title: 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-kappaB(NF-kappaB)-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-kappaB 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.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Medical School, University of Paris René Descartes, Paris, France.
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Ku
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Melinda
authors.initials: M
authors.lastname: Erdös
authors.forename: Axel
authors.initials: A
authors.lastname: Jeurissen
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Horst
authors.initials: H
authors.lastname: von Bernuth
authors.forename: Orchidée
authors.initials: O
authors.lastname: Filipe-Santos
authors.forename: Huey-Hsuan
authors.initials: HH
authors.lastname: Chang
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lawrence
authors.forename: Marc
authors.initials: M
authors.lastname: Raes
authors.forename: László
authors.initials: L
authors.lastname: Maródi
authors.forename: Xavier
authors.initials: X
authors.lastname: Bossuyt
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000917:Antibody Formation; D002443:Ceftriaxone / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D018076:DNA, Complementary; D005091:Exons; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D007375:Interleukin-1 / Q000276:immunology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000378:metabolism; D007438:Introns; D008297:Male; D016328:NF-kappa B / Q000276:immunology; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D022242:Pneumococcal Vaccines / Q000276:immunology; D016133:Polymerase Chain Reaction; D012008:Recurrence; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000737:chemistry / Q000276:immunology*
chemical_list: D000900:Anti-Bacterial Agents; D018076:DNA, Complementary; C491731:IKBKG protein, human; D007375:Interleukin-1; D016328:NF-kappa B; D022242:Pneumococcal Vaccines; D002443:Ceftriaxone; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051550:I-kappa B Kinase