation of mechanism of action of PTH in relat...

Figure 10.4 Diagrammatic representation of the principal steps involved in v...

Figure 10.5 Diagrammatic representation of the ‘phosphate fountain’. FGF23 i...

Figure 10.6 Diagrammatic representation of osteoblast differentiation. BMP, ...

Figure 10.7 Diagrammatic representation of osteoclast differentiation and fu...

Figure 10.8 Diagrammatic representation of the principal responses to a hypo...

Figure 10.9 Diagrammatic representation of the calcium cascade showing the v...

Figure 10.10 Computed tomography image of basal ganglia and frontal lobe cal...

Flowchart 10.1 Acute management of hypocalcaemia in children.

Figure 10.11 Photographs of the face (a), showing the typical rounded facies...

Figure 10.12 Diagrammatic representation of the intron/exon organization of ...

Figure 10.13 Clinical appearances of swelling of the wrists (a), knees (b) a...

Figure 10.14 X‐ray appearances of the wrists (a) and knees (b) in classical ...

Figure 10.15 Stages in the development of vitamin D deficiency.

Flowchart 10.2 Acute management of hypercalcaemia in children.

Figure 10.16 SestaMIBI scan taken in a child with a single right lower parat...

Chapter 11

Figure 11.1 It is still not fully clear how AIRE or FOXP3 deficiency leads t...

Figure 11.2 Incidence of the three most common components of APS1 according ...

Figure 11.3 Ectodermal features of APS1 illustrating the nail dystrophy and ...

Chapter 13

Figure 13.1 Relative proportions and overlap among anterior pituitary defici...

Figure 13.2 Effective sterilizing dose for age at treatment and premature ov...

Figure 13.3 Percentage of subjects with acute ovarian failure (no spontaneou...

Figure 13.4 Probability of developing an underactive thyroid after diagnosis...

Chapter 14

Figure 14.1 Osmoreceptor and baroreceptor circuits and AVP synthesis and sec...

Figure 14.2 AVP action on renal collecting duct cells.

Figure 14.3 Age at disease onset and aetiology of central diabetes insipidus...

Figure 14.4 Central diabetes insipidus: clinical and radiological follow‐up ...

Figure 14.5 Central diabetes insipidus and growth hormone deficit in an 11‐y...

Figure 14.6 Bifocal germinoma. (a) Sagittal T1‐weighted image. (b) Sagittal ...

Figure 14.7 Metastatic germinoma remission and relapse in a 10‐year‐old girl...

Figure 14.8 Langerhans cell histiocytosis. Pre‐contrast sagittal T1‐weighted...

Figure 14.9 Langerhans cell histiocytosis with CNS involvement. (a) Sagittal...

Figure 14.10 CDI: Evolution of findings in lymphocytic infundibulo‐hypophysi...

Chapter 15

Figure 15.1 Age‐standardized incidence of T1DM in children under 14 years of...

Figure 15.2 The modified ‘Eisenbarth’ model of the natural history of T1DM [...

Figure 15.3 Possible role of epigenetic factors in environmental modificatio...

Figure 15.4 Potential time points for primary, secondary and tertiary interv...

Figure 15.5 Postulated mechanisms of immunomodulatory therapies [108]. Sourc...

Figure 15.6 Stem cell strategies for T1DM.

Figure 15.7 Macroencapsulation device [194–197].

Figure 15.8 Glucose‐responsive insulin delivery devices [222]. Source: Repro...

Figure 15.9 Schematic describing the physiologic delay between insulin relea...

Figure 15.10 Flow chart for the management of diabetic ketoacidosis [294]. S...

Figure 15.11 (a) Overview of the reported incidences of T2DM per 100,000 per...

Figure 15.12 Hyperbolic relationship between insulin sensitivity and secreti...

Figure 15.13 The sequence of events leading from intrauterine environment to...

Figure 15.14 Role of genes and the environment in development of obesity and...

Figure 15.15 Pancreatic β‐cell and proteins implicated in MODY pathogenesis ...

Figure 15.16 Suggested approach to MODY genetic testing [502]. Source: Repro...

Figure 15.17 Pathogenesis of decreased insulin secretion in neonatal diabete...

