Congenital Adrenal Hyperplasia

1. Congenital Adrenal Hyperplasia Hala H Mosli PGY-5 January 13, 2010

2. Objectives: • Anatomy and Physiology of the adrenal glands • Definition of CAH • Pathophysiology of CAH • Clinical Features • Diagnosis • Management

3. Adrenal Facts…. • The two adrenal (suprarenal) glands sit on top of the kidneys, one on each side. • They lie in the retroperitoneum at the level of T12 • The adrenals are derived embryologically from the mesoderm and the neural crest.

4. Adrenal gland development and defects Kempna . Flu ̈ck, Best Practice & Research Clinical Endocrinology & Metabolism Vol. 22, No. 1, pp. 77–93, 2008

5. http://academic.kellogg.edu/herbrandsonc/bio201_mckinley?f20-12c-d_adrenal_gland_c.jpghttp://academic.kellogg.edu/herbrandsonc/bio201_mckinley?f20-12c-d_adrenal_gland_c.jpg

6. Adrenal Cortex: • Mineralocorticoids: • Aldosterone: Secreted by the ZonaGlomerulosa of the adrenal cortex through stimulation by renin. • Renin, in turn, is regulated by multiple factors. • Main role is maintenance of fluid and electrolyte balance, thus playing a role in blood pressure control.

7. Epithelial Sodium Channel Mendelian Versus Essential Hypertension, Rossier and Schild, Hypertension. 2008;52:595-600.

8. Glucocorticoids: • Cortisol: secreted by the zonafasciculata of the adrenal cortex. • Overall actions are directed at enhancing the production of glucose and reducing all other metabolic activity not directly involved in this process: • Glucose metabolism: • Protein metabolism: • Lipid metabolism:

9. Anti-inflammatory activity • Causes a leukocytosis that reflects release from the bone marrow of mature cells as well as inhibition of their exit through the capillary wall. • Produces a redistribution of eosinophils and lymphoid tissue (esp T-cells) from the circulation into other compartments, which depletes their numbers and impairs cell-mediated immunity.

11. Cortisol has major effects on body water. It helps regulate the ECFV by inhibiting the migration of water into cells and by promoting renal water excretion, the consequence is to prevent water intoxication by increasing solute-free water clearance. • Glucocorticoids also have weak mineralocorticoid-like properties, and high doses promote renal tubular sodium reabsorption and increased urine potassium excretion. • Can also influence behavior; emotional disorders may occur with either an excess or a deficit of cortisol. • Cortisol suppresses the secretion of pituitary POMC and its derivative peptides (ACTH,β-endorphin, and β-LPT) and the secretion of hypothalamic CRH and vasopressin.

13. Adrenal androgens: • The major androgen secreted by the adrenal is dehydroepiandrosterone (DHEA) and its sulfuric acid ester (DHEAS). • Smaller amounts of androstenedione, 11-hydroxyandrostenedione, and testosterone are secreted. • DHEA and androstenedione are weak androgens and exert their effects via conversion to the potent androgen testosterone in extraglandular tissues.

14. Adrenal androgens have a minimal effect in males whose sexual characteristics are predominately determined by gonadal androgens (testosterone). • In females, adrenal androgens mediate androgen-like effects eg sexual hair. • DHEA also has poorly understood effects on the immune and cardiovascular systems. • Adrenal androgen formation is regulated by ACTH, not by gonadotropins and are suppressed by exogenous glucocorticoid administration

15. Adrenal Medulla: • The adrenal medulla is the location of the majority of the organism’s chromaffin cells, derived embryologically from neuroectoderm • Ganglion cells and sustentacular cells are also found in the medulla. • Chromaffincells store catecholamines in secretory vesicles also known as chromaffingranules and are found in clusters (or nests) and in trabeculae, • Ganglion cells are found singly or in clusters interspersed among the chromaffin cells or in association with nerve fibres. • The sustentacular cells, or support cells, are located at the periphery of clusters of chromaffin cells.

