{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T09:28:51Z","timestamp":1786786131091,"version":"build-2736575974"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsklinikum Hamburg-Eppendorf (UKE)"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Ann Hematol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome. The familial form (fHL), associated with specific genetic alterations, typically manifests in childhood, while secondary forms arise due to triggers such as malignancies or infections. We present the rare case of adult-onset fHL in a 30-year-old female concurrent with T-cell large granular lymphocytic leukemia (T-LGL). After presenting with symptoms of HLH, a bone marrow biopsy revealed T-cell lymphoma, leading to CHOEP treatment. This diagnosis was later revised to T-LGL, prompting a switch to methotrexate for T-LGL treatment. Further genetic testing uncovered an unexpected homozygous missense mutation in\n                    <jats:italic>UNC13D<\/jats:italic>\n                    (p.R414C), associated with fHL type 3. A detailed family history revealed a consanguineous marriage between her parents, which likely increased the risk of the homozygous mutation. Additionally, it was discovered that the patient\u2019s sister had undergone allogeneic stem cell transplantation during childhood for an unspecified lymphoproliferative disorder, with the patient herself serving as the donor. This case highlights the rare occurrence of adult-onset fHL, triggered by the evolution of T-LGL as a possible contributing factor. It underscores the importance of early diagnosis and illustrates how familial history and persistent symptoms can necessitate genetic testing.\n                  <\/jats:p>","DOI":"10.1007\/s00277-026-07177-9","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T14:05:28Z","timestamp":1784124328000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Simultaneous onset of familial hemophagocytic lymphohistiocytosis and T-cell large granular lymphocytic leukemia in an adult"],"prefix":"10.1007","volume":"105","author":[{"given":"Friederike","family":"Dierks","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Finn-Ole","family":"Paulsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Lehmberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Rosenwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Bokemeyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Weisel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Seidel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"issue":"2","key":"7177_CR1","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/pbc.21039","volume":"48","author":"J-I Henter","year":"2007","unstructured":"Henter J-I, Horne A, Aric\u00f3 M et al (2007) HLH-2004. Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr blood cancer 48(2):124\u2013131. https:\/\/doi.org\/10.1002\/pbc.21039","journal-title":"Pediatr blood cancer"},{"issue":"4","key":"7177_CR2","doi-asserted-by":"publisher","first-page":"101515","DOI":"10.1016\/j.berh.2020.101515","volume":"34","author":"G Griffin","year":"2020","unstructured":"Griffin G, Shenoi S, Hughes GC (2020) Hemophagocytic lymphohistiocytosis. An update on pathogenesis, diagnosis, and therapy. Best Pract Res Clin Rheumatol 34(4):101515. https:\/\/doi.org\/10.1016\/j.berh.2020.101515","journal-title":"Best Pract Res Clin Rheumatol"},{"issue":"7","key":"7177_CR3","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1182\/blood-2012-05-425769","volume":"121","author":"J Sumegi","year":"2013","unstructured":"Sumegi J, Nestheide SV, Barnes MG et al (2013) Gene-expression signatures differ between different clinical forms of familial hemophagocytic lymphohistiocytosis. Blood 121(7):14\u201324. https:\/\/doi.org\/10.1182\/blood-2012-05-425769","journal-title":"Blood"},{"issue":"5446","key":"7177_CR4","doi-asserted-by":"publisher","first-page":"1957","DOI":"10.1126\/science.286.5446.1957","volume":"286","author":"SE Stepp","year":"1999","unstructured":"Stepp SE, Dufourcq-Lagelouse R, Le Deist F et al (1999) Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286(5446):1957\u20131959. https:\/\/doi.org\/10.1126\/science.286.5446.1957","journal-title":"Science"},{"issue":"1","key":"7177_CR5","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1086\/302194","volume":"64","author":"R Dufourcq-Lagelouse","year":"1999","unstructured":"Dufourcq-Lagelouse R, Jabado N, Le Deist F et al (1999) Linkage of familial hemophagocytic lymphohistiocytosis to 10q21-22 and evidence for heterogeneity. Am J Hum Genet 64(1):172\u2013179. https:\/\/doi.org\/10.1086\/302194","journal-title":"Am J Hum Genet"},{"issue":"16","key":"7177_CR6","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1182\/blood.2019000936","volume":"135","author":"SW