{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T20:47:43Z","timestamp":1793134063818,"version":"4.5.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"4","funder":[{"DOI":"10.13039\/100000098","name":"National Institutes of Health, Clinical Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Pathologists play a crucial role in the initial diagnosis of germline predisposition to myeloid neoplasia and subsequent surveillance for disease progression. The diagnostic workup can be challenging, particularly if clinical history, laboratory testing, or genetic studies are incomplete or unavailable.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Through case-based examples, we illustrate common diagnostic challenges and pitfalls encountered during bone marrow examination of patients being evaluated for myeloid malignancy with potential germline predisposition to myeloid neoplasia.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Lack of familial disease, the absence of syndromic manifestations, and late-onset hematologic malignancy do not exclude an underlying germline predisposition syndrome. Targeted myeloid sequencing panels can help identify potential germline alterations but may not detect large deletions or insertions, noncoding, or novel variants. Confirmation of the germline nature of an alteration detected in the peripheral blood or bone marrow ideally requires genetic testing using nonhematopoietic germline DNA to definitively distinguish between germline and somatic alterations. The ideal tissue source for germline testing is cultured skin fibroblasts. Certain germline predisposition syndromes can contain characteristic baseline bone marrow dysplastic-appearing features associated with cytopenias without constituting myelodysplastic syndrome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Recognizing germline predisposition to myeloid neoplasia is critical for proper disease management. This recognition is particularly important for patients who will undergo hematopoietic stem cell transplantation to screen potential related donors. Integration of the clinical history, bone marrow findings, cytogenetic studies, and specialized laboratory and molecular genetic testing is often essential for accurate diagnosis and subsequent disease monitoring.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ajcp\/aqad075","type":"journal-article","created":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T11:21:05Z","timestamp":1689592865000},"page":"352-364","source":"Crossref","is-referenced-by-count":12,"title":["How I diagnose myeloid neoplasms with germline predisposition"],"prefix":"10.1093","volume":"160","author":[{"given":"Nisha","family":"Patel","sequence":"first","affiliation":[{"name":"Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health , Bethesda, MD , US"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0771-4191","authenticated-orcid":false,"given":"Katherine R","family":"Calvo","sequence":"additional","affiliation":[{"name":"Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health , Bethesda, MD , US"},{"name":"Myeloid Malignancies Program, National Institutes of Health , Bethesda, MD , US"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,7,18]]},"reference":[{"issue":"10","key":"2024041008304173000_CIT0001","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1182\/blood-2018-10-844662","article-title":"Genetic predisposition to MDS: clinical features and clonal evolution","volume":"133","author":"Kennedy","year":"2019","journal-title":"Blood."},{"issue":"8","key":"2024041008304173000_CIT0002","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1182\/blood-2016-01-690909","article-title":"Inherited DDX41 mutations: 11 genes and counting","volume":"127","author":"Tawana","year":"2016","journal-title":"Blood."},{"issue":"13","key":"2024041008304173000_CIT0003","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.1002\/cncr.31331","article-title":"Improving the detection of patients with inherited predispositions to hematologic malignancies using next-generation sequencing-based leukemia prognostication panels","volume":"124","author":"DiNardo","year":"2018","journal-title":"Cancer."},{"issue":"24","key":"2024041008304173000_CIT0004","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1182\/blood.2022015790","article-title":"Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages","volume":"140","author":"Feurstein","year":"2022","journal-title":"Blood."