ORPHA: 321; DO: 206;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p11.2 | Exostoses, multiple, type 2 | 133701 | Autosomal dominant | 3 | EXT2 | 608210 |
A number sign (#) is used with this entry because multiple exostoses type II (EXT2) is caused by heterozygous mutation in the gene encoding exostosin-2 (EXT2; 608210) on chromosome 11p11.
Hereditary multiple exostoses is an autosomal dominant disorder characterized by multiple exostoses most commonly arising from the juxtaepiphyseal region of the long bones.
For a general phenotypic description and a discussion of genetic heterogeneity of multiple exostoses, see EXT1 (133700).
Fusco et al. (2019) described 27 patients with EXT2. The most commonly affected bones with osteochondroma/exostoses were the long bones of the upper and lower limbs. The second most commonly affected bones were in the chest. The mean number of osteochondromas per patient was approximately 7. Males had more lesions in the hands and feet compared to females.
The transmission pattern of EXT2 in the family reported by Stickens et al. (1996) was consistent with autosomal dominant inheritance.
Cook et al. (1993) concluded that about 70% of multiple exostoses families show linkage to markers in the 8q24.11-q24.13 region (EXT1). Multiple exostoses in the other families appears to be caused by a mutation at another locus, unlinked to markers in that region. Investigating 2 large exostoses pedigrees in which linkage to markers from 8q24 was excluded, Wu et al. (1994) found evidence of linkage to microsatellite markers from the proximal short and long arms of chromosome 11. The highest lod score by 2-point analysis was found with D11S554; maximum lod = 7.148 at theta = 0.03.
Hecht et al. (1995) reported a large multigenerational family with multiple exostosis who demonstrated linkage of the disease to chromosome 11 markers. One family member had a chondrosarcoma. Constitutional and tumor DNAs from the family member with chondrosarcoma were compared using short tandem repeat (STR) markers from chromosomes 8, 11, and 19. Loss of heterozygosity (LOH) in the tumor was observed for chromosome 8 and 11 markers, but chromosome 19 markers were intact. Hecht et al. (1995) observed an apparent deletion of D11S903 in constitutional DNA from all affected individuals and in the tumor sample. These results indicated that the EXT2 gene maps to the region containing D11S903, which is flanked by D11S1355 and D11S1361.
Studying 7 extended multiple exostoses families, all linked to the EXT2 locus, Wuyts et al. (1995) refined the localization of the EXT2 gene to a 3-cM region flanked by D11S1355 and D11S1361/D11S554. The findings indicated that the EXT2 gene is located on 11p12-p11. The refined localization excluded a number of putative candidate genes located in the pericentromeric region of chromosome 11. Blanton et al. (1996) studied 12 large multigenerational EXT families and found that the disorder mapped to 8q24 in 6 and to 11p in 6. The authors noted that the 2 sets of families were clinically indistinguishable. None of the families mapped to the chromosome 19 locus.
McGaughran et al. (1995) described a patient with the combination of multiple exostoses and the WAGR syndrome (Wilms tumor, aniridia, genital anomalies, and mental retardation; 194070), a well-documented contiguous gene syndrome resulting from deletion of 11p13. Their patient showed a del(11)(p14.2p11.2). As pointed out by Potocki et al. (1995), the description of the contiguous gene syndrome resulting from interstitial deletion of 11p, del(11)(p12p11.2), including multiple exostoses as a feature, provided confirmation of the mapping of EXT2. Other features of this contiguous gene syndrome are mental retardation and parietal foramina, known as Catlin marks (168500). Potocki and Shaffer (1996) reported the clinical and molecular findings in another patient with an 11(p12p11.2) deletion. Cytogenetic and molecular analysis demonstrated a de novo, paternally-derived deletion for markers known to be tightly linked to EXT2. The patient had an unusual facies (bilateral epicanthal folds, ptosis, short philtrum, and downturned upper lip), mental retardation, multiple exostoses, brachycephaly, and bilateral parietal foramina.
In affected members of a family with multiple exostoses, Stickens et al. (1996) identified a heterozygous 4-bp deletion in the EXT2 gene (608210.0001), resulting in a premature stop codon and truncated gene product. Stickens et al. (1996) speculated that a second mutation event was necessary for the development of exostoses, thus accounting for the asymmetry of exostoses observed in the long bones.
In 2 families with multiple exostoses, Wuyts et al. (1996) identified 2 different mutations in the EXT2 gene: a nonsense mutation (608210.0002) and a splice site mutation (608210.0003). In 5 of 17 (29%) families with hereditary multiple exostoses, Philippe et al. (1997) identified 4 mutations in the EXT2 gene, including a missense mutation (608210.0004) and 3 alterations that resulted in premature stop codons. Seven (41%) of the families had mutations in the EXT1 gene.
