Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

Sebastian Fuchs, Anne Rensing-Ehl, Ulrich Pannicke, Myriam R. Lorenz, Paul Fisch, Yogesh Jeelall, Jan Rohr, Carsten Speckmann, Thomas Vraetz, Susan Farmand, Annette Schmitt-Graeff, Marcus Krüger, Brigitte Strahm, Philipp Henneke, Anselm Enders, Keisuke Horikawa, Christopher Goodnow, Klaus Schwarz, Stephan Ehl

    Research output: Contribution to journalArticlepeer-review

    36 Citations (Scopus)


    Omenn syndrome (OS) is a severe immunodeficiency associated with erythroderma, lymphoproliferation, elevated IgE, and hyperactive oligoclonal T cells. A restricted T-cell repertoire caused by defective thymic T-cell development and selection, lymphopeniawith homeostatic proliferation, and lack of regulatory T cells are considered key factors inOS pathogenesis.Wereport 2 siblings presentingwith cytomegalovirus (CMV) and Pneumocystis jirovecii infections and recurrent sepsis; one developed all clinical features of OS. Both carried homozygous germline mutations in CARD11 (p.Cys150∗), impairing NF-κB signaling and IL-2 production. A somatic second-site mutation reverting the stop codon to a missense mutation (p.Cys150Leu) was detected in tissue-infiltrating T cells of the OS patient. Expression of p.Cys150Leu in CARD11-deficient T cells largely reconstituted NF-κB signaling. The reversion likely occurred in a prethymic T-cell precursor, leading to a chimeric T-cell repertoire. We speculate that in our patient the functional advantage of the revertant T cells in the context of persistent CMV infection, combined with lack of regulatory T cells, may have been sufficient to favor OS. This first observation of OS in a patient with a T-cell activation defect suggests that severely defective T-cell development or homeostatic proliferation in a lymphopenic environment are not required for this severe immunopathology. (Blood. 2015;126(14):1658-1669).

    Original languageEnglish
    Pages (from-to)1658-1669
    Number of pages12
    Issue number14
    Publication statusPublished - 1 Oct 2015


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