RT Journal Article
T1 Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.
A1 Schwab, Charlotte
A1 Gabrysch, Annemarie
A1 Olbrich, Peter
A1 Patiño, Virginia
A1 Warnatz, Klaus
A1 Wolff, Daniel
A1 Hoshino, Akihiro
A1 Kobayashi, Masao
A1 Imai, Kohsuke
A1 Takagi, Masatoshi
A1 Dybedal, Ingunn
A1 Haddock, Jamanda A
A1 Sansom, David M
A1 Lucena, Jose M
A1 Seidl, Maximilian
A1 Schmitt-Graeff, Annette
A1 Reiser, Veronika
A1 Emmerich, Florian
A1 Frede, Natalie
A1 Bulashevska, Alla
A1 Salzer, Ulrich
A1 Schubert, Desirée
A1 Hayakawa, Seiichi
A1 Okada, Satoshi
A1 Kanariou, Maria
A1 Kucuk, Zeynep Yesim
A1 Chapdelaine, Hugo
A1 Petruzelkova, Lenka
A1 Sumnik, Zdenek
A1 Sediva, Anna
A1 Slatter, Mary
A1 Arkwright, Peter D
A1 Cant, Andrew
A1 Lorenz, Hanns-Martin
A1 Giese, Thomas
A1 Lougaris, Vassilios
A1 Plebani, Alessandro
A1 Price, Christina
A1 Sullivan, Kathleen E
A1 Moutschen, Michel
A1 Litzman, Jiri
A1 Freiberger, Tomas
A1 van de Veerdonk, Frank L
A1 Recher, Mike
A1 Albert, Michael H
A1 Hauck, Fabian
A1 Seneviratne, Suranjith
A1 Pachlopnik Schmid, Jana
A1 Kolios, Antonios
A1 Unglik, Gary
A1 Klemann, Christian
A1 Speckmann, Carsten
A1 Ehl, Stephan
A1 Leichtner, Alan
A1 Blumberg, Richard
A1 Franke, Andre
A1 Snapper, Scott
A1 Zeissig, Sebastian
A1 Cunningham-Rundles, Charlotte
A1 Giulino-Roth, Lisa
A1 Elemento, Olivier
A1 Dückers, Gregor
A1 Niehues, Tim
A1 Fronkova, Eva
A1 Kanderová, Veronika
A1 Platt, Craig D
A1 Chou, Janet
A1 Chatila, Talal A
A1 Geha, Raif
A1 McDermott, Elizabeth
A1 Bunn, Su
A1 Kurzai, Monika
A1 Schulz, Ansgar
A1 Alsina, Laia
A1 Casals, Ferran
A1 Deyà-Martinez, Angela
A1 Hambleton, Sophie
A1 Kanegane, Hirokazu
A1 Taskén, Kjetil
A1 Neth, Olaf
A1 Grimbacher, Bodo
K1 Cytotoxic T-lymphocyte antigen 4
K1 abatacept
K1 autoimmunity
K1 common variable immunodeficiency
K1 hematopoietic stem cell transplantation
K1 hypogammaglobulinemia
K1 immune dysregulation
K1 primary immunodeficiency
K1 sirolimus
AB 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. We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. 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 affected mutation 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. 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.
YR 2018
FD 2018-05-04
LK http://hdl.handle.net/10668/12426
UL http://hdl.handle.net/10668/12426
LA en
DS RISalud
RD Apr 12, 2025