Adult nonclassic P450 oxidoreductase deficiency diagnosed 11 years after reproductive-endocrine suspicion

Nonclassic P450 oxidoreductase (POR) deficiency (PORD) may remain suspected but unconfirmed in adult women with long-standing menstrual irregularity and infertility when skeletal anomalies, virilization, and overt adrenal insufficiency are absent. We report a 45-year-old Japanese woman in whom PORD had been suspected during infertility care at age 34 because of an inappropriately elevated, nonluteal progesterone value with no marked 17-hydroxyprogesterone elevation, but genetic testing was not pursued. Reevaluation for recurrent abnormal uterine bleeding and a large ovarian cyst prompted 3-point liquid chromatography-tandem mass spectrometry (LC-MS/MS) steroid profiling at baseline, after cosyntropin 250 µg, and during combined dexamethasone-hydrocortisone treatment. Adrenocorticotropic hormone (ACTH) stimulation produced disproportionate accumulation of adrenal steroid intermediates, which decreased markedly during combined glucocorticoid treatment, supporting ACTH-dependent adrenal steroid accumulation. Targeted POR sequencing and family segregation analysis supported compound heterozygosity for a maternally inherited p.Arg457His allele and an inferred paternal allele carrying p.Arg550Trp and p.Gly413Ser in cis. This case illustrates the value of resolving a long-standing diagnostic suspicion through dynamic steroid profiling, targeted POR sequencing, and segregation analysis; the combined glucocorticoid time point was supportive but not a stand-alone diagnostic test.