{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:39:42Z","timestamp":1760146782280,"version":"build-2065373602"},"reference-count":38,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,7]],"date-time":"2024-12-07T00:00:00Z","timestamp":1733529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["RRC-2024-23684489"],"award-info":[{"award-number":["RRC-2024-23684489"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Immune dysregulation in Inborn Errors of Immunity (IEI) shows a broad phenotype, including autoimmune disorders, benign lymphoproliferation, and malignancies, driven by an increasing number of implicated genes. Recent findings suggest that childhood cancer survivors (CCSs) may exhibit immunological abnormalities potentially linked to an underlying IEI, along with a well-known increased risk of subsequent malignancies due to prior cancer treatments. We describe a patient with two composite heterozygous pathogenic variants in the interleukin-2-inducible T-cell kinase (ITK) gene and a history of multiple tumors, including recurrent Epstein\u2013Barr virus (EBV)-related nodular sclerosis and Hodgkin\u2019s lymphoma (NSHL), associated with unresponsive multiple hand warts, immune thrombocytopenia, and an impaired immunological profile (CD4+ lymphocytopenia, memory B-cell deficiency, reduction in regulatory T-cells, and B-cell- and T-cell-activated profiles). In our case, ITK-related immune dysregulation and prior exposure to oncological treatments seem to have simultaneously intervened in the same individual, leading to the development of a unique clinical profile. It is essential to raise awareness of the two-way association between immune dysregulation disorders and multiple tumors.<\/jats:p>","DOI":"10.3390\/ijms252313181","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T04:01:37Z","timestamp":1733716897000},"page":"13181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiple Tumors in a Patient with Interleukin-2-Inducible T-Cell Kinase Deficiency: A Case Report"],"prefix":"10.3390","volume":"25","author":[{"given":"Michela","family":"Di Filippo","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences, University of Genoa, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramona","family":"Tallone","sequence":"additional","affiliation":[{"name":"D.O.P.O. Clinic, Department of Pediatric Hematology and Oncology, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5259-7046","authenticated-orcid":false,"given":"Monica","family":"Muraca","sequence":"additional","affiliation":[{"name":"D.O.P.O. Clinic, Department of Pediatric Hematology and Oncology, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2940-3255","authenticated-orcid":false,"given":"Lisa","family":"Pelanconi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences, University of Genoa, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Faravelli","sequence":"additional","affiliation":[{"name":"Genomics and Clinical Genetics, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3097-0388","authenticated-orcid":false,"given":"Valeria","family":"Capra","sequence":"additional","affiliation":[{"name":"Genomics and Clinical Genetics, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8498-3750","authenticated-orcid":false,"given":"Patrizia","family":"De Marco","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3698-9319","authenticated-orcid":false,"given":"Marzia","family":"Ognibene","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5304-3608","authenticated-orcid":false,"given":"Simona","family":"Baldassari","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4545-9873","authenticated-orcid":false,"given":"Paola","family":"Terranova","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Pediatric Hematology and Oncology, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9630-9449","authenticated-orcid":false,"given":"Virginia","family":"Livellara","sequence":"additional","affiliation":[{"name":"Oncology Unit, Department of Pediatric Hematology and Oncology, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5107-1584","authenticated-orcid":false,"given":"Valerio Gaetano","family":"Vellone","sequence":"additional","affiliation":[{"name":"Pathology Unit, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"},{"name":"Department of Integrated Surgical &Diagnostic Sciences (DISC), University of Genoa, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9816-1704","authenticated-orcid":false,"given":"Maurizio","family":"Miano","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Pediatric Hematology and Oncology, IRCCS Giannina Gaslini Institute, 16147 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1950-4754","authenticated-orcid":false,"given":"Loredana","family":"Amoroso","sequence":"additional","affiliation":[{"name":"Pediatric Oncology and Oncohematology Unit, Department of Maternal Infantile and Urological Sciences, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Beccaria","sequence":"additional","affiliation":[{"name":"D.O.P.O. 