The germline gain-of-function mutations in HRAS and MAP2K2 associated with Costello syndrome and CFC syndrome, respectively, argue that the increased transcription of RREB1 target genes HRAS and MAP2K2 observed with single gene loss of RREB1 account for the overlapping phenotypes observed in patients with these syndromes and in the Rreb+/− hemizygous in mice. This evidence concerns the gene HRAS and cardiofaciocutaneous syndrome.