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PubMed2000

rib-2, a Caenorhabditis elegans homolog of the human tumor suppressor EXT genes encodes a novel alpha1,4-N-acetylglucosaminyltransferase involved in the biosynthetic initiation and elongation of heparan sulfate.

The proteins encoded by the EXT1, EXT2, and EXTL2 genes, members of the hereditary multiple exostoses gene family of tumor suppressors, are glycosyltransferases required for the heparan sulfate biosynthesis. Only two homologous genes, rib-1 and rib-2, of the mammalian EXT genes were identified in the Caenorhabditis elegans genome. Although heparan sulfate is found in C. elegans, the involvement of the rib-1 and rib-2 proteins in heparan sulfate biosynthesis remains unclear. In the present study, the substrate specificity of a soluble recombinant form of the rib-2 protein was determined and compared with those of the recombinant forms of the mammalian EXT1, EXT2, and EXTL2 proteins. The present findings revealed that the rib-2 protein was a unique alpha1,4-N-acetylglucosaminyltransferase involved in the biosynthetic initiation and elongation of heparan sulfate. In contrast, the findings confirmed the previous observations that both the EXT1 and EXT2 proteins were heparan sulfate copolymerases with both alpha1,4-N-acetylglucosaminyltransferase and beta1,4-glucuronyltransferase activities, which are involved only in the elongation step of the heparan sulfate chain, and that the EXTL2 protein was an alpha1,4-N-acetylglucosaminyltransferase involved only in the initiation of heparan sulfate synthesis. These findings suggest that the biosynthetic mechanism of heparan sulfate in C. elegans is distinct from that reported for the mammalian system.

Animals↗

PubMed2002

Demonstration of a novel gene DEXT3 of Drosophila melanogaster as the essential N-acetylglucosamine transferase in the heparan sulfate biosynthesis: chain initiation and elongation.

Hereditary multiple exostoses gene (EXT) family members encode glycosyltransferases required for heparan sulfate (HS) biosynthesis in humans as well as in Drosophila. In the present study, we identified a novel Drosophila EXT protein with a type II transmembrane topology and demonstrated its glycosyltransferase activities. The truncated soluble form of this new homolog designated DEXT3 transferred N-acetylglucosamine (GlcNAc) through an alpha1,4-linkage not only to N-acetylheparosan oligosaccharides that represent growing HS chains (alpha-GlcNAc transferase II activity) but also to GlcUAbeta1-3Galbeta1-O-C(2)H(4)NHCbz, a synthetic substrate for alpha-GlcNAc transferase I that determines and initiates HS biosynthesis. The results suggest that DEXT3 is the ortholog of human EXTL3 and Caenorhabditis elegans rib-2. Semiquantitative reverse transcriptase-PCR analysis revealed ubiquitous expression of the DEXT3 mRNA. Based on the findings of the present study and those of a recent study where a fly mutant, deficient in the botv gene identical to DEXT3, affected HS proteoglycan-mediated developmental signalings, it is suggested that DEXT3 with the revealed glycosyltransferase activities is critically involved in HS formation in Drosophila. These results suggest the essential roles of DEXT3, its human ortholog EXTL3, and the C. elegans ortholog rib-2 in the biosynthesis of heparan sulfate and heparin, if present, in the respective organisms.

Amino Acid Sequence↗

PubMed2003

In vitro heparan sulfate polymerization: crucial roles of core protein moieties of primer substrates in addition to the EXT1-EXT2 interaction.

