BACKGROUND:Stapokibart is a novel anti-interleukin-4 receptor α (IL-4Rα) monoclonal antibody approved for the treatment of adults with moderate-to-severe atopic dermatitis (AD). OBJECTIVES:To assess the safety, efficacy, pharmacokinetics, pharmacodynamics and immunogenicity of stapokibart in children with moderate-to-severe AD. METHODS:This was a multicentre open-label single-arm phase Ib/IIa trial (NCT06162507) involving 8 weeks of treatment and 8 weeks of follow-up. Children aged 6-11 years received subcutaneous stapokibart based on a bodyweight-tiered regimen (30-60 kg: 300 mg every 3 weeks for a total of three doses, including a 600-mg loading dose; 15-30 kg: 150 mg every 2 weeks for a total of four doses, including a 300-mg loading dose). RESULTS:Twenty-five patients (13 weighing 30-60 kg; 12 weighing 15-30 kg) received stapokibart; 68% reported mild or moderate adverse events. At week 8, 54% (n = 7/13) of those weighing 30-60 kg and 75% (n = 9/12) of those weighing 15-30 kg achieved a ≥ 75% improvement from baseline in Eczema Area and Severity Index. Stapokibart concentrations increased rapidly following the first dose, climbed further with repeated dosing and gradually declined after treatment discontinuation. Stapokibart reduced inflammatory biomarkers in both groups. No treatment-related antidrug antibodies were detected. No new safety signals emerged. CONCLUSIONS:Stapokibart shows potential in improving disease outcomes and appears to be well tolerated in children aged 6-11 years with moderate-to-severe AD. Larger controlled studies are needed to confirm long-term benefits.

ABSTRACT Background Human papillomaviruses (HPVs) pose a severe threat to global public health by driving nonmelanoma skin cancer (NMSC) and cervical cancer, with NMSC being one of the most common cancers worldwide. Epidermodysplasia verruciformis (EV) is an inborn error of immunity characterized by an increased susceptibility to persistent infection of cutaneous HPV and a high risk of NMSC. The genetic basis remains unknown in many patients with EV. Methods We collected four unrelated pedigrees with EV. Genetic analysis identified five variants in JAK1 encoding the Janus kinase 1. Ex vivo models and patient-derived tissue were employed to evaluate the functional effects of JAK1 variants and delineate the pathogenic mechanisms. Results We identified different variants in JAK1 in four pedigrees with dominant EV. Genetic analysis revealed five novel variants in JAK1 , three of which resulted in nonsense-mediated mRNA decay (NMD). Functional assays identified a decreased phosphorylation of the signal transducers and activators of transcription (STATs), impaired interferon responses, and defective T cell activation. Immune dysregulation in patients, characterized by a reduced CD4⁺/CD8⁺ T cell ratio, decreased CD8⁺ naïve T cell proportion, and accumulated memory T cells, implies impaired antiviral immunity against HPV. Conclusions Our findings confirm that JAK1 loss-of-function (LOF) variants underlie susceptibility to cutaneous HPV infection. [Funded by the National Natural Science Foundation of China (81788101, 81230015, 82394420, and 82394423), the National Key Research and Development Program of China (2022YFC2703900), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018), and the Regione Lombardia, Italy (Innovative Research Project 1137-2010)].

