No abstract

Multiple osteochondromas (MO) is an autosomal dominant disorder caused by germline mutations in EXT1 and/or EXT2. In contrast, solitary osteochondroma (SO) is nonhereditary. Products of the EXT gene are involved in heparan sulfate (HS) biosynthesis. In this study, we investigated whether osteochondromas arise via either loss of heterozygosity (2 hits) or haploinsufficiency. An in vitro three-dimensional chondrogenic pellet model was used to compare heterozygous bone marrow-derived mesenchymal stem cells (MSCs EXT(wt/-)) of MO patients with normal MSCs and the corresponding tumor specimens (presumed EXT(-/-)). We demonstrated a second hit in EXT in five of eight osteochondromas. HS chain length and structure, in vitro chondrogenesis, and EXT expression levels were identical in both EXT(wt/-) and normal MSCs. Immunohistochemistry for HS, HS proteoglycans, and HS-dependent signaling pathways (eg, TGF-β/BMP, Wnt, and PTHLH) also showed no differences. The cartilaginous cap of osteochondroma contained a mixture of HS-positive and HS-negative cells. Because a heterozygous EXT mutation does not affect chondrogenesis, EXT, HS, or downstream signaling pathways in MSCs, our results refute the haploinsufficiency theory. We found a second hit in 63% of analyzed osteochondromas, supporting the hypothesis that osteochondromas arise via loss of heterozygosity. The detection of the second hit may depend on the ratio of HS-positive (normal) versus HS-negative (mutated) cells in the cartilaginous cap of the osteochondroma.

Level III-Retrospective comparative study.

Multiple osteochondromas (MO) are a rare autosomal dominant disorder characterized by the presence of osteochondromas located on the long bones and axial skeleton. Patients present with growth disturbances and angular deformities of the long bones as well as limited motion of affected joints. Forearm involvement is found in a considerable number of patients and may vary from the presence of a simple osteochondroma to severe forearm deformities and radial head dislocation. Patients encounter a variety of problems and symptoms e.g., pain, functional impairment, loss of strength and cosmetic concerns. Several surgical procedures are offered from excision of symptomatic osteochondromas to challenging reconstructions of forearm deformities. We describe visualizing, planning and treating these forearm deformities in MO and, in particular, a detailed account of the surgical correction of Masada type I and Masada type II MO forearm deformities.

Apart from osteochondromas or peripheral chondrosarcomas, multiple osteochondromas are also associated with intraosseous chondroid neoplasms, potentially resulting in central chondrosarcoma. Therefore, intraosseous lesions should not automatically be regarded as innocuous in this patient population.