},{"issue":"8","key":"2024041008304173000_CIT0005","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1182\/blood.2021011354","article-title":"Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML","volume":"139","author":"Yang","year":"2022","journal-title":"Blood."},{"key":"2024041008304173000_CIT0006","volume-title":"WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.","author":"Swerdlow","year":"2017","edition":"4"},{"issue":"1","key":"2024041008304173000_CIT0007","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s13059-016-1110-1","article-title":"New insights into the generation and role of de novo mutations in health and disease","volume":"17","author":"Acuna-Hidalgo","year":"2016","journal-title":"Genome Biol."},{"issue":"2","key":"2024041008304173000_CIT0008","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1053\/j.seminhematol.2017.04.006","article-title":"RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)","volume":"54","author":"Schlegelberger","year":"2017","journal-title":"Semin Hematol."},{"issue":"5","key":"2024041008304173000_CIT0009","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/ng.3253","article-title":"Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia","volume":"47","author":"Noetzli","year":"2015","journal-title":"Nat Genet."},{"issue":"11","key":"2024041008304173000_CIT0010","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."},{"issue":"7","key":"2024041008304173000_CIT0011","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."},{"issue":"4","key":"2024041008304173000_CIT0012","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1111\/bjh.18543","article-title":"Inherited cancer predisposing mutations in patients with therapy-related myeloid neoplasms","volume":"200","author":"Shih","year":"2022","journal-title":"Br J Haematol."},{"issue":"3","key":"2024041008304173000_CIT0013","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3109\/10428194.2015.1115041","article-title":"Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults","volume":"57","author":"Babushok","year":"2016","journal-title":"Leuk Lymphoma."},{"issue":"8","key":"2024041008304173000_CIT0014","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1182\/blood-2015-10-676098","article-title":"Novel germ line DDX41 mutations define families with a lower age of MDS\/AML onset and lymphoid malignancies","volume":"127","author":"Lewinsohn","year":"2016","journal-title":"Blood."},{"issue":"18","key":"2024041008304173000_CIT0015","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1182\/blood-2018-07-861070","article-title":"Donor-derived MDS\/AML in families with germline GATA2 mutation","volume":"132","author":"Galera","year":"2018","journal-title":"Blood."},{"issue":"1","key":"2024041008304173000_CIT0016","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1159\/000490311","article-title":"Myeloid neoplasms with germline predisposition","volume":"86","author":"Geyer","year":"2019","journal-title":"Pathobiology."},{"issue":"2","key":"2024041008304173000_CIT0017","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1053\/j.seminhematol.2017.05.002","article-title":"GATA2 deficiency and related myeloid neoplasms","volume":"54","author":"Wlodarski","year":"2017","journal-title":"Semin Hematol."},{"issue":"6","key":"2024041008304173000_CIT0018","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1182\/blood-2013-07-515528","article-title":"GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity","volume":"123","author":"Spinner","year":"2014","journal-title":"Blood."},{"issue":"2","key":"2024041008304173000_CIT0019","doi-asserted-by":"crossref","first-page":"101275","DOI":"10.1016\/j.beha.2021.101275","article-title":"Distinguishing constitutional from acquired bone marrow failure in the hematology clinic","volume":"34","author":"Groarke","year":"2021","journal-title":"Best Pract Res Clin Haematol."},{"issue":"23","key":"2024041008304173000_CIT0020","doi-asserted-by":"crossref","first-page":"3615","DOI":"10.1182\/blood.V126.23.3615.3615","article-title":"Adenosine deaminase 2 deficiency as a cause of pure red cell aplasia mimicking Diamond Blackfan anemia","volume":"126","author":"Sasa","year":"2015","journal-title":"Blood."},{"issue":"2","key":"2024041008304173000_CIT0021","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.jaci.2016.03.016","article-title":"Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: successful hematopoietic stem cell transplantation","volume":"138","author":"Hsu","year":"2016","journal-title":"J Allergy Clin Immunol."