IRAK-4 deficiency

Other Names: Interleukin receptor-associated kinase deficiency; IRAK4 deficiency

IRAK-4 deficiency is a condition that affects the immune system (primary immunodeficiency). It causes recurring severe infections by a type of bacteria called pyogenic bacteria. (Infection with pyogenic bacteria causes the production of pus.)

Epidemiology

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.

Cause

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 prevents the immune system from triggering 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.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

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 (leading to inflammation and 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. Although fever is a common reaction to bacterial infections, many people with IRAK-4 deficiency do not at first develop a high fever in response to these infections, even if the infection is severe.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Immunodeficiency(Decreased immune function)
• Neutropenia(Low blood neutrophil count)
• Recurrent staphylococcal infections
• Recurrent streptococcus pneumoniae infections

1%-4% of people have these symptoms

• Increased circulating IgE level
• Liver abscess
• Recurrent streptococcal infections

Diagnosis

IRAK-4 deficiency can be diagnosed by very specific immune tests to determine if a person has an impaired response to most Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) agonists. Genetic testing is also available for IRAK-4 deficiency and can be used to confirm the diagnosis.

Treatment

Treatment may include intravenous immunoglobulin therapy (IVIG), taking antibiotics before an infection develops, and vaccines. Althought the infections can be life-threatening, they tend to occur less often as a person gets older.

NIH genetic and rare disease info

• NIH info on IRAK-4 deficiency

IRAK-4 deficiency is a rare disease.