Skip to main content
Erschienen in: Current Hematologic Malignancy Reports 5/2022

25.06.2022 | Germline Predisposition to Myeloid Neoplasms (M. Patnaik, Section Editor)

ANKRD26-Related Thrombocytopenia and Predisposition to Myeloid Neoplasms

verfasst von: Mia J. Sullivan, Elizabeth L. Palmer, Juliana Perez Botero

Erschienen in: Current Hematologic Malignancy Reports | Ausgabe 5/2022

Einloggen, um Zugang zu erhalten

Abstract

Purpose of review

This review describes ANKRD26-related thrombocytopenia (RT) from a molecular, clinical, and laboratory perspective, with a focus on the clinical decision-making that takes place in the diagnosis and management of families with ANKRD26-RT.

Recent findings

ANKRD26-related thrombocytopenia (ANKRD26-RT) is a non-syndromic autosomal dominant thrombocytopenia with predisposition to hematologic neoplasm. The clinical presentation is variable with moderate thrombocytopenia with normal platelet size and absent to mild bleeding being the hallmark which makes it difficult to distinguish from other inherited thrombocytopenias. The pathophysiology involves overexpression of ANKRD26 through loss of inhibitory control by transcription factors RUNX1 and FLI1. The great majority of disease-causing variants are in the 5′ untranslated region. Acute myeloid leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia have been reported to occur in the context of germline variants in ANKRD26, with the development of somatic driver mutations in hematopoietic regulators playing an important role in malignant transformation. In the absence of clear risk estimates of development of malignancy, optimal surveillance strategies and interventions to reduce risk of evolution to a myeloid disorder, multidisciplinary evaluation, with a strong genetic counseling framework is essential in the approach to these patients and their families.

