A novel JAK1 mutation identified in a patient with severe atopic dermatitis phenotype: Mechanistic insights and...

JAK1 gain-of-function (GoF) mutations were considered ultra-rare causes of immune dysregulation, but recent studies suggest a broader clinical spectrum. We report the first Chinese case of a novel likely JAK1 GoF mutation (p.L783F) in a child with early-onset severe atopic dermatitis, eosinophilia, elevated IgE, and growth retardation. Functional assays showed enhanced IL-6-induced STAT1 phosphorylation among tested cytokines; single-cell RNA-sequencing revealed JAK-STAT hyperactivation predominantly in CD16⁺ monocytes. Mass and flow cytometry revealed expansion of a pro-inflammatory CD4⁺ effector subset (CD45RA⁺CCR7^-IFN-γ⁺IL-2⁺TNF-α⁺IL-23⁺CD4⁺ T cells) and Th2-polarized CD4⁺ T cells with increased CD25, CD27, and CRTH2. Given the patient's young age, growth retardation, and dermatitis-predominant clinical phenotype, she was treated with dupilumab, improving skin lesions, pruritus, eosinophilia, and hyper-IgE. This case expands the clinical and mutational spectrum of JAK1 GoF-associated disease (JAACD) and demonstrates that targeting downstream signaling such as dupilumab offers a safe, effective precision therapy for pediatric patients with JAK1 GoF mutations.