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PubMed2002

Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis.

EXT1 and EXT2 are genes that have been shown to cause hereditary multiple exostosis (HME), a syndrome marked by the formation of bony growths juxtaposed to the growth plate. These genes are members of a growing family of proteins with glycosyltransferase activity required for the synthesis of heparan sulfate chains. This protein activity is predicted to play a role in the expression of proteoglycans on the cell surface and in the extracellular matrix. We and others have previously suggested that a two-hit mutational model applies to the development of an exostosis where a germline mutation coupled with a somatic mutation results in the loss of EXT1 or EXT2 function and subsequent tumor formation. We report the direct sequencing and loss of heterozygosity (LOH) analysis of 12 exostoses from 10 HME families, 4 solitary exostoses, and their corresponding constitutional DNA. Of the 16 exostoses screened, we find only one solitary case in which two somatic mutations, a deletion and an LOH, are present. This provides limited support for the two-hit hypothesis involving the EXT1 and EXT2 genes for the development of an exostosis. Alternative models are developed based on the functional significance of EXT proteins in heparan sulfate biosynthesis.

Exostoses, Multiple Hereditary↗
PubMed1997

Identification of novel mutations in the human EXT1 tumor suppressor gene.

Hereditary multiple exostoses (EXT) is a genetically heterogeneous bone disorder caused by genes segregating on human chromosomes 8, 11, and 19 and designated EXT1, EXT2 and EXT3, respectively. Recently, the EXT1 gene has been isolated and partially characterized and appears to encode a tumor suppressor gene. We have identified six mutations in the human EXT1 gene from six unrelated multiple exostoses families segregating for the EXT gene on chromosome 8. One of the mutations we detected is the same 1-bp deletion in exon 6 that was previously reported in two independent EXT families. The other five mutations, in exons 1, 6, 9, and the splice junction at the 3' end of exon 2, are novel. In each case, the mutation is likely to result in a truncated or nonfunctional EXT1 protein. These results corroborate and extend the previous report of mutations in this gene in two EXT families, and provide additional support for the EXT1 gene as the cause of hereditary multiple exostoses in families showing linkage to chromosome 8.

Alternative Splicing↗
PubMed2002

Exostosis following a free gingival graft.

BACKGROUND: There have been few cases reported of exostoses following a free gingival graft. In 1980, a free gingival graft was placed on the facial level of 33-34, developing over the years a significant enlargement. In 1999, since the patient felt progressively uncomfortable with the enlarged area, its surgical reduction was proposed. METHOD: Under local anesthesia, the hard tissue developed under the previously-grafted area, was significantly reduced. The specimen, together with a fragment of the covering soft tissue, was sent for histological analysis. RESULTS: The surgical wound healed uneventfully, and the patient was satisfied with the results. The histology showed the presence of mature bone surrounded by a dense connective tissue, whereas the gingival tissue showed acanthosis and fibrosis. CONCLUSION: The development of exostoses following a free gingival graft can be considered an unpredictable, albeit infrequent side-effect of this procedure. The fact that most of these exostoses appear in the cuspid-premolar area, deserves further consideration.

Adult↗
PubMed1998

The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate.

Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by the formation of cartilage-capped tumours (exostoses) that develop from the growth plate of endochondral bone. This condition can lead to skeletal abnormalities, short stature and malignant transformation of exostoses to chondrosarcomas or osteosarcomas. Linkage analyses have identified three different genes for HME, EXT1 on 8q24.1, EXT2 on 11p11-13 and EXT3 on 19p (refs 6-9). Most HME cases have been attributed to missense or frameshift mutations in these tumour-supressor genes, whose functions have remained obscure. Here, we show that EXT1 is an ER-resident type II transmembrane glycoprotein whose expression in cells results in the alteration of the synthesis and display of cell surface heparan sulfate glycosaminoglycans (GAGs). Two EXT1 variants containing aetiologic missense mutations failed to alter cell-surface glycosaminoglycans, despite retaining their ER-localization.

Animals↗
PubMed1997

[Subungueal exostosis of fingers in hereditary multiple exostosis. 3 cases].

INTRODUCTION: The multiple exostosis syndrome is a rare disease transmitted by autosomal dominant inheritance. Bone growth projecting outward from the long bones is observed in multiple localizations during growth. Prognosis of this benign disease is worsened by the possibility of chondrosarcoma. We report three cases of subungueal exostoses observed in children revealing hereditary exostosis. CASE REPORTS: Clinical examination evidenced progressive deformation of several fingers. In all three patients. There was subungueal tumefaction raising a fissured nail with longitudinal crests. In two cases there were also skeletal deformations. Radiograms showed multiple exostoses of the long bones in all three cases and in one a tumefaction of the scapula in addition to visualizing the subungueal exostoses. There was a family history of such manifestations in all cases. DISCUSSION: Subungueal exostosis is frequent in young adults, usually located in the large toe. These three observations were particularly interesting due to the subungueal localization during the first decade of life. Such localization are rare and usually concern several fingers.