Summary

Gene-specific expertise and a multidisciplinary approach are important in the diagnosis and treatment of patients and families with ANKRD26-RT. These strategies help overcome the challenges faced by clinicians in the evaluation of individuals with a rare, non-syndromic, inherited disorder with predisposition to hematologic malignancy for which large data to guide decision-making is not available.
Literatur
1.
Zurück zum Zitat Pippucci T, 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(1):115–20. CrossRef Pippucci T, 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(1):115–20. CrossRef
2.
Zurück zum Zitat •• Bluteau D, et al. Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation . J Clin Invest, 2014. 124(2): 580–91. Defines the molecular mechanisms of disease in ANKRD26-RT. •• Bluteau D, et al. Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation . J Clin Invest, 2014. 124(2): 580–91. Defines the molecular mechanisms of disease in ANKRD26-RT.
3.
Zurück zum Zitat Savoia A, et al. An autosomal dominant thrombocytopenia gene maps to chromosomal region 10p. Am J Hum Genet. 1999;65(5):1401–5. CrossRef Savoia A, et al. An autosomal dominant thrombocytopenia gene maps to chromosomal region 10p. Am J Hum Genet. 1999;65(5):1401–5. CrossRef
4.
Zurück zum Zitat Drachman JG, Jarvik GP, Mehaffey MG. Autosomal dominant thrombocytopenia: incomplete megakaryocyte differentiation and linkage to human chromosome 10. Blood. 2000;96(1):118–25. CrossRef Drachman JG, Jarvik GP, Mehaffey MG. Autosomal dominant thrombocytopenia: incomplete megakaryocyte differentiation and linkage to human chromosome 10. Blood. 2000;96(1):118–25. CrossRef
5.
Zurück zum Zitat Gandhi MJ, Cummings CL, Drachman JG. FLJ14813 missense mutation: a candidate for autosomal dominant thrombocytopenia on human chromosome 10. Hum Hered. 2003;55(1):66–70. CrossRef Gandhi MJ, Cummings CL, Drachman JG. FLJ14813 missense mutation: a candidate for autosomal dominant thrombocytopenia on human chromosome 10. Hum Hered. 2003;55(1):66–70. CrossRef
6.
Zurück zum Zitat Punzo F, et al. A mutation in the acyl-coenzyme A binding domain-containing protein 5 gene (ACBD5) identified in autosomal dominant thrombocytopenia. J Thromb Haemost. 2010;8(9):2085–7. CrossRef Punzo F, et al. A mutation in the acyl-coenzyme A binding domain-containing protein 5 gene (ACBD5) identified in autosomal dominant thrombocytopenia. J Thromb Haemost. 2010;8(9):2085–7. CrossRef
7.
Zurück zum Zitat Balduini CL, Pecci A, Noris P. Inherited thrombocytopenias: the evolving spectrum. Hamostaseologie. 2012;32(4):259–70. CrossRef Balduini CL, Pecci A, Noris P. Inherited thrombocytopenias: the evolving spectrum. Hamostaseologie. 2012;32(4):259–70. CrossRef
8.
Zurück zum Zitat Balduini CL, Savoia A. Genetics of familial forms of thrombocytopenia. Hum Genet. 2012;131(12):1821–32. CrossRef Balduini CL, Savoia A. Genetics of familial forms of thrombocytopenia. Hum Genet. 2012;131(12):1821–32. CrossRef
9.
Zurück zum Zitat Mazharian A, Watson SP, and Severin S. Critical role for ERK1/2 in bone marrow and fetal liver-derived primary megakaryocyte differentiation, motility, and proplatelet formation . Exp Hematol, 2009. 37(10): 1238–1249 e5. Mazharian A, Watson SP, and Severin S. Critical role for ERK1/2 in bone marrow and fetal liver-derived primary megakaryocyte differentiation, motility, and proplatelet formation . Exp Hematol, 2009. 37(10): 1238–1249 e5.
10.
Zurück zum Zitat Balduini A, et al. Clinic, pathogenic mechanisms and drug testing of two inherited thrombocytopenias, ANKRD26-related thrombocytopenia and MYH9-related diseases. Eur J Med Genet. 2018;61(11):715–22. CrossRef Balduini A, et al. Clinic, pathogenic mechanisms and drug testing of two inherited thrombocytopenias, ANKRD26-related thrombocytopenia and MYH9-related diseases. Eur J Med Genet. 2018;61(11):715–22. CrossRef
11.
Zurück zum Zitat Perez Botero J, Di Paola J. Diagnostic approach to the patient with a suspected inherited platelet disorder: who and how to test . J Thromb Haemost, 2021;19(9): 2127–2136. Perez Botero J, Di Paola J. Diagnostic approach to the patient with a suspected inherited platelet disorder: who and how to test . J Thromb Haemost, 2021;19(9): 2127–2136.
12.
Zurück zum Zitat •• Noris P, et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families . Blood, 2011;117(24):6673–80. Largest clinical cohort presenting clinical, laboratory and molecular characterization of patients with ANKRD26-RT. •• Noris P, et al. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families . Blood, 2011;117(24):6673–80. Largest clinical cohort presenting clinical, laboratory and molecular characterization of patients with ANKRD26-RT.
13.
