PIK3R2-related megalencephaly syndrome: expanded phenotypic spectrum associated with craniosynostosis
4 affiliations
- 1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- 2Radiology, Department of Pediatric Radiology, Karolinska University Hospital, Stockholm, Sweden
- 3Department of Surgical Sciences, Plastic surgery, Uppsala University, Uppsala, Sweden
- 4Department of Laboratory Medicine, Clinical Genetics Department, Faculty of Medicine and Health, Örebro University Hospital, Örebro University, Örebro, Sweden
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.
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BibTeX
@article{digkas2026pik3r2related,
title = {{PIK3R2-related megalencephaly syndrome: expanded phenotypic spectrum associated with craniosynostosis}},
author = {Evangelos Digkas and Izabella Baranowska Körberg and Evangelos Mourtos and Daniel Nowinski and Christos Aravidis},
journal = {Orphanet Journal of Rare Diseases},
year = {2026},
month = oct,
doi = {10.1186/s13023-026-04666-y},
url = {https://doi.org/10.1186/s13023-026-04666-y},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - PIK3R2-related megalencephaly syndrome: expanded phenotypic spectrum associated with craniosynostosis
AU - Evangelos Digkas
AU - Izabella Baranowska Körberg
AU - Evangelos Mourtos
AU - Daniel Nowinski
AU - Christos Aravidis
PY - 2026
DA - 2026/10/22
JO - Orphanet Journal of Rare Diseases
DO - 10.1186/s13023-026-04666-y
UR - https://doi.org/10.1186/s13023-026-04666-y
AB - 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.
SN - 1750-1172
ER -