[De novo NFκB2 gene mutation associated common variable immunodeficiency].

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia and impaired B-cell differentiation.
• The nuclear factor kappa-B subunit 2 (NFκB2) pathway is critical for immune cell development and function.
• Mutations in NFκB2 can lead to severe immune dysregulation.

Observation:

• A 14-month-old boy presented with recurrent pneumonia and otitis media, alongside significantly low immunoglobulin levels (IgG, IgA, IgM).
• Immunological analysis revealed altered T-cell subsets, reduced switched memory B cells and plasmablasts, and impaired natural killer (NK) cell cytotoxicity.
• Whole-exome sequencing identified a de novo heterozygous nonsense mutation (c.2557C>T; p. Arg853X) in the NFκB2 gene, confirming decreased NF-κB2 (p52) protein expression.

Findings:

• The NFκB2 mutation resulted in impaired T and B lymphocyte differentiation and reduced NK-cell cytotoxic activity.
• A review of 28 cases, including this patient, highlighted respiratory infections, autoimmune diseases, and adrenocorticotrophic hormone (ACTH) deficiency as common manifestations.
• Specific mutation types, including nonsense, missense, and frameshift, were associated with varying degrees of immune deficiency.

Implications:

• NFκB2 mutations are a significant cause of CVID, impacting multiple aspects of the immune system.
• Clinical suspicion of NFκB2 mutation should be raised in patients with recurrent infections, hypogammaglobulinemia, and decreased memory B cells/plasma cells.
• The findings underscore the importance of NFκB2 signaling in immune homeostasis and suggest potential therapeutic targets for related immunodeficiencies.