Hyper-IgE and Carcinoma in CADINS Disease

Area of Science:

• Immunology
• Genetics
• Dermatology

Background:

• Atopic dermatitis (AD) affects a significant portion of the population, with severe cases potentially indicating an underlying inborn error of immunity (IEI).
• Hyper-IgE syndromes are a group of IEIs characterized by elevated IgE levels and susceptibility to infections, often linked to specific gene variants.

Observation:

• A case study identified a novel heterozygous CARD11 variant (c.223C>T; p.(Arg75Trp)) in an 18-year-old patient with a history of infections, hypogammaglobulinemia, eosinophilia, and colitis.
• This variant, confirmed to have a dominant-negative effect, was also found in five other family members presenting with severe atopy but not hypogammaglobulinemia.
• Malignancies, including HPV-positive squamous cell carcinoma and cutaneous T-cell lymphoma, occurred in two generations of the affected family.

Findings:

• The identified CARD11 variant is associated with CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS), presenting a broad phenotypic spectrum.
• Disease mechanisms include partial T-cell deficiency, diminished IFN-γ, and increased IL-4 production.
• Malignant disease is a rare but significant association with germline CARD11 dominant-negative variants.

Implications:

• Diagnosis of underlying IEIs like CADINS is crucial for tailoring treatment strategies in patients with severe AD and recurrent infections.
• Management may involve monitoring for malignancies with HPV vaccination and regular screening, alongside treatments like dupilumab for severe eczema.
• Understanding the immunological mechanisms, such as altered cytokine profiles, aids in developing more effective therapies for these complex conditions.