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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↗
PubMed1989

[Multiple exostoses disease (observations in 21 reported cases)].

With reference to 21 cases the authors describe the clinical, radiological and anatomo-pathological findings of multiple exostoses disease. The indications for the surgical treatment are discussed; they are, however, the same to the solitary osteochondroma.

Adolescent↗
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↗
PubMed2001

Hereditary multiple exostoses: from genetics to clinical syndrome and complications.

OBJECTIVE: To give an overview of genetic, clinical and radiological aspects in two families over four generations with known hereditary multiple exostoses (HME). METHODS AND MATERIAL: After linkage analysis in both families to localize the defective gene, mutation analysis was performed in these genes to identify the underlying mutation. In the 31 affected individuals, location, number and morphology and evolution of exostosis, evolution of remodeling defects at the metaphysis, and the extent of possible complications were evaluated on clinical and imaging (plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI)) data over a lifetime period. RESULTS AND CONCLUSIONS: Both families demonstrate the gene defect in the same EXT-2 gene locus on chromosome 11p. Exostoses are preferentially located in the lower extremity (hip, knee and lower leg), humerus, and forearm. Any other bone may be involved, except for the calvaria of the skull and the mandible. Exostoses are rather sessile than pedunculated. Exostosis is rarely present at birth but develops gradually and may persist to grow slowly after closure of the growth plates. Preferential expression of the remodeling defect was seen in the hip, distal femur (trumpet-shaped metaphysis) and forearm (shortening of the ulna with secondary bowing of the radius and development of a pseudo-Madelung deformity). These radiological manifestations start at the age of 4-5 years and become more obvious as the enchondral bone formation progresses with age. Reported complications in these families consist of local entrapment phenomenons (vessel, tendon, nerve), frictional bursitis, and sarcomatous transformation. MRI was able to suggest these complications and is the imaging technique of choice in the evaluation of symptomatic exostoses.

Chromosome Mapping↗
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↗
PubMed1989

Spontaneous hemothorax in a patient with hereditary multiple exostoses.

A case of spontaneous hemothorax in a 7-year-old child secondary to erosion of the diaphragm by an exostosis coming from the left sixth rib is reported. This rare case of hemothorax with hereditary multiple exostoses is made even rarer by the concomitant perforation of the diaphragm.

Child↗
PubMed1997

Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage-capped prominences that develop from the growth centers of the long bones. EXT is genetically heterogeneous, with three loci, currently identified on chromosomes 8q24.1, 11p13, and 19q. The EXT1 gene, located on chromosome 8q24.1, has been cloned and is encoded by a 3.4-kb cDNA. Five mutations in the EXT1 gene have been identified--four germ-line mutations, including two unrelated families with the same mutation, and one somatic mutation in a patient with chondrosarcoma. Four of the mutations identified resulted in frameshifts and premature termination codons, while the fifth mutation resulted in a substitution of leucine for arginine. Loss of heterozygosity (LOH) analysis of chondrosarcomas and chondroblastomas revealed multiple LOH events at loci on chromosomes 3q, 8q, 10q, and 19q. One sporadic chondrosarcoma demonstrated LOH for EXT1 and EXT3, while a second underwent LOH for EXT2 and chromosome 10. A third chondrosarcoma underwent LOH for EXT1 and chromosome 3q. These results agree with previous findings that mutations at EXT1 and multiple genetic events that include LOH at other loci may be required for the development of chondrosarcoma.

Bone Neoplasms↗
PubMed1994

[Familial multiple exostoses].

Case of father and his two sons with multiple osteochondrial exostoses localized on the long bones and impaired joint movements was reported.

Adult↗
PubMed2005

Acute spinal cord compression in hereditary multiple exostoses.

Osteocartilaginous exostoses are benign bone tumors frequently found in the metaphysis of long bones but rarely in the spine. Four patients with acute spinal cord decompensation due to vertebral exostoses spinal cord compression have been previously described in the literature. We report an additional case of rapidly evolving spinal cord compression due to a cervical osteochondroma in a patient with hereditary multiple exostoses (HME), also known as Bessel Hagen disease. Careful analysis of the 5 cases suggested to us that patients with HME should have a systematic spinal imaging screening, in order to prevent rapid neurological decompensation. A minimal risk surgical procedure can be performed at a time of election.

Adult↗
PubMed2001

Successful removal of a giant recurrent chondrosarcoma of the thoracic wall in a patient with hereditary multiple exostoses.

