A Novel GRHL2 Intronic Variant in Familial Posterior Polymorphous Corneal Dystrophy: Clinical, Histopathological, and Genetic Insights Across Generations.

PURPOSE: To describe the clinical, histopathological, and genetic characteristics of a posterior polymorphous corneal dystrophy-4 pedigree spanning 3 generations with a novel GRHL2 variant and to highlight intrafamilial clinical variability.

METHODS

Comprehensive ophthalmic examinations were performed on affected family members. Histopathological evaluation of proband's corneal tissue excised during penetrating keratoplasty was conducted using hematoxylin & eosin, periodic acid-Schiff, and cytokeratin stains. Genomic DNA was analyzed using Sanger sequencing of the promoter and coding regions of ZEB1, GRHL2, and OVOL2.

RESULTS

The proband and her sibling exhibited steep corneas with variable ground-glass haze, vesicular, and band-like endothelial changes. The mother and maternal grandfather showed milder endothelial vesicles and subtle posterior stromal haze, with the grandfather least affected. Histopathology showed posterior stromal thickening with edema, Descemet membrane reduplication, and thinning along with endothelial loss. Genetic analysis identified a novel heterozygous intronic GRHL2 variant (c.20 + 544G > C) segregating in all affected members, absent in 80 controls, and located in a known regulatory hotspot associated with ectopic GRHL2 expression.

CONCLUSIONS

Intronic regulatory variants of GRHL2 can cause familial posterior polymorphous corneal dystrophy (PPCD) with marked phenotypic variability. This is the first report of the c.20 + 544G > C variant and the second implicating the same intronic position in PPCD, underscoring the diagnostic importance of this hotspot and the need to include regulatory regions in targeted genetic testing for PPCD.