Epithelial recurrent erosion dystrophy (ERED) from the splice site altering COL17A1 variant c.3156C>T in families of Finnish-Swedish ancestry.

PURPOSE: To describe four Finnish families with epithelial recurrent erosion dystrophy (ERED) caused by the pathogenic variant c.3156C>T in collagen type XVII alpha 1 chain gene (COL17A1). METHODS: Eleven affected and two unaffected individuals underwent clinical ophthalmological examination, anterior segment photography, and corneal topography. Two of them underwent phototherapeutic keratectomy (PTK). Genetic analysis included both next-generation and Sanger sequencing. Specimens from the manual keratectomy of one patient were available for ophthalmic pathologic examination, including immunohistochemistry. RESULTS: The common splice-site altering synonymous variant c.3156C > T, p.(Gly1052=) in COL17A1 was confirmed in 15 individuals with ERED from the four families. Subepithelial corneal scarring grades varied and increased with age, leading to decreased best-corrected visual acuity. PTK improved vision in 58- and 67-year-old individuals without reactivating the disease. The keratectomy specimens showed an uneven epithelium and a spectrum of basement membrane abnormalities, including breaks, fragmentation, multiplication and entrapment within the subepithelial scar, reflecting recurrent erosions. The stromal cells consisted of varying proportions of bland and activated fibroblasts and myofibroblasts, reflecting different ages of scars. The family with the largest number of known affected generations originated from Southern Sweden. CONCLUSION: The phenotype in the Finnish ERED families is consistent with earlier reports of the c.3156C > T variant, although the severity has varied between reports. The phenotype may be modulated by other genes. This study suggests a likely founder effect of the variant in both Finnish and Swedish populations due to their shared population histories. If vision is compromised, PTK can be considered especially in older patients.

In Vivo Corneal Confocal Microscopy and Histopathology of Keratitis Fugax Hereditaria From a Pathogenic Variant in NLRP3.

PURPOSE: To apply in vivo corneal confocal microscopy (IVCM) to study the pathogenesis of keratitis (keratoendotheliitis) fugax hereditaria, an autosomal dominant cryopyrin-associated periodic keratitis, associated with the c.61G>C pathogenic variant in the NLRP3 gene, in its acute and chronic phase, and to report histopathologic findings after penetrating keratoplasty. DESIGN: This was an observational case series. METHODS: The study population included 6 patients during an acute attack, 18 patients in the chronic phase, and 1 patient who underwent penetrating keratoplasty. Interventions included Sanger sequencing for the NLRP3 variant c.61C>G, a clinical examination, corneal photography, IVCM, light microscopy, and immunohistochemistry. Our primary outcome measures included IVCM and histopathologic findings. RESULTS: During the acute attack, hyperreflective cellular structures consistent with inflammatory cells transiently occupied the anterior to middle layers of the corneal stroma. Other corneal layers were unremarkable. With recurring attacks, central oval stromal opacities accumulated. IVCM revealed that they contained long, hyperreflective, needle-shaped structures in the extracellular matrix. Using light microscopy, the anterior half of the stroma displayed thin and finely vacuolated lamellae, and keratocytes throughout the stroma were immunopositive for syndecan. CONCLUSIONS: The acute attacks and chronic stromal deposits mainly involve the anterior to middle layers of the corneal stroma, and the disease is primarily a keratitis rather than a keratoendotheliitis. IVCM shows that inflammatory cells invade only the stroma during an acute attack. IVCM and light microscopic findings suggest that the central corneal opacities represent gradual deposition of extracellular lipids. The disease could make a good in vivo model to study activation of the NLRP3 inflammasome in cryopyrin-associated periodic syndromes.