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

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Title:	Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects
Author(s):	Schwab, C.; Gabrysch, A.; Olbrich, P.; Patino, V.; Warnatz, K.; Wolff, D.; Hoshino, A.; Kobayashi, M.; Imai, K.; Takagi, M.; Dybedal, I.; Haddock, J.A.; Sansom, D.M.; Lucena, J.M.; Seidl, M.; Schmitt-Graeff, A.; Reiser, V.; Emmerich, F.; Frede, N.; Bulashevska, A.; Salzer, U.; Schubert, Desiree; Hayakawa, S.; Okada, S.; Kanariou, M.; Kucuk, Z.Y.; Chapdelaine, H.; Petruzelkova, L.; Sumnik, Z.; Sediva, A.; Slatter, M.; Arkwright, P.D.; Cant, A.; Lorenz, H.M.; Giese, T.; Lougaris, V.; Plebani, A.; Price, C.; Sullivan, K.E.; Moutschen, M.; Litzman, J.; Freiberger, T.; Veerdonk, F.L. van de ; Recher, M.; Albert, M.H.; Hauck, F.; Seneviratne, S.; Schmid, J.; Kolios, A.; Unglik, G.; Klemann, C.; Speckmann, C.; Ehl, S.; Leichtner, A.; Blumberg, R.; Franke, A.; Snapper, S.; Zeissig, S.; Cunningham-Rundles, C.; Giulino-Roth, L.; Elemento, O.; Duckers, G.; Niehues, T.; Fronkova, E.; Kanderova, V.; Platt, C.D.; Chou, J.; Chatila, T.A.; Geha, R.; McDermott, E.; Bunn, S.; Kurzai, M.; Schulz, A.; Alsina, L.; Casals, F.; Deya-Martinez, A.; Hambleton, S.; Kanegane, H.; Tasken, K.; Neth, O.; Grimbacher, B.
Publication year:	2018
Source:	Journal of Allergy and Clinical Immunology, vol. 142, iss. 6, (2018), pp. 1932-1946
ISSN:	0091-6749
DOI:	https://doi.org/10.1016/j.jaci.2018.02.055
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/200315
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Subject:	Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences
Organization:	Internal Medicine
Journal title:	Journal of Allergy and Clinical Immunology
Volume:	vol. 142
Issue:	iss. 6
Page start:	p. 1932
Page end:	p. 1946
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 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. 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.