Apparent manifesting heterozygosity in P450 oxidoreductase deficiency and its effect on coexisting 21-hydroxylase deficiency.

Context: P450 oxidoreductase (POR) deficiency is a disorder of steroidogenesis affecting the microsomal P450 enzymes that use POR as an electron donor. The clinical presentation is variable; patients can be asymptomatic or can present with genital anomalies and the Antley-Bixler syndrome, characterized by craniosynostosis and other bony anomalies. Obligately heterozygous parents are normal. Combined POR and 21-hydroxylase deficiencies have not been reported.

Objective: The aim was to explore the manifestations of combined deficiencies of 21-hydroxylase and POR and to search for lesions in apparent manifesting POR heterozygotes.

Patients And Methods: A newborn female had craniosynostosis, severe salt wasting, minimal virilization, grossly elevated 17OH-progesterone, and minimally elevated androgens. DNA encoding 21-hydroxylase, POR, and fibroblast growth factor receptor 2 was sequenced. For POR, the first untranslated exon (exon 1U), 5' flanking DNA, and most introns were sequenced in five apparent manifesting POR heterozygotes.

Results: CYP21B mutations were found on both alleles, proving classical 21-hydroxylase deficiency. Fibroblast growth factor receptor 2 exons 8 and 10 were normal. A POR mutation, A287P, was found only on the maternal allele. Five previously reported patients had POR mutations found on only one allele, but their clinical characteristics were indistinguishable from patients with mutations on both alleles. Sequencing of exon 1U, 274 bp of POR 5' flanking DNA, and 12 of the 15 POR introns did not identify additional mutations affecting gene expression or splicing.

Conclusion: Manifesting heterozygosity is a possible feature of POR deficiency and may ameliorate the findings in coexisting 21-hydroxylase deficiency.