Corneal Perforation After Corneal Cross-Linking in Keratoconus Associated With Potentially Pathogenic ZNF469 Mutations

Abstract

Purpose: To report a case of bilateral and repetitive corneal perforations after corneal cross-linking (CXL) for keratoconus in a woman harboring potentially pathogenic variants in the ZNF469 gene and to characterize the keratoconus phenotype in this woman and her daughter who shared the same ZNF469 mutations.

Methods: Clinical characterization of the proband and her daughter followed by sequencing of the genes associated with brittle cornea syndrome, ZNF469 and PRDM5, in both individuals.

Results: An Ashkenazi Jewish woman in her sixth decade presented with diffuse corneal thinning and progressive steepening consistent with keratoconus. After CXL, epithelium-off in the first eye and epithelium-on in the second, she developed spontaneous corneal perforations in each eye. Her daughter in her fourth decade demonstrated a similar pattern of diffuse corneal thinning and progressive corneal steepening but did not undergo CXL and did not develop corneal perforation. Screening of the ZNF469 and PRDM5 genes revealed 3 missense ZNF469 variants (c.2035G>A, c.10244G>C, and c.11119A>G) in cis arrangement on 1 allele of ZNF469 in both proband and her daughter. Although the 3 variants share low (<0.01) global minor allele frequencies, each has significantly higher minor allele frequencies (0.01-0.03) in the Ashkenazi Jewish population, leading to uncertainty regarding a pathogenic role for the identified variants.

Conclusions: CXL may be associated with the development of corneal perforation in particular at-risk individuals with keratoconus. Identifying clinical and genetic risk factors, including screening of ZNF469 and PRDM5, may be useful in the prevention of significant complications after CXL.

Figure 1:

Corneal tomographic imaging of the proband diagnosed with late-onset keratoconus demonstrating significant inferotemporal steepening and high oblique astigmatism in the right eye with diffuse stromal thinning and centrally located minimum thickness of approximately 400 μm in each eye.

Figure 2:

Slit-lamp photos of the proband’s right cornea demonstrating the location of prior temporal paracentral perforations (arrowheads) (A) and diffuse thinning (B). Images obtained 4 months after epi-off CXL. Slit-lamp photos of the proband’s left cornea demonstrating the location of prior temporal paracentral spontaneous perforation that developed 8 days after epi-on CXL (arrowheads) (C). Three months after the third spontaneous perforation in the right cornea, which occurred 3 years after CXL, sutures are present in the location of the corneal perforation (D).

Figure 3:

Corneal tomographic imaging of the proband’s daughter demonstrating mild inferior paracentral steepening with low astigmatism as well as diffuse thinning with centrally located minimum thicknesses of approximately 400 μm in both eyes.