Pathological classification of Fuchs endothelial corneal dystrophy into several types and their relationships with CTG18.1 expansion repeats

Abstract

Late-onset Fuchs endothelial corneal dystrophy (FECD) is the most common primary disease of the corneal endothelium and the leading indication for corneal transplantation in Western countries. It is characterized by progressive accumulation, over two to three decades, of extracellular matrix (ECM) components in Descemet's membrane (DM), leading to the formation of abnormal excrescences, known as guttae, and additional DM layers. Clinical forms and evolutionary profiles vary widely among patients. FECD is strongly associated with intronic CTG trinucleotide repeats (TNRs) in the transcription factor 4 (TCF4) gene. We analysed 500 DMs removed during keratoplasty for FECD across 25 European centres to identify different anatomopathological forms of the disease. Following flat mounting and dehydration, the samples were digitized using transmitted light microscopy and independently assessed by three independent readers. A total of ten parameters - six related to guttae and four on other forms of ECM - were scored. Principal component analysis and an unsupervised clustering method separated three clusters from these parameters. In addition, manual classification was performed by grouping samples with major common features. The number of TNRs in TCF4 was analysed by short tandem repeat (STR)- and triplet repeat primed-polymerase chain reaction (TP-PCR) for 109 patients. We found that (1) five FECD phenotypes exist; (2) guttae and other ECM structures were radially arranged in 95% of samples; (3) 33% of samples exhibited peripheral radial striae that corresponded to a hypertrophied form of similar structures present in healthy corneas; and (4) patients with fewer than 50 TNRs had only two out of five phenotypes and had a significantly higher number of peripheral radial striae (94% versus 49%, p < 0.001). Taken together, these new findings demonstrate the existence of different FECD phenotypes; reveal that lesions affect both the centre and the periphery of the endothelium; and suggest that radial deposits may be produced by pathological cells migrating from the periphery towards the centre. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: CTG18.1 trinucleotide repeat expansion; Descemet's membrane; Fuchs endothelial corneal dystrophy; classification; corneal endothelium; extracellular matrix; phenotypes.