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Deficiency in CYP17 (17alpha-Hydroxylase)

All patients with CYP17 (also called cytochrome P₄₅₀ c17 or 17alpha-hydroxylase) deficiency are female regardless of whether they are XX or XY, because there is a complete block in the biosynthesis of androgens and estrogens both prenatally and postnatally 17alpha-hydroxylase deficiency, CYP17 deficiency, cytochrome P450 c17, 17 alpha-hydroxylase deficiency. Adrenal hyperplasia results from impairment of cortisol biosynthesis and a secondary elevation in ACTH secretion. Consequently, the secretion of both desoxycorticosterone and corticosterone is greatly elevated, causing hypertension and hypokalemia. Renin activity and circulating aldosterone are both suppressed (except in a Japanese variant). Treatment with dexamethasone reduces ACTH secretion and therefore the levels of desoxycorticosterone and corticosterone, and blood pressure returns to normal. Estrogen is given from age 11 years to 46,XY patients who have no uterus and in combination.

Low-dose testosterone is given. The ovaries of 46,XX patients contain numerous follicles. In one case in which testosterone was provided as an aromatizable substrate, follicular maturation could be induced.

Numerous mutations in the gene for CYP17 have been demonstrated in patients with deficiency. Several have been expressed in COS cells, and these show that the activities of both 17alpha-hydroxylase and 17,20-lyase are greatly impaired. This condition is extremely rare.

In this rare disorder, affected XX and XY infants are phenotypic females who lack the ability to secrete any adrenal or gonadal steroids owing to a complete block in cholesterol side-chain cleavage. Salt loss becomes clinically evident within a week of birth, and severe hypoglycemia may also occur. The lips and genitalia are often deeply pigmented.

Because of the apparent absence of cholesterol side-chain cleavage enzyme activity, it was assumed that the defect would reside in the gene encoding P₄₅₀ scc (CYP11A); however, when this gene was cloned, it was found to be structurally normal in all cases of lipoid adrenal hyperplasia. Subsequently, mutations were found in the gene encoding the steroidogenic acute regulatory protein (StAR). This protein regulates the transport of cholesterol into the mitochondrion where it can be acted upon by P₄₅₀ scc (CYP11A). A mutation in the gene encoding StAR results in the accumulation of cholesterol in the cytoplasm. The adrenals become grossly engorged with lipid, hence the name "lipoid adrenal hyperplasia."

Treatment with glucocorticoid, mineralocorticoid, and salt corrects the metabolic abnormality. Estrogen replacement therapy is given to induce puberty (combined with cyclical progestogen in 46,XX cases).