Indications for Testing

• Child with recurrent infections after more common immunodeficiencies have been ruled out

Laboratory Testing

• Screen for more common immunodeficiencies
  • Immunoglobulin testing
  • Complement testing
  • Cell-mediated immunity testing
  • Neutrophil function testing
  • See Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children, and Immunodeficiency Evaluation for Chronic Infections in Infants and Children algorithms
• If hypogammaglobulinemia is present, consider ectodermal dysplasia
• If all above screening tests are normal, order IRAK4 and TLR function testing
  • If IRAK4  and TLR are negative, consider other genetic types (MYD88, TLR3, UNC93B1)

Differential Diagnosis

• Neutropenic disorders
• Chronic granulomatous disease
• Chédiak-Higashi
• Ectodermal dysplasia
• Job syndrome
• Leukocyte adhesion deficiency

Immunodeficiencies associated with impaired innate immunity (nuclear factor kappa-B signaling) include disruptions to signaling pathways for IRAK4, MYD88, and TLR3 and may be associated with recurrent pyogenic bacterial infections.

Epidemiology

• Incidence
  • IRAK4 – rare; <30 affected individuals worldwide as of 2006
  • MYD88 – rare
  • TLR3 – 1/250,000

Inheritance

• Autosomal recessive inheritance; all are familial syndromes

Pathophysiology

• Toll-like receptor (TLR) activation involves adapter genes MYD88 and IRAK4
  • IRAK4 – plays an essential role in TLR and IL1A receptor-mediated signaling
  • TLR3 triggers activation of IL1A
• Broad defect in nuclear factor kappa B signaling with impaired TLR function
• TLRs function as recognition factors for microbial and viral ligands, enabling innate immunity to induce appropriate cytokine pathways (by stimulating TNFα, IL-1ß and IL-6) to prevent infection

Clinical Presentation

• Severe recurrent infections occur in deficiency
  • IRAK4/MYD88
    • Normal appearance
    • Particular susceptibility to Streptococcus pneumoniae, Shigella sonnei and Staphylococcus aureus
      • All invasive infections occur before age 14

  • TLR3, UNC93B1 – selective susceptibility to herpes encephalitis 

Tests generally appear in the order most useful for common clinical situations

General

• Hernandez M, Bastian JF. Immunodeficiency in childhood. Curr Allergy Asthma Rep. 2006; 6 (6) :468-474.PubMed
• Immune Deficiency Foundation. [Accessed: 27 Apr 2009] 
• Ku CL, Yang K, Bustamante J, Puel A, von Bernuth H, Santos OF, Lawrence T, Chang HH, Al-Mousa H, Picard C, Casanova JL. Inherited disorders of human Toll-like receptor signaling: immunological implications. Immunol Rev. 2005; 203 :10-20.PubMed
• Picard C, Puel A, Bustamante J, Ku CL, Casanova JL. Primary immunodeficiencies associated with pneumococcal disease. Curr Opin Allergy Clin Immunol. 2003; 3 (6) :451-459.PubMed
• Picard C, von Bernuth H, Ku CL, Yang K, Puel A, Casanova JL. Inherited human IRAK-4 deficiency: an update. Immunol Res. 2007; 38 (1-3) :347-352.PubMed
• Puel A, Picard C, Ku CL, Smahi A, Casanova JL. Inherited disorders of NF-kappaB-mediated immunity in man. Curr Opin Immunol. 2004; 16 (1) :34-41.PubMed
• Suzuki N, Saito T. IRAK-4--a shared NF-kappaB activator in innate and acquired immunity. Trends Immunol. 2006; 27 (12) :566-572.PubMed
• Yavuz I, Baskan Z, Ulku R, Dulgergil TC, Dari O, Ece A, Yavuz Y, Dari KO. Ectodermal dysplasia: Retrospective study of fifteen cases. Arch Med Res. 2006; 37 (3) :403-409.PubMed

Bruton Agammaglobulinemia
Chronic Granulomatous Disease
Common Variable Immune Deficiency
Complement Deficiency
Immunoglobulin Disorders
Leukocyte Adhesion Deficiency
Neutrophil Disorders
Severe Combined Immunodeficiencies
T-Cell Deficiency Disorders, Inherited