multiple hereditary exostoses

Summary

Summary: Hereditary disorder transmitted by an autosomal dominant gene and characterized by multiple exostoses (multiple osteochondromas) near the ends of long bones. The genetic abnormality results in a defect in the osteoclastic activity at the metaphyseal ends of the bone during the remodeling process in childhood or early adolescence. The metaphyses develop benign, bony outgrowths often capped by cartilage. A small number undergo neoplastic transformation.

Top Publications

  1. Stickens D, Evans G. Isolation and characterization of the murine homolog of the human EXT2 multiple exostoses gene. Biochem Mol Med. 1997;61:16-21 pubmed
    ..The identification of the mouse EXT2 gene will allow functional analysis through insertional inactivation and reverse genetics in mice in order to better understand the formation of exostoses during bone formation...
  2. Matsumoto K, Irie F, Mackem S, Yamaguchi Y. A mouse model of chondrocyte-specific somatic mutation reveals a role for Ext1 loss of heterozygosity in multiple hereditary exostoses. Proc Natl Acad Sci U S A. 2010;107:10932-7 pubmed publisher
    b>Multiple hereditary exostoses (MHE) is one of the most common skeletal dysplasias, exhibiting the formation of multiple cartilage-capped bony protrusions (osteochondroma) and characteristic bone deformities...
  3. Khan I, West C, Sangster G, Heldmann M, Doucet L, Olmedo M. Multiple hereditary exostoses as a rare nonatherosclerotic etiology of chronic lower extremity ischemia. J Vasc Surg. 2010;51:1003-5 pubmed publisher
    ..We report a patient with multiple hereditary exostoses (MHE) presenting with lifestyle-limiting lower extremity claudication and popliteal artery occlusion ..
  4. Alvarez C, De Vera M, Heslip T, Casey B. Evaluation of the anatomic burden of patients with hereditary multiple exostoses. Clin Orthop Relat Res. 2007;462:73-9 pubmed
    ..EXT1 patients were shorter. All limb segments tended to be shorter for EXT1 subjects. EXT1 subjects showed more anatomic burden with respect to lesion quality and height...
  5. Glick R, Khaldi L, Ptaszynski K, Steiner G. Dysplasia epiphysealis hemimelica (Trevor disease): a rare developmental disorder of bone mimicking osteochondroma of long bones. Hum Pathol. 2007;38:1265-72 pubmed
    ..The histologic differences in combination with the distinct clinical and radiographic features should enable a pathologist to differentiate these entities...
  6. Matsubara H, Tsuchiya H, Sakurakichi K, Yamashiro T, Watanabe K, Tomita K. Correction and lengthening for deformities of the forearm in multiple cartilaginous exostoses. J Orthop Sci. 2006;11:459-66 pubmed
    ..In this study, we present the results of exostoses resection, with correction and lengthening with external fixators for functional and cosmetic improvement, and prevention of radial head dislocation...
  7. Ludecke H, Ahn J, Lin X, Hill A, Wagner M, Schomburg L, et al. Genomic organization and promoter structure of the human EXT1 gene. Genomics. 1997;40:351-4 pubmed
    ..Such a promoter is characteristic for housekeeping genes. This finding is in good agreement with the ubiquitous expression of the EXT1 gene...
  8. Benoist Lasselin C, de Margerie E, Gibbs L, Cormier S, Silve C, Nicolas G, et al. Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients. Bone. 2006;39:17-26 pubmed
    b>Multiple hereditary exostoses (MHE) is an autosomal dominant skeletal disorder caused by mutations in one of the two EXT genes and characterized by multiple osteochondromas that generally arise near the ends of growing long bones...
  9. Ahn J, Ludecke H, Lindow S, Horton W, Lee B, Wagner M, et al. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet. 1995;11:137-43 pubmed
    ..However, recent studies in sporadic and exostosis-derived chondrosarcomas suggest that the 8q24.1-encoded EXT1 gene may have tumour suppressor function...

More Information

Publications62

  1. Nadanaka S, Kitagawa H. Heparan sulphate biosynthesis and disease. J Biochem. 2008;144:7-14 pubmed publisher
    ..This review suggests that HS biosynthetic enzymes would be potential candidates for drug targets in various diseases...