Adolescent↗
PubMed2005

Ear problems in swimmers.

Acute diffuse otitis externa (swimmer's ear), otomycosis, exostoses, traumatic eardrum perforation, middle ear infection, and barotraumas of the inner ear are common problems in swimmers and people engaged in aqua activities. The most common ear problem in swimmers is acute diffuse otitis externa, with Pseudomonas aeruginosa being the most common pathogen. The symptoms are itching, otalgia, otorrhea, and conductive hearing loss. The treatment includes frequent cleansing of the ear canal, pain control, oral or topical medications, acidification of the ear canal, and control of predisposing factors. Swimming in polluted waters and ear-canal cleaning with cotton-tip applicators should be avoided. Exostoses are usually seen in people who swim in cold water and present with symptoms of accumulated debris, otorrhea and conductive hearing loss. The treatment for exostoses is transmeatal surgical removal of the tumors. Traumatic eardrum perforations may occur during water skiing or scuba diving and present with symptoms of hearing loss, otalgia, otorrhea, tinnitus and vertigo. Tympanoplasty might be needed if the perforations do not heal spontaneously. Patients with chronic otitis media with active drainage should avoid swimming, while patients who have undergone mastoidectomy and who have no cavity problems may swim. For children with ventilation tubes, surface swimming is safe in a clean, chlorinated swimming pool. Sudden sensorineural hearing loss and some degree of vertigo may occur after diving because of rupture of the round or oval window membrane.

Acute Disease↗
PubMedDate not supplied

[Orthopedic considerations of trichorhinophalangeal syndrome type II].

INTRODUCTION: The trichorhinophalangeal syndrome type II or Langer-Giedion syndrome is regarded as a rare abnormity that is marked by a number of clinical characteristics beside multiple cartilaginous exostoses. RESULTS: The deviation of the fingers within the scope of the TRPS II that is often reported in literature can not be found in the case at issue of a now 14 year old boy. The course of disease was complicated due to consecutive axis deviation of two large joints of the lower extremities being determined by the syndrome. Due to the marked exostoses in the area of the growth plate of the left knee joint a valgus deformity developed there. It was corrected with means of a temporary clamping of the growth plate. With the increasing valgus deformity of the right ankle causing a calcaneovalgus foot deformity the osteochondroma located at the distal fibula was also removed and a temporary clamping of the growth plate was carried out at the right medial malleolus. From earliest childhood repeating cartilaginous exostoses both at the extremities and the trunk attracted attention. Also strongly developed are the facial distinguishing marks which determine the typical shape of the face. CONCLUSION: By the case of a now 14 year old boy with severe orthopedic complications considerations are made concerning therapeutic principles due to the TRPS II.

Adolescent↗
PubMed1986

Scintigraphic findings of multiple osteochondromas.

Multiple osteochondromas (hereditary multiple exostoses, diaphyseal aclasis, cartilagenous exostoses) are anomalies of bone development in which multiple cartilagenous exostoses grow out from the cortical surface, mainly involving ends of the long bones. While radiographic characteristics of multiple osteochondromas have been well documented, there is little information concerning the place of bone imaging in this disease. A patient with multiple osteochondromas whose skeletal scintigrams correlate with the concurrent radiographs is presented. Although there is no specific pattern scintigraphically, the abnormal, irregular increase in radioactivity at the end of the long bones may raise a possibility of this disease entity.

Adult↗
PubMedDate not supplied

Malignant transformation of solitary spinal osteochondroma in two mature dogs.

Canine osteochondroma is an uncommon bony tumor that arises in skeletally immature animals. Consequently, clinical signs typically occur in young dogs as a result of impingement of normal structures by the tumor. Radiographically, osteochondromas are benign in appearance. They are well circumscribed and cause no bony lysis nor periosteal proliferation. Osteochondromas may occur in two forms; solitary or multiple. Although histology and biologic behavior are identical, when in the multiple form the condition has been termed multiple cartilaginous exostoses. Malignant transformation of multiple cartilaginous exostoses has been reported in three mature dogs. We report two dogs with malignant transformation of solitary spinal osteochondromas. Both underwent transformation to osteosarcoma. Despite the benign radiographic appearance of osteochondromas and multiple cartilaginous exostoses, clinical signs should alert the clinician to the possibility of malignant transformation.

