Somatic mosaicisms for MAP2K1-activating mutations are involved in the pathogenesis of melorheostosis; in fact, it has been shown that SMAD3 p.S264 substitutions increase transforming growth factor β (TGF-β) signaling, which in turn leads to an increased Ob proliferation and a consequent bone sclerosis [17,18]. This evidence concerns the gene MAP2K1 and melorheostosis.