Persistently Elevated Serum IgM: A Diagnostic Red Flag for Primary Immunodeficiencies: A Case-Based Review and Clinical Approach.

INTRODUCTION/OBJECTIVE: Persistently elevated serum immunoglobulin M (IgM) is commonly interpreted as a marker of acute infection, autoimmune activity, or lymphoproliferation. Sustained IgM elevation may represent an underrecognized marker of underlying primary immunodeficiency disorders (PIDs), especially those associated with class-switch recombination defects or immune dysregulation. This article aims to highlight the diagnostic value of persistently elevated IgM levels in pediatric PIDs and to propose a practical clinical framework for the evaluation of children with unexplained IgM elevation. METHODS: We performed a case-based narrative review of the literature on primary immunodeficiencies associated with elevated serum IgM, focusing on pathogenic mechanisms, clinical phenotypes, and diagnostic implications. The review was complemented by two pediatric cases from our practice in which persistent IgM elevation served as a clue to the diagnosis of distinct primary immunodeficiencies. RESULTS: Persistently increased IgM levels in PIDs may reflect impaired class-switch recombination, impaired germinal center maturation, or chronic immune activation. The two presented cases, ataxiatelangiectasia with a hyper-IgM phenotype and BENTA disease, illustrate how elevated IgM associated with frequent and severe infections, lymphoproliferation, growth impairment, or syndromic features may guide clinicians toward immunological and genetic evaluation. DISCUSSION: Persistent IgM elevation should be interpreted in its clinical context and should not be dismissed as a nonspecific laboratory abnormality. A structured diagnostic approach may help distinguish secondary causes, classic hyper-IgM syndromes, and hyper-IgM phenotypes. CONCLUSION: Persistently elevated serum IgM should not be dismissed as a transient abnormality in children with recurrent infections or immune dysregulation. When interpreted in its clinical context, it may serve as a practical indicator for further immunological investigation and diagnosis of PIDs.