Age Factors↗
PubMedDate not supplied

A newly recognized pattern of canine osteochondromatosis.

Clinicopathological findings are described for a unique skeletal pattern of osteochondromatosis (syn. multiple osteochondromas) in three crossbred littermate dogs. Multiple nonpainful bilaterally symmetric skeletal lesions arose from focal semiannular and annular areas of periosteal thickening on the cortical surface of the metaphyses and diaphyses of long bones. Flat bones of the skull were spared. In radiographs osteochondromas in different stages of evolution were apparent. Grossly there were smoothly contoured, nodular subperiosteal masses of dense fibrocartilaginous and osseous tissue that were continuous with and overlying apparently normal but thin trabeculae of cancellous bone. Cortical compacta was attenuated or absent beneath exostoses. In histologic sections of the cartilage-capped exostoses a hyperplastic periosteum formed a focal semiannular or annular cap of proliferative hyaline cartilage tissue that underwent endochondral ossification and replacement by cancellous bone at its base. Intertrabecular spaces in the cancellous bone of exostoses were filled with fibro-osseous and hematopoietic tissue. A hereditary origin was suspected for the osteochondromas. Origin of some osteochondromas as semiannular or annular perturbations of the perichondrial ring of metaphyseal physes of long bones likely contributed to limb shortening and a pattern of billaterally symmetric angular limb deformities of all limbs as occurs in some children affected by osteochondromatosis.

Animals↗
PubMed1992

The orthopaedic manifestations of the Langer-Giedion syndrome.

Less than 50 cases of Langer-Giedion syndrome (also known as trichorhinophalangeal syndrome with exostoses) have been reported in the English literature since its first description in 1974. Affected individuals have been described as having a bulbous nose, micrognathia, short stature, multiple cartilaginous exostoses, and large, protruding ears. We recently treated a 5-year-old, mentally retarded boy with Langer-Giedion syndrome for symptomatic multiple exostoses involving his proximal tibia and distal femur. This paper will highlight the musculoskeletal abnormalities found in this child and compare them to those of 43 patients reported in the world literature. The comparison reveals a very distinctive pattern of exostosis, demonstrating a primary altered growth pattern in the lower extremities and deformity secondary to marked ligamentous laxity. Orthopaedic surgeons are frequently the first consultants to see these children for their obvious osteochondromata. They must consider the diagnosis of Langer-Giedion syndrome to facilitate the treatment of its other manifestations.

Child↗
PubMed1990

[Two unusual periosteal exotoses].

After maceration of the skeleton of 2 persons we found 2 different solitary exostoses; one at the sciatic tuber, in the other at the sciatic tuber, in the other at the ventral side of the distal fibula. The exostoses reach a length of 2 cm. Prescher (1987) described a cartilaginous exostosis with a length of 2 cm at the proximal tibia. In our cases the exostoses belong to the periosteal form. We consider them to be bony origins of ligaments: at the sciatic tuber--the bony origin of the sacrotuberal ligament, at the distal fibula--the bony origin of the peroneal compartment of the retinaculum mm extensorum inferius.

Fibula↗
PubMed1985

Periosteal stimulation by artificial tension.

The role of tension in the formation of exostoses in lathyritic rats was studied by applying artificial tension to the tendon of insertion of the adductor longus muscle. Exostoses were formed in the periosteum at the insertion site in rats fed a 50% Lathyrus odoratus diet, given artificial tension and a normal diet, and given artificial tension and a lathyrus diet. The latter were the largest. It is concluded that tension plays an important role in the formation of lathyritic exostoses and that tension alone can cause exostosis formation in the rat.

Animals↗
PubMed2000

Cytoskeletal abnormalities in chondrocytes with EXT1 and EXT2 mutations.

The EXT genes are a group of putative tumor suppressor genes that previously have been shown to participate in the development of hereditary multiple exostoses (HME), HME-associated and isolated chondrosarcomas. Two HME disease genes, EXT1 and EXT2, have been identified and are expressed ubiquitously. However, the only known effect of mutations in the EXT genes is on chondrocyte function as evidenced by aberrant proliferation of chondrocytes leading to formation of bony, cartilage-capped projections (exostoses). In this study, we have characterized exostosis chondrocytes from three patients with HME (one with EXT1 and two with EXT2 germline mutations) and from one individual with a non-HME, isolated exostosis. At the light microscopic level, exostosis chondrocytes have a stellate appearance with elongated inclusions in the cytoplasm. Confocal and immunofluorescence of in vitro and in vivo chondrocytes showed that these massive accumulations are composed of actin bundled by 1.5-microm repeat cross-bridges of alpha-actinin. Western blot analysis shows that exostosis chondrocytes from two out of three patients aberrantly produce high levels of muscle-specific alpha-actin, whereas beta-actin levels are similar to normal chondrocytes. These findings suggest that mutations in the EXT genes cause abnormal processing of cytoskeleton proteins in chondrocytes.

