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PubMed1996

Delineation of a contiguous gene syndrome with multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation, caused by deletions in the short arm of chromosome 11.

A contiguous gene syndrome due to deletions of the proximal short arm of chromosome 11 is described in eight patients belonging to four families. The main clinical features are multiple exostoses, enlarged parietal foramina, craniofacial dysostosis, and mental retardation. The patients have cytogenetic and/or molecular deletions of chromosome 11p11-p13. These deletions are located between the centromere and D11S914 in a region of approximately 20cM. The present study confirms the presence of a multiple exostoses gene on chromosome 11p. Furthermore, it suggests that the gene for isolated foramina parietalie permagna and genes associated with craniofacial dysostosis and mental retardation reside in the same chromosomal region.

Abnormalities, Multiple↗
PubMedDate not supplied

Radiographic diagnosis: cartilaginous exostoses in a dog.

A 6 month-old dog was examined for progressive paraparesis. On physical examination bony malformations were palpated over the cranial lumbar vertebral bodies and on the left metatarsal bone. Neuroanatomic lesion localization for the paraparesis was a T3-L3 spinal cord lesion. Radiographs confirmed bony masses at L1-L2 and on the left 3rd metatarsal bone. Magnetic resonance imaging was performed from T3-L3. Severe spinal cord compression was identified at L1-L2. Surgical decompression and biopsy confirmed the mass to be cartilaginous exostoses. This paper is an example of cartilaginous exostoses imaged with MR.

Animals↗
PubMed1983

Scintigraphy of benign exostoses and exostotic chondrosarcomas.

Technetium-99m diphosphonate scintigraphy of 11 benign exostoses and nine exostotic chondrosarcomas was correlated with pathologic macrosections of the resected tumors. Increased uptake in benign exostoses occurred in areas of enchondral ossification, and uptake in chondrosarcomas occurred in areas where ossification, osteoblastic activity, and hyperemia were found. Uptake was not related to amorphous cartilage calcification. Radiopharmaceutical uptake, therefore, correlated with areas of ossification visible radiographically, and large masses of nonossifying cartilage were not detected. Radionuclide bone imaging did not contribute to the preoperative anatomic evaluation of these tumors, and it did not always distinguish benign from malignant lesions.

Adolescent↗
PubMed1975

Spinal cord compression caused by osteocartilaginous exostoses of the spine in two dogs.

Two dogs, one 4 months old and the other 1 year old, had histories of progressive posterior weakness. In both cases, there was severe asymmetric proprioceptive loss but appreciable preservation of strength. Benign, cystic expansile lesions involving the facets and lamina of the thoracic spine were observed radiographically; a single lesioons was demonstrated in the other. Examination of biopsy speciments taken at the time of laminectomy revealed the lesions to be osteocartilaginous exostoses (osteochondromas, ecchondromas, exostoses). The progress of dogs 1 and 2 has been monitored for 1 1/2 years and 9 months, respectively. Dog 1 has no weakness or proprioceptive loss; dog 2 has a mild proprioceptive loss in the right hindlimb.

Animals↗
PubMed1991

High-resolution real-time sonography and MR imaging in assessment of osteocartilaginous exostoses.

High-resolution real-time ultrasonography (US) and MR imaging, using both spin-echo (SE) and gradient-echo (GE) sequences, were performed prospectively in 14 patients with solitary osteocartilaginous exostoses to assess cartilage cap thickness and bursa formation. Results were compared to surgical and histopathologic findings in all cases. Both US and MR imaging were useful in evaluating exostotic cartilage cap thickness, which is supposed to be the most reliable sign of malignant transformation. Hyaline cartilage matrix had distinctive features in US and MR imaging caused by its specific histologic composition. The formation of bursae over the protruding exostoses, which results in pain and clinically could raise the suspicion of growth and malignant transformation, was demonstrated best using GE sequences. MR imaging was thus superior to US in the detection of bursa formation.

