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

Cedric Shackleton, J Marcos, Wiebke Arlt, BP Hauffa

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    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).
    Original languageEnglish
    Pages (from-to)105-112
    Number of pages8
    JournalAmerican Journal of Medical Genetics. Part A
    Issue number2
    Early online date1 Jan 2004
    Publication statusPublished - 30 Aug 2004


    • apparent pregnene
    • maternal virilization
    • genital ambiguity
    • pregnancy estriol
    • oxidoreductase deficiency
    • Antley-Bixler syndrome
    • hydroxylation deficiency
    • luteoma


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