Hyperostosis corticalis generalisata/Van Buchem disease (VBD)

(OMIM phenotype number #239100)

Endosteal hyperostis include different uncommon disorders are included in this category, such as: the autosomal recessive conditions  (Hyperostosis corticalis generalisata/Van Buchem disease), as well as the autosomal dominant conditions (Van Buchem disease type 2, Osteosclerosis/endosteal hyperostosis), and the autosomal dominant - recessive conditions (Sclerosteosis 1-2).

These disorders are a result of mutations in genes involved in disruption of the Wnt pathway, ultimately leading to an accumulation of β-catenin and activation of osteoblastic activity. Wnt signalling induces inhibition of the complex formed by four proteins (Axin, APC= adenomatous polyposis coli, GSK-3= glycogen synthase kinese 3, and b-catenin) in osteoblasts freeing B-catenin. B-catenin accumulates in the cytoplasm, then in the nucleus of the osteoblast, and ultimately acts as a cofactor to stimulate proliferation and differentiation of osteoblasts. LRP5 (lipoprotein receptor–related protein 5) is a co-receptor needed for activation of Wnt required for osteoblast activity. LRP5 is intermittently inhibited by its binding to another protein, Dickkopf-1 (DKK1). The binding of SOST (sclerostin) to LRP5 also inhibits Wnt signalling in osteoblasts. Defects of SOST or DKK1 binding lead to unchecked osteoblastic activity due to an inability to downregulate LRP5. All the mutations of LRP5 for these disorders are located in the region coding for the amino-terminal part of the LRP5 protein where LRP5 binds DKK1. The reduced affinity to this inhibitor of LRP5 results in a consititutive activation of the Wnt pathway and therefore increased bone formation. While inactivating mutations in the SOST gene cause sclerosteosis in van Buchem disease; a 52-kb deletion on chromsome 17q12 was identified that compromises a downstream enhancer of SOST.

Hyperostosis corticalis generalisata/Van Buchem disease is a rare skeletal dysplasia, that van Buchem et al. first described in 1955. This disease has an autosomal-recessive inheritance pattern and involves a genetic mutation in the SOST gene causing a defect in a downstream enhancer of sclerostin. Its distinguishing characteristics include progressive asymmetrical enlargement of the jaw that occurs during puberty, and overgrowth in the skull. Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients.


SOST gene, 17q21.31 (OMIM gene/locus number #605740)


Progressive skeletal overgrowth (especially skull) and cortical thickening and generalized osteosclerosis, cranial hyperostosis, enlargement of the jaw with wide angle, dental malocclusion (uncommon), flat nasal bridge, frontal prominence, pain of long bone with applied pressure, no fragility fractures (long bones may become painful with applied pressure, but there are no fractures), hypertelorism, proptosis, multiple cranial nerve involvement with recurrent facial nerve palsy, headaches, deafness, optic atrophy from narrowing of cranial foramina.


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Fig. All patients showed the characteristic features of protruding chin, high forehead, and facial nerve paralysis (Van Hul W, Balemans W, Van Hul E, et al. Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21. Am J Hum Genet. 1998 Feb;62(2):391-9). 

Reproduced from Am J Hum Genet, Vol 62, Van Hul W, Balemans W, Van Hul E, et al. Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21, Pages 391-9, Copyright 1998, with permission from Elsevier.

Main biochemical alterations

High bone ALP, high P1NP, decreased sclerostin in VBD, undetectable sclerostin in SOST1 and CDD.


  1. Loots GG, Kneissel M, Keller H, et al. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res. 2005 Jul;15(7):928-35.
  2. Van Hul W, Balemans W, Van Hul E, et al. Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21. Am J Hum Genet. 1998 Feb;62(2):391-9.
  3. Balemans W, Patel N, Ebeling M, et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet. 2002 Feb;39(2):91-7.
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  7. http://www.omim.org