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Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.

ABSTRACT: 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. 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 34 MRI data sets. Statistical analysis of genetic, clinical and neuroimaging data were 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. Thickening of the fornices was not reported previously in FOXG1 syndrome. 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. Interpretation:Combination of specific corpus callosum anomalies with simplified gyral pattern and hyperplasia of the fornices is highly characteristic for FOXG1 syndrome.

SUBMITTER: Pringsheim M

PROVIDER: S-EPMC6469254 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.

Pringsheim Milka M Mitter Diana D Schröder Simone S Warthemann Rita R Plümacher Kim K Kluger Gerhard G Baethmann Martina M Bast Thomas T Braun Sarah S Büttel Hans-Martin HM Conover Elizabeth E Courage Carolina C Datta Alexandre N AN Eger Angelika A Grebe Theresa A TA Hasse-Wittmer Annette A Heruth Marion M Höft Karen K Kaindl Angela M AM Karch Stephanie S Kautzky Torsten T Korenke Georg C GC Kruse Bernd B Lutz Richard E RE Omran Heymut H Patzer Steffi S Philippi Heike H Ramsey Keri K Rating Tina T Rieß Angelika A Schimmel Mareike M Westman Rachel R Zech Frank-Martin FM Zirn Birgit B Ulmke Pauline A PA Sokpor Godwin G Tuoc Tran T Leha Andreas A Staudt Martin M Brockmann Knut K

Annals of clinical and translational neurology 20190303 4

<h4>Objective</h4>FOXG1 syndrome is a rare neurodevelopmental disorder associated with heterozygous <i>FOXG1</i> 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.<h4>Methods</h4>We compiled 34 patients with a heterozygous (likely) pathogenic <i>FOXG1</i> variant. Qualitative assessment of cerebral anomalies was performed by standardi ...[more]

PMID: 31019990

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Project description:Background and purposeCerebral and cervical arterial abnormalities are the most common non-cutaneous anomaly in PHACE syndrome, but the location and type of arterial lesions that occur have not been systematically assessed in a large cohort. Our aim was to characterize the phenotypic spectrum of arteriopathy, assess the frequency with which different arteries are involved, and evaluate spatial relationships between arteriopathy, brain structural lesions, and hemangiomas in PHACE syndrome.Materials and methodsIntracranial MRA and/or CTA images from 70 children and accompanying brain MR images in 59 patients with arteriopathy and PHACE syndrome were reviewed to identify the type and location of arterial lesions and brain abnormalities. Five categories of arteriopathy were identified and used for classification: dysgenesis, narrowing, nonvisualization, primitive embryonic carotid-vertebrobasilar connections, and anomalous arterial course or origin. Univariate logistic regression analyses were performed to test for associations between arteriopathy location, hemangiomas, and brain abnormalities.ResultsBy study design, all patients had arterial abnormalities, and 57% had >1 form of arteriopathy. Dysgenesis was the most common abnormality (56%), followed by anomalous course and/or origin (47%), narrowing (39%), and nonvisualization (20%). Primitive embryonic carotid-vertebrobasilar connections were present in 20% of children. Hemangiomas were ipsilateral to arteriopathy in all but 1 case. The frontotemporal and/or mandibular facial segments were involved in 97% of cases, but no other specific associations between arteriopathy location and hemangioma sites were detected. All cases with posterior fossa anomalies had either ICA anomalies or persistent embryonic carotid-basilar connections.ConclusionsThe arteriopathy of PHACE syndrome commonly involves the ICA and its embryonic branches, ipsilateral to the cutaneous hemangioma, with dysgenesis and abnormal arterial course the most commonly noted abnormalities. Brain abnormalities are also typically ipsilateral.

Dataset Information

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.

Publications

Structural brain anomalies in patients with FOXG1 syndrome and in Foxg1+/- mice.

Similar Datasets

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