Although these complex neurodevelopmental disorders remain a primary interest of the current review, important insights to address this issue were gained from the studies focusing on the APA-linked Mendelian disorders (for example, achondroplasia, Apert and Costello syndromes) and their causal mutations in the FGFR2, FGFR3, PTPN11, HRAS and RET genes. This evidence concerns the gene PTPN11 and Costello syndrome.