Zurück zum Zitat Perez Botero J, et al. Clinical and laboratory characteristics in congenital ANKRD26 mutation-associated thrombocytopenia: a detailed phenotypic study of a family. Platelets. 2016;27(7):712–5. CrossRef Perez Botero J, et al. Clinical and laboratory characteristics in congenital ANKRD26 mutation-associated thrombocytopenia: a detailed phenotypic study of a family. Platelets. 2016;27(7):712–5. CrossRef
14.
Zurück zum Zitat Sharma R, Perez Botero J, Jobe SM. Congenital disorders of platelet function and number . Pediatr Clin North Am, 2018;65(3): 561–578. Sharma R, Perez Botero J, Jobe SM. Congenital disorders of platelet function and number . Pediatr Clin North Am, 2018;65(3): 561–578.
15.
Zurück zum Zitat Noetzli L, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015;47(5):535–8. CrossRef Noetzli L, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015;47(5):535–8. CrossRef
16.
Zurück zum Zitat Noris P, et al. ANKRD26-related thrombocytopenia and myeloid malignancies. Blood. 2013;122(11):1987–9. CrossRef Noris P, et al. ANKRD26-related thrombocytopenia and myeloid malignancies. Blood. 2013;122(11):1987–9. CrossRef
17.
Zurück zum Zitat Beri-Dexheimer M, et al. Clinical phenotype of germline RUNX1 haploinsufficiency: from point mutations to large genomic deletions. Eur J Hum Genet. 2008;16(8):1014–8. CrossRef Beri-Dexheimer M, et al. Clinical phenotype of germline RUNX1 haploinsufficiency: from point mutations to large genomic deletions. Eur J Hum Genet. 2008;16(8):1014–8. CrossRef
18.
Zurück zum Zitat Antony-Debre I, et al. Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia. Leukemia. 2016;30(4):999–1002. CrossRef Antony-Debre I, et al. Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia. Leukemia. 2016;30(4):999–1002. CrossRef
19.
Zurück zum Zitat Martin ES, et al. Spectrum of hematological malignancies, clonal evolution and outcomes in 144 Mayo Clinic patients with germline predisposition syndromes. Am J Hematol. 2021;96(11):1450–60. CrossRef Martin ES, et al. Spectrum of hematological malignancies, clonal evolution and outcomes in 144 Mayo Clinic patients with germline predisposition syndromes. Am J Hematol. 2021;96(11):1450–60. CrossRef
20.
Zurück zum Zitat • Downes K, et al. Clinical management, ethics and informed consent related to multi-gene panel-based high throughput sequencing testing for platelet disorders: communication from the SSC of the ISTH . J Thromb Haemost, 2020. 18(10):2751–2758. Consensus statement on informed consent for patients tested with multi-gene panels for inherited platelet disorders with specific focus on predisposition to maliganncy. • Downes K, et al. Clinical management, ethics and informed consent related to multi-gene panel-based high throughput sequencing testing for platelet disorders: communication from the SSC of the ISTH . J Thromb Haemost, 2020. 18(10):2751–2758. Consensus statement on informed consent for patients tested with multi-gene panels for inherited platelet disorders with specific focus on predisposition to maliganncy.
21.
Zurück zum Zitat Ross LF, et al. Technical report: ethical and policy issues in genetic testing and screening of children. Genet Med. 2013;15(3):234–45. CrossRef Ross LF, et al. Technical report: ethical and policy issues in genetic testing and screening of children. Genet Med. 2013;15(3):234–45. CrossRef
22.
Zurück zum Zitat Perez Botero J, et al. ASXL1 mutated chronic myelomonocytic leukemia in a patient with familial thrombocytopenia secondary to germline mutation in ANKRD26. Blood Cancer J. 2015;5: e315. CrossRef Perez Botero J, et al. ASXL1 mutated chronic myelomonocytic leukemia in a patient with familial thrombocytopenia secondary to germline mutation in ANKRD26. Blood Cancer J. 2015;5: e315. CrossRef
23.
Zurück zum Zitat Richards S, 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. 2015;17(5):405–24. CrossRef Richards S, 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. 2015;17(5):405–24. CrossRef
24.
Zurück zum Zitat Rehm HL, et al. ClinGen–the Clinical Genome Resource. N Engl J Med. 2015;372(23):2235–42. CrossRef Rehm HL, et al. ClinGen–the Clinical Genome Resource. N Engl J Med. 2015;372(23):2235–42. CrossRef
25.
Zurück zum Zitat Boutroux H, et al. Childhood diagnosis of genetic thrombocytopenia with mutation in the ankyrine repeat domain 26 gene. Eur J Pediatr. 2015;174(10):1399–403. CrossRef Boutroux H, et al. Childhood diagnosis of genetic thrombocytopenia with mutation in the ankyrine repeat domain 26 gene. Eur J Pediatr. 2015;174(10):1399–403. CrossRef
26.
Zurück zum Zitat Ferrari S, et al. Spectrum of 5'UTR mutations in ANKRD26 gene in patients with inherited thrombocytopenia: c.-140C>G mutation is more frequent than expected . Platelets, 2017;28(6):621–624. Ferrari S, et al. Spectrum of 5'UTR mutations in ANKRD26 gene in patients with inherited thrombocytopenia: c.-140C>G mutation is more frequent than expected . Platelets, 2017;28(6):621–624.
27.
