Reviewed November 2011
What is IRAK-4 deficiency?
IRAK-4 deficiency is an inherited disorder of the immune system (primary immunodeficiency). This immunodeficiency leads to recurrent infections by a subset of bacteria known as pyogenic bacteria but not by other infectious agents. (Infection with pyogenic bacteria causes the production of pus.) The most common infections in IRAK-4 deficiency are caused by the Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa bacteria. Most people with this condition have their first bacterial infection before age 2, and the infections can be life-threatening in infancy and childhood. Infections become less frequent with age.
Most people with IRAK-4 deficiency have invasive bacterial infections, which can involve the blood (septicemia), the membrane covering the brain and spinal cord (meningitis), or the joints (arthritis). Invasive infections can also cause areas of tissue breakdown and pus production (abscesses) on internal organs. In addition, affected individuals can have localized infections of the upper respiratory tract, skin, or eyes. Many people with IRAK-4 deficiency do not develop a high fever in response to these bacterial infections, even if the infection is severe.
How common is IRAK-4 deficiency?
IRAK-4 deficiency is a very rare condition, although the exact prevalence is unknown. At least 49 individuals with this condition have been described in the scientific literature.
What genes are related to IRAK-4 deficiency?
IRAK-4 deficiency is caused by mutations in the IRAK4 gene, which provides instructions for making a protein that plays an important role in stimulating the immune system to respond to infection. The IRAK-4 protein is part of a signaling pathway that is involved in early recognition of foreign invaders (pathogens) and the initiation of inflammation to fight infection. This signaling pathway is part of the innate immune response, which is the body's early, nonspecific response to pathogens.
Mutations in the IRAK4 gene lead to the production of a nonfunctional protein or no protein at all. The loss of functional IRAK-4 protein blocks the initiation of inflammation in response to pathogens that would normally help fight the infections. Because the early immune response is insufficient, bacterial infections occur often and become severe and invasive.
Changes in this gene are associated with IRAK-4 deficiency.
How do people inherit IRAK-4 deficiency?
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Where can I find information about diagnosis or management of IRAK-4 deficiency?
These resources address the diagnosis or management of IRAK-4 deficiency and may include treatment providers.
- Eunice Kennedy Shriver National Institute of Child Health and Human Development: Primary Immunodeficiency: Diagnosing PI (http://www.nichd.nih.gov/publications/pubs/Pages/primary_immuno.aspx)
- Genetic Testing Registry: IRAK4 deficiency (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1843256)
You might also find information on the diagnosis or management of IRAK-4 deficiency in
Educational resources (http://www.ghr.nlm.nih.gov/condition/irak-4-deficiency/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/irak-4-deficiency/show/Patient+support).
General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook.
Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).
To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.
Where can I find additional information about IRAK-4 deficiency?
You may find the following resources about IRAK-4 deficiency helpful. These materials are written for the general public.
MedlinePlus - Health information
- Encyclopedia: Immune Response (http://www.nlm.nih.gov/medlineplus/ency/article/000821.htm)
- Encyclopedia: Meningitis (http://www.nlm.nih.gov/medlineplus/ency/article/000680.htm)
- Encyclopedia: Septicemia (http://www.nlm.nih.gov/medlineplus/ency/article/001355.htm)
- Health Topic: Immune System and Disorders (http://www.nlm.nih.gov/medlineplus/immunesystemanddisorders.html)
- Genetic and Rare Diseases Information Center - Information about genetic conditions and rare diseases (http://rarediseases.info.nih.gov/gard/10311/resources/resources/1)
- Additional NIH Resources - National Institutes of Health
Eunice Kennedy Shriver National Institute of Child Health and Human Development: Primary Immunodeficiency (http://www.nichd.nih.gov/publications/pubs/pages/primary_immuno.aspx)
- Educational resources - Information pages
Orphanet: Immunodeficiency Due to Interleukin-1 Receptor-Associated Kinase-4 Deficiency (http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=10963&Disease_Disease_Search_diseaseGroup=IRAK4-deficiency&Disease_Disease_Search_diseaseType=Pat&Disease%28s%29/group%20of%20diseases=Immunodeficiency-due-to-interleukin-1-receptor-associated-kinase-4-deficiency--IRAK4-deficiency-&title=Immunodeficiency-due-to-interleukin-1-receptor-associated-kinase-4-deficiency--IRAK4-deficiency-&search=Disease_Search_Simple)
Patient support - For patients and families
- Family Village: Immune Deficiencies & Disorders (http://www.familyvillage.wisc.edu/lib_immu.htm)
- Immune Deficiency Foundation (http://primaryimmune.org/)
- International Patient Organization for Primary Immunodeficiencies (http://www.ipopi.org/)
You may also be interested in these resources, which are designed for healthcare professionals and researchers.
