A Familial TRAPS Phenotype Masquerading as Autoimmune Disease: The Pitfalls of Polyclonal Hypergammaglobulinemia and Low-Titer ANA in Diagnosis

Autoimmune and autoinflammatory disorders can exhibit significant clinical and immunological overlap, often leading to diagnostic delays and therapeutic misdirection. Polyclonal hypergammaglobulinemia and antinuclear antibodies (ANA), although classically associated with autoimmune processes, have been occasionally reported in monogenic autoinflammatory syndromes such as tumor necrosis factor receptor-associated periodic syndrome (TRAPS). We describe a familial cohort of three siblings presenting with recurrent febrile episodes, serositis, arthralgia, and mucocutaneous involvement since childhood. Comprehensive laboratory, immunological, and genetic investigations were performed, including serum protein electrophoresis, IgG subclass quantification, ANA testing by immunofluorescence, autoantibody profiling by immunodot, and next-generation sequencing of autoinflammatory gene panels. All three siblings exhibited marked polyclonal hypergammaglobulinemia with predominant IgM/IgG3/IgG4 elevation, and low-titer ANA (1/160–1/320, speckled) in the absence of specific extractable nuclear antigen antibodies. Inflammatory markers were persistently elevated during flares. Genetic analysis revealed a pathogenic heterozygous variant in TNFRSF1A (p.Phe141Leu), confirming TRAPS. Therapeutically, colchicine was ineffective, whereas IL-1 blockade with anakinra induced rapid and sustained remission in the two treated siblings. This family illustrates that polyclonal hypergammaglobulinemia and nonspecific autoantibodies may accompany TRAPS and mimic autoimmune disease. Such findings should not preclude genetic testing for autoinflammatory syndromes in patients with recurrent systemic inflammation, especially in familial cases. Early IL-1 inhibition represents an effective targeted therapy and may also serve as a diagnostic tool in phenotypically ambiguous cases.