Pediatric endocrinology

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Cover Inside front cover Front matter Pediatric endocrinology Copyright Dedication Foreword to the first edition Preface Acknowledgments Contributors 1 Overview and principles of pediatric endocrinology Historical background Impact of hormonal assays and molecular biology Unique aspects of pediatric endocrinology Fetal origins of adult disease Acquisition of patterns of hormone secretion and action Adaptations in endocrine function at birth Maintenance of body temperature Glucose homeostasis Gonadotropins and sex hormones Evaluating endocrine disorders in infancy and childhood Concluding remarks References 2 Molecular endocrinology and endocrine genetics Introduction Basic molecular tools Isolation and digestion of DNA and southern blotting Restriction fragment length polymorphism and other polymorphic DNA studies Polymerase chain reaction RNA analysis Microrna Detection of mutations in genes Direct methods Indirect methods Positional genetics in endocrinology The principles of positional genetics Genomic identification of “endocrine? genes Impact of modern sequencing in clinical practice Expression studies microarrays, sage Chromosome analysis and molecular cytogenetics Outline of methods Applications Future developments Molecular basis of pediatric endocrinopathies Defects in peptide hormones Genomic deletions causing human endocrine disease Point mutations Defects in peptide hormone receptors Insulin receptor Gh receptor Principles of interpretation of genetic tests in the diagnosis and management of pediatric endocrine diseases Recombinant DNA technology and therapy of pediatric endocrine diseases Concluding remarks References 3 Receptor Transduction Pathways Mediating Hormone Action INTRODUCTION G PROTEIN?COUPLED RECEPTORS CLASS A RECEPTORS THAT TRANSDUCE HORMONE ACTION The Peptide Receptor Group Adrenocorticotropin and Melanocortin-2 Receptors Other Melanocortin Receptors Vasopressin Receptors The Glycoprotein Hormone Receptor Group LHCGR Receptors FSH Receptors TSH Receptors HCG and TSH Receptors during Pregnancy The Gonadotropin-Releasing Hormone Receptor Group Gonadotropin-Releasing Hormone Receptors The Thyrotropin-Releasing Hormone and Secretagogue Receptor Group Thyrotropin-Releasing Hormone Receptors Other Class A Receptors That Transduce Hormone Action Free Fatty Acid Receptor 1 KISS1 Receptor/GPR54 Orexin Receptors Ghrelin Receptors Melanin-Concentrating Hormone Receptors CLASS B RECEPTORS THAT TRANSDUCE HORMONE ACTION Growth Hormone?Releasing Hormone Receptor Gastric Inhibitory Polypeptide Receptors Parathyroid Hormone and Parathyroid Hormone?Related Peptide Receptors Other Class B Receptors That Transduce Hormone Action CLASS C RECEPTORS THAT TRANSDUCE HORMONE ACTION Calcium-Sensing Receptors G PROTEIN GENE DISORDERS Inactivating Mutations of the GNAS Gene Activating Mutations of the GNAS Gene CYTOKINE RECEPTORS Structure and Function of Type 1 Cytokine Receptors Cytokine Receptors That Transduce Hormone Action Growth Hormone Receptors LEPTIN RECEPTORS RECEPTOR TYROSINE KINASES Insulin Receptor Tyrosine Kinase Family THE INSULIN RECEPTOR THE INSULIN-LIKE GROWTH FACTOR-1 RECEPTOR THE FIBROBLAST GROWTH FACTOR RECEPTOR FAMILY Fibroblast Growth Factor Receptor 1 Fibroblast Growth Factor Receptors 2-4 NUCLEAR RECEPTORS General Structure of the Nuclear Receptors SUBFAMILY 1 NUCLEAR RECEPTORS: THYROID HORMONE, VITAMIN D3, AND PEROXISOME PROLIFERATOR?ACTIVATED RECEPTORS Thyroid Hormone Receptors Vitamin D Receptor PPARγ SUBFAMILY 2 NUCLEAR RECEPTORS: HEPATOCYTE NUCLEAR FACTOR AND RETINOID X RECEPTORS HNF Receptors SUBFAMILY 3 NUCLEAR RECEPTORS: THE STEROID RECEPTORS AND GLUCOCORTICOID, ANDROGEN, ESTROGEN, AND MINERALOCORTICOID RECEPTORS Glucocorticoid Receptors Androgen Receptors Estrogen Receptors Mineralocorticoid Receptors SUBFAMILY 0 NUCLEAR RECEPTORS: DAX1 DAX1 Summary References 4 Laboratory methods in pediatric endocrinology Introduction Hormonal assays Immunoassays Competitive immunoassay versus immunometric sandwich assay Potential confounders in immunoassays Limitations of immunoassays Free and bioavailable hormone tests Mass spectrometry Interpretation of test results Preanalytic variables Analytic validation, quality assurance, and quality control Linearity/reportable range Precision Analytic sensitivity Analytic specificity, interferences, and recovery Accuracy/method comparison Sample types and matrix effects Stability Carryover Clinical validation Summary References 5 Ambiguous genitalia Introduction Talking with the parents Terminology Sex determination Development of the reproductive system Urogenital development Germ cell development Human testicular development Human ovary development Development of internal genital structures Development of external genital structures Anogenital distance Sexual differentiation of the brain Mouse models Disorders of gonadal differentiation Wilms tumor gene Wnt4 gene Sf1/nr5a1 gene Chromobox homolog 2 cbx2 46,xy disorders of sex development gonadal dysgenesis Sry Sox9 Dax1 Desert hedgehog Gata4 Fog2 Map3k1 Chromosome 9p