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Diaphyseal aclasis (multiple hereditary exostoses) occurs in the bones developed in cartilage and gives rise to cartilage-capped exostoses. It usually affects the ends of the diaphyses of long bones of extremities (McKusick, 1972). Although the phalanges of the fingers may be shorter than normal, no record could be found of significant deformity. A case of digital deformity is described below.
A patient harboring multiple hereditary exostoses with a long-lasting tetraparesis owing to intraspinal osteochondroma is described. The results of surgical treatment were poor in contrast to the results achieved by other previous authors performing decompression of the spinal cord. The related literature is briefly reviewed and conclusions are drawn in favor of computed tomographic examination of the spine of patients with vertebral complaints.
INTRODUCTION: Intra-acetabular localisation of an osteochondroma causing subluxation of the hip joint is a rare entity in children suffering from multiple hereditary exostoses. In literature only 6 operatively treated cases have been reported. CASE: We add the case of an 8-year-old boy with an intraarticular exostosis of the left acetabulum causing subluxation of the hip. Using an anterolateral approach to the hip joint this exostosis was removed surgically together with some extraarticular exostoses of the proximal femur. The hip could be re-centered in combination with an additional varus derotation osteotomy of the proximal femur. Intraoperatively the femoral head was only subluxated to minimise the risk of avascular necrosis. After a follow-up of two years the patient has complete remission of symptoms and there is no evidence of avascular necrosis radiologically with good remodelling of the left hip. CONCLUSION: The operative treatment of an intraarticular exostosis of the hip joint is a difficult and risky surgical procedure. The reported open surgical procedure allowed resection of the intraarticular exostosis in combination with therapy of additional pathologies of the proximal femur.
Chondrosarcoma is a rare complication in hereditary multiple exostoses. The six patients in this study have had a complete follow-up and constitute the largest group of such cases to have been studied so far. Five patients had histologic evidence of malignancy. Since histologic examination can be very difficult, any other diagnostic features, may it be clinical, radiologic, or scintigraphical, should be taken into account for early surgical treatment. Bone scintigraphic examination is a valuable adjunct to early diagnosis of malignant change by showing highest uptake in malignant areas. It is also very useful for posttherapeutic follow-up.
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.
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.
To gain entry into the host, viruses use host cell surface molecules that normally serve as receptors for other ligands. Herpes simplex virus type 1 (HSV-1) uses heparan sulphate (HS) glycosaminoglycans (GAGs) as receptors for initial attachment to the host cell surface. HS GAGs are both ubiquitous and structurally diverse, and normally serve as critical mediators of interactions between the cell and the extracellular environment. We have used the HS binding ability of HSV-1 to identify the function of a cellular gene, EXT1, which is involved in HS polymerisation. Cellular factors that affect virus growth and replication are often key regulators of the cell cycle and EXT1 is no different-humans with inherited mutations in EXT1 have developmental defects that lead to bone tumours (hereditary multiple exostoses, HME) and sometimes chondrosarcomas. Thus, as a result of using HSV-1 as a molecular probe, a functionally orphaned disease gene now has a defined function. These findings highlight the utility of viruses for investigating important cellular processes.
We describe the results of an optimised DHPLC-based mutation screening of the EXT1 and EXT2 genes in Italian patients affected by multiple osteochondromas [MO; also referred to as hereditary multiple exostoses (HME) in the literature], using a multistep approach. We first analysed 36 unrelated probands for EXT1 mutations by DHPLC analysis and subsequent direct sequencing of all samples with abnormal elution profile. Negative cases were then screened for EXT2 mutations using the same approach. In patients who tested normal at DHPLC screening, all EXT1 and EXT2 exons and splice-site junctions were directly sequenced. In 7 informative families, we also performed a pre-screening linkage analysis to selectively focus the DHPLC testing on the EXT1 or EXT2 gene. We detected 31 MO-related mutations, of which 23 (74%) were novel. Seven polymorphisms were also found. Twenty-four mutations (77%) were found in EXT1 and 7 (23%) in EXT2. No disease-causing mutations were detected in five of 36 patients, with a mutation frequency of 86%. According with previous studies, most mutations (90%) are loss of function. Neither false positive nor false negative results were obtained. This multistep method can be considered a fast and reliable diagnostic strategy for the detection of EXT1/2 mutations, with excellent sensitivity and specificity.
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.
Bone development is a highly regulated process sensitive to a wide variety of hormones, inflammatory mediators and growth factors. One of the most common hereditary skeletal dysplasias, hereditary multiple exostoses (HME), is an autosomal dominant disorder characterized by skeletal malformations that manifest as bony, benign tumours near the end of long bones. HME is usually caused by defects in either one of two genes, EXT1 and EXT2, which encode enzymes that catalyse the biosynthesis of heparan sulphate, an important component of the extracellular matrix. Thus, HME-linked bone tumours, like many other skeletal dysplasias, probably result from disruptions in cell surface architecture. However, despite the recent success in unravelling functions for several members of the EXT gene family, significant challenges remain before this knowledge can be used to develop new approaches for the diagnosis and treatment of disease.
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.
