Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency.
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, lymphopenia with homeostatic proliferation, and lack of regulatory T cells are considered key factors in OS pathogenesis. We report 2 siblings presenting with 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.
Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany;
Sebastian
S
Fuchs
Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Freiburg, Germany;
Anne
A
Rensing-Ehl
Institute for Transfusion Medicine, University of Ulm, Ulm, Germany;
Ulrich
U
Pannicke
Institute for Transfusion Medicine, University of Ulm, Ulm, Germany;
Myriam R
MR
Lorenz
Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany;
Paul
P
Fisch
Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia;
Yogesh
Y
Jeelall
Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Freiburg, Germany; Center of Pediatric and Adolescent Medicine, University Medical Center and University of Freiburg, Freiburg, Germany;
Jan
J
Rohr
Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Freiburg, Germany; Center of Pediatric and Adolescent Medicine, University Medical Center and University of Freiburg, Freiburg, Germany;
Carsten
C
Speckmann
Center of Pediatric and Adolescent Medicine, University Medical Center and University of Freiburg, Freiburg, Germany;
Thomas
T
Vraetz
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; and.
Susan
S
Farmand
Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany;
Annette
A
Schmitt-Graeff
Center of Pediatric and Adolescent Medicine, University Medical Center and University of Freiburg, Freiburg, Germany;
Marcus
M
Krüger
Center of Pediatric and Adolescent Medicine, University Medical Center and University of Freiburg, Freiburg, Germany;
Brigitte
B
Strahm
Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Freiburg, Germany; Center of Pediatric and Adolescent Medicine, University Medical Center and University of Freiburg, Freiburg, Germany;
Philipp
P
Henneke
Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia;
Anselm
A
Enders
Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia;
Keisuke
K
Horikawa
Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia;
Christopher
C
Goodnow
Institute for Transfusion Medicine, University of Ulm, Ulm, Germany; Institute of Clinical Transfusion Medicine and Immungenetics Ulm, German Red Cross Blood Service Baden Württemberg-Hessen, Ulm, Germany.
Klaus
K
Schwarz
Center for Chronic Immunodeficiency (CCI), University Medical Center and University of Freiburg, Freiburg, Germany; Center of Pediatric and Adolescent Medicine, University Medical Center and University of Freiburg, Freiburg, Germany;
Stephan
S
Ehl
D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006162:Guanylate Cyclase / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007223:Infant; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D009154:Mutation; D060888:Real-Time Polymerase Chain Reaction; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology; D035781:Siblings; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D053468:CARD Signaling Adaptor Proteins; C426242:CARD11 protein, human; D006162:Guanylate Cyclase