monosomy Atr-x syndrome Vanishing testes Multiple congenital anomalies Cdkn1c Gli3 Arx Kat6b Chd7 Ovotesticular disorder of sex development 46,xx testicular disorder of sex development Rspo1 XX disorder of sex development/premature ovarian failure Foxl2 Nobox Figla Disorders of cholesterol and steroid biosynthesis also discussed in chapter 13 Luteinizing hormone choriogonadotropin receptor gene Smith-lemli-opitz syndrome Congenital lipoid adrenal hyperplasia Side chain cleavage cytochrome p450 enzyme Virilizing congenital adrenal hyperplasias 21-hydroxylase deficiency 11β-hydroxylase deficiency 3β-hydroxysteroid dehydrogenase deficiency Defects in sex steroid biosynthesis 17α-hydroxylase/17,20-lyase deficiency Cytochrome B5 deficiency 3α-hydroxysteroid dehydrogenase isozyme deficiencies Cytochrome p450 oxidoreductase deficiency 17β-hydroxysteroid dehydrogenase deficiency 5α-reductase deficiency Placental aromatase deficiency Maternal hyperandrogenism Disorders of androgen action Mullerian duct abnormalities Persistent mullerian duct syndrome Mullerian duct abnormalties in 46,xx individuals Hoxa genes Microphallus, hypospadias, and cryptorchidism Hypospadias Cryptorchidism Hypogonadotropic hypogonadism Robinow syndrome Warburg-micro syndrome Mamld1 Environmental disruptors Other disorders Exstrophy of bladder Diagnosis History Physical examination Laboratory studies Treatment Sex of rearing Medical treatment Considerations with regard to surgery Risks for gonadal tumors Transition from pediatrics to adult care Psychological and genetic counseling and support and ethical considerations Conclusions References 6 Hypoglycemia in the newborn and infant Introduction Principles of glucose metabolism Physiology of perinatal glucose homeostasis Glucose metabolism in the fetus Changes at birth: Transition phase Abnormalities of transition Management of hypoglycemia in the first 24 hours Hormonal and metabolic systems of fasting adaptation Definition of hypoglycemia in neonates and infants Clinical symptoms and signs associated with hypoglycemia Diagnostic approach Classification of causes of persistent hypoglycemia in the neonate and infant box 6-2 Disorders of insulin excess or actions Hyperinsulinemic hypoglycemia Transient hyperinsulinism resulting from maternal factors Prolonged neonatal hyperinsulinism: Perinatal stress-induced hyperinsulinism Hyperinsulinism in beckwith-wiedemann syndrome Monogenic hyperinsulinism Katp hyperinsulinism. ​ Focal katp-hyperinsulinism Glutamate dehydrogenase-hyperinsulinism: The hyperinsulinism hyperammonemia syndrome SCHAD-hyperinsulinism. ​ Glucokinase-hyperinsulinism. ​ Uncoupling protein-2 hyperinsulinism. ​ Hepatocyte nuclear factors and hyperinsulinism: HNF1alpha and HNF4alpha-hyperinsulinism. ​ Hypoglycemia due to activating mutations in AKT2 Acquired postprandial hyperinsulinemic hypoglycemia after fundoplication Defects in counter-regulatory response Defects in glycogenolysis and gluconeogenesis Glucose 6-phosphatase deficiency GSD type 1 Disorders of fatty acid oxidation: Medium-chain acyl-coenzyme A dehydrogenase deficiency MCAD Defects of glucose transporters GLUT1 deficiency GLUT2 deficiency Treatment Conclusions References 7 Disorders of the thyroid in the newborn and infant Introduction Embryology, physiology, and physiopathology Development of the thyrotropic axis Placental transfer of iodine, T4, TRH, antithyroid drugs, and immunoglobulins Maturation of thyroid hormone synthesis and secretion Maturation of thyroid hormone metabolism and transport Extrauterine thyroid adaptation Thyroid hormone actions Congenital hypothyroidism Newborn screening Thyroid dysgenesis Thyroid dyshormonogenesis General features Sodium-iodine symporter defects Pendred syndrome Thyroperoxidase defects Defects in H2O2 generation Thyroglobulin defects Dehalogenase defects Abnormal thyroid hormone metabolism Selenium incorporation defects Thyroid hormone resistance Receptor defects Membrane transporter defects Consumptive hypothyroidism Hypothalamo-pituitary hypothyroidism TRH defects Isolated TSH deficiency Transient neonatal hypothyroidism, hyperthyrotropinemia, and hypothyroxinemia Evaluation of newborns with positive screening results Treatment of congenital hypothyroidism Congenital hyperthyroidism Graves disease Nonautoimmune hyperthyroidism Disorders of thyroid hormone transport References 8 Disorders of calcium and phosphorus homeostasis in the newborn and infant Calcium Calcium sensing receptor Phosphate Phosphatonins Magnesium Alkaline phosphatase Parathyroid hormone; parathyroid hormone?related protein; PTH/PTHRP receptors Parathyroid hormone Parathyroid hormone?related protein Parathyroid hormone and parathyroid hormone?related protein receptors Calcitonin Vitamin D Synthesis and biologic activity of vitamin D Vitamin D receptor Skeleton: Cartilage and bone Cartilage and bone differentiation and formation Chondrogenesis Osteoblastogenesis Osteoclastogenesis Bone extracellular matrix and mineralization Bone mineralization Assessment of bone mass and strength Mineral homeostasis during the life cycle References 9 Neonatal diabetes mellitus