The ulno-volar bayonet hand related to the mostly hereditary multiple exostoses is compared to Madelung's forearm deformity under clinical and roentgenological view in differential diagnosis. The ulno-volar bayonet hand is considerably more seldom, basing upon dysplasia of the lower part of the ulna, less inconvenient in function, and hardly tending to the development of early arthrosis.
Hereditary multiple exostoses, characterized by multiple cartilaginous tumors, is ascribed to mutations at three distinct loci, denoted EXT1-3. Here, we report the purification of a protein from bovine serum that harbored the D-glucuronyl (GlcA) and N-acetyl-D-glucosaminyl (GlcNAc) transferase activities required for biosynthesis of the glycosaminoglycan, heparan sulfate (HS). This protein was identified as EXT2. Expression of EXT2 yielded a protein with both glycosyltransferase activities. Moreover, EXT1, previously found to rescue defective HS biosynthesis (McCormick, C., Leduc, Y., Martindale, D., Mattison, K., Esford, L. E., Dyer, A. P., and Tufaro, F. (1998) Nat. Genet. 19, 158-161), was shown to elevate the low GlcA and GlcNAc transferase levels of mutant cells. Thus at least two members of the EXT family of tumor suppressors encode glycosyltransferases involved in the chain elongation step of HS biosynthesis.
Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by inappropriate chondrocyte proliferation and bone growth arising at the juxtaepiphyseal region of the long bones. HME is caused by mutations in the EXT 1 and EXT 2 genes, which have glycosyltransferase activity. These genes are responsible for synthesis of heparan sulfate (HS) chains, which are important signaling molecules in chondrocyte differentiation. HME chondrocytes in monolayer culture have been shown by transmission electron and deconvolution microscopy to contain enormous bundles of actin, cross-linked with muscle specific alpha-actinin. Here additional ultrastructural anomalies in HME chondrocytes are reported, including lobulated nuclei, shortened channels of rER, large numbers of cell processes and podosomes, nontypical junctions, elongated, bulbous-ended mitochondria, and reduced extracellular matrix. Microfilaments are present throughout the cytoplasm, compartmentalizing it, and isolating organelles. The excess microfilaments, attributed to increased cell adhesiveness, are likely to interfere with secretion and cytokinesis, and sterically hinder intracellular organelle differentiation. The observed surface modifications and cytoskeletal abnormalities are proposed to play a role in development of the mutant phenotype, via changes in cell adhesiveness and/or binding of signals to receptors, which results in loss of the unidirectionality of growth in the epiphyseal plate.
Heparan sulfate proteoglycans (HSPG) have been implicated in regulating the signalling activities of secreted morphogen molecules including Wingless (Wg), Hedgehog (Hh) and Decapentaplegic (Dpp). HSPG consists of a protein core to which heparan sulfate (HS) glycosaminoglycan (GAG) chains are attached. The formation of HS GAG chains is catalyzed by glycosyltransferases encoded by members of the EXT family of putative tumor suppressors linked to hereditary multiple exostoses. Previous studies in Drosophila demonstrated that tout-velu (ttv), the Drosophila EXT1, is required for Hh movement. However, the functions of other EXT family members are unknown. We have identified and isolated the other two members of the Drosophila EXT family genes, which are named sister of tout-velu (sotv) and brother of tout-velu (botv), and encode Drosophila homologues of vertebrate EXT2 and EXT-like 3 (EXTL3), respectively. We show that both Hh and Dpp signalling activities, as well as their morphogen distributions, are defective in cells mutant for ttv, sotv or botv in the wing disc. Surprisingly, although Wg morphogen distribution is abnormal in ttv, sotv and botv, Wg signalling is only defective in botv mutants or ttv-sotv double mutants, and not in ttv nor sotv alone, suggesting that Ttv and Sotv are redundant in Wg signalling. We demonstrate further that Ttv and Sotv form a complex and are co-localized in vivo. Our results, along with previous studies on Ttv, provide evidence that all three Drosophila EXT proteins are required for the biosynthesis of HSPGs, and for the gradient formation of the Wg, Hh and Dpp morphogens. Our results also suggest that HSPGs have two distinct roles in Wg morphogen distribution and signalling.
Studies in Drosophila and vertebrate systems have demonstrated that heparan sulfate proteoglycans (HSPGs) play crucial roles in modulating growth factor signaling. We have isolated mutations in sister of tout velu (sotv), a gene that encodes a co-polymerase that synthesizes HSPG glycosaminoglycan (GAG) chains. Our phenotypic and biochemical analyses reveal that HS levels are dramatically reduced in the absence of Sotv or its partner co-polymerase Tout velu (Ttv), suggesting that both copolymerases are essential for GAG synthesis. Furthermore, we find that mutations in sotv and ttv impair Hh, Wg and Decapentaplegic (Dpp) signaling. This contrasts with previous studies that suggested loss of ttv compromises only Hh signaling. Our results may contribute to understanding the biological basis of hereditary multiple exostoses (HME), a disease associated with bone overgrowth that results from mutations in EXT1 and EXT2, the human orthologs of ttv and sotv.
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.
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.