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Multiple osteochondromas (MOs) is an autosomal dominant disease characterised by MOs (previously named exostoses). Their formation requires bi-allelic inactivation of EXT1 or EXT2 genes in growth plate cartilage. They encode glycosyltransferases that catalyse the chain elongation step in heparan sulfate biosynthesis and when mutated cause a variety of growth factor signalling defects, impaired cell–matrix interactions and loss of polarity. Osteochondromas are not clonal neoplasms, but a mixed population of cells harbouring homozygous loss of either EXT genes or cells retaining the EXT wild-type allele. About 1–5% of patients with MO at the age of 30–60 years will eventually develop a secondary chondrosarcoma. Cells harbouring the wild-type alleles of EXT1 and EXT2 genes are thought to preferentially undergo malignant transformation, possibly by inactivation of the CDKN2A locus. This locus encodes INK4a (p16), which regulates RB1, and p19ARF, which regulates P53. Inactivation of CDKN2A by mutation or deletion is a common pathway for oncogenesis. Key Concepts Patients with MO are characterised genetically by germline mutations in EXT1 and EXT2 genes and phenotypically by the development of at least two osteochondromas. Osteochondroma is a benign cartilage-capped bony projection arising on the external surface of bone containing a marrow cavity that is continuous with that of the underlying bone. Osteochondromas are the most frequent cartilaginous lesions, most often found on the femur (21%), humerus (17%) and tibia (11%). Somatic inactivation of both EXT alleles results in significantly shorter heparan sulfate chains. Defective heparan sulfate biosynthesis results in abnormal diffusion and signalling of IHH and FGFR3 causing increased proliferation and delayed differentiation. Approximately 1–5% of patients with MO at the age of 30–60 years will eventually develop a secondary peripheral chondrosarcoma. An osteochondroma cap exceeding 1.5–2 cm in adults is suggestive of malignancy. The most common location for malignant transformation of an osteochondroma is the pelvis, where large lesions can be difficult to excise completely. Cells harbouring the wild-type alleles of EXT1 and EXT2 genes are thought to preferentially undergo malignant transformation. Secondary peripheral chondrosarcoma typically shows chromosome instability with gains and losses and genomic diversity that increases with increasing grade of malignancy. Loss of heterozygosity for the chromosomal bands bearing the RB1 and CDKN2A (p16INK4a) tumour suppressor genes is often found. Keywords: EXT; CDKN2A; heparan sulfate; osteochondroma; chondrosarcoma; cartilage tumours; bone neoplasm |