  2. Hameetman L, David G, Yavas A, White S, Taminiau A, Cleton Jansen A, et al. Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas. J Pathol. 2007;211:399-409 pubmed
    ..We hypothesize that loss of EXT expression disrupts the function of the EXT1/2 complex in HSPG biosynthesis, resulting in the intracellular accumulation of HSPG core proteins that we found in these tumours...
  3. Darilek S, Wicklund C, Novy D, Scott A, Gambello M, Johnston D, et al. Hereditary multiple exostosis and pain. J Pediatr Orthop. 2005;25:369-76 pubmed
    ..The results of this study indicate that the number of individuals with HME who have pain has been underestimated and that pain is a problem that must be addressed when caring for individuals with HME...
  4. Vink G, White S, Gabelic S, Hogendoorn P, Breuning M, Bakker E. Mutation screening of EXT1 and EXT2 by direct sequence analysis and MLPA in patients with multiple osteochondromas: splice site mutations and exonic deletions account for more than half of the mutations. Eur J Hum Genet. 2005;13:470-4 pubmed
    ..In patients suspected to be affected by MO, we recommend a quantitative analysis such as MLPA, followed by direct sequence analysis for the screening of the EXT1 and EXT2 genes...
  5. Stickens D, Brown D, Evans G. EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis. Dev Dyn. 2000;218:452-64 pubmed
    ..We suggest a model for exostoses formation based on the involvement of EXT1 and EXT2 in the Indian hedgehog/parathyroid hormone-related peptide (PTHrP) signaling pathway, an important regulator of the chondrocyte maturation process...
  6. McCormick C, Duncan G, Goutsos K, Tufaro F. The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci U S A. 2000;97:668-73 pubmed
    ..These findings provide a rationale to explain how inherited mutations in either of the two EXT genes can cause loss of activity, resulting in hereditary multiple exostoses...
  7. Lin X, Gan L, Klein W, Wells D. Expression and functional analysis of mouse EXT1, a homolog of the human multiple exostoses type 1 gene. Biochem Biophys Res Commun. 1998;248:738-43 pubmed
    ..These results provide novel information on the function of EXT1 and the etiology of hereditary multiple exostoses...
  8. Wuyts W, Van Hul W, De Boulle K, Hendrickx J, Bakker E, Vanhoenacker F, et al. Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Am J Hum Genet. 1998;62:346-54 pubmed
    ..The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function...
  9. Lonie L, Porter D, Fraser M, Cole T, Wise C, Yates L, et al. Determination of the mutation spectrum of the EXT1/EXT2 genes in British Caucasian patients with multiple osteochondromas, and exclusion of six candidate genes in EXT negative cases. Hum Mutat. 2006;27:1160 pubmed
    ..This technique was found to be sensitive with a detection rate of 100% regarding heterozygote detection for EXT mutation scanning. Furthermore, this technique has a very high throughput and is very cost-effective...
  10. Hall C, Cole W, Haynes R, Hecht J. Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis. Am J Med Genet. 2002;112:1-5 pubmed
    ..Alternative models are developed based on the functional significance of EXT proteins in heparan sulfate biosynthesis...
  11. Han C, Belenkaya T, Khodoun M, Tauchi M, Lin X, Lin X. Distinct and collaborative roles of Drosophila EXT family proteins in morphogen signalling and gradient formation. Development. 2004;131:1563-75 pubmed
    ..Our results also suggest that HSPGs have two distinct roles in Wg morphogen distribution and signalling...
  12. Koziel L, Kunath M, Kelly O, Vortkamp A. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell. 2004;6:801-13 pubmed
    ..Finally, we propose that the development of exostoses in the human Hereditary Multiple Exostoses syndrome can be attributed to activation of Ihh signaling...
  13. White S, Vink G, Kriek M, Wuyts W, Schouten J, Bakker B, et al. Two-color multiplex ligation-dependent probe amplification: detecting genomic rearrangements in hereditary multiple exostoses. Hum Mutat. 2004;24:86-92 pubmed
    ..The approach is especially suited for cases in which the number of patients to be tested is limited, making it financially unattractive to invest in cloning...
