{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T18:42:16Z","timestamp":1793472136870,"version":"4.5.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>CARD11 is primarily expressed in hematopoietic tissues and lymphocytes and plays a crucial role in the proper activation of B and T cells in response to antigen recognition. Pathogenic variants in the <jats:italic>CARD11<\/jats:italic> gene result in a broad spectrum of syndromic immunodeficiencies with variable severity and clinical outcomes. Gain-of-function mutations lead to uncontrolled NF-\u03baB activity in lymphocytes and are associated with BENTA syndrome (B-cell Expansion with NF-\u03baB and T-cell Anergy), an autosomal dominant disorder characterized by resistance to conventional therapies used for lymphoproliferative conditions. In contrast, loss-of-function variants are linked to Hyper-IgE-like syndromes, presenting with varying degrees of immunodeficiency\u2014ranging from combined immunodeficiency to specific humoral defects\u2014accompanied by atopic manifestations and autoimmunity. CARD11-associated diseases may be more prevalent than previously recognized due to their clinical overlap with atopic and hematological syndromic disorders. Consequently, a high index of suspicion for these conditions facilitates early diagnosis and enables personalized treatment. In this review, we summarize the broad spectrum of CARD11-related diseases, their underlying pathophysiological mechanisms, multidisciplinary management strategies, and current therapeutic options, along with potential future approaches.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1626065","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T04:10:30Z","timestamp":1750651830000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["From syndromic clues to diagnosis: understanding CARD11-driven disorders"],"prefix":"10.3389","volume":"16","author":[{"given":"Elena","family":"Garc\u00eda-Mart\u00ednez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Teresa","family":"Schiaffino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa","family":"Di Natale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda de las Mercedes","family":"D\u00edaz Luna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel Alejandro","family":"Viteri \u00c1lvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Alejandra","family":"Mej\u00eda Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(03)00148-1","article-title":"The MAGUK family protein CARD11 is essential for lymphocyte activation","volume":"18","author":"Hara","year":"2003","journal-title":"Immunity"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3070","DOI":"10.1038\/s41467-019-10953-z","article-title":"Structures of autoinhibited and polymerized forms of CARD9 reveal mechanisms of CARD9 and CARD11 activation","volume":"10","author":"Holliday","year":"2019","journal-title":"Nat Commun"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.683714","article-title":"Cooperative control of caspase recruitment domain-containing protein 11 (CARD11) signaling by an unusual array of redundant repressive elements","volume":"291","author":"Jattani","year":"2016","journal-title":"J Biol Chem"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00418-08","article-title":"The protein kinase C-responsive inhibitory domain of CARD11 functions in NF-kappaB activation to regulate the association of multiple signaling cofactors that differentially depend on Bcl10 and MALT1 for association","volume":"28","author":"McCully","year":"2008","journal-title":"Mol Cell Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2013.02.002","article-title":"A new look at TCR signaling to NF-\u03baB","volume":"34","author":"Paul","year":"2013","journal-title":"Trends Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02078","article-title":"The CBM-opathies-A rapidly expanding spectrum of human inborn errors of immunity caused by mutations in the CARD11-BCL10-MALT1 complex","volume":"9","author":"Lu","year":"2018","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2019.03.009","article-title":"Germline CBM-opathies: From immunodeficiency to atopy","volume":"143","author":"Lu","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1020927","article-title":"Expanding spectrum, intrafamilial diversity, and therapeutic challenges from 15 patients with heterozygous CARD11-associated diseases: A single center experience","volume":"13","author":"Urdinez","year":"2022","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e20250003","DOI":"10.70962\/jhi.20250003","article-title":"Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee","volume":"1","author":"Poli","year":"2025","journal-title":"J Hum Immun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3898","article-title":"Germline hypomorphic CARD11 mutations in severe atopic disease","volume":"49","author":"Ma","year":"2017","journal-title":"Nat