Heparan, the common unsulfated precursor of heparan sulfate (HS) and heparin, is synthesized on the glycosaminoglycan-protein linkage region tetrasaccharide GlcUA-Gal-Gal-Xyl attached to the respective core proteins presumably by HS co-polymerases encoded by EXT1 and EXT2, the genetic defects of which result in hereditary multiple exostoses in humans. Although both EXT1 and EXT2 exhibit GlcNAc transferase and GlcUA transferase activities required for the HS synthesis, no HS chain polymerization has been demonstrated in vitro using recombinant enzymes. Here we report in vitro HS polymerization. Recombinant soluble enzymes expressed by co-transfection of EXT1 and EXT2 synthesized heparan polymers with average molecular weights greater than 1.7 x 105 using UDP-[3H]GlcNAc and UDP-GlcUA as donors on the recombinant glypican-1 core protein and also on the synthetic linkage region analog GlcUA-Gal-O-C2H4NH-benzyloxycarbonyl. Moreover, in our in vitro polymerization system, a part time proteoglycan, alpha-thrombomodulin, that is normally modified with chondroitin sulfate served as a polymerization primer for heparan chain. In contrast, no polymerization was achieved with a mixture of individually expressed EXT1 and EXT2 or with acceptor substrates such as N-acetylheparosan oligosaccharides or the linkage region tetrasaccharide-Ser, which are devoid of a hydrophobic aglycon, suggesting the critical requirement of core protein moieties in addition to the interaction between EXT1 and EXT2 for HS polymerization.

Animals↗

PubMed2004

Embryonic fibroblasts with a gene trap mutation in Ext1 produce short heparan sulfate chains.

Mutational defects in either EXT1 or EXT2 genes cause multiple exostoses, an autosomal hereditary human disorder. The EXT1 and EXT2 genes encode glycosyltransferases that play an essential role in heparan sulfate chain elongation. In this study, we have analyzed heparan sulfate synthesized by primary fibroblast cell cultures established from mice with a gene trap mutation in Ext1. The gene trap mutation results in embryonic lethality, and homozygous mice die around embryonic day 14. Metabolic labeling and immunohistochemistry revealed that Ext1 mutant fibroblasts still produced small amounts of heparan sulfate. The domain structure of the mutant heparan sulfate was conserved, and the disaccharide composition was similar to that of wild type heparan sulfate. However, a dramatic difference was seen in the polysaccharide chain length. The average molecular sizes of the heparan sulfate chains from wild type and Ext1 mutant embryonic fibroblasts were estimated to be around 70 and 20 kDa, respectively. These data suggest that not only the sulfation pattern but also the length of the heparan sulfate chains is a critical determinant of normal mouse development.

Animals↗

PubMed1979

Premalignant tumors and conditions of bone.

Most bone sarcomas arise in apparently normal bone. However, some sarcomas arise in preexisting benign bone tumors or in nonneoplastic conditions. Some of the lesions, such as multiple exostoses and Ollier's disease, have a propensity to develop chondrosarcoma. Rarely does a benign giant cell tumor become malignant without prior irradiation, malignant transformation of other benign tumors, such as osteoblastoma and chondroblastoma, is a medical curiosity. Among nonneoplastic conditions, radiation changes, long-standing chronic osteomyelitis, and Paget's disease have definite premalignant connotations. However, the risk of developing cancer in these conditions is still low.

Adult↗

PubMed1998

Osteosarcoma and other bone cancers.

In this review, recent advances in the clinical therapy of osteosarcoma, including results from the European Osteosarcoma Intergroup trial demonstrating the efficacy of a short intensive two drug protocol are discussed as well the evolving role of ifosfamide. Biologically, the area of interest on chromosome 3q, which may contain an osteosarcoma tumor suppressor gene, is being narrowed, and several promising new therapeutic approaches including tumor vaccine have been explored. In chondrosarcoma research, abnormalities in hereditary multiple exostoses genes, which encode protein products essential for normal cartilage development, and a potential mechanism for the characteristic chemotherapy resistance of cartilaginous tumors (overexpression of P-glycoprotein) have been described. Surgical advances include testing of total en bloc spondylectomy for vertebral tumors as well as a noninvasively extendable long bone endoprosthesis. Finally, new insights in diagnostic imaging, including the evolving role of 201Tl, 99mTc-MIBI (methoxyisobutylisonitrile), and newer variations on magnetic resonance imaging are reviewed.

Animals↗

PubMed1998

Costal osteochondroma. A rare cause of spinal cord compression.