Definition Incidence Clinical presentation Classification Transient neonatal diabetes mellitus TNDM TNDM1 TNDM-2 Permanent neonatal diabetes mellitus PNDM KATP and insulin gene mutations Other genetic forms of PNDM GCK PDX-1 HNF1β Syndromic neonatal diabetes mellitus Wollcott-rallison syndrome: Mutations in EIF2AK3 IPEX-FOXP3 GLIS 3 PTF1A Rfx6 Neurog-3 GATA6 Diagnosis and treatment of neonatal diabetes mellitus Available resources Transition to oral therapy Future directions References 10 Disorders of growth hormone/insulin-like growth factor secretion and action Normal growth Measurement Growth charts Body proportions Skeletal maturation Prediction of adult height Parental target height Endocrine regulation of growth The pituitary Growth hormone Chemistry Secretion GH receptor/GH-binding protein GH actions Insulin-like growth factors Historical background IGF structure and molecular biology Assay methodologies for the IGF peptides Serum levels of IGF peptides Measurement of IGF levels in growth disorders IGF receptors IGF-binding protein superfamily Targeted disruption of components of the IGF system Other growth factors The FGF family of peptides and receptors The EGF system Other growth-promoting peptides Growth inhibitory peptides Sex steroids Thyroid hormone Growth retardation Primary growth abnormalities Osteochondrodysplasias Achondroplasia. ​ Hypochondroplasia. ​ Chromosomal abnormalities Down syndrome. ​ Turner syndrome. ​ 18q deletions. ​ Intrauterine growth retardation Russell-silver syndrome Seckel syndrome. ​ Noonan syndrome. ​ Progeria. ​ Cockayne syndrome. ​ Microcephalic osteodysplastic primordial dwarfism. ​ Prader-willi syndrome. ​ Other genetic causes of short stature Secondary growth disorders Malnutrition Chronic diseases Malabsorption. Cardiovascular disease. ​ Renal disease. ​ Hematologic disorders. ​ Diabetes mellitus. ​ Inborn errors of metabolism. ​ Pulmonary disease. ​ Chronic infection. ​ Endocrine disorders Hypothyroidism. Cushing syndrome. ​ Pseudohypoparathyroidism. ​ Rickets. ​ Vitamin D–resistant IGF deficiency. ​ Hypothalamic dysfunction. ​ Molecular defects of GHRH or the GHRH receptor. ​ Trauma of the brain or hypothalamus. ​ Inflammation of the brain or hypothalamus. ​ Tumors of the brain or hypothalamus. ​ Optic gliomas Cystic lesions Irradiation of the brain or hypothalamus. ​ Pituitary GH deficiency. ​ Genetic abnormalities resulting in combined pituitary hormone deficiency. ​ Genetic abnormalities of GH production or secretion resulting in isolated GHD Congenital abnormalities of the pituitary Tumors involving the pituitary. ​ Psychosocial dwarfism. ​ GH neurosecretory dysfunction. ​ Acquired idiopathic isolated GHD. ​ Bio-inactive GH. ​ Primary IGFD and GH insensitivity GHR signaling defects. ​ ALS mutations. ​ IGFI gene defects.  IGFI receptor mutations. ​ Clinical features. ​ Diagnosis of IGF deficiency. ​ Provocative GH testing is nonphysiologic. ​ Arbitrary definitions of “subnormal” response to provocative tests. ​ Age dependency and use of sex steroids. ​ GH assays of limited accuracy. ​ Expense, discomfort, and risks of provocative GH testing. ​ Poor reproducibility of provocative tests. ​ Testing in the neonate. ​ Diagnosis of GHI. ​ Constitutional delay of growth and maturation. ​ Idiopathic short stature. ​ Treatment of growth disorders Treatment of constitutional delay Treatment of growth hormone deficiency Dosing of GH Novel modalities for treatment of GHD Management of multiple pituitary hormone deficiency Monitoring GH therapy Monitoring serum IGF-1 levels Role of serial bone age assessment Assessment of treatment efficacy and optimizing growth response Transition to adult management Growth hormone treatment of other forms of short stature Chronic renal failure Turner syndrome SHOX deficiency Noonan syndrome Down syndrome Intrauterine growth retardation or small for gestational age Prader-willi syndrome Osteochondrodysplasias Idiopathic short stature Miscellaneous causes of growth failure Normal aging and other catabolic states Side effects of growth hormone Development of leukemia Recurrence of CNS tumors and occurrence of second malignancies Pseudotumor cerebri Slipped capital femoral epiphysis Miscellaneous side effects The question of long-term cancer risk Treatment of primary severe IGFD: Use of IGF-i Excess growth and tall stature Tall stature and overgrowth syndromes Overgrowth in the fetus Tall stature and postnatal statural overgrowth Differential diagnosis of tall stature Precocious and delayed puberty Diagnosing familial tall stature Management of constitutional and syndromic tall stature Excess GH secretion and pituitary gigantism Diagnosis of GH excess Treatment of GH oversecretion Conclusions References 11 Disorders of the posterior pituitary Introduction Physiology of osmotic and volume regulation Osmotic sensor and effector pathways Vasopressin and oxytocin biochemistry Regulation of vasopressin secretion and thirst Osmotic regulation.  Nonosmotic regulation. ​ Vasopressin metabolism Sites of vasopressin action Volume sensor and effector pathways Renin-angiotensin-aldosterone system Endocrine renin-angiotensin-aldosterone system Anatomy and biochemistry.  