Fuchs, SebastianRensing-Ehl, A.Pannicke, UlrichLorenz, Myriam R.Fisch, PaulJeelall, YogeshrajRohr, JanSpeckmann, CarstenVraetz, TFramand, SusanSchmitt-Graeff, AnnetteKruger, MarcusStrahm, BrigitteHenneke, PhilippEnders, AnselmHorikawa, KeisukeGoodnow, ChristopherSchwarz, KlausEhl, Stephan2016-02-240006-4971http://hdl.handle.net/1885/98708Omenn 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).201510.1182/blood-2015-03-6313742016-02-24