STUDY DESIGN: Report of a rare cause of spinal cord compression: costal osteochondroma. OBJECTIVE: To describe a very rare cause of spinal cord compression, costal osteochondroma, which was present in a 16-year-old girl with a history of hereditary multiple exostoses. SUMMARY OF BACKGROUND DATA: Only four cases of expansion of costal osteochondroma into the spinal canal through an intervertebral foramen have been reported previously. METHODS AND RESULTS: The origin of the osteochondroma at the head of the right 12th rib, the invasion of the spinal canal through the right T12-L1 intervertebral foramen, and the compression of the spinal cord were shown on computed tomography and magnetic resonance imaging. The exact extent of the osteochondroma, particularly the cartilage cap, was delineated accurately by magnetic resonance imaging. Complete excision followed by full recovery occurred 19 months after surgery. CONCLUSION: Magnetic resonance imaging is the preferred method of investigation in cases of osteochondroma related to spine, because it allows for better pre-operative planning and helps to prevent incomplete excision of the tumor.

Adolescent↗

PubMed2000

Osteochondroma of the C5 lamina with cord compression: case report and review of the literature.

STUDY DESIGN: Case report of a solitary osteochondroma of the cervical spine causing myelopathy in a 66-year-old woman. OBJECTIVES: To review the relevant literature and describe a highly unusual clinical manifestation of solitary osteochondroma. SUMMARY OF BACKGROUND DATA: Osteochondromas are common benign bony lesions that seldom occur in the axial skeleton. These lesions are more commonly reported with neural compression in cases of hereditary multiple exostoses (Bessel-Hagel syndrome, diaphyseal aclasis). METHODS: Chart review, review of relevant radiographic examinations and histopathologic specimens, clinical follow-up with examination, and literature review. RESULTS: Manifestation with new neurologic deficit in a 66-year-old patient was singular. CONCLUSIONS: Osteochondromas are unusual in the axial skeleton, and are rarely signaled by neural compression. Occurrence is generally in young adults in the second and third decades. Initial manifestation with a new neurologic deficit in a 66-year-old patient was highly unusual.

Aged↗

PubMed2003

Secondary chondrosarcoma in osteochondroma: report of 107 patients.

Secondary chondrosarcomas are rare; recognition and diagnosis are difficult. Slow growth and late recurrence require long-term followup to understand the clinical course. In the current study, 107 patients had secondary chondrosarcoma arising in a solitary osteochondroma (61 patients) or multiple exostoses (46 patients). All histologic slides were reviewed without knowledge of the outcome, and radiologic studies were available for review in 71 cases. Patients with secondary chondrosarcoma were one to two decades younger than those with primary chondrosarcoma. Male preponderance and a predilection for flat bones were observed. The radiologic signs of sarcomatous degeneration included irregularity of the margin, inhomogeneous mineralization, and an associated soft tissue mass. The tumors generally were well-differentiated. Only 10 tumors were classified as Grade 2. Five-year and 10-year local recurrence rates were 15.9% and 17.5%, respectively, and 5- and 10-year mortality rates were 1.6% and 4.8% for patients having initial treatment at the authors' institution. Metastasis developed in five patients: in the lung in four patients and in the groin region in one patient. Most patients who died of tumor died of local recurrence. Wide excision had the lowest local recurrence rate. With successful surgical treatment, patients may have long-term disease-free survival.

Adolescent↗

PubMed1987

Chondrosarcoma of the calcaneum and massive soft tissue calcification in a patient with hereditary and acquired connective tissue diseases.

We describe the first case of the coexistence of the hereditary connective tissue disorder multiple exostoses (HME) and an acquired connective tissue disorder manifest by the overlap of dermatomyositis (DM), scleroderma (PSS), high titre speckled pattern antinuclear antibodies, and increased antibodies to double stranded deoxyribonucleic acid (DNA). Furthermore this patient developed chondrosarcoma of the calcaneum (an unusual site for this malignancy) and massive soft tissue calcification (an unusual feature of PSS, adult DM, and systemic lupus erythematosus (SLE)).

Bone Neoplasms↗

PubMedDate not supplied

Imaging of osteochondroma: variants and complications with radiologic-pathologic correlation.

