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Results for “EXOSTOSES, MULTIPLE”

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PubMed1979

The Langer-Giedion-syndrome (tricho-rhino-phalangeal syndrome, type II).

A 15-year-old girl with the Langer-Giedion-syndrome (tricho-rhinophalangeal syndrome, type II) is presented. The features are multiple exostoses, sparse, fine hair and an abnormal face and hands. X-ray examination reveals exostoses and abnormal epiphyses. In this case intelligence is normal; there is severe sensorineural deafness (60--80 dB hearing loss). The genetic aspects of the syndrome are discussed.

Abnormalities, Multiple↗
PubMed2004

Proximal 11p deletion syndrome (P11pDS): additional evaluation of the clinical and molecular aspects.

The combination of multiple exostoses (EXT) and enlarged parietal foramina (foramina parietalia permagna, FPP) represent the main features of the proximal 11p deletion syndrome (P11pDS), a contiguous gene syndrome (MIM 601224) caused by an interstitial deletion on the short arm of chromosome 11. Here we present clinical aspects of two new P11pDS patients and the clinical follow-up of one patient reported in the original paper describing this syndrome. Recognised clinical signs include EXT, FPP, mental retardation, facial asymmetry, asymmetric calcification of coronary sutures, defective vision (severe myopia, nystagmus, strabismus), skeletal anomalies (small hands and feet, tapering fingers), heart defect, and anal stenosis. In addition fluorescence in situ hybridisation and molecular analysis were performed to gain further insight in potential candidate genes involved in P11pDS.

Abnormalities, Multiple↗
PubMed2005

Spinal cord compression due to vertebral osteochondroma: report of two cases.

Osteochondroma, or exostosis, is the most common of all benign bone tumors. Spinal osteochondromas are uncommon but may cause neurological compromise. We report two cases of spinal cord compression by osteochondromas. One patient was a 17-year-old man with hereditary multiple exostoses who was presented with spastic paraparesis, a sensory level at T3-T4, and a pyramidal syndrome. Vertebral exostosis was suspected by magnetic resonance imaging and confirmed by histological examination. Surgical decompression was followed by complete resolution of the neurological impairments. The other patient was a 19-year-old man with spastic paralysis of the right lower limb and a pyramidal syndrome. Whereas magnetic resonance imaging suggested a neurofibroma, histological features were those of osteochondroma. Nine months elapsed from symptom onset to surgery. This delay led to residual neurological impairments, which resolved almost completely after rehabilitation therapy. Vertebral osteochondromas contribute only 1.3-4.1% of all osteochondromas. The lesion may be solitary or a manifestation of hereditary multiple exostosis. Magnetic resonance imaging shows the exact location of the lesion, most notably with relation to neighboring neurological structures. Spinal cord compression is uncommon and usually has a favorable outcome provided surgical decompression is performed before major neurological damage develops.

Adolescent↗
PubMed2001

Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes.

The EXT family of putative tumor suppressor genes affect endochondral bone growth, and mutations in EXT1 and EXT2 genes cause the autosomal dominant disorder Hereditary Multiple Exostoses (HME). Loss of heterozygosity (LOH) of these genes plays a role in the development of exostoses and chondrosarcomas. In this study, we characterized EXT genes in 11 exostosis chondrocyte strains using LOH and mutational analyses. We also determined subcellular localization and quantitation of EXT1 and EXT2 proteins by immunocytochemistry using antibodies raised against unique peptide epitopes. In an isolated non-HME exostosis, we detected three genetic hits: deletion of one EXT1 gene, a net 21-bp deletion within the other EXT1 gene and a deletion in intron 1 causing loss of gene product. Diminished levels of EXT1 and EXT2 protein were found in 9 (82%) and 5 (45%) exostosis chondrocyte strains, respectively, and 4 (36%) were deficient in levels of both proteins. Although we found mutations in exostosis chondrocytes, mutational analysis alone did not predict all the observed decreases in EXT gene products in exostosis chondrocytes, suggesting additional genetic mutations. Moreover, exostosis chondrocytes exhibit an unusual cellular phenotype characterized by abnormal actin bundles in the cytoplasm. These results suggest that multiple mutational steps are involved in exostosis development and that EXT genes play a role in cell signaling related to chondrocyte cytoskeleton regulation.

Actins↗
PubMed2001

Ext-mutation analysis in Italian sporadic and hereditary osteochondromas.

