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Seminars in Diagnostic Pathology Nov 2023The diagnostic work up and surveillance of germline disorders of bone marrow failure and predisposition to myeloid malignancy is complex and involves correlation between... (Review)
Review
The diagnostic work up and surveillance of germline disorders of bone marrow failure and predisposition to myeloid malignancy is complex and involves correlation between clinical findings, laboratory and genetic studies, and bone marrow histopathology. The rarity of these disorders and the overlap of clinical and pathologic features between primary and secondary causes of bone marrow failure, acquired aplastic anemia, and myelodysplastic syndrome may result in diagnostic uncertainty. With an emphasis on the pathologist's perspective, we review diagnostically useful features of germline disorders including Fanconi anemia, Shwachman-Diamond syndrome, telomere biology disorders, severe congenital neutropenia, GATA2 deficiency, SAMD9/SAMD9L diseases, Diamond-Blackfan anemia, and acquired aplastic anemia. We discuss the distinction between baseline morphologic and genetic findings of these disorders and features that raise concern for the development of myelodysplastic syndrome.
Topics: Humans; Anemia, Aplastic; Congenital Bone Marrow Failure Syndromes; Bone Marrow Diseases; Pathologists; Myeloproliferative Disorders; Myelodysplastic Syndromes; Bone Marrow Failure Disorders; Germ Cells; Neoplasms; Intracellular Signaling Peptides and Proteins
PubMed: 37507252
DOI: 10.1053/j.semdp.2023.06.006 -
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... Jun 2021Distinguishing constitutional from immune bone marrow failure (BMF) has important clinical implications. However, the diagnosis is not always straightforward, and immune... (Review)
Review
Distinguishing constitutional from immune bone marrow failure (BMF) has important clinical implications. However, the diagnosis is not always straightforward, and immune aplastic anemia, the commonest BMF, is a diagnosis of exclusion. In this review, we discuss a general approach to the evaluation of BMF, focusing on clinical presentations particular to immune and various constitutional disorders as well as the interpretation of bone marrow histology, flow cytometry, and karyotyping. Additionally, we examine the role of specialized testing in both immune and inherited BMF, and discuss genetic testing, both its role in patient evaluation and interpretation of results.
Topics: Anemia, Aplastic; Bone Marrow; Bone Marrow Diseases; Bone Marrow Failure Disorders; Genetic Testing; Hematology; Humans
PubMed: 34404527
DOI: 10.1016/j.beha.2021.101275 -
Current Opinion in Pediatrics Feb 2023Recent advances in diagnosis and treatment of inherited bone marrow failure syndromes (IBMFS) have significantly improved disease understanding and patient outcomes.... (Review)
Review
PURPOSE OF REVIEW
Recent advances in diagnosis and treatment of inherited bone marrow failure syndromes (IBMFS) have significantly improved disease understanding and patient outcomes. Still, IBMFS present clinical challenges that require further progress. This review aims to provide an overview of the current state of diagnosis and treatment modalities of the major IBMFS seen in paediatrics and present areas of prioritization for future research.
RECENT FINDINGS
Haematopoietic cell transplantation (HCT) for IBMFS has greatly improved in recent years, shifting the research and clinical focus towards cancer predispositions and adverse effects of treatment. Each year, additional novel genes and pathogenic variants are described, and genotype-phenotype mapping becomes more sophisticated. Moreover, novel therapeutics exploring disease-specific mechanisms show promise to complement HCT and treat patients who cannot undergo current treatment options.
SUMMARY
Research on IBMFS should have short-term and long-term goals. Immediate challenges include solidifying diagnostic and treatment guidelines, cancer detection and treatment, and continued optimization of HCT. Long-term goals should emphasize genotype-phenotype mapping, genetic screening tools and gene-targeted therapy.
Topics: Child; Humans; Anemia, Aplastic; Bone Marrow Diseases; Congenital Bone Marrow Failure Syndromes; Fanconi Anemia; Bone Marrow Failure Disorders; Hemoglobinuria, Paroxysmal
PubMed: 36354296
DOI: 10.1097/MOP.0000000000001196 -
Hematology/oncology Clinics of North... Aug 2018Acquired aplastic anemia and inherited bone marrow failure syndromes both present with pancytopenia and must be distinguished because they have differences in treatment... (Review)
Review
Acquired aplastic anemia and inherited bone marrow failure syndromes both present with pancytopenia and must be distinguished because they have differences in treatment decisions and continued monitoring requirements. Advances in the genetic interrogation of patient samples have led to identification of inherited germline diseases and appreciation that patients with inherited bone marrow failure disorders may be normal in appearance with few expected clinical clues. Somatic mutations in aplastic anemia may have prognostic value. Hematopoietic stem cells from inherited marrow failure diseases can correct the proliferative defect and may develop further somatic mutations that progress to myelodysplastic syndrome or acute myeloid leukemia.
