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PubMed1995

[Multiple cartilagenous exostoses].

This is a review of aspects of hereditary multiple exostosis relevant for the orthopedic surgeon. The autosomally dominant hereditary disease with great individual expression is the result of dysplasia of the peripheral growth plate. During growth exostosis can induce severe secondary deformities and reduction of joint mobility, especially the forearm, knee and ankle. Treatment is surgical with the removal of symptom-producing exostoses the most common procedure. For corrective surgery careful preoperative planning, careful choice of treatment modality and sustained follow-up are necessary. The nearly 1% risk of malignant transformation, most frequently to low-grade chondrosarcoma, must be monitored. A rare complication is cervical cord compression.

Cell Transformation, Neoplastic↗
PubMed2006

Spinal cord compression in a patient with multiple hereditary exostoses caused by breast adenocarcinoma metastatic to osteochondromas of the spine: case report.

STUDY DESIGN: Case report. OBJECTIVE: To report on thoracic spinal cord compression caused by a mass in a 66-year-old female with new onset of myelopathic symptoms and a history of multiple hereditary exostoses. SUMMARY OF BACKGROUND DATA: To our knowledge, there have been no previous reports of spinal cord compression in a patient with multiple hereditary exostoses caused by breast adenocarcinoma metastatic to osteochondromas of the spine. METHODS.: Chart, pathologic, and radiographic documentation of the preoperative and postoperative clinical course of the patient was used. RESULTS: The patient had resolution of her neurologic symptoms following wide surgical excision, decompression, and stabilization from T2 to T10. The patient's mass was found to be breast adenocarcinoma metastatic to osteochondromas of the spine. CONCLUSIONS: When faced with a patient with a history of multiple hereditary exostoses with new onset of myelopathic symptoms and a mass compressing the spinal cord, the clinician's differential should be broad and always initially include a metastatic lesion, osteochondroma, or chondrosarcoma.

Adenocarcinoma↗
PubMed1999

The neoplastic pathogenesis of solitary and multiple osteochondromas.

Many theories of osteochondroma pathogenesis have been advanced. Genetic research into the inherited multiple form, hereditary multiple exostoses, has revealed a new family of tumour suppressor genes denoted EXT. Patterns of EXT gene mutation in hereditary multiple exostoses, in solitary and multiple osteochondromas, and in chondrosarcoma are analogous to those found in other tumour suppressor genes responsible for family cancer traits and associated malignancies. With one exception, most features of osteochondroma behaviour are comparable to those of benign neoplasms. The neoplastic pathogenesis of osteochondromas provides an alternative to the traditional 'skeletal dysplasia' theory to explain the growth disturbance associated with hereditary multiple exostoses. Recent studies on the physiological function of EXT genes are reviewed and implications for osteochondroma 'cell-of-origin' theories are discussed.

Bone Neoplasms↗
PubMed1995

Knee deformities in multiple hereditary exostoses. A longitudinal radiographic study.

For a mean period of 7.8 years, the morphology of knee deformity and its annual changes in 8 patients (16 knees; mean age at the initial examination, 8.4 years) with multiple hereditary exostoses were evaluated radiographically. Knee deformity developed during the growth spurt period. Genu valgum with a femorotibial angle that decreased more than 2 standard deviations from the mean of age-matched normal children was observed in 6 of the 16 knees. In 3 of these 6 knees, recurrent dislocation of the patella was observed. Angulation of the femur varied among the knees, but the tibia showed valgus angulation in the proximal metaphysis in all knees. Thus, knee deformity in patients with multiple hereditary exostoses was primarily genu valgum caused by valgus angulation of the tibia.

Child↗
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↗
PubMed1991

[Costal exostoses, complicated in the neonatal period, by brachial plexus paralysis. A distinct entity of exostoses?].

Two highly unusual cases of brachial plexus palsy due to compression by exostosis of the first rib in the neonatal period are reported. Etiologic diagnosis in these patients required elimination of other tumors of the first rib, including multiple exostoses. The contradictions found lead the authors to suggest individualization of a form of multiple exostoses different from classical multiple exostoses by a number of features including growth, complications, and inheritance. At present, it is not known whether this new entity carries the same risk of malignant transformation as classical multiple exostoses.

Bone Neoplasms↗
PubMed1986

Radionuclide bone imaging in diaphyseal aclasis with malignant change.

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.

Adolescent↗
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↗
PubMedDate not supplied

Herpes simplex virus: discovering the link between heparan sulphate and hereditary bone tumours.

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.

Cell Line↗
PubMed1989

Tricho-rhino-phalangeal syndrome type I with severe mental retardation due to interstitial deletion of 8q23.3-24.13.

Here we report on a 13-year-old boy who had an interstitial deletion of the long arm of chromosome 8 [46,XY,del(8)(pter----q23.3::q24.13----qter)]. He had the facial features of the tricho-rhino-phalangeal (TRP) syndrome and severe mental retardation, but lacked multiple exostoses. This is the first report with such a peculiar combination of abnormalities and interstitial deletion of 8q.

Chromosome Banding↗
PubMed2005

Novel EXT1 and EXT2 mutations identified by DHPLC in Italian patients with multiple osteochondromas.

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.

Alternative Splicing↗
PubMed1997

Genomic organization and promoter structure of the human EXT1 gene.

Hereditary predisposition to multiple exostoses is a genetically heterogeneous disease. Recently, we have reported the identification of the EXT1 gene on human chromosome 8. We have now isolated a cDNA clone from a human adult lung cDNA library and have determined the genomic organization and promoter structure of the EXT1 gene. The gene is composed of 11 exons, ranging from 90 to 1735 bp, and spans approximately 350 kb of genomic DNA. Sequence analysis of the promoter region revealed the presence of a CpG island containing GC and CAAT boxes, but no TATA box. Such a promoter is characteristic for housekeeping genes. This finding is in good agreement with the ubiquitous expression of the EXT1 gene.

Adult↗
PubMed1999

New perspectives on the molecular basis of hereditary bone tumours.

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.

Aged↗
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↗
PubMed1999

Molecular and clinical examination of an Italian DEFECT11 family.

The DEFECT11 syndrome is a contiguous gene syndrome associated with deletions in the proximal part of chromosome 11p. In this study, we describe in an Italian family the co-existence of multiple exostoses (EXT) and enlarged parietal foramina (FPP), the two major symptoms of this syndrome, with abnormalities of the central nervous system. The latter may be a yet undescribed feature of DEFECT11 syndrome. FISH and molecular analysis allowed us to identify a small deletion on 11p11-p12, further refining the localisation of the FPP gene involved in the DEFECT11 syndrome.

Adult↗
PubMed1984

The Ale-Calo syndrome in monozygotic twins associated with bilateral cryptorchidism--case report.

A case report of identical male twins with the clinical and radiological features of the rare Ale - Calo or M.E.M.R. (Multiple Exostoses - Mental Retardation) or Langer-Giedion's syndrome - is presented. The additional finding of bilateral cryptorchidism in our case is also very rare in twins, and has hitherto not been described in association with the Ale - Calo syndrome. Differential diagnosis is reviewed briefly.

Child↗
PubMed1981

[Ulno-volar bayonet hand: its differential diagnosis from Madelung's deformity (author's transl)].

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.

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↗