The Antley-Bixler syndrome (ABS) is an exceptionally rare craniosynostosis syndrome characterized by radiohumeral synostosis present from the perinatal period. There is a wide spectrum of anomalies seen in ABS; other features include midface hypoplasia, choanal stenosis or atresia, ... The Antley-Bixler syndrome (ABS) is an exceptionally rare craniosynostosis syndrome characterized by radiohumeral synostosis present from the perinatal period. There is a wide spectrum of anomalies seen in ABS; other features include midface hypoplasia, choanal stenosis or atresia, multiple joint contractures, visceral anomalies (particularly of the genitourinary system), and impaired steroidogenesis (present only in patients with POR mutations). Mortality has been reported to be as high as 80% in the neonatal period, primarily due to airway compromise, and prognosis improves with increasing age (summary by McGlaughlin et al., 2010).
Miller (2008) considered the phenotypic overlap between ABS caused by POR mutations and ABS caused by FGFR2 mutations (ABS2; 207410) impressive. Aside from genital anomalies and disordered pattern of steroidogenesis present in patients with POR mutations, no dysmorphic ... Miller (2008) considered the phenotypic overlap between ABS caused by POR mutations and ABS caused by FGFR2 mutations (ABS2; 207410) impressive. Aside from genital anomalies and disordered pattern of steroidogenesis present in patients with POR mutations, no dysmorphic feature appears to distinguish the 2 groups. Reardon et al. (2000) was impressed with the occurrence of genital abnormalities in patients, especially females, who had been diagnosed as having Antley-Bixler syndrome. They reported abnormalities of steroid biogenesis in 7 of 16 patients with an Antley-Bixler phenotype. Reardon et al. (2000) suggested that ABS with disordered steroidogenesis might be a distinct genetic entity.
In individuals with disordered steroidogenesis with bony features of Antley-Bixler syndrome, including the patient reported by Kelley et al. (2002), Fluck et al. (2004) demonstrated mutations in the POR gene (e.g., 124015.0001). Fluck et al. (2004) proposed that ... In individuals with disordered steroidogenesis with bony features of Antley-Bixler syndrome, including the patient reported by Kelley et al. (2002), Fluck et al. (2004) demonstrated mutations in the POR gene (e.g., 124015.0001). Fluck et al. (2004) proposed that severe mutations in POR without associated disorders of FGF receptors are sufficient to cause the ABS-like phenotype. The grossly dysmorphic embryonic lethal phenotype of POR knockout mice, with neural tube, cardiac, eye, and limb anomalies, suggests that severe disorders of POR may be sufficient to account for the skeletal findings in some individuals with an ABS phenotype (Shen et al., 2002; Otto et al., 2003). By contrast, milder mutations in POR may manifest as mild disorders of steroid synthesis. Huang et al. (2005) sequenced the cytochrome P450 reductase gene and exons 8 and 10 of the FGFR2 gene in 29 individuals diagnosed with Antley-Bixler syndrome with or without hormonal findings suggesting POR deficiency and found that POR and FGFR2 mutations segregated completely. In 15 patients, POR mutations were found on both alleles; in 4, mutations were found on only 1 allele; 6 carried FGFR2 mutations; and 4 patients carried no mutations. One patient, a male infant with an Antley-Bixler syndrome skeletal phenotype and abnormal steroids and genitalia, who had previously been found to carry a missense mutation of unclear significance in the FGFR1 gene (136350.0011) by Hurley et al. (2004), was found to be a compound heterozygote for mutations in the POR gene as well (124015.0015 and 124015.0016). The 34 affected POR alleles included 10 with ala287-to-pro (124015.0002), all from whites, and 7 with arg457-to-his (124015.0005), including 4 Japanese, 1 African, and 2 Caucasians; 17 of the 34 carried 16 'private' mutations, including 9 missense and 7 frameshift mutations. Huang et al. (2005) recreated these 11 missense mutations, plus 10 others found in databases or reported elsewhere, by site-directed mutagenesis and assessed them by 4 assays: assays that were based on cytochrome c, which is not a physiologic substrate for POR, correlated poorly with clinical phenotype, but assays that were based on POR's support of catalysis by P450c17 (the enzyme most closely associated with the hormonal phenotype) provided an excellent genotype/phenotype correlation. Huang et al. (2005) concluded that individuals with an ABS skeletal phenotype and normal steroidogenesis have FGFR mutations, whereas those with ambiguous genitalia and disordered steroidogenesis should be recognized as having a distinct disease: POR deficiency.