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 "early stage" symptom

adrenomyeloneuropathy

allergic bronchopulmonary aspergillosis

aromatase deficiency

cadasil

carcinoma of the gallbladder

child syndrome

cholangiocarcinoma

congenital adrenal hyperplasia

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

harlequin ichthyosis

hereditary cerebral hemorrhage with amyloidosis

hodgkin lymphoma, classical

kindler syndrome

lymphangioleiomyomatosis

neonatal adrenoleukodystrophy

pyomyositis

scrub typhus

sneddon syndrome

typhoid

von hippel-lindau disease

zellweger syndrome

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