Congenital Adrenal Hyperplasia (CAH) refers to a family of inherited disorders caused by enzymatic defects in adrenal steroid biosynthesis. In patients with CAH, reduced cortisol synthesis interrupts feedback inhibition of adrenocorticotropic-hormone (ACTH) release from the pituitary, leading to continual stimulation of the adrenals by ACTH and, consequently, adrenal hyperplasia. Incidence of “classic” CAH, which presents in infancy with signs of adrenal insufficiency and/or ambiguous genitalia, has been estimated at 1:15,000. Prevalence of the “non-classic” form of CAH, which typically presents later in life and with much milder symptoms, may be as high as 1:100 (1-4).

The three major types of adrenal steroid hormones, glucocorticoids, mineralocorticoids, and adrenal androgens, are each produced through a separate biosynthetic pathway. All three pathways, however, share common precursor molecules. If an enzymatic block occurs in any of the three biosynthetic pathways, precursor molecules are shunted into the remaining functional pathway(s). Therefore, defects in a specific biosynthetic enzyme can simultaneously lead to deficiency in one or two types of adrenal steroids and overproduction of the remaining type(s). Presentation and treatment of CAH depend on 1) which of the three major biosynthetic pathways is/are affected by the enzymatic defect in adrenal steroid synthesis, 2) the severity of the enzymatic defect, and 3) whether gonadal steroid synthesis is also affected. The pattern of elevated biosynthetic precursor molecules is highly diagnostic of the type of CAH. Genetic testing can also be used for the differential diagnosis of CAH, since the genes coding for the enzymes involved in steroid biosynthesis have been identified. Loss-of-function mutations in the gene CYP21A2 account for about 90% of all cases of CAH. Other, rarer forms of CAH are due to loss-of-function mutations in the genes CYP11B1, CYP17A1, HSD3B2, or STAR (lipoid CAH). All known forms of CAH show autosomal recessive inheritance. Genetic testing may be more sensitive than biochemical testing in cases of mild enzymatic defects. In addition, genetic testing can facilitate carrier detection, genetic counseling, and the early diagnosis and treatment of affected family members.