Osteochondromas represent the largest group of benign tumors of bone. Multiple osteochondromatosis or hereditary multiple exostoses (EXT) is an autosomal dominant inherited disorder characterized by the presence of multiple benign cartilage-capped exostoses. EXT is genetically heterogeneous with at least 3 chromosomal loci: EXT1 (8q24.1), EXT2 (11p11-p13), and EXT3 (19p). In <5% of EXT patients, the inactivation of both copies of EXT alleles (LOH) is associated with malignant transformation. We have analyzed the EXT1 and EXT2 genes in 9 unrelated EXT families and in a patient with a sporadic osteochondroma, all originating from Italy. Four families show an EXT1 mutation, consisting of a small deletion in 3 of them and a small insertion in the 4th. All these mutations lead to premature termination of translation and thus a truncated EXT1 protein. Three families presented EXT2 mutations consisting of nucleotide substitutions leading to alterations of the third intron splice-site, to an amino acid substitution and to a nonsense mutation. All these mutations cosegregate with the disease phenotype. The sporadic osteochondroma patient carried a novel missense mutation in exon 11 of EXT2 gene, leading to an amino acid substitution. Seven of these mutations have never been described before. EXT2 missense mutations were also confirmed by amino acids conservation between human and mouse and by analysis of a healthy control population. In conclusion, our study provide further evidence that loss of function of the EXT1 or EXT2 gene is the main cause of EXT supporting the putative tumor-suppressor function of these genes.

Adolescent↗
PubMed2004

Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells.

Germline mutations in the Exostoses-1 gene (EXT1) are found in hereditary multiple exostoses syndrome, which is characterized by the formation of osteochondromas and an increased risk of chondrosarcomas and osteosarcomas. However, despite its putative tumor-suppressor function, little is known of the contribution of EXT1 to human sporadic malignancies. Here, we report that EXT1 function is abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of EXT1, a glycosyltransferase, leads to the loss of heparan sulfate (HS) synthesis. Reduced HS production can be reversed by the use of a DNA demethylating agent. Furthermore, the re-introduction of EXT1 into cancer cell lines displaying methylation-dependent silencing of EXT1 induces tumor-suppressor-like features, e.g. reduced colony formation density and tumor growth in nude mouse xenograft models. Screening a large collection of human cancer cell lines (n=79) and primary tumors (n=454) from different cell types, we found that EXT1 CpG island hypermethylation was common in leukemia, especially acute promyelocytic leukemia and acute lymphoblastic leukemia, and non-melanoma skin cancer. These findings highlight the importance of EXT1 epigenetic inactivation, leading to an abrogation of HS biosynthesis, in the processes of tumor onset and progression.

Animals↗
PubMed2005

Peroneal nerve compression resulting from fibular head osteophyte-like lesions.

BACKGROUND: The anatomical relationship of the fibular head with the fibular nerve is a critical point in regard to injuries of peripheral nerves in the lower extremities. In this location, the peroneal nerve may be injured due to several mechanisms, and osteophyte-like lesions can be considered as a differential diagnosis. METHODS: The suitable literature concerning this association is reviewed and a case is presented. A 15-year-old adolescent boy presented with right peroneal nerve palsy on admission. The radiological examinations (computed tomography and magnetic resonance imaging) demonstrated an osteophytic lesion in the head of the right fibula. The patient underwent surgical decompression of the nerve and resection of the lesion. Postoperatively, there was a complete recovery of the deficits. CONCLUSIONS: The association of osteophyte-like bone changes and peroneal nerve palsy is rare. The differential diagnoses of these lesions include cartilaginous exostoses and osteochondromas, which may be related to hereditary multiple exostoses syndrome. The timing of the treatment plays an important role in the neurological recovery.

Adolescent↗
PubMed2004

Hereditary multiple and isolated sporadic exostoses in the same kindred: identification of the causative gene (EXT2) and detection of a new mutation, nt112delAT, that distinguishes the two phenotypes.

Hereditary multiple exostoses (HME) is a well known autosomal dominant hereditary orthopedic disorder. Isolated exostoses, on the other hand, occur as sporadic events or as secondary post-traumatic sequel. The occurrence of solitary exostoses in individuals from pedigrees affected with HME may distort conclusions about carrier status and/or diagnosis. Both conditions are potentially malignant and both are associated with genetic alterations in either EXT1 or EXT2 genes. In this study, we present a seven-generation family from western Sweden consisting of 170 blood relatives, 38 of whom had multiple cartilaginous exostoses, while 8 had isolated exostoses. Linkage analysis aimed to discern one of the known EXT genes demonstrated linkage of the HME phenotype to the EXT2 gene. Subsequent mutation analysis revealed a novel mutation, nt112delAT, in this gene. All carriers of the detected mutation had multiple exostoses, indicating full penetrance. None of the pedigree members with isolated exostoses were carriers of the detected mutation. Two of the mutation carriers developed chondrosarcoma yielding a 5.2% risk of malignant development for this mutation. The detection of this mutation has enabled us to provide appropriate genetic counseling concerning this complex situation.

