Vol. 8, Issue 1, Part A (2026)

Macrocephaly is a common pediatric finding, but severe or rapidly progressive head growth (OFC >+3 SD) often serves as a sentinel sign for underlying genetic pathologies, such as PTEN Hamartoma Tumor Syndrome (PHTS).

We report the case of a 3-year-old girl presenting with severe, progressive macrocephaly reaching +5 SD at 9 months of age. Clinical findings included café-au-lait-like spots and enlarged perivascular spaces on brain MRI, while hydrocephalus and metabolic disturbances were excluded. Genetic testing identified a heterozygous likely pathogenic PTEN variant: c.377C>G p.(Ala126Gly). This specific neomorphic variant is known to alter lipid phosphatase activity, shifting it toward a 5-phosphatase function and potentially carrying distinct oncogenic implications through increased PI3K/AKT signaling. The patient remains neurodevelopmentally stable under multidisciplinary surveillance.

This case highlights the importance of integrating molecular testing into the diagnostic work-up of severe macrocephaly. Early recognition of PHTS is crucial, as it allows for the immediate implementation of lifelong, structured cancer surveillance (targeting thyroid, breast, and renal malignancies) and facilitates accurate genetic counseling. For pediatricians, awareness of PHTS is essential to ensure timely diagnosis and long-term management strategies that significantly alter the patient's prognosis.