Adolescent↗
PubMed1996

Hereditary multiple exostoses: confirmation of linkage to chromosomes 8 and 11.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage capped prominences that develop from the epiphyses of the long bones. EXT is heterogeneous with three different locations currently identified on chromosomes 8, 11, and 19. Recently, we identified and studied 12 large multigenerational EXT families. Linkage analyses demonstrates that 6 of these families map to 8q24 and 6 to 11p. None of the families map to the chromosome 19 locus. The results suggest that there are two major loci, on chromosomes 8 and 11, involved in the cause of EXT. The locus on chromosome 19 remains to be confirmed.

Chromosomes, Human, Pair 11↗
PubMed1998

Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas.

BACKGROUND: Osteochondroma most frequently arises sporadically and as a solitary lesion, but also may arise as multiple lesions characterizing the autosomal dominant disorder hereditary multiple exostoses (HME) and the contiguous gene syndromes Langer-Giedion and DEFECT-11 syndromes. HME is genetically heterogeneous with association of three loci including 8q24.1 (EXT1), 11p11-12 (EXT2), and 19p (EXT3). Constitutional chromosomal microdeletions of 8q24.1 and 11p11-12 are features of the Langer-Giedion and DEFECT-11 syndromes, respectively. Cytogenetic studies of osteochondroma are rare. METHODS: Cytogenetic analysis was performed on 34 osteochondroma specimens from 22 patients with sporadic lesions and 4 patients with HME utilizing standard methodologies. Fluorescence in situ hybridization with chromosome specific probes was performed on three cases to define structural rearrangements further. RESULTS: Clonal abnormalities were detected in ten cases. Notably, deletion of 11p11-13 was observed in one case (a sporadic tumor) and loss or rearrangement of 8q22-24.1 in eight cases (seven sporadic and one hereditary tumor). CONCLUSIONS: These findings: 1) confirm previous observations of 8q24.1 karyotypic anomalies in sporadic osteochondroma, 2) reveal the presence of somatic chromosomal anomalies in hereditary osteochondromata, 3) suggest that similar to hereditary lesions, sporadic osteochondromas also are genetically heterogeneic (involvement of both 8q24.1 and 11p11-12), and 4) support the hypothesis that loss or mutation of EXT1 and EXT2, two putative tumor suppressor genes, may be important in the pathogenesis of sporadic as well as hereditary osteochondromata.

Adolescent↗
PubMed1998

A novel splice site mutation of the EXT2 gene in a Finnish hereditary multiple exostoses family. Mutations in brief no. 197. Online.

Hereditary multiple exostoses is a dominantly inherited disease characterized by multiple benign osteochondromas. The affected individuals have an increased risk of developing sarcoma. A large Finnish family with hereditary multiple exostosis was analyzed to find the disease-causing mutation. Blood samples were obtained from 35 family members, including 21 affected and 14 unaffected individuals. Using 2-point linkage analysis the EXT phenotype was shown to be linked to the recently cloned EXT2 gene on chromosome 11p11. The coding region of the gene was sequenced and a previously unreported splice site mutation found. This G to T transversion within a 5-prime splice donor site following exon 6 was shown to cause aberrant splicing of RNA. The described change is considered to be a novel disease-causing mutation in the EXT2 gene.

Alternative Splicing↗
PubMed2001

Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses.

Hereditary multiple exostoses (EXT) is an autosomal dominant bone disease characterized by the formation of cartilage-capped prominences. EXT is genetically heterogeneous with at least four chromosomal loci. Among the four loci, the exostosis type 1 gene (EXT1) and type 2 gene (EXT2) have been cloned. Previous studies have shown that disease-type-specific frequency of mutations is different among various ethnic populations. To determine those frequencies in the Japanese, we conducted a large-scale mutation screening on both genes. In 23 of 43 Japanese families examined, we found 21 different mutations, of which 18 are novel. Seventeen (40%) of the 23 families had a mutation in EXT1 and six (14%) had a mutation in EXT2, suggesting that the former mutations are more frequent than the latter in Japanese EXT families. Of the 17 families with EXT1 mutations, 13 had those causing premature termination of the EXT1 protein and four showed missense mutations, whereas five of the six families with EXT2 mutations had those causing premature termination and one showed missense mutation. Interestingly, all four EXT1 missense mutations occurred in an arginine residue at codon 340 (R340) that is known as a critical site for expression of heparan sulfate glycosaminoglycans, suggesting that the region encompassing the arginine residue may play an important role in the function of the EXT1 protein. These results expand our knowledge of the ethnic difference of EXT and the structure-function relationship of the EXT genes.

