EXT-Mutation Analysis and Loss of Heterozygosity in Sporadic and Hereditary Osteochondromas and Secondary Chondrosarcomas

Departments of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
The American Journal of Human Genetics (Impact Factor: 10.93). 10/1999; 65(3):689-98. DOI: 10.1086/302532
Source: PubMed

ABSTRACT Osteochondromas occur as sporadic solitary lesions or as multiple lesions, characterizing the hereditary multiple exostoses syndrome (EXT). Approximately 15% of all chondrosarcomas arise within the cartilaginous cap of an osteochondroma. EXT is genetically heterogeneous, and two genes, EXT1 and EXT2, located on 8q24 and 11p11-p12, respectively, have been cloned. It is still unclear whether osteochondroma is a developmental disorder or a true neoplasm. Furthermore, it is unclear whether inactivation of both alleles of an EXT gene, according to the tumor-suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a dominant negative way. We therefore studied loss of heterozygosity and DNA ploidy in eight sporadic and six hereditary osteochondromas. EXT1- and EXT2-mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. We demonstrated osteochondroma to be a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild-type allele in three osteochondromas, 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. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations were found in the EXT2 gene.

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    • "Due to the dominant inheritance of the disease, two models, haploinsufficiency and lossof-heterozygosity (LOH), have been discussed as the molecular cause of MO. First studies analyzing tissue samples of MO patients detected loss of the wild type allele only in a subset of osteochondromas and the remaining, apparently heterozygous cases, led to ongoing discussions about haploinsufficiency as cause of MO (Bovee et al., 1999; Legeai-Mallet et al., 2000; Hall et al., 2002). A more recent study showed second hits in 63% of analyzed osteochondromas and revealed a mixture of HS positive and negative cells in the cartilage caps. "
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    ABSTRACT: Most elements of the vertebrate skeleton are formed by endochondral ossification. This process is initiated with mesenchymal cells that condense and differentiate into chondrocytes. These undergo several steps of differentiation from proliferating into hypertrophic chondrocytes, which are subsequently replaced by bone. Chondrocyte proliferation and differentiation are tightly controlled by a complex network of signaling molecules. During recent years, it has become increasingly clear that heparan sulfate (HS) carrying proteoglycans play a critical role in controlling the distribution and activity of these secreted factors. In this review we summarize the current understanding of the role of HS in regulating bone formation. In human, mutations in the HS synthetizing enzymes EXT1 and EXT2 induce the Multiple Osteochondroma Syndrome, a skeletal disorder characterized by short stature and the formation of benign cartilage-capped tumors. We review the current insight into the origin of the disease and discuss its possible molecular basis. In addition, we summarize the existing insight into the role of HS as a regulator of signal propagation and signaling strength in the developing skeleton.
    Matrix biology: journal of the International Society for Matrix Biology 12/2013; 35. DOI:10.1016/j.matbio.2013.11.003 · 5.07 Impact Factor
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    • "Approximately 10% of patients have a de novo mutation10. Loss of the wild-type allele in hereditary cases indicates that inactivation of both EXT alleles is required for osteochondroma formation11, confirming their tumour suppressor action that results in a loss of chondrocyte polarization12. However, the inactivation of both alleles probably occurs only in some of the cells in the cartilaginous cap of osteochondromas1213. "
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    ABSTRACT: Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel.
    Scientific Reports 02/2013; 3:1346. DOI:10.1038/srep01346 · 5.58 Impact Factor
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    • "There are a number of TMJ lesions that are characterized by tissue growth, but which have not been clearly established as true tumors (9-11) (osteochondroma, pigmented villonodular synovitis, eosinophilic granuloma). There is widespread agreement that synovial chondromatosis corresponds to metaplastic transformation of synovial tissue into chondroid tissue. "
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    ABSTRACT: Objective: To review the pseudotumors and tumors of the temporomandibular joint (TMJ) published in journals included in Journal Citation Reports (JCR), and to evaluate whether there are clinical and radiological signs capable of differentiating between pseudotumors and tumors and between malignant and benign tumors. Material and Methods: A systematic Medline search was made of clinical cases of tumors and pseudotumors of the TMJ covering a 20-year period and published in journals included in JCR. Only cases with histological confirmation were included. A description is provided of the general characteristics of TMJ tumors, with comparison of the clinical, diagnostic, therapeutic and evolutive variables referred to pseudotumors, benign tumors and malignant tumors. Results: We identified 285 TMJ tumors published in 181 articles of 15 journals. The most frequent lesions were pseudotumors (synovial chondromatosis, pigmented villonodular synovitis, eosinophilic granuloma and osteochondroma). The mean age was 42 years and one month ± 16 years and two months. Tumors were more common in females. The mean time from symptoms onset to consultation was 30 months and 8 days ± 41 months and 9 days, and almost 19.6% of the cases initially had been diagnosed and treated as TMJ dysfunction. The most frequent clinical manifestations were pain, swelling and the limitation of joint movements. The most common radiological findings in the case of benign and malignant lesions were radiopacities and radiotransparencies, respectively. No panoramic X-ray alterations were observed in 14.6% of the benign tumors and in 7.7% of the malignant lesions. Surgery was the usual form of treatment. Sequelae were recorded in 18.2% of the cases, with tumor relapse in 9.1%. The four-year survival rate in the case of malignant tumors was 72.2%. Key words:Tumor, temporomandibular joint, metaplasia, pseudotumor, condyle.
    Medicina oral, patologia oral y cirugia bucal 02/2013; 18(3). DOI:10.4317/medoral.18799 · 1.17 Impact Factor
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