Figure 15.18 Approach to genetic testing for neonatal diabetes. If it is unc...

Chapter 16

Figure 16.1 Summary of the effects of insulin and counter‐regulatory hormone...

Figure 16.2 Metabolic adaptation to feeding and fasting.

Figure 16.3 Outline of the pancreatic β‐cell showing the role of K

ATP

channe...

Figure 16.4 Diagnostic workup for hypoglycaemia.

Chapter 17

Figure 17.1 The calories overflow hypothesis. Surplus energy consumption lea...

Figure 17.2 Causes of increasing overweight in children and adolescents. Chi...

Figure 17.3 Interaction of food intake and energy homeostasis. There is a cl...

Figure 17.4 Human mutations involved in weight regulation. Leptin regulates ...

Figure 17.5 Regulators of adipose tissue. Extrinsic and intrinsic substances...

Figure 17.6 Physiological response to food. Substrates, hormones, mechanical...

Chapter 18

Figure 18.1 A diagnostic approach to genetic obesity syndromes.

Figure 18.2 Schematic of the hypothalamic leptin–melanocortin pathway. *Indi...

Figure 18.3 A 3‐year‐old boy with congenital leptin deficiency, weighing 42 ...

Guide

Cover

Table of Contents

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Brook’s Clinical Pediatric Endocrinology

Seventh Edition

Edited by

Mehul T. Dattani, MD FRCP FRCPCH

Professor and Head of Paediatric EndocrinologyGenetics and Genomic Medicine ProgrammeUCL Great Ormond Street Institute of Child HealthGreat Ormond Street Hospital for Children NHS Foundation TrustLondon, UK

Charles G. D. Brook, MA MD FRCP

Emeritus Professor of Paediatric EndocrinologyUniversity College LondonLondon, UK

This edition first published 2020© 2020 John Wiley & Sons Ltd

Edition HistoryWiley-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 endocrinologyDescription: 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 | InfantClassification: LCC RJ418 (ebook) | LCC RJ418 (print) | NLM WS 335 | DDC 618.92/4–dc23LC record available at https://lccn.loc.gov/2019003272

Cover Design: WileyCover Image: © VikiVector/Getty Images

List of Contributors

Mario AbinunHonorary Clinical Senior Lecturer Newcastle University; andDepartment of Paediatric Immunology Royal Victoria InfirmaryNewcastle upon TyneUK

John C. AchermannGenetics & Genomic Medicine Programme UCL Great Ormond Street Institute of Child Health London, UK

Kyriaki‐Sandy AlatzoglouConsultant in Paediatrics & Endocrinology, Chelsea & Westminster Hospital NHS Foundation Trust London, UK

Jeremy AllgroveConsultant Paediatric Endocrinologist, Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children Foundation Trust, London, UK

G.R. AmblerInstitute of Endocrinology and Diabetes, The Children's Hospital at Westmead and Clinical School The University of Sydney, Sydney, Australia

Anu BashambooHuman Developmental Genetics, Institut Pasteur Paris, France

Gerhard BinderUniversity Children's Hospital, Pediatric Endocrinology and Diabetology, Tübingen, Germany

F.J. CameronDepartment of Endocrinology and Diabetes Royal Children's Hospital, Parkville, Victoria Australia

Jean‐Claude CarelAssistance Publique‐Hôpitaux de Paris, Robert Debré University Hospital, Paediatric Endocrinology Diabetology Department, Reference Center for Growth and Development Endocrine Diseases Paris Diderot University, INSERM U1141 Paris, France

P.E. ClaytonDivision of Developmental Biology and MedicineSchool of Medical Sciences, Faculty of BiologyMedicine and Health, University of Manchester;andDepartment of Paediatric EndocrinologyRoyal Manchester Children’s HospitalManchester, UK

Tim D. CheethamUniversity Reader and Honorary Consultant in Paediatric Endocrinology, Newcastle University;andDepartment of Paediatric EndocrinologyRoyal Victoria Infirmary, Newcastle upon Tyne, UK

Wassim ChemaitillyDepartment of Pediatric Medicine‐Division of Endocrinology, St. Jude Children’s Research Hospital;andDepartment of Epidemiology and Cancer ControlSt. Jude Children’s Research Hospital Memphis, TN, USA

