Disordered Steroidogenesis Due To Cytochrome P450 Oxidoreductase Deficiency

A number sign (#) is used with this entry because this form of disordered steroidogenesis is caused by homozygous or compound heterozygous mutations in the POR gene (124015), which encodes cytochrome p450 oxidoreductase, on chromosome 7q11.2. Mutations in this gene also result in a form of Antley-Bixler syndrome (ABS1; 201750).

Description

This rare variant of congenital adrenal hyperplasia, caused by mutations in the POR gene, results in apparent combined deficiency of P450C17 (609300) and P450C21 (613815) and accumulation of steroid metabolites. The most striking phenotypic feature is that affected girls are born with ambiguous genitalia, indicating intrauterine androgen excess. After birth, however, virilization does not progress and amounts of circulating androgens are low or normal. Affected boys are sometimes born undermasculinized. Boys and girls can present with bone malformations, sometimes suggesting the pattern seen in patients with Antley-Bixler syndrome (see 207410) (summary by Arlt et al., 2004).

Clinical Features

In a 6-month-old 46,XY infant with a female phenotype and ambiguous genitalia, Peterson et al. (1985) found an unusual pattern of plasma and urinary steroids indicating that the child had multiple abnormalities of steroid-biosynthetic microsomal mixed-function oxidases: 21-hydroxylase, 17-alpha-hydroxylase, and 17,20-desmolase. Individually, each is responsible for a form of congenital adrenal hypoplasia; see 201910 and 202110. The deficit in activities of the first 2 enzymes resulted in decreased cortisol synthesis with subsequent increased ACTH secretion and adrenocortical hyperplasia. The male pseudohermaphroditism results from deficient testosterone synthesis due to deficiency of 17-alpha-hydroxylase and 17,20-desmolase. The family resided in the Dominican Republic. The mother and 2 sisters of the affected child, with normal phenotype, had mild 17-alpha-hydroxylase deficiency. The father had a normal urinary steroid profile. Peterson et al. (1985) proposed that since cytochrome P450 is the terminal oxidase for all 3 of these steroid microsomal mixed-function oxidases, impairment of translocation of P450 into the endoplasmic reticulum of the adrenocortical microsomes may represent a single defect affecting the activity of the 3 oxidases. Insertion of newly synthesized cytochrome P-450 into liver microsomes is known to require a signal-recognition particle bound to P-450 (Sakaguchi et al., 1984).

Arlt et al. (2004) described 3 patients with apparent combined P450C17 and P450C21 deficiency. In 1 family an affected sister showed bony changes similar to those seen in Antley-Bixler syndrome, as well as ambiguous genitalia; her brother with congenital adrenal hyperplasia had normal male genitalia at birth and no skeletal abnormalities. In a third sporadic case, the girl showed at 13 years of age a marfanoid habitus, scoliosis, arachnodactyly, dysplastic ears, and long slim limbs.

Williamson et al. (2006) reported a girl with a mild Antley-Bixler-like phenotype, ambiguous genitalia, impaired steroidogenesis, and compound heterozygosity for mutations in the POR gene. There was brachycephaly with a flat occiput, frontal bossing, and broad forehead. In addition, there was significant midface hypoplasia with a small mouth. Cranial, ovarian, uterine, and adrenal sonograms were normal. Skeletal survey at 5 weeks was normal except for advanced bone age of 6 months. There was no evidence of craniosynostosis, femoral bowing, or radiohumeral synostosis. Her ratio of pregnanediol to cortisol metabolites was more than twice normal and her other steroid ratios were higher than normal, but not as high as other published cases, demonstrating that the spectrum of biochemical severity is wider than previously suggested. The mother had undetectable serum unconjugated estriol at 18 weeks' gestation, but fetal morphology was normal on ultrasound at 20 weeks. Williamson et al. (2006) stated that a very low or negligible maternal serum unconjugated estriol is highly suspicious and warrants investigation for POR deficiency even in the presence of a normal fetal ultrasound.

Hershkovitz et al. (2008) reported 4 undervirilized males of an extended Bedouin family. All 4 were 46,XY. None of the mothers became virilized during their pregnancies. Onset of puberty was normal in 2 patients, but inadequate virilization required testosterone replacement in both. One patient retained one dysfunctional testis and a small penis. No skeletal malformation, dysmorphism, or limited limb movements were found, and X-rays showed no radioulnar or radiohumeral synostosis.

Biochemical Features

Shackleton et al. (2004) monitored the second pregnancy of the mother of 2 children with P450 oxidoreductase deficiency reported by Arlt et al. (2004). The mother's estriol excretion failed to increase normally and she showed signs of virilization at 23 weeks of gestation, but there was no evidence for aromatase deficiency. Urine steroid analysis showed gradually increasing excretion of epiallopregnanediol, which the authors believed was the maternal urinary excretion product of fetal 5-pregnene-3-beta,20-alpha-diol, the principal metabolite of pregnenolone. Shackleton et al. (2004) proposed that excessive excretion of epiallopregnanediol together with low estriol may be diagnostic for fetal P450 oxidoreductase deficiency.

Molecular Genetics

In a phenotypically normal woman with amenorrhea and disordered steroidogenesis, Fluck et al. (2004) found compound heterozygosity for mutations in the POR gene (124015.0003-124015.0004). Fluck et al. (2004) hypothesized that milder mutations in POR may manifest as mild disorders of steroid synthesis, whereas severe mutations in POR without associated disorders of FGF receptors are sufficient to cause the ABS phenotype.

All 3 patients with apparent combined P450C17 and P450C21 deficiency described by Arlt et al. (2004) were compound heterozygotes (see 124015.0005 and 124015.0007-124015.0009), whereas their parents and an unaffected sib were heterozygotes.

Hershkovitz et al. (2008) reported 4 undervirilized males of an extended Bedouin family. One of these had been reported (Biason-Lauber et al., 1997) to carry mutations in the CYP17A1 gene (609300), encoding P450c17, causing isolated 17,20-lyase deficiency (202110). Gas chromatography-mass spectrometry (GC-MS) urinary steroid profiling and serum steroid measurements showed combined deficiencies of 17,20-lyase and 21-hydroxylase. Sequencing of exons 1 and 8 of CYP17A1 in 2 different laboratories showed no mutations. Sequencing of the POR gene showed that all 4 patients were homozygous for G539R (124015.0016), which was shown by Huang et al. (2005) to retain 46% of normal 17-alpha-hydroxylase activity but only 8% of the 17,20-lyase activity of P450c17. Hershkovitz et al. (2008) conclude that POR deficiency can masquerade clinically as isolated 17,20-lyase deficiency.