Osteochondroma represents the most common bone tumor and is a developmental lesion rather than a true neoplasm. It constitutes 20%-50% of all benign bone tumors and 10%-15% of all bone tumors. Its radiologic features are often pathognomonic and identically reflect its pathologic appearance. Osteochondromas are composed of cortical and medullary bone with an overlying hyaline cartilage cap and must demonstrate continuity with the underlying parent bone cortex and medullary canal. Osteochondromas may be solitary or multiple, the latter being associated with the autosomal dominant syndrome, hereditary multiple exostoses (HME). Complications associated with osteochondromas are more frequent with HME and include deformity (cosmetic and osseous), fracture, vascular compromise, neurologic sequelae, overlying bursa formation, and malignant transformation. Malignant transformation is seen in 1% of solitary osteochondromas and in 3%-5% of patients with HME. Continued lesion growth and a hyaline cartilage cap greater than 1.5 cm in thickness, after skeletal maturity, suggest malignant transformation. Variants of osteochondroma include subungual exostosis, dysplasia epiphysealis hemimelica, turret and traction exostoses, bizarre parosteal osteochondromatous proliferation, and florid reactive periostitis. Recognition of the radiologic spectrum of appearances of osteochondroma and its variants usually allows prospective diagnosis and differentiation of the numerous potential complications, thus helping guide therapy and improving patient management.

Biopsy↗

PubMed1994

Oxalosis associated with aluminum bone disease: a new type of mixed renal osteodystrophy.

An 18-year-old man suffering from uremia was hospitalized because of severe skeletal pain and multiple exostoses. The patient had been treated for 5 years by regular hemodialysis; primary oxalosis was the suspected cause of uremia. Transiliac bone biopsy and subsequent histomorphometric analysis of undecalcified bone specimen as well as specific aluminum staining revealed a picture of oxalosis combined with osteomalacia and a marked accumulation of aluminum at the front of mineralization. This combination of histological features of oxalosis and aluminum bone disease suggests a new type of mixed renal osteodystrophy.

Adolescent↗

PubMed2003

Developmental pathways in musculoskeletal neoplasia: involvement of the Indian Hedgehog-parathyroid hormone-related protein pathway.

There are many crucial genes and signaling pathways in the proper development of an organism. Pathologies may arise from a deregulation of these pathways. The Indian Hedgehog-PTH-related protein (Ihh-PTHrP) pathway is vital in the proper development of endochondral bones, such as the long bones. The Ihh-PTHrP pathway regulates the rate at which chondrocytes within the growth plate proliferate and differentiate. Thus, this pathway allows for the longitudinal growth of bones. However, a disruption in this pathway may lead to enchondromas and osteochondromas, which are both childhood cartilaginous neoplasms. Recently, our lab identified a mutant receptor for PTHrP in enchondroma samples. Mice expressing this mutant receptor and mice with increased Ihh activity develop conditions similar to human enchondromatosis. Linkage analysis shows an association between EXT genes and osteochondromas in hereditary multiple exostoses syndrome. Studies in Drosophila and mice suggest EXT gene products play a role in the diffusion of hedgehog proteins. A mutation in EXT genes may result in an abnormal Ihh diffusion pattern leading to an osteochondroma. There are agents that inhibit Hedgehog signaling. These agents may be useful in the treatment of enchondromas and osteochondromas. This review will discuss the discovery of the Ihh-PTHrP pathway and its involvement in neoplasia, and will suggest possible novel therapeutic agents in the treatment of these cartilaginous neoplasms.

Bone Development↗

PubMed1999

Osteochondroma with compression of the spinal cord. A report of two cases.

We report two cases of vertebral osteochondroma. In one patient a solitary cervical lesion presented as entrapment neuropathy of the ulnar nerve and in the other as a thoracic tumour associated with hereditary multiple exostoses producing paraplegia. We highlight the importance of an adequate preoperative evaluation in such patients.

Adolescent↗

PubMed2005

Ulnar focal cortical indentation: a previously unrecognised form of ulnar dysplasia.

