BACKGROUND: Epidermal differentiation disorders (EDD) are inherited keratinization disorders with remarkable clinical and genetic heterogeneity. Defects in epidermal lipid metabolism and corneocyte lipid envelope assembl...BACKGROUND: Epidermal differentiation disorders (EDD) 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 EDD. Epoxide hydrolase 3 (EH3), encoded by EPHX3, mediates 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. We also assessed the impact of EH3 deficiency on epidermal lipid processing. METHODS: Whole-exome sequencing was performed in three unrelated families with nEDD 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 employed 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 nEDD 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* and 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 on the patient's skin lesion revealed reduced and redistributed lipids, suggesting a disturbed stratum corneum lipid barrier. 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.
BACKGROUND: Multiple basal cell carcinomas (BCCs) can result from a genetic disease, such as basal cell nevus syndrome (BCNS) or develop without a genetic predisposition, known as high-frequency BCC (HF-BCC). Multiple BC...BACKGROUND: Multiple basal cell carcinomas (BCCs) can result from a genetic disease, such as basal cell nevus syndrome (BCNS) or develop without a genetic predisposition, known as high-frequency BCC (HF-BCC). Multiple BCCs require frequent interventions, which may impact quality of life (QoL). Data on QoL in these patients and the influence of number of BCCs on QoL remain scarce. OBJECTIVES: To evaluate QoL in patients with BCNS and HF-BCC and the impact of number of BCCs on QoL. METHODS: Patients with BCNS were recruited through the Maastricht University Medical Centre (MUMC+), the online national BCNS patient platform and through the Dutch Society for Dermatology and Venereology (NVDV). Patients with HF-BCC (≥9 BCCs in 3 years or ≥6 in 10 years) were recruited from the MUMC+ and Catharina Hospital Eindhoven. QoL was measured with the Skindex-29 and severity of QoL impact was calculated based on pre-defined cut-off scores. RESULTS: Seventy-five patients with BCNS and 59 with HF-BCC were included. Patients with BCNS were often younger (median 48 versus 74 years), 61%(46/75) were female versus 34%(20/59) of patients with HF-BCC, and 48%(36/75) had > 100 BCCs versus 1.7%(1/59) of HF-BCC patients. A substantial proportion of patients with BCNS reported severe impact on emotions and functioning (36.0%(27/75) and 22.7%(17/75), respectively) and mean scores of 32.2±20.8 and 18.9±19.6 respectively. Adjusting for age and sex, the overall Skindex-29 score was higher in the BCNS group, with a between group difference of 10 (95% CI 2.5-17.5). Among patients with BCNS, BCC burden was negatively associated with QoL, with significantly higher scores in patients with >100 compared to <30 BCCs (mean total score of 32.0±19.6 versus 15.8±11.6). This trend was not observed in HF-BCC. CONCLUSIONS: These findings highlight an increased QoL impairment in patients with BCNS compared to others with multiple BCCs, especially with respect to emotional and functional well-being. This can be partly explained by the high BCC burden in this patient group. Our findings suggest that a high BCC burden is an indicator of psychosocial burden, and underscores that disease-related challenges in emotional and social domains should be considered during consultations to improve patient support.
BACKGROUND: The skin microbiome plays a pivotal role in regulating epidermal barrier integrity and immune homeostasis. However, the molecular mechanisms through which microbial dysbiosis drives dermatological disease and...BACKGROUND: The skin microbiome plays a pivotal role in regulating epidermal barrier integrity and immune homeostasis. However, the molecular mechanisms through which microbial dysbiosis drives dermatological disease and in particular, the pathways by which alterations in the scalp microbiome give rise to the pathological features of dandruff are not fully understood. OBJECTIVES: This study aimed to establish and validate microbially colonised, full-thickness human skin equivalents (HSEs) that incorporate scalp-relevant bacterial and fungal microbiome species, to dissect the molecular pathways linking microbiome composition to epidermal morphology, barrier function and skin homeostasis. METHODS: We engineered HSEs colonised with microbial consortia representing healthy (5M) and dandruff-associated (5MP) scalp microbiomes. Morphological and histological analyses were used to assess epidermal architecture and barrier integrity. Expression of key barrier proteins and enzymes involved in corneodesmosome hydrolysis was quantified. Bulk RNA-sequencing was performed to identify differentially regulated signalling pathways, followed by protein validation using immunofluorescence analysis. Key findings were further corroborated with human scalp biopsy specimens from individuals with and without dandruff. RESULTS: HSEs colonised with the 5M microbiome maintained normal epidermal morphology and expression of barrier-associated proteins. In contrast, HSEs colonised with the 5MP microbiome developed hallmark dandruff-like phenotypes, including altered epidermal morphology, reduced barrier protein expression, and abnormal corneodesmosome degradation. Transcriptomic analysis and protein validation revealed significant attenuation of the aryl hydrocarbon receptor (AhR) signalling pathway in 5MP-colonised HSEs. Consistent downregulation of AhR and associated proteins was observed in dandruff patient samples, confirming the clinical relevance. CONCLUSIONS: Microbial dysbiosis on the scalp can compromise AhR signalling. This study provides mechanistic evidence linking microbiome composition to pathological epidermal changes. The developed microbially colonised HSE model provides a versatile and clinically relevant tool for advancing our understanding of microbiome-driven skin pathology and translating mechanistic insights into precision interventions.
BACKGROUND: Striae gravidarum (SG) is a common skin condition characterized by disrupted dermal extracellular matrix (ECM) homeostasis. Despite its high prevalence, the underlying cellular and molecular pathogenesis rema...BACKGROUND: Striae gravidarum (SG) is a common skin condition characterized by disrupted dermal extracellular matrix (ECM) homeostasis. Despite its high prevalence, the underlying cellular and molecular pathogenesis remains poorly understood, particularly regarding fibroblast heterogeneity and metabolic dysregulation. OBJECTIVES: This study aimed to delineate the cellular landscape and molecular mechanisms of SG at single-cell resolution, with a focus on fibroblast subpopulation dynamics, intercellular communication, and metabolic reprogramming. METHODS: We performed integrated single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) on dermal specimens from human SG lesions and matched normal skin. Functional validation was conducted using qPCR, histological staining (H&E, EVG, picrosirius red), immunofluorescence, and Mendelian randomization analysis. RESULTS: SG skin exhibited significant cellular reorganization, with fibroblasts showing the most profound transcriptional changes. Intercellular communication analysis identified a dysregulated sender-receiver axis between the inflammatory, metabolically active sC7 subset and the reparative sC5 subset. Pseudotime analysis indicated a blocked differentiation from sC7 to sC5. The sC7 subset underwent specific fatty acid metabolic reprogramming, marked by upregulation of key enzymes including ACSBG1. Triacsin C treatment in primary PDPN⁺ reticular fibroblasts suppressed ECM gene expression and attenuated pro-fibrotic markers; notably, it also downregulated representative sC7-associated genes while upregulating sC5-associated genes, suggesting partial restoration of a reparative transcriptional program. Furthermore, local Acsbg1 silencing in dorsal skin alleviated SG-like dermal remodeling in the mouse model, with improved dermal architecture, collagen organization, and elastic fiber integrity. CONCLUSIONS: Targeting ACSBG1-mediated fatty acid metabolic reprogramming in pro-fibrotic fibroblast subsets restores a reparative transcriptional programme and ameliorates dermal ECM disruption in SG. These findings identify ACSBG1 as a potential therapeutic target for SG.