Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.

Ultraviolet-A light associated with riboflavin CXL is an efficient procedure to stabilize and improve progressive keratoconus. The results reinforce previous studies highlighting the efficacy and safety of the procedure. A large prospective randomized clinical trial is needed.

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This experimental study suggests that I-CXL is a promising alternative methodology for riboflavin delivery in crosslinking treatments, preserving the epithelium.

Background Corneal intraepithelial dyskeratosis is an extremely rare condition. The classical form, affecting Native American Haliwa-Saponi tribe members, is called hereditary benign intraepithelial dyskeratosis (HBID). Herein, we present a new form of corneal intraepithelial dyskeratosis for which we identified the causative gene by using deep sequencing technology. Methods and results A seven member Caucasian French family with two corneal intraepithelial dyskeratosis affected individuals (6-year-old proband and his mother) was ascertained. The proband presented with bilateral complete corneal opacification and dyskeratosis. Palmoplantar hyperkeratosis and laryngeal dyskeratosis were associated with the phenotype. Histopathology studies of cornea and vocal cord biopsies showed dyskeratotic keratinisation. Quantitative PCR ruled out 4q35 duplication, classically described in HBID cases. Next generation sequencing with mean coverage of 50× using the Illumina Hi Seq and whole exome capture processing was performed. Sequence reads were aligned, and screened for single nucleotide variants and insertion/deletion calls. In-house pipeline filtering analyses and comparisons with available databases were performed. A novel missense mutation M77T was discovered for the gene NLRP1 which maps to chromosome 17p13.2. This was a de novo mutation in the proband’s mother, following segregation in the family, and not found in 738 control DNA samples. NLRP1 expression was determined in adult corneal epithelium. The amino acid change was found to destabilise significantly the protein structure. Conclusions We describe a new corneal intraepithelial dyskeratosis and how we identified its causative gene. The NLRP1 gene product is implicated in inflammation, autoimmune disorders, and caspase mediated apoptosis. NLRP1 polymorphisms are associated with various diseases.

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BackgroundDupilumab is approved for use in moderate‐to‐severe atopic dermatitis (AD) and as an add‐on maintenance treatment in patients suffering from severe asthma with type 2 inflammation. Ocular adverse events (OAEs) have been reported with dupilumab almost exclusively in patients treated for AD.ObjectivesThe objectives of this study were to describe the incidence and nature of dupilumab‐induced OAEs and to assess the potential predisposing factors.Patients and methodsWe conducted a prospective, single‐centre, real‐life study in adult AD patients treated with dupilumab, who were systematically examined by an ophthalmologist before and during treatment.ResultsForty‐six patients were included prospectively with a median age of 41.1 years and a median initial SCOring Atopic Dermatitis of 46.0 (IQR: 34.5–55.5). OAEs concerned 34.8% of patients and were mostly of mild to moderate severity. Two patients had to discontinue treatment due to OAE. The majority of patients developed or aggravated dry eye disease, with superficial punctate keratitis (SPK). Six patients developed conjunctivitis. Dupilumab‐induced OAEs were associated with the following pre‐existing parameters: dry eye disease with SPK (Odds ratio (OR); 6.3 [95% confidence interval (CI): 1.3–31.6]), eyelid eczema (OR: 8.7 [95%CI: 1.8–40.6]), history of food allergy (OR 3.8 (95% CI: 1.002–14,070) and IgE serum level> 1000 kU/L (OR:10.6 [CI 95%: 1.2–91.3]).ConclusionAtopic dermatitis patients with eyelid eczema or dry eye disease symptoms may be referred to an ophthalmologist before starting dupilumab to consider initiating preventive eye hydration measures. Further multicentric and translational studies are warranted to better explain OAEs pathophysiology.

Keratoconus was associated with a significant reduction in quality of life but it did not result in social exclusion.