SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
A case of hereditary multiple exostoses with spinal cord compression by a costal exostosis is reported in a 12-year-old boy. Paraplegia is an unusual complication of hereditary multiple exostoses. In the patient with spinal cord signs, the offending exostoses should be defined with appropriate roentgenograms and myelographic and CT scanning investigations.
Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function.
Hereditary multiple exostosis (EXT) is an autosomal dominant condition mainly characterized by the presence of multiple exostoses on the long bones. These exostoses are benign cartilaginous tumors (enchondromata). Three different EXT loci on chromosomes 8q (EXT1), 11p (EXT2) and 19p (EXT3) have been reported, and recently the EXT1 gene was identified by positional cloning. To isolate the EXT2 gene, we constructed a contig of yeast artificial chromosomes (YAC) and P1 clones covering the complete EXT2 candidate region on chromosome 11p11-p12. One of the transcribed sequences isolated from this region corresponds to a novel gene with homology to the EXT1 gene, and harbours inactivating mutations in different patients with hereditary multiple exostoses. This indicates that this gene is the EXT2 gene. EXT2 has an open reading frame encoding 718 amino acids with an overall homology of 30.9% with EXT1, suggesting that a family of related genes might be responsible for the development of EXT.
Hereditary multiple exostosis is a genetic disorder characterized by multiple osteochondromas that can cause pain, deformity, and potential malignant degeneration. Linkage analysis has identified a family of EXT genes which, if mutated, can lose heterozygosity and potentially cause osteochondromas. A database was established of 43 patients with hereditary multiple exostoses treated at a tertiary pediatric healthcare system. Twenty patients had a known family history of the disorder. All patients were diagnosed between birth and 13 years. Symptoms or deformity were observed in the forearms of 29 patients, the knees of 37 patients, and the ankles of 28 patients. Valgus knee deformity related to hereditary multiple exostoses, previously reported to be attributable to proximal tibial changes alone, resulted from proximal tibial or distal femoral valgus deformities in this series. Twenty-seven patients required between one and five surgeries to address their lesions. No patient had malignant degeneration of an osteochondroma; however, three patients had first-degree relatives with transformation of an osteochondroma to chondrosarcoma. This database now may be a resource for additional analysis. By correlating specific genetic mutations with clinical manifestations, it may be possible to stratify patients into subtypes of hereditary multiple exostoses and identify genetic markers associated with malignant degeneration.
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.
OBJECTIVES/HYPOTHESIS: This study was undertaken to assess a transcanal osteotome technique for removing symptomatic ear canal exostoses. Outcome measures included healing rates and the rate of complications. STUDY DESIGN: Prospective study in a private practice. METHODS: A straight 1-mm osteotome and a curved 1-mm osteotome were used by way of a transcanal approach to incrementally remove obstructive ear canal exostoses. If anterior or superior bone growths were closely approximating the tympanic membrane, they were partially removed with a 1.5 mm cylindrical end- and side-cutting burr. Healing rates were monitored with weekly postoperative visits. RESULTS: Two hundred twenty-one ear canals (140 patients) were consecutively treated with this technique. Healing was achieved at 2 to 8 (average 3.50) weeks, with 90% healed by 4 weeks. There were 4 mobilizations of a full-thickness segment of anterior bony canal wall; 3 exposures of periosteum anterior to the anterior bony wall; 1 tear of the tympanic membrane requiring a tympanoplasty; 18 anterior and 11 posterior tympanic membrane tears that healed spontaneously; 3 instances of sensorineural hearing decrease; 3 cases of new-onset postoperative tinnitus; and 1 instance of postoperative positioning vertigo. There were no lacerations of the tympanic membrane by an osteotome, no facial nerve injuries, no soft tissue stenoses of an ear canal, and no skin grafting of an ear canal. CONCLUSIONS: The described technique of using osteotomes transcanal for removal of symptomatic obstructive ear canal exostoses promoted rapid healing and was effective and safe.
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.
Hereditary multiple exostoses is a dominantly inherited skeletal disorder which alters enchondral bone during growth and is characterised by exostoses of the juxta-epiphyseal regions. Using polymorphic DNA probes, we have been able to exclude the disease gene from close proximity to the 8q24.1 region where a dominant syndrome with multiple exostoses, the trichorhinophalangeal syndrome type II (TRP II, Langer-Giedion syndrome, MIM 15025), has been previously localised (pairwise linkage Z = -8.96 at theta = 0 with probe L48 at locus D8S51). Multipoint linkage analysis using probes L48, L24, and L1 consistently excluded the HME gene from a large area of the distal long arm of chromosome 8, spanning the smallest region of overlap assigned to the TRP II gene. These studies support the clinical view that HME and TRP II are distinct entities.
Computed tomograms of 16 benign exostoses and 15 exostotic chondrosarcomas were generally accurate in delineating anatomy for purposes of planning surgery, but they were inaccurate in the detection and measurement of the cartilage caps of the lesions. CT studies of 14 of the benign exostoses failed to show any cartilage cap, although the maximum cartilage thickness of these 14 lesions ranged from 0.1 to 2.5 cm pathologically. CT did demonstrate thick cartilage in 14 of the 15 chondrosarcomas, but the CT measurements of maximum thickness often were imprecise. Altogether, 15 CT studies failed to show any cartilage cap; 14 of these lesions were benign. CT did not reliably detect cartilage caps less than 2.5 cm in maximum thickness, and CT measurement of cartilage thickness was imprecise when the cartilage was 1.5 to 2.5 cm thick. For this reason, CT did not solve the difficult problem of distinguishing between benign exostoses with relatively thick cartilage caps and exostotic chondrosarcomas with relatively thin cartilage.
