Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Familial acute leukemia and myelodysplastic syndromes

Jane E Churpek, MD
Lucy A Godley, MD, PhD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD


Familial forms of acute leukemia (AL) and/or myelodysplastic syndrome (MDS) have been traditionally considered rare, especially among adults affected by these malignancies. However, attention to the family history and genetic investigations of families in whom AL and/or MDS cases cluster have identified nine genes that cause inherited forms of these diseases that can present throughout the lifespan.

Here we discuss the recognized syndromes that cause a predisposition to AL and/or MDS as the main presenting feature. The many other disorders with an inherited predisposition to AL and/or MDS that have other prominent systemic manifestations, such as Down syndrome or neurofibromatosis type I, are reviewed in more detail separately, as are the inherited bone marrow failure syndromes, such as Fanconi anemia and Shwachman-Diamond syndrome, which most frequently present in childhood. (See "Down syndrome: Clinical features and diagnosis" and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Inherited aplastic anemia in children and adolescents" and "Shwachman-Diamond syndrome".)


The incidence of the known familial AL and MDS syndromes (table 1) is not well characterized. In a study that used next-generation sequencing to determine the contribution of germline predisposition mutations in sporadic pediatric cancer, mutations that were deemed to be pathogenic or probably pathogenic were identified in 26 of 588 (4 percent) patients with pediatric leukemia [1]. However, many families in whom MDS and AL cluster test negative for mutations in all of the currently known genes, suggesting that additional causative genes remain to be identified. Because many of the genes that cause the familial AL and MDS syndromes when mutated in the germline or constitutional state are also found as somatic or acquired mutations, prior studies that sequenced these genes at diagnosis in large numbers of presumably de novo AL and MDS cases provide estimates of the maximum number of cases that could be accounted for by each inherited syndrome. Details regarding the maximum prevalence for each described entity are provided in the sections below.

Variation by race, ethnicity, and geography are not currently known. The families described in most of the familial AL and MDS syndromes appear to have their own private inherited mutations, suggesting independent events rather than a "founder" mutation occurring on an ancestral allele in a particular population.


Whom, when, and how to screen — All patients with AL and MDS should be screened at the time of initial diagnosis or referral to rule out the presence of a familial AL and MDS syndrome [2]. Similar screening is also essential during the initial pre-donation health screening evaluation for all individuals (related and unrelated) who wish to serve as an allogeneic hematopoietic cell donor for a person with a hematologic malignancy, either related or unrelated [3]. Screening consists of obtaining a careful medical and family history aimed at identifying signs and symptoms of the known familial AL and MDS syndromes. Specific information to elicit includes (figure 1):


