IRAK4 deficiency

IRAK4 deficiency is a primary immunodeficiency condition caused by pathogenic genetic variants in IRAK4, a signalling protein in the Toll-like receptor (TLR) pathway. Affected patients present with severe, life-threatening bacterial infections in the absence of fever, owing to impaired recognition and response to pathogen-associated molecular patterns. This results in defective cytokine production, particularly reducing levels of inflammatory cytokines.

Patients with IRAK4 deficiency typically present in early childhood with recurrent, severe bacterial infections from:

• Streptococcus pneumoniae;
• Staphylococcus aureus; and
• Pseudomonas aeruginosa.

Infections typically affect the respiratory tract, skin and meninges.

Characteristically, patients do not develop fever during infective episodes. This can delay diagnosis and treatment, leading to infection-related complications such as bronchiectasis and neurological deficit.

IRAK4 deficiency is caused by biallelic pathogenic genetic variants in the IRAK4 gene. The gene encodes IRAK4, a signal transduction molecule in the TLR pathway.

Reported pathogenic variants include nonsense, frameshift and splice site variants that result in truncated, non-functional or absent IRAK-4 protein, leading to impaired signalling in the TLR pathway.

Biallelic complete loss-of-function variants tend to present earlier in life with a more severe phenotype, although variability has been reported between and within affected families.

Diagnosis should be considered in patients with recurrent or severe infections from early childhood with absent or minimal fever. There may be a family history of similar episodes.

Laboratory tests do not show overt immunological deficit, but raised white cell count may be indicative of infection in the absence of fever or raised acute phase reactants.

CD62 ligand (L-selectin) shedding assay measures the ability of neutrophils to shed CD62L in response to specific ligands. Patients with IRAK4 deficiency or other defects in this pathway will show impaired CD62L shedding.

Definitive diagnosis occurs through the identification of pathogenic genetic variants.

The European Society for Immunodeficiencies diagnostic criteria are listed below.

• Recurrent and/or severe infections; and at least two of the following:
  • normal T and B cell responses;
  • mild inflammatory reaction;
  • polysaccharide-specific serum antibodies deficiency; and/or
  • anhidrotic ectodermal dysplasia features (in some patients).

For information about testing, see ‘Infant or child presenting with severe, recurrent, persistent and/or unusual infections‘.

IRAK4 deficiency may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

IRAK4 deficiency is a rare primary immunodeficiency caused by biallelic pathogenic genetic variants in the IRAK4 gene. It is inherited in an autosomal recessive pattern.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Note that de novo variants may also arise, and that heterozygous carriers are typically asymptomatic.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1-in-4 (25%) chance of the child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1-in-2 (50%) chance of the child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1-in-4 (25%) chance of the child inheriting both normal copies and being neither affected nor a carrier.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

The main goal of treatment is to prevent severe infections and infection-related complications. This includes:

• antibiotic prophylaxis: patients may require life-long antibiotics, but may be able to use them intermittently in adulthood, when infection frequency is reduced;
• immunoglobulin replacement therapy, which may be considered in patients with recurrent infections in whom prophylaxis is ineffective or not taken;
• the avoidance of live vaccinations in some patients, though other vaccinations can be given, along with annual influenza and coronavirus vaccinations; and
• an infection management plan: patients require low treatment threshold, emergency action plans and monitoring of white cell count and IL-6 levels if requiring hospital assessment.

IRAK4 deficiency may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• European Society for Immunodeficiencies: Diagnostic criteria
• OMIM: 607676 Immunodeficiency 67

References:

• Picard C, von Bernuth H, Ghandil P and others. ‘Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency‘. Medicine 2010: volume 89, issue 6, pages 403–425. DOI: 10.1097/MD.0b013e3181fd8ec3
• Picard C, von Bernuth H, Ku CL and others. ‘Inherited human IRAK-4 deficiency: an update‘. Immunologic Research 2007: volume 38, issue 1–3, pages 347–352. DOI: 10.1007/s12026-007-0006-2

For patients

• Immunodeficiency UK