PIK3R2-related megalencephaly syndrome: expanded phenotypic spectrum associated with craniosynostosis

Abstract Background Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a rare neurodevelopmental disorder caused by activating variants in the PI3K-AKT-mTOR signaling pathway, most frequently in PIK3R2. The recurrent variant c.1117G > A (p.Gly373Arg) has been associated with classical MPPH features including megalencephaly, bilateral polymicrogyria, hydrocephalus, and polydactyly. However, the phenotypic spectrum is still expanding. Methods We describe a 7-year-old girl with developmental delay, epilepsy, and structural brain anomalies. Trio-based whole exome sequencing followed by Sanger validation was performed. Clinical and radiological evaluations were conducted, including brain MRI, CT, and ophthalmological assessment. Results The patient exhibited congenital megalencephaly, bilateral perisylvian and parietotemporal polymicrogyria, and hypotonia. She lacked polydactyly but presented with complex bicoronal and sagittal craniosynostosis, representing a potential novel association with this variant. Imaging revealed signs of chronic intracranial hypertension, including optic nerve tortuosity, papilledema, pituitary flattening, and gyral impressions. A heterozygous de novo PIK3R2 c.1117G > A (p.Gly373Arg) variant was identified and classified as pathogenic. Conclusion This report broadens the phenotypic spectrum of PIK3R2-related MPPH syndrome by describing a potential novel association with craniosynostosis, accompanied by radiologic signs of intracranial hypertension. The findings support the inclusion of PIK3R2 in genetic work-ups for patients with cortical malformations, megalencephaly, and syndromic presentations—even in the absence of polydactyly.