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Blood Mar 2023Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to... (Review)
Review
Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The pathobiology of SDS results from impaired ribosomal maturation due to the deficiency of SBDS and the inability to evict the antiassociation factor eIF6 from the 60S ribosomal subunit. Clinical outcomes for patients with SDS who develop myeloid malignancies are extremely poor because of high treatment-related toxicities and a high rate of refractory disease/relapse even after allogeneic hematopoietic stem cell transplant (HSCT). Registry data indicate that outcomes are improved for patients with SDS who undergo routine bone marrow surveillance and receive an HSCT before developing an overt malignancy. However, the optimal approach to hematologic surveillance and the timing of HSCT for patients with SDS is not clearly established. Recent studies have elucidated distinct patterns of somatic blood mutations in patients with SDS that either alleviate the ribosome defect via somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints, resulting in increased leukemogenic potential (heterozygous TP53 inactivation). Genomic analysis revealed that most myeloid malignancies in patients with SDS have biallelic loss-of-function TP53 mutations. Single-cell DNA sequencing of SDS bone marrow samples can detect premalignant biallelic TP53-mutated clones before clinical diagnosis, suggesting that molecular surveillance may enhance the detection of incipient myeloid malignancies when HSCT may be most effective. Here, we review the clinical, genetic, and biologic features of SDS. In addition, we present evidence supporting the hematologic surveillance for patients with SDS that incorporates clinical, pathologic, and molecular data to risk stratify patients and prioritize transplant evaluation for patients with SDS with high-risk features.
Topics: Humans; Shwachman-Diamond Syndrome; Bone Marrow Diseases; Exocrine Pancreatic Insufficiency; Lipomatosis; Neoplasm Recurrence, Local; Myeloproliferative Disorders; Disease Susceptibility
PubMed: 36542827
DOI: 10.1182/blood.2022017739 -
[Rinsho Ketsueki] the Japanese Journal... 2022Inherited bone marrow failure syndrome (IBMFS) is a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and an increased... (Review)
Review
Inherited bone marrow failure syndrome (IBMFS) is a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and an increased risk of malignancy. The p53 tumor suppressor protein is a transcription factor activated in response to various cellular stresses and induces genes involved in apoptosis, cell cycle arrest, and DNA repair. Several lines of evidence suggest that p53 activation is central to the pathogenesis of IBMFS. We discovered germline TP53 activating mutations in IBMFS cases mimicking Diamond-Blackfan anemia using whole-exome sequencing. These cases were recognized as having a novel disorder, germline TP53 activation syndrome (bone marrow failure syndrome 5; OMIN). Recently, additional cases with the same TP53 mutations were reported, further clarifying the phenotype of this disease. This discovery confirms the hypothesis that p53 activation causes IBMFS. This review focuses on this novel IBMFS and discusses the link between p53 hyperactivation and IBMFS.
Topics: Anemia, Aplastic; Anemia, Diamond-Blackfan; Bone Marrow Diseases; Bone Marrow Failure Disorders; Congenital Bone Marrow Failure Syndromes; Hemoglobinuria, Paroxysmal; Humans; Mutation; Pancytopenia; Transcription Factors; Tumor Suppressor Protein p53
PubMed: 36198537
DOI: 10.11406/rinketsu.63.1115 -
American Journal of Hematology Nov 1994Bone marrow necrosis is most frequently diagnosed at postmortem examination. Antemortem diagnosis is still uncommon. In a recent review of world literature, we have... (Review)
Review
Bone marrow necrosis is most frequently diagnosed at postmortem examination. Antemortem diagnosis is still uncommon. In a recent review of world literature, we have found 133 cases of bone marrow necrosis diagnosed during life. It has been observed during the course of a wide variety of diseases, most commonly in association with acute and chronic leukemia, carcinoma, malignant lymphoma, infections, and sickle cell disease. We report two intravitally diagnosed cases of bone marrow necrosis occurring in two patients with high-grade B-cell lymphoproliferative disease. These cases are unusual in that both patients had a triad of bone marrow necrosis, high-grade B-cell lymphoproliferative disease, and hypercalcemia. Despite chemotherapy, both cases ultimately proved fatal, with progressive involvement of the central nervous system.
