Considered together, these findings support the notion that CCM disease can be caused by mutations in other genes besides the three CCM genes identified to date, as well as that a local upregulation of the PI3K/Akt and MAPK pathways induced by either somatic mosaic mutations in regulatory genes or microenvironmental events is likely to exert a key pathogenetic role. This evidence concerns the gene PIK3CA and cerebral cavernous malformation.