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Hematology/oncology Clinics of North... Aug 2018GATA2 deficiency is an immunodeficiency and bone marrow failure disorder caused by pathogenic variants in GATA2. It is inherited in an autosomal-dominant pattern or can... (Review)
Review
GATA2 deficiency is an immunodeficiency and bone marrow failure disorder caused by pathogenic variants in GATA2. It is inherited in an autosomal-dominant pattern or can be due to de novo sporadic germline mutation. Patients commonly have B-cell, dendritic cell, natural killer cell, and monocytopenias, and are predisposed to myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Patients may suffer from disseminated human papilloma virus and mycobacterial infections, pulmonary alveolar proteinosis, and lymphedema. The bone marrow eventually takes on a characteristic hypocellular myelodysplasia with loss of monocytes and hematogones, megakaryocytes with separated nuclear lobes, micromegakaryocytes, and megakaryocytes with hypolobated nuclei.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; GATA2 Deficiency; GATA2 Transcription Factor; Genetic Predisposition to Disease; Germ-Line Mutation; Hemoglobinuria, Paroxysmal; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 30047422
DOI: 10.1016/j.hoc.2018.04.004 -
Seminars in Hematology Jul 2022Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by insufficient blood cell production and increased risk of... (Review)
Review
Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by insufficient blood cell production and increased risk of transformation to myeloid malignancies. While genetically diverse, IBMFS are collectively defined by a cell-intrinsic hematopoietic stem cell (HSC) fitness defect that impairs HSC self-renewal and hematopoietic differentiation. In IBMFS, HSCs frequently acquire mutations that improve cell fitness, a phenomenon known as somatic compensation. Somatic compensation can occur via distinct genetic processes such as loss of the germline mutation or somatic alterations in pathways affected by the disease-causing gene. While the clinical implications of somatic compensation in IBMFS remain to be fully discovered, understanding these mutational processes can help understand disease pathophysiology and may inform future diagnostic and therapeutic approaches. In this review, we highlight current understanding about somatic compensation in IBMFS.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Congenital Bone Marrow Failure Syndromes; Hemoglobinuria, Paroxysmal; Humans
PubMed: 36115694
DOI: 10.1053/j.seminhematol.2022.07.002 -
Blood Nov 2017Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure,... (Review)
Review
Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Hematopoietic Stem Cell Transplantation; Hemoglobinuria, Paroxysmal; Humans; Inheritance Patterns
PubMed: 29167174
DOI: 10.1182/blood-2017-05-781799 -
Hematology. American Society of... Dec 2017Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure,... (Review)
Review
Patients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.
Topics: Allografts; Bone Marrow Diseases; Genetic Diseases, Inborn; Hematopoietic Stem Cell Transplantation; Humans; Syndrome
PubMed: 29222241
DOI: 10.1182/asheducation-2017.1.88 -
Best Practice & Research. Clinical... Dec 2023The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or... (Review)
Review
The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.
Topics: Adult; Humans; Child; Anemia, Aplastic; Bone Marrow Diseases; Australia; Bone Marrow Failure Disorders; Syndrome; Registries
PubMed: 38092475
DOI: 10.1016/j.beha.2023.101516 -
Blood Oct 2014Our understanding of the pathophysiology of aplastic anemia is undergoing significant revision, with implications for diagnosis and treatment. Constitutional and... (Review)
Review
Our understanding of the pathophysiology of aplastic anemia is undergoing significant revision, with implications for diagnosis and treatment. Constitutional and acquired disease is poorly delineated, as lesions in some genetic pathways cause stereotypical childhood syndromes and also act as risk factors for clinical manifestations in adult life. Telomere diseases are a prominent example of this relationship. Accelerated telomere attrition is the result of mutations in telomere repair genes and genes encoding components of the shelterin complex and related proteins. Genotype-phenotype correlations show genes responsible for X-linked (DKC1) and severe recessive childhood dyskeratosis congenita, typically with associated mucocutaneous features, and others (TERC and TERT) for more subtle presentation as telomeropathy in adults, in which multiorgan failure may be prominent. Telomerase mutations also are etiologic in familial pulmonary fibrosis and cryptic liver disease. Detection of a telomere disease requires awareness in the clinic, appropriate laboratory testing of telomere content, and genetic sequencing. In treatment decisions, genetic screening of related donors for hematopoietic stem cell transplantation is critical, and androgen therapy may be helpful. Telomeres shorten normally with aging, as well as under environmental circumstances, with regenerative stress and oxidative damage. Telomere biology is complexly related to oncogenesis: telomere attrition is protective by enforcing senescence or apoptosis in cells with a long mitotic history, but telomere loss also can destabilize the genome by chromosome rearrangement and aneuploidy.
