NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation

Area of Science:

• Immunology
• Genetics

Background:

• Nuclear factor kappa B (NF-κB) signaling regulates immune responses.
• Dysfunctional NF-κB is linked to malignancies and primary immunodeficiencies (PIDs).
• NF-κB1 haploinsufficiency has been recently associated with common variable immunodeficiency (CVID).

Observation:

• A patient presented with recurrent infections and hypogammaglobulinemia.
• Immunological workup revealed impaired B-cell maturation and T-cell proliferation.
• Genetic analysis identified a novel heterozygous NFKB1 frameshift mutation (c.491delG; p.G165A*31).

Findings:

• The NFKB1 mutation reduced p105 phosphorylation and p50 protein levels.
• The patient experienced severe Epstein-Barr virus (EBV)-associated lymphoproliferative disease.
• The patient's father, a carrier of the same mutation, exhibited a milder phenotype.

Implications:

• NF-κB1 deficiency presents a broader clinical spectrum than previously recognized.
• EBV lymphoproliferative disease is a newly identified feature of NF-κB1 deficiency.
• Understanding NF-κB1's role is crucial for diagnosing and managing complex immunodeficiencies.