Patients with
adrenal insufficiency, genital anomalies and bony malformations resembling the
Antley- Bixler syndrome (a
craniosynostosis syndrome), are likely to have P450
oxidoreductase (
POR) deficiency. Since our first report in 2004, about 26 recessive POR mutations have been identified in 50 patients. POR is the obligate electron donor to all microsomal (type II)
P450 enzymes, including the steroidogenic
enzymes CYP17A1, CYP21A2 and CYP19A1.
POR deficiency may cause disordered sexual development manifested as genital undervirilization in 46,XY newborns as well as overvirilization in those who are 46,XX. This may be explained by impaired aromatization of fetal
androgens which may also lead to maternal
virilization and low urinary
estriol levels during pregnancy. A role for the alternate 'backdoor' pathway of
androgen biosynthesis, leading to
dihydrotestosterone production bypassing
androstenedione and
testosterone, has been suggested in
POR deficiency but remains unclear. POR variants may play an important role in
drug metabolism, as most drugs are metabolized by hepatic microsomal
P450 enzymes. However, functional assays studying the effects of specific POR mutations on steroidogenesis showed that several POR variants impaired CYP17A1, CYP21A2 and CYP19A1 activities to different degrees, indicating that each POR variant must be studied separately for each potential target
P450 enzyme. Thus, the impact of POR mutations on
drug metabolism by hepatic P450s requires further investigation.