FOXC1-associated phenotypes in humans may not always exhibit corneal neovascularization

The transcription factor gene FOXC1 has been implicated with Axenfeld–Rieger syndrome (ARS) in humans. Mutations in this gene have been suggested to contribute to the mechanism leading to developmental defects in the anterior chamber of the eye. In PNAS, Seo et al. (1) demonstrated that mutations in FOXC1 led to corneal angiogenesis in mice and in anterior segment anomalies like ARS in humans. Although the data on mice are very convincing, we provide a different perspective based on our observations in two different patient cohorts with FOXC1 mutations. Our screening of patients (n = 10) with Axenfeld–Rieger anomaly (ARA) for FOXC1 mutations did not reveal any form of corneal neovascularization among the heterozygous mutation carriers (2). We also screened the FOXC1 gene in a large cohort (n = 210) of another related disease, primary congenital glaucoma (PCG) without any anterior segment anomalies, and, similarly, the mutations carriers were devoid of any corneal neovascularization as observed in our ARA cohort (3). Interestingly, the results were consistent across PCG cases that harbored heterozygous alleles of FOXC1 alone or in combination with an accompanying allele of CYP1B1.

Classically, ARS presents with iris and angle abnormalities in the absence of any other primary corneal abnormality except for posterior embryotoxon and associated micro/megalocornea. Thus, in view of this well-defined phenotypic description for the diagnosis of ARS along with the involvement of FOXC1 mutations in developmental anomalies of the anterior chamber, we wonder if the phenotypic description of patients harboring FOXC1 mutations and corneal neovascularization by Seo et al. (1) may be suggestive of sclerocornea. It is possible that because of the absence of development of the limbal anlage in humans, the cornea gets opacified and exhibits peripheral vascularization. Hence, this type of vascularization could be attributable to the lack of differentiation of the cornea from the scleral architecture. The genetics of sclerocornea are poorly understood, but the condition has been suggested to coexist with iridocorneal adhesions and anterior segment dysgenesis (4).

It is important to note that, clinically, there is a tremendous overlap of various anterior segment developmental anomalies and congenital corneal opacities, which makes accurate clinical diagnosis very challenging. Additionally, congenital corneal opacity exhibits genetic heterogeneity and several genes, including FOXC1, PAX6, PITX2, FOXE3, B3GALTL, and KARA, have been implicated in the disease pathogenesis (5). It has also been shown that different clinical entities in the anterior segment may coexist either bilaterally or unilaterally. Thus, based on this evidence, we conclude that corneal neovascularization as observed in mice may not be a universal phenomenon across different FOXC1-associated phenotypes in humans.