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(C) Osteochondromas on proximal humerus (indicated by white arrows). (A, B) Multiple osteochondromas on the femurs, tibiae, and fibulae of the legs (indicated by white arrows). Clinical features of the proband with HME. Empty symbols indicate unaffected individuals, filled symbols indicate affected individuals, and oblique lines indicate deceased.FIG. The black arrow notes the proband (III-2). Pedigree of a family with Hereditary multiple exostoses (HME). Informed consent was obtained from all subjects recruited in this study, which was approved by the Ethics Committee of Zhejiang Provincial People's Hospital.FIG. Venous blood samples (5 mL) were drawn from seven family members (I-2, II-1, II-2, II-3, II-4, III-1, and III-2) using EDTA-anticoagulant vacuum blood collection tubes. The subject manifested MO of the proximal and distal tibiae, distal femur, and proximal fibula. The proband (III-2) was a 12-year-old male who was admitted to Zhejiang Provincial People's Hospital (Hangzhou, China) due to a deformity of the left leg, which led to limitation of physical activity.Īfter a careful examination and through inquiry of medical history, the proband was diagnosed with HME.
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Subjects and clinical evaluationIn this report, three generations of a family were studied, including three individuals with HME. A novel mutation c.1056GT (p.Gln352His) was identified in exon 2 of the EXT1 gene that resulted in structural changes of EXT1 protein.
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In this study, a Chinese family with three affected individuals was investigated by examining all exons of the EXT1 and EXT2 genes, to discover pathogenic mutations related to the disorder. To date, over 650 mutations in EXT1 and EXT2 have been identified, most of which are nonsense, frameshift, or splice site and which result in the synthesis of truncated EXT protein with dysfunctional activity (Jennes et al., Ciavarella et al., ).With the rapid development of DNA sequencing technologies, exome sequencing has already been applied in the investigation of genetic diseases, revealing novel and pathogenic genetic variants within whole exomes and/or targeted sequences (Huang et al., Liu et al., ).
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Patients with HME typically do not have symptoms, unless the increasing osteochondroma results in pressure in the adjacent muscles, tendons, nerves, or blood vessels, which leads to clinical manifestations that include pain, joint deformity, limited range of motion, and shortened stature (Jones et al., Wu et al., ).Īlthough HME is a benign tumor, malignant transformation into chondrosarcoma occurs in 1–2% of patients (Jennes et al., Tian et al., ).The molecular mechanisms underlying HME are still not clear, but previous studies have reported that the majority of patients have mutations in the exostosin-1 ( EXT1) and exostosin-2 ( EXT2) genes, which are located on chromosomes 8q24.1 and 11p13, respectively (Wu et al., Wuyts et al., ). The incidence of HME is greater in males than females, and the mutations exert incomplete penetrance (Legeai-Mallet et al., ). With a recorded prevalence of 1 in 50,000 in the western population (Schmale et al., ), osteochondromas are the most common benign bone tumors. In 1814, the first HME patient was described by Boyer (Peterson, Ryckx et al., ). IntroductionHereditary multiple exostoses (HME), also referred to as multiple exostoses (MO), is an autosomal dominant, inherited skeletal disorder characterized by the development of multiple benign cartilage-capped tumors that appear as outgrowth from the metaphyses of the long bones. Aims: Multiple exostoses (MO), also referred to as hereditary multiple exostoses (HME), is an autosomal dominant inherited skeletal disorder that has been found to be associated with mutations in the EXT1 and EXT2 genes.