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Schwab, Charlotte; Gabrysch, Annemarie; Olbrich, Peter; Patino, Virginia; Warnatz, Klaus; Wolff, Daniel; Hoshino, Akihiro; Kobayashi, Masao; Imai, Kohsuke; Takagi, Masatoshi; Dybedal, Ingunn; Haddock, Jamanda A.; Sansom, David M.; Lucena, Jose M.; Seidl, Maximilian; Schmitt-Graeff, Annette; Reiser, Veronika; Emmerich, Florian; Frede, Natalie; Bulashevska, Alla; Salzer, Ulrich; Schubert, Desiree; Hayakawa, Seiichi; Okada, Satoshi; Kanariou, Maria; Kucuk, Zeynep Yesim; Chapdelaine, Hugo; Petruzelkova, Lenka; Sumnik, Zdenek; Sediva, Anna; Slatter, Mary; Arkwright, Peter D.; Cant, Andrew; Lorenz, Hanns-Martin; Giese, Thomas; Lougaris, Vassilios; Plebani, Alessandro; Price, Christina; Sullivan, Kathleen E.; Moutschen, Michel; Litzman, Jiri; Freiberger, Tomas; Veerdonk, Frank L. van de; Recher, Mike; Albert, Michael H.; Hauck, Fabian; Seneviratne, Suranjith; Schmid, Jana Pachlopnik; Kolios, Antonios; Unglik, Gary; Klemann, Christian; Speckmann, Carsten; Ehl, Stephan; Leichtner, Alan; Blumberg, Richard; Franke, Andre; Snapper, Scott; Zeissig, Sebastian; Cunningham-Rundles, Charlotte; Giulino-Roth, Lisa; Elemento, Olivier; Dueckers, Gregor; Niehues, Tim; Fronkova, Eva; Kanderova, Veronika; Platt, Craig D.; Chou, Janet; Chatila, Talal A.; Geha, Raif; McDermott, Elizabeth; Bunn, Su; Kurzai, Monika; Schulz, Ansgar; Alsina, Laia; Casals, Ferran; Deya-Martinez, Angela; Hambleton, Sophie; Kanegane, Hirokazu; Tasken, Kjetil; Neth, Olaf; Grimbacher, Bodo (2018): Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. In: Journal of Allergy and Clinical Immunology, Vol. 142, No. 6: pp. 1932-1946
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Abstract

Background: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. Objective: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. Methods: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. Results: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%;median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16%(n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affectedmutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. Conclusions: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

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