16. The major secretory products of the adrenal medulla are the catecholamines epinephrine, and to a lesser extent norepinephrine. • Their release is stimulated predominantly by cholinergic innervation through the splanchnic nerve. The synthesis of epinephrine from norepinephrine is catalyzed by the enzyme phenylethanolamine N- methyltransferase (PNMT) • Also produce, store, and secrete a whole series of neuropeptides. • A minority of these cells also migrate to form paraganglia on both sides of the aorta, referred to as the organ of Zuckerkandl.

18. Congenital Adrenal Hyperplasia

19. Definition • Congenital adrenal hyperplasia is a group of autosomal recessive disorders resulting from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. • Owing to this loss of enzyme function, patients with 21-hydroxylase deficiency cannot synthesize cortisol efficiently, and as a result, the adrenal cortex is stimulated by corticotropin and overproduces cortisol precursors

20. Congenital Adrenal Hyperplasia ,Speiser& White, N Engl J Med 2003;349:776-88.

21. The most frequent type is steroid 21-hydroxylase deficiency, accounting for more than 90% of cases. • Three other enzyme deficiencies in the steroid biosynthesis pathway, along with one cholesterol transport protein defect, account for the remaining cases.

22. The overall incidence of CAH due to 21OHD is approximately 1 in 16,000, with variations seen in different ethnic and racial groups. • The inheritance is autosomal recessive. • The activity of 21-hydroxylase is mediated by cytochrome p450c21, found in the endoplasmic reticulum. • The 21-hydroxylase genes (CYP21) lie within the class III region of the human major histocompatibility complex on chromosome 6.

23. Congenital Adrenal Hyperplasia ,Speiser& White, N Engl J Med 2003;349:776-88.

24. 75%

26. Clinical Manifestations • Classic, salt-wasting CAH: • Classic, simple virilizing CAH: • Non-Classic CAH

27. A. Classic, salt-wasting CAH: • Salt-wasting: • In the classic, salt-wasting type • Due to inadequate synthesis of aldosterone • Elevated levels of 21-OHase precursors may act as mineralocorticoid antagonists, exacerbating the effects of aldosterone deficiency.

28. Excessive renal sodium-wasting leads to intravascular depletion and hypovolemia as well as hypereninemia • Abnormal renal handling of potassium leads to hyperkalemia, especially in infancy • Also have catecholamine deficiency, potentially further exacerbating shock • Patients with the salt-wasting form are identified through the measurement of serum electrolytes, aldosterone, and plasma renin and the finding of expected abnormalities — hyperkalemia, low levels of aldosterone, and hyperreninemia.

29. Cortisol deficiency: • contributes to poor cardiac function, poor vascular response to catecholamines, a decreased GFR, and increased secretion of ADH. • The combination of cortisol and aldosterone deficiency leads to significant hypovolemia and shock. • Patients with salt-wasting form frequently present with acute adrenal crisis, often within the first few weeks after birth.

30. Typical Signs and Symptoms of Acute Adrenal Crisis • Decreased activity/fatigue • Altered sensorium/unresponsiveness • Poor feeding/weak suck • Dry mucous membranes • Hyperpigmentation • Abdominal pain • Vomiting • Hyponatremia • Hyperkalemia • Hypoglycemia • Metabolic acidosis • Hypothermia • Hypotension • Dehydration • Lack of weight gain

31. Hyperpigmentation of skin creases and genitalia may be early signs of adrenal insufficiency. • Affected infants initially demand frequent feedings, possibly due to dehydration or salt craving. • Poor feeding is a late sign of CAH and severe adrenal crisis

32. Androgen excess: • Males are usually not affected by this. • Females mainly affected. • Girls with classic 21-hydroxylase deficiency are exposed to high systemic levels of adrenal androgens from approximately the seventh week of gestation

33. Consequences of exposure to high levels of androgens: • Ambiguous genitalia: • In the severe classic form • 21OHD has been recognized as the most common cause of ambiguous genitalia in a genetically female fetus. • The phenotypic virilization varies from simple clitoromegaly, with or without partial fusion of the labioscrotal folds, to the appearance of a penile urethra.

