{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T11:47:55Z","timestamp":1764071275410,"version":"3.45.0"},"reference-count":16,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Molecular bases of disease dissemination in lymphoid malignancies to optimize curative therapeutic strategies","award":["5 \u00d7 1000 No. 21198"],"award-info":[{"award-number":["5 \u00d7 1000 No. 21198"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hematology Reports"],"abstract":"<jats:p>Background and Clinical Significance: Mastocytosis and mast cell activation syndrome (MCAS) include conditions in which patients manifest signs, symptoms, and laboratory findings consistent with mast cell activation and can only be diagnosed in the presence of specific criteria. Mutations of ZRSR2, a gene involved in RNA splicing, are not closely associated with mast cell disorders, but rather with myelodysplastic syndromes development. Case Presentation: We report a case of a 37-year-old man who was referred to our institution for anaphylaxis after a bee sting and elevated serum tryptase levels (17.8 ng\/mL in the first sample and 19.2 ng\/mL in the second sample). Complete blood count was unremarkable. Bone marrow biopsy showed signs of dysplasia and some CD25+ mast cells. ASO-qPCR and targeted myeloid NGS analysis did not detect the KIT p.D816V mutation, but rather showed the presence of a pathogenetic variant of the ZRSR2 gene (p.S447_R448del) with a variant allele frequency of 7.4%. Mastocytosis could not be diagnosed based on the established diagnostic criteria. The patient\u2019s symptoms were not recurrent and tryptase release was not event-related; therefore, a diagnosis of MCAS could not be made either. Taken together, these findings led to the diagnosis of clonal hematopoiesis of indeterminate potential (CHIP). A watch and wait strategy consisting of clinical evaluations, blood tests, and cardiovascular risk assessment was initiated. Conclusions: This case report highlights the importance of combining clinical and laboratory findings, hematopathology, and molecular analyses to establish the most probable diagnosis in challenging cases. It also underscores the possible relevance of identifying predisposing conditions, such as CHIP, in order to guide counseling and follow-up strategy.<\/jats:p>","DOI":"10.3390\/hematolrep17060064","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T10:46:18Z","timestamp":1764067578000},"page":"64","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diagnostic Challenges in a Young Man with a Suspected Mast Cell Disorder, Dysplastic Bone Marrow Morphology, and a ZRSR2 Mutation"],"prefix":"10.3390","volume":"17","author":[{"given":"Riccardo","family":"Dondolin","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"},{"name":"Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0 di Novara, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nawar","family":"Maher","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"},{"name":"Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0 di Novara, 28100 Novara, Italy"},{"name":"Azienda Ospedaliero-Universitaria di Alessandria, 15121 Alessandria, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Andorno","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0 di Novara, 28100 Novara, Italy"},{"name":"Division of Pathology, Department of Health Sciences, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayed Masoud","family":"Sayedi","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"},{"name":"Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0 di Novara, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Reshad","family":"Nawabi","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"},{"name":"Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0 di Novara, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4415-2906","authenticated-orcid":false,"given":"Andrea","family":"Patriarca","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"},{"name":"Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0 di Novara, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4681-0151","authenticated-orcid":false,"given":"Gianluca","family":"Gaidano","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"},{"name":"Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0 di Novara, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo","family":"Moia","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Translational Medicine, Universit\u00e0 del Piemonte Orientale, 28100 Novara, Italy"},{"name":"Azienda Ospedaliero-Universitaria Maggiore della Carit\u00e0 di Novara, 28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s00428-022-03423-3","article-title":"The international consensus classification of mastocytosis and related entities","volume":"482","author":"Leguit","year":"2023","journal-title":"Virchows Arch."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms","volume":"36","author":"Khoury","year":"2022","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1182\/blood.2022015850","article-title":"International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: Integrating morphologic, clinical, and genomic data","volume":"140","author":"Arber","year":"2022","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1182\/blood-2016-09-731893","article-title":"Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts","volume":"129","author":"Valent","year":"2017","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1159\/000524532","article-title":"Mast Cell Activation Syndromes: Collegium Internationale Allergologicum Update 2022","volume":"183","author":"Valent","year":"2022","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.jaci.2010.08.035","article-title":"Mast cell activation syndrome: Proposed diagnostic criteria","volume":"126","author":"Akin","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.jaci.2019.08.023","article-title":"AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management","volume":"144","author":"Weiler","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1038\/s41375-022-01674-2","article-title":"Concurrent Zrsr2 mutation and Tet2 loss promote myelodysplastic neoplasm in mice","volume":"36","author":"Liquori","year":"2022","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Chiereghin, C., Travaglino, E., Zampini, M., Saba, E., Saitta, C., Riva, E., Bersanelli, M., and Della Porta, M.G. (2021). The Genetics of Myelodysplastic Syndromes: Clinical Relevance. Genes, 12.","DOI":"10.3390\/genes12081144"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sprinzl, B., Greiner, G., Uyanik, G., Arock, M., Haferlach, T., Sperr, W.R., Valent, P., and Hoermann, G. (2021). Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052458"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1182\/blood.2023023727","article-title":"Molecular taxonomy of myelodysplastic syndromes and its clinical implications","volume":"144","author":"Bernard","year":"2024","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1182\/blood.2021011320","article-title":"Clinical relevance of clonal hematopoiesis in persons aged \u226580 years","volume":"138","author":"Rossi","year":"2021","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1038\/s41375-024-02374-9","article-title":"Characterisation and prognostic impact Of ZRSR2 mutations in myeloid neoplasms","volume":"38","author":"Yacout","year":"2024","journal-title":"Leukemia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7858","DOI":"10.1038\/s41467-024-52302-9","article-title":"Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis","volume":"15","author":"Uddin","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3211","DOI":"10.1182\/blood-2011-12-400994","article-title":"Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes","volume":"119","author":"Damm","year":"2012","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1158\/2159-8290.CD-20-1513","article-title":"Sex-Biased ZRSR2 Mutations in Myeloid Malignancies Impair Plasmacytoid Dendritic Cell Activation and Apoptosis","volume":"12","author":"Togami","year":"2022","journal-title":"Cancer Discov."}],"container-title":["Hematology Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2038-8330\/17\/6\/64\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T11:44:26Z","timestamp":1764071066000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2038-8330\/17\/6\/64"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":16,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["hematolrep17060064"],"URL":"https:\/\/doi.org\/10.3390\/hematolrep17060064","relation":{},"ISSN":["2038-8330"],"issn-type":[{"value":"2038-8330","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]}}}