JCS in not the only syndrome showing phenotypic overlap with NF1: other examples are represented by the ‘neuro-cardio-facial-cutaneous’ syndrome (with a variable degree of cognitive impairment, facial dysmorphism, congenital heart defects and skin abnormalities), related to mutations in the genes that encode other components of the RAS-MAPK pathway, such as PTPN11, KRAS8 and SOS1 in Noonan syndrome, PTPN11 in LEOPARD syndrome, HRAS13 in Costello syndrome, KRAS14, BRAF14,15, MEK1 and MEK2 in cardio-facio-cutaneous syndrome [46]. The gene discussed is MAP2K2; the disease is Costello syndrome.