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Adrenal Disorders in Infants and Children Anzar Haider, M.D. Staff Pediatric Endocrinologist CCF Pediatric Board Review Symposium August 2012 ARS Question #1 The adrenal glands are located: A. Next to the pancreas B. Near the thyroid gland C. Adjacent to the pituitary gland D. On top of the kidneys E. Near the ovaries Adrenal Gland Location Embryology • Cortex derived from mesoderm • Medulla derived from neuroectoderm • Gonadal differentiation: 6 weeks • Adrenal function : 9-12 weeks Fetal Adrenal • Large fetal zone functions similar to Reticularis; regresses afterbirth • Transient zone functions similar to Fasciculata • Outer zone (Definite zone) evolve to Glomerulosa ARS Question #2 The principal hormones of the adrenal cortex include all of the following EXCEPT: A. Renin B. Aldosterone C. DHEA D. Androstendione E. Cortisol Adrenal Physiology 15 % Zona glomerulosa Mineralocorticoids 75% Zona fasiculata Glucocorticoids Zona reticularis Androgens Medulla Catecholamines 10 % Steroidogenesis • Begins with cholesterol; mostly dietary • Adrenal can synthesize cholesterol from acetate • Adrenal and gonadal have similar enzymes • 2 important enzyme groups in steroidogenesis – Cytochrome P-450 – Hydroxysteroid dehydrogenesis Adrenal Physiology Control of Adrenal Cortex Na, K, BP Stress CRH Renin-Angiotensin ACTH Aldosterone Cortisol Androgens ARS Question #3 Causes of primary adrenal failure include all of the following EXCEPT: A. Infection (TB, HIV) B. Genetic defect C. Autoimmune D. Hemorrhage E. Hypopituitarism Primary Adrenal Insufficiency Congenital • Congenital Adrenal Hypoplasia • Congenital Adrenal Hyperplasia • Familial Glucocorticoid Deficiency (ACTH Res) • Metabolic Disease : ALD; Wolmans, SLO Congenital Adrenal Hypoplasia:Etiologies • DAX-1: Dosage-sensitive sex reversalAdrenal hypoplasia congenital gene on the X-chromosome, gene 1 • SF-1: defect may cause adrenal failure and or XY sex reversal • Autosomal Recessive defect • IMAGe: Intrauterine growth retardation, metaphyseal dysplasia, adrenal insufficiency,genital abnormalities Congenital Adrenal Hypoplasia • May develop hyperpigmentation from ACTH. • Signs of dehydration are often present. • Hypotension and neuroglycopenia may be present. • Testes often undescended and micropenis is rare. Other urologic anomalies have occasionally been reported. • X linked and autosomal recessive forms DAXDAX-1 Gene • Important in hypothalamic, gonads, adrenal dev • Presents with adrenal crises in neonatal sometimes may present late with growth failure, primary adrenal insufficiency, hypogonadotropic hypogonadism • Impaired spermatogenesis • May be part of Contiguous gene deletion (Duchenne Muscular dystrophy, Glycerol kinase deficiency SFSF-1 gene defects • Crtical for dev & function of adrenal glands, gonads, gonadotropes • May cause adrenal failure, XY sex reversal, • Isolated adrenal failure in females Other Genetics form of Adrenal insufficiency • Adrenoleuokodystrophy: (Lorenzo’s oil) – X Linked ABCD1 gene defect causing peroxisomal disorder – Characterized by accumulation of VLCFA in the adrenal cortex , myelin of the CNS, Leydig cells of the testes – Treatment: gluco and mineralocorticoid; BMT • Wolman disease: lipid storage disease with adrenal calcification. – Acquired Adrenal Disorders • In developed countries most common cause is autoimmune destruction – Isolated disorder or part of polyglandular syndrome – Type 1 polyglandular syndrome in first decade – Type 2 polyglandular syndrome in second decade Type 1 Polyglandular syndrome • Hypoparathyroidism • Adrenal insufficiency • Mucocutaneous candidiasis – Other features include hypothyroidism, gonadal failure, Diabetes mellitus type 1, vitiligo, alopecia, chronic active hepatitis, and pernicious anemia • Mutations in AIRE gene Type 2 Polyglandular Syndrome • Adrenal insufficiency • Hypothyroidism (Schmidt syndrome) • Type 1 diabetes mellitus (Carpenter ) – Other features include pernicious anemia, vitiligo, gonadal failure, celiac, Sjogrens, Graves disease, Myasthenia gravis • Associated with HLAs DR3 &DR4 Acquired Adrenal Insufficiency • Adrenal hemorrhage ( newborn with prolong labor, traumatic birth, Waterhouse Fredrichsen syndrome) • Infections (e.g., TB, HIV, fungal, CMV, Histoplasmosis, ) • Neoplastic