Alternative titles; symbols
SNOMEDCT: 59763006; ORPHA: 3416; DO: 0080036;
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38) : 17:42,800,001-46,800,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.31 | van Buchem disease | 239100 | Autosomal recessive | 4 |
A number sign (#) is used with this entry because van Buchem disease (VBCH), also known as hyperostosis corticalis generalisata, is caused by a 52-kb deletion approximately 35 kb downstream of the SOST gene (605740) that removes a SOST-specific regulatory element (see MOLECULAR GENETICS).
Van Buchem disease (VBCH) is an autosomal recessive bone dysplasia characterized by a symmetrically increased thickness of bones, most frequently found as an enlarged jawbone, but also an enlargement of the skull, ribs, diaphysis of long bones, as well as tubular bones of hands and feet, resulting in increased cortical bone density. The clinical consequences of increased thickness of the skull include facial nerve palsy causing hearing loss, visual problems, neurologic pain, and very rarely, blindness resulting from optic atrophy. Bone anomalies appear in the first decade of life and progress with age (summary by Wergedal et al., 2003).
Van Buchem et al. (1962) found osteosclerosis of the skull, mandible, clavicles, ribs, and diaphysis of the long bones beginning during puberty and sometimes leading to optic atrophy and perceptive deafness from nerve pressure. The same disorder was probably reported earlier by Garland (1946) as 'generalized leontiasis ossea' and by Halliday (1949) as bone dystrophy. Fryns and Van den Berghe (1988) described a 7.5-year-old boy with van Buchem disease which was discovered when headaches prompted x-ray examination. At the age of 2 months, left-sided peripheral facial nerve palsy had developed at a time when skull x-rays were normal, suggesting that encroachment of cranial nerves may occur as early as the first months of life, even before sclerosis of the skull is radiologically visible.
By hand x-ray analysis, Wergedal et al. (2003) studied the morphology of the metacarpals of 6 adult subjects and 2 juveniles with van Buchem disease along with 9 normal adults and 9 adult carriers of the disorder. Van Buchem patients had increased metacarpal outer diameter, inner diameter, cortical thickness, and bone mineral density. Calculated bone volume and derived polar moment of inertia were markedly elevated, consistent with increased bone strength. Serum type I procollagen peptide (see 120150), osteocalcin (112260), and urinary type I collagen cross-linked N-telopeptide were significantly elevated in van Buchem patients.
The transmission pattern of VBCH in the family reported by Van Hul et al. (1998) and Balemans et al. (2002) was consistent with autosomal recessive inheritance.
Balemans et al. (1997) studied 11 van Buchem disease patients from a highly inbred Dutch family living in a small ethnic isolate in the Netherlands. All patients had a common ancestor about 9 generations ago. In a genomewide search for linkage using more than 300 microsatellite markers with an average spacing of 10 cM, the investigators found a maximum lod score of 9.33 at theta = 0.01 with marker D17S1299. They narrowed the assignment to a region of less than 1 cM between markers D17S1787 and D17S934. No recombination was found with an intragenic microsatellite marker for the thyroid hormone receptor alpha-1 gene (190120), which maps to 17q11.2. See Van Hul et al. (1998) for the full report.
Sclerosteosis (269500) is an uncommon, autosomal recessive, progressive sclerosing bone dysplasia characterized by generalized osteosclerosis and hyperostosis of the skeleton, affecting mainly the skull and mandible. In most patients, this causes facial paralysis and hearing loss. Other features are gigantism and hand abnormalities. By 2-point linkage analysis in 2 consanguineous families with sclerosteosis, Balemans et al. (1999) assigned the locus for this disease to 17q12-q21, the same general region as the locus for van Buchem disease. Because of the clinical similarities between sclerosteosis and van Buchem disease, Beighton et al. (1984) suggested that these conditions are caused by mutations in the same gene. The study of Balemans et al. (1999) provided genetic support for this hypothesis. The major clinical differences between the 2 diseases are gigantism and hand abnormalities, which are seen in most patients with sclerosteosis but never in patients with van Buchem disease.
The possibility that sclerosteosis and van Buchem disease are caused by mutation in the same gene appeared to have been excluded by the study of Brunkow et al. (2001), in which mutations in the coding region of the SOST gene were found in cases of sclerosteosis but not in cases of van Buchem disease.
Staehling-Hampton et al. (2002) refined the critical area for van Buchem disease to a less than 1-Mb region between D17S2250 and D17S2253. Within this region they identified a 52-kb deletion encompassing D17S1789 that was concordant with the disorder. Although the deletion did not appear to disrupt the coding region of any known gene, Staehling-Hampton et al. (2002) suggested that it may interfere with the transcriptional regulation of 2 nearby genes: MEOX1 (600147), which is known to be important for development of the axial skeleton, and SOST.
In affected members from the large consanguineous Dutch family with van Buchem disease studied by Van Hul et al. (1998), Balemans et al. (2002) identified a homozygous 52-kb deletion located approximately 35 kb downstream of the SOST gene. Three additional Dutch patients with van Buchem disease also had the deletion. The parents of affected individuals were heterozygous for the deletion. Analysis of the sequences flanking the deletion breakpoints showed the presence of Alu repeats on either side, suggesting an Alu-mediated, unequal homologous recombination event as the mechanism causing the deletion. As no coding sequences could be identified within the deleted region, Balemans et al. (2002) suggested that the deletion may alter transcription of the SOST gene in patients with van Buchem disease.
