21-hydroxylase-deficient nonclassic adrenal hyperplasia

Inherited adrenal enzymatic deficiencies causing hyperandrogenic symptoms some time after birth are defined as nonclassical adrenal hyperplasia (NC-CAH). While 21-hydroxylase (21-OH) deficiency accounts for the vast majority of NC-CAH, deficiencies in 11/3-hydroxylase and 3/3-hydroxysteroid dehydrogenase may rarely result in the disorder. Endocrinologically evident 21-OH-deficient NC-CAH appears to affect between 1% and 10% of hyperandrogenic women. Clinically evident deficiencies of 21-OH result from mutations of the CYP21 gene. The Leu-281 mutation is present in approximately 60%, Ser-453 in 25%, and Pro-30 in 10% of NC-CAH patients. Androgenic symptoms in NC-CAH generally appear peripubertally, frequently coinciding with adrenarche. The clinical presentation, which is usually mild, cannot be used to distinguish 21-OH deficient NC-CAH patients from other hyperandrogenic patients. The hormonal profile is also nondiagnostic, with the exception of the basal follicular phase 17-hydroxyprogesterone (17-HP) level. In untreated patients a 17-HP level of S2 ng/mL (6.0 nmol/L) effectively rules out NC-CAH. Alternatively, 20% of hyperandrogenic patients demonstrating a 17-HP level of > ng/mL (>nmol/L) have NC-CAH. Endocrinologically, NC-CAH is diagnosed by a 17-HP level 30 to 60 minutes after the acute IV administration of ACTH-[1–24] exceeding 10 ng/mL (30.3 nmol/L), and more frequently, 15 ng/mL (45.4 nmol/L). In NC-CAH ovulatory function responds well to glucocorticoids and/or clomiphene citrate, although many patients with NC-CAH become pregnant without requiring treatment. Hirsute NC-CAH generally require the addition of anti-androgen therapy to their glucocorticoid therapy.