Actinin↗
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↗
PubMed2000

EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis.

Hereditary multiple exostoses (HME) is a genetically heterogeneous disease characterized by the development of bony protuberances at the ends of all long bones. Genetic analyses have revealed HME to be a multigenic disorder linked to three loci on chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (EXT3). The EXT1 and EXT2 genes have been cloned and defined as glycosyltransferases involved in the synthesis of heparan sulfate. EST database analysis has demonstrated additional gene family members, EXT-like genes (EXTL1, EXTL2, and EXTL3), not associated with a HME locus. The mouse homologs of EXT1 and EXT2 have also been cloned and shown to be 99% and 95% identical to their human counterparts, respectively. Here, we report the identification of the mouse EXTL1 gene and show it is 74% identical to the human EXTL1 gene. Expression studies of all three mouse EXT genes throughout various stages of embryonic development were carried out and whole-mount in situ hybridization in the developing limb buds showed high levels of expression of all three EXT genes. However, in situ hybridization of sectioned embryos revealed remarkable differences in expression profiles of EXT1, EXT2, and EXTL1. The identical expression patterns found for the EXT1 and EXT2 genes support the recent observation that both proteins form a glycosyltransferase complex. We suggest a model for exostoses formation based on the involvement of EXT1 and EXT2 in the Indian hedgehog/parathyroid hormone-related peptide (PTHrP) signaling pathway, an important regulator of the chondrocyte maturation process.

Amino Acid Sequence↗
PubMed2006

Rearrangement of the COL12A1 and COL4A5 genes in subungual exostosis: molecular cytogenetic delineation of the tumor-specific translocation t(X;6)(q13-14;q22).

Subungual exostosis is a benign bone- and cartilage-producing tumor occurring in the hands and feet of children and young adults. The recent identification of a recurrent chromosomal translocation t(X;6)(q24-q26;q15-21) in short-term-cultured tumor cells strongly suggests that subungual exostosis is a neoplastic lesion caused by rearrangement of genes in the two breakpoints. To identify the genes that are critical for neoplastic transformation, we have studied five subungual exostoses by interphase or metaphase FISH. The results of these analyses demonstrated a clustering of the breakpoints to the regions harboring the collagen genes COL12A1 and COL4A5 in chromosome bands 6q13-14 and Xq22, respectively. Furthermore, in all but one case, these two genes were shown to colocalize on the derivative chromosomes X and 6, strongly suggesting that at least one of them is consistently involved in the formation of a chimeric fusion gene or in the exchange of regulatory sequences. Because collagen molecules are important for tissue remodeling during physiologic growth and differentiation, both COL12A1 and COL4A5 constitute good candidate target genes in the pathogenesis of subungual exostosis. Further investigations on the transcript level are required to elucidate the functional outcome of the t(X;6) translocation in subungual exostoses.

Adolescent↗
PubMed2002

Transgenic expression of the EXT2 gene in developing chondrocytes enhances the synthesis of heparan sulfate and bone formation in mice.

Hereditary multiple exostoses (HME), a dominantly inherited disorder characterized by multiple cartilaginous tumors, is caused by mutations in the gene for, EXT1 or EXT2. Recent studies have revealed that EXT1 and EXT2 are required for the biosynthesis of heparan sulfate and exert maximal transferase activity as a complex. The Drosophila homologue of EXT1 (tout-velu) regulates the movement and signaling of Hedgehog protein, which plays an important role in the regulation of chondrocyte differentiation and bone development. In this study, to investigate the biological role of EXT2 in bone development in vivo and the pathological role of HME mutations in the development of exostoses, we generated transgenic mice expressing EXT2 or mutant EXT2 in developing chondrocytes. Histological analyses and micro-CT scanning showed that the biosynthesis of heparan sulfate and the formation of trabeculae were upregulated in EXT2-transgenic mice, but not in mutant EXT2-transgenic mice. The expression of EXT1 is concomitantly upregulated in EXT2-transgenic and even mutant EXT2-transgenic mice, suggesting an interactive regulation of EXT1 and EXT2 expression. These findings support that the EXT2 gene encodes an essential component of the glycosyltransferase complex required for the biosynthesis of heparan sulfate, which may eventually modulate the signaling involved in bone formation.

Animals↗