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PubMed1993

The gradual correction of forearm deformities in multiple hereditary exostoses.

Careful preoperative planning, fixator selection and design, surgical technique, and sustained follow-up care are essential for successful gradual correction of pediatric forearm deformities. The sequence of planning gradual deformity correction can be created by establishing a problem list and using this as the basis for design of the gradual correction. Viewing limb length and deformity correction as a "process," rather than a procedure, is of value. Using a hybrid fixation formula that combines half pins with wires can minimize the potential for neurovascular injury. The combination of radial osteotomy, excision of osteochondromas, and gradual ulnar lengthening by distraction osteogenesis improves forearm appearance and function in most patients with multiple hereditary exostoses.

Biomechanical Phenomena↗
PubMed1993

Multiple hereditary exostoses. An epidemiologic study of an isolated community in Manitoba.

From 1986 through 1988, 266 persons (149 adults and 117 children) were screened for multiple hereditary exostosis (MHE) in an isolated northern Ojibway community. Physical examination and confirmation by roentgenogram skeletal survey disclosed 21 children (19.4%) and 14 adults (9.5%) affected with MHE. Forty-one percent of children had lesions detectable before ten years of age, some as early as two years of age. Seventy-four percent of the lesions were characteristically sessile. Although lesions about the knee were most common, sites previously thought to be uncommon such as the metatarsals, hand, and spine were involved in 40% of the children. No cases of malignant degeneration have occurred in the adult population. Severity and multiplicity of lesions in successive generations point to an oncogenic gene origin. This study shows striking variance from current literature and provides a unique and valuable baseline assessment of research on the cause and natural history of MHE.

Adolescent↗
PubMed2000

EXT 1 gene mutation induces chondrocyte cytoskeletal abnormalities and defective collagen expression in the exostoses.

Hereditary multiple exostoses (HME), an autosomal skeletal disorder characterized by cartilage-capped excrescences, has been ascribed to mutations in EXT 1 and EXT 2, two tumor suppressor-related genes encoding glycosyltransferases involved in the heparan sulfate proteoglycan (HSPG) biosynthesis. Taking advantage of the availability of three different exostoses from a patient with HME harboring a premature termination codon in the EXT 1 gene, morphological, immunologic, and biochemical analyses of the samples were carried out. The cartilaginous exostosis, when compared with control cartilage, exhibited alterations in the distribution and morphology of chondrocytes with abundant bundles of actin filaments indicative of cytoskeletal defects. Chondrocytes in the exostosis were surrounded by an extracellular matrix containing abnormally high amounts of collagen type X. The unexpected presence of collagen type I unevenly distributed in the cartilage matrix further suggested that some of the hypertrophic chondrocytes detected in the cartilaginous caps of the exostoses underwent accelerated differentiation. The two mineralized exostoses presented lamellar bone arrangement undergoing intense remodeling as evidenced by the presence of numerous reversal lines. The increased electrophoretic mobility of chondroitin sulfate and dermatan sulfate proteoglycans (PGs) extracted from the two bony exostoses was ascribed to an absence of the decorin core protein. Altogether, these data indicate that EXT mutations might induce a defective endochondral ossification process in exostoses by altering actin distribution and chondrocyte differentiation and by promoting primary calcification through decorin removal.

Adolescent↗
PubMed1998

Structure, chromosomal location, and expression profile of EXTR1 and EXTR2, new members of the multiple exostoses gene family.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder that is characterized by the appearance of multiple outgrowths of the long bones (exostoses) at their epiphyses. Genetical heterogeneities have segregated at least on chromosome 8, 11, and 19 and been designated EXT1, EXT2, and EXT3, respectively. Recently, the responsible genes for EXT1 and EXT2 have been isolated and appeared to define a structurally related gene family. In the present study, we have identified novel genes which share significant sequence homologies with the EXT genes. The predicted protein products of the novel EXT-related genes, EXTR and EXTR2 (for EXT-related genes 1 and 2), consist of 919 and 330 amino acid residues, respectively. These genes were transcribed ubiquitously in various tissues. Based on PCR-assisted analyses of both a human/rodent mono-chromosomal hybrid cell panel and a radiation hybrid mapping panel, EXTR1 was localized to the chromosome 8p21 region, where loss of heterozygosity has been frequently observed in various tumors, and EXTR2 was assigned to the chromosome 1p21 region, where osteopetrosis, a dominant hereditary disease of bone, has been mapped by genetic linkage analysis, implying that the protein products of these two EXT-related genes, as well as of the EXT genes, have potential tumor suppressor activity.

