P450 oxidoreductase deficiency and Antley-Bixler syndrome

Antley-Bixler syndrome is a congenital malformation syndrome that primarily manifests with craniofacial abnormalities but may include skeletal malformations. Some cases have been shown to be caused by fibroblast growth factor receptor 2 mutations and, recently, it was revealed that others are caused by mutations in the electron donor enzyme P450 oxidoreductase (POR). P450 oxidoreductase deficiency, however, is not only associated with the malformations but frequently presents with disordered sex development in affected patients of both sexes. Furthermore, biochemical work-up invariably reveals impairment of 17-hydroxylase and 21-hydroxylase activities, two steroidogenic enzymes dependent on electron transfer from POR. While we begin to gain insight into the pathogenesis of disease, detailed genotype-phenotype studies are still lacking and POR deficiency presents several challenges for research. Firstly, the exact pathogenesis of the skeletal malformations as a consequence of POR mutations is unclear, though impaired sterol biosynthesis has been implicated. Secondly, it needs to be explained, why the external genitalia in affected boys may appear under-virilized while affected girls can be severely virilized. Further evidence is required for the proposed alternative pathway in human androgen synthesis that might explain the apparently contradictory finding of low circulating androgens and severely virilised external genitalia in affected girls. Recent studies have provided evidence for a differential interaction of specific POR mutations with different electron-accepting P450 enzymes and this may provide the key for further understanding of the complex pathogenesis of this complex disease.