Chondrosarcoma represents the most common malignant tumour of the chest wall, with a tendency for local recurrence after resection. Here we report the successful complete resection of a giant, local recurrent chondrosarcoma of the chest wall (max. diameter 25 cm), in a patient with hereditary multiple exostoses, who had had a wide resection 8 years before. Clinical features and surgical management are described.

Bone Neoplasms↗
PubMed1994

An association between psoriasis and hereditary multiple exostoses. A clue for the mapping of a psoriasis susceptibility gene?

Chronic plaque psoriasis affects approximately 1.6% of the U.K. population. Population, family and twin studies all strongly suggest an important genetic component in the pathogenesis of the disease, although genetic linkage studies have, so far, failed to identify susceptibility genes. We describe a family in which psoriasis cosegregates through three generations with a known autosomal dominant disorder, hereditary multiple exostoses (HME). A major locus for HME has recently been mapped to chromosome 8q. Observations in this family may provide a mapping clue for a psoriasis susceptibility gene.

Adult↗
PubMed1997

The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by multiple cartilage-capped outgrowths from the epiphyses of long bones. In some cases, these osteochondromas progress to malignant chondrosarcomas. Alterations in at least three genes (EXT1, EXT2, and EXT3) can cause this disorder. Two of these have been isolated (EXT1 and EXT2) and encode related members of a putative tumor suppressor family. We report here the genomic structure of the human EXT2 gene consisting of 14 exons (plus 2 alternative exons) covering an estimated 108 kb of chromosome 11p11-13. We have derived the DNA sequences at all exon/intron boundaries throughout this gene-information that is important for the detailed study of mutations in EXT2. We have also characterized the mouse EXT2 cDNA and have mapped the mouse locus to chromosome 2 between D2Mit15 and Pax6. This mouse homolog should enable transgenic knockout experiments to be initiated to further elucidate gene function. Interestingly, sequence comparisons reveal that the human and mouse EXT genes have at least two homologs in the invertebrate Caenorhabditis elegans, indicating that they do not function exclusively as regulators of bone growth. This observation opens the way for a functional analysis of these genes in nematodes and other lower organisms.

Amino Acid Sequence↗
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↗
PubMed1995

Autism, mental retardation, multiple exostoses and short stature in a female with 46,X,t(X;8)(p22.13;q22.1).

A young adult female with multiple exostoses, short stature, autism, mental retardation and 46,X,t(X;8)(p22.13;q22.1) is described. Although the clinical features and translocation breakpoints raise the possibility of a number of specific conditions, the constellation of problems is not consistent with any previously reported genetic syndrome. It is argued that her clinical disorder is likely due to the chromosomal abnormality and that further detailed molecular genetic investigation may shed light on the genetic basis to various components of her phenotype including the autism.

Abnormalities, Multiple↗
PubMed1989

[Neurologic complications in hereditary multiple exostoses].

Based on the radiological and clinical findings in two patients suffering from hereditary multiple cartilaginous exostoses, the importance of identification and x-ray confirmation of neurological signs within the framework of the overall disease patterns is shown. This is a rare complication, bat it is highly important for the patient. Early clarification is imperative; if surgical intervention is not instituted directly, a closely meshed control network is considered mandatory to prevent severe irreversible neurological deficits.

Adult↗
PubMed1989

[Multiple cartilaginous exostoses].

Multiple cartilaginous exostosis (MKE) is an autosomally dominant hereditary disease with great individual expression. The disease becomes apparent most frequently at the age of 2-5 years and approximately 80% of the cases have been diagnosed before the age of ten years. The exostoses continue to grow until shortly after puberty. The exostoses may give rise to severe deformation of the skeleton particularly around the knee, ankle and wrist joints. Reduction of joint mobility is frequently observed either on account of the size of the exostoses and their localization or on account of the joint deformity. Treatment of MKE is surgical and corrective surgery with removal of symptom-producing exostoses is the commonest intervention. Osteotomies or introduction of joint-prostheses may prove necessary in cases with the severest joint deformities. The exostoses may undergo malignant transformation, most frequently to chondrosarcomata which grow relatively slowly and metastasize late. Treatment of these must be undertaken in a tumour centre where limb-saving tumour surgery is available in cooperation between the orthopaedic surgeon and the oncologist. Families with MKE should be given patho-genetic advice.

Adult↗