Expanding the Spectrum of Selective IgM Deficiency: From Infections to Immune Dysregulation

IgM plays a central role in early immune responses, yet the clinical significance of its deficiency remains poorly defined. Current diagnostic criteria focus on selective IgM deficiency (sIgMD), characterized by persistently low IgM concentrations and recurrent infections, potentially overlooking patients with isolated IgM deficiency and non-infectious manifestations. In this retrospective study, we analyzed a pediatric cohort with isolated IgM deficiency, irrespective of infectious history. Clinical features-including cytopenia, lymphoproliferation, autoimmunity, allergy, and inflammation-were similarly distributed in patients with and without infections. Importantly, 26% of patients received a molecular diagnosis consistent with inborn errors of immunity (IEIs), including several without recurrent infections. Longitudinal analysis revealed a dynamic course of IgM concentrations over time, allowing classification into chronic, intermittent, progressive, and resolved subtypes. These findings challenge the current definition of sIgMD, highlight the limitations of relying solely on infectious history, and suggest that isolated IgM deficiency may represent a broader and heterogeneous immunological phenotype. Molecular testing and extended follow-up may help identify underlying inborn errors of immunity and clarify long-term risks, even in patients initially lacking infectious complications. A redefinition of IgM deficiency is warranted.