P450 oxidoreductase deficiency and Antley–Bixler syndrome

Abstract

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 undervirilized 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.

Isolated 17,20-Lyase Deficiency due to the Cytochrome b5 Mutation W27X

“…These patients have a broad range of disorders: mutations in the gene encoding POR have been demonstrated in patients with a combined 17-hydroxylase/21-hydroxylase deficiency, in most cases associated with the Antley-Bixler syndrome and polycystic ovary syndrome (17)(18)(19). These patients invariably had a defect in 17,20-lyase activity, whereas the defects in other steroidogenic reactions were variable.…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…Cognitive function is usually normal. At the mildest end of the phenotypic spectrum are individuals with only subtle defects of steroidogenesis, such as amenorrhea, polycystic ovarian syndrome, and infertility in both sexes ( 308,319,320 ).…”

“…ABS is unique among the variant forms of congenital adrenal hyperplasia in that the DSD affects both sexes, with underdeveloped genitalia and cryptorchidism in affected 46,XY males and external virilization, with clitoromegaly and fused labia, in 46,XX females ( 316,317,319,320 ). In contrast to classic congenital adrenal hyperplasia, there is no postnatal progression of the virilization in untreated females.…”

“…Although the majority of mutant alleles are missense mutations, compound heterozygotes with one missense and one frameshift or splice site mutation have been described. To date, no individuals have been described with two null alleles, and it has been suggested that this combination would be lethal, similar to the Por knockout mouse (see below) ( 312,319 ).…”

Kraniofaziale und humeroradiale Synostosen

“…Auffälliger fazialer Aspekt mit kurzer, breiter Nasenwurzel und Mittelgesichtshypoplasie. ( [3]. Eine gute Übersichtsarbeit hinsichtlich der Beschreibung der kraniofazialen Fehlanlagen beim ABS sowie weiterer Malformationen mit Diskussion von Therapie und Prognose am Beispiel verschiedener Langzeitverläufe legten Bradley et al [4] vor.…”