Background: Monogenic disorders of immune regulation are predominantly recognised in children. In adults, they may present with multisystem autoimmune/inflammatory manifestations frequently assessed across specialties—often without fulfilling classical classification criteria for systemic connective tissue diseases—resulting in diagnostic delay and prolonged exposure to empiric immunosuppressive and biologic therapies.

Case Presentation: A woman was diagnosed at 50 years of age after a disease course beginning in late adolescence. The initial presentation was severe chronic enteropathy with weight loss and histology consistent with coeliac disease, refractory to a gluten-free diet and conventional immunosuppression. Over subsequent decades, autoimmune/inflammatory manifestations accumulated, including renal interstitial inflammation and inflammatory parotid involvement, accompanied by severe infectious complications. Tumour necrosis factor inhibitors (TNFi) were introduced with transient improvement but were complicated by a severe systemic inflammatory reaction during infliximab treatment. Subsequently, the patient developed severe interstitial lung disease (ILD) during adalimumab therapy, leading to TNFi discontinuation and glucocorticoid dependency. The occurrence of ILD during biologic therapy generated a key diagnostic dilemma—drug-related pulmonary toxicity versus a shared inborn mechanism underlying a cumulative multisystem phenotype. Key immunological abnormalities included lymphopenia (500–800/µL) with reduced CD4 ⁺ T cells (134/µL; ref 500–1300) and NK cells (34/µL; ref 90–630), severe hypogammaglobulinemia (IgG 254 mg/dL; ref 700–1600) with elevated IgA (615 mg/dL; ref 70–400; monoclonal component), and inflammation/electrolyte disturbances (CRP 3.8 mg/dL; ref <0.5; Na 128, K 2.9). Pulmonary function testing showed TLC 79% predicted and TLCO 35% predicted. Careful physical examination identified subtle facial dysmorphic features, prompting genetic evaluation. Genetic testing identified a pathogenic heterozygous STAT3 p.Arg152Trp variant with concomitant HLA-DQ2.5 haplotype, establishing a unifying diagnosis and reframing management toward pathway-directed strategies (JAK–STAT modulation) alongside immunoglobulin replacement.