Moira CheungConsultant Paediatric Endocrinologist, Evelina Children’s Hospital, Guy’s and St Thomas’ Hospital NHS Foundation Trust, London, UK

Tinh‐Hai ColletUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust‐MRC Institute of Metabolic Science, Addenbrooke’s Hospital Cambridge, UK

Martine CoolsGhent University Hospital – Princess Elizabeth Children’s Hospital, Ghent University, Ghent, Belgium

Mehul T. DattaniProfessor 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 TrustLondon, UK

Leo DunkelCentre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London London, UK

I. Sadaf FarooqiUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust‐MRC Institute of Metabolic Science, Addenbrooke’s Hospital Cambridge, UK

Emma FootitDepartment of Metabolic Medicine Great Ormond Street Children’s Hospital London, UK

Hoong‐Wei GanClinical Research Fellow & Paediatric Endocrinology Registrar, Genetics & Genomic Medicine Programme UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

Evelien F. GeversDepartment of Pediatric Endocrinology, Royal London Children's Hospital, Barts Health NHS Trust; andCentre for Endocrinology, William Harvey Research Institute, Queen Mary University of LondonLondon, UK

Helena GleesonConsultant EndocrinologistUniversity of Birmingham HospitalsBirmingham, UK

Sasha R. HowardCentre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London London, UK

Melissa M. HudsonDepartment of Epidemiology and Cancer ControlSt. Jude Children’s Research Hospital; andDepartment of Oncology, Division of Cancer Survivorship, St. Jude Children’s Research Hospital Memphis, TN, USA

Claire R. HughesCentre for Endocrinology, William Harvey Research Institute, Queen Mary University of London & Royal London Children’s Hospital, Barts Health NHS Trust London, UK

Natascia Di IorgiDepartment of Pediatrics, Istituto Giannina Gaslini University of Genova, Genova, Italy

K. JoshiDepartment of Endocrinology and Diabetes, Royal Children's Hospital, Parkville, Victoria, Australia

Ritika KapoorDepartment of Paediatric Endocrinology, Kings College Hospital London, London, UK

Harshini KatugampolaGreat Ormond Street Hospital for Children NHS Foundation Trust; andGenetics & Genomic Medicine Programme, UCL GOS Institute of Child Health, London, UK

Wieland KiessHospital for Children and Adolescents, Centre of Paediatric Research, Department of Women & Child Health, University of Leipzig, Leipzig, Germany

Birgit Köhler†Department of Paediatric Endocrinology and Diabetology, Charité, Universitätsmedizin Berlin Germany

Juliane LegerAssistance Publique‐Hôpitaux de Paris, Robert Debré University Hospital, Paediatric Endocrinology Diabetology Department, Reference Center for Growth and Development Endocrine Diseases, Paris Diderot University, INSERM U1141 Paris, France

Mohamad MaghnieDepartment of Pediatrics, Istituto Giannina Gaslini University of Genova, Genova, Italy

Elim ManPaediatric Endocrinology, Queen Mary Hospital, The University of Hong Kong, HKSAR, Hong Kong; andGenetics & Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health London, UK

Ken McElreaveyHuman Developmental Genetics, Institut PasteurParis, France

Giovanni MoranaDepartment of Pediatric Neuroradiology, Istituto Giannina Gaslini, Genova, Italy

P.G. MurrayDivision of Developmental Biology and Medicine School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester; andDepartment of Paediatric EndocrinologyRoyal Manchester Children’s HospitalManchester, UK

Flavia NapoliDepartments of Pediatrics, Istituto Giannina Gaslini Genova, Italy

Catherine J. OwenConsultant in Paediatric EndocrinologyDepartment of Paediatric EndocrinologyRoyal Victoria InfirmaryNewcastle upon TyneUK

Simon H.S. PearceProfessor of EndocrinologyInstitute of Genetic MedicineNewcastle UniversityNewcastle upon TyneUK

Catherine PetersConsultant Paediatric Endocrinologist, Great Ormond Street Hospital, London, UK

