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
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Published Online First 1 September 2006
↵* Current address: Laboratory of Dendritic Cells Immunobiology, Institut Pasteur, Paris, France.
↵† These authors contributed equally to this study.
Funding: The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from the Schlumberger and BNP Paribas Foundations, the Deutsche Forschungsgemeinschaft (VO 995-1/1) and EU grant QLK2-CT-2002-00846. Grants from the Hungarian Research Fund (OTKA T 038095 and OTKA T 049017) and the European Commission (EURO-PID-NAS QLQ1-CT-2001-01395) to LM supported this work.
Competing interests: XB is a senior clinical investigator of the Fund for Scientific Research—Flanders. J-LC is an International Scholar of the Howard Hughes Medical Institute.