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: May 4, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Zhang J, Walsh MF, Wu G, et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 2015; 373:2336.
  2. Churpek JE, Lorenz R, Nedumgottil S, 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.
  3. Churpek JE, Nickels E, Marquez R, et al. Identifying familial myelodysplastic/acute leukemia predisposition syndromes through hematopoietic stem cell transplantation donors with thrombocytopenia. Blood 2012; 120:5247.
  4. Lu KH, Wood ME, Daniels M, et al. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol 2014; 32:833.
  5. Horwitz M, Goode EL, Jarvik GP. Anticipation in familial leukemia. Am J Hum Genet 1996; 59:990.
  6. Savage SA, Bertuch AA. The genetics and clinical manifestations of telomere biology disorders. Genet Med 2010; 12:753.
  7. Tegg EM, Thomson RJ, Stankovich JM, et al. Anticipation in familial hematologic malignancies. Blood 2011; 117:1308.
  8. https://www.genetests.org/ (Accessed on September 23, 2014).
  9. Ewalt M, Galili NG, Mumtaz M, et al. DNMT3a mutations in high-risk myelodysplastic syndrome parallel those found in acute myeloid leukemia. Blood Cancer J 2011; 1:e9.
  10. Rasi S, Bruscaggin A, Rinaldi A, et al. Saliva is a reliable and practical source of germline DNA for genome-wide studies in chronic lymphocytic leukemia. Leuk Res 2011; 35:1419.
  11. Heinrichs S, Li C, Look AT. SNP array analysis in hematologic malignancies: avoiding false discoveries. Blood 2010; 115:4157.
  12. Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012; 481:506.
  13. Busque L, Patel JP, Figueroa ME, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 2012; 44:1179.
  14. Welch JS, Ley TJ, Link DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012; 150:264.
  15. Owen C, Barnett M, Fitzgibbon J. Familial myelodysplasia and acute myeloid leukaemia--a review. Br J Haematol 2008; 140:123.
  16. Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med 2004; 351:2403.
  17. Pabst T, Eyholzer M, Haefliger S, et al. 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.
  18. Green CL, Tawana K, Hills RK, et al. GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations. Br J Haematol 2013; 161:701.
  19. Stelljes M, Corbacioglu A, Schlenk RF, et al. Allogeneic stem cell transplant to eliminate germline mutations in the gene for CCAAT-enhancer-binding protein α from hematopoietic cells in a family with AML. Leukemia 2011; 25:1209.
  20. Tawana K, Wang J, Renneville A, et al. Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood 2015; 126:1214.
  21. Pabst T, Eyholzer M, Fos J, Mueller BU. Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer 2009; 100:1343.
  22. Preudhomme C, Sagot C, Boissel N, et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 2002; 100:2717.
  23. Taskesen E, Bullinger L, Corbacioglu A, et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 2011; 117:2469.
  24. Xiao H, Shi J, Luo Y, et al. First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation. Blood 2011; 117:5257.
  25. Polprasert C, Schulze I, Sekeres MA, et al. Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell 2015; 27:658.
  26. Lewinsohn M, Brown AL, Weinel LM, et al. Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies. Blood 2016; 127:1017.
  27. Zhang Z, Yuan B, Bao M, et al. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol 2011; 12:959.
  28. Parvatiyar K, Zhang Z, Teles RM, et al. The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat Immunol 2012; 13:1155.
  29. Balduini CL, Pecci A, Noris P. Diagnosis and management of inherited thrombocytopenias. Semin Thromb Hemost 2013; 39:161.
  30. Owen CJ, Toze CL, Koochin A, et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood 2008; 112:4639.
  31. Song WJ, Sullivan MG, Legare RD, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 1999; 23:166.
  32. Arepally G, Rebbeck TR, Song W, et al. Evidence for genetic homogeneity in a familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML). Blood 1998; 92:2600.
  33. Béri-Dexheimer M, Latger-Cannard V, Philippe C, et al. Clinical phenotype of germline RUNX1 haploinsufficiency: from point mutations to large genomic deletions. Eur J Hum Genet 2008; 16:1014.
  34. Buijs A, Poddighe P, van Wijk R, et al. A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies. Blood 2001; 98:2856.
  35. Churpek JE, Garcia JS, Madzo J, et al. Identification and molecular characterization of a novel 3′ mutation in RUNX1 in a family with familial platelet disorder. Leuk Lymphoma 2010; 51:1931.
  36. Kirito K, Sakoe K, Shinoda D, et al. A novel RUNX1 mutation in familial platelet disorder with propensity to develop myeloid malignancies. Haematologica 2008; 93:155.
  37. Michaud J, Wu F, Osato M, et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood 2002; 99:1364.
  38. Preudhomme C, Renneville A, Bourdon V, et al. High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder. Blood 2009; 113:5583.
  39. Churpek JE, Pyrtel K, Kanchi KL, et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood 2015; 126:2484.
  40. Yoshimi A, Toya T, Kawazu M, et al. Recurrent CDC25C mutations drive malignant transformation in FPD/AML. Nat Commun 2014; 5:4770.
  41. Nickels EM, Soodalter J, Churpek JE, Godley LA. Recognizing familial myeloid leukemia in adults. Ther Adv Hematol 2013; 4:254.
  42. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368:2059.
  43. Chen CY, Lin LI, Tang JL, et al. RUNX1 gene mutation in primary myelodysplastic syndrome--the mutation can be detected early at diagnosis or acquired during disease progression and is associated with poor outcome. Br J Haematol 2007; 139:405.
  44. Tang JL, Hou HA, Chen CY, et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 2009; 114:5352.
