The Clinical Spectrum of Granular Corneal Dystrophy Caused by the R124H Mutation in the TGFBI Gene

Abstract

Abstract: : Purpose: To characterize the intrafamilial and interfamilial clinical and histopathologic phenotype associated with the R124H mutation in the TGFBI gene. Methods: Patients diagnosed as having granular corneal dystrophy (GCD) were investigated. A mutational analysis of the TGFBI gene was performed on these individuals; pedigrees were established on those with the R124H mutation. All available clinical records and photographs were reviewed and any available corneal tissue was studied by light microscopy. Results: We studied more than 100 individuals from more than 10 families with the R124H mutation. An autosomal dominant mode of inheritance was confirmed in all but one family. Clinically, the GCD became apparent at 6 to 40 years of age. The symptoms at onset included: foreign body sensation, glare, impaired visual acuity, and occasional pain accompanying corneal erosions. Slit lamp biomicroscopy and photographs revealed multiple bilateral roundish planar gray and white opacities mainly in the superficial central corneal stroma. These deposits sometimes resembled snowflakes and several had a polygonal shape. The vast majority of corneas lacked a network of linear opacities comparable to lattice corneal dystrophy, but an occasional cornea contained a rare linear opacity. Sometimes spicular opacities were identified which occasionally formed stellate shapes. Light microscopy of the corneal tissue disclosed prominent extracellular deposits of fuscinophilic material indistinguishable from what is found in typical GCD. Mild deposits of amyloid were usually found in the corneal stroma, but often only found after a diligent search. Conclusions: The terms granular corneal dystrophy type II, Avellino dystrophy, and combined granular–lattice corneal dystrophy have been used as synonyms for the phenotype resulting from the R124H mutation in the TGFBI gene. However, the apparently characteristic clinical phenotype resulting from this genotype usually lacks typical lattice lines and the amyloid deposits are often trivial. Hence, the designation as a combined granular–lattice corneal dystrophy is not appropriate. Moreover, because most cases do not trace their ancestry to the Avellino district in Italy, the term Avellino dystrophy is imprecise. We consider the designation granular corneal dystrophy type II more appropriate than either phrase.

Keywords: cornea: clinical science • genetics • pathology: human