Topics: Adolescent; Adult; Bone Marrow; Bone Marrow Diseases; Female; Humans; Incidence; Lymphoproliferative Disorders; Male; Necrosis
PubMed: 7942788
DOI: 10.1002/ajh.2830470314 -
International Journal of Hematology Jul 2022Inherited bone marrow failure syndromes (IBMFSs) are a group of rare genetic disorders characterized by bone marrow failure with unique phenotypes and predisposition to... (Review)
Review
Inherited bone marrow failure syndromes (IBMFSs) are a group of rare genetic disorders characterized by bone marrow failure with unique phenotypes and predisposition to cancer. Classical IBMFSs primarily include Fanconi anemia with impaired DNA damage repair, dyskeratosis congenita with telomere maintenance dysfunction, and Diamond-Blackfan anemia with aberrant ribosomal protein biosynthesis. Recently, comprehensive genetic analyses have been implemented for the definitive diagnosis of classic IBMFSs, and advances in molecular genetics have led to the identification of novel disorders such as AMeD and MIRAGE syndromes. Allogeneic hematopoietic cell transplantation (HCT), a promising option to overcome impaired hematopoiesis in patients with IBMFSs, does not correct nonhematological defects and may enhance the risk of secondary malignancies. Disease-specific management is necessary because IBMFSs differ in underlying defects and are associated with varying degrees of risk for clonal evolution and early or late complications after HCT. In addition, long-term follow-up is essential to detect complications related to the IBMFS or HCT. This review provides a summary of current clinical practices along with the latest data on HCT in IBMFSs.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Congenital Bone Marrow Failure Syndromes; Hematopoietic Stem Cell Transplantation; Hemoglobinuria, Paroxysmal; Humans
PubMed: 35633493
DOI: 10.1007/s12185-022-03362-4 -
The American Journal of Medicine Mar 1976The clinical findings of bone marrow necrosis in 13 patients undergoing bone marrow examination to investigate a peripheral blood cytopenia or leukoerythroblastic blood...
The clinical findings of bone marrow necrosis in 13 patients undergoing bone marrow examination to investigate a peripheral blood cytopenia or leukoerythroblastic blood smear were reviewed and compared to those in the literature. Excluding sickle cell disease, all cases of bone marrow necrosis diagnosed during life were associated with a neoplastic process involving the marrow. A myeloproliferative disorder was found in five patients, metastatic carcinoma in five patients, a lymphoma in two patients, and both a myeloproliferative disorder and metastatic carcinoma in one patient. Marrow necrosis was found to involve the marrow at multiple sites in a piecemeal fashion with areas of necrotic marrow and structurally intact marrow adjacent to each other. Severe bone pain without roentgenographic abnormality was the major symptom in 85% of the patients. Marrow and fat emboli, hypercalcemia and peripheral blood cytopenias were identified as direct complications of marrow necrosis. The prognosis of patients with marrow necrosis secondary to neoplastic disease was found to be extremely poor with a median survival of less than one month. However, one patient responded to antineoplastic chemotherapy and showed healing of the bone marrow.
Topics: Adenocarcinoma; Adult; Aged; Bone Marrow Diseases; Bone Marrow Examination; Carcinoma; Cystadenoma; Female; Humans; Leukemia, Myeloid; Lung Neoplasms; Lymphoma; Middle Aged; Necrosis; Neoplasm Metastasis; Ovarian Neoplasms; Prognosis; Stomach Neoplasms
PubMed: 1062933
DOI: 10.1016/0002-9343(76)90752-x -
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 -
[Rinsho Ketsueki] the Japanese Journal... Feb 2016Inherited bone marrow failure syndromes comprise a series of disorders caused by various gene mutations. Genetic tests were formerly difficult to perform because of the... (Review)
Review
Inherited bone marrow failure syndromes comprise a series of disorders caused by various gene mutations. Genetic tests were formerly difficult to perform because of the large size and number of causative genes. However, recent advances in next-generation sequencing has enabled simultaneous testing of all causative genes to be performed at an acceptable cost. We collaboratively conducted a series of whole-exome sequencing studies of patients with inherited bone marrow failure syndromes and discovered RPS27/RPL27 and FANCT as causative genes of Diamond-Blackfan anemia and Fanconi anemia, respectively. Furthermore, we established a target gene sequencing system to cover 189 genes associated with pediatric blood diseases to assist genetic diagnoses in clinical practice. In this review, discovery of new causative genes and possible roles of next-generation sequencing in the genetic diagnosis of inherited bone marrow failure syndromes are discussed.
