The genotype-phenotype correlation of hereditary multiple exostoses

Department of Orthopaedics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Clinical Genetics (Impact Factor: 3.93). 09/2006; 70(2):122-30. DOI: 10.1111/j.1399-0004.2006.00653.x
Source: PubMed


Hereditary multiple exostoses (HME) is an autosomal dominant condition with a wide spectrum of clinical presentations. The purpose of this study was to determine the relationship between the genotype and the phenotype in HME. Thirty-two affected individuals from 10 families participated in the study. An extensive description of HME phenotype in terms of the anatomical burden of disease involved clinical and radiographic examinations and evaluation of 76 parameters. Mutations were determined by sequencing the EXT 1 and EXT 2 genes. Mutations were found in eight families (26 individuals), with one mutation previously reported in the literature and seven novel mutations. There were seven subjects with an EXT 1 mutation and 16 with an EXT 2 mutation. Patients with EXT 1 mutation were found to have more exostoses, more limb malalignment with shorter limb segments and height, and more pelvic and flatbone involvement. A genotype-phenotype correlation exists in HME, with patients with EXT 1 mutations having a higher degree of anatomical burden.

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    • "The degree of severity was classified as mild (M) or severe (S). Four subcategories were defined in patients with a severe phenotype (from types IS to IVS)1618. "
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    ABSTRACT: Multiple osteochondromatosis (MO), or EXT1/EXT2-CDG, is an autosomal dominant O-linked glycosylation disorder characterized by the formation of multiple cartilage-capped tumors (osteochondromas). In contrast, solitary osteochondroma (SO) is a non-hereditary condition. EXT1 and EXT2, are tumor suppressor genes that encode glycosyltransferases involved in heparan sulfate elongation. We present the clinical and molecular analysis of 33 unrelated Latin American patients (27 MO and 6 SO). Sixty-three percent of all MO cases presented severe phenotype and two malignant transformations to chondrosarcoma (7%). We found the mutant allele in 78% of MO patients. Ten mutations were novel. The disease-causing mutations remained unknown in 22% of the MO patients and in all SO patients. No second mutational hit was detected in the DNA of the secondary chondrosarcoma from a patient who carried a nonsense EXT1 mutation. Neither EXT1 nor EXT2 protein could be detected in this sample. This is the first Latin American research program on EXT1/EXT2-CDG.
    Full-text · Article · Sep 2014 · Scientific Reports
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    • "AS shows a striking correlation with antigen HLA-B27 (5). Hereditary multiple exostoses (HME) is a genetically heterogeneous disorder that is correlated with mutations in the exostoses gene family (EXT1, EXT2) (6). The incidence of HME is 1 per 50,000. "
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    ABSTRACT: Coexisting ankylosing spondylitis and hereditary multiple exostoses have rarely been reported (three patients) previously. A 27-year-old man with hereditary multiple exostoses is presented as a fourth report. At the age of 15 years, the patient had multiple exostoses around the knee, ankle and shoulder joints. He was diagnosed with ankylosing spondylitis 3 years ago. The patient's sister and his 3 brothers also have multiple exostoses without any family history of spondyloarthropathy or inflammatory arthritis. The aim of this report is to discuss an interesting coexistence of these two diseases. The increasing number of reported patients who have a coexistence of these two diseases might suggest that the association of these two diseases is stronger than a coincidence.
    Full-text · Article · Jan 2014 · Iranian Journal of Radiology
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    • "It has been suggested that MO is caused in large part by EXT1 mutations [10], [11], [12]. The MO caused by EXT1 gene mutations presents a greater risk for malignant transformation than the MO caused by EXT2 gene mutations [13], [14]. No linkage evidence has been reported for EXT-like genes. "
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    ABSTRACT: Multiple osteochondromas (MO) is an inherited skeletal disorder, and the molecular mechanism of MO remains elusive. Exome sequencing has high chromosomal coverage and accuracy, and has recently been successfully used to identify pathogenic gene mutations. In this study, exome sequencing followed by Sanger sequencing validation was first used to screen gene mutations in two representative MO patients from a Chinese family. After filtering the data from the 1000 Genome Project and the dbSNP database (build 132), the detected candidate gene mutations were further validated via Sanger sequencing of four other members of the same MO family and 200 unrelated healthy subjects. Immunohistochemisty and multiple sequence alignment were performed to evaluate the importance of the identified causal mutation. A novel frameshift mutation, c.1457insG at codon 486 of exon 6 of EXT1 gene, was identified, which truncated the glycosyltransferase domain of EXT1 gene. Multiple sequence alignment showed that codon 486 of EXT1 gene was highly conserved across various vertebrates. Immunohistochemisty demonstrated that the chondrocytes with functional EXT1 in MO were less than those in extragenetic solitary chondromas. The novel c.1457insG deleterious mutation of EXT1 gene reported in this study expands the causal mutation spectrum of MO, and may be helpful for prenatal genetic screening and early diagnosis of MO.
    Full-text · Article · Aug 2013 · PLoS ONE
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