PA10 Mosaic PIK3CA mutation: a rare presentation with unilateral plantar keratoderma and an epidermal naevus

Abstract

A White child presented at birth with linear hypopigmented streaks affecting the left lower limb. At 9 weeks of age, a skin biopsy demonstrated hyperkeratosis, acanthosis and papillomatosis, consistent with an epidermal naevus. Magnetic resonance imaging of the brain performed as part of epidermal naevus syndrome screening in infancy was normal. She subsequently developed neurodevelopmental diagnoses, including self-limiting focal seizures, autism spectrum disorder and learning difficulties. At 9 years of age, she re-presented to dermatology with a 2-year history of left-sided progressive, unilateral diffuse plantar keratoderma. There was no associated hyperhidrosis, although mal­odour was intermittently reported. Linear verrucous papules consistent with the known epidermal naevus persisted on the same limb. She also exhibited toenail dystrophy, mild overgrowth of the left foot and mild facial dysmorphism. Topical keratolytics, antifungals and systemic retinoids were ineffective, and ongoing podiatry input was necessitated for painful fissuring. Extensive genetic testing from blood, including targeted panels for mosaic skin disorders, palmoplantar keratoderma and ichthyosis, was initially uninformative. Subsequent whole-genome sequencing from lesional skin identified a pathogenic mosaic PIK3CA variant, c.3140A>G (p.His1047Arg), confirming PIK3CA-related overgrowth spectrum (PROS). Cardiac assessment, limb imaging and consideration of oral sirolimus were recommended. PROS conditions are characterized by segmental tissue overgrowth with or without dysplasia, commonly due to postzygotic gain-of-function mutations in PIK3CA. This encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), resulting in hyperactivation of the PI3K–AKT–mTOR (mammalian target of rapamycin) signalling pathway. Palmoplantar keratodermas are genetically heterogeneous, with over 60 implicated genes. However, the first case of unilateral focal palmoplantar keratoderma due to mosaic PIK3CA mutation was reported in a Chinese patient in 2024, in which whole-exome and Sanger sequencing identified the same c.3140A>G variant confined to lesional epidermis, causing increased PI3K–AKT–mTOR signalling and elevated Ki67-positive keratinocytes. To our knowledge, this represents only the second reported case of palmoplantar keratoderma secondary to a mosaic PIK3CA mutation.