Thickened Fornices and Other Structural Brain Anomalies in Patients with FOXG1 Syndrome and in Foxg1+/− Mice

Objective: FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous FOXG1 variants or chromosomal microaberrations in 14q12. The study aimed at assessing the scope of structural cerebral anomalies revealed by neuroimaging to delineate the genotype and neuroimaging phenotype associations.

Material and Methods: We compiled 34 patients with a heterozygous (likely) pathogenic FOXG1 variant. Qualitative assessment of cerebral anomalies was performed by standardized re-analysis of all MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data was performed. We quantified clinical and neuroimaging phenotypes using severity scores. Telencephalic phenotypes of adult Foxg1+/- mice were examined using immunohistological stainings followed by quantitative evaluation of structural anomalies.

Results: Characteristic neuroimaging features included corpus callosum anomalies (82%), thickening of the fornix (74%), simplified gyral pattern (56%), enlargement of inner CSF spaces (44%), hypoplasia of basal ganglia (38%), and hypoplasia of frontal lobes (29%). We observed a marked, filiform thinning of the rostrum as recurrent highly typical pattern of corpus callosum anomaly in combination with distinct thickening of the fornix as a characteristic feature. Simplified gyral pattern occurred significantly more frequently in patients with early truncating variants. Higher clinical severity scores were significantly associated with higher neuroimaging severity scores. Modeling of Foxg1 heterozygosity in mouse brain recapitulated the associated abnormal cerebral morphology phenotypes, including the striking enlargement of the fornix.

Discussion: While corpus callosum anomalies, simplified gyral pattern, enlarged ventricles, and hypoplasia of frontal lobes were described previously in patients with FOXG1 syndrome, thickening of the fornix (in 25 out of 34 patients) and, less specifically, hypoplasia of basal ganglia (in 13 out of 34 patients) have not been reported before. Fornix thickening is thus a major highlight in this current investigation.

Interpretation: Based on both, previous observations and the results presented here, a highly characteristic pattern of neuroimaging features in FOXG1 syndrome is emerging. The combination of corpus callosum anomaly with simplified gyral pattern and hyperplasia of the fornices is possibly pathognomonic for FOXG1 syndrome. All these three features were present in 16 (47%) of the 34 patients in this study, any two of them were found in further nine cases (26%). Particularly, the combination of genu corporis callosi agenesis with fornix hyperplasia consistently points to FOXG1 syndrome.

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