Van Buchems disease and sclerosteosis

Van Buchem's disease and sclerosteosis have very similar phenotypes with large increases in the amount of bone tissue (Janssens and Van Hul, 2002). Van Buchem's disease usually begins during puberty, with osteosclerosis of the skull, mandible, clavicles, ribs, and long bone diaphyses. In scle-rosteosis mainly the skull and mandible are affected, although osteosclerosis and hyperostosis can be more generalized. In both disorders optic atrophy and deafness can occur secondary to bone encroachment on nerves. Facial paralysis is common in sclerosteosis, and may be present at birth or develop shortly thereafter. Sclerosteosis tends to be more severe, and excess height and weight (gigantism) and syndactyly are found in most patients. In a cohort of South Africans followed over a 38-year period, almost half died during the course of the survey (mean age of 33 years), usually from increased intracranial pressure (Hamersma et al., 2003). The gene(s) responsible for van Buchem's disease and sclerosteosis was linked to chromosome 17q12-q21 (Balemans et al., 1999; Van Hul et al., 1998) suggesting that the diseases were allelic. Nonsense and splice variant mutations were found in a novel gene that was named Sclerostin (SOST) (Balemans et al., 2001; Brunkow et al., 2001). These mutations were found in several sclerosteosis patients, but not in a family with van Buchem's disease (Balemans et al., 2001), where instead a 52 kb deletion 35 kb downstream of the SOST gene has been reported (Balemans et al., 2002; Staehling-Hampton et al., 2002). The deletion was postulated to suppress the expression of sclerostin (Balemans et al., 2002; Staehling-Hampton et al., 2002), although effects on the adjacent downstream gene MEOX1, which is also involved in axial skeletal development, have not been ruled out. SOST belongs to a family of genes whose products function as decoy receptors that antagonize the actions of BMPs and thus serve as negative regulators of bone formation

(Kusu et al., 2003; van Bezooijen et al., 2005; Winkler et al., 2003). Thus, mutations that reduce sclerostin expression or its binding to BMPs, would be expected to increase bone formation and account for the osteosclerotic phenotype. Consistent with this prediction, overexpression of wild type sclerostin in mice results in an opposite phenotype, with decreased osteoblast activity, decreased bone formation, and low bone mass (Winkler et al., 2003).

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