Of 26 EXT families originating from 9 countries, Wuyts et al. (1998) found that 10 families had an EXT1 mutation and 10 had an EXT2 mutation. Twelve of these mutations had not previously been described. From a review of these and previously reported mutations, Wuyts et al. (1998) concluded that mutations in either the EXT1 or the EXT2 gene are responsible for most cases of multiple exostoses. Most of the mutations in these 2 genes cause premature termination of the EXT proteins, whereas missense mutations are rare. The authors concluded that the development of exostoses is mainly due to loss of function of EXT genes, consistent with the hypothesis that the EXT genes have a tumor suppressor function.
Wuyts and Van Hul (2000) stated that 49 different EXT1 and 25 different EXT2 mutations had been identified in patients with multiple exostoses, and that mutations in these 2 genes were responsible for over 70% of the EXT cases.
Among 35 unrelated Italian patients with multiple exostoses type II, Fusco et al. (2019) identified 25 different heterozygous mutations in the EXT2 gene, of which 19 were novel. The mutations were identified by direct sequencing or by MLPA analysis followed by confirmation with quantitative real-time PCR. The mutations included 13 frameshift, 6 nonsense, 4 missense, and 2 intragenic rearrangements. The most common mutation was N288S (608210.0013), which occurred in 10 families. To evaluate the functional importance of EXT2 domains, Fusco et al. (2019) tested the effects of 2 truncating mutations (Pro243Glnfs27 and Leu335Tyrfs101), comprising the N-terminal domain or glycosyltransferase 64 C-terminal domain, in U2OS cells. They also tested the effects of the P351L mutation (608210.0014). The mutated proteins had abnormal localization patterns in the cell. When these mutant EXT2 proteins were expressed in HEK293 cells, the cells had slower growth compared to cells expressing the wildtype EXT2.
Francannet et al. (2001) identified mutations in 36 of the 38 families linked to EXT1 or EXT2. No mutations were found in 2 EXT1-linked families. Nine of the mutations occurred in the EXT2 gene. A severe phenotype ('S') was shown to be significantly associated with EXT1 mutations, whereas a moderate phenotype ('M') was associated with EXT2 mutations. One subgroup of the S phenotype, IS (10 to 25 exostoses, no vertebral exostoses, height below the 10th centile), was associated with mutations in EXT1 or EXT2. Mutations associated with another S subgroup, IVS (very short stature), were located in exon 1 of EXT1. Chondrosarcomas were found only in patients with EXT1 mutations.
In 7 patients with EXT1 mutations and 16 patients with EXT2 mutations, Alvarez et al. (2006) analyzed the anatomic burden of disease by clinical and radiographic examination and evaluation of 76 phenotypic parameters. Patients with EXT1 mutation were found to have more exostoses, more limb malalignment with shorter limb segments and height, and more pelvic and flatbone involvement.
Heinritz et al. (2009) identified 9 different mutations in the EXT2 gene in 11 of 23 German patients with multiple exostoses. Eleven other patients had mutations in the EXT1 gene; 1 patient had no detectable mutations. Among the EXT2 mutations, there were 3 recurrent mutations, Q172X (608210.0002), D227N (608210.0004), and Q258X (608210.0006), and 6 novel mutations (see, e.g., 608210.0007). Multiple splice site defects were identified. Although clinical details were limited, those with EXT1 mutations tended to have a more severe phenotype.
Fusco et al. (2019) described genotype/phenotype correlations for 42 Italian patients with EXT1 and 27 Italian patients with EXT2. The patients included 38 females and 31 males, ranging in age from 4 to 74 years. There were no significant differences for age and sex between the EXT1 and EXT2 groups. The long bones of the upper and lower limbs were the most commonly affected bones with osteochondroma/exostoses. The second most commonly affected bones were the chest bones. Occasional vertebral osteochondroma/exostoses were identified in EXT1 patients, whereas none were identified in EXT2 patients. Impaired intellectual development was reported in 2 patients with EXT1, both of whom had a heterozygous nonsense variant in EXT1 (Q213X and C355X). The average number of total osteochondromas was approximately 10 in patients with EXT1 and approximately 7 in patients with EXT2. Osteochondroma/exostoses were more frequently reported in the distal humerus, distal ulna, ribs, proximal humerus, and distal radius in patients with EXT1 compared to patients with EXT2. Males with EXT1 had more total osteochondromas compared to males with EXT2, and more specifically had more osteochondromas in the distal humerus, distal ulna, ribs, and hands. The overall number of osteochondromas was comparable between females with EXT1 and EXT2. However, more osteochondromas were observed in the distal humerus and distal radius in females with EXT1 and in the proximal humerus in females with EXT2.