Genetic Testing Registry - Repository of genetic test information
- Genetic Testing Registry: IRAK4 deficiency (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1843256)
- PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/pubmed?term=((irak4%20deficiency%5BTIAB%5D)%20OR%20(IRAK-4%20deficiency%5BTIAB%5D))%20AND%20english%5Bla%5D%20AND%20human%5Bmh%5D)
- OMIM - Genetic disorder catalog (http://omim.org/entry/607676)
What other names do people use for IRAK-4 deficiency?
For more information about naming genetic conditions, see the Genetics Home Reference
Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide)
How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.
What if I still have specific questions about IRAK-4 deficiency?
Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).
What glossary definitions help with understanding IRAK-4 deficiency?
autosomal recessive ;
immune response ;
immune system ;
You may find definitions for these and many other terms in the Genetics Home Reference
- Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, Chrabieh M, Issekutz AC, Cunningham CK, Gallin J, Holland SM, Roifman C, Ehl S, Smart J, Tang M, Barrat FJ, Levy O, McDonald D, Day-Good NK, Miller R, Takada H, Hara T, Al-Hajjar S, Al-Ghonaium A, Speert D, Sanlaville D, Li X, Geissmann F, Vivier E, Maródi L, Garty BZ, Chapel H, Rodriguez-Gallego C, Bossuyt X, Abel L, Puel A, Casanova JL. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med. 2007 Oct 1;204(10):2407-22. Epub 2007 Sep 24. (http://www.ncbi.nlm.nih.gov/pubmed/17893200?dopt=Abstract)
- Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med. 2003 Aug 18;198(4):521-31. (http://www.ncbi.nlm.nih.gov/pubmed/12925671?dopt=Abstract)
- Picard C, Casanova JL, Puel A. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IκBα deficiency. Clin Microbiol Rev. 2011 Jul;24(3):490-7. doi: 10.1128/CMR.00001-11. Review. (http://www.ncbi.nlm.nih.gov/pubmed/21734245?dopt=Abstract)
- Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A, Casanova JL. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003 Mar 28;299(5615):2076-9. Epub 2003 Mar 13. (http://www.ncbi.nlm.nih.gov/pubmed/12637671?dopt=Abstract)
- Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, McDonald D, Geha RS, Takada H, Krause JC, Creech CB, Ku CL, Ehl S, Maródi L, Al-Muhsen S, Al-Hajjar S, Al-Ghonaium A, Day-Good NK, Holland SM, Gallin JI, Chapel H, Speert DP, Rodriguez-Gallego C, Colino E, Garty BZ, Roifman C, Hara T, Yoshikawa H, Nonoyama S, Domachowske J, Issekutz AC, Tang M, Smart J, Zitnik SE, Hoarau C, Kumararatne DS, Thrasher AJ, Davies EG, Bethune C, Sirvent N, de Ricaud D, Camcioglu Y, Vasconcelos J, Guedes M, Vitor AB, Rodrigo C, Almazán F, Méndez M, Aróstegui JI, Alsina L, Fortuny C, Reichenbach J, Verbsky JW, Bossuyt X, Doffinger R, Abel L, Puel A, Casanova JL. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore). 2010 Nov;89(6):403-25. doi: 10.1097/MD.0b013e3181fd8ec3. (http://www.ncbi.nlm.nih.gov/pubmed/21057262?dopt=Abstract)
The resources on this site should not be used as a substitute for
professional medical care or advice. Users seeking information about
a personal genetic disease, syndrome, or condition should consult with a qualified
See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.