MYD88 Deficiency

MyD88 deficiency is an autosomal recessive defect of Toll like receptor and IL-1 receptor signalling that causes life threatening invasive bacterial infection in early childhood. It resembles IRAK4 deficiency, with minimal fever and CRP elevation.

Pathophysiology. MyD88 is the adaptor that connects Toll like receptors (except TLR3) and IL-1 family receptors to IRAK4 and NF-kappa-B. Its loss silences the innate cytokine response to bacteria, so the inflammatory signals that normally warn of infection are missing.

It is very rare. The first invasive infection usually occurs in infancy or the first years.

Adaptive immunity is normal, and the risk of invasive infection falls from adolescence.

• Invasive pneumococcal disease: meningitis, sepsis, pneumonia, arthritis
• Staphylococcus aureus skin and deep abscesses, osteomyelitis
• Pseudomonas aeruginosa infection
• Deep infection with little or no fever and a low CRP
• Cold abscesses and omphalitis in infancy
• Death in early childhood in a large share without prophylaxis

• CRP and temperature can be falsely low during infection.
• Blood count, immunoglobulins, lymphocyte subsets and specific antibody responses: usually normal.
• Functional TLR and IL-1 assay: absent IL-6 and TNF response in whole blood or monocytes after TLR agonist and IL-1 beta stimulation.
• MyD88 protein expression by immunoblot or flow cytometry, and genetic testing of MYD88, with parental testing.
• Microbiology: cultures, and imaging for deep infection.

Differential diagnosis.

• IRAK4 deficiency
• NEMO deficiency and other NF-kappa-B defects
• Complement C3 deficiency and other complement deficiencies
• Splenic hypofunction
• STAT3 loss-of-function (hyper IgE) syndrome
• X-linked agammaglobulinaemia

• Prophylactic antibiotics from diagnosis to at least late adolescence: phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily).
• Immunoglobulin replacement for recurrent invasive infection despite prophylaxis, or proven poor antibody function: intravenous immunoglobulin 400 to 600 mg/kg every 3 to 4 weeks, or subcutaneous immunoglobulin 100 to 150 mg/kg weekly, with a trough IgG of at least 6 g/L, usually 7 to 9 g/L.
• Early treatment of any suspected infection without waiting for fever or a raised CRP: after blood cultures, ceftriaxone 2 g intravenously once daily (children 50 to 80 mg/kg, maximum 2 g), then adjust to cultures. Provide an emergency letter and a low threshold for admission.
• Vaccination: all routine inactivated vaccines, including pneumococcal conjugate vaccine then pneumococcal polysaccharide vaccine at least 8 weeks later, Haemophilus influenzae type b vaccine and meningococcal vaccines. Live vaccines are safe since cellular immunity is intact.
• Abscesses: drainage and culture directed antibiotics.
• Haematopoietic stem cell transplantation is not used routinely because the risk falls with age.

Special groups.

• Infants under 2 years: highest risk of fatal infection, so admit early with any illness.
• Families: genetic counselling, since each pregnancy has a 1 in 4 risk.

Monitoring. Review every 3 months in the first years and then every 6 months. Immunoglobulins and vaccine titres yearly. Trough IgG every 3 to 6 months on replacement.

Referral and escalation. Refer to paediatric immunology. Emergency for any febrile or unwell child with this diagnosis, regardless of CRP.