DNA↗
PubMed1984

The tricho-rhino-phalangeal syndrome with exostoses (or Langer-Giedion syndrome): four additional patients without mental retardation and review of the literature.

We report on four patients with tricho-rhino-phalangeal syndrome with exostoses (TRPSE) who were not mentally retarded and review 32 previously published cases. These data enable more complete delineation of the phenotype and document the variability of the clinical and radiographic manifestations. Information on the genetics and the association with del(8q) is discussed, as are management and avenues for further investigation. The apparent variability of intelligence in TRPSE patients together with the high incidence of other problems, including significant delay in speech development and hearing loss, make systematic multidisciplinary evaluation and long-term treatment necessary to achieve the best outcome.

Abnormalities, Multiple↗
PubMed2003

Reciprocal translocation associated with multiple exostoses in seven members of a three generation family and discovered through an infertile male.

We report a four generations family with multiple exostoses segregating with a reciprocal translocation t(8;19)(q24.11;q13.13) in 8 members of three generations. FISH investigations detected a breakage of the dosage-sensitive EXT1 gene. Although three members of the family died perinatally from unknown causes and one carrier had four spontaneous abortions, the translocation was discovered only when the cytogenetic analysis was requested in an affected male because of oligozoospermia. In fact, it is well known that infertile males may be carriers of reciprocal or Robertsonian translocations with a higher frequency than the general population. This family stresses the importance of requesting the cytogenetic analysis in all cases in which a dominant disease segregates with repeated miscarriages and/or newborn deaths of unknown cause.

Adult↗
PubMed1994

Mapping of the 8q23 translocation breakpoint of t(8;13) observed in a patient with multiple exostoses.

A detailed cytogenetic map was constructed around the chromosomal breakpoint of t(8;13) observed in a patient with multiple exostoses. The order of seven loci defined by cosmid clones mapped to 8q23 was determined by means of two-color fluorescence in situ hybridization (FISH) on elongated prophase chromosomes, and localizations of these markers relative to the breakpoint were examined. The results indicated that loci defined by cC18-553 and cC18-1512 flank the breakpoint. By pulsed-field gel electrophoresis of DNA digested with BssHII and Southern hybridization with cC18-1512, DNA from the patient showed a band which was not observed in DNA isolated from either parent. As the normal size of this BssHII fragment is 600 kb, the chromosomal breakpoint probably lies less than 600 kb away from cC18-1512.

Cell Line↗
PubMed2004

Two-color multiplex ligation-dependent probe amplification: detecting genomic rearrangements in hereditary multiple exostoses.

Genomic deletions and duplications play an important role in the etiology of human disease. Versatile tests are required to detect these rearrangements, both in research and diagnostic settings. Multiplex ligation-dependent probe amplification (MLPA) is such a technique, allowing the rapid and precise quantification of up to 40 sequences within a nucleic acid sample using a one-tube assay. Current MLPA probe design, however, involves time-consuming and costly steps for probe generation. To bypass these limitations we set out to use chemically synthesized oligonucleotide probes only. The inherent limitations of this approach are related to oligonucleotide length, and thus the number of probes that can be combined in one assay is also limited. This problem was tackled by designing a two-color assay, combining two sets of probes, each amplified by primers labeled with a different fluorophore. In this way we successfully combined 28 probes in a single reaction. The assay designed was used to screen for the presence of deletions and duplications in patients with hereditary multiple exostoses (HME). Screening 18 patients without detectable point mutations in the EXT1 and EXT2 genes revealed five cases with deletions of one or more exons: four in EXT1 and one in EXT2. Our results show that a two-color MLPA assay using only synthetic oligonucleotides provides an attractive alternative for probe design. The approach is especially suited for cases in which the number of patients to be tested is limited, making it financially unattractive to invest in cloning.

