SOST – Van Buchem Disease (Hyperostosis Corticalis Generalisata)

Van Buchem disease (hyperostosis corticalis generalisata) is a rare autosomal recessive sclerosing bone dysplasia characterized by generalized cortical hyperostosis, predominantly of the skull and mandible, leading to cranial nerve entrapment, facial paresis and optic atrophy. Biallelic loss‐of‐function in the SOST gene, encoding the secreted Wnt antagonist sclerostin, underlies this disorder through failure to restrain osteoblastic bone formation (ClinGen Definitive).

In a German sibship, two siblings presented with classic Van Buchem features and were homozygous for a novel splice‐site mutation in SOST (c.IVS1+1G>C) disrupting exon 1 donor sequence (2 probands) (PMID:15869924). Segregation in the family confirmed autosomal recessive inheritance with both parents heterozygous and unaffected.

In an extended Dutch kindred, all affected individuals carried a homozygous 52 kb deletion ~35 kb downstream of SOST that abolishes a distant bone‐specific enhancer and downregulates SOST transcription, with co‐segregation in multiple affected relatives (PMID:11836356). This structural variant recapitulates the Van Buchem phenotype without coding‐sequence change.

Functional assays of the deleted region in transgenic mice demonstrated loss of human SOST expression in bone and impaired enhancer activity in osteoblast‐like cells, confirming the cis‐regulatory mechanism (15965026). Moreover, in vitro and in vivo studies show that sclerostin inhibits canonical Wnt signaling by binding LRP5/6, and its absence leads to unchecked osteogenesis (17052975).

Together, these genetic and experimental data establish that autosomal recessive loss of sclerostin function—via coding splice‐site mutations or deletion of a long‐range enhancer—causes Van Buchem disease through haploinsufficiency of SOST. This evidence meets ClinGen criteria for a Definitive gene–disease association.

Key Take-home: Genetic testing for SOST loss‐of‐function variants—both coding and regulatory—is essential for definitive diagnosis of Van Buchem disease and informs prognosis and genetic counseling.

References

• Bone • 2005 • A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. PMID:15869924
• Journal of Medical Genetics • 2002 • Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. PMID:11836356
• Genome Research • 2005 • Genomic deletion of a long‐range bone enhancer misregulates sclerostin in Van Buchem disease. PMID:15965026
• The Journal of Biological Chemistry • 2006 • LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. PMID:17052975

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