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Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1080\/10428194.2019.1672056","article-title":"Primary immunodeficiencies and lymphoma: A systematic review of literature","volume":"61","author":"Herber","year":"2020","journal-title":"Leuk. Lymphoma"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1056\/NEJM199501193320303","article-title":"Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy","volume":"332","author":"Mackall","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1182\/blood.V90.9.3662","article-title":"Long-term depletion of naive T cells in patients treated for Hodgkin\u2019s disease","volume":"90","author":"Watanabe","year":"1997","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/pbc.20341","article-title":"Immune thrombocytopenia following successful treatment of cancer in children","volume":"46","author":"Price","year":"2006","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/MPH.0000000000000697","article-title":"Immune Dysfunction After Completion of Childhood Leukemia Therapy","volume":"39","author":"Perkins","year":"2017","journal-title":"J. Pediatr. Hematol.\/Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ballow, M., S\u00e1nchez-Ram\u00f3n, S., and Walter, J.E. (2022). Secondary Immune Deficiency and Primary Immune Deficiency Crossovers: Hematological Malignancies and Autoimmune Diseases. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.928062"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/nrc722","article-title":"Second cancers in survivors of childhood cancer","volume":"2","author":"Bhatia","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1016\/S0140-6736(17)31610-0","article-title":"The cumulative burden of surviving childhood cancer: An initial report from the St Jude Life time Cohort Study (SJLIFE)","volume":"390","author":"Bhakta","year":"2017","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/0002-9343(92)90680-A","article-title":"Second malignancies in very-long-term survivors of childhoodcancer","volume":"93","author":"Blatt","year":"1992","journal-title":"Am. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ghosh, S., Drexler, I., Bhatia, S., Adler, H., Gennery, A.R., and Borkhardt, A. (2018). Interleukin-2-Inducible T-Cell Kinase Deficiency-New Patients, New Insight?. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00979"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.4049\/jimmunol.168.5.2163","article-title":"Defective Fas ligand expression and activation-induced cell death in the absence of IL-2-inducible T cell kinase","volume":"168","author":"Miller","year":"2002","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1093\/cid\/ciy942","article-title":"Inherited Interleukin 2-Inducible T-Cell (ITK) Kinase Deficiency in Siblings with Epidermodysplasia Verruciformis and Hodgkin Lymphoma","volume":"68","author":"Youssefian","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.clim.2018.12.016","article-title":"Management of XLP-1 and ITK deficiency: The challenge sposed by PID with anunpredictable spectrum of disease manifestations","volume":"198","author":"Shadur","year":"2019","journal-title":"Clin. Immunol."},{"key":"ref_16","first-page":"22","article-title":"ProtocolliAIEOP MH\u201983-89-96 per la terapiadel Linfomadi Hodgkin (LH) in et\u00e0pediatrica. Sopravvivenza a lungotermine e secondeneoplasiemaligne","volume":"4","author":"Burnelli","year":"2012","journal-title":"Pediatr. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.ejca.2021.06.004","article-title":"European Pan Care Follow Up Recommendations for surveillance of late effects of childhood, adolescent, and young adult cancer","volume":"154","author":"Kremer","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1161\/CIRCULATIONAHA.105.169404","article-title":"American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolicsyndrome: An American Heart Association\/National Heart, Lung, and Blood Institute Scientific Statement","volume":"112","author":"Grundy","year":"2005","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1046\/j.0902-4441.2003.00199.x","article-title":"Reference values for peripheral blood lymphocytephenotypesapplicable to the healthy adult population in Switzerland","volume":"72","author":"Bisset","year":"2004","journal-title":"Eur. J. Haematol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Riaz, I.B., Faridi, W., Patnaik, M.M., and Abraham, R.S. (2019). A Systematic Review on Predispositionto Lymphoid (Band T cell) Neoplasias in Patients with Primary Immunode ficiencies and Immune Dysregulatory Disorders (Inborn Errors of Immunity). Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00777"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Orange, J.S., and Chinen, J. (2020). ITK Deficiency. Encyclopedia of Medical Immunology, Springer.","DOI":"10.1007\/978-1-4614-8678-7"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1007\/s10875-014-0110-8","article-title":"Interleukin-2-inducible T-cell kinase (ITK) deficiency-clinical and molecular aspects","volume":"34","author":"Ghosh","year":"2014","journal-title":"J. Clin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7","DOI":"10.21037\/aol-20-34","article-title":"Narrative review of chronicactive EBV infection\u2014Advances in clinical management","volume":"5","author":"Sawada","year":"2021","journal-title":"Ann. Lymphoma"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wu, X., Xiao, Y., Guo, D., Zhang, Z., and Liu, M. (2022). Reduced NK Cell Cytotoxicity by Papillomatosis-Derived TGF-\u03b2 Contributing to Low-Risk HPV Persistence in JORRP Patients. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.849493"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s12985-022-01776-4","article-title":"Increased expression of TIGIT and KLRG1 correlates with impaired CD56bright NK cell immunity in HPV 16-related cervical intraepithelial neoplasia","volume":"19","author":"Nie","year":"2022","journal-title":"Virol. J."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ma, Y., Bao, Y., and Zheng, M. (2023). Epstein\u2013Barrvirus-associated B-cell lymphoproliferative disorder meeting the definitionof CAEBV B cell disease: A case report. BMC Infect. Dis., 23.","DOI":"10.1186\/s12879-023-08430-6"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1086\/605610","article-title":"Identification of Epstein-Barr Virus (EBV)\u2013Infected Lymphocyte Subtypes by Flow Cytometric In Situ Hybridizationin EBV-Associated Lymphoproliferative Diseases","volume":"200","author":"Kimura","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Schiavo, E., Martini, B., Attardi, E., Consonni, F., CiulliniMannurita, S., Coniglio, M.L., Tellini, M., Chiocca, E., Fotzi, I., and Luti, L. (2022). Autoimmune Cytopenias and Dysregulated Immunophenotype Actas Warning Signs of Inborn Errors of Immunity: Resultsfroma Prospective Study. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.790455"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Gereige, J.D., and Maglione, P.J. (2019). Current Under standing and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02753"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"245","DOI":"10.2174\/1573396315666190917154058","article-title":"Primary Immuno deficiency and Cancer in Children; A Review of the Literature","volume":"15","author":"Kebudi","year":"2019","journal-title":"Curr. Pediatr. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.jaci.2017.05.024","article-title":"Cancer in primary immuno deficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry","volume":"141","author":"Mayor","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.jaci.2013.12.1077","article-title":"European Society for Immunodeficiencies Registry Working Party. Clinical picture and treatment of 2212 patients with common variable immuno deficiency","volume":"134","author":"Gathmann","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.jaci.2021.07.015","article-title":"Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders","volume":"149","author":"Forbes","year":"2022","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_34","first-page":"3725","article-title":"Enhanced radio sensitivity of cultured fibroblastsfromataxiatelangiectasiaheterozygotesmanifested by defectivecolony-forming ability and reduced DNA repair replication after hypoxicgamma-irradiation","volume":"39","author":"Paterson","year":"1979","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2","DOI":"10.14293\/genint.13.1.003","article-title":"Oxidative Damage Induced Telomere Mediated Genomic Instability in Cells from Ataxia Telangiectasia Patients","volume":"13","author":"Srikanth","year":"2022","journal-title":"Genome Integr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/cge.12710","article-title":"Health risks for ataxia-telangiectasia mutated heterozygotes: A systematic review, meta-analysis and evidence-based guideline","volume":"90","author":"Roeleveld","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1016\/j.prro.2023.09.001","article-title":"Breast Irradiation Is Well Tolerated in Carriers of a Pathogenic ATM Variant","volume":"14","author":"Zureick","year":"2024","journal-title":"Pract. Radiat. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1053\/j.seminhematol.2016.05.008","article-title":"Hodgkinlymphoma: Late effects of treatment and guidelines for surveillance","volume":"53","author":"Ng","year":"2016","journal-title":"Semin. Hematol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/13181\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:49:34Z","timestamp":1760114974000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/13181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,7]]},"references-count":38,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252313181"],"URL":"https:\/\/doi.org\/10.3390\/ijms252313181","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,12,7]]}}}