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

Cheng Lung Ku, Capucine Picard*, Melinda Erdõs, Axel Jeurissen, Jacinta Bustamante, Anne Puel, Horst Von Bernuth, Orchidée Filipe-Santos, Huey Hsuan Chang, Tatiana Lawrence, Marc Raes, László Maródi, Xavier Bossuyt, Jean Laurent Casanova

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

125 Scopus citations


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 interteukin (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.

Original languageEnglish
Pages (from-to)16-23
Number of pages8
JournalJournal of Medical Genetics
Issue number1
StatePublished - 01 2007
Externally publishedYes


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