Introduction: Genetic syndromes predisposing to myeloid neoplasia
Inherited forms of myelodysplastic syndrome (MDS) and myeloid or lymphoid leukemia have long been associated with several constitutional disorders in children. The first report on an inherited bone marrow failure syndrome (IBMFS) with high risk for the development of myeloid neoplasia (MN) dates back to exactly 90 years ago when the Swiss pediatrician Guido Fanconi described a series of patients with physical anomalies and pernicious anemia. Since then a number of additional IBMFS and inherited conditions with leukemia predisposition such as Down syndrome, Ras-pathway disorders or Li-Fraumeni syndrome and other hereditary ...
Source: Seminars in Hematology - May 4, 2017 Category: Hematology Authors: Marcin Wlodarski, Charlotte Niemeyer Source Type: research
Down Syndrome, Rasopathies, and Other Rare Syndromes
In this article we discuss the occurrence of myeloid neoplasms in patients with a range of syndromes that are due to germline defects of the RAS signaling pathway and in patients with trisomy 21. Both, RAS mutations and trisomy 21 are common somatic events contributing to leukemogenis. Thus, the increased leukemia risk observed in children affected by these conditions is biologically highly plausible. Children with myeloid neoplasms in the context of these syndromes require different treatments than children with sporadic myeloid neoplasms and provide an opportunity to study the role of trisomy 21 and RAS signaling during ...
Source: Seminars in Hematology - April 27, 2017 Category: Hematology Authors: Christian P. Kratz, Shai Izraeli Source Type: research
DDX41-related myeloid neoplasia
While early presentation of familial leukemia syndromes is typical, long disease anticipation may mask cases of familial traits in seemingly spontaneous disease. Germline mutations in DDX41 gene have been discovered in several leukemia families, as well as in mostly adult patients with seemingly spontaneous disease but having strong family histories of myeloid neoplasia. As with other familial genes, DDX41 mutation carriers can develop neoplasia through acquisition of another somatic mutation, thereby affecting both DDX41 alleles. (Source: Seminars in Hematology)
Source: Seminars in Hematology - April 21, 2017 Category: Hematology Authors: Jaroslaw P. Maciejewski, Richard A. Padgett, Anna L. Brown, Carsten M üller-Tidow Source Type: research
DDX41 related myeloid neoplasia
While early presentation of familial leukemia syndromes is typical, long disease anticipation may mask cases of familial traits in seemingly spontaneous disease. Germ line mutations in DDX41 gene have been discovered in several leukemia families as well as in mostly adult patients with seemingly spontaneous disease but having strong family histories of myeloid neoplasia. As with other familial genes, DDX41 mutation carriers can develop neoplasia through acquisition of another somatic mutation, thereby affecting both DDX41 alleles. (Source: Seminars in Hematology)
Source: Seminars in Hematology - April 21, 2017 Category: Hematology Authors: Jaroslaw P. Maciejewski, Richard A. Padgett, Anna L. Brown, Carsten M üller –Tidow Source Type: research
Recognition of familial myeloid neoplasia in adults
Hereditary hematologic malignancy syndromes are increasingly recognized as causative of adult hematopoietic cancers, and the advent of next-generation sequencing has accelerated the discovery of new syndromes based on dense clustering of these diseases in particular families.Updated classifications schemes for myeloid malignancies will now include recommendations for taking a family history on all patients diagnosed with hematopoietic malignancies and for genetic counseling and testing of appropriate individuals and families. (Source: Seminars in Hematology)
Source: Seminars in Hematology - April 18, 2017 Category: Hematology Authors: Anna L. Brown, Jane E. Churpek, Luca Malcovati, Hartmut D öhner, Lucy A. Godley Source Type: research
RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)
In this review, we discuss disease-causing alterations of RUNT-related transcription factor 1 (RUNX1), a master regulator of hematopoietic differentiation. Familial platelet disorder with predisposition to myeloid leukemia (FPDMM) typically present with 1) mild to moderate thrombocytopenia with normal-sized platelets; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL. Hematological neoplasms in carriers of a germline RUNX1 mutation need additional secondary mutations or chromosome aberrations to develop. (Source: Seminars in Hematology)
Source: Seminars in Hematology - April 14, 2017 Category: Hematology Authors: Brigitte Schlegelberger, Paula G. Heller Source Type: research
Classical inherited bone marrow failure syndromes with high risk for myelodysplastic syndrome and acute myelogenous leukemia
The inherited marrow failure syndromes (IBMFS) are a heterogeneous group of diseases characterized by failure in the production of one or more blood lineage. The clinical manifestations of the IBMFS vary according to the type and number of blood cell lines involved, including different combinations of anemia, leukopenia, and thrombocytopenia. In some IBMFS, systemic non-hematologic manifestations, including congenital malformations, mucocutaneous abnormalities, developmental delay, and other medical complications, may be present. (Source: Seminars in Hematology)
