From Genetic Dysregulation to Targeted Therapy: Managing Autoimmunity in Down Syndrome with JAK Inhibitors

Introduction Chromosome 21 encodes multiple interferons and their receptors. Under normal conditions (disomy 21), interferon binding activates the kinases JAK1 and TYK2, leading to STAT1 phosphorylation and transcription of interferon-stimulated genes (ISGs). In trisomy 21, overexpression of these receptors results in dysregulated, chronic activation of this pathway, causing baseline inflammation, tissue damage, and increased susceptibility to autoimmunity. Case Report We present a 9-year-old male from Guanajuato, Mexico, with karyotype-confirmed trisomy 21. During infancy, he was diagnosed with patent ductus arteriosus and autoimmune thyroiditis, managed with levothyroxine. At age 2, he developed alopecia areata treated with topical steroids and minoxidil. One year later, he exhibited vitiligo vulgaris, partially responsive to topical tacrolimus and corticosteroids. Inflammatory bowel disease was ruled out despite chronic diarrhea. Immunological assessment revealed positive antinuclear antibodies (ANAs) and antiphospholipid profile, persistent lymphopenia affecting CD3+, CD4+, and CD19 populations, with preserved humoral response to polysaccharide antigens. Due to refractory autoimmune manifestations and evidence of chronic interferon–JAK/STAT pathway activation, treatment with ruxolitinib, a selective JAK1/2 inhibitor, was initiated, resulting in progressive clinical improvement and immunological stabilization. Discussion This case exemplifies the immune dysregulation in trisomy 21, where hyperactivation of interferon–JAK/STAT signaling contributes to a complex autoimmune phenotype. The coexistence of polyglandular autoimmunity, vitiligo, and autoantibodies reflects this dysregulation. Although increased type I interferon sensitivity in trisomy 21 is established, recent transcriptomic, proteomic, and functional studies have further elucidated its role in shaping the altered immune profile. The positive response to ruxolitinib underscores the potential of JAK inhibitors as targeted therapies for refractory autoimmunity in this population. Further studies are warranted to confirm their safety and efficacy in individuals with Down syndrome.