Bacterial susceptibility due to TLR signaling pathway deficiency (ORPHA:183713)
Pyogenic bacterial infection due to MyD88 deficiency is a primary immunodeficiency characterized by increased susceptibility to pyogenic bacterial infections, including invasive pneumococcal, invasive staphylococcal and pseudomonas disease.
Epidemiology
Prevalence is unknown. Only 24 cases have been reported.
Clinical description
The disease presents in childhood with recurrent, life-threatening, pyogenic bacterial infections caused by Streptococcus pneumoniae, Staphylococcus aureus or Pseudomonas aeruginosa. Patients are normally resistant to most other agents. This predisposition to life-threatening infections seems transient and lasts during the first 10 years of life in the cases reported so far. Acute phase responses seen in invasive infections such as elevated temperature and C-reactive protein (CrP) levels may be lower or absent.
Etiology
MyD88 deficiency, resulting from mutations in the MYD88 gene (3p22-3p21.3), generally abolishes the cytokine responses of the blood cells.
Diagnostic methods
MyD88 deficiency should be suspected in patients with recurrent pyogenic bacterial infections. Diagnosis can be suspected if whole blood cells do not produce inflammatory cytokines upon activation with IL-1beta or Toll-like receptor agonists. Diagnosis can be confirmed by observation of mutations in the MYD88 gene.
Differential diagnosis
Differential diagnoses include interleukin-1 receptor associated kinase-4 (IRAK4) deficiency (see this term), which can be ruled out by the absence of mutations in the IRAK4 gene, NF-kappaB essential modulator (NEMO) deficiency and inhibitor of NFkappaB essential modulator (IkappaB-alpha) deficiency (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible by trophoblast biopsy when the mutation is identified in the family.
Genetic counseling
Transmission is autosomal recessive and the disease has been observed in consanguineous and nonconsanguineous families. Genetic counseling is available.
Management and treatment
Treatment is based on prophylactic antibiotic therapy to prevent infections. Additional IgG substitution may be considered, in particular for patients with impaired antibody responses to polysaccharides. The most important advice for the families and physicians of MyD88-deficient patients is to initiate empiric parenteral antibiotic treatment against Streptococcus pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa, as soon as an infection is suspected or if the patient develops a moderate fever, without taking inflammatory parameters into account, as patients may die from rapid invasive bacterial infection despite appropriate prophylaxis. Secondary adaptation of antibiotic treatment should be done once the causal bacterium has been documented.
Prognosis
Prognosis in infancy and early childhood is poor, in particular if the disease is not known to parents and physicians. With appropriate prophylactic antibiotic treatment, the prognosis for most patients improves, with infections becoming less frequent with age.

                            Last update: 
                            May 2012


                            - Expert reviewer(s): 
                            Pr Jean-Laurent CASANOVA  - Pr Capucine PICARD  - Pr Horst VON BERNUTH