Background A trio exome sequencing study identified a previously unreported NLRP1 gene variant resulting in a p.Leu813Pro substitution of the LRR (leucine-rich repeats) domain of the NLRP1 protein (NACHT, LRR and PYD domains-containing protein 1). This homozygous mutation was shared by two sisters with different clinical presentation: the younger sister had generalized inflammatory nodules with keratotic plugs, clinically resembling multiple keratoacanthomas, while the older had manifestations of familial keratosis lichenoides chronica. Objectives To analyse the consequences of this NLRP1 variant in two siblings with a different clinical spectrum of severity. Methods To demonstrate the pathogenicity, p.Leu813Pro was recombinantly expressed, and its effect on inflammasome assembly was assessed. Exome sequencing and RNA-Seq were performed to identify factors with potentially modifying effects on the severity of the skin manifestation between each sibling. Results The variant p.Leu813Pro triggered activation of the NLRP1 inflammasome leading to ASC (apoptosis-associated speck-like protein containing a CARD) speck formation and interleukin (IL)-1β release. The more severely affected sister had several additional genomic variants associated with atopy and psoriasis that were not present in her sibling. IL-5 and IL-17 emerged as dominant cytokines driving prominent inflammation in the skin of the severely affected sibling. Conclusions To the best of our knowledge, this is the first report of a NLRP1 variant that leads to a different clinical spectrum of severity within the same sibship. IL-5 and IL-17 were the main cytokines expressed in the inflammatory lesions of the severely affected patient and might be regarded as disease modifying factors, and therefore may be considered as therapeutic targets.

Background Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity. Objective Epidemiological data from different countries have been published, but none are available from Germany. Methods In this population‐based cross‐sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization. Results Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log‐linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries. Conclusions Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision‐making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.

Background Non-syndromic congenital ichthyosis describes a heterogeneous group of hereditary skin disorders associated with erythroderma and scaling at birth. Although both severe and mild courses are known, the prediction of the natural history in clinical practice may be challenging.Objectives To determine clinical course and genotype-phenotype correlations in children affected by non-syndromic congenital ichthyosis in a case series from south-western Germany.Methods We performed a retrospective observational study of 32 children affected by non-syndromic congenital ichthyoses seen in our genodermatosis clinic between 2011 and 2020. Follow-ups included assessment of weight and severity of skin involvement utilizing a modified Ichthyosis Area Severity Index (mIASI). mIASI was calculated as a sum comprising the previously published IASI score and an additional novel score to evaluate palmoplantar involvement. Linear regression was assessed using Pearson correlation, and statistical analysis was performed using the Wilcoxon-Mann-Whitney test. ResultsThis study included 23 patients with autosomal recessive congenital ichthyosis, seven with keratinopathic ichthyosis and two with harlequin ichthyosis. Cutaneous manifestations improved in more than 70% of the children during the follow-up. Especially in patients with mutations in ALOXE3 and ALOX12B, mIASI scores dropped significantly. The most common phenotype observed in this study was designated 0 mild fine scaling ichthyosis 0 . Severe palmoplantar involvement occurred in patients with KRT1 and ABCA12 mutations; most patients demonstrated hyperlinearity as a sign of dryness and scaling. Weight was mainly in the normal range and negatively correlated with the severity of skin involvement.Conclusions Congenital ichthyosis that self-improves and evolves with mild fine scaling ichthyosis was the most common phenotype observed in our patients. This type might be underdiagnosed if the genetic diagnosis is not performed in the first year of life. mIASI is an easy and fast instrument for scoring disease severity and adding additional points for palmoplantar involvement might be valuable.