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J Med Genet 44:16-23 doi:10.1136/jmg.2006.044446
  • Original article

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

  1. Cheng-Lung Ku1,
  2. Capucine Picard1,
  3. Melinda Erdös2,
  4. Axel Jeurissen3,
  5. Jacinta Bustamante1,
  6. Anne Puel1,
  7. Horst von Bernuth1,
  8. Orchidée Filipe-Santos1,
  9. Huey-Hsuan Chang1,*,
  10. Tatiana Lawrence1,
  11. Marc Raes4,,
  12. László Maródi2,,
  13. Xavier Bossuyt3,,
  14. Jean-Laurent Casanova1,
  1. 1Laboratory of Human Genetics of Infectious Diseases, Necker Medical School, University of Paris René Descartes, Paris, France
  2. 2Department of Infectology and Paediatric Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary
  3. 3Experimental Laboratory Medicine, University Hospital Leuven, Leuven, Belgium
  4. 4Department of Paediatrics, Virga Jesse Hospital, Hasselt, Belgium
  1. Correspondence to:
 Capucine Picard
 MD, PhD, Laboratory of Human Genetics of Infectious Diseases, Necker Medical School, University of Paris René Descartes-INSERM U550, 156 rue de vaugirard, 75015 Paris, France;picardc{at}necker.fr
  • Received 2 June 2006
  • Accepted 17 August 2006
  • Revised 11 August 2006
  • Published Online First 1 September 2006

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.

Footnotes

  • 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.