Source: Seminars in Hematology - April 7, 2017 Category: Hematology Authors: Sharon A. Savage, Carlo Dufour Source Type: research
Classical inherited bone marrow failure syndromes with high risk for MDS and AML
The inherited marrow failure syndromes (IBMFS) are a heterogeneous group of diseases characterized by failure in the production of one or more blood lineage. The clinical manifestations of the IBMFS vary according to the type and number of blood cell lines involved, including different combinations of anemia, leukopenia, and thrombocytopenia. In some IBMFS, systemic non-hematologic manifestations including congenital malformations, mucocutaneous abnormalities, developmental delay, and other medical complications may be present. (Source: Seminars in Hematology)
Source: Seminars in Hematology - April 7, 2017 Category: Hematology Authors: S.A. Savage, C. Dufour Source Type: research
ETV6 in hematopoiesis and leukemia predisposition
The ETV6 (also known as TEL) gene encodes a transcriptional repressor that plays a critical role in hematopoiesis and in embryonic development. While somatic ETV6 translocations and missense mutations are frequently observed in human cancers, the role of ETV6 in malignant transformation was unclear. Recently, autosomal dominant germline ETV6 mutations were discovered in families with inherited thrombocytopenia and a propensity to develop hematological malignancy, unequivocally demonstrating a role for ETV6 in leukemogenesis. (Source: Seminars in Hematology)
Source: Seminars in Hematology - April 7, 2017 Category: Hematology Authors: Hanno Hock, Akiko Shimamura Source Type: research
Familial CEBPA-mutated acute myeloid leukemia
(AML) represents a recognized leukemia predisposition syndrome, with several families described in the literature since the initial report in 2004. The pathological features and long-term survival of individuals with familial CEBPA-mutated AML are reminiscent of sporadic CEBPAdm AML. Germline mutations predominantly localize to the N-terminal and are associated with near complete penetrance, with age of AML onset from 2–50 years, frequently accompanied by the acquisition of a second CEBPA mutation in C-terminal domain. Patients appear to have a significant risk of late AML recurrence and these typically repres...
Source: Seminars in Hematology - April 6, 2017 Category: Hematology Authors: Kiran Tawana, Ana Rio-Machin, Claude Preudhomme, Jude Fitzgibbon Source Type: research
Familial CEBPA-mutated Acute Myeloid Leukaemia
Familial CEBPA-mutated AML represents a recognised leukemia predisposition syndrome with several families described in the literature, since the initial report in 2004. The pathological features and long term survival of individuals with familial CEBPA-mutated AML are reminiscent of sporadic CEBPAdm AML. Germline mutations predominantly localise to the N-terminal and are associated with near complete penetrance, with age of AML onset from 2-50 years of age, frequently accompanied by the acquisition of a second CEBPA mutation in C-terminal domain. Patients appear to have a significant risk of late relapse and th...
Source: Seminars in Hematology - April 6, 2017 Category: Hematology Authors: K. Tawana, A. Rio-Machin, C. Preudhomme, J. Fitzgibbon Source Type: research
Practical Considerations for Diagnosis and Management of Patients and Carriers
Newly diagnosed children and adults with MDS or AML need to be screened for presence of a genetic predisposition syndrome because the information on the genetic status is likely to influence clinical care and management of the patient and the family. Scenarios in which genetic counseling is advised include presence of a mutation on somatic screen which can be associated with a germline predisposition, hematologic or cytogenetic characteristics suggestive of an underlying susceptibility syndrome, non-hematological phenotype suspicious for a familial condition, history of previous malignancy, or a family history of cancer, c...
Source: Seminars in Hematology - April 6, 2017 Category: Hematology Authors: Charlotte Niemeyer, Cristina Mecucci Source Type: research
Cancer predisposition syndromes associated with myeloid malignancy
The majority of myeloid malignancies are caused by sporadic somatic events rather than cancer predisposition. Nonetheless, the identification of hereditary cancer predisposition syndromes is critical when caring for patients with myeloid malignancies since detection may direct decisions related to cancer treatment and surveillance. A positive genetic test result also has important implications for other family members who can use this information to undergo their own testing to determine their cancer risk. (Source: Seminars in Hematology)
Source: Seminars in Hematology - April 6, 2017 Category: Hematology Authors: Emily Quinn, Kim E. Nichols Source Type: research
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Source: Seminars in Hematology - April 1, 2017 Category: Hematology Source Type: research
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Source: Seminars in Hematology - April 1, 2017 Category: Hematology Source Type: research
