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P450 oxidoreductase (POR) is the essential electron donor to all microsomal cytochrome P450 proteins including the steroid metabolizing CYP17A1, CYP19A1, and CYP21A2, as well as CYP51A1 and CYP26B1 which are involved in bone formation. Human POR mutations therefore present with a very broad phenotype comprising congenital adrenal hyperplasia, disordered sexual and pubertal development, and skeletal malformations resembling the Antley–Bixler craniosynostosis syndrome. Clinical manifestation may be severe with as early as prenatal, or very mild and adult onset. Diagnosis of POR deficiency may be suspected from the clinical examination, but requires biochemical assessment of combined 21- and 17-hydroxylase deficiencies seen by urinary gas chromatographic mass spectrometric steroid profiling. However, confirmation of PORD requires genetic analysis. So far more than 200 mutations and polymorphisms have been reported in the POR gene. The A287P is the most frequently reported mutation in European patients, while R457H predominates in Japanese patients. Overall, genotype–phenotype correlation is rather poor for POR variants. This is mostly due to variable effects on interacting partner proteins. POR also supports drug metabolizing P450s with proven adverse effects of several POR variants in in vitro and in vivo tests.

Human sexual determination is initiated by a cascade of genes that lead to the development of the fetal gonad. Whereas development of the female external genitalia does not require fetal ovarian hormones, male genital development requires the action of testicular testosterone and its more potent derivative dihydrotestosterone (DHT). The "classic" biosynthetic pathway from cholesterol to testosterone in the testis and the subsequent conversion of testosterone to DHT in genital skin is well established. Recently, an alternative pathway leading to DHT has been described in marsupials, but its potential importance to human development is unclear. AKR1C2 is an enzyme that participates in the alternative but not the classic pathway. Using a candidate gene approach, we identified AKR1C2 mutations with sex-limited recessive inheritance in four 46,XY individuals with disordered sexual development (DSD). Analysis of the inheritance of microsatellite markers excluded other candidate loci. Affected individuals had moderate to severe undervirilization at birth; when recreated by site-directed mutagenesis and expressed in bacteria, the mutant AKR1C2 had diminished but not absent catalytic activities. The 46,XY DSD individuals also carry a mutation causing aberrant splicing in AKR1C4, which encodes an enzyme with similar activity. This suggests a mode of inheritance where the severity of the developmental defect depends on the number of mutations in the two genes. An unrelated 46,XY DSD patient carried AKR1C2 mutations on both alleles, confirming the essential role of AKR1C2 and corroborating the hypothesis that both the classic and alternative pathways of testicular androgen biosynthesis are needed for normal human male sexual differentiation.