Radiohumeral Fusions With Other Skeletal And Craniofacial Anomalies

A number sign (#) is used with this entry because of evidence that radiohumeral fusions with other skeletal and craniofacial anomalies can be caused by homozygous mutation in the CYP26B1 gene (605207), encoding a retinoic acid-degrading enzyme, on chromosome 2p13.

Clinical Features

Laue et al. (2011) reported 3 sibs and an unrelated Turkish patient with craniosynostosis and multiple skeletal anomalies. The 3 sibs, born to first-cousin parents, exhibited occipital encephalocele, radiohumeral fusions, oligodactyly, advanced osseous maturation, and calvarial mineralization defects. The proband presented as a fetal death in utero at 35 weeks' gestation; the pregnancies of his sibs were terminated at 15 and 12 weeks' gestation after ultrasonography showed them to be affected. The Turkish patient, born to consanguineous parents, had coronal and lambdoid craniosynostosis, a large sagittal skull defect, limited elbow extension, and arachnodactyly. She died from unknown causes at age 5 months. She was thought to have Antley-Bixler syndrome (see 207410), but no mutations were found in the FGFR2 (176943) or POR (124015) genes or in the FGF9 gene (600921).

Mapping

By autozygosity mapping in 2 sibs with radiohumeral fusions and other skeletal and craniofacial anomalies, Laue et al. (2011) identified only one tract of shared homozygosity greater than 2 Mb on chromosome 2.

Molecular Genetics

By sequencing 6 genes in a region of homozygosity in sibs with radiohumeral fusions and other skeletal and craniofacial anomalies, Laue et al. (2011) identified a homozygous null mutation (R363L; 605207.0001) in the CYP26B1 gene in all 3 affected sibs. In an unrelated Turkish patient with a similar phenotype, they identified a homozygous hypomorphic mutation (S146P; 605207.0002) in the CYP26B1 gene. Laue et al. (2011) analyzed murine embryos exposed to a chemical inhibitor of Cyp26 enzymes and zebrafish lines with mutations in cyp26b1 and suggested that the endochondral bone fusions are due to unrestricted chondrogenesis at the presumptive sites of joint formation within cartilaginous templates, whereas craniosynostosis is induced by a defect in osteoblastic differentiation. Ultrastructural analysis, in situ expression studies, and in vitro quantitative RT-PCR experiments of cellular markers of osseous differentiation indicated that the most likely cause for these phenomena is aberrant osteoblast-osteocyte transitioning.