PIK3CA – Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome

Megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome is a congenital overgrowth disorder characterized by megalencephaly, cutaneous capillary malformations, polymicrogyria, segmental body overgrowth, and variable connective tissue dysplasia ([HP:0001355], [HP:0000965], [HP:0000256], [HP:0001770]). MCAP arises from postzygotic, gain-of-function variants in PIK3CA, resulting in constitutive activation of the PI3K-AKT-mTOR pathway and mosaic autosomal dominant inheritance.

Somatic mosaic PIK3CA mutations have been identified in the majority of clinically diagnosed MCAP cases. Initial exome sequencing in 23 individuals revealed postzygotic PIK3CA variants in 15 probands with MCAP ([PMID:22729224]). Subsequent cohorts totaling over 100 additional patients have consistently detected mosaic PIK3CA hotspots—most frequently c.2740G>A (p.Gly914Arg), c.1635G>T (p.Glu545Asp), and c.3139C>T (p.His1047Tyr)—in affected tissues but not in blood or saliva ([PMID:32778138]; [PMID:33005459]; [PMID:35483878]).

Functional evidence demonstrates that helical- and kinase-domain PIK3CA mutations confer a 2- to 10-fold increase in lipid kinase activity, leading to hyperphosphorylation of AKT and downstream effectors. In vitro assays of hotspot mutants show constitutive PI3K signaling, growth factor independence, and transformation of mammary epithelial and fibroblast models, while PI3K inhibitors normalize pathway activation ([PMID:15950905]; [PMID:18268322]; [PMID:19903845]). Single-cell RNA sequencing of capillary malformation fibroblast populations further elucidates aberrant PIK3CA expression in PAX3⁺ fibroblast subtypes ([PMID:39455600]).

No Mendelian segregation has been observed given the postzygotic mosaic mechanism; affected relatives have not been reported. There are no conflicting reports disputing the role of PIK3CA in MCAP, and functional data across multiple systems concordantly support gain-of-function as the pathogenic mechanism.

The PIK3CA–MCAP association meets ClinGen criteria for a definitive gene-disease relationship based on robust genetic and experimental evidence across >10 independent studies over >10 years. Genetic testing of affected tissues and emerging minimally invasive assays such as CSF-derived cell-free DNA improve diagnostic yield, enabling early intervention and informing targeted use of PI3K inhibitors.

Key Take-home: Postzygotic, gain-of-function PIK3CA variants are the definitive cause of MCAP syndrome; sensitive molecular assays in lesional tissues are essential for accurate diagnosis and therapeutic decision-making.

References

• Nature genetics • 2012 • De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes PMID:22729224
• Orphanet journal of rare diseases • 2020 • Detailed analysis of phenotypes and genotypes in megalencephaly-capillary malformation-polymicrogyria syndrome caused by somatic mosaicism of PIK3CA mutations PMID:32778138
• Frontiers in genetics • 2023 • Case report: Progressive pulmonary artery hypertension in a case of megalencephaly-capillary malformation syndrome PMID:37614820
• Cold Spring Harbor molecular case studies • 2022 • The utility of cerebrospinal fluid-derived cell-free DNA in molecular diagnostics for the PIK3CA-related megalencephaly-capillary malformation (MCAP) syndrome: a case report PMID:35483878
• Scientific reports • 2024 • Defining the transcriptome of PIK3CA-altered cells in a human capillary malformation using single cell long-read sequencing PMID:39455600
• Clinical genetics • 2021 • Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials PMID:33415748

Evidence Based Scoring (AI generated)