Clinical and Histopathologic Characteristics and Template of the TGFBI p.(His626Arg) Missense Variant Lattice Corneal Dystrophy.

PURPOSE: The aim of this study was to define, following the IC3D template format, the clinical and histopathologic phenotype of the p.(His626Arg) missense variant lattice corneal dystrophy (LCDV-H626R), the most common variant lattice dystrophy, and to record long-term outcome of corneal transplantation in this dystrophy. METHODS: A database search and a meta-analysis of published data on LCDV-H626R were conducted. A patient diagnosed with LCDV-H626R who underwent bilateral lamellar keratoplasty followed by rekeratoplasty of 1 eye is described, including histopathologic examination of the 3 keratoplasty specimens. RESULTS: One hundred forty-five patients from at least 61 families and 11 countries diagnosed with LCDV-H626R were found. This dystrophy is characterized by recurrent erosions, asymmetric progression, and thick lattice lines that extend to corneal periphery. The median age is 37 (range, 25-59) years at the onset of symptoms, 45 (range, 26-62) years at the time of diagnosis, and 50 (range, 41-78) years at the time of the first keratoplasty, suggesting a median interval from the first symptoms to diagnosis and to keratoplasty of 7 and 12 years, respectively. Clinically unaffected carriers have been of age 6 to 45 years. Central anterior stromal haze and centrally thick, peripherally thinner branching lattice lines in the anterior to midstroma of the cornea were noted preoperatively. Histopathology of the host anterior corneal lamella showed a subepithelial fibrous pannus, a destroyed Bowman layer, and amyloid deposits extending to the deep stroma. In the rekeratoplasty specimen, amyloid localized to scarring along the Bowman membrane and to the margins of the graft. CONCLUSIONS: The IC3D-type template for LCDV-H626R should help diagnose and manage variant carriers. The histopathologic spectrum of findings is broader and more nuanced than what has been reported.

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.