  14. Feldman F, Vanheertum R, Saxena C. 18Fluoro-deoxyglucose positron emission tomography evaluation of benign versus malignant osteochondromas: preliminary observations. J Comput Assist Tomogr. 2006;30:858-64 pubmed
    ..To determine the contribution of 18fluoro-deoxyglucose positron emission tomography (18FDG PET) in distinguishing benign from malignant osteochondromas...
  15. Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul E, et al. Positional cloning of a gene involved in hereditary multiple exostoses. Hum Mol Genet. 1996;5:1547-57 pubmed
    ..EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT...
  16. Hosalkar H, Greenberg J, Gaugler R, Garg S, Dormans J. Abnormal scarring with keloid formation after osteochondroma excision in children with multiple hereditary exostoses. J Pediatr Orthop. 2007;27:333-7 pubmed
    b>Multiple hereditary exostoses (MHE) is an autosomal dominant condition characterized by numerous cartilage-capped exostoses/osteochondromas in areas of actively growing bone...
  17. Bridge J, Nelson M, Orndal C, Bhatia P, Neff J. Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer. 1998;82:1657-63 pubmed
    ..1 (EXT1), 11p11-12 (EXT2), and 19p (EXT3). Constitutional chromosomal microdeletions of 8q24.1 and 11p11-12 are features of the Langer-Giedion and DEFECT-11 syndromes, respectively. Cytogenetic studies of osteochondroma are rare...
  18. Akita S, Murase T, Yonenobu K, Shimada K, Masada K, Yoshikawa H. Long-term results of surgery for forearm deformities in patients with multiple cartilaginous exostoses. J Bone Joint Surg Am. 2007;89:1993-9 pubmed
    ..The purpose of the present study was to determine the reasonable indications for operative treatment and to evaluate long-term results of forearm surgery in these patients...
  19. Legeai Mallet L, Munnich A, Maroteaux P, Le Merrer M. Incomplete penetrance and expressivity skewing in hereditary multiple exostoses. Clin Genet. 1997;52:12-6 pubmed
    ..001) gives support to the variable penetrance of EXT genes among sexes. Whether this incomplete penetrance is associated with one of the disease genes recently identified in EXT is currently under investigation...
  20. Herman T, Chines A, McAlister W, Gottesman G, Eddy M, Whyte M. Metachondromatosis: report of a family with facial features mildly resembling trichorhinophalangeal syndromePediatr Radiol 1997 Nov;27(11):864. Pediatr Radiol. 1997;27:436-41 pubmed
    ..The radiographic manifestations and evolution of metachondromatosis are depicted in this report...
  21. Wuyts W, Radersma R, Storm K, Vits L. An optimized DHPLC protocol for molecular testing of the EXT1 and EXT2 genes in hereditary multiple osteochondromas. Clin Genet. 2005;68:542-7 pubmed
    ..The protocol described here, therefore, provides a sensitive and cost-sparing alternative for direct sequencing analysis of the MO-causing genes...
  22. Bovee J. Multiple osteochondromas. Orphanet J Rare Dis. 2008;3:3 pubmed publisher
    ..For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumour-free margins, preferably in a bone tumour referral centre, should be performed...
  23. Roach J, Klatt J, Faulkner N. Involvement of the spine in patients with multiple hereditary exostoses. J Bone Joint Surg Am. 2009;91:1942-8 pubmed publisher
    ..Three existing patients with multiple hereditary exostoses at our institution had development of neurologic findings and were found to have exostoses in the ..
  24. Hennekam R. Hereditary multiple exostoses. J Med Genet. 1991;28:262-6 pubmed
  25. Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K. The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem. 1998;273:26265-8 pubmed
    ..Thus at least two members of the EXT family of tumor suppressors encode glycosyltransferases involved in the chain elongation step of HS biosynthesis...
  26. Bovée J, Sakkers R, Geirnaerdt M, Taminiau A, Hogendoorn P. Intermediate grade osteosarcoma and chondrosarcoma arising in an osteochondroma. A case report of a patient with hereditary multiple exostoses. J Clin Pathol. 2002;55:226-9 pubmed
  27. Park K, Shin K, Ku J, Cho T, Lee S, Choi I, et al. Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses. J Hum Genet. 1999;44:230-4 pubmed
    ..This missense mutation cosegregated with the disease phenotype in this family, suggesting that it is the disease-causing mutation. These two mutations identified in EXT1 and EXT2 are novel ones...
