To report long-term outcomes and to search for immunological and genetic risk factors in Terrien marginal degeneration (TMD). Retrospective, in part prospective, hospital-based longitudinal follow-up study of 32 eyes of 16 Finnish patients from 2012 to 2023. Median follow-up was 7.3 years (range, 0.3-15.2). Symptoms, best corrected visual acuity, pattern in axial power map, astigmatism, corneal thickness, higher order irregularity, cavities, progression and human leukocyte antigen genes were analysed. In 13 blood samples, 483 corneal and inflammatory disease-related genes were analysed with exome sequencing. The median age at first examination was 61 years (range, 13-89). Eleven (69%) patients were male, and 13 (81%) had bilateral disease. The median annual rate of progression of topographic astigmatism and new thinning was 0.03 D (range, -1.50 to 3.60) and 12.9 μm (range, -107.8 to 93.0), respectively; 0.15 D (range -1.50 to 1.17) and 21.6 μm (range, 1.3-93.0) in 6 (38%) patients with fast progression, and 0.02 D (range, -0.06 to 3.60) and 4.1 μm (range, -107.8 to 24.7) in 10 (72%) patients with slow progression. Topographic pattern, unilaterality, cavities, sectoral hyperaemia, poor response to medical treatment and new thinning after surgery were associated with fast progression. Thickness at maximal thinning fell below 450 μm only with fast progression. Five eyes changed the topographic pattern. Coexisting keratitis fugax hereditaria was found in one patient. A subtype of TMD progresses faster. The most sensitive indicators of progression were thinning and topographic astigmatism. No shared genetic cause for TMD was identified.

To study errors and delays in diagnosing keratitis fugax hereditaria (KFH), an autosomal-dominant periodic corneal autoinflammatory disease caused by the NLRP3 variant c.61G>C, by reviewing the medical records of genetically confirmed Finnish patients with KFH and by determining the frequency of the c.61G>C variant in selected biobank samples. A retrospective cohort and a cross-sectional biobank study. Medical records of 96 clinically diagnosed, genetically confirmed patients with KFH, and 2010 DNA samples from patients with anterior uveitis, herpes keratitis, nonulcerative keratitis, or corneal opacity in the 2 largest Finnish biobanks. The age, sex, ocular and other diagnoses, and laboratory results were reviewed in the retrospective cohort. The c. 61G>C variant was genotyped from the biobank samples using restriction fragment length polymorphism analysis. Sanger sequencing was used for validation. The most common causes of anterior uveitis, such as rheumatoid arthritis, or infectious keratitis were exclusion criteria. Misdiagnoses and differential diagnoses of KFH, diagnostic delays, and the frequency of the c. 61G>C variant in biobank samples. The most common misdiagnoses in the retrospective cohort were anterior uveitis or anterior chamber cell reaction (40% of patients and 79% of misdiagnoses), conjunctivitis (14% and 27%, respectively), and recurrent corneal erosion (13% and 25%, respectively). Time from the onset of symptoms to KFH diagnosis ranged from 0 to 62 years (median, 19; interquartile range, 8-44). Of the 2010 biobank samples from patients with anterior uveitis, herpes keratitis, nonulcerative keratitis, or corneal opacity without an obvious cause, 12 (0.6%) carried the c.61G>C variant: 11 were diagnosed with anterior uveitis, 1 with unspecified keratitis, and 3 correctly with KFH. KFH in Finland is most likely misdiagnosed as anterior uveitis. We suggest prospectively evaluating the addition of the NLRP3 variant c.61G>C to laboratory test packages for differential diagnosis of anterior uveitis. KFH should be considered in the differential diagnosis of anterior uveitis, especially in the Nordic countries and populations originating from them. Symptoms similar to those of KFH may also occur in other NLRP3-linked autoinflammatory syndromes.

