Neuroimaging Findings in Axenfeld-Rieger Syndrome: A Case Series

Abstract

Axenfeld-Rieger syndrome is an autosomal dominant condition associated with multisystemic features including developmental anomalies of the anterior segment of the eye. Single nucleotide and copy number variants in the paired-like homeodomain transcription factor 2 (PITX2) and forkhead box C1 (FOXC1) genes are associated with Axenfeld-Rieger syndrome as well as other CNS malformations. We determined the association between Axenfeld-Rieger syndrome and specific brain MR imaging neuroradiologic anomalies in cases with or without a genetic diagnosis. This case series included 8 individuals with pathogenic variants in FOXC1; 2, in PITX2; and 2 without a genetic diagnosis. The most common observation was vertebrobasilar artery dolichoectasia, with 46% prevalence. Other prevalent abnormalities included WM hyperintensities, cerebellar hypoplasia, and ventriculomegaly. Vertebrobasilar artery dolichoectasia and absent/hypoplastic olfactory bulbs were reported in >50% of individuals with FOXC1 variants compared with 0% of PITX2 variants. Notwithstanding the small sample size, neuroimaging abnormalities were more prevalent in individuals with FOXC1 variants compared those with PITX2 variants.

FIGURE.

A, A 49-year-old woman with a PITX2 mutation had superior vermian volume loss on the T1-weighted sagittal image (A1) and optic chiasm thinning on the T2-weighted coronal image (A2). B, A 2-month-old girl with an unsolved mutation had inferior vermian hypoplasia and a widened tegmentovermian angle on the T1-weighted sagittal image (B1) and malrotated hippocampi on the T2-weighted coronal image (B2). C, A 43-year-old man with a FOXC1 mutation had mega cisterna magna and an ectatic basilar artery and a hypoplastic left cerebellar hemisphere on the T2-weighted axial image (C1) and hypoplastic olfactory bulbs on the T2-weighted coronal image (C2). D, A 46-year-old man with a FOXC1 mutation had a tortuous basilar artery and an ectatic cavernous segment of the left ICA on axial TOF angiography (D1); a short mesencephalon with loss of the normal relationship among the mesencephalon, pons, and medulla; loss of volume in the superior vermis and ectatic basilar artery; and flow void seen end-on on the T2-weighted sagittal image (D2). E, A 41-year-old woman with a FOXC1 mutation had a tortuous basilar artery flow void on the T2-weighted axial image (E1), a short mesencephalon with loss of the normal relationship among the mesencephalon, pons, and medulla, and bowing of the corpus callosum secondary to ventriculomegaly on the T1-weighted sagittal image (E2). F, A 3-month-old boy with an unsolved mutation had absent olfactory bulbs on the T2-weighted coronal image. G, A 31-year-old woman with an unsolved mutation had a thickened splenium and tonsillar ectopia on the T1-weighted sagittal image.