Hereditary Multiple Exostoses—A Review of the Molecular Background, Diagnostics, and Potential Therapeutic Strategies

Hereditary multiple exostoses (HMEs) syndrome, also known as multiple osteochondromas, represents a rare and severe human skeletal disorder. The disease is characterized by multiple benign cartilage-capped bony outgrowths, termed exostoses or osteochondromas, that locate most commonly in the juxta-epiphyseal portions of long bones. Affected individuals usually complain of persistent pain caused by the pressure on neighboring tissues, disturbance of blood circulation, or rarely by spinal cord compression. However, the most severe complication of this condition is malignant transformation into chondrosarcoma, occurring in up to 3.9% of HMEs patients. The disease results mainly from heterozygous loss-of-function alterations in the EXT1 or EXT2 genes, encoding Golgi-associated glycosyltransferases, responsible for heparan sulfate biosynthesis. Some of the patients with HMEs do not carry pathogenic variants in those genes, hence the presence of somatic mutations, deep intronic variants, or another genes/loci is suggested. This review presents the systematic analysis of current cellular and molecular concepts of HMEs along with clinical characteristics, clinical and molecular diagnostic methods, differential diagnosis, and potential treatment options.

Identification of a Novel EXT Mutation in A Kindred With Hereditary Multiple Exostoses Using Whole-Exome Sequencing and Overview of Mutation Spectrum

Background: Hereditary Multiple Osteochondromas(HMO) is a rare genetic musculoskeletal disorder characterized by multiple osteochondromas that form near to the growth plates of many bones. Loss-of-function mutations in EXT1 or EXT2 that encode glycosyltrasferases are the causal mutations for most HMO patients.Methods: After collecting the family history and clinical information, we used Whole-Exome Sequencing to find the pathogenic mutations in one Chinese Hereditary Multiple Exostoses pedigree. Sanger sequencing and relevant online databases were used to validate the screened variants. Lollipop plots were drew to map the reported mutations from online databases (Multiple Osteochondroma Mutation Database and clinvar)on a linear protein domains by MutationMapper.Results: A novel heterozygous splicing-site mutation in gene EXT1 (NM_000127:exon5:c.1417+1G>C，chr8:118834703) was found in this pedigree and mutation spectrum of genes EXT1 and EXT2 were demonstrated.Conclusions: Our results help this pedigree to identify the pathogenic variant and guide the prenatal diagnosis, also expand the mutation spectrum in Hereditary Multiple Osteochondromas.

Risk factors for ankle valgus in children with hereditary multiple exostoses: a retrospective cross-sectional study

Purpose The aim of this study was to identify risk factors for ankle valgus in children with hereditary multiple exostoses (HME). Methods We retrospectively reviewed the medical records of patients with HME who were examined at our hospital between 2010 and 2020. Patients’ age and sex were recorded along with radiographic variables including mechanical axis deviation (MAD), mechanical lateral distal tibia angle (LDTA), fibula/tibia length ratio (F/T); distal fibula station according to Malhotra’s classification, location of exostoses at the ankle joint and fibular neck/physis width (N/P) ratio, which were measured from radiographs. Binary logistic regression analysis was performed to identify significant independent risk factors for ankle valgus. Results There were 61 children (20 girls and 41 boys; 122 ankles) who met the inclusion criteria. The mean age was 10.4 years (sd 3.4) and mean LDTA was 83° (sd 7°). Ankle valgus was found in 64 ankles (52%). In addition to younger age, exostoses involving the lateral aspects of the distal tibial and the medial aspect of the distal fibula (odds ratio (OR) = 4.091; 95% confidence interval (CI) 1.065 to 15.712; p = 0.040), F/T ratio < 0.96 (OR = 4.457; 95% CI 1.498 to 13.261; p = 0.007) and N/P ratio > 1.6 (OR = 2.855; 95% CI 1.031 to 7.907; p = 0.043) were associated with an increased risk of developing ankle valgus, while sex and MAD were unrelated to its occurrence. Conclusion Young age, exostoses involving both the distal tibia and fibula, the F/T ratio < 0.96 and fibular N/P width ratio > 1.6 seemed to be risk factors of developing ankle valgus. Levels of evidence Prognostic studies, IV