PIK3CA-Related Phenotypes due to Germline and Somatic Mosaic Variants: A two-Case Report

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 2 unrelated patients - 1 with a somatic mosaic and 1 with a de novo germline PIK3CA variant - with longitudinal clinical follow-up.

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.

These 2 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.