Regulation of secretion. ​ Local renin-angiotensin systems Anatomy and biochemistry. Regulation of secretion. ​ The natriuretic peptide system Anatomy and biochemistry. ​ Regulation of secretion and action. ​ Approach to the patient: Differential diagnosis of disorders of water metabolism Hyponatremia Polyuria, polydipsia, and hypernatremia Specific disorders of water metabolism Hyponatremia with normal regulation of vasopressin Hyponatremia with appropriate decreased secretion of vasopressin Increased water ingestion Decreased renal free water clearance. ​ Treatment. ​ Hyponatremia with appropriate increased secretion of vasopressin Causes Systemic dehydration. Primary loss of sodium chloride. ​ Decreased effective plasma volume. ​ Treatment. ​ Precautions in the emergency treatment of hyponatremia. ​ Hyponatremia with abnormal regulation of vasopressin Hyponatremia with inappropriate increased secretion of vasopressin or increased vasopressin V2 receptor activity syndrome ... Causes of SIAD.  Treatment of siad. ​ Hyponatremia with inappropriate decreased secretion of vasopressin, due to increased secretion of atrial natriuretic peptide Treatment of cerebral salt wasting Other causes of true and factitious hyponatremia Hypernatremia with inappropriate decreased vasopressin secretion or action Central diabetes insipidus Causes of central diabetes insipidus.  Genetic causes. ​ Trauma. ​ Neurosurgical intervention. ​ Congenital anatomic defects. ​ Neoplasms. ​ Infiltrative, autoimmune, and infectious diseases. ​ Brain death. ​ Increased metabolism of vasopressin. ​ Drugs. ​ Children with primary enuresis. ​ Treatment of central diabetes insipidus Fluid therapy. Vasopressin and vasopressin analogs. ​ Nephrogenic diabetes insipidus Causes of nephrogenic diabetes insipidus.  Genetic causes. Congenital, X-linked diabetes insipidus: V2 receptor mutations. Congenital, autosomal nephrogenic diabetes insipidus: Aquaporin-2 mutations. Acquired cause. ​ Treatment of nephrogenic diabetes insipidus. ​ Concluding remarks References 12 Thyroid disorders in children and adolescents Introduction Thyroid hormones and their action Regulation of thyroid function Clinical and biochemical assessment of thyroid status Clinical evaluation of thyroid function Biochemical evaluation of thyroid function Hypothyroidism Hashimoto or autoimmune thyroiditis Hashitoxicosis Subclinical hypothyroidism Juvenile acquired hypothyroidism Iodine-induced hypothyroidism Hypothalamic-pituitary dysfunction Giant hemangiomas Hypothyroidism in cancer survivors Thyroid hormone resistance Hyperthyroidism Graves disease Medical therapy Radioactive iodine therapy Surgery Stratification of treatment Other causes of hyperthyroidism Neonatal thyrotoxicosis Infectious thyroiditis Subacute thyroiditis Hyperfunctioning nodules Toxic multinodular goiters Thyroid nodules and thyroid cancer Nodule evaluation Thyroid cancer Surgical options Radioactive iodine therapy Levothyroxine therapy Follow-up Medullary thyroid carcinoma Synopsis References 13 Adrenal cortex and its disorders History, embryology, and anatomy History Embryology Anatomy Steroid hormone synthesis Early steps: Cholesterol uptake, storage, and transport Steroidogenic enzymes Cytochrome P450 Hydroxysteroid dehydrogenases P450scc Transport of electrons to P450scc: Adrenodoxin reductase and adrenodoxin Mitochondrial cholesterol uptake: The steroidogenic acute regulatory protein, StARst 3β-hydroxysteroid dehydrogenase/̿5ℿ̿4 isomerase P450c17 Electron transport to P450c17: P450 oxidoreductase and cytochrome b5 P450c21 P450c11β and P450c11as 17β-hydroxysteroid dehydrogenase Steroid sulfotransferase and sulfatase Aromatase: P450aro 5α-reductase 11β-hydroxysteroid dehydrogenase 3α-hydroxysteroid dehydrogenases Fetal adrenal steroidogenesis Regulation of steroidogenesis The hypothalamic-pituitary-adrenal axis Hypothalamus: CRF and AVP Pituitary: ACTH and POMC Actions of ACTH Diurnal rhythms of ACTH and cortisol Adrenal: Glucocorticoid feedback Mineralocorticoid secretion: The renin-angiotensin system Adrenal androgen secretion and the regulation of adrenarche Plasma steroids and their disposal Structure and nomenclature Circulating steroids Steroid catabolism Clinical and laboratory evaluation of adrenal function Clinical evaluation Laboratory evaluation Plasma concentrations of cortisol and other steroids Plasma renin Urinary steroid excretion Plasma ACTH and other POMC peptides Secretory rates Dexamethasone suppression test Stimulation tests Metyrapone test Genetic lesions in steroidogenesis Congenital lipoid adrenal hyperplasia Disorders resembling lipoid cah: P450scc deficiency and sf1 deficiency 3β-hydroxysteroid dehydrogenase deficiency 17α-hydroxylase/17,20-lyase deficiency P450 oxidoreductase deficiency Cytochrome B5 deficiency 21-hydroxylase deficiency Pathophysiology Clinical forms of 21-hydroxylase deficiency Salt-wasting CAH. ​ Simple virilizing CAH. ​ Nonclassic CAH. ​ Incidence of 21-hydroxylase deficiency Genetics of the 21-hydroxylase locus 21-hydroxylase genes.  