  28. Simmons A, Musy M, Lopes C, Hwang L, Yang Y, Lovett M. A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses. Hum Mol Genet. 1999;8:2155-64 pubmed
    ..The EXT2-GalNAc-T5 interaction provides the first direct physical link between EXT proteins and known components of glycosamino-glycan synthesis...
  29. Wuyts W, Van Hul W. Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Hum Mutat. 2000;15:220-7 pubmed
    ..The majority of these mutations are mutations causing loss of function, which is consistent with the presumed tumor suppressor function of the EXT genes...
  30. Faiyaz ul Haque M, Ahmad W, Zaidi S, Hussain S, Haque S, Ahmad M, et al. Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis). Clin Genet. 2004;66:144-51 pubmed
    b>Multiple hereditary exostoses (HME) is an autosomal dominant developmental disorder exhibiting multiple osteocartilaginous bone tumors that generally arise near the ends of growing long bones...
  31. Porter D, Lonie L, Fraser M, Dobson Stone C, Porter J, Monaco A, et al. Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study. J Bone Joint Surg Br. 2004;86:1041-6 pubmed
    ..The sarcoma risk in EXT1 carriers is similar to the risk of breast cancer in an older population subjected to breast-screening, suggesting that a role for regular screening in patients with hereditary multiple exostoses is justifiable...
  32. McCormick C, Leduc Y, Martindale D, Mattison K, Esford L, Dyer A, et al. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet. 1998;19:158-61 pubmed
    ..Two EXT1 variants containing aetiologic missense mutations failed to alter cell-surface glycosaminoglycans, despite retaining their ER-localization...
  33. Le Merrer M, Legeai Mallet L, Jeannin P, Horsthemke B, Schinzel A, Plauchu H, et al. A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet. 1994;3:717-22 pubmed
  34. Xu L, Xia J, Jiang H, Zhou J, Li H, Wang D, et al. Mutation analysis of hereditary multiple exostoses in the Chinese. Hum Genet. 1999;105:45-50 pubmed
    ..Our findings suggest a possibly different genetic spectrum of this disease in different populations...
  35. 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. 2001;38:430-4 pubmed
    ..These findings provide the first genotype-phenotype correlation in HME and will, it is hoped, facilitate the clinical management of these patients...
  36. Bovée J, Hameetman L, Kroon H, Aigner T, Hogendoorn P. EXT-related pathways are not involved in the pathogenesis of dysplasia epiphysealis hemimelica and metachondromatosis. J Pathol. 2006;209:411-9 pubmed
    ..Downstream targets of EXT, which are downregulated in osteochondroma, are expressed in DEH and MC, suggesting that EXT signalling is not disturbed...
  37. Jager M, Westhoff B, Portier S, Leube B, Hardt K, Royer Pokora B, et al. Clinical outcome and genotype in patients with hereditary multiple exostoses. J Orthop Res. 2007;25:1541-51 pubmed
    ..c) 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:1541-1551, 2007...
  38. Cook A, Raskind W, Blanton S, Pauli R, Gregg R, Francomano C, et al. Genetic heterogeneity in families with hereditary multiple exostoses. Am J Hum Genet. 1993;53:71-9 pubmed
    ..11, with the most likely position of EXT between D8S85 and D8S199. Thus there are at least two genes that are capable of causing hereditary multiple exostoses, one in the Langer-Giedion region and one at another, unlinked location...
  39. Seki H, Kubota T, Ikegawa S, Haga N, Fujioka F, Ohzeki S, et al. Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses. Am J Med Genet. 2001;99:59-62 pubmed
    ..These results expand our knowledge of the ethnic difference of EXT and the structure-function relationship of the EXT genes...
  40. Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, et al. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nat Genet. 1996;14:25-32 pubmed
    ..Both EXT1 and EXT2 show significant homology with one additional expressed sequence tag, defining a new multigene family of proteins with potential tumour suppressor activity...
  41. Raskind W, Conrad E, Matsushita M, Wijsman E, Wells D, Chapman N, et al. Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. Hum Mutat. 1998;11:231-9 pubmed
    ..Combined mutational and heterogeneity analyses in this set of families with multiple exostoses suggest that 66% of our total sample, including 45% of isolated and 77% of familial cases, are attributable to abnormalities in EXT1...
