Mosaic Variant in Unilateral Woolly Hair in a Girl With PIK3CA ‐Related Overgrowth Spectrum

ABSTRACT The phosphatidylinositol‐3‐kinase (PI3K)‐AKT‐mTOR pathway plays a central role in cellular growth and survival, and somatic activating variants in PIK3CA cause PIK3CA‐related overgrowth spectrum (PROS). Because these variants arise postzygotically, affected individuals exhibit somatic mosaicism, making molecular diagnosis challenging, particularly when only peripheral blood is available. We report an infant with PROS presenting with hemimegalencephaly, facial infiltrating lipomatosis, epidermal nevi, and unilateral woolly hair. A hotspot PIK3CA variant (c.1633G>A, p.Glu545Lys) was identified in the resected brain tissue but not in the peripheral blood. Notably, the variant was detected in DNA extracted from hair follicles of curly hair on the affected side of the scalp, whereas it was absent in follicles from straight hair on the contralateral side. Droplet digital PCR demonstrated variant allele fractions of 24.7%–27.6% in brain tissue and 32.3% in curly hair. These findings highlight the utility of hair follicles as a minimally invasive and accessible source of DNA for detecting somatic mosaic variants in PROS. The spatial concordance between genotype and hair phenotype suggests a possible association between PIK3CA mosaicism and localized hair abnormalities, although causality remains to be established.