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.

• Authors: Wenlin Zhang, J Ben Margines, Deborah S Jacobs, Yaron S Rabinowitz, Evelyn Maryam Hanser, Tulika Chauhan, Doug Chung, Yelena Bykhovskaya, Ronald N Gaster, Anthony J Aldave
• Journal: Cornea (Cornea) Vol. 38 Issue 8 Pg. 1033-1039 (Aug 2019) ISSN: 1536-4798 [Electronic] United States
• PMID: 31107761 (Publication Type: Case Reports, Journal Article)

Chemical References

• Cross-Linking Reagents
• DNA-Binding Proteins
• PRDM5 protein, human
• Photosensitizing Agents
• Transcription Factors
• ZNF469 protein, human
• Collagen

Topics

• Adult
• Collagen (metabolism)
• Corneal Perforation (diagnosis, etiology)
• Corneal Stroma (metabolism)
• Corneal Topography
• Cross-Linking Reagents (adverse effects)
• DNA-Binding Proteins (genetics)
• Female
• Humans
• Jews (genetics)
• Keratoconus (drug therapy, genetics, metabolism)
• Middle Aged
• Mutation, Missense
• Photochemotherapy (adverse effects)
• Photosensitizing Agents (adverse effects)
• Polymerase Chain Reaction
• Transcription Factors (genetics)
• Ultraviolet Rays