Pathophysiology
Clinical meaning
Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders caused by enzymatic defects in adrenal corticosteroid biosynthesis, most commonly 21-hydroxylase deficiency, which accounts for approximately 90-95% of all CAH cases. The incidence of classic 21-hydroxylase deficiency is approximately 1 in 14,000-18,000 live births, making it one of the most common inborn errors of metabolism. To understand CAH pathophysiology, it is essential to understand normal adrenal steroidogenesis. The adrenal cortex synthesizes three classes of steroid hormones from the common precursor cholesterol: glucocorticoids (cortisol) from the zona fasciculata, mineralocorticoids (aldosterone) from the zona glomerulosa, and adrenal androgens (DHEA, androstenedione) from the zona reticularis. These biosynthetic pathways share common intermediate steps but diverge at critical enzymatic branch points. 21-Hydroxylase (CYP21A2) is a cytochrome P450 enzyme located in the endoplasmic reticulum of adrenal cortical cells. It catalyzes the hydroxylation of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol in the glucocorticoid pathway, and progesterone to 11-deoxycorticosterone (DOC) in the mineralocorticoid pathway. When 21-hydroxylase is deficient, both cortisol and aldosterone synthesis are impaired, while precursors proximal to the enzymatic block (17-OHP, progesterone) accumulate. The accumulated 17-OHP...