Progressive symmetric erythrokeratodermia (PSEK) is a group of hereditary cornification disorders characterized by symmetrical, progressive erythroderma and hyperkeratosis over the body. Loss-of-function variants in SLURP1, encoding secreted Ly-6/uPAR-related protein 1, is known to cause Mal de Meleda, an autosomal recessive palmoplantar keratoderma. To identify the genetic basis and the pathogenesis of a sporadic patient with PSEK. Whole-exome sequencing and Sanger sequencing were performed to identify the pathogenic variant(s). The expression of SLURP1 was assessed on the patient's skin tissue by immunofluorescence. Western blotting (WB) and immunofluorescence (IF) were performed on eukaryotic overexpression systems to evaluate the signal peptide (SP) cleavage, subcellular localization and secretion of the mutant SLURP1. Combined WB and IF analyses were conducted on cells co-transfected with FLAG-tagged wild-type SLURP1 and untagged SLURP1-Ala22Asp. We identified a de novo heterozygous variant in SLURP1 (c.65A > C, p.Ala22Asp) affecting the first residue before SP cleavage site in a patient with PSEK. This variant abolished the cleavage site of SP, resulting in translocation deficiency to the Golgi apparatus and decreased secretion of the mutant SLURP1. We also found that the SLURP1-Ala22Asp exerted a dominant-negative effect by impeding the SP cleavage of the wild-type SLURP1 and affecting its subcellular localization and secretion in a dose-dependent manner. We reported the first autosomal-dominant variant in SLURP1 associated with a new phenotype of PSEK in a patient, emphasizing the genetic and clinical heterogeneity of SLURP1-associated genodermatoses.

Mal de Meleda (MDM) is a rare hereditary skin disorder classified as an autosomal recessive palmoplantar keratoderma, with an estimated prevalence of 1 in 100,000 individuals. It is commonly linked to consanguineous parentage and typically presents during early childhood. The hallmark features of the condition include transient thickening of the palms and soles, skin sclerosis and atrophy, scleroatrophic erythematous lesions, pseudoainhum formation around the digits, and erythema around the mouth. Due to its rarity, many dermatologists may lack clinical familiarity with MDM. Moreover, there is considerable phenotypic similarity between Mal de Meleda and other forms of palmoplantar keratoderma, as well as certain erythrokeratodermas, making clinical differentiation particularly difficult. Therefore, genetic testing to identify causative mutations plays a crucial role in confirming the diagnosis. Genetic alterations in the SLURP1 gene, which encodes the secreted Ly-6/uPAR-related protein 1, have been identified as key contributors to the development of Mal de Meleda (MDM). SLURP1 plays a critical role in maintaining epidermal equilibrium by regulating essential processes such as keratinocyte (KC) proliferation, terminal differentiation, programmed cell death (apoptosis), and cornification. Furthermore, reduced SLURP1 expression has been linked to the pathogenesis of various epithelial cancers, suggesting its broader significance in maintaining epithelial tissue integrity and suppressing tumors. The management of Mal de Meleda remains a clinical challenge, as current therapeutic approaches are largely limited to alleviating symptoms rather than addressing the underlying cause. Systemic retinoids, particularly acitretin, have demonstrated efficacy in reducing epidermal hyperkeratosis and enhancing clinical outcomes. Nonetheless, prolonged administration may lead to significant side effects, necessitating close clinical supervision. This case report contributes to the medical literature by documenting a rare presentation of Mal de Meleda, highlighting the importance of recognizing atypical clinical features and implementing accurate diagnostic and therapeutic interventions. Psoriasis is a chronic, immune-mediated inflammatory dermatosis that exerts a profound effect on patients' quality of life. The disease typically follows a relapsing-remitting course and is frequently associated with a spectrum of comorbid conditions. In pediatric populations, the etiology of psoriasis is multifactorial, involving a combination of genetic susceptibility, environmental triggers, psychosocial stressors, obesity, physical trauma, cutaneous irritation, and exposure to certain pharmacological agents such as lithium, β-blockers, and tumor necrosis factor (TNF) inhibitors. Moreover, systemic inflammatory disorders like Crohn's disease and juvenile idiopathic arthritis have been linked to an increased risk of psoriasis in children. The disease burden is considerable in adults, but poses even greater challenges in pediatric patients, where atypical clinical presentations may hinder timely and accurate diagnosis. It is essential for dermatologists to accurately differentiate Mal de Meleda (MDM) from psoriasis, as these conditions may exhibit overlapping clinical features yet diverge significantly in therapeutic response and long-term prognosis. Distinctive diagnostic clues-such as very early disease onset, autosomal recessive mode of inheritance, and the hallmark transgradient pattern of palmoplantar keratoderma-can aid in distinguishing MDM from the more prevalent psoriasis vulgaris. Although biologic therapies targeting TNF-α and IL-17A have shown limited efficacy in MDM, systemic retinoids continue to represent a clinically effective therapeutic option for managing this rare genodermatosis.

