Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients.

Context: Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder characterized by skeletal dysplasia, adrenal dysfunction, disorders of sex development (DSD), and maternal virilization during pregnancy. Although multiple studies have been performed for this condition, several matters remain to be clarified, including the presence of manifesting heterozygosity and the underlying factors for clinical variability. Objective: The objective of the study was to examine such unresolved matters by detailed molecular studies and genotype-phenotype correlations. Patients: Thirty-five Japanese patients with POR deficiency participated in the study. Results: Mutation analysis revealed homozygosity for R457H in cases 1–14 (group A), compound heterozygosity for R457H and one apparently null mutation in cases 15–28 (group B), and other combinations of mutations in cases 29–35 (group C). In particular, FISH and RT-PCR sequencing analyses revealed an intragenic microdeletion in one apparent ...