Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects

Authors	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 Jiří FREIBERGER Tomáš VAN DE VEERDONK Frank L. 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 Oliver DUCKERS 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
Year of publication	2018
Type	Article in Periodical
Magazine / Source	Journal of allergy and clinical immunology
MU Faculty or unit	Faculty of Medicine
Citation
Doi	http://dx.doi.org/10.1016/j.jaci.2018.02.055
Keywords	Cytotoxic T-lymphocyte antigen 4; primary immunodeficiency; autoimmunity; hypogammaglobulinemia; hematopoietic stem cell transplantation; abatacept; sirolimus; immune dysregulation; common variable immunodeficiency
Description	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.