Nicolas de RouxBiochemistry Laboratory, INSERM U1141, Robert Debré Hospital, Paris Diderot University Paris, France

Emmanouil SaloustrosDivision of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA

Nadia SchoenmakersWellcome Trust‐Medical Research Council Institute of Metabolic Science, University of Cambridge Cambridge, UK

Pratik ShahDepartment of Paediatric Endocrinology, Great Ormond Street Children’s Hospital, London, UK

Constantine A. StratakisDivision of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA

D.K. WherrettDivision of Endocrinology, Department of Paediatrics Hospital for Sick Children, University of Toronto Toronto, ON, Canada

Note

Deceased

Preface

It is nearly 40 years since I wrote the preface to the first edition of this book. There have not been fundamental changes in the clinical practice of pediatric endocrinology during those years but the era of molecular biology has changed completely the understanding of the causation of many of the disorders seen and described in this edition of the book. In years to come it will impinge on clinical practice.

Major changes have occurred in the access to information through the internet and also in the ways that a book is now assembled, prepared and printed in different parts of the world. The ready access to original literature seemed likely to make text books like this redundant but the plethora and complexity of the information available makes even more relevant the authoritative digestion of data and their presentation in a clinically useful format. This has always been the aim of the book.

One loss with the internet is the close personal relationships which used to exist between editors, authors and their publisher; so many people are now involved in the actual production of a book that it is no longer possible to identify exactly who does what. Nevertheless I thank our authors and all at Wiley for their endeavours.

Although I have claimed the right to be the sole author of the preface for this edition of Clinical Pediatric Endocrinology (which will be the last in which I shall be involved), it will be clear that the brains behind the book are those of my long‐term colleague, now mentor and friend, Mehul T. Dattani. His time in many roles in what was my department and is now his spans 30 years. I and many others respect and admire his achievements and this edition would never have seen the light of day without him. My contribution has been trying to make the book readable, which is not always an easy task.

The number of practitioners of clinical pediatric endocrinology worldwide has increased by at least two orders of magnitude since 1981 and so no longer is this edition dedicated to just the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society but to all who strive to advance our field. Lastly, I should acknowledge with love and gratitude the way my wife Catherine has put up with this cuckoo in our nest for so many years.

Charles G. D. BrookHadspen Farm, Somerset, UK

Acknowledgement

I would also like to thank my children Seyan Dattani and Arushi Dattani for their help in checking the proofs.

About the Companion Website

This book is accompanied by a companion website:

www.wiley.com/go/dattani/brookcpe7

The website includes:

MCQs

1Genetics and Genomics

Anu Bashamboo and Ken McElreavey

Human Developmental Genetics, Institut Pasteur, Paris, France

Introduction

The Human Genome Project was completed in 2003 but it is only now that we are truly in the genomic era. Next‐generation sequencing (NGS), which allows genome‐wide detection of variants, is transforming on an unprecedented scale our understanding of pediatric and endocrine diseases by identifying mutations that are pathogenic or confer disease risk: new genes that cause human disease are being identified at the rate of 3 per week. We all differ in our DNA sequence and medical geneticists aim to understand the significance of this genetic diversity in health and disease, which has led to the age of genomic medicine.

Understanding genetic diversity is essential to understanding the biology of diseases of various kinds, from simple Mendelian or monogenic disorders to more complex multifactorial disease, and how we respond to treatment at both population and individual levels. We have the capacity to study the human genome as an entity rather than one gene at a time and medical and clinical genetics has become part of the broader field of genomic or precision medicine, which seeks to apply a large‐scale analysis of the human genome to provide an individual and knowledge‐based approach to medical care.

Many web resources and web‐based tools have been developed to help the clinicians navigate and interpret the tremendous amount of genomic data that are being generated (Table 1.1).

Table 1.1 Commonly used databases in human genetic and genomic analysis.

