What are the other Names for this Condition? (Also known as/Synonyms)

• Interleukin Receptor-Associated Kinase Deficiency
• IRAK4 Deficiency Disorder

What is IRAK-4 Deficiency Disorder? (Definition/Background Information)

• IRAK-4 Deficiency Disorder is a condition that affects the immune system (primary immunodeficiency). It causes recurring severe infections by a type of bacteria called pyogenic bacteria
• Individuals with IRAK-4 Deficiency Disorder seem to be particularly susceptible to infections caused by bacteria called Streptococcus pneumoniae
• The deficiency is caused by mutations in the IRAK4 gene and is inherited in an autosomal recessive pattern
• The treatment of IRAK-4 Deficiency Disorder may include intravenous immunoglobulin therapy (IVIG), taking antibiotics before an infection develops, and vaccines
• Although the infections can be life-threatening, they tend to occur less often as a person gets older

(Source: IRAK-4 Deficiency Disorder; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets IRAK-4 Deficiency Disorder? (Age and Sex Distribution)

• IRAK-4 Deficiency is an extremely rare congenital disorder, with only about 15 individuals (across 8 families) reported in the medical history 
• The presentation of symptoms typically occurs in childhood
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for IRAK-4 Deficiency Disorder? (Predisposing Factors)

• A positive family history may be an important risk factor, since IRAK-4 Deficiency Disorder can be inherited
• Currently, no other risk factors have been clearly identified for this deficiency disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of IRAK-4 Deficiency Disorder? (Etiology)

IRAK-4 Deficiency is caused by mutation(s) in the IRAK-4 gene, which codes for the enzyme interleukin-1 receptor-associated kinase 4.

• The deficiency of the enzyme makes an affected individual susceptible to bacterial infections, leading to the signs and symptoms of the condition
• The pathogenic bacteria may include Streptococcus pneumoniae, Staphylococcus aureus and Psuedomonas aeruginosa
• The IRAK-4 gene mutations causing the deficiency of this enzyme are inherited in an autosomal recessive manner

Autosomal recessive pattern of inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of IRAK-4 Deficiency Disorder?

The signs and symptoms of IRAK-4 Deficiency Disorder may include:

• Neutropenia
• Recurrent staphylococcal infections
• Recurrent streptococcus pneumoniae infections

(Source: IRAK-4 Deficiency Disorder; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is IRAK-4 Deficiency Disorder Diagnosed?

IRAK-4 Deficiency Disorder is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests, which may include diminished response of an affected individual’s blood cells and fibroblasts with interleukin-receptor or toll-like receptor ligands, as well as whole bacterial cells
• Imaging studies
• Biopsy studies, if necessary
• Molecular genetic testing to check for or confirm causative IRAK-4 gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of IRAK-4 Deficiency Disorder?

The complications of IRAK-4 Deficiency Disorder may include:

• Pneumonia
• Bacterial meningitis
• Septic arthritis
• Osteomyelitis, causing severe pain

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is IRAK-4 Deficiency Disorder Treated?

There is no cure for IRAK-4 Deficiency Disorder, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. The treatment methods may involve:

• Vaccination with pneumococcal conjugated vaccine
• Prophylactic antibiotics
• Intravenous immunoglobulin therapy

How can IRAK-4 Deficiency Disorder be Prevented?

Currently, IRAK-4 Deficiency Disorder may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of IRAK-4 Deficiency Disorder? (Outcomes/Resolutions)

• The prognosis of IRAK-4 Deficiency Disorder is good in most cases, since the frequency of infections decreases with age
• However, severe complications, such as meningitis or pneumonia, especially in infants, can be serious and even fatal

Additional and Relevant Useful Information for IRAK-4 Deficiency Disorder:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/