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Conditions

MYD88 deficiency

MYD88 deficiency is a rare genetic condition caused by defects in the innate immune Toll-like receptor pathway. It features increased susceptibility to bacterial infections, and presents with serious infections in the absence of fever.

Overview

MYD88 deficiency is a very rare primary immunodeficiency condition that is caused by defects in MYD88, a signalling molecule in the Toll-like receptor (TLR) pathway. This is a critical innate immune pathway involved in the detection of pathogens, in which dysfunction causes defective cytokine production and susceptibility to bacterial infections. It is characterised by recurrent severe, invasive infections in the absence of fever. The latter can delay diagnosis and treatment, resulting in high morbidity and mortality in affected patients.

Clinical features

Patients with MYD88 deficiency typically present in early childhood with recurrent severe bacterial infections from:

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

The infections typically affect the respiratory tract, skin and meninges. Characteristically, patients do not develop fever during infective episodes, which can delay diagnosis and treatment, and lead to infection-related complications, such as bronchiectasis and neurological deficit. MYD88 deficiency has a high mortality rate in early childhood.

Genomics

MYD88 deficiency is caused by biallelic pathogenic variants in the MYD88 gene. The gene encodes MYD88, a signal transduction molecule in the TLR pathway.

Biallelic protein-truncating variants, such as nonsense or frameshift variants, cause complete loss of function and tend to present within the first six months of life with a more severe phenotype, although variability has been reported between and within affected families.

The most commonly reported variant is L93P, which occurs in the N-terminal death domain, required for TLR interaction. An MYD88 founder variant has been reported in the Roma population in Europe.

Diagnosis

Diagnosis of MYD88 deficiency 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 MYD88 deficiency or other defects in this pathway will show impaired or absent CD62L shedding. TLR3 signalling is also absent in MYD88 deficiency.

Definitive diagnosis occurs through identification of pathogenic genetic variants.

The European Society for Immunodeficiencies diagnostic criteria for MYD88 deficiency is outlined 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 with severe, recurrent, persistent and/or unusual infections‘.

MYD88 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.

Inheritance and genetic counselling

MYD88 deficiency is a rare primary immunodeficiency caused by biallelic pathogenic genetic variants in the MYD88 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 will be 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.

Management

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 which prophylaxis is ineffective or not taken;
  • the avoidance of live vaccinations in some patients, though other vaccinations can be given, including 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 level if requiring hospital assessment.

MYD88 deficiency may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 01/08/2025
  • Next review due: 01/08/2027
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay