Osteochondroma

Osteochondromas are the most common benign tumors of the bones. The tumors take the form of cartilage capped bony projections or outgrowth on the surface of bones exostoses. It is characterized as a type of overgrowth that can occur in any bone where cartilage forms bone. Tumors most commonly affect long bones about the knee and in the forearm. Hereditary multiple exostoses usually present during childhood. Yet, the vast majority of affected individuals become clinically manifest by the time they reach adolescence. Osteochondromas occur in 3% of the general population and represent 35% of all benign tumors and 8% of all bone tumors. The majority of these tumors are solitary non hereditary lesions and approximately 15% of osteochondromas occur as hereditary multiple exostoses preferably known as hereditary multiple osteochondromas (HMOs). Osteochondromas do not result from injury and the exact cause remains unknown. Recent research has indicated that multiple osteochondromas is an autosomal dominant inherited disease. Germ line mutations in EXT1 and EXT2 genes located on chromosomes 8 and 11 have been associated with the cause of the disease. The treatment choice for osteochondroma is surgical removal of solitary lesion or partial excision of the outgrowth, when symptoms cause motion limitations or nerve and blood vessel impingements. 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.

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. They show a clear picture of dense structures of bones, and will also indicate bone growth pertaining to osteochondroma. A biopsy of the tissue sample of the tumor can also be taken to check for cancer. A type that contains fat is known as an osteolipochondroma (osteo, bone, lipos, fat, + chondros, cartilage, oma, tumor).

Osteochondromas are benign lesions and do not affect life expectancy. Osteochondromas have a low rate of malignancy (<1%) and resection of the tumor is suggested if symptoms such as pain, limitation of movement, or impingement on nerves or vessels occur. Resection of the tumor also takes place when the tumor increases in size and progresses towards malignancy. During surgical resection, the entire lesion along with the cartilaginous cap should be removed to minimize any chances of reoccurrences. Surgical treatment becomes the sole treatment of choice if common complications such as fractures, symptoms of peripheral nerves such as paresthesia, paraplegia, peroneal neuropathy, and upper limb neuropathy take place. A prophylactic resection is suggested if the lesion lies next to a vessel. Depending on the size and location of the tumor, the time it takes to return to normal daily activities varies between individuals. Limitation on some activities is advised if pain or discomfort persists after surgical excision.

Research done using Zebrafish dackel (dak) have shown that in EXT2 / Zebrafish, chondrocytes fail to undergo terminal differentiation and bone formation fails to progress from pre osteoblasts stage to osteoblasts. Instead, abnormal lipid deposition and premature adipocyte differentiation takes place. The expression of xbp1, master regulator of osterix gets reduced, suggesting that unfolded proteins responses may play a role in pathogenesis of multiple osteochondroma. The research concludes that heparan sulphates are required for terminal differentiation and formation of scaffold that is needed for bone development. At least one copy of EXT2 gene is needed for proper bone development and to maintain the balance between bone and fat cell lineages. Due to homozygous loss of EXT2 function, leads to imbalance between cartilage, bone, and fat cell lineages. These observations in null zebrafish points toward the musculoskeletal defects observed in patients with multiple osteochondroma. Due to the findings of bone fat imbalance in Zebra fish model, future studies should address status of lipid composition in patients with multiple osteochondroma. Research conducted using sequencing methods has identified a novel frame shift mutation at the glycosyltransferase domain (c.1457insG) located at codon 486 of exon 6 of the EXT1 gene, that causes multiple osteochondromas. This study was conducted in two multiple osteochondroma (MO) patients from the Chinese descent (same family) and the results were validated with four other members of the same MO family and 200 unrelated healthy subjects. The results of the mutations were validated using two different sequencing methods (Exome and Sanger). 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.