Exploring the histopathological signature of repeat-mediated Fuchs endothelial corneal dystrophy.

Purpose: To determine the histological differences between Fuchs endothelial corneal dystrophy (FECD) cases with and without the most common genetic risk factor, expansion of a CTG repeat (CTG18.1) within the TCF4 gene.

Methods: Formalin-fixed paraffin-embedded corneal tissues were compared retrospectively, and CTG18.1 status was determined from blood-derived gDNA. Cases were defined as expansion-positive (Exp⁺) if at least one CTG18.1 allele had ≥ 50 repeats. Tissue was assigned as either 'typical' if there were several prominent exophytic or buried guttae or 'not typical' if there were only a few shallow guttae or no status could be confidently assigned.

Results: In total, 72 unrelated corneal specimens (43 from endothelial keratoplasty and 29 from penetrating keratoplasty) with corresponding genetic data were analysed. We assigned a 'typical' histopathological guttae appearance to 88% (53/60) of Exp⁺ and 83% (10/12) of Exp^- cases. No significant difference was observed between the proportion of 'typical' and 'not typical' assignments within these genotypically distinct groups (Fisher's exact test; odds ratio [OR], 1.5; 95% CI: 0.14-9.7; p = 0.6393). Without adjustment for multiple testing, 'not typical' samples were more likely to be from males (7/9 vs. 17/63; OR, 0.11; 95% CI: 0.01-0.65; p = 0.005017) and more frequently from cases with coexisting keratoconus (4/9 vs. 3/63; OR = 0.07; 95% CI: 0.01-0.54; p = 0.004208).

Conclusion: Histopathological guttae appearance was not found to correlate with CTG18.1 expansion status. However, male sex or coexisting keratoconus was more frequently associated with histology categorised as 'not typical'.