PIK3CA-related phenotypes due to germline and somatic mosaic variants: A two-case report

Objective: Somatic mosaic activating PIK3CA variants are a well-established cause of segmental overgrowth phenotypes, whereas germline PIK3CA variants are rare and clinically heterogeneous. We report two unrelated patients—one with a somatic mosaic and one with a de novo germline PIK3CA variant—with longitudinal clinical follow-up. Case Presentation: Patient 1 carried NM_006218.4:c.1412C>T; p.(Pro471Leu) in the C2 domain and presented with macrocephaly, generalized overgrowth, epilepsy, and structural brain anomalies; mosaicism was supported by an attenuated mutant signal on Sanger sequencing. Patient 2 harbored a de novo NM_006218.4:c.323G>A; p.(Arg108His) in the N-terminal p85-binding region and showed macrocephaly, attention-deficit/hyperactivity disorder, and mitral annular disjunction/mitral valve prolapse with aortic root dilatation. Conclusion: These two cases illustrate PIK3CA-related phenotypes arising from somatic mosaic and germline contexts and document their clinical course over time. Larger, well-characterized cohorts and complementary functional assays are needed to refine genotype–phenotype relationships, inform clinical care, and evaluate targeted therapies.