Zurück zum Zitat Karczewski KJ, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43. CrossRef Karczewski KJ, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43. CrossRef
28.
Zurück zum Zitat DeSanto C, et al. WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome . J Med Genet, 2015. 52(11):754–61. DeSanto C, et al. WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome . J Med Genet, 2015. 52(11):754–61.
29.
Zurück zum Zitat Al Daama SA, et al. A missense mutation in ANKRD26 segregates with thrombocytopenia. Blood. 2013;122(3):461–2. CrossRef Al Daama SA, et al. A missense mutation in ANKRD26 segregates with thrombocytopenia. Blood. 2013;122(3):461–2. CrossRef
30.
Zurück zum Zitat • Wahlster L, et al. Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript . J Exp Med, 2021. 218(6). Case of ANKRD26-RT caused by a structural varaint out side of the 5′ UTR where all most disease causing variants cluster. • Wahlster L, et al. Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript . J Exp Med, 2021. 218(6). Case of ANKRD26-RT caused by a structural varaint out side of the 5′ UTR where all most disease causing variants cluster.
31.
Zurück zum Zitat Marconi C, et al. 5’UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia. J Hematol Oncol. 2017;10(1):18. CrossRef Marconi C, et al. 5’UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia. J Hematol Oncol. 2017;10(1):18. CrossRef
32.
Zurück zum Zitat Rahbari R, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48(2):126–33. CrossRef Rahbari R, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48(2):126–33. CrossRef
33.
Zurück zum Zitat Mangaonkar AA, Patnaik MM. Hereditary predisposition to hematopoietic neoplasms: when bloodline matters for blood cancers. Mayo Clin Proc. 2020;95(7):1482–98. CrossRef Mangaonkar AA, Patnaik MM. Hereditary predisposition to hematopoietic neoplasms: when bloodline matters for blood cancers. Mayo Clin Proc. 2020;95(7):1482–98. CrossRef
34.
Zurück zum Zitat Pecci A. Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists. Int J Hematol. 2013;98(1):34–47. CrossRef Pecci A. Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists. Int J Hematol. 2013;98(1):34–47. CrossRef
35.
Zurück zum Zitat Godley LA. Inherited predisposition to acute myeloid leukemia. Semin Hematol. 2014;51(4):306–21. CrossRef Godley LA. Inherited predisposition to acute myeloid leukemia. Semin Hematol. 2014;51(4):306–21. CrossRef
36.
Zurück zum Zitat Stockley J, et al. Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects. Blood. 2013;122(25):4090–3. CrossRef Stockley J, et al. Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects. Blood. 2013;122(25):4090–3. CrossRef
37.
Zurück zum Zitat Gerrard JM, et al. Inherited platelet-storage pool deficiency associated with a high incidence of acute myeloid leukaemia. Br J Haematol. 1991;79(2):246–55. CrossRef Gerrard JM, et al. Inherited platelet-storage pool deficiency associated with a high incidence of acute myeloid leukaemia. Br J Haematol. 1991;79(2):246–55. CrossRef
38.
Zurück zum Zitat Perez Botero J, et al. Clinical characteristics and platelet phenotype in a family with RUNX1 mutated thrombocytopenia. Leuk Lymphoma. 2017;58(8):1963–7. CrossRef Perez Botero J, et al. Clinical characteristics and platelet phenotype in a family with RUNX1 mutated thrombocytopenia. Leuk Lymphoma. 2017;58(8):1963–7. CrossRef
39.
Zurück zum Zitat Topka S, et al. Germline ETV6 mutations confer susceptibility to acute lymphoblastic leukemia and thrombocytopenia. PLoS Genet. 2015;11(6): e1005262. CrossRef Topka S, et al. Germline ETV6 mutations confer susceptibility to acute lymphoblastic leukemia and thrombocytopenia. PLoS Genet. 2015;11(6): e1005262. CrossRef
40.
Zurück zum Zitat Zhang MY, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet. 2015;47(2):180–5. CrossRef Zhang MY, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet. 2015;47(2):180–5. CrossRef
Metadaten
Titel
ANKRD26-Related Thrombocytopenia and Predisposition to Myeloid Neoplasms
verfasst von
Mia J. Sullivan
Elizabeth L. Palmer
Juliana Perez Botero
Publikationsdatum
25.06.2022
Verlag
Springer US
Erschienen in
Current Hematologic Malignancy Reports / Ausgabe 5/2022
Print ISSN: 1558-8211
Elektronische ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-022-00666-4

Weitere Artikel der Ausgabe 5/2022

Current Hematologic Malignancy Reports 5/2022 Zur Ausgabe

Germline Predisposition to Myeloid Neoplasms (M Patnaik, Section Editor)

Germline and Somatic Defects in DDX41 and its Impact on Myeloid Neoplasms

Myeloproliferative Neoplasms (P Bose, Section Editor)

Novel Therapies in Myelofibrosis: Beyond JAK Inhibitors

Chronic Myeloid Leukemias (V Oehler, Section Editor)

Management of Chronic Myeloid Leukemia in Children and Young Adults

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.