Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Needle in a haystack or elephant in the room? Identifying germline predisposition syndromes in the setting of a new myeloid malignancy diagnosis

Leukemia volume 37, pages 1589–1599 (2023)Cite this article

Subjects

Abstract

Myeloid malignancies associated with germline predisposition syndromes account for up to 10% of myeloid neoplasms. They are classified into three categories by the proposed 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors: (1) neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction, (2) neoplasms with germline predisposition and pre-existing platelet disorder, or (3) neoplasms with germline predisposition and potential organ dysfunction. Recognizing these entities is critical because patients and affected family members benefit from interfacing with hematologists who specialize in these disorders and can facilitate tailored treatment strategies. However, identification of these syndromes in routine pathology practice is often challenging, as characteristic findings associated with these diagnoses at baseline are frequently absent, nonspecific, or impossible to evaluate in the setting of a myeloid malignancy. Here we review the formally classified germline predisposition syndromes associated with myeloid malignancies and summarize practical recommendations for pathologists evaluating a new myeloid malignancy diagnosis. Our intent is to empower clinicians to better screen for germline disorders in this common clinical setting. Recognizing when to suspect a germline predisposition syndrome, pursue additional ancillary testing, and ultimately recommend referral to a cancer predisposition clinic or hematology specialist, will ensure optimal patient care and expedite research to improve outcomes for these individuals.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Age at initial diagnosis of myeloid malignancies for select diagnostic entities.
Fig. 2: Schematics of CEBPA and DDX41 genes and regions associated with germline and acquired mutations.
Fig. 3: Characteristic findings in the settings of germline RUNX1, ANKRD26, or GATA2 mutation.
Fig. 4: Suggested workflow for the identification and triage of new myeloid malignancy diagnoses and potential referral for germline testing.

Similar content being viewed by others

References

  1. Murati A, Brecqueville M, Devillier R, Mozziconacci M-J, Gelsi-Boyer V, Birnbaum D. Myeloid malignancies: mutations, models and management. BMC Cancer. 2012;12:304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shallis RM, Wang R, Davidoff A, Ma X, Zeidan AM. Epidemiology of acute myeloid leukemia: recent progress and enduring challenges. Blood Rev. 2019;36:70–87.

    Article  PubMed  Google Scholar 

  3. SEER*Explorer. https://seer.cancer.gov/explorer/ Accessed 2 Aug 2022.

  4. Volpe VO, Garcia-Manero G, Komrokji RS. Myelodysplastic syndromes: a new decade. Clin Lymphoma Myeloma Leuk. 2022;22:1–16.

    Article  CAS  PubMed  Google Scholar 

  5. Niemeyer CM. JMML genomics and decisions. Hematol Am Soc Hematol Educ Program. 2018;2018:307–12.

    Article  Google Scholar 

  6. Gilad O, Dgany O, Noy-Lotan S, Krasnov T, Yacobovich J, Rabinowicz R, et al. Syndromes predisposing to leukemia are a major cause of inherited cytopenias in children. Haematologica. 2022;107:2081–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Feurstein S, Trottier AM, Estrada-Merly N, Pozsgai M, McNeely K, Drazer MW, et al. Germ line predisposition variants occur in myelodysplastic syndrome patients of all ages. Blood. 2022;140:2533–48.

    Article  CAS  PubMed  Google Scholar 

  8. Yang F, Long N, Anekpuritanang T, Bottomly D, Savage JC, Lee T, et al. Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML. Blood. 2022;139:1208–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36:1703–19.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kanagal-Shamanna R. The emerging role of hematopathologists and molecular pathologists in detection, monitoring, and management of myeloid neoplasms with germline predisposition. Curr Hematol Malig Rep. 2021;16:336–44.

    Article  PubMed  Google Scholar 

  11. Weinberg OK, Kuo F, Calvo KR. Germline predisposition to hematolymphoid neoplasia. Am J Clin Pathol. 2019;152:258–76.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Tawana K, Brown AL, Churpek JE. Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges. Br J Haematol. 2022;196:1293–310.

    Article  CAS  PubMed  Google Scholar 

  13. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med J Am Coll Med Genet. 2015;17:405–24.

    Google Scholar 

  14. Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International consensus classification of myeloid neoplasms and acute leukemia: integrating morphological, clinical, and genomic data. Blood. 2022;140:1200–28. blood.2022015850

    Article  CAS  PubMed  Google Scholar 

  15. Tawana K, Wang J, Renneville A, Bödör C, Hills R, Loveday C, et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood. 2015;126:1214–23.

