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PubMed1999

[Identification of mutations in the human EXT1 and EXT2 genes].

OBJECTIVE: To investigate further the genetic basis of hereditary multiple exostoses (EXT) and provide useful information for gene diagnosis of the disease. METHODS: Polymerase chain reaction-single strand conformation polymorphism was used to examine the entire coding regions of EXT(1) gene on chromosome 8 and EXT(2) gene on chromosome 11 for mutation in thirty EXT families. Mutations were further identified by sequencing. RESULTS: Two frameshift mutations were identified in two unrelated EXT families. One was the deletion of one base(T) in exon 6 of the EXT(1) gene, and the other was the deletion of four bases (tgtt) in exon 2 of the EXT(2) gene. Both of the mutations resulted in a frameshift and premature termination of translation. CONCLUSION: EXT is a genetically heterogeneous bone disorder caused by the mutation of EXT tumor suppressor gene. These results could be directly applied in the genetic counseling and prenatal genetic diagnosis of EXT.

Chromosome Deletion↗
PubMed1975

[Hereditary multiple exostosis with spinal cord compression].

A case of hereditary multiple exostoses successfully operated is reported. The patient, a 15 year-old white brazilian boy, was admitted with tetraplegia and Babinski's sign. Early diagnosis followed by prompt surgery may prevent permanent spinal cord damage.

Adolescent↗
PubMed1998

[Molecular cloning of EXT2 and EXT4 gene].

Hereditary multiple exostose(EXT) is an autosomal dominant disorder of skeletal system. Three genetic loci have been identified at 8q24.1(EXT1), 11p11(EXT2) and 19p(EXT3) respectively. In this paper, EXT2 gene was cloned with positional cloning and homologous screening. SSCP and sequencing analysis have been done in 37 EXT patients who came from 20 EXT families, 2 mutations of insertion were tested in 2 patients. This confirmed that the gene cloned in this paper was EXT2 gene which locus at 11p11. Additionally EXT4 gene was cloned with homologous screening and located at 1p36.1 with FISH in this paper.

Amino Acid Sequence↗
PubMedDate not supplied

Osteochondromatosis (diaphyseal aclasis): a case report and literature review.

An unusual case of osteochondromatosis is presented with a review of the literature. Osteochondromatosis, also known as hereditary multiple exostoses or diaphyseal aclasis, are inherited, benign, cartilaginous neoplasms that consist of a pedicle of normal bone covered with proliferating cartilage cells. Pathologic, clinical, and radiographic findings will be discussed.

Bone Neoplasms↗
PubMed1981

Effect of excessive exposure to sodium fluoride on composition and crystallinity of equine bone tumors.

Sodium fluoride (5 mg/kg of body weight) was fed for 20 months to horses with hereditary multiple exostoses (HME), a skeletal disorder that primarily affects endochondral bones during skeletal development. Rib biopsies were performed on both HME horses not fed fluoride (control) and HME horses that were fed fluoride to obtain comparable specimens for chemical analyses and x-ray diffraction. Fluoride content of the rib from a horse fed fluoride for 20 months was approximately 20 to 30 times higher than that from a control horse. Fluoride content of the bone tumors was higher than those of normal bones in both control and fluoride-fed horses. The effect of fluoride uptake on the Ca/P ratio was slight. The Ca/P ratios did not differ significantly between tumorous and normal ribs. X-ray diffraction studies showed that the crystallinity (ie, crystal size/perfection) of the mineral apatite in tumor of the rib from the control horse was lower than that of normal bone from the same rib. Fluoride, however, induced a marked change in the crystallinity at both the tumorous and the normal bone sites. The crystallinity of the tumor apatite in the fluoride-fed horse exceeded that of normal bone in the control horse. Otherwise, there were not demonstrable fluoride-induced gross or radiographic changes in the bone tumors.

Animals↗
PubMed1996

Osteochondroma of the thoracic spine: an unusual cause of spinal cord compression.

A 24-year-old man with hereditary multiple exostoses had numbness of the lower extremities and difficulty walking. CT displayed a calcified extradural mass lesion within the spinal canal at T-8 causing cord compression. MR imaging showed it to be contiguous with the upper endplate of T-8, suggesting the diagnosis of osteochondroma, a rare cause of cord compression, and distinguishing the lesion from a calcified disk fragment.