HLA linkage. ​ Other genes in the 21-hydroxylase locus. ​ P450c21 gene lesions causing 21-hydroxylase deficiency Mapping of P450c21 genes in normals and in CAH. ​ Gene conversions and microconversions causing CAH. ​ Mutations causing simple virilizing and nonclassic CAH. ​ Prenatal diagnosis of CAHst Diagnosis Treatment Experimental prenatal treatment of CAH Experimental postnatal treatment of CAH Antiandrogens and aromatase inhibitors. ​ Adrenalectomy. ​ Growth hormone and GnRH agonist therapy. ​ Lesions in isozymes of P450c11 11β-hydroxylase deficiency Corticosterone methyl oxidase deficiencies Glucocorticoid-suppressible hyperaldosteronism Lesions in isozymes of 11β-hydroxysteroid dehydrogenase Lesions in 11βhsd1: Lesions in 11βhsd2: Apparent mineralocorticoid excess Adrenal insufficiency Acute primary adrenal insufficiency Chronic primary adrenal insufficiency Autoimmune disorders Type 1 autoimmune polyendocrine syndrome. ​ Type 2 autoimmune polyendocrine syndrome. ​ Adrenal hypoplasia congenita X-linked adrenal hypoplasia congenita. ​ Autosomal forms of adrenal hypoplasia. ​ IMAGe syndrome. ​ ACTH resistance syndromes MC2R mutations: Familial glucocorticoid deficiency type 1 MRAP mutations: Familial glucocorticoid deficiency type2 Other forms of familial glucocorticoid deficiency. ​ Triple A Metabolic disorders Adrenoleukodystrophy Peroxisome biogenesis disorders.  Wolman disease. ​ Smith-lemli-opitz syndrome. ​ Mitochondrial disorders. ​ Other causes Secondary adrenal insufficiency Hypothalamic causes ACTH deficiency Disorders of POMC Long-term steroid therapy Adrenal excess Cushing syndrome Clinical findings Cushing disease Other causes of cushing syndrome Ectopic ACTH syndrome.  Adrenal tumors.  ACTH-independent multinodular adrenal hyperplasias. ​ Differential diagnosis Virilizing and feminizing adrenal tumors Other disorders Primary hyperaldosteronism: Conn syndrome Familial glucocorticoid resistance Pseudohypoaldosteronism Glucocorticoid therapy and withdrawal Replacement therapy Commonly used glucocorticoid preparations Pharmacologic therapy Withdrawal of glucocorticoid therapy Stress doses of glucocorticoids Mineralocorticoid replacement Concluding remarks References Pheochromocytoma and multiple endocrine neoplasia syndromes Introduction Genetic counseling and testing Pheochromocytoma and paraganglioma Biosynthesis and actions of catecholamines Clinical presentation Evaluation Biochemical diagnosis Radiographic studies Genetic issues Management Surgical therapy Medical preparation for surgery Prognosis and follow-up Medullary thyroid carcinoma Clinical presentation Evaluation and management Prognosis Hereditary endocrine neoplasia syndromes Carney complex Familial isolated pituitary adenomas Familial paraganglioma syndromes Hyperparathyroidism-jaw tumor syndrome Multiple endocrine neoplasia 1 men1 Epidemiology and pathogenesis Clinical presentation and management Primary hyperparathyroidism Gastroenteropancreatic-neuroendocrine tumors GEP-NETs Gastrinoma. ​ Insulinoma. ​ Glucagonoma. ​ VIPoma. ​ Nonfunctioning pancreatic neuroendocrine tumors Pituitary adenomas Other clinical manifestations Carcinoid tumors.  Adrenocortical tumors. ​ Cutaneous manifestations. ​ Genetic testing and presymptomatic screening Multiple endocrine neoplasia 2 MEN2 Multiple endocrine neoplasia 4 MEN4 Von hippel-lindau disease Other tumor syndromes associated with endocrine neoplasia APC-associated polyposis Beckwith-wiedemann syndrome Carney triad Li-fraumeni syndrome Neurofibromatosis type 1 Peutz-Jeghers syndrome PTEN hamartoma tumor syndrome Tuberous sclerosis complex Summary and future developments References 15 Puberty and its disorders in the female Introduction Development of the female reproductive system Maturation of the neuroendocrine-ovarian axis Fetus Neuroendocrine unit.  Ovary. ​ Placenta. Infant and child Neuroendocrine unit. Ovary. Adolescent Adult Follicular Luteal Regulation of the neuroendocrine-ovarian axis Factors controlling the onset of puberty Regulation of gonadotropin secretion Regulation of ovarian secretion Adrenarche and the regulation of adrenal androgen secretion Hormonal secretion, transport, metabolism, and action Peptide hormones Steroid hormones Maturation of sex hormone target organs Genital tract Mammary glands Pilosebaceous unit Bone Adipose tissue Central nervous system Other targets of sex hormone action Normal sexual maturation: Hormonal and physical stages The fetus and neonate Childhood Adolescence Hormonal Clinical Adult menstrual cycle Normal variations in pubertal development Premature thelarche Premature pubarche Constitutional delay of pubertal development Physiologic adolescent anovulation Other normal adolescent variations Abnormal puberty Abnormal development Disorders of sex development Other dysgenetic disorders Precocious puberty Causes Complete precocious puberty. ​ Incomplete precocity. ​ Differential diagnosis Management Hypogonadism Causes Primary ovarian failure. ​ Gonadotropin deficiency Differential diagnosis Management Nonhypoestrogenic menstrual disturbances Hypothalamic anovulation Causes. Differential diagnosis. Management. Dysfunctional