We report studies on the second pregnancy of a woman who had previously given birth to a virilized female infant. The cause of the
virilization had not been established, but common forms of
congenital adrenal hyperplasia (CAH) were excluded. Longitudinal monitoring of the second pregnancy revealed that
estriol excretion failed to increase normally, reaching a maximum 0.7 mg/24 hr at the end of pregnancy (normal mean 30 mg/24 hr). The mother showed signs of
virilization by the 23rd week of gestation and
aromatase deficiency was suspected. However, predicted urinary metabolites for diagnosis of
aromatase deficiency (for example, 16alpha-hydroxyandrosterone) were not increased significantly during the pregnancy. Interestingly, excretion of the
androgen metabolite
androsterone increased rapidly at the beginning of pregnancy and peaked around the 20th week, suggesting increased production of
testosterone and 5alphaDHT, probably the cause of maternal
virilization. Urine
steroid analysis by GC/MS showed gradually increasing excretion (9 mg/24 hr) of the normally minor metabolite 5alpha-pregnane-3beta,20alpha-diol (epiallopregnanediol), an epimer of the dominant
progesterone metabolite
pregnanediol (5beta-pregnane-3alpha,20alpha-diol). We believe epiallopregnanediol is largely the maternal urinary excretion product of fetal
5-pregnene-3beta,20alpha-diol, the principal metabolite of
pregnenolone, implying a build-up of the latter
steroid in the fetal adrenal. These findings suggested that the 'block' in the
estriol biosynthetic pathway occurs at an early stage with 17-hydroxylation of
pregnenolone being affected. The male baby born of this pregnancy had normal genitalia but showed a urinary
steroid profile indicating partial deficiencies of P450c17 and P450c21. However, no mutations in the corresponding
CYP17 and CYP21 genes were identified. Urinary
steroid analysis carried out on his virilized older sibling showed the same pattern of metabolites. Recently, we determined that this disorder is caused by mutations in P450
oxidoreductase (OR), the essential redox partner for
CYP17 and CYP21
hydroxylases. The novel metabolic profile has now been seen in many patients, most diagnosed with the skeletal dysplasia
Antley-Bixler syndrome. We propose that excessive excretion of epiallopregnanediol together with low
estriol may be prenatally diagnostic for OR deficiency (ORD).