D3.334 - Severe Early-Onset Atopy With Recurrent Anaphylaxis and Infections as Indicators of CADINS Disease

Background

Severe atopic disease is often managed as an isolated allergic condition. However, the coexistence of early-onset severe atopy, recurrent anaphylaxis, and recurrent respiratory tract infections should prompt evaluation for an underlying inborn error of immunity (IEI). CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) is a rare IEI caused by heterozygous dominant-negative CARD11 variants. Defective antigen receptor–mediated NF-κB signaling results in impaired host defense alongside pronounced allergic inflammation, leading to frequent clinical misclassification as severe allergy.

Case Report

We report a 19-year-old male with severe childhood-onset atopy, multiple food and drug allergies, recurrent anaphylaxis, and frequent upper and lower respiratory tract infections since infancy. Retrospective analysis of pediatric records revealed recurrent infections beginning in early infancy and requiring repeated antibiotic therapy, with the first documented severe drug-related anaphylactic reaction occurring at two months of age.

Immunological assessment included quantitative immunoglobulin analysis, lymphocyte and B-cell subset profiling, complement testing, and targeted genetic analysis. The evaluation demonstrated combined hypogammaglobulinemia affecting IgG and IgM, markedly elevated serum IgE levels, and mannose-binding lectin deficiency. Preserved switched memory B cells allowed exclusion of common variable immunodeficiency. Targeted genetic testing identified a heterozygous dominant-negative CARD11 variant consistent with CADINS.

Initiation of immunoglobulin replacement therapy was complicated by recurrent anaphylactic reactions to multiple preparations, representing a significant therapeutic challenge. Following careful individualization, monthly subcutaneous immunoglobulin replacement therapy resulted in sustained normalization of IgG levels, a marked reduction in respiratory tract infections, and long-term clinical stabilization without further anaphylactic events. Targeted biologic therapy was not required.

Conclusion

This case illustrates that severe, early-onset atopy accompanied by recurrent anaphylaxis and recurrent infections should prompt evaluation for an underlying inborn error of immunity rather than being interpreted as an isolated allergic phenotype. In CADINS, prioritizing immune stabilization through individualized immunoglobulin replacement may be sufficient to achieve clinical control, even in the absence of targeted biologic therapy. Improved recognition of CARD11-associated disorders is essential to reduce diagnostic delay and guide effective, mechanism-based management.