Aged↗
PubMed1997

Dedifferentiated chondrosarcoma in patients with multiple osteochondromatosis: report of a case and review of the literature.

Multiple osteochondromatosis (MOS) is a familial disorder of autosomal dominant transmission characterized by the development of multiple exostoses and often derangements of epiphyseal cartilage, sometimes resulting in long bone growth retardation. Patients with the disorder appear to be at increased risk for developing secondary chondrosarcomas. Rarely, dedifferentiated chondrosarcomas may also occur. We report a single case of a 27-year-old man with multiple osteochondromatosis who developed a fatal dedifferentiated chondrosarcoma. Radiographically, the neoplasm arose from the pelvis completely destroying the left pubic ramus. Subsequently, the patient underwent preoperative chemotherapy followed by a left external hemipelvectomy. On pathologic examination, the tumor was characterized by high-grade pleomorphic sarcoma sharply juxtaposed to a low-grade chondrosarcoma. The patient ultimately died of widespread metastatic sarcoma.

Adult↗
PubMed2002

Heparan sulfate abnormalities in exostosis growth plates.

Hereditary multiple exostoses (HME), a condition associated with development and growth of bony exostoses at the ends of the long bones, is caused by germline mutations in the EXT genes. EXT1 and EXT2 function as glycosyltransferases that participate in the biosynthesis of heparan sulfate (HS) to modify proteoglycans. HS proteoglycans, synthesized by chondrocytes and secreted to the extracellular matrix of the growth plate, play critical roles in growth plate signaling and remodeling. As part of studies to delineate the mechanism(s) by which an exostosis develops, we have systematically evaluated four growth plates from two HME and two solitary exostoses. Mutational events were correlated with the presence/absence and distribution of HS and the normally abundant proteoglycan, perlecan (PLN). DNA from the HME exostoses demonstrated heterozygous germline EXT1 or EXT2 mutations, and DNA from one solitary exostosis demonstrated a somatic EXT1 mutation. No loss of heterozygosity was observed in any of these samples. The chondrocyte zones of four exostosis growth plates showed absence of HS, as well as diminished and abnormal distribution of PLN. These results indicate that, although multiple mutational events do not occur in the EXT1 or EXT2 genes, a complete loss of HS was found in the exostosis growth plates. This functional knockout of the exostosis chondrocytes' ability to synthesize HS chains further supports the observations of cytoskeletal abnormalities and chondrocyte disorganization associated with abnormal cell signaling.

Child↗
PubMed1999

EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.

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.

Adolescent↗
PubMed2005

Distinct tissue-specificity of three zebrafish ext1 genes encoding proteoglycan modifying enzymes and their relationship to somitic Sonic hedgehog signaling.

Proteins of the EXT (Exostosin) 1 family are known for their role in human disease. Mutations in EXT1 cause hereditary multiple exostoses (HME), benign outgrowths of the bones, and therefore were classed as tumor suppressors. More recently, their role during embryonic development of Drosophila and mouse was addressed, revealing important functions of EXT1 genes in major signaling pathways. Here, we report the isolation of three zebrafish members of the EXT1 family, which we named ext1a, ext1b, and ext1c, respectively. They are expressed in restricted temporal and spatial domains during development. Both ext1a and ext1b are provided maternally and expressed during gastrulation: ext1a in the neurectoderm and ext1b in the embryonic midline and in the involuting mesendoderm of the germ ring. During somitogenesis stages, transcripts of all three ext genes can be found in the somitic mesoderm. Furthermore, ext1a is expressed in the dorsal neural tube. These expression domains become more pronounced at 24 hr postfertilization (hpf). At 48 hpf, ext1 genes are present in the brain, while somitic expression ceases. Zebrafish have three members of the EXT1 family, in contrast to only one EXT1 gene in mammals or Xenopus, consistent with the occurrence of partial genome duplications in the teleost lineage. Our expression analysis reveals that the three ext genes have distinct expression patterns, reflecting functional divergence after duplication. In addition, expression of ext1a and ext1c responds to elevated and reduced levels of Sonic hedgehog (shh) signaling in the somites, whereas expression of ext1b does not. This suggests a differential relationship between the shh pathway and individual ext gene function in zebrafish.

Amino Acid Sequence↗