The aim of this study was to report a novel heterozygous variant c.1712G>T (p.Gly571Val) in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain-containing 3 gene ( NLRP3 ) in a previously unreported non-Finnish individual with keratitis fugax hereditaria (KFH). Ophthalmologic examination of the proband was performed with slit-lamp biomicroscopy and anterior segment optical coherence tomography. Saliva was collected as a source of DNA, after which targeted exome sequencing of candidate genes was performed using a commercially available panel. Identified presumed pathogenic variants were confirmed by Sanger sequencing. Slit-lamp examination of the 52-year-old female proband revealed peripheral arcus-like degeneration and bilateral central corneal opacification, observed on anterior segment optical coherence tomography to involve the anterior half of the corneal stroma. Examination of the proband's parents revealed clear corneas in each eye. Genetic testing of the proband identified the presence of a novel heterozygous NLRP3 missense mutation (c.1712G>T, p.Gly571Val), which was confirmed by Sanger sequencing. This mutation was absent in the proband's parents. Although KFH has been reported only in individuals of Finnish descent and only in association with a missense mutation in exon 1 of NLRP3 , we report an individual of non-Finnish descent with KFH associated with a novel heterozygous variant in exon 2 of NLRP3 . Thus, ophthalmologists should be aware of the ethnic and genetic heterogeneity associated with KFH.

To elucidate the effect of NLRP3 variant c.61G>C on interleukin-1β (IL-1β) secretion in keratitis fugax hereditaria (KFH), a cryopyrin-associated periodic syndrome limited to the eye, and to probe the potential modifying role of prednisolone. Peripheral blood mononuclear cells (PBMCs) isolated from whole blood of patients with KFH and healthy controls were grown under steady-state conditions or primed with lipopolysaccharide (LPS) with or without prednisolone, and subsequently activated with ATP. Cell lysates and proteins precipitated from the cell culture media were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. NLRP3, procaspase-1, and IL-1β were visualised by western blotting. The concentration of secreted IL-1β in the culture media was quantified by ELISA. Following priming of the NLRP3 inflammasome with LPS, a lower threshold for IL-1β secretion was observed in patient-derived PBMCs, compared with healthy controls (median, 124 vs 10 pg/mL, respectively). Interestingly, in PBMCs derived from patients with frequent KFH symptoms, LPS priming alone was able to trigger substantial IL-1β secretion (median, 522 pg/mL), whereas those of patients experiencing occasional KFH attacks showed a subtler release of IL-1β (median, 85 pg/mL). NLRP3 expression was significantly enhanced with LPS stimulation (p=0.03) whereas procaspase-1 expression was not affected. LPS and ATP treated PBMCs from patients with KFH showed significantly diminished IL-1β secretion with prednisolone treatment (p=0.04). PBMCs from patients with KFH are more prone to secrete IL-1β, confirming the presumption that the c.61G>C is a gain-of-function variant. Furthermore, prednisolone is confirmed as a potent drug to reduce IL-1β secretion in KFH.

The NLRP3 inflammasome is one of the NOD-like receptor family members with the most functional characterization and acts as a key player in innate immune system, participating in several physiological processes including, among others, the modulation of the immune system response and the coordination of host defences. Activation of the inflammasome is a crucial signaling mechanism that promotes both an acute and a chronic inflammatory response, which can accelerate the production of pro-inflammatory cytokines, mainly Interleukin (IL)-1β and IL-18, leading to an exacerbated inflammatory network. Cryopyrin associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disorder, clinically characterized by cutaneous and systemic, musculoskeletal, and central nervous system inflammation. Gain-of-function mutations in NLRP3 gene are causative of signs and inflammatory symptoms in CAPS patients, in which an abnormal activation of the NLRP3 inflammasome, resulting in an inappropriate release of IL-1β and gasdermin-D-dependent pyroptosis, has been demonstrated both in in vitro and in ex vivo studies. During recent years, two new hereditary NLRP3-related disorders have been described, deafness autosomal dominant 34 (DFN34) and keratitis fugax hereditaria (KFH), with an exclusive cochlear- and anterior eye- restricted autoinflammation, respectively, and caused by mutations in NLRP3 gene, thus expanding the clinical and genetic spectrum of NLRP3-associated autoinflammatory diseases. Several crucial mechanisms involved in the control of activation and regulation of the NLRP3 inflammasome have been identified and researchers took advantage of this to develop novel target therapies with a significant improvement of clinical signs and symptoms of NLRP3-associated diseases. This review provides a broad overview of NLRP3 inflammasome biology with particular emphasis on CAPS, whose clinical, genetic, and therapeutic aspects will be explored in depth. The latest evidence on two "new" diseases, DFN34 and KFH, caused by mutations in NLRP3 is also described.