Search

BACKGROUND Peeling skin syndrome type 1 (PSS1) is a rare and severe autosomal recessive form of congenital ichthyosis. Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin. The disease is caused by nonsense mutations or complete deletion of the CDSN gene encoding for corneodesmosin (CDSN). PSS1 severely impairs quality of life and therapeutic approaches are totally unsatisfactory. OBJECTIVES The objective of this study was to develop the first steps towards a specific protein replacement therapy for CDSN deficiency. Using this approach, we aimed to restore the lack of CDSN and improve cell-cell cohesion in the transition area of the stratum granulosum (SG) to the stratum corneum. METHODS Human CDSN was recombinantly expressed in Escherichia coli. A liposome-based carrier system, prepared with a cationic lipopeptide to mediate the transport to the outer membrane of keratinocytes, was developed. This formulation was chosen for CDSN delivery into the skin. The liposomal carrier system was characterized with respect to size, stability and toxicity. Furthermore, the interaction with primary keratinocytes and human epidermal equivalents was investigated. RESULTS The liposomes showed an accumulation at the membranes of keratinocytes. CDSN-deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG. Finally, the penetration assay and histological examinations revealed an improved epidermal integrity for CDSN-deficient epidermal equivalents, if they were treated with liposomal encapsulated CDSN. CONCLUSIONS This study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients affected by PSS1.

These guidelines for the management of congenital ichthyoses have been developed by a multidisciplinary group of European experts following a systematic review of the current literature, an expert conference held in Toulouse in 2016, and a consensus on the discussions. These guidelines summarize evidence and expert-based recommendations and intend to help clinicians with the management of these rare and often complex diseases. These guidelines comprise two sections. This is part two, covering the management of complications and the particularities of some forms of congenital ichthyosis.What's already known about this topic?Various symptomatic treatment options exist for congenital ichthyoses, but there are no European guidelines.What does this study add?These European guidelines for the management of congenital ichthyosis may help to improve outcomes and quality of life for patients.Linked Comment: Akiyama. Br J Dermatol 2019; 180:449-450. Plain language summary available online

International audience

Background Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous group of rare Mendelian skin disorders characterized by cornification and differentiation defects of keratinocytes. Mutations in nine genes including PNPLA1 are known to cause non-syndromic forms of ARCI. To date, only ten distinct pathogenic mutations in PNPLA1 have been reported. Objectives To identify new causative PNPLA1 mutations, we screened genetically unresolved cases including our ARCI collection comprising more than 700 families. Here, we report on 16 novel mutations present in patients from 17 families. Methods The screening for mutations was performed either by direct Sanger sequencing or in combination with a multi gene panel, followed by sequence and mutation analysis. Results While all previously reported mutations and most of our novel mutations are located within the core patatin domain, here we report on five novel PNPLA1 mutations, which are downstream of this domain. Thus, as recently described for PNPLA2, we hypothesize that a region larger than core domain is required for full enzymatic activity of PNPLA1 in human skin barrier formation. Conclusions We estimate the frequency of PNPLA1 mutations amongst ARCI patients to around 3%. Most of our patients were born as collodion babies and showed a relatively mild ichthyosis phenotype. In four unrelated patients we observed a cyclic scaling course, which seems to be a potential phenotype variation in a small percentage of patients with PNPLA1 mutations. The variability of the clinical manifestations as well as the lack of typical clinical features are specific for patients with PNPLA1 mutations, and emphasize the importance of DNA sequencing for differential diagnosis of ARCIs. This article is protected by copyright. All rights reserved.

Summary Background Epidermolytic ichthyosis (EI) is a hereditary keratinization disorder caused by mutations in the keratin 1 (KRT1) or keratin 10 (KRT10) genes. In most cases of severe EI, heterozygous single point mutations are found at the highly conserved helix boundary motifs of KRT1 and KRT10 that play a critical role in filament formation. The presence of palmoplantar keratoderma suggests KRT1 mutations, whereas KRT10 mutations in most instances give rise to the nonpalmoplantar variants. Objectives To identify the underlying mutations in patients with EI and to correlate genotype and phenotype. Methods Mutation analysis was performed in 28 patients with EI by direct sequencing of KRT1 and KRT10 genes. Results We identified 14 different mutations, of which four have not been published previously. Conclusions Identification of novel mutations and genotype–phenotype correlations in EI allows improved understanding of disease pathogenesis as well as better patient management.

Summary Background Ichthyosis vulgaris (IV) is a genetic disorder with a prevalence of 1 : 250–1000 caused by filaggrin (FLG) mutations, which also predispose to atopic diseases. Objectives To study the genotype/phenotype relationship in IV and to analyse whether the suggested skin barrier defect is associated with differences of epidermal dendritic cells. Patients/methods We evaluated a cohort of 26 German patients with IV, established an IV severity score and analysed epidermal ultrastructure, histology, filaggrin and CD1a antigens. Mutations were screened by restriction enzyme analysis. Particular sequencing techniques allowed the complete FLG analysis to reveal novel mutations. Results The combined null allele frequency of R501X and 2282del4 was 67·3%. Patients also showed the mutations S3247X and R2447X as well as five novel FLG mutations: 424del17 and 621del4 (profilaggrin S100 domain), 2974delGA (repeat 2), R3766X (repeat 101) and E4265X (repeat 102). Their combined allele frequency in controls was

Summary Background Plasminogen activator inhibitor-2 (PAI-2), a regulatory serpin of the plasminogen activator (PA) system, has been described as a potential component of the cornified cell envelope (CE). Protease inhibitors are essential for skin homeostasis and in particular for the regulation of the desquamation process. Therefore, an aberrant expression of PAI-2 could be involved in the pathogenesis of certain cornification disorders. Objectives Evaluation of the expression of PAI-2 in different types of congenital ichthyosis, especially in lamellar ichthyosis/nonbullous congenital ichthyosiform erythroderma (LI/NCIE) and in Netherton syndrome (NTS). Demonstration of the functional relationship between PAI-2 and transglutaminase (TGase)-1. Patients and methods Using immunohistochemistry we evaluated cryosections from individuals suffering from LI/NCIE (n = 67), NTS (n = 6), ichthyosis–follicularis–atrichia–photophobia syndrome (n = 2) and Harlequin ichthyosis (n = 1) in comparison with psoriasis vulgaris and healthy skin. Moreover, we assessed the respective TGase-1 activity and the presence of TGase-1 protein. A functional assay was developed to elucidate whether PAI-2 is a substrate for TGase-1. Results PAI-2 is expressed in different types of congenital ichthyosis and there is a strong correlation between TGase-1 activity and PAI-2 protein signal. Double staining revealed a strong colocalization of TGase-1 activity and PAI-2 protein. The epidermal incorporation of the specific PAI-2 peptide containing a TGase binding site revealed a strong pericellular staining in the stratum granulosum in healthy skin. In contrast, TGase-1-deficient skin showed only a lamellar staining in the stratum corneum. Conclusions We provide in vivo evidence that PAI-2 is a substrate of TGase-1. The normal expression of PAI-2 in a large group of TGase-1-proficient LI/NCIE patients makes it rather unlikely that PAI-2 alone is a primary molecular cause of LI/NCIE.