uterine bleeding Causes. Differential diagnosis. ​ Management. ​ Perimenstrual symptoms Dysmenorrhea. Premenstrual syndrome. Hyperandrogenism in adolescence Causes Polycystic ovary syndrome. Clinical manifestations Laboratory manifestations Pathogenesis. ​ Etiology. Other causes of functional ovarian hyperandrogenism. Other causes of functional adrenal hyperandrogenism. Peripheral androgen overproduction. Tumoral hyperandrogenism. Androgenic drugs. Differential diagnosis. Diagnostic approach Management Future directions References 16 Turner syndrome Historical background Genetics Chromosomal origins Epidemiology Turner karyotypes X chromosome genes and turner syndrome X chromosome genomic imprinting Diagnostic tests Indications for karyotype testing Differential diagnosis Prenatal diagnosis Phenotypic features Lymphatic obstruction Skeletal anomalies and short stature Ovarian insufficiency Gonadoblastoma Cardiovascular system Spectrum and etiology of congenital cardiovascular malformations Aortic complications Other cardiovascular issues Cardiovascular screening in turner syndrome Ongoing cardiac care Risk for premature atherosclerotic disease Renal anomalies Otologic disorders Autoimmunity Gastrointestinal disorders Liver disease Gastrointestinal bleeding Inflammatory bowel disease Carbohydrate intolerance Neuropsychological features Medical management Initial and follow-up evaluation Y chromosome Growth hormone Puberty Reproductive options Transition to adult care References 17 Puberty and its disorders in the male Prenatal neurobiology of puberty Testicular differentiation and development Prenatal testicular development Postnatal testicular development The androgen receptor Physiology of puberty Endocrinology Neuroendocrine regulation of pubertal onset Somatic changes Regulation of the timing of puberty Genetics Genetic disorders causing GnRH deficiency Normosmic hypogonadotropic hypogonadism Kallmann syndrome Other genes associated with HH Genetic variation in normal puberty Candidate gene-based studies Genome-wide association GWA studies External factors and secular trends in the timing of puberty Effect of BMI on pubertal timing Effect of endocrine disrupting chemicals Precocious puberty GnRH-dependent forms of precocious puberty GnRH-independent forms of precocious puberty Evaluation of the boy with precocious development of secondary sexual characteristics Treatment of the child with precocious puberty Central precocious puberty Peripheral precocity Delayed puberty Etiologies of delayed puberty CDGP Hypogonadotropic hypogonadism Pituitary-dependent hypogonadism Hypothalamic and pituitary-dependent hypogonadism Functional hypogonadotropic hypogonadism Hypergonadotropic hypogonadism Klinefelter syndrome XX males Gonadal dysgenesis Syndromes associated with delayed puberty Defects in steroidogenesis or steroid hormone action Chemotherapy, radiation therapy, and cancer survival Other disorders of the male reproductive endocrine axis Androgen Receptor AR mutations Persistent mullerian duct syndrome Testicular regression syndrome anorchia, cryptorchidism, and hypospadias Testis tumors Germ cell tumors Nongerm cell tumors Gynecomastia Evaluation of the child with delayed puberty Initial evaluation History Physical examination Testing Additional evaluation Treatment of delayed puberty Testosterone: The hypogonadal male athlete and the individual with a DSD Conclusion References 18 Disorders of mineral homeostasis in children and adolescents Hypocalcemia Hypocalcemia in the neonate and infant Early neonatal hypocalcemia Late neonatal hypocalcemia Hypoparathyroidism Evaluation and management Hypocalcemia in the child and adolescent Etiology Evaluation Management Hypercalcemia Hypercalcemia in the neonate and infant Etiology Evaluation and management Hypercalcemia in the child and adolescent Etiology Evaluation Management Disorders of magnesium metabolism Hypomagnesemia Hypermagnesemia Disorders of skeletal mineralization Disorders of bone mineralization in the neonate and infant Low bone mass/rickets Increased bone mass Disorders of bone mineralization and formation in the child and adolescent Rickets Calciopenic rickets. ​ Phosphopenic rickets. ​ Disorders of alkaline phosphatase activity. ​ Chronic kidney disease-mineral and bone disorder Disorders of bone mineralization Low bone mass Evaluation and management of low bone mass Osteogenesis imperfecta Fibrous dysplasia High bone mass Heterotopic bone formation/ectopic calcification Osteochondrodysplasias Concluding remarks Addendum References 19 Diabetes mellitus Introduction Classification Type 1 diabetes mellitus Type 2 diabetes Type 1 diabetes mellitus Epidemiology Etiology, pathogenesis, and genetics Prediction and prevention Insulin biosynthesis Insulin secretion Insulin action Pathophysiology Clinical manifestations of diabetes mellitus Diagnosis Diabetic ketoacidosis Treatment of diabetes mellitus Treatment of diabetic ketoacidosis Fluid and electrolyte therapy Cerebral edema Electrolytes Alkali therapy Insulin therapy Treatment of type 1 diabetes mellitus t1dm General principles Goals