Monday 25 April 2005
The most common skeletal anomalies are radiohumeral synostosis, craniosynostosis, multiple joint contractures, arachnodactyly, femoral and ulnar bowing, camptodactyly, synostoses of carpal and tarsal bones, clubfoot, and vertebral body anomalies. The facial anomalies include: midface hypoplasia often with choanal stenosis or atresia, proptosis, a "pear-shaped nose", and dysplasic ears.
- large anterior fontanelle
- frontal bossing
- midface hypoplasia
- long philtrum
- dysplastic ears
- stenotic external auditory canals
- depressed nasal bridge
- choanal atresia or stenosis
- craniosynostosis, coronal and lambdoidal
- narrow pelvis
- radiohumeral synostosis
- femoral bowing
- neonatal femoral fractures
- ulnar bowing
- joint contractures
- rocker-bottom feet
germline mutations in the gene encoding cytochrome P450 reductase (POR)(MIM.124015)
germline mutations in fibroblast growth factor receptor-2 (FGFR2) (MIM.176943)
Antley-Bixler syndrome (MIM.207410) is one of a large number of craniosynostosis syndromes.
Antley-Bixler syndrome appears to affect a heterogenous group of patients with multiple genetic and teratogenic etiologies. Mutations of the FGF receptor 2 gene (FGFR2) have been reported in a number of patients with an Antley-Bixler–like phenotype.
Mutations of FGF receptor gene family members (FGFR1, FGFR2, and FGFR3) are common in craniosynostosis syndromes. Reardon et al. identified FGFR2 mutations in seven of sixteen Antley-Bixler patients and described various abnormalities of steroid biogenesis in a different subset of these patients.
Although only one of the patients exhibited both an abnormality in steroid biogenesis and an FGFR2 mutation, this group has proposed that some cases of Antley-Bixler syndrome might be digenic in origin, with abnormal steroid biogenesis or an alteration of the steroid environment potentiating the effects of a hypomorphic FGFR2 mutation.
Reardon et al. also reviewed the role of fluconazole in the genesis of teratogenic cases of Antley-Bixler syndrome. This synthetic triazole antifungal agent appears to be a teratogen, causing a malformation syndrome with a phenotype similar to that of Antley-Bixler syndrome.
Fluconazole inhibits the cytochrome P450 enzyme lanosterol 14-α-demethylase, which demethylates lanosterol.
Based on this association with lanosterol 14-α-demethylase inhibition, Kelley et al. hypothesized that autosomal recessive cases of Antley-Bixler syndrome might be due to a deficiency CYP51, which encodes this enzyme.
They showed that lymphoblasts from one Antley-Bixler patient who did not have a mutation of FGFR2 exhibited markedly increased levels of lanosterol and dihydrolanosterol.
While the subject studied appeared to be free of pathogenic mutations in CYP51, these data support the idea that loss of lanosterol 14-α-demethylase activity during embryonic development underlies at least some cases of autosomal recessive Antley-Bixler syndrome.
Malformation syndromes due to inborn errors of cholesterol synthesis. Forbes D. Porter http://www.jci.org/articles/view/16386