destruction • Medications: Ketoconazole, Megace ARS Question #4 Patients with secondary adrenal insufficiency may have all EXCEPT: A. Weakness and fatigue B. Hypoglycemia C. Hyponatremia D. Hyperkalemia E. Hypotension Adrenal Insufficiency : Clinical Features Symptoms Signs Fatigue Orthostatic Labs cortisol Dizziness Hypotension PRA Anorexia Tender abdomen Glucose Abdominal pain Dehydration sodium Weight loss Shock calcium Primary Adrenal Insufficiency: Salt craving Hyperpigmentation ACTH Potassium Aldosterone Secondary Adrenal Insufficiency • Loss of adrenal glucocorticoids and androgens • Normal mineralocorticoid production • May have hyponatremia but normal serum potassium levels • Due to deficiency of ACTH or CRH, or resistance of adrenal gland to ACTH Secondary Adrenal Insufficiency • CNS processes that affect hypothalamus or pituitary • Defects in ACTH receptor (MCR2) • Allgrove syndrome (4-A Syndrome) – AR loss of AAAS gene – Adrenal insufficiency, Achalasia, Alacrima – Autonomic abnormalities – May be variable expressivity ARS Question #5 21 hydroxylase deficiency CAH is associated with all of the following EXCEPT: A. Genital ambiguity B. Growth failure C. Infertility D. Irregular menses E. Acne Pathophysiology of Various Forms Of Congenital Adrenal Hyperplasia • Specific deficiency of one of the enzymes needed for cortisol biosynthesis • Resulting in: – Decreased cortisol production – Increased ACTH – Adrenal hyperplasia – Increased precursors to cortisol Common Enzyme Defects that Cause CAH • 21-OHase deficiency accounts for 95% – Salt wasting (60-75%) – Simple virilizing – Non-classical (late onset) • 11-OHase deficiency – Hypertension • 3-HSD (type II) – Ambiguous genitalia – Salt wasting 21 hydroxylase defect Cholesterol SCC CYP11A1 Pregnenolone17OHlase17-OH-Pregnenelone CYP17 3HSD 3HSDII 3HSD 3HSDII 17,20lyase DHEA CYP17 3HSD 3HSDII 17,20lyase 17OHlase 17-OH-Progesterone Androstenedione CYP17 17 ketoreductase HSD3 21OHlase CYP21A2 21OHlase CYP21A2 DOC 11-deoxycortisol 11OHlase CPY11B1 11OHlase CPY11B1 Corticosterone Cortisol Testosterone 5 reductase SRD5A2 DHT 18OHlase CYP11B2 18-OH-Corticosterone Aldo Synth CYP11B2 Aldosterone 11 hydroxylase defect Cholesterol SCC CYP11A1 Pregnenolone17OHlase17-OH-Pregnenelone CYP17 3HSD 3HSDII 3HSD 3HSDII 17,20lyase DHEA CYP17 3HSD 3HSDII 17,20lyase Progesterone 17OHlase 17-OH-Progesterone CYP17 21OHlase CYP21A2 DOC 21OHlase CYP21A2 11-deoxycortisol 11OHlase CPY11B1 11OHlase CPY11B1 Corticosterone Cortisol 18OHlase CYP11B2 18-OH-Corticosterone Aldo Synth CYP11B2 Aldosterone Androstenedione 17 ketoreductase HSD3 Testosterone 5 reductase SRD5A2 DHT 3 β HSD defect Cholesterol SCC CYP11A1 Pregnenolone17OHlase17-OH-Pregnenelone CYP17 3HSD 3HSDII 3HSD 3HSDII 17,20lyase DHEA CYP17 3HSD 3HSDII 17,20lyase Progesterone 17OHlase 17-OH-Progesterone CYP17 21OHlase CYP21A2 DOC 21OHlase CYP21A2 Androstenedione 17 ketoreductase HSD3 11-deoxycortisol 11OHlase CPY11B1 11OHlase CPY11B1 Corticosterone Cortisol Testosterone 5 reductase SRD5A2 DHT 18OHlase CYP11B2 18-OH-Corticosterone Aldo Synth CYP11B2 Aldosterone Various Forms of 2121-hydroxylase Deficiency With Different Phenotypes • Classic or early onset – Simple virilizing form (<10% enzyme activity) – Salt-wasting form (<1% enzyme activity) • Non-classic or late onset – (30-50% enzyme activity) – Premature pubarche or adrenarche – Severe acne or hirsutism – Menstrual abnormalities – Female pattern baldness CAH DUE TO 2121-OHase DEFICIENCY • Occurs frequently in sibs • Salt wasters become hyperkalemic before hyponatremic • Sex ratio is about 1:1 • Parents are not affected • Genetic disorder transmitted as an autosomal recessive trait Mutations 2121-hydroxylase (CYP21) Gene C4a CYP21P C4b CYP21 • Two CYP21 genes in tandem with two C4 genes on 6p21 within HLA locus • Genetic instability of unit – Misalignment and unequal crossover in meiosis – Gene conversion during mitosis • Gene conversions account for most mutations Why Screen for CAH? • Early screening detects the 70% of boys and 25% of girls with CAH missed on clinical examination. • Early treatment prevents adrenal crisis and infant death • Makes earlier gender assignment possible (3 days versus 23 days) • Prenatal diagnosis permits dexamethasone treatment (before 7 weeks) to reduce risk of virilization