NFKB1 Deficiency

NFKB1 deficiency is an autosomal dominant immune disorder from heterozygous loss-of-function variants in NFKB1, which encodes p105 and p50. It is the commonest monogenic cause of common variable immunodeficiency in people of European ancestry.

Pathophysiology. Reduced p50 weakens B cell survival, class switching and plasma cell formation, so antibody levels fall. Disturbed NF-kappa-B balance also lets autoimmunity and autoinflammation develop.

It accounts for about 4% of common variable immunodeficiency. Penetrance is incomplete, and onset ranges from childhood to late adulthood.

Disease differs widely, even within one family.

• Recurrent sinopulmonary infection and bronchiectasis
• Autoimmune cytopenias: immune thrombocytopenia, haemolytic anaemia
• Lymphadenopathy and splenomegaly
• Enteropathy and chronic diarrhoea
• Autoinflammation: recurrent oral and genital ulcers, Behçet like disease, uveitis, arthritis
• Chronic EBV or CMV viraemia
• COPD-like lung disease
• Lymphoma, and other cancers in some

• Immunoglobulins: low IgG with low IgA and/or IgM, and poor vaccine response.
• B cell phenotype: low class switched memory B cells, raised CD21-low B cells and transitional B cells.
• Genetic testing of NFKB1 (heterozygous loss-of-function), with family testing.
• Autoimmune workup: full blood count, direct antiglobulin test, thyroid function, autoantibodies.
• Viral PCR for EBV and CMV.
• Imaging: high resolution CT chest, spirometry with gas transfer, abdominal ultrasound.
• Endoscopy with biopsy for enteropathy.

Differential diagnosis.

• Common variable immunodeficiency without a known gene
• NFKB2 deficiency
• CTLA-4 haploinsufficiency
• Activated PI3K delta syndrome
• Behçet disease
• Inflammatory bowel disease
• Secondary hypogammaglobulinaemia

• Immunoglobulin replacement: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, adjusted to a trough IgG of at least 6 g/L, usually 7 to 9 g/L, and higher with bronchiectasis. Slow the infusion after a reaction; for anaphylaxis give adrenaline 0.5 mg intramuscularly (0.01 mg/kg in children, maximum 0.5 mg).
• Antibiotic prophylaxis: azithromycin 500 mg orally three times weekly in adults (children 10 mg/kg three times weekly, maximum 500 mg), after ECG shows QTc under 450 ms and sputum is clear of non-tuberculous mycobacteria. Treat chest infection with amoxicillin 1 g orally three times daily or doxycycline 200 mg on day 1 then 100 mg daily for 10 to 14 days, by culture.
• Pneumocystis prophylaxis with immunosuppression: co-trimoxazole 960 mg orally three times weekly (children trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week).
• Autoimmune cytopenia: prednisolone 1 mg/kg orally daily (maximum 60 mg) tapered over 4 to 8 weeks, or intravenous immunoglobulin 1 g/kg once. Rituximab 375 mg/m2 intravenously weekly for 4 doses for relapse, after hepatitis B screening.
• Autoinflammation: colchicine 500 micrograms orally once or twice daily (reduce with renal impairment; avoid strong CYP3A4 and P-glycoprotein inhibitors), or anakinra 1 to 2 mg/kg subcutaneously once daily (maximum 100 mg), for ulcers or arthritis. Sirolimus 1 to 2 mg once daily in adults, trough 5 to 10 microgram/L, for lymphoproliferation.
• Enteropathy: exclude infection, then budesonide 9 mg orally once daily or prednisolone.
• Cancer surveillance: biopsy of new or asymmetric nodes, with imaging for symptoms.
• Vaccines: inactivated only; avoid live vaccines.
• Haematopoietic stem cell transplantation is rarely used, and only for severe disease.

Special groups.

• Relatives who carry the variant need testing of immunoglobulins and clinical review, because penetrance is incomplete.

Monitoring. Trough IgG every 3 to 6 months. Full blood count, liver enzymes and creatinine every 6 months. Spirometry with gas transfer yearly. High resolution CT every 2 to 3 years with lung disease. EBV and CMV PCR with symptoms.

Referral and escalation. Refer to immunology. Urgent for cytopenia, rapidly enlarging nodes, B symptoms, or invasive infection.