Multiple osteochondromas (MO)

2008-07-01   Christianne MA Reijnders , Judith VMG Bovée 

Department of Pathology, Leiden University Medical Center, P1-30, Albinusdreef 2, 2333 ZA Leiden, The Netherlands



Multiple osteochondromas (MO)


Hereditary multiple exostosis (HME) , Multiple hereditary exostoses (MHE) , Diaphyseal aclasis , Multiple hereditary osteochondromatosis , Multiple cartlaginous exostoses


Autosomal dominant disorder, genetically heterogeneous. Males are more often affected, possibly partly due to an incomplete penetrance in females. Approximately 62% of the patients have a positive family history.


133700 , 133701




321 Multiple osteochondromas




Phenotype and clinics

MO is characterized by the presence of multiple osteochondromas (osteocartilaginous exostosis), i.e. bony protrusions covered by a cartilaginous cap on the outer surface of bone. This results in a variety of orthopaedic deformities such as disproportionate short stature and bowing of the forearm. Osteochondromas are the most common benign bone tumours, representing approximately 50% of all primary benign tumours of bone. They gradually develop and increase in size in the first decade of life. The stratified zones of chondrocytes that are normally found in the growth plate can still be recognised on the interface of cartilage and bone in osteochondroma. Consequently, osteochondromas cease growing as the growth plates close during puberty. The majority of osteochondromas is asymptomatic and is located in bones that developed from cartilage, especially the long bones in the extremities. Patients with an 1 mutation have a more severe phenotype than patients with an 2 mutation.

Neoplastic risk

Malignant transformation is low in solitary osteochondromas (<1%) but is estimated to occur in 0.5-5% of cases of multiple osteochondromas (MO).


Osteochondromas can be surgically removed for cosmetic or functional reasons.


Cancer cytog

Clonal karyotypic abnormalities in the cartilaginous cap of osteochondroma involving 8q22-24.1 were found in ten out of 30 sporadic and in 1 out of 13 multiple osteochondromas, supporting a neoplastic origin. This was confirmed since aneuploidy was found in 4 out of 10 osteochondromas and LOH was almost exclusively found at the 1 locus in 5 out of 14 osteochondromas. Aberrations of chromosome 1p (1p13-p22) were found in five of seven osteochondromas.

Genes involved and Proteins


MO is a genetically heterogeneous disorder for which at present, two genes, 1 and 2 located respectively on 8q24 and 11p11-p12, have been isolated. The EXT1 gene was reported to show linkage in 44%-66% of the MO families, whereas EXT2 would be involved in 27%.
Additional linkage to chromosome 19p has been found, suggesting the existence of an 3 -gene, although loss of heterozygosity studies could not confirm this and the gene has not been identified so far. Two patients with MO demonstrated a germline mutation in 1 combined with loss of the remaining wild type allele in three osteochondromas, confirming the tumour suppressor function of the EXT genes and indicating that in cartilaginous cells of the growth plate inactivation of both copies of the EXT1-gene is required for osteochondroma formation in hereditary cases. Homozygous deletions of EXT1 identified in seven out of eight non-hereditary osteochondromas further support the two hit model. However, loss of the remaining wildtype allele can be demonstrated in only a subset of osteochondromas in MO patients.


The 1 gene is composed of 11 exons, and the 2 gene consists of 16 exons.


Both 1 and 2 mRNA is ubiquitously expressed. A high level of expression of EXT1 and EXT2 mRNA has been found in developing limb buds of mouse embryos and expression was demonstrated to be confined to the proliferating and prehypertrophic chondrocytes of the growth plate.


A tumour suppressor function is suggested for the genes. The gene products, exostosin-1 (1) and exostosin-2 (EXT2), are endoplasmic reticulum localized type II transmembrane glycoproteins which form a Golgi-localized hetero-oligomeric complex that catalyzes heparan sulphate (HS) polymerization. Heparan sulphate proteoglycans (HSPG) are large macromolecules composed of heparan sulphate glycosaminoglycan chains linked to a protein core. Four HSPG families are syndecan, glypican, perlecan and isoforms of CD44. HSPGs are required for high-affinity binding of fibroblast growth factor to its receptor. Furthermore, studies in Drosophila have shown that EXT (tout-velu, Ttv) is required for the diffusion of the morphogens: Hedgehog (Hh, human homologues Indian Hedgehog (IHh) and Sonic Hedgehog (SHh), decapentaplegic (dpp, human homologues TGF-beta and BMP) and wingless (human homologue Wnt). It was therefore hypothesized that EXT mutations affect IHh \/ PTHLH, TGF-beta\/BMP and Wnt signaling pathways within the normal growth plate. Indeed, altered levels of the EXT1 and EXT2 protein and of their putative downstream effectors (IHh\/PTHrP, TGF-beta\/BMP and Wnt signalling pathways) were demonstrated in both sporadic and hereditary osteochondroma. In addition, due to impaired EXT1\/EXT2 function the HSPGs appear to be retained in the Golgi apparatus and cytoplasm of the tumour cell, instead of being transported to the cell surface and\/or extra cellular matrix where they normally exert their function. Moreover, EXT mutations were described to induce cytoskeletal abnormalities (altered actin distribution) in osteochondroma chondrocytes.


Germline mutations of 1 and 2 in MO patients have been studied extensively in Caucasian as well as Asian populations.


One sporadic osteochondroma was described to harbour a deletion of one 1 gene combined with an inactivating mutation in the other 1 gene. No somatic mutations were found in the EXT1 and EXT2 gene in 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas tested.


Pubmed IDLast YearTitleAuthors
75503401995Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).Ahn J et al
168791942006The genotype-phenotype correlation of hereditary multiple exostoses.Alvarez C et al
175893612007Evaluation of the anatomic burden of patients with hereditary multiple exostoses.Alvarez CM et al
96651331998Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion.Bellaiche Y et al
111697662001Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes.Bernard MA et al
150566092004Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways.Bornemann DJ et al
182719662008Multiple osteochondromas.Bovée JV et al
104415751999EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.Bovée JV et al
83175011993Genetic heterogeneity in families with hereditary multiple exostoses.Cook A et al
63333061984Hereditary multiple exostoses. Report of a family.Crandall BF et al
123932802002Cytogenetic and molecular cytogenetic evidence of recurrent 8q24.1 loss in osteochondroma.Feely MG et al
122397112002Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis.Hall CR et al
173417312007The role of EXT1 in nonhereditary osteochondroma: identification of homozygous deletions.Hameetman L et al
149989282004Distinct and collaborative roles of Drosophila EXT family proteins in morphogen signalling and gradient formation.Han C et al
89819501997Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.Hecht JT et al
176766242007Clinical outcome and genotype in patients with hereditary multiple exostoses.Jäger M et al
80813571994A gene for hereditary multiple exostoses maps to chromosome 19p.Le Merrer M et al
109346472000EXT 1 gene mutation induces chondrocyte cytoskeletal abnormalities and defective collagen expression in the exostoses.Legeai-Mallet L et al
104293611999Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses.Park KJ et al
93263171997Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.Philippe C et al
107392912000Clinical and radiographic analysis of osteochondromas and growth disturbance in hereditary multiple exostoses.Porter DE et al
154465352004Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study.Porter DE et al
95214251998Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses.Raskind WH et al
125052522002Recurring breakpoints of 1p13 approximately p22 in osteochondroma.Sawyer JR et al
87828161996The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes.Stickens D et al
77020951995Natural history study of hereditary multiple exostoses.Wicklund CL et al
94633331998Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.Wuyts W et al
104803541999Mutation analysis of hereditary multiple exostoses in the Chinese.Xu L et al