Chromosome Aberrations↗
PubMed2000

Association of EXT1 and EXT2, hereditary multiple exostoses gene products, in Golgi apparatus.

We prepared the specific antibodies for EXT1 and EXT2, hereditary multiple exostoses (HME) gene products, and characterized their expression, subcellular localization, and protein association among EXT members. Biochemical analyses indicate that EXT1 and EXT2 can associate and form homo/hetero-oligomers in vivo with or without HME-linked mutations, EXT1 (R340C) and EXT2 (D227N), when exogenously expressed in COS-7 cells. An immunocytochemical analysis showed that both EXT1 and EXT2 localized in Golgi apparatus, irrespective of HME mutations. An immunohistochemical analysis on developing bones further showed that both EXT1 and EXT2 were concomitantly expressed in hypertrophic chondrocytes of forelimb bones from 1-day-old neonatal mouse, but down-regulated in maturing chondrocytes of developing cartilage from 21-day-old mouse. Taken together with the recent finding that EXTs encode for the glycosyltransferase required for the synthesis of heparan sulfate [Lind, T., Tufaro, F., McCormick, C., Lindahl, U., and Lindholt, K. (1998) J. Biol. Chem. 273, 26265-26268], our results implied a molecular basis that a HME-linked mutation found in EXT genes could interfere the physiological function(s) of EXT homo/hetero-oligomers as glycosyltransferases in the developing bones of HME patients.

Animals↗
PubMed1997

Cervical spinal cord compression in hereditary multiple exostoses. Report of a case and a review of the literature.

Spinal cord compression is an extremely serious complication of hereditary multiple exostoses (HME). A case of HME with compression of the cervical spinal cord is reported. Complete recovery following surgery was achieved. A review of the relevant literature revealed 51 previous cases of HME with cord/cauda equina compression. Most patients were under 30 years of age with more men affected than women. The family history was positive in 60%. The cervical and thoracic areas were predominantly affected, with the symptoms usually developing slowly. Recovery following surgery is to be expected in the majority of cases. In patients with HME and suffering from neurological symptoms, the possibility of spinal cord compression should be considered. Prompt diagnosis and surgical excision provide the best prognosis.

Adolescent↗
PubMed2005

[Hereditary multiple exostoses. Molecular genetic analysis of the EXT1 gene in an unusual family].

Hereditary multiple exostosis (HME), a disorder inherited in an autosomal dominant manner, is characterized by multiple projections of bone, mainly at the extremities. The risk of malignant transformation of the exostoses is estimated to be up to 2%. The most common underlying cause of the disease involves mutations in either the EXT1 or the EXT2 gene. We report on the clinical and molecular findings in a family affected with HME.A mother and her three children from different partnerships, all clinically diagnosed with HME, were referred for genetic counseling. Subsequently, molecular analysis of the EXT1 gene was performed according to standard procedures. We identified a mutation in the EXT1 gene in all four affected family members (delA in codon 133). This mutation has not been previously described and is suggested to cause the disease in this family. Identification of disease causing mutations in patients with HME and their relatives can help to improve the clinical management of tumor prevention, early tumor detection, and orthopedic therapy.

Adolescent↗
PubMedDate not supplied

Hereditary multiple exostoses with pseudoaneurysm.

A 16-year-old male patient with hereditary multiple exostoses (HME) was found to have a pseudoaneurysm of the left popliteal artery caused by osteochondroma in the lower femur. The diagnosis was confirmed by ultrasound, magnetic resonance imaging and magnetic resonance angiography without the need to perform an angiogram. The osteochondroma was excised and the popliteal artery was repaired with a saphenous graft. Vascular complications are extremely rare in HME, pseudoaneurysm being the most common and mostly located in the popliteal artery. This complication should be considered in young HME patients with a mass at the knee region. The radiological spectrum of investigations allows the diagnosis of this complication with proper and less invasive management procedures for the patient.

Adolescent↗