Importance:Acanthosis nigricans (AN) is commonly associated with impaired glucose tolerance, but early, severe presentation in individuals with normoglycemia may identify individuals at risk for systemic disease. While gain of function epidermal growth factor receptor (EGFR) pathogenic variants are associated with pulmonary cancers, their role in syndromic skin disease has not been clearly defined. This study identified activating EGFR variants that were associated with a syndrome characterized by generalized acquired keratoderma accentuated at flexural sites, woolly hair, palmoplantar keratoderma, and pulmonary disease with lung nodules, and the results suggest EGFR inhibitor therapeutic efficacy. Objectives:To determine the genetic basis of early-onset, syndromic AN and assess response to pathogenesis-directed therapy. Design, Setting, and Participants:Patients included 2 individuals with normoglycemia with early-onset periorificial hyperpigmentation and flexural skin thickening that subsequently generalized and 1 individual with an original diagnosis of widespread epidermal nevus. Participants underwent whole-exome sequencing and studies of affected skin and keratinocytes. Main Outcomes and Measures:EGFR variant identification and assessment of pathway activation in lesional skin and keratinocytes, pulmonary function testing, lung imaging, and clinical response to EGFR inhibition. Results:All 3 participants (aged 8, 18, and 17 years; 2 male individuals and 1 female individual) had an EGFR L858R variant, which arose as either de novo in generalized cases or a somatic variant in mosaic disease. Lesional skin and cultured keratinocytes demonstrated increased EGFR pathway activity, which was suppressed by pharmacologic inhibition in vitro. Systemic treatment with EGFR inhibitors was associated with skin disease regression, improvement in pulmonary disease, and resolution or reduction of the number of pulmonary nodules. Conclusions and Relevance:The findings of this case series study define a syndromic disorder with increased risk of pulmonary disease and lung nodules in patients with acquired, generalized AN that is associated with activating EGFR variants. Pulmonary nodules are precursor lesions for lung cancer, and treatment with EGFR inhibitions is associated with near-complete resolution of skin and pulmonary disease. Early recognition of syndromic EGFR AN will permit identification of individuals at risk for systemic disease who are candidates for EGFR-targeted therapy.

Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of nonsyndromic epidermal differentiation disorders (nEDD). Variants in PNPLA1, which encodes a transacylase essential for the formation of epidermal lipid barrier, underlie ARCI10. This study aims to unveil the underlying genetic basis in ten Chinese cases diagnosed with ARCI, and to determine the origin of a prevalent variant. Ten cases, encompassing twelve patients with ARCI, were recruited for this study. Whole-exome sequencing combined with Sanger sequencing was used to detect the underlying variants. Haplotype analysis using flanking highly polymorphic SNPs was used to trace the origin of the c.1300delG variant in the PNPLA1 gene. All patients developed generalized fine scales and erythema shortly after birth. Marked phenotypic heterogeneity was observed among the affected individuals, leading to diagnosis of either generalized or localized nEDD. In total, we detected three recurrent variants (c.1300delG, p.A434Hfs*22; c.434 T > C, p.Ile145Thr; c.488C > T, p.Pro163Leu) and five novel variants (c.205 + 1G > A, splicing; c.74C > T, p.Ser25Phe; c.473G > A, p.Cys158Tyr; c.731A > G, p.Tyr244Cys; c.1318C > T, p.Arg440*) in PNPLA1. The c.1300delG variant, prevalent in 7 unrelated ARCI cases, was associated with a common haplotype. Furthermore, we presented the beneficial effect of secukinumab treatment in one of our patients. Our findings suggest that the c.1300delG variant is a highly prevalent variant in Chinese PNPLA1-associated nEDD patients, and indicate that the recurrent variant may originate from a common ancestor in southern China, suggesting a regional founder effect. The observed response with secukinumab in one patient suggests that it might represent a potential therapeutic option for PNPLA1-nEDD patients.

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome is a rare disorder in which atypical presentations may delay diagnosis. We report a molecularly confirmed case mimicking Hailey-Hailey disease without classical unilateral involvement or skeletal abnormalities. This case highlights an important diagnostic pitfall, emphasizes the value of NSDHL genetic testing, and demonstrates the clinical benefit of pathogenesis-directed topical simvastatin/cholesterol therapy.

We report two gain-of-function IRF6 variants (p.Ile218_Ser220delinsSerSerGlyAla; p.Ile218Asn) as the genetic basis of early-onset hidradenitis suppurativa, ectodermal dysplasia and deafness (HSEDD) - a novel syndrome expanding IRF6-related disorders beyond developmental phenotypes. These variants constitutively hyperactivate IL-1 beta and IFN pathways in keratinocytes and patient tissues. This work establishes IRF6-driven autoinflammation as a therapeutic target for HSEDD and related skin disorders.

This case report describes a patient with a postzygotic FGFR3 variant leading to severe achondroplasia with developmental delay and acanthosis nigricans accompanied by both acanthosis nigricans and generalized epidermal nevus.

