Finally, given the recent discovery that activating mutations in genes involved in the PI3K/Akt signaling pathway, including PIK3CA and Akt, are implicated in CCM disease pathogenesis [14,15,16,44], it would be intriguing to address whether the PTEN c.959dup p.(Leu320PhefsTer5) frameshift variant identified in case #4 may be also implicated. This evidence concerns the gene AKT1 and cerebral cavernous malformation.