    Article  CAS  PubMed  Google Scholar 

  16. Pabst T, Eyholzer M, Haefliger S, Schardt J, Mueller BU. Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol. 2008;26:5088–93.

    Article  CAS  PubMed  Google Scholar 

  17. Tawana K, Rio-Machin A, Preudhomme C, Fitzgibbon J. Familial CEBPA-mutated acute myeloid leukemia. Semin Hematol. 2017;54:87–93.

    Article  PubMed  Google Scholar 

  18. Makishima H, Saiki R, Nannya Y, Korotev SC, Gurnari C, Takeda J, et al. Germline DDX41 mutations define a unique subtype of myeloid neoplasms. Blood. 2022. blood.2022018221.

  19. Li P, Brown S, Williams M, White T, Xie W, Cui W, et al. The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms. Blood. 2022;140:716–55.

    Article  CAS  PubMed  Google Scholar 

  20. Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, et al. Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell. 2015;27:658–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Churpek JE, Smith-Simmer K. DDX41-associated familial myelodysplastic syndrome and acute myeloid leukemia. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ et al. (eds). GeneReviews®. University of Washington, Seattle: Seattle (WA), 1993 http://www.ncbi.nlm.nih.gov/books/NBK574843/ (accessed 16 Aug2022).

  22. Guha T, Malkin D. Inherited TP53 mutations and the Li-fraumeni syndrome. Cold Spring Harb Perspect Med. 2017;7:a026187.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Penkert J, Strüwe FJ, Dutzmann CM, Doergeloh BB, Montellier E, Freycon C, et al. Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry. J Hematol OncolJ Hematol Oncol. 2022;15:107.

    Article  CAS  Google Scholar 

  24. Zebisch A, Lal R, Müller M, Lind K, Kashofer K, Girschikofsky M, et al. Acute myeloid leukemia with TP53 germ line mutations. Blood. 2016;128:2270–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Correa H. Li-fraumeni syndrome. J Pediatr Genet. 2016;5:84–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol J Am Soc Clin Oncol. 2009;27:e108–109. author reply e110.

    Article  Google Scholar 

  27. Bougeard G, Renaux-Petel M, Flaman J-M, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol J Am Soc Clin Oncol. 2015;33:2345–52.

    Article  CAS  Google Scholar 

  28. Kratz CP, Freycon C, Maxwell KN, Nichols KE, Schiffman JD, Evans DG, et al. Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set: An International Agency for Research on Cancer TP53 Database Analysis. JAMA Oncol. 2021;7:1800–5.

    Article  PubMed  Google Scholar 

  29. Swaminathan M, Bannon SA, Routbort M, Naqvi K, Kadia TM, Takahashi K, et al. Hematologic malignancies and Li-Fraumeni syndrome. Cold Spring Harb Mol Case Stud. 2019;5:a003210.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Churpek JE, Lorenz R, Nedumgottil S, Onel K, Olopade OI, Sorrell A, et al. Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome/acute leukemia predisposition syndromes. Leuk Lymphoma. 2013;54:28–35.

    Article  PubMed  Google Scholar 

  31. Schlegelberger B, Heller PG. RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM). Semin Hematol. 2017;54:75–80.

    Article  PubMed  Google Scholar 

  32. Bellissimo DC, Speck NA. RUNX1 mutations in inherited and sporadic leukemia. Front Cell Dev Biol. 2017;5:111.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Al-Harbi S, Aljurf M, Mohty M, Almohareb F, Ahmed SOA. An update on the molecular pathogenesis and potential therapeutic targeting of AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1. Blood Adv. 2020;4:229–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brown AL, Arts P, Carmichael CL, Babic M, Dobbins J, Chong C-E, et al. RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv. 2020;4:1131–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Luddy RE, Champion LA, Schwartz AD. A fatal myeloproliferative syndrome in a family with thrombocytopenia and platelet dysfunction. Cancer. 1978;41:1959–63.

    Article  CAS  PubMed  Google Scholar 

  36. Stockley J, Morgan NV, Bem D, Lowe GC, Lordkipanidzé M, Dawood B, et al. Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects. Blood. 2013;122:4090–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jalagadugula G, Mao G, Kaur G, Goldfinger LE, Dhanasekaran DN, Rao AK. Regulation of platelet myosin light chain (MYL9) by RUNX1: implications for thrombocytopenia and platelet dysfunction in RUNX1 haplodeficiency. Blood. 2010;116:6037–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kanagal-Shamanna R, Loghavi S, DiNardo CD, Medeiros LJ, Garcia-Manero G, Jabbour E, et al. Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. Haematologica. 2017;102:1661–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gaidzik VI, Teleanu V, Papaemmanuil E, Weber D, Paschka P, Hahn J, et al. RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features. Leukemia. 2016;30:2160–8.

