NFKB2 Deficiency

NFKB2 deficiency is an autosomal dominant immune disorder from heterozygous variants in the C-terminal region of NFKB2, which blocks processing of p100. It combines antibody deficiency with endocrine and ectodermal features and is often called DAVID syndrome (deficient anterior pituitary with variable immune deficiency).

Pathophysiology. Failed p100 processing disrupts non-canonical NF-kappa-B signalling, which is needed for B cell maturation, lymphoid organ formation and pituitary development. B cell numbers and immunoglobulins fall, and ACTH production may fail.

It is rare. Immune symptoms begin in early childhood, and endocrine disease can appear later.

ACTH deficiency can cause fatal adrenal crisis if unrecognised.

• Recurrent sinopulmonary infection, bronchiectasis, and herpesvirus infection
• Central adrenal insufficiency (ACTH deficiency): fatigue, vomiting, hypoglycaemia in childhood
• Other pituitary deficits: growth hormone, TSH, and rarely others
• Alopecia areata or totalis, and trachyonychia (nail dystrophy)
• Autoimmune disease: cytopenias, thyroid disease, coeliac disease, vitiligo
• Enteropathy and lymphoproliferation
• Lymphoma and other cancers in some

• Immunoglobulins: low IgG with low IgA and/or IgM, and poor vaccine response.
• B cell phenotype: low B cells and low class switched memory B cells.
• Genetic testing of NFKB2 (C-terminal variant).
• Endocrine workup: 9 am cortisol and ACTH, short synacthen (tetracosactide 250 micrograms) test if the morning cortisol is borderline, IGF-1, TSH and free thyroxine, and prolactin. Pituitary hormone testing is repeated at intervals because deficits evolve.
• MRI of the pituitary: small anterior pituitary.
• Dermatology and nail examination.
• Autoimmune workup and imaging as symptoms require.

Differential diagnosis.

• Common variable immunodeficiency
• NFKB1 deficiency
• Isolated ACTH deficiency
• Autoimmune polyendocrine syndromes
• Combined pituitary hormone deficiency from other causes
• Alopecia areata without immunodeficiency

• Hydrocortisone replacement for ACTH deficiency: in adults 15 to 25 mg orally daily in 2 or 3 divided doses (for example 10 mg on waking, 5 mg at midday, 5 mg in the late afternoon); in children 8 to 10 mg/m2 daily in 3 divided doses. Adjust to symptoms and weight, not to cortisol levels. Fludrocortisone is not needed in central adrenal insufficiency.
• Sick day rules: double the dose for fever over 37.5 degrees Celsius or other illness, and triple it for fever over 39 degrees Celsius, for the duration of the illness (usually 2 to 3 days); if vomiting or unable to take tablets, give hydrocortisone 100 mg intramuscularly or intravenously (children 2 mg/kg, maximum 100 mg) and go to hospital. Provide a steroid emergency card, a medical alert bracelet and an injection kit with training.
• Adrenal crisis: hydrocortisone 100 mg intravenously at once (children 2 mg/kg, maximum 100 mg), 0.9% sodium chloride 1 litre over the first hour (20 mL/kg in children), glucose if hypoglycaemic, then hydrocortisone 200 mg over 24 hours by infusion or 50 mg every 6 hours.
• Perioperative cover: hydrocortisone 100 mg intravenously at induction, then 200 mg over 24 hours until eating normally.
• Other hormones: levothyroxine for TSH deficiency (start 1.6 microgram/kg daily, titrate to free thyroxine), growth hormone for proven deficiency in children.
• Immunoglobulin replacement: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• 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.
• Autoimmunity and alopecia: potent topical corticosteroid for patchy alopecia; immunosuppression for cytopenias with prednisolone 1 mg/kg daily (maximum 60 mg), and Pneumocystis prophylaxis with co-trimoxazole 960 mg orally three times weekly in adults (children trimethoprim 150 mg/m2 daily in two divided doses on 3 days each week).
• Vaccines: inactivated only.
• Haematopoietic stem cell transplantation is considered for severe immune disease, but does not correct pituitary deficits.

Special groups.

• Children with unexplained hypoglycaemia and low immunoglobulins need urgent cortisol testing.
• Women: increase hydrocortisone in the third trimester and give parenteral cover in labour.

Monitoring. Symptoms and growth at each visit. Pituitary hormones yearly. Trough IgG every 3 to 6 months. Full blood count and thyroid function every 6 to 12 months.

Referral and escalation. Refer to immunology and endocrinology. Urgent for vomiting, hypotension or drowsiness in a patient on hydrocortisone, which signals adrenal crisis.