Are Alterations in Corneal Thickness a Common Feature of Anterior Segment Developmental Gene Mutation? Implications for Paediatric Glaucoma

Abstract

Abstract: : Purpose Mutations in human and murine versions of the same gene generally cause similar phenotypes. However in the case of FOXC1, severe corneal phenotypes have only been observed in mice. We hypothesised that such discrepancies might provide an opportunity for identifying unrecognised human phenotypes. Methods Three families with early onset glaucoma secondary to duplications encompassing FOXC1, underwent detailed phenotyping including ultrasonic pachymetry. Central corneal thickness (CCT) was also measured in 50 patients with differing (clinical and genetic) types of anterior segment dysgenesis (ASD). CCT was measured in histological sections from mice with mutations in genes (Foxc1 / Foxe3) involved in anterior segment development. Results CCT in each of the 3 duplication pedigrees was significantly increased in affected individuals (mean 600µm, n = 27) compared to unaffected relatives (mean 532µm, n = 20) (P = 0.003 to 0.044) or population controls (mean 539µm, n = 144). Statistically significant alterations in corneal thickness were present in Foxe3 hetero and homozygotes but not in Foxc1 mutants. 25 of 50 ASD patients had CCT <495 or >600µm (range 413 - 816µm). In the congenital glaucoma and Axenfeld-Rieger subgroups (n = 41 and 31 eyes respectively) 9 and 8 eyes had CCT > 600µm whilst 8 and 4 eyes had CCT < 495µm. These frequently asymmetric changes were present in eyes with normal specular microscopy and were not correlated with alterations in anterior segment or ocular size. Conclusions Increases or decreases in CCT affect the measurement of IOP, the cornerstone of glaucoma management, leading to treatment to lower a falsely-elevated IOP (increased CCT) or undertreatment (decreased CCT). Increased CCT may result in overdiagnosis of glaucoma especially in ASD patients with a strong family history of glaucoma. This provides a possible explanation for the higher prevalence of glaucoma (90-100%) in UK pedigrees with FOXC1 duplication compared with mutation or deletion (~50%). The prevalence of altered corneal thickness in a broad spectrum of ASD, including mutation in four genes (FOXC1, Foxe3, PITX2, CYP1B1) and two species, suggests it is a common feature of mutations in genes involved in anterior segment development. Analysis of murine mutants and development of murine pachymetry may clarify whether other ocular structures are similarly affected.

Keywords: genetics • anterior segment