Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype.

[aromatase deficiency]

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 , 16 alpha-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 20 th week , suggesting increased production of testosterone and 5 alphaDHT , 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 5 alpha-pregnane-3 beta ,20 alpha-diol (epiallopregnanediol ), an epimer of the dominant progesterone metabolite pregnanediol (5 beta -pregnane-3 alpha ,20 alpha-diol ). We believe epiallopregnanediol is largely the maternal urinary excretion product of fetal 5 -pregnene-3 beta ,20 alpha-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 P 450 c 17 and P 450 c 21 . However , no mutations in the corresponding CYP 17 and CYP 21 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 P 450 oxidoreductase (OR ), the essential redox partner for CYP 17 and CYP 21 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 ).

Diseases
Validation

Diseases presenting "common forms" symptom

allergic bronchopulmonary aspergillosis

alpha-thalassemia

aromatase deficiency

cadasil

fabry disease

holt-oram syndrome

oligodontia

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