Genet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"103810","DOI":"10.1016\/j.isci.2022.103810","article-title":"Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants","volume":"25","author":"Bedsaul","year":"2022","journal-title":"iScience"},{"key":"B12","doi-asserted-by":"publisher","first-page":"24247","DOI":"10.1038\/s41598-024-71673-z","article-title":"A new-disease-causing dominant-negative variant in CARD11 gene in a Chinese case with recurrent fever","volume":"14","author":"Zhao","year":"2024","journal-title":"Sci Rep"},{"key":"B13","doi-asserted-by":"publisher","first-page":"102255","DOI":"10.1016\/j.coi.2022.102255","article-title":"Elevated IgE from attenuated CARD11 signaling: lessons from atopic mice and humans","volume":"79","author":"Pomerantz","year":"2022","journal-title":"Curr Opin Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"5555","DOI":"10.1038\/ncomms6555","article-title":"Clustering of CARMA1 through SH3\u2013GUK domain interactions is required for its activation of NF-\u03baB signalling","volume":"6","author":"Hara","year":"2015","journal-title":"Nat Commun"},{"key":"B15","doi-asserted-by":"publisher","first-page":"100890","DOI":"10.1016\/j.jbior.2022.100890","article-title":"CARD11 signaling in regulatory T cell development and function","volume":"84","author":"Carter","year":"2022","journal-title":"Adv Biol Regul"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2001233","article-title":"Pathway-specific defects in T, B, and NK cells and age-dependent development of high IgE in mice heterozygous for a CADINS-associated dominant negative CARD11 allele","volume":"207","author":"Hutcherson","year":"2021","journal-title":"J Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1016\/j.jaci.2017.06.047","article-title":"Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)","volume":"141","author":"Dadi","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.08.013","article-title":"Hypomorphic CARD11 mutations associated with diverse immunologic phenotypes with or without atopic disease","volume":"143","author":"Dorjbal","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00893-5","article-title":"CADINS in an adult with chronic sinusitis and atopic disease","volume":"41","author":"Izadi","year":"2021","journal-title":"J Clin Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.12.1006","article-title":"Dominant negative CARD11 mutations: Beyond atopy","volume":"143","author":"B\u00e9ziat","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.01.032","article-title":"Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency","volume":"131","author":"Jun","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1016\/j.jaci.2021.04.006","article-title":"Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency","volume":"148","author":"Lu","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s43042-024-00489-3","article-title":"Novel homozygous CARD11 variants in two patients with combined immunodeficiency and atopic skin disease","volume":"25","author":"Meshaal","year":"2024","journal-title":"Egypt J Med Hum Genet"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-023-01440-8","article-title":"Autosomal recessive inflammatory skin disease caused by a novel biallelic loss-of-function variant in CARD11","volume":"43","author":"Nguyen","year":"2023","journal-title":"J Clin Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-11-123513","article-title":"Multiple ITAM-coupled NK-cell receptors engage the Bcl10\/Malt1 complex via Carma1 for NF-kappaB and MAPK activation to selectively control cytokine production","volume":"112","author":"Gross","year":"2008","journal-title":"Blood"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2015.06.031","article-title":"Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity","volume":"136","author":"P\u00e9rez de Diego","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aaw5618","article-title":"Pathogenic CARD11 mutations affect B cell development and differentiation through a noncanonical pathway","volume":"4","author":"Wei","year":"2019","journal-title":"Sci Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1364957","article-title":"CARD11 regulates the thymic Treg development in an NF-\u03baB-independent manner","volume":"15","author":"Hu","year":"2024","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-03-631374","article-title":"Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency","volume":"126","author":"Fuchs","year":"2015","journal-title":"Blood"},{"key":"B30","unstructured":"BENTA disease or CARD11 gain-of-function? A novel variant with atypical features and a literature review ScienceDirect"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02105","article-title":"Mechanisms of regulated and dysregulated CARD11 signaling in adaptive immunity and disease","volume":"9","author":"Bedsaul","year":"2018","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"676386","DOI":"10.3389\/fimmu.2021.676386","article-title":"Identification