Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Cerebral cavernous malformations (CCMs) are vascular disorders with diverse clinical and radiological presentations.
• CCMs can arise from sporadic somatic mutations (MAP3K3, PIK3CA) or inherited germline mutations.

Purpose of the Study:

• To elucidate the clinical, genetic, and pathological characteristics of CCMs.
• To analyze genotypic and phenotypic differences in a multicenter cohort of Chinese patients.

Main Methods:

• Analysis of 290 surgical CCM specimens from symptomatic patients.
• Utilized whole-exome sequencing, droplet digital PCR, targeted panel sequencing, and immunohistology.
• Examined genotype-phenotype correlations and histopathological differences.

Main Results:

• 201 out of 290 cases had identified MAP3K3, PIK3CA, or germline CCM mutations.
• Mutations correlated significantly with hemorrhage risk, lesion size, epilepsy, Zabramski classification, DVA presence, and MRI edema.
• PIK3CA mutations showed higher hemorrhage risk; specific variants (p.H1047R vs. p.E545K) impacted bleeding risk. MAP3K3 mutations were associated with higher non-hemorrhagic epilepsy risk.
• Histopathology revealed distinct features: PIK3CA lesions had cyst walls and pS6-positive capillaries, while MAP3K3 lesions showed classic CCM features with SMA/KLF4-positive vessels, collagen, and calcification.

Conclusions:

• CCMs exhibit significant diversity in clinical, genomic, and histopathological profiles.
• Mutation subtypes and MRI findings may serve as predictive markers for CCM behavior and outcomes.
• Understanding these genotype-phenotype correlations is crucial for managing CCM patients.