ABSTRACT
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.
Subject(s)
Corneal Dystrophies, Hereditary , Transforming Growth Factor beta , Corneal Dystrophies, Hereditary/diagnosis , Corneal Dystrophies, Hereditary/genetics , Corneal Dystrophies, Hereditary/pathology , DNA Mutational Analysis , Extracellular Matrix Proteins/genetics , Finland , Humans , Mutation , Pedigree , Transforming Growth Factor beta/geneticsABSTRACT
PURPOSE: To refine the diagnostic criteria for peripheral hypertrophic subepithelial corneal degeneration (PHSD) and characterize its clinical phenotype, histopathology and immunohistochemical features. METHODS: Diagnostic criteria were refined on the basis of literature data. Fourteen patients (13 women and one man; median age 52 years, range 33-66) were identified based on these criteria. Keratectomy specimens were evaluated via routine and immunohistochemical stainings. The main outcome measures were symptoms, clinical phenotype, immunological status and histopathologic results. RESULTS: We defined the diagnostic criteria of typical PHSD as elevated circumferential and perilimbal subepithelial fibrosis with focal superficial corneal neovascularization, which were supported by female sex (93%), bilaterality (86%), the centre being in the upper quadrants (81%) and irregular astigmatism of two dioptres or more. The typical symptoms were reduced vision (86%) and the symptoms of ocular surface disease (64%). Light microscopy showed fibrosis with abundant collagen deposition but no inflammation in all patients. An immunohistochemical analysis of nine patients showed uniform staining for vimentin in three distinct types of fibroblasts in variable proportions: keratocyte-like cells that were positive for CD34, myofibroblasts that were positive for smooth muscle actin (SMA) and fibroblasts that were negative for CD34 and SMA. Small numbers of CD68-positive macrophages were also found. CONCLUSIONS: Peripheral hypertrophic subepithelial degeneration is characteristic of middle-aged women, in whom it is typically a bilateral idiopathic degeneration of the cornea associated with ocular surface disease and reduced vision. The fibrotic lesions probably undergo remodelling, inducing changes in corneal contour. A smouldering low-grade inflammation favouring low TGF-ß1 concentrations is postulated as the primary pathological process leading to PHSD.
Subject(s)
Corneal Dystrophies, Hereditary/diagnosis , Corneal Neovascularization/diagnosis , Epithelium, Corneal/pathology , Actins/metabolism , Adult , Aged , Antigens, CD/metabolism , Antigens, CD34/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Biomarkers/metabolism , Corneal Dystrophies, Hereditary/metabolism , Corneal Dystrophies, Hereditary/surgery , Corneal Keratocytes/metabolism , Corneal Neovascularization/metabolism , Epithelium, Corneal/metabolism , Female , Fibrosis , Humans , Hypertrophy , Immunoenzyme Techniques , Male , Middle Aged , Phenotype , Vimentin/metabolismABSTRACT
PURPOSE: To evaluate the efficacy of keratectomy in treating irregular astigmatism caused by peripheral hypertrophic subepithelial corneal degeneration (PHSD) and to study the possible underlying immunological risk factors. MATERIALS AND METHODS: Patients (14 eyes) with diagnosed PHSD were treated with superficial keratectomy with or without the assistance of phototherapeutic keratectomy (VisX S4; VisX Inc., Santa Ana, CA, USA). Thirteen patients were subjected to analysis of human leucocyte antigen (HLA) genes, complement C4 gene numbers and total plasma immunoglobulin levels. Immunological risk factors between patients and a control group comprising 150 individuals were compared. RESULTS: The mean preoperative best spectacle corrected visual acuity (BCVA) improved from 0.16 ± 0.22 (LogMAR scale range 0-0.7) to 0.06 ± 0.13 (-0.1-0.4) (p < 0.01). The mean preoperative astigmatism decreased significantly from 3.8 ± 2.1 D (range 1.2-8.2) to 2.1 ± 1.4 (range 0.6-5.0, p = 0.02) based on corneal topography. The HLA-B*44 allele and the ancestral haplotype (AH) 8.1 were found significantly more often in PHSD patients than in controls (both p = 0.03). No differences in the C4 genes were found. CONCLUSIONS: Astigmatism secondary to PHSD can be effectively treated with keratectomy. Peeling of the fibrotic tissue reduced astigmatism and improved visual performance. We suggest that HLA-B*44 allele and AH 8.1 haplotype are immunological factors predisposing to the development of PHSD. The consequent disruption/alteration of the limbal barrier may lead to corneal peripheral fibrous formation inducing astigmatism.