of therapy Types of insulin Human regular insulin Rapid-acting analogs Intermediate-acting insulin Long-acting insulin analogs Premixed insulin Syringes versus pens Initiating insulin therapy Insulin regimens Multiple daily injection MDI regimens Insulin pump therapy Indications for pumps in pediatrics Pump features Nph-based treatment regimens Blood glucose monitoring Continuous glucose monitoring Medical nutrition therapy Exercise Residual β-cell function Hypoglycemia Sick day management Associated autoimmune diseases Associated psychosocial problems Outpatient care Management during surgery The future is now: Closed-loop insulin delivery Non-autoimmune type 1 diabetes Csii-based treatment regiments Basal insulin rates Verifying basal insulin rate settings Temporary basal rates and basal insulin suspend Bolus insulin dosages Bolus insulin for food coverage Bolus insulin for correction of hyperglycemia Specific considerations and acute complications of insulin pump therapy Insulin pump therapy in kindergarten and school Type 2 diabetes mellitus Typical Genetic defects of beta cell function Mody syndromes Other forms of monogenic diabetes Mitochondrial diabetes Wolfram syndrome Thiamine-responsive diabetes mellitus roger syndrome Drug or chemical induced Diseases of the exocrine pancreas Ionizing radiation to the abdomen Pancreatectomy Virus infections Genetic defects in insulin action Type A insulin resistance with acanthosis nigricans Type B insulin resistance Leprechaunism donohue syndrome Rabson-mendenhall syndrome Lipoatrophic diabetes Acquired defects in insulin action Genetic syndromes with diabetes and insulin resistance or insulin deficiency Gestational diabetes Neonatal diabetes Impaired glucose tolerance Pancreas and islet transplantation Concluding remarks References 20 Autoimmune polyglandular syndromes Introduction Mechanisms underlying generation of autoimmunity Introduction Central t-cell tolerance Peripheral t-cell tolerance B-cell tolerance Autoimmune diseases Defects in tolerance that cause autoimmune diseases Classification of the autoimmune polyglandular syndromes Clinical aspects Aps I Aps II Immune dysregulation, polyendocrinopathy, enteropathy, and x-linked inheritance IPEX Diagnostic approach and follow-up Treatment Genetics of aps I Genetics of aps II Autoantibodies in autoimmune polyglandular syndromes Non?organ-specific autoantibodies Anti-interferon autoantibodies AIA Autoantibodies to IL-17A, IL-17F, and IL-22 Organ-specific autoantibodies Adrenal cytoplasmic autoantibodies ACA Adrenal enzyme autoantibodies Adrenal enzyme autoantibodies in aps I Adrenal enzyme autoantibodies in aps II Steroidal cell/gonadal autoantibodies SCA Autoantibodies in hypoparathyroidism Other autoantibodies in aps I and II Summary References 21 Hypoglycemia in the toddler and child Introduction Physiologic development of glucose metabolism during infancy and childhood Glucose utilization and production Fasting adaptation to longer feeding intervals Symptoms, signs, and effects of hypoglycemia Definition of hypoglycemia Major causes of hypoglycemia in the infant, child, and young adult Hyperinsulinism KATP channel hyperinsulinism Glutamate dehydrogenase hyperinsulinism Glucokinase hyperinsulinism SCHAD or HADH hyperinsulinism Hnf4a hyperinsulinism Hnf1a hyperinsulinism Exercise-induced hyperinsulinemic hypoglycemia Carbohydrate-deficient glycoprotein hyperinsulinism Uncoupling protein 2 hyperinsulinism Hyperinsulinism in tyrosinemia Akt2 hypoglycemia Hyperinsulinemic hypoglycemia associated with insulin resistance Factitious hyperinsulinism Autoimmune hypoglycemia Insulinoma Hyperinsulinism after gastrointestinal surgery Hyperinsulinemic hypoglycemia prodromal to diabetes mellitus Nonislet tumor hypoglycemia Glycogen storage diseases Glucose 6-phosphatase deficiency types 1a and 1b GSD Amylo-1,6-glucosidase deficiency debrancher deficiency, GSD type 3 Liver phosphorylase and phosphorylase kinase deficiency GSD types 6 and 9 Glycogen synthase deficiency Glycogen branching enzyme deficiency type 4 GSD Fanconi-bickel syndrome Ketotic hypoglycemia Hormone deficiency Growth hormone deficiency and hypopituitarism Growth hormone resistance and igf-1 deficiency Cortisol and adrenocorticotropin deficiencies Epinephrine and glucagon deficiencies Genetic disorders of gluconeogenesis Pyruvate carboxylase deficiency Phosphoenolpyruvate carboxykinase deficiency Fructose 1,6-diphosphatase deficiency Hereditary fructose intolerance Defects of fatty acid oxidation Defects of organic or amino acid metabolism Hypoglycemia in fasting, starvation, illness, and stress Hypoglycemia during starvation and malnutrition Hypoglycemia with prolonged exercise Diarrheal illness Sepsis Specific infections Hypoglycemia in organ system disease Hypoglycemia in the intensive care unit Hypoglycemia induced by exogenous agents Alcohol-induced hypoglycemia Salicylate intoxication Reactive hypoglycemia and “spells? History of the reactive hypoglycemia controversy Approach to the patient with episodic “hypoglycemic? symptoms Behavior problems as effects of hypoglycemia or dietary sugar Artifactual hypoglycemia Fasting system approach to diagnosis History Clinical examination Critical sample Emergency treatment of hypoglycemia References 22 Obesity, metabolic syndrome, and disorders of energy balance Introduction Neuroendocrine regulation of energy balance The afferent system Alimentary afferents Hunger The afferent vagus.  