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

Abstract

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).

Metabolic evidence for impaired 17α-hydroxylase activity in a kindred bearing the E305G mutation for isolate 17,20-lyase activity

“…All our subjects under investigation were older. In all our subjects investigated, the androsterone/etiocholanolone ratio was not elevated and thus not indicative of an active back door pathway (16). The fact that our patients presented at birth with micropenis and hypospadias and not with female genitalia indicates that they had sufficient testosterone and dihydrotestosterone levels during embryogenesis for the development of a penis; however, the low levels of testosterone and dihydrotestosterone during the third trimester diminished penis growth and resulted in micropenis with hypospadias.…”

Cytochrome P450 Oxidoreductase Deficiency in Three Patients Initially Regarded as Having 21-Hydroxylase Deficiency and/or Aromatase Deficiency: Diagnostic Value of Urine Steroid Hormone Analysis

“…Third, Shackleton et al (22) have suggested that urine pregnadienol (the artifact of pregnenediol disulfate detectable exclusively in PORD) can be viewed as a hallmark analyte, although it was not measured in this study. Lastly, Shackleton et al (21) have also reported that steroid profile analysis of the maternal urine can detect the "backdoor" pathway derived steroids including androsterone, thereby permitting the prenatal diagnosis of PORD.…”

Genetic and Clinical Features of P450 Oxidoreductase Deficiency

“…In contrast, girls with POR deficiency are frequently virilized, but with no postnatal progression, unlike girls with untreated 21-hydroxylase deficiency [55]. There are two hypotheses as to the origin of this virilization, although neither has been definitively proven [3, 51, 56]. POR deficiency impairs the activity of P450aro (aromatase) which converts fetal 19-carbon androgen precursors to estrogens.…”

“…These patients are clinically indistinguishable from those with two mutations, pointing toward possible mutations in as yet unidentified regulatory regions [7]. Patients with the same mutations, even siblings, can be phenotypically different [3, 27, 28, 51]. However, patients with POR mutations always have hormonal profiles compatible with partial deficiencies of 21-hydroxylase and 17α-hydroxylase/ 17,20-lyase.…”

“…POR deficiency impairs the activity of P450aro (aromatase) which converts fetal 19-carbon androgen precursors to estrogens. Placental aromatase deficiency leads to maternal virilization and low maternal estriol and estrone [57] levels, both of which have been described in POR deficiency [2,3,4,27,28,29, 51]. However, the main fetoplacental substrates for P450aro, 16αOH-DHEA and androstenedione, are low in POR deficiency, and the usual urinary metabolites seen in placental aromatase deficiency are not always found in POR deficiency [3].…”