The detection of isocitrate dehydrogenase (IDH1 and IDH2) heterozygous mutations, affecting only single alleles of the gene, in 50–70% of enchondromas and conventional central and periosteal CS but not in other mesenchymal tumors, fostered the understanding of CS natural history and malignancy [26]. The gene discussed is IDH2; the disease is Cowden syndrome 1.