Adult↗
PubMed1998

[Vertebral body exocytosis and spinal cord compression].

Osteochondroma is a cartilaginous tumor, the most common benign tumor of bone. It may involve solitary or multiple exostoses (or osteochondromatosis) usually in hereditary multiple exostosis. The authors report a case of 13-year-old girl with a family history of hereditary multiples exostoses who presented with bilateral sciatica and cauda equina compression. The MRI showed a tumor of the L1 vertebral body. After surgery, pathologic specimens revealed the lesion to be an osteochondroma. Involvement of the vertebral column has been estimated from 1.3 to 4%. Spinal cord compression is rare. CT provides the analysis of the components of the tumor and clearly demonstrates it's intracanalar extension. MRI is superior in visualizing spinal cord compression. The prognosis is favorable after a surgical decompression.

Adolescent↗
PubMed2000

The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate.

Hereditary multiple exostoses, a dominantly inherited genetic disorder characterized by multiple cartilaginous tumors, is caused by mutations in members of the EXT gene family, EXT1 or EXT2. The proteins encoded by these genes, EXT1 and EXT2, are endoplasmic reticulum-localized type II transmembrane glycoproteins that possess or are tightly associated with glycosyltransferase activities involved in the polymerization of heparan sulfate. Here, by testing a cell line with a specific defect in EXT1 in in vivo and in vitro assays, we show that EXT2 does not harbor significant glycosyltransferase activity in the absence of EXT1. Instead, it appears that EXT1 and EXT2 form a hetero-oligomeric complex in vivo that leads to the accumulation of both proteins in the Golgi apparatus. Remarkably, the Golgi-localized EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone, which suggests that the complex represents the biologically relevant form of the enzyme(s). These findings provide a rationale to explain how inherited mutations in either of the two EXT genes can cause loss of activity, resulting in hereditary multiple exostoses.

Amino Acid Sequence↗
PubMed2006

Three novel EXT1 and EXT2 gene mutations in Taiwanese patients with multiple exostoses.

Multiple osteochondromatosis, also known as hereditary multiple exostoses (HME), is an inherited autosomal dominant disorder characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different exostosis (EXT) loci on chromosomes 8q (exostosin 1, EXT1), 11p (exostosin 2, EXT2) and 19p (exostosin 3, EXT3) have been reported. Recently, the EXT1 and EXT2 genes were identified by positional cloning. Using polymerase chain reaction and direct sequencing, we analyzed the EXT1 and EXT2 genes in three familial cases and one sporadic case of HME in Taiwanese patients. We found three novel mutations (S277X in the EXT1 gene, and G194X and 939+1G>A in the EXT2 gene) and a known mutation (Q172X in the EXT2 gene). Mutation analysis in families with HME allows for genetic counseling and prenatal diagnosis.

DNA Mutational Analysis↗
PubMed1999

Popliteal pseudoaneurysm caused by an adjacent osteochondroma: a case report and review of the literature.

A male 17-year-old with multiple hereditary exostoses presented with a mass in the distal left thigh several days after lifting weights. An arteriogram showed a popliteal artery pseudoaneurysm adjacent to a femoral osteochondroma. The osteochondroma was excised and the artery was repaired with a saphenous vein interposition graft. A review of the literature identified 23 similar reports. The average age of the patients was 21.3 years. Seventy-eight percent were men and half of the patients had multiple hereditary exostoses. Ten patients were initially misdiagnosed. The clinician should consider the diagnosis of pseudoaneurysm in a young patient with an osteochondroma and a mass about the knee.

Adolescent↗
PubMed1997

The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by multiple cartilage-capped outgrowths from the epiphyses of long bones. In some cases, these osteochondromas progress to malignant chondrosarcomas. Alterations in at least three genes (EXT1, EXT2, and EXT3) can cause this disorder. Two of these have been isolated (EXT1 and EXT2) and encode related members of a putative tumor suppressor family. We report here the genomic structure of the human EXT2 gene consisting of 14 exons (plus 2 alternative exons) covering an estimated 108 kb of chromosome 11p11-13. We have derived the DNA sequences at all exon/intron boundaries throughout this gene-information that is important for the detailed study of mutations in EXT2. We have also characterized the mouse EXT2 cDNA and have mapped the mouse locus to chromosome 2 between D2Mit15 and Pax6. This mouse homolog should enable transgenic knockout experiments to be initiated to further elucidate gene function. Interestingly, sequence comparisons reveal that the human and mouse EXT genes have at least two homologs in the invertebrate Caenorhabditis elegans, indicating that they do not function exclusively as regulators of bone growth. This observation opens the way for a functional analysis of these genes in nematodes and other lower organisms.