Canna","year":"2020","unstructured":"Canna SW, Marsh RA (2020) Pediatric hemophagocytic lymphohistiocytosis. Blood 135(16):1332\u20131343. https:\/\/doi.org\/10.1182\/blood.2019000936","journal-title":"Blood"},{"issue":"4","key":"7177_CR7","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/S0092-8674(03)00855-9","volume":"115","author":"J Feldmann","year":"2003","unstructured":"Feldmann J, Callebaut I, Raposo G et al (2003) Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115(4):461\u2013473. https:\/\/doi.org\/10.1016\/S0092-8674(03)00855-9","journal-title":"Cell"},{"issue":"6","key":"7177_CR8","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1093\/hmg\/ddi076","volume":"14","author":"U Zur Stadt","year":"2005","unstructured":"Zur Stadt U, Schmidt S, Kasper B et al (2005) Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 14(6):827\u2013834. https:\/\/doi.org\/10.1093\/hmg\/ddi076","journal-title":"Hum Mol Genet"},{"issue":"1\u20132","key":"7177_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jim.2010.11.006","volume":"364","author":"TS Johnson","year":"2011","unstructured":"Johnson TS, Villanueva J, Filipovich AH et al (2011) Contemporary diagnostic methods for hemophagocytic lymphohistiocytic disorders. J Immunol Methods 364(1\u20132):1\u201313. https:\/\/doi.org\/10.1016\/j.jim.2010.11.006","journal-title":"J Immunol Methods"},{"issue":"4","key":"7177_CR10","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.ajhg.2009.09.005","volume":"85","author":"U Zur Stadt","year":"2009","unstructured":"Zur Stadt U, Rohr J, Seifert W et al (2009) Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 85(4):482\u2013492. https:\/\/doi.org\/10.1016\/j.ajhg.2009.09.005","journal-title":"Am J Hum Genet"},{"issue":"12","key":"7177_CR11","doi-asserted-by":"publisher","first-page":"2754","DOI":"10.1182\/blood-2011-08-374199","volume":"119","author":"YT Bryceson","year":"2012","unstructured":"Bryceson YT, Pende D, Maul-Pavicic A et al (2012) A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood 119(12):2754\u20132763. https:\/\/doi.org\/10.1182\/blood-2011-08-374199","journal-title":"Blood"},{"issue":"22","key":"7177_CR12","doi-asserted-by":"publisher","first-page":"2308","DOI":"10.1182\/blood.2024025077","volume":"144","author":"JI Henter","year":"2024","unstructured":"Henter JI, Sieni E, Eriksson J et al (2024) Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited. Blood 144(22):2308\u20132318. https:\/\/doi.org\/10.1182\/blood.2024025077","journal-title":"Blood"},{"issue":"9","key":"7177_CR13","doi-asserted-by":"publisher","first-page":"2613","DOI":"10.1002\/art.38690","volume":"66","author":"L Fardet","year":"2014","unstructured":"Fardet L, Galicier L, Lambotte O et al (2014) Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 66(9):2613\u20132620. https:\/\/doi.org\/10.1002\/art.38690","journal-title":"Arthritis Rheumatol"},{"issue":"5","key":"7177_CR14","doi-asserted-by":"publisher","first-page":"1508","DOI":"10.1016\/j.jaip.2018.05.031","volume":"6","author":"S Ehl","year":"2018","unstructured":"Ehl S, Astigarraga I, von Bahr Greenwood T et al (2018) Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract 6(5):1508\u20131517. https:\/\/doi.org\/10.1016\/j.jaip.2018.05.031","journal-title":"J Allergy Clin Immunol Pract"},{"issue":"9","key":"7177_CR15","doi-asserted-by":"publisher","first-page":"e44649","DOI":"10.1371\/journal.pone.0044649","volume":"7","author":"E Sieni","year":"2012","unstructured":"Sieni E, Cetica V, Piccin A et al (2012) Familial hemophagocytic lymphohistiocytosis may present during adulthood: clinical and genetic features of a small series. PLoS ONE 7(9):e44649. https:\/\/doi.org\/10.1371\/journal.pone.0044649","journal-title":"PLoS ONE"},{"issue":"9","key":"7177_CR16","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1182\/blood-2016-08-692590","volume":"129","author":"T Lamy","year":"2017","unstructured":"Lamy T, Moignet A, Loughran TP (2017) LGL leukemia. From pathogenesis to treatment. Blood 129(9):1082\u20131094. https:\/\/doi.org\/10.1182\/blood-2016-08-692590","journal-title":"Blood"},{"issue":"1","key":"7177_CR17","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1111\/pai.13323","volume":"32","author":"P Amirifar","year":"2021","unstructured":"Amirifar P, Ranjouri MR, Abolhassani H et al (2021) Clinical, immunological and genetic findings in patients with UNC13D deficiency (FHL3). A systematic review. Pediatr Allergy Immunol 32(1):186\u2013197. https:\/\/doi.org\/10.1111\/pai.13323","journal-title":"Pediatr Allergy Immunol"},{"issue":"1","key":"7177_CR18","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s00018-011-0835-y","volume":"69","author":"E Sieni","year":"2012","unstructured":"Sieni E, Cetica V, Mastrodicasa E