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Original article
IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease

Abstract

Background: About 2% of childhood episodes of invasive pneumococcal disease (IPD) are recurrent, and most remain unexplained.

Objective: To report two cases of otherwise healthy, unrelated children with recurrent IPD as the only clinical infectious manifestation of an inherited disorder in nuclear factor-κB(NF-κB)-dependent immunity.

Results: One child carried two germline mutations in IRAK4, and had impaired cellular responses to interleukin (IL)1 receptor and toll-like receptor (TLR) stimulation. The other child carried a hemizygous mutation in NEMO, associated with a broader impairment of NF-κB activation, with an impaired cellular response to IL-1R, TLR and tumour necrosis factor receptor stimulation. The two patients shared a narrow clinical phenotype, associated with two related but different genotypes.

Conclusions: Otherwise healthy children with recurrent IPD should be explored for underlying primary immunodeficiencies affecting the IRAK4-dependent and NEMO-dependent signalling pathways.

  • CRP, C reactive protein
  • EDA, ectodermal dysplasia
  • IPD, invasive pneumococcal disese
  • PCR, polymerase chain reaction
  • PID, primary immunodeficiency
  • PMN, polymorphonuclear neutrophil
  • RT-PCR, reverse transcription PCR
  • TLR, toll like receptor
  • TNF, tumour necrosis factor

https://doi.org/10.1136/jmg.2006.044446

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