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

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 the abnormal accumulation, over 2 to 3 decades, of extracellular matrix (ECM) components in the form of Descemets membrane (DM) excrescents, known as guttae, as well as additional DM layers. Clinical forms and evolutionary profiles vary greatly from patient to patient. It is strongly associated with intronic CTG trinucleotide repeats (TNR) in the transcription factor 4 (TCF4) gene. To determine if there are different anatomopathological forms of FECD, we analysed 500 DM removed during keratoplasty for FECD in 25 European centres. After flat mounting and dehydration, the samples were digitized using transmitted light microscopy and observed by 3 independent readers. Ten parameters (6 on guttae and 4 on other forms of ECM) were scored. A principal component analysis and unsupervised clustering method separated 3 clusters from these parameters. In addition, a manual classification, grouping together samples with major common features, isolated 5 types of FECD. The number of TNR in TCF4 was analysed by ST- and TP-PCR for 109 patients. We found that: 1) 5 phenotypes of FECDs existed, 2) guttae and other ECM structures were radially arranged in 95% of samples, 3) 33% had peripheral radial striae that corresponded to a hypertrophied form of similar structures present in healthy corneas, and 4) the patients with fewer than 50 TNRs had only 2 phenotypes out of 5 and significantly more often peripheral radial striae (94% vs. 49%, P<0.001). Taken together, these new descriptions demonstrate the existence of different FECD phenotypes, reveal that lesions affect both the centre and periphery of the endothelium and suggest that radial deposits may be produced by pathological cells migrating from the periphery to the centre.