Steroid 21-hydroxylase deficiency

The steroid hormone cortisol is synthesized from cholesterol in the adrenal cortex in five enzymatic steps: the cholesterol side-chain is cleaved to form pregnenolone, which is dehydrogenated to progesterone, and successively hydroxylated at the 17α, 21, and 11β positions to yield cortisol. Deficiencies in any of the corresponding enzymatic activities prevent cortisol from being synthesized normally, resulting in the syndrome of congenital adrenal hyperplasia. More than 90% of cases of congenital adrenal hyperplasia result from a deficiency of 21-hydroxylase activity. In this disorder, accumulated cortisol precursors are shunted into the androgen biosynthetic pathway, and so males and females have signs and symptoms of androgen excess including ambiguous genitalia (in females); rapid somatic growth with accelerated skeletal maturation and short adult stature; and abnormal pubertal development. About 75% of patients with the severe, classic form of this disorder also have an impairment in their ability to synthesize the mineralocorticoid hormone, aldosterone, and may die shortly after birth from renal salt loss if untreated. Such patients are said to have ''salt-wasting'' disease, whereas patients with apparently unimpaired aldosterone biosynthesis have ''simple virilizing'' disease. The classic form of 21-hydroxylase deficiency occurs in about 1 in 13,000 births. A mild, often asymptomatic, ''nonclassic'' form of the enzyme deficiency is extremely common; it is found in about 1% of the general Caucasian population and in 3% of Ashkenazi (European descent) Jews (Speiser et al., Am J Hum Genet 1985, 37:650-667). This article summarizes the recent literature concerning genetics and prenatal diagnosis of 21-hydroxylase deficiency. This disorder and other forms of congenital adrenal hyperplasia are reviewed in greater detail by White et al. (N Engl J Med 1987, 316:1519-1524, 1580-1586) and New et al. (in Scriver et al., The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1989, pp 1881-1918).