Corneal Dystrophy Classification

History

The word dystrophy derived from the Greek ( dys = wrong, difficult; trophe = nourishment) was introduced into the ophthalmology literature in 1890 by Arthur Groenouw when he published his classic paper describing two patients with “Noduli Corneae.” In the preslit lamp era, Groenouw did not initially appreciate the differences between the two conditions described, one patient having granular dystrophy and the other macular dystrophy. Nevertheless, the two diseases later became known as corneal dystrophies. The word “dystrophy” continued to be used by Ernst Fuchs, Wilhelm Uhthoff, and later by Yoshiharu Yoshida.

Corneal Dystrophy Definition

The term “corneal dystrophy” typically refers to a group of inherited corneal diseases that are usually bilateral, symmetric, slowly progressive, and not related to environmental or systemic factors. However, exceptions to each part of this definition exist. Hereditary pattern is not present in most patients with epithelial basement membrane dystrophy (EBMD). Unilateral corneal changes may be found in some patients with posterior polymorphous corneal dystrophy (PPCD). Systemic changes are found in macular dystrophy, in which the level of antigenic serum keratan sulfate correlates with the immunophenotypes of the disease.

Corneal Dystrophy Classification in the Literature

The first classification of corneal dystrophies by Bücklers described the differences between granular, macular, and lattice dystrophy. The most commonly used classification system is anatomically based. The dystrophies were typically classified by the level of the cornea that is involved, which separates these entities into epithelial and subepithelial, Bowman layer, stromal, and endothelial dystrophies. ^,

Shortcomings of Corneal Dystrophy Nomenclature and Classification

There have been many misconceptions and errors in the corneal dystrophy nomenclature and classification. For example, the dystrophy previously called “Schnyder crystalline corneal dystrophy” (SCCD) is a rare dystrophy often misdiagnosed precisely because of the deceptive name. While many publications emphasize the necessity of demonstrating corneal crystals to make the diagnosis of SCD, examination of large pedigrees of affected individuals demonstrates that only 50% of affected patients actually have corneal crystals.

Errors in the dystrophy literature include the fact that some of the early papers describing the ultrastructure of Reis-Bücklers corneal dystrophy had actually analyzed tissue from patients with Thiel-Behnke corneal dystrophy. Some entities described as corneal dystrophies may actually be corneal degenerations and have no hereditary tendency. The original publication on central cloudy dystrophy of François indicated this corneal opacification was inherited, but there have been only a few other publications that have described an entire family with this disease. ^, Furthermore, central cloudy dystrophy of François appears clinically indistinguishable from the degenerative condition, posterior crocodile shagreen. Without additional affected pedigrees or genetic studies, it is possible that central cloudy dystrophy of François and posterior crocodile shagreen are the same entity.

Another flaw in the corneal dystrophy classification is the relative lack of scrutiny that has been required to call something a new corneal dystrophy . Prior to the 1970s, new corneal dystrophies were identified and characterized almost exclusively by their clinical appearance, and sometimes, the report of a single family signaled the creation of a new dystrophy. In some such cases, a variant of a previously described dystrophy was instead given a different name and misclassified as a new dystrophy. For example, the dystrophy named Waardenburg and Jonkers was not a unique entity and was actually identical to the previously described Thiel-Behnke dystrophy.

The Impact of Genotyping on Corneal Dystrophy Nomenclature

Genotypic analysis has revealed other inaccuracies of dystrophy nomenclature. Different genes ( KRT3 and KRT12 ) can result in a single dystrophy phenotype such as Meesmann dystrophy, and one single gene (TGFBI) can cause multiple allelic dystrophy phenotypes (Reis-Bücklers, Thiel-Behnke, granular type 1, granular type 2, and lattice type 1). Newer genetic information has clearly demonstrated the flaws in the older system of phenotypic classification of corneal dystrophies.

Since the first descriptions of granular, macular, and lattice dystrophies over a century ago, the word dystrophy has lost significance as the distinctive name of many of the individual dystrophies has become less meaningful. While a more meaningful classification would be called “inherited corneal diseases,” it is likely that “the popular designation of corneal dystrophy will probably keep its place.” The importance of genotypic information in redefining our understanding of the corneal dystrophies is typified by our evolving knowledge about a more recently recognized entity, the epithelial recurrent erosion dystrophies (EREDs). ERED was discovered to be caused by mutations in COL17A1 gene on chromosome 10.

Subsequently, the COL17A1 mutation was also identified in a family formerly thought to have Thiel-Behnke corneal dystrophy, although the abnormality had been mapped to chromosome 10q23-q24 instead of TGFBI . ^, Consequently, it was the genetic information that clarified that this family had been erroneously diagnosed to have Thiel-Behnke corneal dystrophy and instead actually had the more recently recognized entity, ERED. This underscores that phenotypic information may not be sufficient to determine an accurate diagnosis. Genotypic information may contradict our prior phenotypic diagnostic assumptions.

The International Committee for Classification of Corneal Dystrophies

The International Committee for Classification of Corneal Dystrophies (IC3D) was created in 2005 in order to revise the corneal dystrophy nomenclature and create a current and accurate corneal dystrophy classification system. An international panel of interested world experts possessing firsthand experience with the clinical, genetic, and histopathologic findings of all the corneal dystrophies was recruited to evaluate critically the past literature and to distill the facts and remove outdated inaccurate information. The goal was to establish a new nomenclature that would reflect current clinical, pathologic, and genetic knowledge, be easily adaptable to advances in understanding from the continued discovery of new genes and mutations, and be linked to the old nomenclature for ease of use. The revised dystrophy classification was initially published in 2008 with a second edition incorporating further changes published in 2015.

The IC3D Classification—an Anatomically Based Classification System

The IC3D corneal dystrophy classification system is anatomically based, with dystrophies divided according to the layer chiefly affected, similar to the former classification system. They are epithelial and subepithelial, epithelial-stromal TGFBI , stromal, and endothelial corneal dystrophies. For ease of use, the majority of the dystrophy names are identical or similar to those in the current nomenclature. However, dystrophies with a known common genetic basis, that is, TGFBI dystrophies, have been grouped together.

The IC3D Category System to Denote the Evolution of a Corneal Dystrophy

One challenge in revising the dystrophy nomenclature was to devise a classification that would be flexible enough to facilitate the expansion of knowledge from other sources, including genotyping.

When a corneal dystrophy is first described, there is usually a predictable chain of events. First, an entity is identified and characterized clinically. Subsequently, if tissue evaluations of the diseased cornea are available, these may lead to the establishment of distinct clinicopathologic entities. Finally, genetic linkage studies lead to the mapping of the chromosomal locus of the disorder, especially if the condition has a simple Mendelian inheritance pattern. This task becomes more complex when more than one gene is involved or if there is an interaction between genetic and environmental factors. Ultimately, there is identification of the relevant gene and isolation of specific mutations that are responsible for different phenotypical forms of the disorder. Finally, the mechanism of the disorder will eventually be understood, with identification of the gene product.

In order to reflect the natural evolution of a corneal dystrophy and indicate the level of evidence supporting the existence of a given dystrophy, four descriptive, evidential categories were created in the IC3D classification ( Box 69.1 ). While the category assigned to a specific corneal dystrophy will change as knowledge advances, all valid corneal dystrophies should eventually have a category 1 classification. Conversely, as further information is gathered over time, some category 4 dystrophies may be shown not to be distinct entities and may be removed ( Box 69.2 ).