Topics: Animals; Bone Marrow; Bone Marrow Diseases; Genetic Association Studies; Humans; Neoplasms; Telomerase; Telomere
PubMed: 25237198
DOI: 10.1182/blood-2014-05-526285 -
Blood Oct 2014
Topics: Animals; Bone Marrow; Bone Marrow Diseases; DNA Repair; Humans; Mutation; Ribosomes; Syndrome
PubMed: 25237202
DOI: 10.1182/blood-2014-08-587394 -
International Journal of Molecular... Oct 2022In recent years, it has become increasingly apparent that bone marrow (BM) failures and myeloid malignancy predisposition syndromes are characterized by a wide... (Review)
Review
In recent years, it has become increasingly apparent that bone marrow (BM) failures and myeloid malignancy predisposition syndromes are characterized by a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of children and adults with unexplained hematopoiesis defects. Clinically, hypocellular BM failure still represents a challenge in pathobiology-guided treatment. There are three fundamental topics that emerged from our review of the existing data. An exogenous stressor, an immune defect, and a constitutional genetic defect fuel a vicious cycle of hematopoietic stem cells, immune niches, and stroma compartments. A wide phenotypic spectrum exists for inherited and acquired BM failures and predispositions to myeloid malignancies. In order to effectively manage patients, it is crucial to establish the right diagnosis. New theragnostic windows can be revealed by exploring BM failure pathomechanisms.
Topics: Adult; Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Child; Hematopoietic Stem Cells; Humans; Pancytopenia; Workflow
PubMed: 36233062
DOI: 10.3390/ijms231911765 -
Proceedings of the Royal Society of... Jan 1952
Topics: Bone Marrow; Bone Marrow Diseases; Primary Myelofibrosis
PubMed: 14911853
DOI: No ID Found -
Best Practice & Research. Clinical... Jun 2021Inherited bone marrow failure syndromes (IBMFS) are a heterogenous group of diseases caused by pathogenic germline variants in key pathways associated with... (Review)
Review
Inherited bone marrow failure syndromes (IBMFS) are a heterogenous group of diseases caused by pathogenic germline variants in key pathways associated with haematopoiesis and genomic stability. Germline variants in IBMFS-related genes are known to reduce the fitness of hematopoietic stem and progenitor cells (HSPC), which has been hypothesized to drive clonal selection in these diseases. In many IBMFS, somatic mosaicism predominantly impacts cells by two distinct mechanisms, with contrasting effects. An acquired variation can improve cell fitness towards baseline levels, providing rescue of a deleterious phenotype. Alternatively, somatic mosaicism may result in a fitness advantage that results in malignant transformation. This review will describe these phenomena in IBMFS and delineate their relevance for diagnosis and clinical management. In addition, we will discuss which samples and methods can be used for detection of mosaicism according to clinical phenotype, type of mosaicism, and sample availability.
Topics: Bone Marrow Diseases; Cell Transformation, Neoplastic; Congenital Bone Marrow Failure Syndromes; Hematopoiesis; Hematopoietic Stem Cells; Humans; Mosaicism
PubMed: 34404533
DOI: 10.1016/j.beha.2021.101279