A Copy Number Gain in NFKB2 in a Patient with Immune Dysregulation

Pathogenic variants in the NFKB2 gene are strongly associated with B cell dysregulation. Here, we present a copy number gain of the entire NFKB2 gene in a patient with immune dysregulation. An 18-year-old young man previously diagnosed with immune thrombocytopenic purpura (ITP) at the age of 4 was admitted for pneumococcal meningitis. Regarding his prior history, he had been on eltrombopag, although required oral corticosteroids several times annually for ITP crises. The patient reported intermittent lymphadenopathy; a cervical lymph node biopsied at age 10 showed reactive lymphocytes. Two previous bone marrow biopsies revealed hypocellular marrow but no other significant abnormalities. Prior immune evaluation demonstrated poor vaccine responses despite boosters, although there were no previous serious infections. His mother reported she had autoimmune pancreatitis and the patient’s brother having vitiligo. Imaging during admission demonstrated extensive sinus disease, enhancement concerning for bacterial meningitis, an incidental Chiari type 1 malformation, and a sinus venous thrombosis in the superior sagittal sinus. He was treated with a prolonged course of antibiotics and a bivalirudin drip and transitioned to apixaban upon discharge. Given the history of long-standing ITP and a serious invasive infection, further evaluation for immune dysregulation was performed. Laboratory evaluation was remarkable for hypogammaglobulinemia, absent tetanus, diphtheria, pneumococcal, measles, mumps, and varicella titers, and low class-switched memory B cells. Abdominal ultrasound showed a spleen size at the upper limit of normal. Genetic testing via an inborn errors of immunity (IEI) and cytopenias panel revealed an NFKB2 gain (entire coding sequence), copy number = 3 of uncertain significance. Currently, a monogenic cause is found in less than 30% of patients with IEIs, specifically in those with immune dysregulation. Including copy number variants (CNVs) will improve diagnostic yields for IEIs as CNVs may modify disease expression. In our patient, the copy number gain may lead to overactivation of NFKB2, causing immune dysregulation and inflammation. Parental testing is pending, and functional validation is being pursued. As genetic testing becomes standard of care, integrating CNV analysis into routine sequencing will aid in diagnosis and improve treatment options for patients.