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We investigated 11 families with hereditary multiple exostoses (EXT) by linkage analysis using 8 short-tandem-repeat (CA)n polymorphic markers on chromosomes 8, 11 and 19. The Lod score in four families indicated that the gene responsible for EXT is located in the pericentromeric region of chromosome 11.
A case of osteosarcoma arising from a multiple exostoses lesion is presented. Poorly differentiated osteosarcoma occurred in a twelve-year-old girl's proximal tibia where an exostosis was confirmed from radiographs. We treated this patient with preoperative chemotherapy, thigh amputation and postoperative chemotherapy, but she died of multiple pulmonary metastases seven months after surgery. The osteosarcoma, complicated by multiple exostoses, had a very poor prognosis because it was resistant to various anticancer agents.
OBJECTIVE: To study the gene mutation in a patient with multiple exostoses, identify the disease-causing gene mutation. METHODS: Polymerase chain reaction and DNA sequencing were used to screen the EXT1 or EXT2 gene mutation, while mismatch primer amplification and restriction endonuclease digestion were performed to confirm the mutation. RESULTS: By DNA sequencing, a mutation in the seventh intron was detected and located at 26 bp of 3' splice site upstream in EXT1 gene, which was unreported before. Mismatch primer amplification and restriction fragment length polymorphism analysis suggested that this mutation was not detected in the normal control. CONCLUSION: The mutation 1633-26(C-->A) may be the disease-causing mutation in this patient with multiple exostoses.
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In a large family with 37 members with multiple exostoses, only one person has developed sarcomatous degeneration of a lesion. Our review of published reports revealed great variation in the incidence of malignancy in multiple exostoses (10 to 25%). Most studies had sampling errors leading to the apparent overstatement of risk. In large pedigrees with essentially complete ascertainment of affected subjects, the risk of malignancy is nearer 3% or less. This lower risk for malignancy may be more appropriate in counselling affected subjects.
Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of exostoses, which are cartilage-capped bony protuberances mainly located on long bones. Two genes, EXT1 and EXT2, and at least one other unidentified gene, are known to be involved in the formation of exostoses. To date, 49 different EXT1 and 25 different EXT2 mutations have been found in EXT patients, and there is evidence that mutations in these two genes are responsible for over 70% of the EXT cases. Among the 49 EXT1 mutations there are 9 nonsense, 21 frameshift, and 5 splice site mutations; 2 in-frame deletions of 1 and 5 amino acids respectively; and 12 missense mutations. For EXT2, 8 nonsense, 11 frameshift, 3 splice site and 3 missense mutations are described. The majority of these mutations are mutations causing loss of function, which is consistent with the presumed tumor suppressor function of the EXT genes.
Substantiated myelopathy in hereditary multiple exostoses is very rare. A few cases have been reported previously. We report a case of a 17-year-old boy with two exostoses in the cervical spine, in one of which caused a high cervical cord compression.
A female, 10 years of age, with hereditary multiple exostoses presented with shoulder drop and asymmetry. The results of neurologic examination were normal and winging was not accentuated by active maneuvers of the shoulder. Scapular exostosis was demonstrated to be the structural cause of scapular winging. Only a few cases of children with scapular winging caused by scapular tumors have been reported. However, tumors of the scapula should be excluded in children with static winging of the scapula.
This is a report of a family with major focus on the daughter who was of short stature. The mother had hypochondroplasia and the father had multiple exostoses. The daughter's skeletal roentgenograms show features of both hypochondroplasia and multiple exostoses. The roentgenographic, clinical and genetic aspects of these skeletal dysplasias are reviewed and hypochondroplasia is contrasted with achondroplasia. The genetic and counseling implications of the association of hypochondroplasia and multiple exostoses are discussed.
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.
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Two boys from separate families presented with hereditary multiple exostoses (EXT) and autism associated with mental retardation. Their fathers both expressed a clinical phenotype of hereditary multiple exostoses milder than those of the patients and without the associated mental disorder. The EXT1 and EXT2 genes from lymphocytes of the affected individuals were analyzed by using denaturing high-performance liquid chromatography and direct sequencing. A novel deletion mutation, 1742delTGT-G in exon 9 of EXT1, causing a frameshift was detected in one boy and his father. Another novel deletion mutation, 2093delTT in exon 11 of EXT1, causing transcription termination was detected in the other affected boy and his father. EXT1 is expressed in the brain, and both EXT1 and EXT2 proteins are associated with glycosyltransferase activities required for the biosynthesis of heparan sulfate, which also has activity in the brain. The coincidental association of mental disorders in the boys was not completely excluded. However, these results suggest the involvement of EXT1 in the development of mental disorders, including mental retardation and autism.
Hereditary multiple exostoses (EXT) is an autosomal dominant disorder of enchondral bone formation characterized by multiple bony outgrowths (exostoses), with progression to osteosarcoma in a minority of cases. The exclusive involvement of skeletal abnormalities distinguishes EXT from the clinically more complex Langer-Giedion syndrome (LGS), which is associated with deletions at chromosome 8q24. Previously, linkage analysis has revealed a locus for EXT in the LGS region on chromosome 8q24. However, locus heterogeneity was apparent with 30% of the families being unlinked to 8q24. We report on two large pedigrees segregating EXT in which linkage to the LGS region was excluded. To localize the EXT gene(s) in these families we performed a genome search including 254 microsatellite markers dispersed over all autosomes and the X chromosome. In both families evidence was obtained for linkage to markers from the proximal short and long arms of chromosome 11. Two-point analysis gave the highest lod score for D11S554 (Zmax = 7.148 at theta = 0.03). Multipoint analysis indicated a map position for the EXT gene between D11S905 and D11S916, with a peak multipoint lod score of 8.10 at 6 cM from D11S935. The assignment of a second locus for EXT to the pericentromeric region of chromosome 11 implicates an area that is particularly rich in genes responsible for developmental abnormalities and neoplasia.
We report an 18-year-old male with multiple exostoses, dysmorphic features, mental retardation and myopathy. The case is discussed in the light of previously reported disorders in which multiple exostoses are associated with neurological impairment.
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.
Analysis of 330 exostoses in 18 patients affected by hereditary multiple exostoses disease suggested a new classification of exostoses as eccentric or full-thickness. Radiographically arrest of metaphyseal remodeling with failure of coning and persistence of the primary metaphyseal trabeculae was evident in full-thickness exostoses. Similar bone lesions can be obtained experimentally with inhibitors of bone turn-over. A localized, peripheral defect in remodeling over a limited time can give a satisfactory explanation also for the origin of eccentric exostoses. The thesis that this is the basic mechanism of exostosis formation is presented.
Hereditary multiple exostoses usually involve the long bones, but occasionally the spine. When the spine is involved, serious neurologic deficits may occur. We report a case of a 12-year-old girl with an exostosis in the cervical spine (C5), which caused a spastic quadriplegia.