The final step in Cortisol synthesis is blocked in this condition. In classic 11 ??-hydroxylase deficiency, 11-deoxycortisol is not converted to Cortisol. Accumulated precursors are shunted into androgen biosynthesis with virilization similar to that seen with 21-hydroxylase deficiency. However, a parallel defect also exists so that deoxycorticosterone (DOC) is not converted to corticosterone. This pathway is used in the zona glomerulosa to synthesize aldosterone, and the degree to which aldosterone levels are affected lends clinical heterogeneity to the classic presentation of H??-hydroxylase deficiency (virilization, hypertension, volume overload).

Usually as a result of 11 ??-hydroxylase deficiency, metabolically active precursors of corticosterone and Cortisol add to excess androgen synthesis as further liabilities of ACTH-induced hyperplasia. Hypertension and hypokalemic alkalosis are induced by elevated DOC with reduced renin and aldosterone. Virilization is caused by androgens of the "deoxy" type (dehydroepiandrosterone [DHA], dehydroepiandrosterone sulfate [DHAS], and androstenedione). The diagnosis is confirmed by high plasma DOC and compound S (11-deoxycortisol) levels.

About two-thirds of untreated patients with 11 ??-hydroxylase deficiency become hypertensive, usually of mild to moderate degree (150/90 mm Hg) and only after several years of life. A mild nonclassic form of 11 ??-hydroxylase deficiency, as in 21-hydroxylase defects, has also been documented; it is characterized by mild biochemical abnormalities, and the patients are only mildly virilized and rarely hypertensive.

Contrary to 21-hydroxylase deficiency, the 11 ??-hydroxylase deficiency locus is remote from the HLA complex. The gene for the enzyme is on the long arm of chromosome 8, and the deficiency is inherited in autosomal recessive fashion.