In vivo assessment of retinal phenotypes in Axenfeld-Rieger syndrome

Abstract

Purpose : Axenfeld-Rieger syndrome (ARS) is characterized by specific ocular anomalies, typically posterior embryotoxon, iridocorneal adhesions, corectopia/iris hypoplasia, and developmental glaucoma. Pathogenic variants in PITX2 or FOXC1 explain 41% and 30% of ARS, respectively. While anterior segment defects and glaucoma contribute to lowered visual acuity in ARS, additional unidentified factors in the posterior segment may also play a role but have never been systematically explored. We used high-resolution retinal imaging to test the hypothesis that individuals with ARS have posterior segment pathology.

Methods : Three individuals with FOXC1-ARS and ten with PITX2-ARS completed slit lamp and fundus photography, optical coherence tomography (OCT), OCT-angiography, and adaptive optics scanning light ophthalmoscopy (AOSLO). The cohort included 8 females, 5 males; 12 White, 1 Hispanic aged 12-52 [mean ± SD, 27.2 ± 14.3] years. Genetic analyses were performed by exome/genome sequencing.

Results : All participants demonstrated typical anterior segment phenotypes. Average and minimum ganglion cell and inner plexiform layer thickness was lower in PITX2-ARS, consistent with the higher rate of glaucoma requiring surgery in this cohort. A novel phenotype of foveal hypoplasia was noted in 40% of individuals with PITX2-ARS and none with FOXC1-ARS. Moreover, the depth and volume of the foveal pit were significantly lower in PITX2-ARS compared to normal controls (depth, p<0.0001; volume, p=0.0002), a difference that persisted even after removing the individuals with foveal hypoplasia (depth, p=0.0001; volume, p=0.024). Analysis of TYR, SLC38A8, ATF6, OCA2, and PAX6 genetic variants including TYR hypomorphic allele status failed to identify an alternative explanation for the observed phenotype. Two individuals, one with PITX2-ARS and one with FOXC1-ARS, demonstrated additional retinal defects. Foveal cone density was measured in seven individuals and found to be normal in the six subjects with normal fovea with the remaining individual with foveal hypoplasia showing decreased cone packing, consistent with previous observations.

Conclusions : These findings implicate PITX2 in the development of the posterior segment, particularly the fovea, in humans. The identified retinal phenotypes are likely to contribute to visual acuity deficits in individuals with PITX2-ARS.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.