VAN-BUCHEM-DISEASE (HYPEROSTOSIS CORTICALIS GENERALISATA) MAPS TO CHROMOSOME 17Q12-Q21

Van Buchem disease (hyperostosis corticalis generalisata; OMIM 239100 [http://www3.ncbi.nlm.nih.gov: 80/htbin-post/Omim/dispmim?239100]) is an autosomal recessive disorder characterized by hyperostosis of the s kull, mandible, clavicles, ribs, and diaphyseal cortices of the long b ones. The most striking clinical features are the enlargement of the j aw and the thickness of the skull, which may lead to facial nerve pals y, hearing loss, and optic atrophy. Increased formation, by osteoblast s, of qualitatively normal bone has been proposed as the underlying pa thological mechanism, but the molecular defect is unknown. We studied 11 van Buchem patients and their highly inbred family, who live in The Netherlands in a small ethnic isolate, that had a common ancestor sim ilar to 9 generations ago. A genomewide search with highly polymorphic microsatellite markers showed linkage to marker D17S1299 on chromosom e 17q12-21 (maximum LOD score of 8.82 at a recombination fraction [the ta] of .01). Analysis of additional markers from that region delineate d a candidate region of <1 cM between markers D17S1787 and D17S934. In terestingly, the only marker not showing recombination with the diseas e locus was an intragenic marker of the thyroid-hormone receptor alpha 1 (THRA1) gene, which generated a LOD score of 12.84 at theta = .00. Since thyroid hormones are known to stimulate bone resorption, the THR A1 gene might be involved in the etiology and pathogenesis of van Buch em disease. Unraveling the underlying mechanism for this disorder coul d contribute to the understanding of the regulatory processes conditio ning bone density and the underlying pathological processes.