Alvarez, C., Tredwell, S., De Vera, M., Hayden, M. The genotype-phenotype correlation of hereditary multiple exostoses. Clin. Genet. 70: 122-130, 2006. [PubMed: 16879194] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00653.x]
Blanton, S. H., Hogue, D., Wagner, M., Wells, D., Young, I. D., Hecht, J. T. Hereditary multiple exostoses: confirmation of linkage to chromosomes 8 and 11. Am. J. Med. Genet. 62: 150-159, 1996. [PubMed: 8882395] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960315)62:2<150::AID-AJMG7>3.0.CO;2-#]
Cook, A., Raskind, W., Blanton, S. H., Pauli, R. M., Gregg, R. G., Francomano, C. A., Puffenberger, E., Conrad, E. U., Schmale, G., Schellenberg, G., Wijsman, E., Hecht, J. T., Wells, D., Wagner, M. J. Genetic heterogeneity in families with hereditary multiple exostoses. Am. J. Hum. Genet. 53: 71-79, 1993. [PubMed: 8317501]
Francannet, C., Cohen-Tanugi, A., Le Merrer, M., Munnich, A., Bonaventure, J., Legeai-Mallet, L. Genotype-phenotype correlation in hereditary multiple exostoses. J. Med. Genet. 38: 430-434, 2001. [PubMed: 11432960] [Full Text: https://doi.org/10.1136/jmg.38.7.430]
Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others. Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants. Hum. Molec. Genet. 28: 2133-2142, 2019. [PubMed: 30806661] [Full Text: https://doi.org/10.1093/hmg/ddz046]
Hecht, J. T., Hogue, D., Strong, L. C., Hansen, M. F., Blanton, S. H., Wagner, M. Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8. Am. J. Hum. Genet. 56: 1125-1131, 1995. [PubMed: 7726168]
Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G. New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas. Ann. Hum. Genet. 73: 283-291, 2009. [PubMed: 19344451] [Full Text: https://doi.org/10.1111/j.1469-1809.2009.00508.x]
McGaughran, J. M., Ward, H. B., Evans, D. G. R. WAGR syndrome and multiple exostoses in a patient with del(11)(p11.2p14.2). J. Med. Genet. 32: 823-824, 1995. [PubMed: 8558565] [Full Text: https://doi.org/10.1136/jmg.32.10.823]
Philippe, C., Porter, D. E., Emerton, M. E., Wells, D. E., Simpson, A. H. R. W., Monaco, A. P. Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. Am. J. Hum. Genet. 61: 520-528, 1997. [PubMed: 9326317] [Full Text: https://doi.org/10.1086/515505]
Potocki, L., Greenberg, F., Shaffer, L. G. Interstitial deletion of 11(p12p11.2): a rare chromosomal syndrome with mental retardation, parietal foramina, and multiple exostoses. (Abstract) Am. J. Hum. Genet. 57: A123, 1995.
Potocki, L., Shaffer, L. G. Interstitial deletion of 11(p11.2p12): a newly described contiguous gene deletion syndrome involving the gene for hereditary multiple exostoses (EXT2). Am. J. Med. Genet. 62: 319-325, 1996. [PubMed: 8882796] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960329)62:3<319::AID-AJMG22>3.0.CO;2-M]
Stickens, D., Clines, G., Burbee, D., Ramos, P., Thomas, S., Hogue, D., Hecht, J. T., Lovett, M., Evans, G. A. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nature Genet. 14: 25-32, 1996. [PubMed: 8782816] [Full Text: https://doi.org/10.1038/ng0996-25]
Wu, Y.-Q., Heutink, P., de Vries, B. B. A., Sandkuijl, L. A., van den Ouweland, A. M. W., Niermeijer, M. F., Galjaard, H., Reyniers, E., Willems, P. J., Halley, D. J. J. Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11. Hum. Molec. Genet. 3: 167-171, 1994. [PubMed: 8162019] [Full Text: https://doi.org/10.1093/hmg/3.1.167]
Wuyts, W., Ramlakhan, S., Van Hul, W., Hecht, J. T., van den Ouweland, A. M. W., Raskind, W. H., Hofstede, F. C., Reyniers, E., Wells, D. E., de Vries, B., Conrad, E. U., Hill, A., Zalatayev, D., Weissenbach, J., Wagner, M. J., Bakker, E., Halley, D. J. J., Willems, P. J. Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11. Am. J. Hum. Genet. 57: 382-387, 1995. [PubMed: 7668264]
Wuyts, W., Van Hul, W., De Boulle, K., Hendrickx, J., Bakker, E., Vanhoenacker, F., Mollica, F., Ludecke, H.-J., Sayli, B. S., Pazzaglia, U. E., Mortier, G., Hamel, B., Conrad, E. U., Matsushita, M., Raskind, W. H., Willems, P. J. Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Am. J. Hum. Genet. 62: 346-354, 1998. [PubMed: 9463333] [Full Text: https://doi.org/10.1086/301726]
Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E., De Boulle, K., de Vries, B. B. A., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M. W., McGaughran, J., Halley, D. J. J., Willems, P. J. Positional cloning of a gene involved in hereditary multiple exostoses. Hum. Molec. Genet. 5: 1547-1557, 1996. [PubMed: 8894688] [Full Text: https://doi.org/10.1093/hmg/5.10.1547]
Wuyts, W., Van Hul, W. Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Hum. Mutat. 15: 220-227, 2000. [PubMed: 10679937] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(200003)15:3<220::AID-HUMU2>3.0.CO;2-K]