Common variable immunodeficiency (CVID) is diagnosed at ages ≥4 years with hypogammaglobulinemia across more than two immunoglobulin classes, leading to impaired vaccine responses, frequent infectious, autoimmune, and granulomatous complications. The underlying genetic mechanisms for CVID are poorly understood, and over 20 genetic causes have been described.
Importantly, NFKB2 is a central component of the non-canonical NFKB pathway, and its variants are among monogenic drivers of CVID-like phenotypes.
A 4-year-old girl, born at 38w2d via spontaneous vaginal delivery, experienced near-weekly illnesses since 6 months of age, including croup, post-viral cough lasting 4–6 weeks, gastroenteritis, and recurrent bilateral otitis media refractory to four antibiotic courses. Immunologic testing revealed low IgG (343 mg/dL), low IgA (12 mg/dL), and low IgM (14 mg/dL), reduced B cells (244 cells/uL), and reduced responses to vaccines. Genetic testing identified a NFKB2 c.2594A>G (p.Asp865Gly) mutation. Patient’s 38-year-old father was also found to have the same NFKB2 mutation and subsequently diagnosed with CVID. He also had a history of recurrent sinusitis, alopecia areata, and viral encephalitis. Labs showed low immunoglobulins of IgG (301 mg/dL), IgA (24 mg/dL), and IgM (9 mg/dL), low B cells (42 cells/uL), and an appropriate vaccine response. He received one dose of intravenous immunoglobulin (IVIG) following excision of newly diagnosed stage I colon cancer.
Previous studies suggest this mutation causes an autosomal dominant syndrome of antibody deficiency. Although penetrance for NFKB2-related disorders is incomplete, the presentation in our patient and her father is supportive of an autosomal-dominant inheritance pattern. The patient’s father was counseled on the 50% recurrence risk with strongly encouraged genetic testing for first-degree family members. The option of in vitro fertilization (IVF) with preimplantation genetic diagnosis was discussed, and the patient will also require adulthood counseling. Based on the father’s diagnosis of colon cancer at age 38, all first-degree relatives were advised to start colorectal cancer screening at age 28. This case builds on previous studies of the hereditary nature of this NFKB2 mutation and its suspected role in the pathogenesis of familial inheritance of CVID, emphasizing the importance of timely genetic testing and counseling.