},{"issue":"3","key":"2024041008304173000_CIT0022","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1093\/ajcp\/aqz067","article-title":"Germline predisposition to hematolymphoid neoplasia","volume":"152","author":"Weinberg","year":"2019","journal-title":"Am J Clin Pathol."},{"issue":"10","key":"2024041008304173000_CIT0023","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.3324\/haematol.2017.167726","article-title":"Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation","volume":"102","author":"Kanagal-Shamanna","year":"2017","journal-title":"Haematologica."},{"issue":"6","key":"2024041008304173000_CIT0024","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1046\/j.1365-2141.2003.04229.x","article-title":"Transient leukaemia\u2014a benign form of leukaemia in newborn infants with trisomy 21","volume":"120","author":"Zipursky","year":"2003","journal-title":"Br J Haematol."},{"issue":"11","key":"2024041008304173000_CIT0025","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1038\/ng.2759","article-title":"The landscape of somatic mutations in Down syndrome-related myeloid disorders","volume":"45","author":"Yoshida","year":"2013","journal-title":"Nat Genet."},{"issue":"6","key":"2024041008304173000_CIT0026","first-page":"52","article-title":"Transient abnormal myelopoiesis and mosaic Down syndrome in a phenotypically normal newborn","volume":"7","author":"Prudowsky","year":"2020","journal-title":"Children (Basel)"},{"issue":"14","key":"2024041008304173000_CIT0027","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1182\/blood-2016-05-670240","article-title":"How I diagnose and manage individuals at risk for inherited myeloid malignancies","volume":"128","author":"University of Chicago Hematopoietic Malignancies Cancer Risk Team","year":"2016","journal-title":"Blood."},{"issue":"1","key":"2024041008304173000_CIT0028","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/mgg3.350","article-title":"Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype","volume":"6","author":"Asur","year":"2018","journal-title":"Mol Genet Genomic Med."},{"issue":"3","key":"2024041008304173000_CIT0029","doi-asserted-by":"crossref","first-page":"101197","DOI":"10.1016\/j.beha.2020.101197","article-title":"Germline predisposition in myeloid neoplasms: unique genetic and clinical features of GATA2 deficiency and SAMD9\/SAMD9L syndromes","volume":"33","author":"Sahoo","year":"2020","journal-title":"Best Pract Res Clin Haematol."},{"issue":"23","key":"2024041008304173000_CIT0030","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1182\/blood.2021012781","article-title":"Association of unbalanced translocation der(1;7) with germline GATA2 mutations","volume":"138","author":"Kozyra","year":"2021","journal-title":"Blood."},{"issue":"3","key":"2024041008304173000_CIT0031","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1182\/bloodadvances.2021005065","article-title":"ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome","volume":"6","author":"West","year":"2022","journal-title":"Blood Adv."},{"issue":"10","key":"2024041008304173000_CIT0032","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1038\/s41591-021-01511-6","article-title":"Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9\/SAMD9L syndromes","volume":"27","author":"Sahoo","year":"2021","journal-title":"Nat Med."},{"issue":"22","key":"2024041008304173000_CIT0033","doi-asserted-by":"crossref","first-page":"5583","DOI":"10.1182\/blood-2008-07-168260","article-title":"High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder","volume":"113","author":"Preudhomme","year":"2009","journal-title":"Blood."},{"issue":"31","key":"2024041008304173000_CIT0034","doi-asserted-by":"crossref","first-page":"5088","DOI":"10.1200\/JCO.2008.16.5563","article-title":"Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia","volume":"26","author":"Pabst","year":"2008","journal-title":"J Clin Oncol."},{"issue":"5","key":"2024041008304173000_CIT0035","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.ccell.2015.03.017","article-title":"Inherited and somatic defects in DDX41 in myeloid neoplasms","volume":"27","author":"Polprasert","year":"2015","journal-title":"Cancer Cell"},{"issue":"4","key":"2024041008304173000_CIT0036","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/leu.2017.44","article-title":"Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation","volume":"31","author":"Kobayashi","year":"2017","journal-title":"Leukemia."