Identification of a novel mutation in EXT2 in a fourth‐generation Korean family with multiple osteochondromas and overview of mutation spectrum

Multiple osteochondromas (MOs) or hereditary multiple exostoses is a rare autosomal‐dominant disease characterized by growths of MOs, which are benign cartilage‐capped bone tumors that grow away from the growth plates. Almost 90% of MOs have a molecular explanation and 10% are unexplained. MOs are genetically heterogeneous with two causal genes on 8q24.11 (EXT1) and 11p12 (EXT2), with a higher frequency in EXT1. MO is a very rare genetic disorder, and the genotype–phenotype of MO with EXT2 mutation has not been well investigated in Korea. We present the clinical radiographic and molecular analysis of a four‐generation Korean family with 11 MO‐affected members (seven males and four females). The affected members from the third generation available for molecular analysis and their detailed medical histories showed moderate‐to‐severe phenotypes (clinical classes II–III), including bony deformities and limb misalignment with pain requiring surgical correction. The x‐rays showed MOs in multiple sites. A novel EXT2 frameshift mutation (c.590delC, p.P197Qfs*73) was revealed by targeted exome sequencing in the affected members of this family. In this article, we not only expand the phenotypic–genotypic spectrum of MOs but also highlight the phenotypic heterogeneity in a family with the same mutation. In addition, we compiled the mutation spectrum of EXT2 from a literature review and identified that exon 2 of EXT2 is a mutation hot spot. Early medical attention with diagnosis of MO through careful examination of the clinical manifestations and genetic analysis can provide the opportunity to establish coordinated multispecialty management of the patient.