Ghrelin. ​ Satiety Peptide YY 3-36 Glucagon-like peptide-1 Cholecystokinin Metabolic afferents Leptin. Insulin. ​ Central processing Anorexigenesis, POMC/α-MSH, and CART Orexigenesis, NPY, and AgRP Other neuroendocrine modulators of energy balance Norepinephrine Serotonin Melanin-concentrating hormone Orexins A and B.  Endocannabinoids Melanocortin receptors MCR and central neural integration The efferent system The sympathetic nervous system SNS and energy expenditure The efferent vagus and energy storage CNS modulation of food intake The hypothalamus and the starvation response The nucleus accumbens and the hedonic pathway of food reward The amygdala and the stress response Leptin resistance Energy excess?obesity Definition Prevalence and epidemiology Global prevalence Racial and ethnic considerations Predictive factors Metabolic impact of childhood obesity Insulin resistance Hepatic insulin resistance Adipose tissue insulin resistance Muscle insulin resistance Assessment of insulin resistance Lipid partitioning Vascular changes Adipocytokines Leptin Adiponectin Myokines and natriuretic peptides. ​ Inflammatory cytokines. ​ Reactive oxygen species Others. ​ Comorbidities related to insulin resistance The metabolic syndrome Nonalcoholic fatty liver disease NAFLD Polycystic ovarian syndrome PCOS Other endocrine comorbidities Other nonendocrine comorbidities Factors associated with the current epidemic of obesity Genetics Epigenetics and developmental programming Environmental factors Stress and cortisol Sleep deprivation Television viewing and “screen time? Dietary factors Dietary fat versus carbohydrate Trans-unsaturated fatty acids trans fats Glycemic index and fiber Fructose Branched-chain amino acids Ethanol Calcium and dairy Trace minerals Infectious causes Medications Disorders of obesity “classic? endocrine disorders with an obesity phenotype Monogenetic disorders of the negative feedback pathway Leptin deficiency Leptin receptor LEPR deficiency POMC splicing mutation Prohormone convertase-1 PC-1 deficiency Melanocortin-3 receptor MC3R mutation Melanocortin-4 receptor MC4R mutation SIM-1 mutation Chromosome 16p11.2 Brain-derived neurotrophic factor deletion Pleiotropic obesity/mental retardation disorders Prader-willi syndrome PWS Bardet-biedl syndrome TrkB mutation Carpenter syndrome Cohen syndrome Alstrom syndrome Börjeson-forssman-lehmann syndrome Rapid onset obesity, hypoventilation, hypothalamic, autonomic and thermal dysregulation, with and without neural tumor ROHHAD Insulin dynamic disorders Hypothalamic obesity and insulin hypersecretion Primary insulin resistance Evaluation and treatment of the obese child Diagnostic approach Lifestyle modification Dietary intervention Physical activity intervention School intervention Family intervention Pharmacotherapy Indications for pharmacotherapy Reduction of energy absorption: Orlistat Improvement of insulin resistance: Metformin Suppression of insulin hypersecretion: Octreotide Other targeted therapies Leptin. Growth hormone GLP-1 analogs. ​ The future of pediatric obesity pharmacotherapy Bariatric surgery Indications for bariatric surgery Restrictive: Laparoscopic adjustable gastric banding LAGB Combination: Roux-en-Y gastric bypass RYGB Laparoscopic sleeve gastrectomy LSG Who should perform bariatric surgery in children? Energy inadequacy Starvation versus cachexia Failure to thrive Definition Classification and etiology Diagnosis and evaluation Management Prognosis Cancer cachexia Diencephalic syndrome Anorexia nervosa AN Definition Endocrine associations Hypothalamic-pituitary-thyroid axis. ​ Growth hormone-IGF-1 axis. ​ Hypothalamic-pituitary-adrenal axis. ​ Bone metabolism. ​ Hypothalamic-pituitary-gonadal axis. ​ Fat-derived hormones. ​ Treatment Conclusions References 23 Lipid disorders in children and adolescents Introduction Metabolism Primary dyslipidemias Disorders of cholesterol metabolism Familial hypercholesterolemia Autosomal dominant and autosomal-recessive hypercholesterolemia Familial ligand-defective apob-100 Sitosterolemia Disorders of overproduction of vldl Disorders of marked hypertriglyceridemia Familial hypertriglyceridemia Familial chylomicronemia syndrome Hypolipidemias Low HDL cholesterol Abetalipoproteinemia Hypobetalipoproteinemia Disorders with lipoprotein clearance via apoe pathways Secondary causes Vascular changes and dyslipidemia Screening for lipid disorders Routine screening Genetic testing Diet therapy in managing dyslipidemia Pharmacologic management Bile acid?binding agents Hmg-coa reductase inhibitors Inhibitors of cholesterol absorption Fibric acid derivatives Niacin Dietary additives and supplements LDL apheresis Conclusions and future directions References Index A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Inside back cover