Variants in PTEN Are Associated With a Diverse Spectrum of Cortical Dysplasia

Background: Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited.Methods: Retrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging.Results: Neuroimaging analysis revealed four main cerebral phenotypesdhemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed macrocephaly with complicated gyral pattern (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants.Conclusions: A spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment.& COPY; 2023 Elsevier Inc. All rights reserved.

Automated summary

This study found that inactivating mutations in PTEN are one of the causes of megalencephaly, and activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are associated with cortical brain malformations. The study identified four main phenotypes of cortical dysplasias caused by PTEN mutations and found favorable long-term outcomes.