Twenty-two cases of multiple hereditary exostoses revealed pathological changes in two areas: the first group caused by epiphyseal disturbances, and the second group due to mechanical problems created by the exostoses. The epiphyseal disturbances resulted in ankle valgus, shortened metatarsals, and angular deformities of the necks of the metatarsals. The exostoses produced local tenderness, synostosis of the medical subtalar facet resulting is loss of subtalar motion, and asymptomatic synostosis of the lower tibial fibular syndesmosis.
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.
Multiple hereditary exostoses is an autosomal dominant skeletal disorder in which there are numerous cartilage-capped excrescences in areas of actively growing bone. The condition is genetically heterogeneous, and at least three genes, ext1, ext2 and ext3 are involved. The reported risk for malignant transformation to chondrosarcoma has been from 0.6% to 2.8%. We have reviewed six generations of a family with 114 living adult members, 46 of them with multiple exostoses. Four have had operations for chondrosarcoma, giving the risk for malignant transformation as 8.3% in this family. Clinical and radiological examination revealed two additional patients with a suspicion of malignancy, but in whom the histological findings were benign. Reported elsewhere in detail, genetic linkage analysis mapped the causative gene to chromosome 11 and molecular studies revealed a guanine-to-thymine transversion in the ext2 gene. Patients with multiple hereditary exostoses carry a relatively high risk of malignant transformation. They should be informed of this possibility and regularly reviewed.
Hereditary multiple exostoses is an autosomal dominant disorder characterised by multiple osteochondromata, most commonly affecting the forearm, knee and ankle. Osteochondromata of the proximal femur have been reported to occur in 30% to 90% of affected patients with coxa valga in 25%. Acetabular dysplasia is rare but has been described. This is the first report of a patient requiring surgical intervention. A girl was seen at the age of nine with hereditary multiple exostoses and when 12 developed bilateral pain in the groin. Radiographs showed severely dysplastic acetabula with less than 50% coverage of the femoral heads and widening of the medial joint space. Large sessile osteochondromata were present along the medial side of the femoral neck proximal to the lesser trochanter, with associated coxa valga. The case illustrates the importance of obtaining initial skeletal surveys in children with hereditary multiple exostoses to identify potential problems such as acetabular dysplasia and subluxation of the hip.
Hereditary multiple exostoses is a relatively uncommon disorder of endochondral bone characterized by the presence of multiple, cartilaginous-capped exostoses arising from the metaphyses. A rare presentation of hereditary multiple exostoses in the calcaneus of a 35-year-old man is reviewed and discussed. A brief review of the literature is provided, as well as a discussion of the patient's family history.
27 patients treated surgically at Child Orthopaedic Clinic of Pomeranian Medical Academy between 1974-1996 for multiple cartilaginous exostosis (Aclasia Diaphysealis Keith) were classified into three groups according to the Taniguchi classification. This classification is based on whether multiple cartilaginous exostoses are present on distal forearm. Group I--no involvement of the distal forearm (n = 2), in group II involvement of the distal forearm without shortening of either bone (n = 7) was stated. Group III consists of members with involvement of the distal forearm with shortening the radius or the ulna (n = 18). Groups were compared with regard to: number of lesions, distribution of exostoses in different body areas, age of onset of the Keith disease, height of children, presence of valgus deformity of the ankle, dislocation of the radial head and presence of exostoses around hip area. This classification should be useful in estimating severity of Keith disease, identifying cases at high risk for complications like dislocation of the radial and malignant transformation.
Hereditary multiple exostoses (HME) is traditionally described as a skeletal dysplasia. However, the discovery that the EXT family of tumour suppressor genes are responsible for HME suggests that it is more appropriate to classify HME as a familial neoplastic trait. In a clinical and radiographic analysis of paired bone length and exostoses number and dimensions in a HME cohort, the local presence of osteochondromas was consistently associated with growth disturbance. In particular, an inverse correlation between osteochondroma size and relative bone length (p<0.01) was found. These data suggest that the growth retardation in HME may result from the local effects of enlarging osteochondromas rather than a skeletal dysplasia effect. This study provides the first clinical rationale for ablation of rapidly enlarging exostoses to reduce growth disturbance.
The clinicopathologic aspects of multiple cartilaginous exostoses (MCE) in 2 dogs were compared with those in 9 previously reported cases of MCE in dogs. Although a familial tendency is probable, there is apparently no sex or breed predilection. Only bones that developed by endochondral ossification were affected. The vertebrae, ribs, and long bones were the most frequent location of exostoses. Bones of the carpal and tarsal joints and the skull were not affected in the cases evaluated. Physical examination and radiography may provide strong supportive evidence for a diagnosis of MCE, but a definitive diagnosis must be based on microscopic evaluation of osseous lesions. Treatment is unnecessary unless growth of exostoses results in clinical sequelae. Surgical extirpation of lesions should be considered if dysfunction of the skeletal, muscular, or neurologic systems develops. The prognosis is variable, being dependent on the location and number of lesions, the age of the patient at the time of diagnosis, and the presence or absence of clinical complications.
Hereditary multiple exostoses is an autosomal dominant disorder characterised by the presence of multiple osteochondromas, resulting in a variety of skeletal deformities. It is a genetically heterogeneous condition for which two genes, EXT1 and EXT2, have been isolated. The EXT1 gene, located at 8q24, has been shown to harbour mutations in 44-66% of the hereditary multiple exostoses-families. Mutations in the EXT2 gene, located at 11p11-p12, are detected in about 30% of the families. Additional linkage to chromosome 19p suggests the existence of an EXT3 gene. EXT1 has been shown to act as a tumour suppressor gene in hereditary multiple exostoses, resulting in osteochondroma formation when both copies of EXT1 are lost. Diagnostic germ-line mutation analysis is operative in the Clinical Genetic Center Leiden, the Netherlands.