IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease.
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.
Ku
Cheng-Lung
CL
Laboratory of Human Genetics of Infectious Diseases, Necker Medical School, University of Paris René Descartes, Paris, France.
Picard
Capucine
C
Erdös
Melinda
M
Jeurissen
Axel
A
Bustamante
Jacinta
J
Puel
Anne
A
von Bernuth
Horst
H
Filipe-Santos
Orchidée
O
Chang
Huey-Hsuan
HH
Lawrence
Tatiana
T
Raes
Marc
M
Maródi
László
L
Bossuyt
Xavier
X
Casanova
Jean-Laurent
JL
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*
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