BACKGROUND:Epidermal differentiation disorders (EDDs) are inherited keratinization disorders with remarkable clinical and genetic heterogeneity. Defects in epidermal lipid metabolism and corneocyte lipid envelope assembly account for a subset of EDDs. Epoxide hydrolase 3 (EH3), encoded by EPHX3, mediates the hydrolysis of linoleate-derived lipid epoxides during barrier formation. While Ephx3-deficient mice exhibit impaired skin barrier function, no human disorders caused by EPHX3 variants have been reported to date. OBJECTIVES:To determine the genetic basis of a new subtype of nonsyndromic EDD (nEDD) presenting from early infancy with generalized erythematous patches and plaques, xerosis and skin peeling; and to assess the impact of EH3 deficiency on epidermal lipid processing. METHODS:Whole-exome sequencing was performed in three unrelated families with nEDDs to investigate the underlying genetic causes. The skin biopsy from one representative patient was analysed using immunofluorescence staining and lipid staining. Liquid chromatography-mass spectrometry was used to quantify EH3 activity. Patient-derived primary keratinocytes were used to generate three-dimensional (3D) skin equivalents to assess epidermal differentiation. RESULTS:Three affected individuals from Chinese, Pakistani Irish and Russian families with nEDDs were enrolled. Biallelic EPHX3 variants (c.74G>A, p.Trp25*; c.289G>T, p.Gly97*; c.524G>A, p.Gly175Asp; c.908G>A, p.Trp303*; c.1033delC, p.Gln345Argfs*51) were identified in the patients. Total trihydroxyoctadecenoic acid was reduced in tape-stripping stratum corneum extracts from affected individuals, suggesting reduced EH3-dependent epoxide hydrolysis in vivo. Consistently, carriers of EPHX3 variants showed markedly reduced epoxide hydrolase activity in vitro. Nile red staining of the patient's skin lesion revealed reduced and redistributed lipids, suggesting a disturbed stratum corneum lipid barrier. The patient's keratinocyte-constructed 3D skin equivalent showed disrupted stratum corneum, more extensive keratin 1, increased loricrin and Ki-67, and reduced claudin-1 staining. CONCLUSIONS:We report biallelic loss-of-function EPHX3 variants causing a new subtype of nEDD. Our study also supports an important role of EH3-dependent epoxide hydrolysis in epidermal barrier lipid processing.

Ceramides are essential skin lipids for maintaining the mammalian skin permeability barrier, which protects against external stimuli. The precursor of epidermal ceramides, glucosylceramides (GlcCer), is synthesized within granular keratinocytes while its precise cellular transport mechanisms remain poorly characterized. Here, we identified 3 pathogenic variants in the GLTP gene, which encodes glycolipid transfer protein, in 5 unrelated families with nonsyndromic epidermal differentiation disorder presenting with generalized skin scaling. The biallelic GLTPvariants resulted in loss of competent GLTP expression. CRISPR/Cas9-generated Gltp-knockout mice exhibited lethal barrier defects, partially recapitulating the clinical features of our patients. We demonstrated that GLTP facilitated GlcCer transport in differentiated keratinocytes, with its deficiency causing impaired GlcCer trafficking and consequent aberrant retention in lysosomes, thereby disrupting lysosome function. The lysosomal dysfunction impaired autophagy flux, resulting in delayed keratinocyte terminal differentiation, which is expected to compromise the skin barrier integrity and ultimately lead to abnormal scaling. Pharmacological inhibition of GlcCer synthesis effectively rescued both autophagy and keratinocyte differentiation defects. Our findings establish GLTP as a novel underlying gene for nonsyndromic epidermal differentiation disorders and unravel its essential role in maintaining skin homeostasis during terminal differentiation by mediating epidermal GlcCer transport.

This case report describes a young woman with diffuse pruritic erythematous plaques and papules since birth who presented with coalesced spiked keratotic papules on the palms and chalky white fingernails.

BACKGROUND: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. OBJECTIVE:To identify the genetic basis and the pathogenesis of a sporadic patient with PSEK. METHODS: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. RESULTS: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. CONCLUSION: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.

A 3-month-old male infant presented with vesicular and erythematous facial lesions and tested positive for anti-SSA/Ro antibodies, leading to a diagnosis of neonatal lupus erythematosus. The condition, caused by transplacental maternal antibody transfer, manifested with typical cutaneous findings and resolved within 2 weeks.