Cerebral cavernous malformations do not fall in the spectrum of PIK3CA-related overgrowth

Abstract

Somatic gain-of-function (GOF) mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), the catalytic subunit of phosphoinositide 3-kinase (PI3K), have been recently discovered in cerebral cavernous malformations (CCMs), raising the possibility that the activation of PI3K pathways is a possible universal regulator of vascular morphogenesis. However, there have been contradicting data presented among various groups and studies. To enhance the current understanding of vascular anomalies, it is essential to explore this possible relationship between altered PI3K signalling pathways and its influence on the pathogenesis of CCMs. GOF PIK3CA-mutants have been linked to overgrowth syndromes, allowing this group of disorders, resulting from somatic activating mutations in PIK3CA, to be collectively named as PIK3CA-related overgrowth spectrum disorders. This paper reviews and attempts to conceptualise the relationships and differences among clinical presentations, genotypic and phenotypic correlations and possible coexistence of PIK3CA and CCM mutations/phenotypes in CCM lesions. Finally, we present a model reflecting our hypothetical understanding of CCM pathogenesis based on a systematic review and conceptualisation of data obtained from other studies.

Keywords: cerebrovascular; cerebrovascular disease; epilepsy; genetics; stroke.