Site

Content

URL

National Center for Biotechnology Information

A portal that provides access to a wealth of biomedical and genomic information. Includes PubMed, OMIM, dbSNP, Clinvar, expression data sets. Suite of tools for data and sequence analysis (e.g. BLAST)

http://www.ncbi.nlm.nih.gov

Mendelian Inheritance in Man (MIM)

A comprehensive database of human genes and genetic disorders

http://www.ncbi.nlm.nih.gov/omim

ClinGen

Authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research

https://www.clinicalgenome.org

Ensembl

Genome browser for vertebrate genomes that supports research in comparative genomics, evolution, sequence variation and transcriptional regulation. Annotates genes, computes multiple alignments, predicts regulatory function and collects disease data

http://www.ensembl.org

University California, Santa Cruz (UCSC), genome browser

Genome browser offering access to genome sequence data from vertebrate and invertebrate species and major model organisms. Integrated with a large collection of analysis tools

https://genome.ucsc.edu

GeneCards

Provides comprehensive information on all human genes. It integrates gene data from ~125 web sources, including genomic, transcriptomic, proteomic, genetic, clinical and functional information

http://www.genecards.org

Human Gene Mutation Database (HGMD)

Collates published gene lesions responsible for human inherited disease

www.hgmd.cf.ac.uk/ac

Mouse Genome Informatics at the Jackson Laboratories

International database resource for the laboratory mouse, providing integrated genetic, genomic, and biological data to facilitate the study of human health and disease

http://www.informatics.jax.org

DECIPHER database

Collects clinical information about rare genomic variants and displays this information on the human genome map

https://decipher.sanger.ac.uk

Database of Genomic Variants (DGV)

A curated catalogue of human genomic structural variation

http://dgv.tcag.ca/dgv/app/home

Exome Aggregation Consortium (ExAC) browser

Exome data set >60,000 unrelated individuals. Provides both a reference set of allele frequencies and constraint metrics giving information on whether a gene is tolerant or intolerant to variation

http://exac.broadinstitute.org

ClinVar

Aggregates information about genomic variation and its relationship to human health.

http://www.ncbi.nlm.nih.gov/clinvar

Sequence Variant Nomenclature

Provides guidelines for sequence variation nomenclature

http://varnomen.hgvs.org

dbSNP

Genetic variation within and across different species. Not limited to SNPs, it contains a range of molecular variation

http://www.ncbi.nlm.nih.gov/SNP

F‐SNP

Provides integrated information about the functional effects of SNPs obtained from 16 bioinformatics tools and databases. Helps identify and focus on SNPs with potential pathological effect to human health

http://compbio.cs.queensu.ca/F‐SNP

Biological General Repository for Interaction Datasets (BioGRID)

Database of protein–protein interactions, genetic interactions, chemical interactions, and post‐translational modifications

http://thebiogrid.org

PhenomicDB

A multi‐organism phenotype–genotype database including human, mouse, fruit fly,

C. elegans

, and other model organisms

http://www.phenomicdb.de

Phencode

Connects human phenotype and clinical data in various locus‐specific mutation databases with data on genome sequences, evolutionary history and function in the UCSC Genome Browser

http://phencode.bx.psu.edu

Human Epigenome Atlas

Includes human reference epigenomes and the results of their integrative and comparative analyses. Provides details of locus‐specific epigenomic states like histone marks and DNA methylation across tissues and cell types, developmental stages, physiological conditions, genotypes and disease states

http://www.genboree.org/epigenomeatlas

Encyclopedia of DNA Elements (ENCODE)

Catalogue of functional elements in the human genome, including elements that act at the protein and RNA levels and regulatory elements that control cells and circumstances in which a gene is active

https://www.encodeproject.org

Genomics England 100,000 Genomes Project

The project will sequence 100,000 genomes from around 70,000 people. Participants are National Health Service (UK) patients with a rare disease, plus their families, and patients with cancer

www.genomicsengland.co.uk/the‐100000‐genomes‐project

The term ‘‐omics’ aims at the collective characterization and quantification of pools of biological molecules that translate into the structure, function and dynamics of an organism. Genomics can be divided into comparative genomics, the study of the relationship of genome structure and function across different biological species or strains; functional genomics, which describes gene and protein functions and interactions; metagenomics, the study of genetic material recovered directly from environmental samples; and epigenomics, which is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome.

