Deficiency of 21-hydroxylase results in the impairment of the conversion of 17αhydroxyprogesterone to 11-deoxycortisol and of progesterone to deoxycorticosterone (Fig. 29.20). As a consequence, precursors accumulate, and there is increased conversion to adrenal androgens. Because the development of the external genitalia is controlled by androgens, in the classic form of this disorder, girls are born with ambiguous genitalia, including an enlarged clitoris and fusion of the labioscrotal folds and the urogenital sinus. The internal female organs (including the uterus, fallopian tubes, and ovaries) develop normally because they are not affected by the increased androgen levels. In three-quarters of cases with classic 21-hydroxylase deficiency, salt-wasting occurs, as defined by hyponatremia, hyperkalemia, and hypotension. It is important to recognize that the extent of virilization may be the same in simple virilizing and salt-wasting CAH. Thus, even a mildly virilized newborn with 21-hydroxylase deficiency should be observed for signs of a potentially life-threatening crisis within the first weeks of life. During childhood, untreated girls with the classic form grow rapidly but have advanced bone ages, enter puberty early, experience early closure of their epiphyses, and ultimately are short in stature as adults. CAH, with appropriate therapy, is the only inherited disorder of sexual differentiation in which normal pregnancy and childbearing are possible. The classic forms of 21-hydroxylase deficiency are easily diagnosed based on the presence of genital ambiguity and markedly elevated levels of 17α-hydroxyprogesterone. Some states in the US initiated neonatal screening programs to detect 21-hydroxylase deficiency at birth.
3β-Hydroxysteroid Dehydrogenase Deficiency of 3β-hydroxysteroid dehydrogenase (3βHSD), caused by mutations in the HSD3B2 gene that encodes the 3β-HSDII enzyme, affects the synthesis of glucocorticoids, mineralocorticoids, and sex steroids. Typically, levels of 17hydroxypregnenolone and DHEA are elevated (Fig. 29.20). The classic form of the disorder, detectable at birth, is quite rare, and affected girls may be masculinized only slightly. In severe cases, salt wasting may be present.
A nonclassic form of this disorder may be associated with heterosexual precocious pubertal development (as is the classic form if untreated), but postpubertal hyperandrogenism occurs more often. The androgen excess in individuals with nonclassic 3β-HSD deficiency appears to result from androgens derived from the peripheral conversion of increased serum concentrations of DHEA. This disorder is inherited in autosomal recessive fashion, with allelism at the 3β-HSD gene on chromosome 1 believed to be responsible for the varying degrees of enzyme deficiency.
11-Hydroxylase Deficiency The classic form of 11-hydroxylase deficiency is believed to constitute 5% to 8% of all cases of CAH. Deficiency in 11-hydroxylase, caused by mutations in the CYP11B1 gene, results in the inability to convert 11-deoxycortisol to cortisol and the consequent accumulation of androgen precursors (Fig. 29.20). Markedly elevated levels of 11deoxycortisol and deoxycorticosterone are present in the disorder. Because deoxycorticosterone acts as a mineralocorticoid, many individuals with this disorder become hypertensive. A mild