Corneal Dystrophies

Corneal dystrophies have classically referred to inherited, bilateral disease without systemic findings, although there are several exceptions to this definition. 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). TGFBI gene mutation (p.His572del) is associated with a unilateral, late-onset variant of lattice corneal dystrophy. Among all dystrophies, macular corneal dystrophy and posterior amorphous corneal dystrophy are associated with decreased corneal thickness. The International Committee for Classification of Corneal Dystrophies (IC3D) was created in 2005 to revise the corneal dystrophy nomenclature and create a current and accurate corneal dystrophy classification system. Evidential categories were created in the IC3D classification for reflecting the natural evolution of a corneal dystrophy and indicate the level of evidence supporting the existence of a given dystrophy.

Deterioration of Avellino corneal dystrophy in a Chinese family after LASIK

AIM: To reveal the importance of TGFBI gene screening for candidates with a family history of corneal disease or granular opacities in corneal stroma before refractive surgery. METHODS: A 37-year-old male (proband) underwent bilateral laser-assisted in situ keratomileusis (LASIK) in 2002, with right vision decreased significantly in 2006. The proband and other 32 members of the family underwent a detailed ophthalmic examination, including vision acuity, intraocular pressure, slit-lamp photograph, fundus examination, optical coherence tomography (OCT) of cornea, and in vivo confocal microscope (IVCM) and peripheral blood was used for genomic DNA extraction. Seventeen TGFBI gene exons were analyzed via polymerase chain reaction amplification and direct sequencing. RESULTS: Slit-lamp, IVCM, and OCT images showed that a large amount of dense and confluent granular opaque were seen at the interfaces of the flap and remnant stromal bed in right and light degree in left eye. Sanger sequencing showed that there was a 371G>A mutation (CGC>CAC) in exon 4, which indicated that he harbored a heterozygote R124H mutation, identifying the diagnosis of Avellino corneal dystrophy (ACD). Among the other 32 family members, 6 of them harbored the identical mutation to that in the proband. CONCLUSION: ACD will worsen and recur after LASIK. Preoperative gene-screening for TGFBI mutations is important in diagnosing ACD.

A novel missense TGFBI variant p.(Ser591Phe) in a Finnish family with variant lattice corneal dystrophy

Introduction: We describe the phenotype of a variant lattice corneal dystrophy (LCD) potentially caused by a novel variant c.1772C>T p.(Ser591Phe) in exon 13 of the transforming growth factor beta-induced (TGFBI) gene. Case report: The proband, a 71-year-old woman referred because of bilateral LCD, first seen at the age of 65 years, with recent progressive symptoms, underwent a clinical ophthalmological examination, anterior segment optical coherence tomography and confocal microscopy. Additionally, three siblings and three children were examined. The identified TGFBI variant was screened in six family members using Sanger sequencing. A corneal dystrophy gene screen was performed for the proband. Translucent subepithelial irregularities and central to midperipheral stubby branching corneal stromal lattice lines, asymmetric between the right and the left eye, were visible and resulted in mild deterioration of vision in one eye. Genetic testing revealed a novel variant c.1772C>T in TGFBI, leading to the amino acid change p.(Ser591Phe). One daughter carried the same variant but had only thick stromal nerve fibres at the age of 49 years. The other family members neither had corneal abnormalities nor carried the variant. No keratoplasty is yet planned for the proband. Conclusions: We classify the novel variant in TGFBI as possibly pathogenic, potentially causing the late-onset, asymmetric variant LCD. Our findings add to the growing number of TGFBI variants associated with a spectrum of phenotypes of variant LCD.

Genotypic Homogeneity in Distinctive Transforming Growth Factor-Beta Induced (TGFBI) Protein Phenotypes

Background: To evaluate the distribution of the transforming growth factor-beta induced (TGFBI) corneal dystrophies in a multi-ethnic population in Singapore, and to present the different phenotypes with the same genotype. Methods: This study included 32 patients. Slit lamp biomicroscopy was performed for each patient to determine the disease phenotype. Genomic DNA was extracted from the blood samples and the 17 exons of the TGFBI gene were amplified by PCR and sequenced bi-directionally for genotype analysis. Results: Regarding phenotypes, the study patients comprised 11 (34.4%; 8 with R555W and 3 with R124H mutation) patients with granular corneal dystrophy type 1 (GCD1), 6 (18.8%; 5 with R124H and 1 with R124C mutation) patients with GCD2, 13 (40.6%; 7 with R124C, 2 with H626R, 2 with L550P, 1 with A620D and 1 with H572R) patients with lattice corneal dystrophy (LCD) and 2 (6.3%; 1 with R124L and 1 with R124C) patients with Reis–Bückler corneal dystrophy. Regarding genotype, R124H mutation was associated with GCD2 (5 cases; 62.5%) and GCD1 (3 cases; 37.5%). R124C mutation was associated with LCD (7 cases; 87.5%) and GCD2 (1 case; 12.5%). All the 8 cases (100%) of R555W mutation were associated with GCD1. Conclusions: Although the association between genotype and phenotype was good in most cases (65.7%; 21 of 32 patients), genotype/phenotype discrepancy was observed in a significant number.

Novel mutation in the TGFBI gene in a Moroccan family with atypical corneal dystrophy: a case report

Background: Corneal dystrophies (CDs) are a heterogeneous group of bilateral, genetically determined, noninflammatory bilateral corneal diseases that are usually limited to the cornea. CD is characterized by a large variability in the age of onset, evolution and visual impact and the accumulation of insoluble deposits at different depths in the cornea. Clinical symptoms revealed bilateral multiple superficial, epithelial, and stromal anterior granular opacities in different stages of severity among three patients of this family. A total of 99 genes are involved in CDs. The aim of this study was to identify pathogenic variants causing atypical corneal dystrophy in a large Moroccan family and to describe the clinical phenotype with severely different stages of evolution. Case presentation: In this study, we report a large Moroccan family with CD. Whole-exome sequencing (WES) was performed in the three affected members who shared a phenotype of corneal dystrophy in different stages of severity. Variant validation and familial segregation were performed by Sanger sequencing in affected sisters and mothers and in two unaffected brothers. Whole-exome sequencing showed a novel heterozygous mutation (c.1772C>A; p.Ser591Tyr) in the TGFBI gene. Clinical examinations demonstrated bilaterally multiple superficial, epithelial and stromal anterior granular opacities in different stages of severity among three patients in this family. Conclusions: This report describes a novel mutation in the TGFBI gene found in three family members affected by different phenotypic aspects. This mutation is associated with Thiel-Behnke corneal dystrophy; therefore, it could be considered a novel phenotype genotype correlation, which will help in genetic counselling for this family.