Topics: Anemia, Aplastic; Anemia, Diamond-Blackfan; Animals; Bone Marrow Diseases; Bone Marrow Failure Disorders; Fanconi Anemia; Genetic Testing; Hemoglobinuria, Paroxysmal; Humans; Mutation
PubMed: 26935625
DOI: 10.11406/rinketsu.57.98 -
Journal of Clinical and Experimental... 2018Bone marrow failure (BMF) is a rare but life-threatening disorder that usually manifests as (pan)cytopenia. BMF can be caused by a variety of diseases, but inherited BMF... (Review)
Review
Bone marrow failure (BMF) is a rare but life-threatening disorder that usually manifests as (pan)cytopenia. BMF can be caused by a variety of diseases, but inherited BMF (IBMF) syndromes are a clinically important cause, especially in children. IBMF syndromes are a heterogeneous group of genetic disorders characterized by BMF, physical abnormalities, and predisposition to malignancy. An accurate diagnosis is critical, as disease-specific management, surveillance, and genetic counselling are required for each patient. The major differential diagnoses of IBMF syndromes are acquired aplastic anemia (AA) and refractory cytopenia of childhood (RCC). These diseases have overlapping features, such as BM hypocellularity and/or dysplastic changes, which make the differential diagnosis challenging. RCC has been defined as a histomorphologically distinct entity. Therefore, understanding the BM histopathology of these diseases is essential for the differential diagnosis. However, the BM histopathological features have not been characterized in detail, as descriptions of BM histopathology are very limited due to the rarity of the diseases. This review provides a detailed description of the BM histopathology in cases of RCC, AA, and the four most common IBMF syndromes: Fanconi anemia (FA), dysketatosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS). An overview, including the clinical features and diagnosis, is also provided.
Topics: Adolescent; Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Child; Child, Preschool; Diagnosis, Differential; Female; Hemoglobinuria, Paroxysmal; Histological Techniques; Humans; Infant; Male
PubMed: 29998978
DOI: 10.3960/jslrt.18018 -
MMW Fortschritte Der Medizin Jun 2019
Review
Topics: Bone Marrow Diseases; Edema; Humans; Magnetic Resonance Imaging; Syndrome
PubMed: 31230304
DOI: 10.1007/s15006-019-0663-9 -
Molecular Genetics & Genomic Medicine May 2018ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and... (Review)
Review
BACKGROUND
ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and craniofacial abnormalities. The aim of this study was to further define the genetic and phenotypic spectrum of the disorder by summarizing the five published cases and an additional case that we identified through whole-exome sequencing performed at the University of Toronto.
METHODS
Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Whole exome sequencing was performed to identify causative mutations.
RESULTS
All six cases had homozygous truncating mutations either at or upstream of the helicase domain of ERCC6L2. All patients displayed bone marrow failure, learning or developmental delay and microcephaly. Our patient was unique in displaying features of cerebellar disease, including ataxia and dysmetria as well as an interval deterioration of the corpus callosum and generalized volume loss on MRI. Another unique feature of our patient was retinal dystrophy with macular involvement. Along with one other patient, our patient displayed craniofacial abnormalities by presenting with low-set prominent ears, a pointed prominent chin, and deep-set eyes. Leukemia is common among patients with inherited bone marrow failure, but thus far, none of the patients have developed this complication.
CONCLUSIONS
ERCC6L2-associated disorder is a multisystem disorder. The phenotype spectrum includes bone marrow failure, cerebral, and craniofacial abnormalities, as well as cerebellar and retinal abnormalities.
Topics: Adolescent; Adult; Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Canada; Child; Child, Preschool; Craniofacial Abnormalities; DNA Helicases; Developmental Disabilities; Exome; Female; Hemoglobinuria, Paroxysmal; Homozygote; Humans; Infant; Intellectual Disability; Male; Microcephaly; Mutation; Nervous System Malformations; Pedigree; Phenotype
PubMed: 29633571
DOI: 10.1002/mgg3.388