    Article  CAS  PubMed  Google Scholar 

  40. Noris P, Perrotta S, Seri M, Pecci A, Gnan C, Loffredo G, et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families. Blood. 2011;117:6673–80.

    Article  CAS  PubMed  Google Scholar 

  41. Pippucci T, Savoia A, Perrotta S, Pujol-Moix N, Noris P, Castegnaro G, et al. Mutations in the 5’ UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am J Hum Genet. 2011;88:115–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sullivan MJ, Palmer EL, Botero JP. ANKRD26-related thrombocytopenia and predisposition to myeloid neoplasms. Curr Hematol Malig Rep. 2022. https://doi.org/10.1007/s11899-022-00666-4.

    Article  PubMed  Google Scholar 

  43. Al Daama SA, Housawi YH, Dridi W, Sager M, Otieno FG, Hou C, et al. A missense mutation in ANKRD26 segregates with thrombocytopenia. Blood. 2013;122:461–2.

    Article  CAS  PubMed  Google Scholar 

  44. Di Paola J, Porter CC. ETV6-related thrombocytopenia and leukemia predisposition. Blood. 2019;134:663–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Melazzini F, Palombo F, Balduini A, De Rocco D, Marconi C, Noris P, et al. Clinical and pathogenic features of ETV6-related thrombocytopenia with predisposition to acute lymphoblastic leukemia. Haematologica. 2016;101:1333–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Di Paola J, Fisher MH. ETV6-related thrombocytopenia and platelet dysfunction. Platelets. 2021;32:141–3.

    Article  PubMed  Google Scholar 

  47. Noetzli L, Lo RW, Lee-Sherick AB, Callaghan M, Noris P, Savoia A, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015;47:535–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nishii R, Baskin-Doerfler R, Yang W, Oak N, Zhao X, Yang W, et al. Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia. Blood. 2021;137:364–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123:809–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Katsumura KR, Bresnick EH. Group the GFM. The GATA factor revolution in hematology. Blood. 2017;129:2092–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hsu AP, Johnson KD, Falcone EL, Sanalkumar R, Sanchez L, Hickstein DD, et al. GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. Blood. 2013;121:3830–7. S1-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Johnson KD, Hsu AP, Ryu M-J, Wang J, Gao X, Boyer ME, et al. Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity. J Clin Invest. 2012;122:3692–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bresnick EH, Jung MM, Katsumura KR. Human GATA2 mutations and hematologic disease: how many paths to pathogenesis? Blood Adv. 2020;4:4584–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ping N, Sun A, Song Y, Wang Q, Yin J, Cheng W, et al. Exome sequencing identifies highly recurrent somatic GATA2 and CEBPA mutations in acute erythroid leukemia. Leukemia. 2017;31:195–202.

    Article  CAS  PubMed  Google Scholar 

  55. Calvo KR, Vinh DC, Maric I, Wang W, Noel P, Stetler-Stevenson M, et al. Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications. Haematologica. 2011;96:1221–5.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Narumi S. Discovery of MIRAGE syndrome. Pediatr Int J Jpn Pediatr Soc. 2022;64:e15283.

    Google Scholar 

  57. Tanase-Nakao K, Olson TS, Narumi S MIRAGE Syndrome. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ et al. (eds). GeneReviews®. University of Washington, Seattle: Seattle (WA), 1993 http://www.ncbi.nlm.nih.gov/books/NBK564655/ (accessed 12 Sep2022).

  58. Bluteau O, Sebert M, Leblanc T, Peffault de Latour R, Quentin S, Lainey E, et al. A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. Blood. 2018;131:717–32.

    Article  CAS  PubMed  Google Scholar 

  59. Schwartz JR, Ma J, Lamprecht T, Walsh M, Wang S, Bryant V, et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun. 2017;8:1557.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Narumi S, Amano N, Ishii T, Katsumata N, Muroya K, Adachi M, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48:792–7.

    Article  CAS  PubMed  Google Scholar 

  61. Buonocore F, Kühnen P, Suntharalingham JP, Del Valle I, Digweed M, Stachelscheid H, et al. Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Invest 2017;127:1700–13.

    Article  Google Scholar 

  62. Ahmed IA, Farooqi MS, Vander Lugt MT, Boklan J, Rose M, Friehling ED, et al. Outcomes of hematopoietic cell transplantation in patients with germline SAMD9/SAMD9L mutations. Biol Blood Marrow Transpl J Am Soc Blood Marrow Transpl. 2019;25:2186–96.