of affected female fetus Timing Of Blood Collection For CAH Screening • Adrenal crisis occurs at 2-3 weeks of age – Median age of diagnosis in boys is 21 days without screening and 9 days with screening1 • Many European programs test after 48 h • Most U.S. programs test – Within first 48 h and then repeat at 2 wk – If before 24 h, then repeat at 48 h – NICU on admission, then repeat 1Thilen et al., Pediatrics 1998;101. Congenital Adrenal Hyperplasia • Laboratory evaluation – 17OHP best screen and diagnostic test • 17OHP > 10,000 ng/dL in classic type • 17OHP > 1,000 ng/dL non classic type – Newborn screening programs use cutoff values based on gestational age ARS Question #6 • The clinical features of Cushing syndrome include all of the following EXCEPT: A. Hypertension B. Obesity and striae C. Alopecia D. Growth failure E. Precocious body hair distribution Growth in Cushing Syndrome • Obesity and Cushing syndrome share many common features • Weight increases in both obesity and Cushing syndrome • Growth velocity increases in obesity • Growth velocity decreases in Cushing syndrome Clinical Features of Cushing Syndrome • Appearance can differ from adults with gross obesity rather than central obesity • Thin skin, bruising, and violaceous striae • Pubic hair, acne, virilization, fuzzy hair • Hypertension • Muscle weakness and osteoporosis • Glucose intolerance • Psychosis Cushing Syndrome • Excess secretion of cortisol with loss of diurnal variation • Cushing syndrome refers to excessive exposure to endogenous or exogenous steroids • Cushing disease refers to pituitarydependent ACTH production – Pituitary adenoma or hypothalamic defect Cushing Syndrome in Children • Most common cause is iatrogenic • Endogenous disease is rare • Young children more likely to have adrenal adenoma • Older children more likely to have pituitary dependent disease • Nodular adrenal hyperplasia can cause cyclical Cushing syndrome Evaluation • Select patients carefully – this is rare! • Avoid random serum cortisol levels • Midnight salivary cortisol is ideal • 24 hour urinary free cortisol collection • Overnight dexamethasone suppression • Androgens (T and DHEA) also high • Image CNS/adrenals AFTER lab confirmation! Adrenal Tumors • Adrenal cortical tumors are rare • Often malignant in children • May secrete several hormones – Glucocorticoids – Mineralocorticoids – Androgens – Estrogens High Morbidity and Mortality • Perforated viscera and opportunistic fungal infections. • Suppression of the HPA axis, with full recovery taking up to 1 year • After resolution patients are at risk for developing an adrenal crisis. • A primary pituitary tumor may cause panhypopituitarism and visual loss. Adrenal Medullary Disorders • Pheochromocytoma – Very rare (1:100,000 persons) – 90% are benign and unilateral – 90% are sporadic – May be part of a familial syndrome • Secrete excess catecholamines – Sporadic tumors & non adrenal source secrete norepinephrine – Familial tumors & adrenal secrete epinephrine ARS Question #7 Pheochromocytoma is associated with all of the following disorders EXCEPT: A. Neurofibromatosis B. Von Hippel Landau syndrome C. MEN 1 D. MEN 2A E. MEN 2B VON HIPPELHIPPEL- Landau Syndrome • • • • • • • • • V isual defect O cular defect (retinal angioma) N ephron (renal Ca) H emangioblastoma of Cerebellum I ncreased intra cranial pressure P heochromocytoma P ancreatic Cyst E ctopic erythropoetin L iver cyst Pheochromocytoma Evaluation • Headache, palpitations, diaphoresis and nausea • 90% of patients have hypertension • May have hyperglycemia or hypercalcemia • 24 hr urine total catecholamines, vanillylmandelic acid (VMA), and metanephrines • Plasma metanephrine and normetanephrine • Localize tumor with MRI, use 131I-MIBG only if MRI is negative Pheochromocytoma Evaluation Once pheochromocytoma is diagnosed rule out a familial syndrome: • MEN 2A and MEN2B – Serum levels of PTH and calcitonin – RET gene analysis is commercially available • Von Hippel Landau – MRI of brain for cerebellar hemangioblastomas – VHL gene testing is available • Neurofibromatosis Summary • CAH is most important adrenal disorder – 21 hydroxyase deficiency – 17OHP screening test • Childhood Cushing syndrome – Delayed bone age and short stature • Pheochromocytoma – Part of several familial syndromes