  42. Cheung P, McCormick C, Crawford B, Esko J, Tufaro F, Duncan G. Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity. Am J Hum Genet. 2001;69:55-66 pubmed
    ..The corresponding missense mutations may therefore represent rare genetic polymorphisms in the EXT1 gene or may interfere with as yet undefined functions of EXT1 that are involved in HME pathogenesis...
  43. Alvarez C, Tredwell S, De Vera M, Hayden M. The genotype-phenotype correlation of hereditary multiple exostoses. Clin Genet. 2006;70:122-30 pubmed
    ..A genotype-phenotype correlation exists in HME, with patients with EXT 1 mutations having a higher degree of anatomical burden...
  44. Vanhoenacker F, Van Hul W, Wuyts W, Willems P, De Schepper A. Hereditary multiple exostoses: from genetics to clinical syndrome and complications. Eur J Radiol. 2001;40:208-17 pubmed
    ..To give an overview of genetic, clinical and radiological aspects in two families over four generations with known hereditary multiple exostoses (HME)...
  45. Yoo W, Kim J, Jang K, Lee S, Park J. Rapidly developed huge bursitis associated with scapular osteochondroma of the multiple exostosis: a case report. Rheumatol Int. 2009;29:317-9 pubmed publisher
  46. Rambeloarisoa J, El Guedj M, Legeai Mallet L, Zagdanski A, Delepine G, Le Merrer M, et al. [Hereditary multiple exostoses after 40 years of development: a case report]. Rev Med Interne. 2002;23:657-64 pubmed
    ..Malignant degeneration is a rare (about 2%) but classical complication in patients with hereditary multiple exostoses. At least 3 loci identified as EXT 1, EXT 2 and EXT 3 are involved in this skeletal disease...
  47. Tanigawa N, Kariya S, Kojima H, Komemushi A, Fujii H, Sawada S. Lower limb ischaemia caused by fractured osteochondroma of the femur. Br J Radiol. 2007;80:e78-80 pubmed
    ..We have encountered a patient with multiple hereditary exostoses, in whom the osteochondroma located in the distal portion of the femur fractured as a result of an ..
  48. Hecht J, Hogue D, Wang Y, Blanton S, Wagner M, Strong L, et al. Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies. Am J Hum Genet. 1997;60:80-6 pubmed
    ..These results agree with previous findings that mutations at EXT1 and multiple genetic events that include LOH at other loci may be required for the development of chondrosarcoma...
  49. Matsumoto Y, Matsuda S, Matono K, Oda Y, Tsuneyoshi M, Iwamoto Y. Intra-articular osteochondroma of the knee joint in a patient with hereditary multiple osteochondromatosis. Fukuoka Igaku Zasshi. 2007;98:425-30 pubmed
    ..Thus, other joint disorders, such as osteochondritis dissecans should be ruled out in such cases. We herein report a case with an intra-articular OC in a knee joint cavity in the patient with HMO...
  50. van der Meij E, Becking A, Van der Waal I. Fibrodysplasia ossificans progressiva. An unusual cause of restricted mandibular movement. Oral Dis. 2006;12:204-7 pubmed
    ..The clinical, histopathological, and molecular biological aspects of this uncommon disorder will be discussed. Furthermore, dental and surgical guidelines will be described...
  51. Noonan K, Feinberg J, Levenda A, Snead J, Wurtz L. Natural history of multiple hereditary osteochondromatosis of the lower extremity and ankle. J Pediatr Orthop. 2002;22:120-4 pubmed
    ..These findings document measurable decreases in ankle function and suggest that correction or prevention of excessive tibiotalar tilt may be warranted to improve outcome...
  52. Bolton P, Powell J, Rutter M, Buckle V, Yates J, Ishikawa Brush Y, et al. Autism, mental retardation, multiple exostoses and short stature in a female with 46,X,t(X;8)(p22.13;q22.1). Psychiatr Genet. 1995;5:51-5 pubmed
  53. Hall C, Wu Y, Shaffer L, Hecht J. Familial case of Potocki-Shaffer syndrome associated with microdeletion of EXT2 and ALX4. Clin Genet. 2001;60:356-9 pubmed
    ..Our results suggest that genes related to mental retardation and craniofacial development must be located outside of the D11S1785-D11S1385 region...