and characterization of a germiline mutatiopn in CARD11 from a chinese case of B cell expansion with NF-\u03baB and T cell anergy","volume":"12","author":"Zhao","year":"2021","journal-title":"Frton Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-019-00729-x","article-title":"A novel, heterozygous three base-pair deletion in CARD11 results in B cell expansion with NF-\u03baB and T cell anergy disease","volume":"40","author":"Shields","year":"2020","journal-title":"J Clin Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00850-12","article-title":"A quantitative signaling screen identifies CARD11 mutations in the CARD and LATCH domains that induce Bcl10 ubiquitination and human lymphoma cell survival","volume":"33","author":"Chan","year":"2013","journal-title":"Mol Cell Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20120831","article-title":"Congenital B cell lymphocytosis explained by novel germline CARD11 mutations","volume":"209","author":"Snow","year":"2012","journal-title":"J Exp Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3444","article-title":"Genomic profiling of S\u00e9zary syndrome identifies alterations of key T cell signaling and differentiation genes","volume":"47","author":"Wang","year":"2015","journal-title":"Nat Genet"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.671755","article-title":"Primary immune regulatory disorders with an autoimmune lymphoproliferative syndrome-like phenotype: immunologic evaluation, early diagnosis and management","volume":"12","author":"L\u00f3pez-Nevado","year":"2021","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1021\/bi101052d","article-title":"Oncogenic CARD11 mutations induce hyperactive signaling by disrupting autoinhibition by the PKC-responsive inhibitory domain","volume":"49","author":"Lamason","year":"2010","journal-title":"Biochemistry"},{"key":"B39","doi-asserted-by":"publisher","first-page":"104129","DOI":"10.1016\/j.cellimm.2020.104129","article-title":"Gain-of-function mutations in CARD11 promote enhanced aggregation and idiosyncratic signalosome assembly","volume":"353","author":"Stinson","year":"2020","journal-title":"Cell Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/ced.14686","article-title":"Efficacy of dupilumab for controlling severe atopic dermatitis with dominant-negative CARD11 variant","volume":"46","author":"Charvet","year":"2021","journal-title":"Clin Exp Dermatol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1007\/s10875-023-01636-y","article-title":"Management of atopy with dupilumab and omalizumab in CADINS disease","volume":"44","author":"Diaz-Cabrera","year":"2024","journal-title":"J Clin Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.06.015","article-title":"The CARD11-BCL10-MALT1 (CBM) signalosome complex: stepping into the limelight of human primary immunodeficiency","volume":"134","author":"Turvey","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2012.11.050","article-title":"Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects","volume":"131","author":"Stepensky","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2019.00552","article-title":"Hematopoietic stem cell transplantation for combined immunodeficiencies, on behalf of IEWP-EBMT","volume":"7","author":"Neven","year":"2020","journal-title":"Front Pediatr"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01049","article-title":"Clinical, immunological, and molecular findings in four cases of B cell expansion with NF-\u03baB and T cell anergy disease for the first time from India","volume":"9","author":"Gupta","year":"2018","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1007\/s10875-025-01872-4","article-title":"Successful treatment with sirolimus of a patient with a novel CARD11 germline mutation in B-cell expansion with nuclear factor kappa B and T-cell anergy: case report and literature review","volume":"45","author":"Nishinosono","year":"2025","journal-title":"J Clin Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/med.21799","article-title":"MALT1 as a promising target to treat lymphoma and other diseases related to MALT1 anomalies","volume":"41","author":"Liang","year":"2021","journal-title":"Med Res Rev"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e1138","DOI":"10.1002\/cti2.1138","article-title":"Screening for primary immunodeficiency diseases by next-generation sequencing in early life","volume":"9","author":"Sun","year":"2020","journal-title":"Clin Transl Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1626065\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T04:10:32Z","timestamp":1750651832000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1626065\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,23]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2025.1626065"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1626065","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,23]]},"article-number":"1626065"}}