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.

Epidemiology of Corneal Neovascularization and Its Impact on Visual Acuity and Sensitivity: A 14-Year Retrospective Study

Purpose: To quantify the severity and location of corneal neovascularization (cNV) and its impact on the visual acuity and corneal sensitivity in a cohort of the patients referred to a specialist cornea clinic and also to describe the etiology of cNV in the cohort.Methods: We retrospectively evaluated the charts of 13,493 subjects referred to the San Raffaele Cornea Unit between January 2004 and December 2018 to search for cNV diagnosis. The corneal neovascularization severity was measured in the quadrants (range: 1–4) and location was defined as superficial, deep, or both. Best spectacle corrected visual acuity (BSCVA) was measured in logMar. We used the multiple regression analysis to identify the independent predictors of logMAR, after adjusting for age, gender, keratoconus, herpes keratitis, penetrating keratoplasty, trauma, and cataract surgery.Results: Corneal neovascularization was diagnosed in 10.4% of the patients analyzed. The most prevalent etiology of cNV in our population was non-infectious corneal dystrophies/degenerations followed by herpes simplex virus infection. cNV affected OD, OS, or both eyes in 35.6, 40.2, and 24.2 of cases, respectively. Mean BSCVA (SD) was 0.59 (0.76), 0.74 (0.94), and 1.24 (1.08) in cNV one, two, and three or four of the quadrant groups. Superficial, deep, or mixed cNV occurred in 1,029, 348, and 205 eyes. Severe cNV (three or four of the quadrants) was a significant predictor of low visual acuity (p < 0.001) and reduced corneal sensitivity (p < 0.05). cNV location and its severity were associated (p < 0.05). In addition, corneal anesthesia was associated with lower BSCVA (p < 0.001).Conclusion: Severe and deep cNV are associated with the reduced visual acuity and corneal sensitivity. Our data strongly support the relevance of appropriate follow-up as cNV is a major risk factor for graft rejection.

Detailed corneal and genetic characteristics of a pediatric patient with macular corneal dystrophy - case report

Background Corneal dystrophies are a group of rare, inherited disorders that are usually bilateral, symmetric, slowly progressive, and not related to environmental or systemic factors. The majority of publications present the advanced form of the disease with a typical clinical demonstration. The initial signs and symptoms of different epithelial and stromal corneal dystrophies are not specific; therefore, it is very important to establish the early characteristic corneal features of these disorders that could guide the diagnostic process. Case presentation The main purpose of this study was to report the differential diagnosis of a pediatric patient with bilateral anterior corneal involvement suspected of corneal dystrophy. An 8-year-old male patient presented with asymptomatic, persistent, superficial, bilateral, diffuse, anterior corneal opacities. Slit lamp examination results were not specific. Despite the lack of visible stromal involvement on the slit lamp examination, corneal analysis based on confocal microscopy and optical coherence tomography revealed characteristic features of macular corneal dystrophy (MCD). The diagnosis of MCD was confirmed by CHST6 gene sequencing. The early corneal characteristic features of MCD, established based on the findings of this case report, include corneal astigmatism (not specific), diffuse corneal thinning without a pattern of corneal ectasia (specific), and characteristic features on confocal microscopy (specific), including multiple, dark, oriented striae at different corneal depths. Conclusions The clinical examination should be complemented with corneal imaging techniques, such as confocal microscopy and optical coherence tomography. In patients suspected of corneal dystrophy, genetic testing plays an important role in establishing the final diagnosis.

Expression and Function of ZEB1 in the Cornea

ZEB1 is an important transcription factor for epithelial to mesenchymal transition (EMT) and in the regulation of cell differentiation and transformation. In the cornea, ZEB1 presents in all three layers: the epithelium, the stroma and the endothelium. Mutations of ZEB1 have been linked to multiple corneal genetic defects, particularly to the corneal dystrophies including keratoconus (KD), Fuchs endothelial corneal dystrophy (FECD), and posterior polymorphous corneal dystrophy (PPCD). Accumulating evidence indicates that dysfunction of ZEB1 may affect corneal stem cell homeostasis, and cause corneal cell apoptosis, stromal fibrosis, angiogenesis, squamous metaplasia. Understanding how ZEB1 regulates the initiation and progression of these disorders will help us in targeting ZEB1 for potential avenues to generate therapeutics to treat various ZEB1-related disorders.

