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Cerebrovascular disease
Review
Cerebral cavernous malformations do not fall in the spectrum of PIK3CA-related overgrowth
  1. Jun Zhang1,
  2. Johnathan Abou-Fadel1,
  3. Mellisa Renteria1,
  4. Ofek Belkin1,
  5. Bixia Chen2,
  6. Yuan Zhu2,
  7. Philipp Dammann2,
  8. Daniele Rigamonti3
  1. 1 Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA
  2. 2 Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany
  3. 3 Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA
  1. Correspondence to Dr Jun Zhang, Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA; jun.zhang2000{at}gmail.com

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.

  • cerebrovascular disease
  • cerebrovascular
  • epilepsy
  • genetics
  • stroke

http://dx.doi.org/10.1136/jnnp-2022-328901

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    Footnotes

    • Twitter @drrigamonti

    • Contributors JZ: conceptualisation, methodology, investigation, writing—original draft preparation, writing—reviewing and editing; JA-F—investigation, software, data curation, validation, reviewing and editing, OB, MR, BC and YZ: investigation, visualisation, writing—reviewing and editing; PD and DR: writing—reviewing and editing.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.