    Article  CAS  Google Scholar 

  63. Chen D-H, Below JE, Shimamura A, Keel SB, Matsushita M, Wolff J, et al. Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L. Am J Hum Genet. 2016;98:1146–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gorcenco S, Komulainen-Ebrahim J, Nordborg K, Suo-Palosaari M, Andréasson S, Krüger J, et al. Ataxia-pancytopenia syndrome with SAMD9L mutations. Neurol Genet. 2017;3:e183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nagamachi A, Matsui H, Asou H, Ozaki Y, Aki D, Kanai A, et al. Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell. 2013;24:305–17.

    Article  CAS  PubMed  Google Scholar 

  66. Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, et al. Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes. Blood. 2018;132:2309–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tummala H, Walne A, Dokal I. The biology and management of dyskeratosis congenita and related disorders of telomeres. Expert Rev Hematol. 2022;15:685–96.

    Article  CAS  PubMed  Google Scholar 

  68. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018;103:30–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kratz CP, Izraeli S. Down syndrome, RASopathies, and other rare syndromes. Semin Hematol. 2017;54:123–8.

    Article  PubMed  Google Scholar 

  70. Patnaik MM, Lasho TL. Genomics of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes. Hematol Am Soc Hematol Educ Program. 2020;2020:450–9.

    Article  Google Scholar 

  71. Dh G, Re F, Rh L, Br K, Pl W, Kj J. Neurofibromatosis type 1. Nat Rev Dis Primer. 2017; 3. https://doi.org/10.1038/nrdp.2017.4.

  72. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet Lond Engl. 2013;381:333–42.

    Article  CAS  Google Scholar 

  73. Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pr Res Clin Endocrinol Metab. 2011;25:161–79.

    Article  CAS  Google Scholar 

  74. Leardini D, Messelodi D, Muratore E, Baccelli F, Bertuccio SN, Anselmi L, et al. Role of CBL mutations in cancer and non-malignant phenotype. Cancers. 2022;14:839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Niemeyer CM, Flotho C. Juvenile myelomonocytic leukemia: who’s the driver at the wheel? Blood. 2019;133:1060–70.

    Article  CAS  PubMed  Google Scholar 

  76. Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergsträsser E, Emanuel PD, et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood. 2005;106:2183–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kratz CP, Niemeyer CM. Juvenile myelomonocytic leukemia. Hematol Amst Neth. 2005;10:100–3.

    Google Scholar 

  78. Niemeyer CM. RAS diseases in children. Haematologica. 2014;99:1653–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Boucher AC, Caldwell KJ, Crispino JD, Flerlage JE. Clinical and biological aspects of myeloid leukemia in Down syndrome. Leukemia. 2021;35:3352–60.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Roberts I, Alford K, Hall G, Juban G, Richmond H, Norton A, et al. GATA1-mutant clones are frequent and often unsuspected in babies with Down syndrome: identification of a population at risk of leukemia. Blood. 2013;122:3908–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Goemans BF, Noort S, Blink M, Wang Y-D, Peters STCJ, van Wouwe JP, et al. Sensitive GATA1 mutation screening reliably identifies neonates with Down syndrome at risk for myeloid leukemia. Leukemia. 2021;35:2403–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Pine SR, Guo Q, Yin C, Jayabose S, Druschel CM, Sandoval C. Incidence and clinical implications of GATA1 mutations in newborns with Down syndrome. Blood. 2007;110:2128–31.

    Article  CAS  PubMed  Google Scholar 

  83. Cunniff C, Bassetti JA, Ellis NA. Bloom’s syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition. Mol Syndromol. 2017;8:4–23.

    Article  CAS  PubMed  Google Scholar 

  84. Hafsi W, Badri T, Rice AS. Bloom Syndrome. In: StatPearls. StatPearls Publishing: Treasure Island (FL), 2022 http://www.ncbi.nlm.nih.gov/books/NBK448138/ Accessed 22 Nov 2022.

  85. Thomas ERA, Shanley S, Walker L, Eeles R. Surveillance and treatment of malignancy in Bloom syndrome. Clin Oncol R Coll Radio G B. 2008;20:375–9.

    Article  CAS  Google Scholar 

  86. Niraj J, Färkkilä A, D’Andrea AD. The fanconi anemia pathway in cancer. Annu Rev Cancer Biol. 2019;3:457–78.

    Article  PubMed  Google Scholar 

  87. Glanz A, Fraser FC. Spectrum of anomalies in Fanconi anaemia. J Med Genet. 1982;19:412–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. West AH, Churpek JE. Old and new tools in the clinical diagnosis of inherited bone marrow failure syndromes. Hematol Am Soc Hematol Educ Program. 2017;2017:79–87.