},{"issue":"19","key":"2024041008304173000_CIT0037","doi-asserted-by":"crossref","first-page":"5257","DOI":"10.1182\/blood-2010-12-326322","article-title":"First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation","volume":"117","author":"Xiao","year":"2011","journal-title":"Blood."},{"issue":"12","key":"2024041008304173000_CIT0038","doi-asserted-by":"crossref","first-page":"4639","DOI":"10.1182\/blood-2008-05-156745","article-title":"Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy","volume":"112","author":"Owen","year":"2008","journal-title":"Blood."},{"issue":"5526","key":"2024041008304173000_CIT0039","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/257501a0","article-title":"Is Fanconi\u2019s anaemia defective in a process essential to the repair of DNA cross links","volume":"257","author":"Sasaki","year":"1975","journal-title":"Nature."},{"issue":"8","key":"2024041008304173000_CIT0040","first-page":"1829","article-title":"A high susceptibility of Fanconi\u2019s anemia to chromosome breakage by DNA cross-linking agents","volume":"33","author":"Sasaki","year":"1973","journal-title":"Cancer Res."},{"issue":"4","key":"2024041008304173000_CIT0041","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1182\/blood-2017-02-735290","article-title":"Genetic predisposition to hematologic malignancies: management and surveillance","volume":"130","author":"Godley","year":"2017","journal-title":"Blood."},{"issue":"1","key":"2024041008304173000_CIT0042","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1182\/blood-2014-06-580340","article-title":"GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia","volume":"125","author":"Ganapathi","year":"2015","journal-title":"Blood."},{"issue":"13","key":"2024041008304173000_CIT0043","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1182\/blood.2022017764","article-title":"The spectrum of GATA2 deficiency syndrome","volume":"141","author":"Calvo","year":"2023","journal-title":"Blood."},{"key":"2024041008304173000_CIT0044","first-page":"PO.18.00301","article-title":"Germline genetic predisposition to myeloid neoplasia from GATA2 gene mutations: lessons learned from two cases","volume":"3","author":"Abou Dalle","year":"2019","journal-title":"JCO Precis Oncol"},{"issue":"6","key":"2024041008304173000_CIT0045","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/j.ajhg.2016.04.009","article-title":"Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L","volume":"98","author":"Chen","year":"2016","journal-title":"Am J Hum Genet."},{"issue":"4","key":"2024041008304173000_CIT0046","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1172\/JCI129301","article-title":"Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases","volume":"130","author":"de Jesus","year":"2020","journal-title":"J Clin Invest."},{"issue":"1","key":"2024041008304173000_CIT0047","first-page":"67","article-title":"Diamond Blackfan anemia: genetics, pathogenesis, diagnosis and treatment","volume":"30","author":"Engidaye","year":"2019","journal-title":"EJIFCC"},{"issue":"10","key":"2024041008304173000_CIT0048","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1056\/NEJMoa1307361","article-title":"Early-onset stroke and vasculopathy associated with mutations in ADA2","volume":"370","author":"Zhou","year":"2014","journal-title":"N Engl J Med."},{"key":"2024041008304173000_CIT0049","doi-asserted-by":"crossref","first-page":"811473","DOI":"10.3389\/fimmu.2021.811473","article-title":"The spectrum of the deficiency of adenosine deaminase 2: an observational analysis of a 60 patient cohort","volume":"12","author":"Barron","year":"2022","journal-title":"Front Immunol."}],"container-title":["American Journal of Clinical Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajcp\/article-pdf\/160\/4\/352\/57195455\/aqad075.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajcp\/article-pdf\/160\/4\/352\/57195455\/aqad075.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T08:53:54Z","timestamp":1712739234000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajcp\/article\/160\/4\/352\/7225157"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,18]]},"references-count":49,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,7,18]]},"published-print":{"date-parts":[[2023,10,3]]}},"URL":"https:\/\/doi.org\/10.1093\/ajcp\/aqad075","relation":{},"ISSN":["0002-9173","1943-7722"],"issn-type":[{"value":"0002-9173","type":"print"},{"value":"1943-7722","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,10,1]]},"published":{"date-parts":[[2023,7,18]]}}}