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

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.

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.

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).

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'.