Using transgenic mice, Loots et al. (2005) characterized expression of human SOST from the wildtype allele and an allele carrying the van Buchem disease-associated 52-kb noncoding deletion downstream of SOST. Only the wildtype allele expressed high levels of human SOST in adult bone and had an impact on bone mineral density. Loots et al. (2005) identified 7 evolutionarily conserved regions (ECRs) within the van Buchem disease-associated deletion. They examined skeletal structures of transgenic mouse embryos expressing each of these human ECRs and found that the 250-bp ECR5 enhanced SOST expression in cartilage of ribs, vertebrae, and skull plates. ECR5 was also capable of activating the human SOST promoter in osteoblast-like cell lines. Loots et al. (2005) concluded that van Buchem disease is caused by deletion of a SOST-specific regulatory element and is allelic to sclerosteosis.
Balemans, W., Patel, N., Ebeling, M., Van Hul, E., Wuyts, W., Lacza, C., Dioszegi, M., Dikkers, F. G., Hildering, P., Willems, P. J., Verheij, J. B. G. M., Lindpaintner, K., Vickery, B., Foernzler, D., Van Hul, W. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J. Med. Genet. 39: 91-97, 2002. [PubMed: 11836356] [Full Text: https://doi.org/10.1136/jmg.39.2.91]
Balemans, W., Van Den Ende, J., Paes-Alves, A. F., Dikkers, F. G., Willems, P. J., Vanhoenacker, F., de Almeida-Melo, N., Alves, C. F., Stratakis, C. A., Hill, S. C., Van Hul, W. Localization of the gene for sclerosteosis to the van Buchem disease-gene region on chromosome 17q12-q21. Am. J. Hum. Genet. 64: 1661-1669, 1999. [PubMed: 10330353] [Full Text: https://doi.org/10.1086/302416]
Balemans, W., Van Hul, W., Van Hul, E., Dikkers, F., Stokroos, R., Van Camp, G., Willems, P. J. Localisation of the gene for Van Buchem disease to a candidate region of less than 1 cM on chromosome 17. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A12 only, 1997.
Beighton, P., Barnard, A., Hamersma, H., van der Wouden, A. The syndromic status of sclerosteosis and van Buchem disease. Clin. Genet. 25: 175-181, 1984. [PubMed: 6323069] [Full Text: https://doi.org/10.1111/j.1399-0004.1984.tb00481.x]
Brunkow, M. E., Gardner, J. C., Van Ness, J., Paeper, B. W., Kovacevich, B. R., Proll, S., Skonier, J. E., Zhao, L., Sabo, P. J., Fu, Y.-H., Alisch, R. S., Gillett, L., Colbert, T., Tacconi, P., Galas, D., Hamersma, H., Beighton, P., Mulligan, J. T. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am. J. Hum. Genet. 68: 577-589, 2001. [PubMed: 11179006] [Full Text: https://doi.org/10.1086/318811]
Eastman, J. R., Bixler, D. Generalized cortical hyperostosis (van Buchem disease): nosologic considerations. Radiology 125: 297-304, 1977. [PubMed: 198845] [Full Text: https://doi.org/10.1148/125.2.297]
Fryns, J. P., Van den Berghe, H. Facial paralysis at the age of 2 months as a first clinical sign of van Buchem disease (endosteal hyperostosis). Europ. J. Pediat. 147: 99-100, 1988. [PubMed: 3276528] [Full Text: https://doi.org/10.1007/BF00442624]
Garland, L. H. Generalized leontiasis ossea. Am. J. Roentgen. Radium Ther. 55: 37-43, 1946. [PubMed: 21011630]
Halliday, J. A rare case of bone dystrophy. Brit. J. Surg. 37: 52-63, 1949. [PubMed: 18135657] [Full Text: https://doi.org/10.1002/bjs.18003714509]
Loots, G. G., Kneissel, M., Keller, H., Baptist, M., Chang, J., Collette, N. M., Ovcharenko, D., Plajzer-Frick, I., Rubin, E. M. Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res. 15: 928-935, 2005. [PubMed: 15965026] [Full Text: https://doi.org/10.1101/gr.3437105]
Staehling-Hampton, K., Proll, S., Paeper, B. W., Zhao, L., Charmley, P., Brown, A., Gardner, J. C., Galas, D., Schatzman, R. C., Beighton, P., Papapoulos, S., Hamersma, H., Brunkow, M. E. A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am. J. Med. Genet. 110: 144-152, 2002. [PubMed: 12116252] [Full Text: https://doi.org/10.1002/ajmg.10401]
van Buchem, F. S. P., Hadders, H. N., Hansen, J. F., Woldring, M. G. Hyperostosis corticalis generalisata: report of seven cases. Am. J. Med. 33: 387-397, 1962. [PubMed: 13924477] [Full Text: https://doi.org/10.1016/0002-9343(62)90235-8]
Van Hul, W., Balemans, W., Van Hul, E., Dikkers, F. G., Obee, H., Stokroos, R. J., Hildering, P., Vanhoenacker, F., Van Camp, G., Willems, P. J. Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12-q21. Am. J. Hum. Genet. 62: 391-399, 1998. [PubMed: 9463328] [Full Text: https://doi.org/10.1086/301721]
Wergedal, J. E., Veskovic, K., Hellan, M., Nyght, C., Balemans, W., Libanati, C., Vanhoenacker, F. M., Tan, J., Baylink, D. J., Van Hul, W. Patients with Van Buchem disease, an osteosclerotic genetic disease, have elevated bone formation markers, higher bone density, and greater derived polar moment of inertia than normal. J. Clin. Endocr. Metab. 88: 5778-5783, 2003. [PubMed: 14671168] [Full Text: https://doi.org/10.1210/jc.2003-030201]