  45. Schnittger S, Dicker F, Kern W, et al. RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis. Blood 2011; 117:2348.
  46. Liew E, Owen C. Familial myelodysplastic syndromes: a review of the literature. Haematologica 2011; 96:1536.
  47. Noris P, Perrotta S, Seri M, 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.
  48. Marquez R, Hantel A, Lorenz R, et al. A new family with a germline ANKRD26 mutation and predisposition to myeloid malignancies. Leuk Lymphoma 2014; 55:2945.
  49. Noris P, Favier R, Alessi MC, et al. ANKRD26-related thrombocytopenia and myeloid malignancies. Blood 2013; 122:1987.
  50. Pippucci T, Savoia A, Perrotta S, 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.
  51. Al Daama SA, Housawi YH, Dridi W, et al. A missense mutation in ANKRD26 segregates with thrombocytopenia. Blood 2013; 122:461.
  52. Bluteau D, Balduini A, Balayn N, et al. Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. J Clin Invest 2014; 124:580.
  53. Noetzli L, Lo RW, Lee-Sherick AB, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet 2015; 47:535.
  54. Zhang MY, Churpek JE, Keel SB, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet 2015; 47:180.
  55. Topka S, Vijai J, Walsh MF, et al. Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS Genet 2015; 11:e1005262.
  56. Hahn CN, Chong CE, Carmichael CL, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 2011; 43:1012.
  57. Wlodarski MW, Hirabayashi S, Pastor V, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood 2016; 127:1387.
  58. Ostergaard P, Simpson MA, Connell FC, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet 2011; 43:929.
  59. Dickinson RE, Griffin H, Bigley V, et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood 2011; 118:2656.
  60. Hsu AP, Sampaio EP, Khan J, et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 2011; 118:2653.
  61. Spinner MA, Sanchez LA, Hsu AP, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 2014; 123:809.
  62. Ishida H, Imai K, Honma K, et al. GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia. Eur J Pediatr 2012; 171:1273.
  63. Pasquet M, Bellanné-Chantelot C, Tavitian S, et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood 2013; 121:822.
  64. Dickinson RE, Milne P, Jardine L, et al. The evolution of cellular deficiency in GATA2 mutation. Blood 2014; 123:863.
  65. Micol JB, Abdel-Wahab O. Collaborating constitutive and somatic genetic events in myeloid malignancies: ASXL1 mutations in patients with germline GATA2 mutations. Haematologica 2014; 99:201.
  66. West RR, Hsu AP, Holland SM, et al. Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation. Haematologica 2014; 99:276.
  67. Bödör C, Renneville A, Smith M, et al. Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival. Haematologica 2012; 97:890.
  68. Cuellar-Rodriguez J, Gea-Banacloche J, Freeman AF, et al. Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. Blood 2011; 118:3715.
  69. Holme H, Hossain U, Kirwan M, et al. Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia. Br J Haematol 2012; 158:242.
  70. Kirwan M, Walne AJ, Plagnol V, et al. Exome sequencing identifies autosomal-dominant SRP72 mutations associated with familial aplasia and myelodysplasia. Am J Hum Genet 2012; 90:888.
  71. Saliba J, Saint-Martin C, Di Stefano A, et al. Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nat Genet 2015; 47:1131.
  72. Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev 2010; 24:101.
  73. Dokal I, Vulliamy T. Inherited bone marrow failure syndromes. Haematologica 2010; 95:1236.
  74. Alter BP, Giri N, Savage SA, et al. Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol 2010; 150:179.
  75. Dror Y, Donadieu J, Koglmeier J, et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci 2011; 1242:40.
  76. Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 2003; 101:1249.
  77. Rosenberg PS, Greene MH, Alter BP. Cancer incidence in persons with Fanconi anemia. Blood 2003; 101:822.
  78. Savage SA, Dokal I, Armanios M, et al. Dyskeratosis congenita: the first NIH clinical research workshop. Pediatr Blood Cancer 2009; 53:520.
  79. Rosenberg PS, Alter BP, Ebell W. Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry. Haematologica 2008; 93:511.
  80. Heiss NS, Knight SW, Vulliamy TJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 1998; 19:32.
  81. Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol 2013; 6:327.
  82. Fogarty PF, Yamaguchi H, Wiestner A, et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet 2003; 362:1628.
  83. Dietz AC, Orchard PJ, Baker KS, et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transplant 2011; 46:98.
  84. Nishio N, Takahashi Y, Ohashi H, et al. Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita. Pediatr Transplant 2011; 15:161.
  85. Ayas M, Nassar A, Hamidieh AA, et al. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure. Bone Marrow Transplant 2013; 48:1168.
  86. Auer F, Rüschendorf F, Gombert M, et al. Inherited susceptibility to pre B-ALL caused by germline transmission of PAX5 c.547G>A. Leukemia 2014; 28:1136.
  87. Shah S, Schrader KA, Waanders E, et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet 2013; 45:1226.
  88. Powell BC, Jiang L, Muzny DM, et al. Identification of TP53 as an acute lymphocytic leukemia susceptibility gene through exome sequencing. Pediatr Blood Cancer 2013; 60:E1.
  89. Perez-Garcia A, Ambesi-Impiombato A, Hadler M, et al. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood 2013; 122:2425.
  90. Kuehn HS, Boisson B, Cunningham-Rundles C, et al. Loss of B Cells in Patients with Heterozygous Mutations in IKAROS. N Engl J Med 2016; 374:1032.
  91. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009; 27:1250.
  92. Heymann S, Delaloge S, Rahal A, et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Radiat Oncol 2010; 5:104.
Topic Outline