    Article  Google Scholar 

  89. Mehta PA, Ebens C Fanconi Anemia. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ et al. (eds). GeneReviews®. University of Washington, Seattle: Seattle (WA), 1993 http://www.ncbi.nlm.nih.gov/books/NBK1401/ Accessed 14 Sep 2022.

  90. Nelson A, Myers K Shwachman-Diamond Syndrome. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ et al. (eds). GeneReviews®. University of Washington, Seattle: Seattle (WA), 1993 http://www.ncbi.nlm.nih.gov/books/NBK1756/ Accessed 14 Sep 2022.

  91. Bezzerri V, Cipolli M. Shwachman-diamond syndrome: molecular mechanisms and current perspectives. Mol Diagn Ther. 2019;23:281–90.

    Article  CAS  PubMed  Google Scholar 

  92. Reilly CR, Shimamura A. Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: Biological insights and clinical advances. Blood. 2022. blood.2022017739

  93. Furutani E, Liu S, Galvin A, Steltz S, Malsch MM, Loveless SK, et al. Hematologic complications with age in Shwachman-Diamond syndrome. Blood Adv. 2022;6:297–306.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Da Costa L, Leblanc T, Mohandas N. Diamond-Blackfan anemia. Blood. 2020;136:1262–73.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Sieff C Diamond-Blackfan Anemia. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ et al. (eds). GeneReviews®. University of Washington, Seattle: Seattle (WA), 1993 http://www.ncbi.nlm.nih.gov/books/NBK7047/ Accessed 14 Sep 2022.

  96. Means RT. Pure red cell aplasia. Blood. 2016;128:2504–9.

    Article  CAS  PubMed  Google Scholar 

  97. Vlachos A, Rosenberg PS, Atsidaftos E, Alter BP, Lipton JM. Incidence of neoplasia in diamond blackfan anemia: a report from the diamond blackfan anemia registry. Blood. 2012;119:3815–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rosenberg PS, Zeidler C, Bolyard AA, Alter BP, Bonilla MA, Boxer LA, et al. Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br J Haematol. 2010;150:196–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Dale DC, Bolyard AA, Schwinzer BG, Pracht G, Bonilla MA, Boxer L, et al. The severe chronic neutropenia international registry: 10-year follow-up report. Support Cancer Ther. 2006;3:220–31.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr. Catherine Leith, Dr. Erik Ranheim, and Dr. David Yang for helpful discussions and comments.

Funding

This work was supported by National Institute of Health (K08 DK127244 and T32 HL007899) and The Hartwell Foundation to DRM, and by the Evans Foundation to JEC.

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Wisconsin—Madison, Madison, WI, USA

    Erica F. Reinig, Apoorva T. Patil & Daniel R. Matson

  2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Jeremy D. Rubinstein

  3. Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Jeremy D. Rubinstein

  4. Department of Surgery, University of Wisconsin—Madison, Madison, WI, USA

    Amanda L. Schussman

  5. Center for Human Genomics and Precision Medicine, University of Wisconsin—Madison, Madison, WI, USA

    Amanda L. Schussman

  6. Wisconsin State Laboratory of Hygiene, University of Wisconsin-Madison, Madison, WI, USA

    Vanessa L. Horner

  7. Department of Hematopathology and Molecular Diagnostics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Rashmi Kanagal-Shamanna

  8. Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin—Madison, Madison, WI, USA

    Jane E. Churpek

  9. Wisconsin Blood Cancer Research Institute, Madison, WI, USA

    Jane E. Churpek & Daniel R. Matson

Authors
  1. Erica F. Reinig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeremy D. Rubinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Apoorva T. Patil
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amanda L. Schussman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vanessa L. Horner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rashmi Kanagal-Shamanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jane E. Churpek
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daniel R. Matson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DRM, EFR, VLH, RKS, and JEC reviewed the literature; DRM, EFR, and JEC developed and wrote the manuscript; JDR, VLH, RKS, ATP, and ALS provided feedback and edited manuscript.

Corresponding author

Correspondence to Daniel R. Matson.

Ethics declarations

Competing interests

JEC receives honoraria from UpToDate, Inc related to an educational article on hereditary hematologic malignancies. VHL is an employee and shareholder of Exact Sciences. The authors otherwise declare no conflicts of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reinig, E.F., Rubinstein, J.D., Patil, A.T. et al. Needle in a haystack or elephant in the room? Identifying germline predisposition syndromes in the setting of a new myeloid malignancy diagnosis. Leukemia 37, 1589–1599 (2023). https://doi.org/10.1038/s41375-023-01955-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-023-01955-4

This article is cited by

Search

Advanced search

Quick links