The Clinical and Genetic Landscape of Junctional Skin Disorder in Children: A Scoping Review

Cellular junctions, including desmosomes, hemidesmosomes, adherens, tight, and gap junctions, are essential for epidermal integrity, barrier function, and cell signaling. Variants in genes encoding proteins involved in cellular junctions lead to a spectrum of skin disorders, commonly referred to as junctional genodermatoses, often presenting with phenotypic overlaps and multisystemic involvement in pediatric patients. This systematic scoping review aims to comprehensively map pediatric genodermatoses, correlating specific genetic variants with clinical manifestations to improve diagnostic and prognostic accuracy. A systematic literature review was conducted in PubMed, Web of Science, Embase and Scopus. The key terms included genetic skin disease and cellular junctions; case reports, case series, or observational studies of pediatric patients with skin diseases, specified junctional genes, and detailed clinical descriptions were considered. From 9,409 records, 159 studies were included, covering 25 key genes across five junctional complexes. Defects in anchoring complexes primarily manifested as skin fragility and blistering, including lethal neonatal forms of genodermatoses. Tight junction mutations were associated with syndromic ichthyoses, while gap junction variants showed high pleiotropy, ranging from palmoplantar keratoderma to keratitis-ichthyosis-deafness syndrome. Adherent junction defects were specifically associated with hypotrichosis. Extracutaneous involvement, including sensorineural hearing loss and arrhythmogenic cardiomyopathy, emerged as critical sentinel features in several junctional syndromes. In conclusion, pediatric junctional genodermatoses feature overlapping skin manifestations, but the specific complex dictates the primary disease mechanism. Early genetic characterization is determinant to guide multidisciplinary surveillance for life-threatening systemic comorbidities.