Localization of the gene for X-linked calvarial hyperostosis to chromosome Xq27.3-Xqter.

X-linked calvarial hyperostosis is a rare disorder characterized by isolated calvarial thickening. Symptoms are prominent frontoparietal bones, a flat nasal root and a short upturned nose, a high forehead with ridging of the metopic and sagittal sutures, and lateral frontal prominences. The mandible is normal, as are the clavicles, pelvis and long bones. The thickened bone in the skull appears to be softer than normal bone. Despite calvarial hyperostosis, increased intracranial pressure and cranial nerve entrapment do not occur. The major disability seems to be cosmetic. The disease segregates with an X-linked recessive mode of inheritance. Female carriers do not show any clinical symptoms. To date, only one family has been described with X-linked calvarial hyperostosis including three affected individuals. In order to localize the disease causing gene, 31 polymorphic microsatellite markers that spread across the X-chromosome were analyzed. Genotypes were combined in haplotypes to delineate the region. A chromosomal region spanning from Xq27.3 to Xqter cosegregates with the disorder. This region encompasses 23.53cM or 8.2Mb according to the deCODE map and contains 165 genes. CNV-analysis did not show small duplications or deletions in this region. Exome sequencing was performed on a male patient in this family. However, this did not reveal any putative mutation. These results indicate that a non-coding regulatory sequence might be involved in the pathogenesis of this disorder.