Basic Concepts in Human Genetics and Genomics

Genes and Chromosomes

Genetic information is stored in DNA in the chromosomes within the cell nucleus. DNA is a polymeric nucleic acid macromolecule composed of a five‐carbon sugar (deoxyribose), a nitrogen‐containing base and a phosphate group. The bases are of two types, purines and pyrimidines. In DNA, there are two purine bases, adenine (A) and guanine (G), and two pyrimidine bases, thymine (T) and cytosine (C). DNA is organized in a helical structure in which two polynucleotide chains run in opposite directions, held together by hydrogen bonds between pairs of bases, A of one chain pairing with T of the other and G with C. In the coding sequences of a gene, each set of three bases constitutes a codon that encodes for a particular amino acid. Genome refers to the totality of genetic information carried by a cell or an organism, whereas genotype is the genetic constitution of an individual cell or organism. With the exception of cells that develop into gametes (the germline), all cells that contribute to the body are termed somatic cells.

The human genome contained in the nucleus of the somatic cells consists of 46 chromosomes arranged in 23 pairs, 22 of which are common in both males and females and are termed autosomes, and the remaining pair being the sex chromosomes, two X chromosomes in females and an X and a Y chromosome in males. Homologous chromosomes refer to members of a pair of chromosomes which carry the same genes in a similar organization.

A gene is a sequence of DNA in the genome required for the expression of a functional product, including a polypeptide or RNA molecule (Figure 1.1). The majority of human genes are organized as coding regions called exons interrupted by one or more non‐coding regions termed introns. Introns are initially transcribed into RNA in the nucleus but are not present in mature mRNA, which also has flanking 5′ and 3′ untranslated regions (UTRs). The latter contains a signal for the addition of adenosine residues (the polyA tail) to the end of the mature mRNA.

Figure 1.1 Example of a typical mammalian gene structure. A typical gene has regulatory regions preceding the coding exons interspersed by non‐coding introns. The individual labelled features are discussed in detail in the text.

Other sequences within the 3′ UTR are important for translation efficiency, localization and stability, whereas the 5′ UTR is important in the regulation of RNA translation. It is important when discussing genes to define what is meant by the terms trans and cis. trans‐Acting usually means ‘acting from a different molecule’, whereas cis‐acting means ‘acting from the same molecule’. In genetics and genomics, cis‐acting elements refer to DNA sequences in the vicinity of a gene that are required for gene expression; trans‐acting factors, either proteins or some classes of RNA molecules, bind to the cis‐acting sequences to control gene expression.

Many genes produce not just one but multiple proteins, which is achieved either by alternative splicing of the coding segments of genes or by numerous types of biochemical modifications of the resulting proteins so that the 19,000 genes in the human genome are estimated to generate over a million different proteins. The other point to remember is that individual proteins rarely work by themselves. The cell is composed of modular supramolecular complexes and each complex performs an independent, discrete biological function that could not be achieved by the independent components of the complex. The transfer of information from the DNA strand to the protein is mediated by RNA, which directs the synthesis and sequence of polypeptides.

Genetic information is stored in genes in the form of a genetic code in which the sequence of adjacent bases determines the sequence of amino acids in the polypeptide. RNA is synthesized from DNA by transcription and the RNA carrying the coded information is termed messenger RNA (mRNA), which is transported from the nucleus to the cytoplasm where it is translated to synthesize the protein. This constitutes the central dogma of molecular biology.

Regulation of Gene Expression

Gene expression is the production of correct RNA, which is a complex process where the RNA must be expressed in the appropriate cell type in the correct amount and, in some cases, at a precise developmental time. Nucleic acid sequences flanking the coding sequences and in some cases within the coding sequences provide the molecular signals for gene transcription. A promoter region that contains sequences necessary for the initiation of transcription lies at the 5′ end of most genes. An enhancer is a short (50–1500 bp) region of DNA that can be bound by proteins (transcription factors) to increase the likelihood that transcription of a particular gene will occur. Enhancers are generally located up to 1 Mbp away from the gene and can be upstream or downstream of the gene it regulates. The orientation of an enhancer may even be inverted without having an effect on its function.

Genes that are necessary for complex and multiple developmental processes usually have a number of enhancers with overlapping functions. A good example is the SOX9 locus: the developmental timing and tissue‐specific transcriptional regulation of SOX9