Genetic and Clinical Features of P450 Oxidoreductase Deficiency

Abstract

P450 oxidoreductase (POR) deficiency is an autosomal recessive disorder of steroidogenesis with multiple clinical manifestations. POR is the electron donor for all microsomal P450 enzymes, including the three steroidogenic enzymes P450c17 (17α-hydroxylase/17,20-lyase), P450c21 (21-hydroxylase), and P450aro (aromatase). Since the first description of POR mutations in 2004, about 50 patients have been reported. Serum steroid profiles indicate partial deficiencies in 21-hydroxylase, 17α-hydroxylase and 17,20-lyase. The 17-OH progesterone levels are elevated, as in 21-hydroxylase deficiency, while androgen levels are low; cortisol may be normal but is poorly responsive to adrenocorticotropic hormone. Most patients also have associated skeletal malfor- mations (craniosynostosis, radio-ulnar synostosis, midface hypoplasia, bowed femora) termed Antley-Bixler syndrome. Antley-Bixler syndrome with normal steroidogenesis is caused by autosomal dominant gain-of-function mutations in fibroblast growth factor receptor 2. Males with POR deficiency are often undervirilized, while females can be virilized. The prognosis for patients with POR deficiency appears to depend on the severity of the bony malformations and their timely treatment. The potential impact of POR mutations on drug metabolism by other hepatic P450 enzymes requires further investigation. Given the varied physical and biochemical phenotype of POR deficiency and the risk of adrenal insufficiency, clinicians should be alert to this potential diagnosis.

46,XX DSD and Antley-Bixler syndrome due to novel mutations in the cytochrome P450 oxidoreductase gene

“…The reported patient did not present neonatal signs of skeletal malformations; however, during childhood, she developed a few osteoarticular abnormalities, such as carpal and tarsal synostosis, reduced skull diameter and "hammered-silver" appearance (suggestive of craniosynostosis), and limited forearm pronosupination, indicating that periodic clinical and image evaluations were necessary (6,10,11,17,18). Considering that p.Arg223* is a null allele in the compound heterozygosis with p.Met408Lys, it can be inferred that the residual activity of p.Met408Lys missense carrying allele is defining the patient's phenotype.…”

“…This autosomal recessive disorder was described for the first time in 2004, when mutations in POR encoding gene were identified (4,5). PORD has a wide spectrum of clinical signs and symptoms, including partial and combined enzymatic adrenal dysfunction associated with disorders of sex development (DSD) in 46,XX and 46,XY individuals, and skeletal abnormalities of Antley-Bixler syndrome (OMIN #201750) (6). Maternal hyperandrogenism and virilization during pregnancy can also be observed.…”

“…Maternal hyperandrogenism and virilization during pregnancy can also be observed. Skeletal malformations observed in many, but not all, patients with PORD are considered to be due to impairment of enzyme activities involved in sterol synthesis, such as 14α-lanosterol demethylase (CYP51A1) and squalene epoxidase, disruption of retinoic acid metabolism catalyzed by CYP26 isozymes (6,7), and hepatic drug metabolism (8).…”

Long-term follow-up of a female with congenital adrenal hyperplasia due to P450-oxidoreductase deficiency

“…Patients with PORD may also exhibit bone defects that are characteristics of Antley-Bixler syndrome because of the impairment of enzymes involved in the sterol synthesis pathway, such as lanosterol 14a-demethylase (CYP51A1), and enzymes involved in retinoic acid metabolism (CYP26) (11). Bone defects such as craniosynostosis, midface hypoplasia, radiohumeral and/ or radio-ulnar synostosis, camptodactyly, and femoral steels were described (12).…”

Preimplantation genetic diagnosis of P450 oxidoreductase deficiency and Huntington Disease using three different molecular approaches simultaneously

“…Approximately 40 cases have been reported since the first mutations were described in 2004 [9]. The characteristic traits are steroid abnormalities, craniofacial, skeletal and urogenital anomalies and, commonly, a reduction of cognitive functions and delay in development (reviewed in [10]). This disorder often results in infant death.…”