Polymicrogyria is associated with pathogenic variants in PTEN

Objective: Congenital structural brain malformations have been described in patients with pathogenic PTEN variants, but the frequency of cortical malformations in PTEN variants and their impact on clinical phenotype are not well understood. Our goal was to systematically characterize brain malformations in patients with PTEN variants and assess the relevance of their brain malformations to clinical presentation.

Methods: We systematically searched a local radiology database for patients with pathogenic PTEN variants who had available brain magnetic resonance imaging (MRI). MRIs were reviewed systematically for cortical abnormalities. We reviewed EEG data and evaluated the electronic medical record to for evidence of epilepsy and developmental delay.

Results: In total we identified 22 patients with PTEN pathogenic variants for which brain MRIs were available (age range 0.4 years - 17 years). Twelve among these 22 (54%) had polymicrogyria (PMG). Variants associated with PMG or atypical gyration encoded regions of the phosphatase or C2 domains of PTEN. Interestingly, epilepsy was present in only 2 of the 12 patients with PMG. We found a trend toward higher rates of GDD, ID, and motor delay in individuals with cortical abnormalities, though cohort size limited statistical significance.

Interpretation: Malformations of cortical development, PMG in particular, represent an underrecognized phenotype associated with PTEN pathogenic variants and may have an association with cognitive and motor delays. Epilepsy was infrequent compared to the high risk of epilepsy in patients with PMG reported previously. This article is protected by copyright. All rights reserved.