IL-12 Receptor Beta-1 Deficiency

IL-12 receptor beta-1 (IL-12Rbeta1) deficiency is an autosomal recessive defect in the IL-12 and IL-23 receptor that is the commonest genetic cause of Mendelian susceptibility to mycobacterial disease. Patients are prone to BCG disease, non-tuberculous mycobacteria, Salmonella and Candida.

Pathophysiology. Without IL-12Rbeta1, T and NK cells cannot respond to IL-12 and make little interferon gamma, so macrophage killing of intracellular organisms fails. Defective IL-23 signalling lowers IL-17 immunity, which explains mucocutaneous candidiasis.

Onset is in childhood in most, but late onset presentations occur. Disease severity is lower than in complete interferon gamma receptor deficiency.

Penetrance is incomplete, and some carriers of two variants remain well for years.

• BCG disease after vaccination: lymphadenitis, osteomyelitis, disseminated disease
• Non-tuberculous mycobacterial infection (Mycobacterium avium complex and others), and tuberculosis
• Recurrent non-typhoidal Salmonella infection: bacteraemia, osteomyelitis, gastroenteritis
• Chronic mucocutaneous candidiasis
• Histoplasmosis, coccidioidomycosis, paracoccidioidomycosis in some
• Granulomatous inflammation in lymph nodes, liver and spleen
• Poor weight gain during active infection

• IL-12Rbeta1 expression on activated T cells by flow cytometry (usually absent).
• IFN-gamma and IL-12 whole blood stimulation assay: low IFN-gamma after BCG plus IL-12, with a normal response to interferon gamma.
• Genetic testing of IL12RB1 (biallelic variants), with family testing.
• Mycobacterial and Salmonella cultures from blood, nodes, bone and tissue, with species identification and susceptibility testing.
• HIV test, immunoglobulins, lymphocyte subsets, and neutrophil oxidative burst test.
• Imaging: chest CT, bone scintigraphy or MRI.
• Biopsy with acid fast staining.

Differential diagnosis.

• Other causes of Mendelian susceptibility to mycobacterial disease (IFNGR1, IFNGR2, IRF8, STAT1, IL12B)
• Chronic granulomatous disease
• GATA2 deficiency
• HIV infection
• Severe combined immunodeficiency
• Autoimmune anti-interferon-gamma antibodies in adults (Asia)

• BCG disease or non-tuberculous mycobacteria: combination treatment for at least 12 months. For BCG, isoniazid 5 mg/kg orally once daily (children 10 mg/kg; maximum 300 mg) with pyridoxine 10 mg daily, rifampicin 10 mg/kg once daily (children 15 mg/kg; maximum 600 mg) and ethambutol 15 mg/kg once daily; pyrazinamide is not used, since BCG is intrinsically resistant. For Mycobacterium avium complex use clarithromycin 500 mg twice daily (children 7.5 mg/kg twice daily, maximum 500 mg), ethambutol and rifampicin, adding amikacin 15 mg/kg intravenously once daily for the first 2 to 3 months in severe disease.
• Tuberculosis: isoniazid, rifampicin, pyrazinamide 25 mg/kg daily (maximum 2 g) and ethambutol for 2 months, then isoniazid and rifampicin for at least 7 to 10 months, with pyridoxine.
• Safety monitoring: liver enzymes monthly at first, visual acuity and colour vision monthly on ethambutol, ECG for QTc under 450 ms on macrolides, and drug interaction review with rifampicin.
• Non-typhoidal Salmonella: ceftriaxone 2 g intravenously once daily (children 50 to 80 mg/kg, maximum 2 g) for 14 days, then ciprofloxacin 500 mg orally twice daily (children by weight) to complete 4 to 6 weeks; longer for osteomyelitis.
• Interferon gamma 1b: 50 microgram/m2 subcutaneously three times weekly (1.5 microgram/kg for body surface area 0.5 m2 or less) as an adjunct for refractory or recurrent disease, with paracetamol 15 mg/kg orally before doses for fever.
• Secondary prophylaxis after treatment, for years or life: 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.
• Candidiasis: fluconazole 100 to 200 mg orally daily, maximum 400 mg (children 3 to 6 mg/kg daily).
• Haematopoietic stem cell transplantation for recurrent, refractory or severe disease.
• Vaccines: no BCG or other live bacterial vaccines.

Special groups.

• Children in endemic tuberculosis regions: defer BCG vaccination if a sibling had mycobacterial disease until the diagnosis is excluded.

Monitoring. Liver enzymes and full blood count monthly during mycobacterial treatment. Cultures monthly until negative. Visual acuity and colour vision monthly on ethambutol. Growth and weight at each visit.

Referral and escalation. Refer to paediatric or adult immunology and infectious diseases. Urgent for sepsis, persistent fever, bone pain, or disseminated disease.