et al (2012) Familial hemophagocytic lymphohistiocytosis: a model for understanding the human machinery of cellular cytotoxicity. Cell Mol Life Sci 69(1):29\u201340. https:\/\/doi.org\/10.1007\/s00018-011-0835-y","journal-title":"Cell Mol Life Sci"},{"key":"7177_CR19","doi-asserted-by":"publisher","first-page":"395","DOI":"10.3389\/fimmu.2019.00395","volume":"10","author":"Y Miao","year":"2019","unstructured":"Miao Y, Zhu H-Y, Qiao C et al (2019) Pathogenic Gene Mutations or Variants Identified by Targeted Gene Sequencing in Adults With Hemophagocytic Lymphohistiocytosis. Front Immunol 10:395. https:\/\/doi.org\/10.3389\/fimmu.2019.00395","journal-title":"Front Immunol"},{"issue":"8","key":"7177_CR20","doi-asserted-by":"publisher","first-page":"2515","DOI":"10.3324\/haematol.2023.283893","volume":"109","author":"F Pegoraro","year":"2024","unstructured":"Pegoraro F, Chinnici A, Beneforti L et al (2024) Outcome of primary hemophagocytic lymphohistiocytosis: a report on 143 patients from the Italian Registry. Haematologica 109(8):2515\u20132524. https:\/\/doi.org\/10.3324\/haematol.2023.283893","journal-title":"Haematologica"},{"issue":"22","key":"7177_CR21","doi-asserted-by":"publisher","first-page":"5794","DOI":"10.1182\/blood-2011-07-370148","volume":"118","author":"K Zhang","year":"2011","unstructured":"Zhang K, Jordan MB, Marsh RA et al (2011) Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood 118(22):5794\u20135798. https:\/\/doi.org\/10.1182\/blood-2011-07-370148","journal-title":"Blood"},{"issue":"11","key":"7177_CR22","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1002\/cncr.32011","volume":"125","author":"A L\u00f6fstedt","year":"2019","unstructured":"L\u00f6fstedt A, Ahlm C, Tesi B et al (2019) Haploinsufficiency of UNC13D increases the risk of lymphoma. Cancer 125(11):1848\u20131854. https:\/\/doi.org\/10.1002\/cncr.32011","journal-title":"Cancer"},{"key":"7177_CR23","doi-asserted-by":"publisher","first-page":"944","DOI":"10.3389\/fimmu.2017.00944","volume":"8","author":"PE Gray","year":"2017","unstructured":"Gray PE, Shadur B, Russell S et al (2017) Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D. Front Immunol 8:944. https:\/\/doi.org\/10.3389\/fimmu.2017.00944","journal-title":"Front Immunol"},{"issue":"7","key":"7177_CR24","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1182\/blood.2021012764","volume":"139","author":"A Zoref-Lorenz","year":"2022","unstructured":"Zoref-Lorenz A, Murakami J, Hofstetter L et al (2022) An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis. Blood 139(7):1098\u20131110. https:\/\/doi.org\/10.1182\/blood.2021012764","journal-title":"Blood"}],"container-title":["Annals of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00277-026-07177-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00277-026-07177-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00277-026-07177-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T09:20:29Z","timestamp":1786785629000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00277-026-07177-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,15]]},"references-count":24,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["7177"],"URL":"https:\/\/doi.org\/10.1007\/s00277-026-07177-9","relation":{},"ISSN":["1432-0584"],"issn-type":[{"value":"1432-0584","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,15]]},"assertion":[{"value":"21 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Written informed consent for publication was obtained from the patient.","order":1,"name":"Ethics","label":"Informed consent","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Competing interests: CB declares involvement in advisory boards for Astra Zeneca, Bayer Healthcare, BioNTech, Hexal, Lindis Biotech, Merck Serono, Oncology Drug Consult CRO and Sanofi Aventis as well as a compensation as an invited speaker for AOK Germany, Astra Zeneca, med update, Merck Serono and Roche Pharma. He received personal fees from AOK Germany, Astra Zeneca, Bayer Healthcare, BioNTech, Hexal, Lindis Biotech, med update, Merck Serono, Oncology Drug Consult CRO, Roche Pharma and Sanofi Aventis.Non-financial competing interests: CB has served on advisory boards for the DGHO (Deutsche Gesellschaft f\u00fcr H\u00e4matologie und Medizinische Onkologie) and the German Cancer Society. CB is on the board of directors of the Northern German Society of Internal Medicine and the Oncology Center Certification Committee of the German Cancer Society and occupies a leadership role in the Hamburg Cancer Society and the National Network of German Cancer Centers (DKH). The other authors have no competing interests to declare that are relevant to the content of this article.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"334"}}