Abstract
Antley-Bixler syndrome (ABS) arising from P450 oxidoreductase deficiency (PORD) is a rare, distinct craniosynostosis syndrome, accompanied by ambiguous genitalia and impaired steroidogenesis. It is reported that this disorder is caused by mutations in the P450 oxidoreductase (POR; OMIM #124015) gene via autosomal recessive inheritance. In this study, we performed a molecular analysis to verify the genetic etiology of ABS in an infant. Initially, medical exome sequencing was applied using the parents' peripheral blood genome DNA. Next, bidirectional Sanger sequencing and quantitative real-time PCR (qRT-PCR) were conducted to confirm the sequencing results. The infant was diagnosed as ABS at birth, with typical midface hypoplasia, craniosynostosis, femoral bowing, radio-ulnar synostosis, and genital anomalies. She died two months later due to severe pneumonia and congenital heart disease. The medical exome sequencing and Sanger sequencing revealed the missense mutation c.1370G>A (p.R457H) in exon 12 of POR was inherited from the father. In addition, the qRT-PCR analysis verified an exon 5 microdeletion in the POR gene of the infant and her mother. While p.R457H is a well-known pathogenic mutation, the POR exon 5 deletion is absent from the public databases. However, it is classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines based on the evidence of PVS1, PM2, and PM3. In conclusion, this infant with ABS carried compound heterozygotic mutations in the POR gene; one was a paternal missense mutation, and the other was a maternal novel microdeletion. The mutations were inherited from the paternal grandfather and maternal grandfather, respectively. This detailed case report enriches our knowledge of the POR mutation spectrum and ABS pathogenesis.