Amino Acid Sequence↗
PubMed1998

Expression and functional analysis of mouse EXT1, a homolog of the human multiple exostoses type 1 gene.

Hereditary multiple exostoses (EXT) is a genetically heterogeneous, autosomal dominant skeletal disorder. The gene for EXT1 maps to human chromosome 8q24.1 and encodes an evolutionary conserved protein that is a member of a multigene family. The mouse homolog of human EXT1 protein is 99% similar to its human counterpart. Here, we present the expression profiles of the mouse EXT1 gene. EXT1 mRNA is initially expressed at 6.5 days post-coitum (d.p.c.), which coincides with gastrulation of the mouse embryo. Whole mount in situ hybridization with 10.5 to 12.5 d.p.c. mouse embryos showed a high level of expression of EXT1 mRNA in developing limb buds. Epitope tagging experiments revealed the endoplasmic reticulum localization of EXT1 protein. This localization was consistent with a hydrophobic stretch of amino acids present at the N-terminal end of the EXT1 protein. These results provide novel information on the function of EXT1 and the etiology of hereditary multiple exostoses.

3T3 Cells↗
PubMed1997

Identification and localization of the gene for EXTL, a third member of the multiple exostoses gene family.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by multiple bony outgrowths from the juxtaepiphyseal region of long bones. In a small proportion of cases, these exostoses progress to malignant chondrosarcomas. Genetic linkage of this disorder has been described to three independent loci on chromosomes 8q24.1 (EXT1), 11p11-13 (EXT2), and 19p (EXT-3). The EXT1 and EXT2 genes were isolated recently and show extensive sequence homology to each other. These genes are deleted in exostoses-derived tumors, supporting the hypothesis that they encode tumor suppressors. We have identified a third gene that shows striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels, and have derived its entire coding sequence. Although the mRNA transcribed from this gene is similar in size to that from EXT1 and EXT2, its pattern of expression is quite different. We have localized this gene by fluorescence in situ hybridization to metaphase chromosomes and by whole genome radiation hybrid mapping to chromosome 1p36.1 between DIS458 and DIS511, region that frequently shows loss of heterozygosity in a variety of tumor types. This gene, EXTL (for EXT-like), is therefore a new member of the EXT gene family and is a potential candidate for several disease phenotypes.

Amino Acid Sequence↗
PubMed2005

Mice deficient in Ext2 lack heparan sulfate and develop exostoses.

Hereditary multiple exostoses (HME) is a genetically heterogeneous human disease characterized by the development of bony outgrowths near the ends of long bones. HME results from mutations in EXT1 and EXT2, genes that encode glycosyltransferases that synthesize heparan sulfate chains. To study the relationship of the disease to mutations in these genes, we generated Ext2-null mice by gene targeting. Homozygous mutant embryos developed normally until embryonic day 6.0, when they became growth arrested and failed to gastrulate, pointing to the early essential role for heparan sulfate in developing embryos. Heterozygotes had a normal lifespan and were fertile; however, analysis of their skeletons showed that about one-third of the animals formed one or more ectopic bone growths (exostoses). Significantly, all of the mice showed multiple abnormalities in cartilage differentiation, including disorganization of chondrocytes in long bones and premature hypertrophy in costochondral cartilage. These changes were not attributable to a defect in hedgehog signaling, suggesting that they arise from deficiencies in other heparan sulfate-dependent pathways. The finding that haploinsufficiency triggers abnormal cartilage differentiation gives insight into the complex molecular mechanisms underlying the development of exostoses.

Amino Acid Sequence↗