Topics: Anemia, Aplastic; Bone Marrow; Bone Marrow Diseases; Bone Marrow Failure Disorders; Genetic Diseases, Inborn; Hemoglobinuria, Paroxysmal; Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes
PubMed: 30047411
DOI: 10.1016/j.hoc.2018.04.008 -
Hematology. American Society of... 2002This chapter describes the clinical presentation and molecular basis of two inherited bone marrow failure syndromes, Fanconi anemia (FA), and Diamond-Blackfan anemia... (Review)
Review
This chapter describes the clinical presentation and molecular basis of two inherited bone marrow failure syndromes, Fanconi anemia (FA), and Diamond-Blackfan anemia (DBA). It also provides an update on diagnostic and therapeutic approaches to bone marrow failure of all types (inherited and acquired) in pediatric patients. In Section I, Dr. Alan D'Andrea reviews the wide range of clinical manifestations of Fanconi anemia. Significant advances have been made in understanding the molecular pathogenesis of FA. On the basis of these advances, new diagnostic assays and treatment options are now available. In Section II, Dr. Niklas Dahl examines the clinical features and molecular pathogenesis of Diamond-Blackfan anemia. The possible links between the RPS19 gene (DBA gene) and the erythropoiesis defect are considered. In Section III, Drs. Eva Guinan and Akiko Shimamura provide an algorithm for the diagnostic evaluation and treatment of children with inherited or acquired aplastic anemia. Through the presentation of a case study of a pediatric patient with bone marrow failure, he provides an overview of the newest tests and treatment options.
Topics: Adult; Anemia, Diamond-Blackfan; Bone Marrow Diseases; Child; Erythropoiesis; Fanconi Anemia; Humans; Proteins; Ribosomal Proteins
PubMed: 12446419
DOI: 10.1182/asheducation-2002.1.58 -
Hematology/oncology Clinics of North... Aug 2018
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Genetic Diseases, Inborn; Hemoglobinuria, Paroxysmal; Humans; Portraits as Topic
PubMed: 30047424
DOI: 10.1016/j.hoc.2018.05.001 -
AJR. American Journal of Roentgenology Oct 2011Many disorders produce similar or overlapping patterns of bone marrow edema in the ankle. Bone marrow edema may present in a few hindfoot bones simultaneously or in a... (Review)
Review
OBJECTIVE
Many disorders produce similar or overlapping patterns of bone marrow edema in the ankle. Bone marrow edema may present in a few hindfoot bones simultaneously or in a single bone. The purpose of this pictorial essay is to provide guidelines based on clinical history and specific MRI patterns and locations to accurately identify the cause of ankle bone marrow edema. We will first focus on bone marrow edema in general disease categories involving multiple bones, such as reactive processes, trauma, neuroarthropathy, and arthritides. A discussion of bone marrow edema in individual bones of the ankle and hindfoot including the tibia, fibula, talus, and calcaneus will follow. Helpful hints for arriving at the correct diagnosis will be provided in each section.
CONCLUSION
After review of this article, radiologists should be able to use their knowledge of clinical history and specific MRI patterns and locations to accurately distinguish between the various causes of bone marrow edema in the ankle and hindfoot.
Topics: Ankle; Bone Marrow Diseases; Edema; Foot; Humans; Magnetic Resonance Imaging
PubMed: 21940545
DOI: 10.2214/AJR.10.5880 -
Blood Jan 2019Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The 2 major modes of programmed cell death, apoptosis and...
Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The 2 major modes of programmed cell death, apoptosis and necroptosis, share molecular machinery but diverge in outcome with important implications for the microenvironment; apoptotic cells are removed in an immune silent process, whereas necroptotic cells leak cellular contents that incite inflammation. Given the importance of cytokine-directed cues for hematopoietic cell survival and differentiation, the impact on hematopoietic homeostasis of biasing cell death fate to necroptosis is substantial and poorly understood. Here, we present a mouse model with increased bone marrow necroptosis. Deletion of the proapoptotic Bcl-2 family members Bax and Bak inhibits bone marrow apoptosis. Further deletion of the BH3-only member Bid (to generate triple-knockout [TKO] mice) leads to unrestrained bone marrow necroptosis driven by increased Rip1 kinase (Ripk1). TKO mice display loss of progenitor cells, leading to increased cytokine production and increased stem cell proliferation and exhaustion and culminating in bone marrow failure. Genetically restoring Ripk1 to wild-type levels restores peripheral red cell counts as well as normal cytokine production. TKO bone marrow is hypercellular with abnormal differentiation, resembling the human disorder myelodysplastic syndrome (MDS), and we demonstrate increased necroptosis in MDS bone marrow. Finally, we show that Bid impacts necroptotic signaling through modulation of caspase-8-mediated Ripk1 degradation. Thus, we demonstrate that dysregulated necroptosis in hematopoiesis promotes bone marrow progenitor cell death that incites inflammation, impairs hematopoietic stem cells, and recapitulates the salient features of the bone marrow failure disorder MDS.
Topics: Animals; BH3 Interacting Domain Death Agonist Protein; Bone Marrow; Bone Marrow Diseases; Cells, Cultured; Cytokines; Hematopoietic Stem Cells; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelodysplastic Syndromes; Necrosis; Receptor-Interacting Protein Serine-Threonine Kinases; bcl-2 Homologous Antagonist-Killer Protein
PubMed: 30413413
DOI: 10.1182/blood-2018-05-847335