A number sign (#) is used with this entry because of evidence that cerebral cavernous malformations-4 (CCM4) is caused by somatic mutation in the PIK3CA gene (171834) on chromosome 3q26.

Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system that are composed of abnormally enlarged capillary cavities without intervening brain parenchyma. CCMs manifest primarily as subclinical bleeding, but can also lead to seizures and hemorrhagic stroke with substantial neurologic complications, especially when localized in the brainstem. More than 80% of CCMs occur sporadically (summary by Peyre et al., 2021).

For a phenotypic description and discussion of genetic heterogeneity of cerebral cavernous malformations, see CCM1 (116860).

Peyre et al. (2021) reported 34 unrelated adult patients with CCMs who had no family history of the disorder, suggesting sporadic occurrence. Clinical details were limited, but the CCMs occurred in various brain regions, including the cerebellum and brainstem.

In 34 (39%) of 88 sporadic CCM samples, Peyre et al. (2021) identified 1 of 3 somatic missense mutations in the PIK3CA gene (H1047R, 171834.0001; H1047L, 171834.0002; and E542K, 171834.0009). The mutations were found by targeted DNA sequencing after studies in mice suggested that Pik3ca mutations can lead to CCM formation (see ANIMAL MODEL). Four of the samples with PIK3CA mutations also had mutations in the CCM-related genes CCM1 (KRIT1; 604214), CCM2 (607929), and AKT1 (164730). The authors noted that cooccurrence of mutations is frequently seen in tumors. PIK3CA-mutant CCMs in humans and mice showed increased phosphorylation of myosin light chain and activation of the PI3K-AKT-mTOR pathway, consistent with activating mutations. Peyre et al. (2021) noted that the incidence of activating mutations in the PIK3CA gene in sporadic CCMs far exceeds that of mutations in CCM1, CCM2, or CCM3, all of which cause familial disease. PIK3CA mutations were not observed in 11 samples of arteriovenous malformations.

Hong et al. (2021) identified a somatic mutation in the MAP3K3 gene (I441M; 602359.0001) in 41 patients and a somatic mutation (C420R, E542K, E545K or H1047R) in the PIK3CA gene in 45 patients. Fourteen of the patients had somatic mutations in both MAP3K3 and PIK3CA. The mutations were identified by whole-exome sequencing and digital droplet PCR. The PIK3CA mutation frequencies ranged from 0.4% to 24.4% in the CCM tissue. Single cell RNA sequencing was performed in tissue from 2 CCMs with MAP3K3 mutations, 3 CCMs with PIK3CA mutations, and 1 CCM with mutations in both genes. CCMs with only PIK3CA mutations demonstrated downregulated apoptosis and increased expression of SERPINA5 and GDF15 compared to the CCMs with MAP3K3 mutations or both MAP3K3 and PIK3CA mutations. Hong et al. (2021) hypothesized that PIK3CA mutations in CCM tissue may lead to increased vascular stress, endothelial dysfunction, and hemorrhagic risk.

Hong et al. (2021) compared clinical characteristics between CCMs with somatic mutations in the MAP3K3 gene, PIK3CA gene, or in both genes. CCMs with mutations in only the PIK3CA gene were more likely to be overtly hemorrhagic and were significantly larger compared to the CCMs with mutations in the MAP3K3 gene or in both genes.

Peyre et al. (2021) found that mutant mice selectively expressing the Pik3ca H1047R mutation in PGDS (602598)-expressing cells developed intraparenchymal CCM lesions, most of which were localized to the brainstem. Histologically, the lesions ranged from intraparenchymal vessel dilatations to capillary telangiectasia and the formation of young cavernous lesions. A subset of mice developed meningothelial proliferations. Peyre et al. (2021) noted that PGDS is expressed in pericytes surrounding intraparenchymal vessels, which is consistent with it being the most likely cell of origin.