The most common enzymatic defect of
steroid synthesis is adrenal
steroid 21-hydroxylase deficiency. Inhibited formation of
cortisol causes increased pituitary release of
ACTH, driving the adrenal cortex to overproduce
androgens, whose synthesis does not involve the
21-hydroxylase enzyme. This hormonal setting is established in the embryonic period and affects development of genetic females, misdirecting differentiation of the external genitalia toward male type. At birth, the genitalia are visibly ambiguous (enlarged clitoris, fused labia) or in some cases even male in appearance (phallus with urethral opening, rugated scrotal sac), leading to wrong sex assignment. Adrenal
steroid 21-hydroxylase deficiency is the most common basis of
female pseudohermaphroditism. These females, however, have normal fertility and potential for gestation (gonads are functional and the internal duct-derived structures are well-formed), thus the sex of rearing should always be female. Management is by life-long hormonal (
glucocorticoid) replacement, with surgical correction of the
genital ambiguity. Prenatal diagnosis of
21-hydroxylase deficiency, first possible by
steroid assay of the amniotic fluid, has utilized HLA typing for identification of loci (
antigens B and DR) in close linkage with the
21-hydroxylase gene, and now increasingly relies on
DNA analysis for linked HLA or C4 genes or for mutant
21-hydroxylase alleles directly by molecular genetic techniques. The most recent clinical advance is a program of combined prenatal diagnosis with karyotyping and suppression of fetal
androgen production in genetic females by
steroid administration to the mother. This is the first instance of an inborn metabolic error to be prenatally treated. A series of 85 managed pregnancies is reported on, including accuracy of diagnosis, response of the mother to
steroid treatment, and outcome for treated and untreated male and female fetuses (of 77 born by 6/91). Prenatal diagnosis by current techniques is accurate. Normal growth and development patterns postnatally suggest that
dexamethasone treatment is safe.