In reminiscence of Knudson’s two-hit model for retinoblastoma [13], DNA sequencing and immunohistochemical analyses of human CCMs demonstrated that CCM1, CCM2, or CCM3 gene expression is completely inactivated by a germline and a second somatic mutation or by two somatic mutations in many cavernous malformations [10], [12], [14], [15], [16], [17]. Here, KRIT1 is linked to cerebrocostomandibular syndrome.