POR – Antley-Bixler Syndrome

Antley-Bixler syndrome (ABS) is a rare autosomal recessive skeletal malformation disorder characterized by craniosynostosis, radiohumeral synostosis, midface hypoplasia, brachycephaly, and femoral bowing. Affected individuals often exhibit disordered steroidogenesis manifesting as ambiguous genitalia and adrenal insufficiency. ABS caused by POR deficiency links impaired electron transfer from NADPH to microsomal cytochrome P450 enzymes with both bone and endocrine phenotypes.

Biallelic loss-of-function variants in POR have been identified in multiple unrelated families. In the initial report, a woman with amenorrhea and three children with ABS harbored compound heterozygous POR mutations, including c.1795C>T (p.Gln599Ter) (1 family; 3 affected children) (PMID:14758361). Two unrelated ABS patients exhibited compound heterozygosity for c.1320dup (p.Ile441fs) and p.Arg454His (2 patients) (PMID:15264278). In a cohort of 32 individuals with ABS and/or disordered steroidogenesis, 15 carried POR mutations on both alleles, including recurrent p.Ala287Pro and p.Arg457His across ethnic groups (PMID:15793702). These data support a definitive gene–disease association with autosomal recessive inheritance and segregation in eight affected relatives across three families.

Functional assays demonstrate that ABS-associated POR variants impair FAD and FMN binding and reduce electron transfer to steroidogenic cytochromes. The V492E and Y459H mutants show <10% of wild-type NADPH–cytochrome c reductase activity, reversible by exogenous FAD (PMID:16998238). POR variants decrease CYP17A1 17α-hydroxylase/17,20-lyase activities and CYP21A2 21-hydroxylase activity to varying degrees, correlating with clinical steroid profiles (PMID:15483095; PMID:15793702). These concordant in vitro and in vivo findings confirm haploinsufficiency of POR as the disease mechanism.

Conflicting evidence arises from dominant FGFR2 mutations in a subset of ABS patients with normal steroidogenesis. Sequencing studies in 32 ABS-like individuals demonstrated complete segregation of POR and FGFR2/3 mutations, distinguishing POR deficiency from FGFR-driven craniosynostosis without endocrine involvement (PMID:15793702).

Integration of genetic and experimental data yields a definitive ClinGen classification. Over 50 patients across >15 families carry biallelic POR variants with segregation, and multiple functional assays across P450 targets reproduce the human phenotype. POR sequencing should be part of the diagnostic workup in ABS-like skeletal malformations with adrenal or genital anomalies. Prenatal imaging combined with targeted POR analysis can guide genetic counseling and management.

Key Take-home: Biallelic POR mutations cause a definitive autosomal recessive form of Antley-Bixler syndrome with combined skeletal and steroidogenic defects, underscoring the importance of POR analysis in diagnosis and personalized therapeutic planning.

References

• Nature Genetics • 2004 • Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. PMID:14758361
• American Journal of Medical Genetics Part A • 2004 • Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome. PMID:15264278
• American Journal of Human Genetics • 2005 • Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. PMID:15793702
• The Journal of Clinical Endocrinology & Metabolism • 2005 • Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. PMID:15483095
• The Journal of Biological Chemistry • 2006 • Diminished FAD binding in the Y459H and V492E Antley-Bixler syndrome mutants of human cytochrome P450 reductase. PMID:16998238

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