The biosynthesis of HS takes place in the Golgi apparatus and endoplasmic reticulum, where glycosaminoglycans chains are maintained by type II glycosyltransferases encoded by EXOSTOSIN genes EXT1 and EXT2. Decreased levels of HS leads to mutations in EXT1 or EXT2 causing skeletal abnormality. The underlying mechanism for solitary and multiple osteochondromas have been associated with genetic alterations in EXT1 or EXT2 genes located on chromosomes 8 and 11. Approximately 65% of osteochondromas arise in the EXT1 gene loci on chromosome 8 and 35% arise in EXT2 gene loci on chromosome 11. About 70–75% of multiple osteochondromas are caused by point mutations, often involving deletion of single or multiple axons as found in 10% of all hereditary cases. In about 10–15% of all cases no genomic alterations are detected. The mechanism behind the formation of multiple osteochondroma is large genomic deletions of EXT1 and EXT2 genes. The identified mechanism behind solitary osteochondromas is the homozygous deletions of the EXT1 gene. However, the exact cause of osteochondroma is unknown. Additionally, the molecular basis of genetics and clinical variability of multiple osteochondroma as well as the underlying causes for the malignant transformation and the onset of osteochondroma in EXT negative patients is also currently unknown. Diagnosis
Osteochondromas are often asymptomatic and may not cause any kind of discomfort. They are often found accidentally when an X-ray is done for an unrelated reason. X-rays are the first tests performed that characterize a lesion.
The results of immunohistochemistry and multiple sequence alignment supports the cause of MO being a mutation in EXT1 gene. However, the exact molecular mechanism of multiple osteochondroma remains unclear. The EXT1 gene encodes the endoplasmic reticulum-resident type II transmembrane glycosyltransferase, which catalyzes polymerization of heparin sulfate chain at the endoplasmic reticulum and the Golgi apparatus. Heparin sulfate regulates signal transduction during chondrocyte differentiation, ossification, and apoptosis. Malfunction in heparin sulfate synthesis causes chondrocytes to rapidly differentiate. Based on these results future studies should elucidate the underlying molecular mechanism of the glycosyltransferase domain of the EXT1 and its involvement in the development of multiple osteochondromas. Osteochondromas are associated with secondary peripheral chondrosarcomas, but the pathogenesis of the malignant bone tumor remains unknown. Research has demonstrated that chondrocytes with dysfunctional EXT1 is present in solitary osteochondromas, but the EXT1 is functional in sporadic (solitary) secondary peripheral chondrosarcomas. Research indicates that osteochondromas creates a special niche in which wild type cells are mixed in with EXT functional cells. Then these EXT functional cells undergo other mutations, that give rise to secondary peripheral chondrosarcoma, indicating the involvement of an alternative mechanism for the pathogenesis of secondary peripheral chondrosarcoma. Future studies should address the contributing gene that causes the formation of peripheral chondrosarcoma. It should also illustrate what causes chondrocytes functional with EXT1 and EXT2 within the osteochondroma to become more susceptible to mutations leading to malignancy. References
External links
Humpath #2790 (Pathology images)
American Academy of Orthopedic Surgeons