Deformity of the forearm due to growth disturbance of the ulna occurs in a number of conditions such as ulnar deficiency, multiple exostoses, and neurofibromatosis. We report a previously unrecognised form, caused by focal cortical indentation. We have treated five children with this condition, three girls and two boys; the mean age at presentation was 5 years (2 to 8). The deformity was first recognised about the age of two years, and progressed gradually. The radiological findings were the same in all cases. The focal cortical indentation was seen at the distal end of the ulna with anteromedial bowing and dysplasia. The radial head was dislocated posterolaterally. In one patient the histological findings at the site of indentation were of a fold of tissue resembling periosteum, which interfered with enchondral ossification. Treatment by ulnar lengthening using an external fixator and osteotomy which corrected both the ulnar deformity and reduced the dislocated radial head in two cases gave the best results.

Bone Diseases, Developmental↗

PubMed1997

Multiple hereditary osteochondromatosis. Two cases with ankle and knee deformities.

Two case histories of multiple hereditary osteochondromatosis are presented. Multiple hereditary exostoses are the most common inherited systemic disorder of bone. The presence of ankle deformity in 50% of the cases and the potential for malignant transformation make this an important disease for the clinician to be familiar with.

Adult↗

PubMed1999

Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma.

Chondrosarcomas are malignant cartilaginous tumors arising centrally in bone (central chondrosarcoma), or secondarily within the cartilaginous cap of a hereditary or sporadic exostosis (peripheral chondrosarcoma). Loss of heterozygosity (LOH) was studied by microsatellite analysis at the loci harboring the EXT genes (implicated in hereditary multiple exostoses), the EXT-like genes, and at 9p21, 13q14, 17p13, and chromosome 10. Nineteen of 20 peripheral chondrosarcomas showed LOH at all loci tested, while only 3 of 12 central chondrosarcomas exhibited LOH, restricted to 9p21, 10, 13q14, and 17p13. LOH at 9p21 did not appear to involve the CDKN2A gene, as assessed by SSCP analysis. DNA flow cytometry demonstrated a wide variation in the ploidy status in peripheral chondrosarcomas (DNA indexes, 0.56-2.01), whereas central chondrosarcomas were predominantly peridiploid. Near-haploidy found in peripheral chondrosarcomas could explain part of the high LOH percentages. Ki-67 immunohistochemistry suggested a higher proliferation rate in peripheral chondrosarcomas. Our results indicate that peripheral chondrosarcomas, arising secondarily to an exostosis, may obtain genetic alterations during malignant transformation, with subsequent genetic instability as demonstrated by a high percentage of LOH and a wide variation in ploidy status. In contrast, peridiploidy and a low percentage of LOH in central tumors suggest that a different oncogenic molecular mechanism may be operative.

Adolescent↗

PubMed1976

[Study by gel electrophoresis, of alpha chains and of CNBr peptides of collagen from epiphyseal cartilage in chondrodysplasia].

The alpha chains and the major CNBr - derived peptides of collagen of growth cartilage were studied in the following syndromes: thanatophoric dwarfism, pseudothanatophoric dwarfism, achondroplasia, pseudoachondroplasia, diastrophic dwarfism, metatropic dwarfism, Kniest disease, parastremmatic dwarfism, multiple exostoses, Blount disease and pycnodysostosis. After extraction of proteoglycans the collagen was solubilized by limited pepsin digestion purified, and the alpha chains were analysed by electrophoresis. The major CNBr - derived peptides were obtained by cleaving directly the cartilage after proteoglycan extraction. In some syndromes purified collagen was also cleaved. The CNBr peptides were analyzed by disc electrophoresis in SDS-polyacrylamide. Human normal growth cartilage and baboon cartilage were used as controls. The pattern of alpha chains and of major CNBr peptides was similar in all the cases studied, except one case of lethal diastrophic dwarfism in which the pattern of peptides showed the presence of type I collagen in quantities detectable by the present method. However in a milder case of diastrophic dwarfism the pattern of CNBr peptides was found normal. The present study does not exclude possible abnormalities of collagen at a higher lever of supramolecular organization in osteochondrodysplasias.

Adolescent↗