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Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency
Interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency is an immunodeficiency associated with increased susceptibility to invasive infections caused by pyogenic bacteria.
ORPHA:70592Classification level: Disorder
It has been described in less than 15 patients from eight families with onset occurring during childhood.
The most common recurrent infections in these patients were caused by Streptococcus pneumoniae or Staphylococcus aureus, leading to a range of clinical manifestations such as pneumonia, septic arthritis, cellulitis, osteomyelitis, otitis media, meningitis and sinusitis. In contrast, the patients appeared to be resistant to infection caused by most other bacteria, parasites and viruses but fungal infections have been reported. Although routine immunological evaluations generally gave normal results, the patients displayed reduced inflammatory responses and neutropenia during infectious episodes.
IRAK-4 deficiency is caused by mutations in the IRAK-4 gene (chromosome 12q12). IRAK-4 is a member of the IRAK protein kinase family and is involved in the toll-interleukin 1 (TIR) signalling pathway.
IRAK-4 deficiency should be suspected in patients with a failure to sustain antibody responses and recurrent pyogenic bacterial infections. Diagnosis can be confirmed by detection of IRAK-4 gene mutations and through characterisation of the reduced response of blood cells and fibroblasts to stimulation with a large range of interleukin-1 receptor (IL-1R) and toll-like receptor (TLR) ligands and whole bacteria (S. aureus, Escherichia coli and Mycobacterium tuberculosis).
Management and treatment
Intravenous immunoglobulin therapy (IVIG), antibiotic prophylaxis and administration of the heptavalent pneumococcal-conjugated vaccine have provided successful results in some cases.
The prognosis for most patients is good, with infections becoming less frequent with age. However, bacterial meningitis has lead to death in a few cases, particularly when it occurred during infancy.