ORIGINAL ARTICLE

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

Cheng-Lung Ku¹, Capucine Picard¹, Melinda Erdös², Axel Jeurissen³, Jacinta Bustamante¹, Anne Puel¹, Horst von Bernuth¹, Orchidée Filipe-Santos¹, Huey-Hsuan Chang^1,*, Tatiana Lawrence¹, Marc Raes^4,, László Maródi^2,, Xavier Bossuyt^3,, Jean-Laurent Casanova^1,

¹ Laboratory of Human Genetics of Infectious Diseases, Necker Medical School, University of Paris René Descartes, Paris, France
² Department of Infectology and Paediatric Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary
³ Experimental Laboratory Medicine, University Hospital Leuven, Leuven, Belgium
⁴ Department of Paediatrics, Virga Jesse Hospital, Hasselt, Belgium

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

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-B(NF-B)-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-B 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.

Abbreviations: 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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