Snapshot A 27-year-old G1P0 woman present to the labor and delivery floor for labor. She received little prenatal care due to poor insurance. After 2 hours, she successfully delivered vaginally a 7 lbs baby girl. A physical examination of the newborn demonstrates clitoral enlargement and labial fusion. A week later, the infant is brought to the emergency room for inability to feed. She is underweight and dehydrated by appearance with a low blood pressure. (21-hydroxylase deficiency) Introduction Introduction clinical definition refers to several disorders characterized by genetic defects in the proteins and enzymes involved in cortisol biosynthesis includes: 17α-hydroxylase deficiency 21-hydroxylase deficiency 11β-hydroxylase deficiency demographics 21-hydroxylase deficiency is the most common form (over 95% of cases) pathogenesis decreased cortisol production (due to defective proteins/enzymes) releases the feedback inhibition of cortisol on the pituitary and increases the production of corticotropin (ACTH) high levels of ACTH causes adrenal hyperplasia, excessive accumulation of cortisol precursors, and/or overproduction of ACTH-dependent adrenal steroids within other pathways clinical syndromes Overview of Congenital Adrenal Hyperplasia Enzyme Deficiency Presentation Blood Pressure Mineralocorticoids Sex Hormones Cortisol [K+] 17 α-hydroxylase XY: ambiguous genitalia, undescended tests XX: lacks secondary sexual development ↑ ↑ ↓ ↓ ↓ 21- hydroxylase XX: virilization Salt-wasting in infancy Precocious puberty in children ↓ ↓ ↑ ↓ ↑ 11 β-hydroxylase XX: virilization ↑ ↓ Aldosterone↑ 11-deoxycorticosterone (↑ BP) ↑ ↓ ↓ 17α-hydroxylase Deficiency Defect of the CYP17A1 gene, leading to defective CYP17A1 enzyme, which catalyzes both the 17-hydroxylase and the 17,20-lyase reaction Leads to accumulation of cortisol precursor with mineralocorticoid activity demographics prevalence is the highest in Brazil Presentation hypertension hypokalemia primary amenorrhea absence of secondary sexual characteristics ambiguous genitalia during infancy (in 46,XY patients with partial form) diffuse skin pigmentation Studies elevated 17-hydroxyprogesterone/androstenedione ratio elevated corticosterone elevated ACTH low cortisol, androgens, and estrogens genetic testing Treatment spironolactone blocks mineralocorticoid receptor low-dose estrogen for puberty induction genital surgery and testosterone replacement may be indicated for 46,XY patients with disorder of sex development Complications disorder of sex development testicular adrenal rest tumors 21-hydroxylase Deficiency Most common form Defects of the CYP21A2 gene leads to defective 21-hydroxylase enzyme, which is responsible for the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol Large amounts of 17-hydroxyprogesterone is diverted to the synthesis of androgens and its precursors Presentation diffuse skin hyperpigmentation and hypotension classic form (more severe) present during the neonatal/early infancy period adrenal insufficiency with salt wasting genital ambiguity in females simple virilizing (childhood-onset) genital ambiguities during toddler years mineralocorticoid deficiency is less significant no salt-wasting non-classic form (late-onset) present later in life with signs of androgen excess premature pubarche females may present with hirsutism, menstrual irregularity, infertility, and acne no neonatal genital ambiguity some patients may remain asymptomatic Imaging adrenal ultrasound abnormal results (e.g., adrenal limb width > 4mm, lobulated surface, or abnormal echogenicity) Studies high 17OHP levels the USA offers this as a part of neonatal screen cosyntropin (ACTH) stimulation test will demonstrate absent/low response high renin activity genetic testing Treatment emergent management of any salt-wasting crisis glucocorticoid replacement mineralocorticoid replacement consider reconstructive surgery for virilized 46,XX patients Complications salt-wasting crisis disorder of sex development growth abnormalities (due to high estradiol) testicular adrenal rest tumors 11β-hydroxylase Deficiency Defect of CYP11B1 gene leads to defective 11β-hydroxylase activity, which is responsible for the conversion 11-doxycorticosterone (DOC) and 11-deoxycortisol to corticosterone and cortisol respectively Accumulation of 11-dexosyteroid precursors leads to the overproduction of mineralocorticoid DOC and androgen precursor dehydroepiandrosterone sulfate (DHEAS) demographics accounts for up to 5% of adrenal steroidogenic defects Presentation hypertension hypokalemia female newborns have ambiguous genitalia premature adrenarche signs of hyperandrogenism (e.g., hirsutism, menstrual irregularities, and acne) Studies high levels of serum 11-dexoycortisol concentrations cosyntropin (ACTH) stimulation test will demonstrate absent/low response genetic testing low renin activity Treatment glucocorticoid replacement spironolactone eplerenone is used in male patients surgical reconstruction may be inidicated in 46.XX with virilization Complications disorder of sexual development adrenal crisis testicular adrenal rest tumors