Abstract for presentation at 11th International Congress of Human Genetics

IRAK-4 deficiency: A Tale of Two Sisters

  • Tiong Yang Tan, Genetic Health Services Victoria, Royal Children’s Hospital, Melbourne, Australia, Australia
  • Sam Mehr, Department of Immunology, Royal Children’s Hospital, Melbourne, Australia, Australia
  • Mac Gardner, Genetic Health Services Victoria, Royal Children’s Hospital, Melbourne, Australia, Australia
  • Mimi Tang, Department of Immunology, Royal Children’s Hospital, Melbourne, Australia, Australia
  • Joanne Smart, Department of Immunology, Royal Children’s Hospital, Melbourne, Australia, Australia
  • Klaus Schwarz, The Institute for Clinical Transfusion Medicine and Immunogenetics, Universitiy of Ulm, Ulm, Germany, Germany
  • Stephan Ehl, Center for Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany, Germany

    • We report the case of two sisters in whom we made the posthumous diagnosis of a genetic cause for the invasive pneumococcal disease that had caused their deaths. Invasive pneumococcal infections associated with a reduced inflammatory response raise the possibility of a defect in the Nuclear Factor Kappa-B (NF-KB) pathway. NF-KB is an important inflammatory mediator, and is activated by a variety of stimuli such as cytokines and bacterial and viral particles. Interleukin-1 receptor associated kinase-4 (IRAK-4) is a molecule involved in the activation of the NF-KB pathway. Deficiency of IRAK-4 (OMIM#607676), caused by homozygous mutations in the IRAK-4 gene, has been recently described in children with recurrent infections and poor inflammatory response in whom all known primary immunodeficiencies were excluded. Only seven cases of IRAK-4 deficiency have been reported so far. We undertook post mortem molecular analysis in two sisters who had died of unrecognized invasive pneumococcal disease, and confirmed that they had both had homozygous mutations resulting in a stop codon in the IRAK-4 gene. Their consanguineous parents were heterozygous for the mutation. Previous cases of IRAK-4 deficiency are summarized.

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