Epidermal differentiation disorders [EDDs; ichthyosis and palmoplantar keratoderma (PPK)] are heritable skin conditions characterized by localized or generalized skin scaling and erythema. To identify novel genetic variants that cause PPK and progressive symmetric erythrokeratoderma (PSEK) phenotypes. We performed whole-exome sequencing in a large cohort of people with EDD, including PPK and PSEK phenotypes, to identify novel genetic variants. We investigated the variant consequence using in silico predictions, assays in patient keratinocytes, high-resolution spatial transcriptomics and quantitative cytokine profiling. We identified three unrelated kindreds with autosomal dominant transmission of heterozygous SLURP1 variants affecting the same amino acid within the signal peptide (c.65C > A, p.A22D and c.65C > T, p.A22V). One (p.A22V) had isolated PPK; the other two (p.A22D) had PSEK and PPK. In silico modelling suggested that both variants alter pro-SLURP1 cleavage, appending two amino acids to the secreted protein, which we subsequently confirmed with mass spectrometry. In patient keratinocytes we found increased differentiation-induced SLURP1 expression and secretion compared to healthy control cells. Spatial transcriptomics revealed increased nuclear factor-κB (NF-κB) signalling and innate immune activity, which may contribute to epidermal hyperproliferation in dominant SLURP1-PPK/PSEK. Our results expand the phenotypic spectrum of EDD due to SLURP1 pathogenic variants. While autosomal recessive Mal de Meleda is due to biallelic loss-of-function SLURP1 variants, our finding of autosomal dominant SLURP1 pathogenic variants in kindreds with PPK and PSEK suggests a novel mechanism of action. We found that heterozygous p.A22V and p.A22D SLURP1 variants append two amino acids to secreted SLURP1, increase differentiation-induced SLURP1 expression and secretion and upregulate NF-κB signalling in people with PSEK. Epidermal differentiation disorders (‘EDD’) are skin diseases that cause redness, scaling and thickening in one area or all over the body. We looked for genetic causes of EDD in the conditions known as PPK and PSEK. PPK causes scaling and thickening of the skin on the palms of the hands and soles of the feet only. PSEK causes red scaly plaques. We found damaging variants of a gene called ‘SLURP1’ in three unrelated families with PPK, with or without PSEK. Changes in this gene affected the SLURP1 signal peptide, which is needed for the normal release of the SLURP1 protein. These gene variants led to increased SLURP1 protein production and secretion. We found that the variants also change where the SLURP1 protein is ‘cut’ during processing. This changes the SLURP1 protein sequence. High-resolution examination of gene expression in the skin showed swelling and immune activity. Our findings suggest that changes in the SLURP1 gene affect how the SLURP1 protein works, causing the immune system to become more active. This research shows that more skin conditions may be due to harmful changes in the SLURP1 gene.

Nagashima-type palmoplantar keratosis (NPPK) has been shown to represent a form of autosomal recessive palmoplantar keratosis due to biallelic pathological variants of SERPINB7, which encodes a serine protease inhibitor expressed in the epidermis. Approximately 10 years have elapsed since NPPK was demonstrated to be an independent genetic disease, and the most prevalent palmoplantar keratoderma (PPK) in East Asian countries due to a high prevalence of founder mutations in SERPINB7. Since then, it has become evident that biallelic pathological variants of SERPINA12, which encodes a serine protease inhibitor expressed in the epidermis, can also manifest symptoms analogous to those of NPPK. Furthermore, a pathological variant of SERPINB7 was identified as a risk factor for the development of atopic dermatitis in a genome-wide association study (GWAS) of atopic dermatitis, indicating that the frequent co-occurrence of NPPK and atopic dermatitis is not a mere coincidence. Despite the documentation of NPPK cases in Japan since the 1970s, there have been no reports of individuals with similar symptoms from other regions, including Europe and the USA. Consequently, the existence and independence of the disease remained uncertain until its genetic cause was identified. The disease's independence was established through the accumulation of data on affected individuals, including the provision of accurate descriptions of their symptoms, which enabled the identification of the genetic cause. This review presents a comprehensive overview of the history and prospects of NPPK with a particular focus on the history of the process of establishing NPPK as an independent disease.