Amino Acid Sequence↗
PubMed1999

The tumor suppressor EXT-like gene EXTL2 encodes an alpha1, 4-N-acetylhexosaminyltransferase that transfers N-acetylgalactosamine and N-acetylglucosamine to the common glycosaminoglycan-protein linkage region. The key enzyme for the chain initiation of heparan sulfate.

We previously demonstrated a unique alpha-N-acetylgalactosaminyltransferase that transferred N-acetylgalactosamine (GalNAc) to the tetrasaccharide-serine, GlcAbeta1-3Galbeta1-3Galbeta1-4Xylbeta1-O-Ser (GlcA represents glucuronic acid), derived from the common glycosaminoglycan-protein linkage region, through an alpha1,4-linkage. In this study, we purified the enzyme from the serum-free culture medium of a human sarcoma cell line. Peptide sequence analysis of the purified enzyme revealed 100% identity to the multiple exostoses-like gene EXTL2/EXTR2, a member of the hereditary multiple exostoses (EXT) gene family of tumor suppressors. The expression of a soluble recombinant form of the protein produced an active enzyme, which transferred alpha-GalNAc from UDP-[3H]GalNAc to various acceptor substrates including GlcAbeta1-3Galbeta1-3Galbeta1-4Xylbeta1-O-Ser. Interestingly, the enzyme also catalyzed the transfer of N-acetylglucosamine (GlcNAc) from UDP-[3H]GlcNAc to GlcAbeta1-3Galbeta1-O-naphthalenemethanol, which was the acceptor substrate for the previously described GlcNAc transferase I involved in the biosynthetic initiation of heparan sulfate. The GlcNAc transferase reaction product was sensitive to the action of heparitinase I, establishing the identity of the enzyme to be alpha1, 4-GlcNAc transferase. These results altogether indicate that EXTL2/EXTR2 encodes the alpha1,4-N-acetylhexosaminyltransferase that transfers GalNAc/GlcNAc to the tetrasaccharide representing the common glycosaminoglycan-protein linkage region and that is most likely the critical enzyme that determines and initiates the heparin/heparan sulfate synthesis, separating it from the chondroitin sulfate/dermatan sulfate synthesis.

Acetylgalactosamine↗
PubMed2005

Spinal exostoses: analysis of twelve cases and review of the literature.

STUDY DESIGN: Retrospective review of spinal exostoses treated at our institution and literature review. OBJECTIVES: Review of 12 cases of spinal exostoses treated at our institution compared with 165 cases of spinal exostoses reported in the literature. SUMMARY OF BACKGROUND DATA: Spinal exostoses are uncommon. Most reports consist of 1 to 3 cases. The relationship between solitary exostoses and those associated with multiple hereditary exostoses (MHE), as well as the incidence of intraspinal and extraspinal location, symptoms presentation, and results of treatment are unclear. METHODS: The medical records, operative reports, and diagnostic imaging of 12 patients with spinal exostoses treated at our institution between 1972 and 2002 were reviewed. The literature was reviewed using MEDLINE search of English literature and bibliographies of published manuscripts. RESULTS: Solitary spinal exostoses were more common than those associated with MHE. Lesions were most common in the upper cervical spine and originated from the posterior elements. Patients with exostoses associated with MHE were significantly younger and had a higher incidence of symptoms consistent with neural structure compression than patients with solitary exostoses. Complete excision resulted in resolution of preoperative symptoms. Intralesional excision resulted in recurrence in all cases. CONCLUSIONS: Spinal exostoses are more common than reported previously. Patients with MHE that present with back pain or neurological symptoms should produce a high index of suspicion. Evaluation should include both computed tomography and magnetic resonance imaging to define the origin of the exostosis and the presence of neural structure compression. Surgical excision should be preformed en bloc.

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↗