A Genotype-Phenotype Study Of Hereditary Multiple Osteochondromas

Objective:Hereditary multiple osteochondromas is an autosomal dominant skeletal disorder.In almost 90% of patients germline mutations in two genes EXT1 or EXT2.The clinical manifestations of patients with HMO is variable.The purpose of this study is to evaluate the general clinical phenotypic severity of HMO by using a scoring system and try to find the correlation between the genotype and the phenotype in HMO patients,and further to provide genetic evidence for the treatment and prognosis of the disease.Methods: The patients diagnosed by radiographic examination from different families were prospectively enrolled.The mutations were identified by direct sequencing of PCR-amplified genomic DNA or by multiplex ligation-dependent probe amplification(MLPA).Several variables including demographic data,height,age of onset,number of anatomical sites,forearm deformity,and lower extremity alignment were recorded and analyzed according to genotype and gender.Each patient has a detail radiographic evaluation of upper and lower extremities,the skeletal affected sites was recorded.The forearm deformity was classified by Masada type.The lower limb mechanical axis are evaluated by three measures described on a long standing AP view include: mechanical axis deviation(MAD),neck shaft angle(NSA),lateral distal tibial angle(LDTA).A scoring system was used to assess the severity of the clinical phenotype,the scores for those variables were added up as the total score of each patient.The total score means the grade of the phenotype,the higher the score,the more severe the phenotype.The statistical analysis was performed with using Statistical Package for the Social Sciences version 17.0.Descriptive statistical significance was assigned to P values <0.05.Result: Fifty patients’ data from different families were recorded,including 30(60%)in EXT1 mutations and 16(32%)in EXT2 mutations;four patients(8%)with no identifiable mutations were excluded from the study.There were 46 patients including33 males(EXT1/EXT2,22/11)and 13 females(EXT1/EXT2,8/5),with a mean age of9.39 years.The mean age of onset was 2.96 years.The mean number of involved anatomical sites was 15.35.The number of anatomical sites,forearm deformity,and gene valgus deformity and clinical total score were positively correlated with age in patients with HMO(p<0.05).The height evaluation illustrated that 67% of the patients(31 of 46)were below the 50 th percentile,and the patients with EXT1 mutations were shorter than those with EXT2 mutations(p = 0.005).Moreover,a higher total score was found in patients with EXT1mutations(p = 0.001).A significant correlation was found between the forearm deformity and the number of involved anatomical sites(r = 0.382,p = 0.009).Conclusion: We have confirmed that several clinical features of HMO in Chinese patients are similar to those in most Western populations,mutations in EXT1 account for 70% of this series.Patients with HMO are frequently of short stature;EXT1 patients were shorter in stature and have a more severe clinical phenotype than EXT2 patients by using our scoring system.Patients with severer forearm deformity means lower extremity malalignments and more involved anatomical sites,an adequate follow-up is recommended.The increased severity of clinical phenotype was related with the children’s age in hereditary multiple osteochondromas.