34. A sex-determining region on the Y chromosome is required for differentiation of testes from the early bipotential gonads between 6 and 8 weeks of gestation. • Whether male or female internal genitalia develop depends on the presence of two hormones produced by the fetal testis: testosterone, secreted by the Leydig cells, and anti-Mu ̈llerian hormone (AMH), secreted by the Sertoli cells. • By 8 weeks of gestation, a normal male fetus is able to secrete these two hormones.

35. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A4106http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A4106

36. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A4106http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=dbio&part=A4106

38. In males: subtle penile enlargement and slight hyperpigmentation.

39. Postnatal virilization: • In patients who either are not treated or are inadequately treated, long-term exposure to high levels of sex hormones promotes rapid somatic growth (predominantly an androgen effect) and advanced skeletal age, which leads to premature epiphyseal fusion (predominantly an effect of extragonadal aromatization of androgens to estrogens). • Pubic and axillary hair may develop early. • Clitoral growth may continue in girls

40. In boys: • May have penile growth despite having small testes, since the androgens are adrenal in origin. • Long-term exposure to androgens may activate the hypothalamic–pituitary–gonadal axis, causing centrally mediated precocious puberty.

41. Linear growth: • Linear growth is affected by congenital adrenal hy- perplasia, even with close therapeutic monitoring. • A meta-analysis of data from 18 centers showed that adult heights in patients with classic congenital adrenal hyperplasia averaged 1.4 SD below the population mean. • Both undertreatment and overtreatment put patients at risk for short stature.

42. Reproductive function: • Females: • Oligomenorrhea or amenorrhea may develop in ado-lescence. • Prenatal exposure to androgens may influence subsequent sex-role behavior. • Most affected females have been reported to exhibit increased behavior more typical of boys during childhood in terms of toy preferences, rough play, and aggressiveness. • However, most women are heterosexual, and their sexual identity is almost invariably female.

43. The issue of fertility is inextricably related to psychosocial adjustment • With improved therapy, more women with 21- hydroxylase deficiency have successfully completed pregnancies and given birth, most by cesarean section. • About 80% of women with simple virilizing disease and approximately 60% of those with the severe salt-wasting form are fertile.

44. In males: • Affected men have fewer problems with reproductive function, specifically gonadal function. • Most have normal sperm counts and are able to father children. • One relatively common form of gonadal abnormality in affected males is the development of testicular adrenal rests, detectable by sonographic imaging before they become palpable. • Such tumors have been detected even in childhood.

45. In males with salt wasting, testicular rest tissue may be accompanied by deficient spermatogenesis despite treatment. • These tumors, although almost invariably benign, have prompted biopsies and even partial orchiectomy. • Proper medical treatment consists of pituitary suppression with dexamethasone, since the tumors are usually responsive to corticotropin.

46. B. Classic, simple virilizing CAH: • Patients with simple virilizing 21-hydroxylase deficiency do not synthesize cortisol efficiently, but adequate aldosterone secretion remains and thus sodium balance is maintained. • Usually diagnosed in female patients shortly after birth owing to genital ambiguity,

47. In males, the diagnosis is often delayed for several years. • Without newborn screening, affected boys are usually identified when signs of androgen excess develop. • Later diagnosis is associated with greater difficulty in achieving hormonal control, abnormal tempo of puberty, and short stature.

48. Non-Classic CAH: • Nonclassic 21OHD may be the most common autosomal recessive disorder in humans. • Its prevalence rate is approximately 3.7% (1 in 27) in Ashkenazi Jews and 0.1% (1 in 1,000) in white populations • These patients produce normal amounts of cortisol and aldosterone at the expense of mild-to-moderate overproduction of sex hormone precursors.

49. A few non-classic cases are detected by newborn-screening programs, but most are missed because of the relatively low baseline levels of 17-hydroxyprogesterone. • It is not known what proportion of cases diagnosed by neonatal screening eventually become symptomatic. • Some children grow rapidly or have advanced bone age, and pubic or axillary hair prematurely develops in some.

50. Hirsutism is the single most common symptom at presentation in approximately 60% of symptomatic women, followed by oligomenorrhea (54%) and acne (33 percent), as well male-pattern baldness. • Can also have PCOS. • Short-stature, insulin resistance and severe cystic acne can occur in both males and females with non-classic CAH