Compound heterozygous mutations in TGFBI cause a severe phenotype of granular corneal dystrophy type 2

We investigated the clinical and genetic features of patients with severe phenotype of granular corneal dystrophy type 2 (GCD2) associated with compound heterozygosity in the transforming growth factor-β-induced (TGFBI) gene. Patients with severe GCD2 underwent ophthalmic examination (best-corrected visual acuity test, intraocular pressure measurement, slit-lamp examination, and slit-lamp photograph analysis) and direct Sanger sequencing of whole-TGFBI. The patient’s family was tested to determine the pedigrees. Five novel mutations (p.(His174Asp), p.(Ile247Asn), p.(Tyr88Cys), p.(Arg257Pro), and p.(Tyr468*)) and two known mutations (p.(Asn544Ser) and p.(Arg179*)) in TGFBI were identified, along with p.(Arg124His), in the patients. Trans-phase of TGFBI second mutations was confirmed by pedigree analysis. Multiple, extensive discoid granular, and increased linear deposits were observed in the probands carrying p.(Arg124His) and other nonsense mutations. Some patients who had undergone phototherapeutic keratectomy experienced rapid recurrence (p.(Ile247Asn) and p.(Asn544Ser)); however, the cornea was well-maintained in a patient who underwent deep anterior lamellar keratoplasty (p.(Ile247Asn)). Thus, compound heterozygosity of TGFBI is associated with the phenotypic variability of TGFBI corneal dystrophies, suggesting that identifying TGFBI second mutations may be vital in patients with extraordinarily severe phenotypes. Our findings indicate the necessity for a more precise observation of genotype–phenotype correlation and additional care when treating TGFBI corneal dystrophies.

Current issues of differential diagnosis and treatment of congenital corneal opacities in children

Purpose. To analyze the literature on the topic of congenital corneal opacities, their diagnosis, differential diagnosis, as well as the choice of optimal treatment tactics. Congenital corneal opacities (CCO), when effective treatment is delayed, usually lead to permanent loss of visual function. This diagnosis requires urgent measures. On the other hand, the rarity of neonatal corneal pathology and difficulties associated with evaluation of newborns yield the situation when more or less defined clinical practice patterns in such cases remain unclear for most pediatric ophthalmologists. Based on our own experience and the literature data, we describe the main issues of differential diagnosis and management of CCO in newborns. A broad range of developmental anomalies, congenital hereditary corneal dystrophies and metabolic diseases as the main causes of CCO are reviewed. In addition to this diagnostic paradigm, the prognosis in every particular pathology as well as treatment recommendations are given. Conclusion. Based on the presented review, the prognosis and therapeutic recommendations for a particular congenital pathology of the cornea are given. Key words: congenital malformations of the eye, children, corneal opacity, keratoplasty, low vision.

Cornea Confocal Microscopy: Utilities and Perspectives

The cornea is the ocular refractive medium with the greatest refractive power of the eye. The study of it is of vital importance for the diagnosis and follow-up of ophthalmological diseases with the aim of achieving high standards of visual acuity in our patients. Confocal microscopy of the cornea allows in-depth study of it, quickly, safely, painlessly, obtaining high-resolution images of the corneal sublayers. This chapter summarizes the procedure for performing corneal confocal microscopy, the normal characteristics of the tissue with real images of our patients, as well as a brief explanation of the main applications of this technology in the study of corneal dystrophies (keratoconus), in refractive surgery, corneal transplantation, infectious keratitis, glaucoma filtration bulla, among other topics.

Compound Heterozygous Mutations in TGFBI Cause a Severe Phenotype of Granular Corneal Dystrophy Type 2

We investigated the clinical and genetic features of patients with severe phenotype of granular corneal dystrophy type 2 (GCD2) associated with compound heterozygosity in the transforming growth factor-β-induced (TGFBI) gene. Patients with severe GCD2 underwent ophthalmic examination (best-corrected visual acuity test, intraocular pressure measurement, slit-lamp examination, and slit-lamp photograph analysis) and direct Sanger sequencing of whole-TGFBI. The patient’s family was tested to determine the pedigrees. Five novel mutations (p.His174Asp, p.Ile247Asn, p.Tyr88Cys, p.Arg257Pro, and p.Tyr468*) and two known mutations (p.Asn544Ser and p.Arg179*) in TGFBI were identified, along with p.Arg124His, in the patients. Trans-phase of TGFBI second mutations was confirmed by pedigree analysis. Multiple, extensive discoid granular, and increased linear deposits were observed in the probands carrying p.Arg124His and other nonsense mutations. Some patients who had undergone phototherapeutic keratectomy experienced rapid recurrence (p.Ile247Asn and p.Asn544Ser); however, the cornea was well-maintained in a patient who underwent deep anterior lamellar keratoplasty (p.Ile247Asn). Thus, compound heterozygosity of TGFBI is associated with the phenotypic variability of TGFBI corneal dystrophies, suggesting that identifying TGFBI second mutations may be vital in patients with extraordinarily severe phenotypes. Our findings indicate the necessity for a more precise observation of genotype-phenotype correlation and additional care when treating TGFBI corneal dystrophies.

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.