-
Expert Review of Clinical Immunology Feb 2023VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described, late-onset, acquired autoinflammatory disorder caused by mutations in... (Review)
Review
INTRODUCTION
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described, late-onset, acquired autoinflammatory disorder caused by mutations in the gene. The various clinical manifestations of VEXAS broadly divided into inflammatory or haematological. VEXAS defines a new disease category - the hematoinflammatory disorders triggered by somatic mutations restricted to blood but causing systemic inflammation with multi-organ involvement and associated with aberrant bone marrow status. VEXAS causes significant morbidity and reduced life expectancy, but the optimum standard of care remains undefined.
AREAS COVERED
This review describes the discovery of VEXAS, relevant genetic causes and immunopathology of the disease. A detailed account of its various clinical manifestations and disease mimics is provided. Current treatment and management options are discussed.
EXPERT OPINION
New rare variants in and VEXAS-like negative cases are reported. Consensus diagnostic criteria might be required to define VEXAS and its related disorders. Investigation of sporadic, VEXAS-like cases will require the application of deep sequencing using DNA obtained from various cellular or tissue locations. Prospective studies are needed to define the optimal supportive and treatment options for patients with varying disease severity and prognosis. VEXAS-specific hematopoietic stem cell transplant selection criteria also require development.
Topics: Humans; Consensus; Inflammation; Mutation; Myelodysplastic Syndromes
PubMed: 36537591
DOI: 10.1080/1744666X.2023.2157262 -
La Clinica Terapeutica 2022The term "bone marrow edema" was used for the first time in 1988 by Wilson. He noticed a high signal on fluid-sensitive sequences at MRI located in the subchondral bone.... (Review)
Review
The term "bone marrow edema" was used for the first time in 1988 by Wilson. He noticed a high signal on fluid-sensitive sequences at MRI located in the subchondral bone. We can find bone marrow edema in many musculoskeletal diseases such as Inflammatory and Rheumatic diseases (Rheumatoid Arthritis, Spondylarthritis, etc.), Osteoarthritis (BMLs) and Bone Marrow Edema Syndromes (BMES). This classification is based on pathophysiological, histological and clinical differences despite the same imaging evidence. The distinction is useful also in terms of treatment. Bisphosphonates in association with NSAIDs or corticosteroids are the main therapy while TNF-a Inhibitors are used for the specific inflammatory origin. Bone marrow edema has become an important aspect to consider in the diagnostic path of the main musculoskeletal diseases. This paper starts from a systematic review of literature. We chose the most decisive contributions in order to develop a better description of the pathogenetic features about this "new" evidence.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Bone Marrow; Bone Marrow Diseases; Diphosphonates; Edema; Humans; Magnetic Resonance Imaging; Male; Osteoarthritis, Knee
PubMed: 36155729
DOI: 10.7417/CT.2022.2459 -
The Journal of the American Academy of... Oct 2020Bone marrow edema (BME) is a descriptive term used to describe high-signal intensity changes detected on magnetic resonance fluid-sensitive sequences that could be... (Review)
Review
Bone marrow edema (BME) is a descriptive term used to describe high-signal intensity changes detected on magnetic resonance fluid-sensitive sequences that could be attributed to a number of underlying pathologies. Regardless of the cause, physiologic remodeling of the subchondral bone can be limited because of ongoing joint forces, increased focalization of stress, and reduced healing capacity of the subchondral bone. BME is a known prognostic factor associated with pain, dysfunction, and progressive cartilage damage. This review summarizes the current known causes of BMEs, theories related to histopathological changes, and current treatment options including novel biologic surgical options.
Topics: Adult; Bone Marrow Diseases; Bone Substitutes; Calcium Phosphates; Cartilage, Articular; Conservative Treatment; Diffusion Magnetic Resonance Imaging; Edema; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Orthopedic Procedures; Pain; Prognosis
PubMed: 32701688
DOI: 10.5435/JAAOS-D-20-00142 -
Hematology. American Society of... Dec 2021Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome, characterized as a rare congenital bone marrow erythroid hypoplasia (OMIM#105650). Erythroid...
Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome, characterized as a rare congenital bone marrow erythroid hypoplasia (OMIM#105650). Erythroid defect in DBA results in erythroblastopenia in bone marrow as a consequence of maturation blockade between the burst forming unit-erythroid and colony forming unit-erythroid developmental stages, leading to moderate to severe usually macrocytic aregenerative (<20 × 109/L of reticulocytes) anemia. Congenital malformations localized mostly in the cephalic area and in the extremities (thumbs), as well as short stature and cardiac and urogenital tract abnormalities, are a feature of 50% of the DBA-affected patients. A significant increased risk for malignancy has been reported. DBA is due to a defect in the ribosomal RNA (rRNA) maturation as a consequence of a heterozygous mutation in 1 of the 20 ribosomal protein genes. Besides classical DBA, some DBA-like diseases have been identified. The relation between the defect in rRNA maturation and the erythroid defect in DBA has yet to be fully defined. However, recent studies have identified a role for GATA1 either due to a specific defect in its translation or due to its defective regulation by its chaperone HSP70. In addition, excess free heme-induced reactive oxygen species and apoptosis have been implicated in the DBA erythroid phenotype. Current treatment options are either regular transfusions with appropriate iron chelation or treatment with corticosteroids starting at 1 year of age. The only curative treatment for the anemia of DBA to date is bone marrow transplantation. Use of gene therapy as a therapeutic strategy is currently being explored.
Topics: Adult; Anemia, Diamond-Blackfan; Bone Marrow; Bone Marrow Transplantation; Child, Preschool; Disease Management; Female; Humans; Infant; Male; Mutation; Ribosomal Proteins
PubMed: 34889440
DOI: 10.1182/hematology.2021000314 -
The Journal of Bone and Joint Surgery.... Jan 2022Bone marrow edema (BME) is a nonspecific but relevant finding, usually indicating the presence of an underlying pathology. (Review)
Review
➤
Bone marrow edema (BME) is a nonspecific but relevant finding, usually indicating the presence of an underlying pathology.
➤
The gold standard technique for detecting BME is magnetic resonance imaging (MRI), as it allows for a correct diagnosis to be made, which is extremely important given the heterogeneity of BME-related diseases.
➤
Depending on the severity of painful symptomatology and the MRI evidence, different treatment strategies can be followed: physical modalities, pharmacological options, and surgical therapy.
Topics: Bone Marrow Diseases; Diagnosis, Differential; Edema; Humans; Magnetic Resonance Imaging
PubMed: 34780382
DOI: 10.2106/JBJS.21.00300 -
Virchows Archiv : An International... Jan 2023Updating the classification of hematologic neoplasia with germline predisposition, pediatric myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML)... (Review)
Review
The International Consensus Classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia.
Updating the classification of hematologic neoplasia with germline predisposition, pediatric myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML) is critical for diagnosis, therapy, research, and clinical trials. Advances in next-generation sequencing technology have led to the identification of an expanding group of genes that predispose to the development of hematolymphoid neoplasia when mutated in germline configuration and inherited. This review encompasses recent advances in the classification of myeloid and lymphoblastic neoplasia with germline predisposition summarizing important genetic and phenotypic information, relevant laboratory testing, and pathologic bone marrow features. Genes are organized into three major categories including (1) those that are not associated with constitutional disorder and include CEBPA, DDX41, and TP53; (2) those associated with thrombocytopenia or platelet dysfunction including RUNX1, ANKRD26, and ETV6; and (3) those associated with constitutional disorders affecting multiple organ systems including GATA2, SAMD9, and SAMD9L, inherited genetic mutations associated with classic bone marrow failure syndromes and JMML, and Down syndrome. A provisional category of germline predisposition genes is created to recognize genes with growing evidence that may be formally included in future revised classifications as substantial supporting data emerges. We also detail advances in the classification of pediatric myelodysplastic syndrome (MDS), expanding the definition of refractory cytopenia of childhood (RCC) to include early manifestation of MDS in patients with germline predisposition. Finally, updates in the classification of juvenile myelomonocytic leukemia are presented which genetically define JMML as a myeloproliferative/myelodysplastic disease harboring canonical RAS pathway mutations. Diseases with features overlapping with JMML that do not carry RAS pathway mutations are classified as JMML-like. The review is based on the International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms as reported by Arber et al. (Blood 140(11):1200-1228, 2022).
Topics: Humans; Child; Leukemia, Myelomonocytic, Juvenile; Consensus; Genetic Predisposition to Disease; Myelodysplastic Syndromes; Hematologic Neoplasms; Myeloproliferative Disorders; Germ-Line Mutation; Intracellular Signaling Peptides and Proteins
PubMed: 36445482
DOI: 10.1007/s00428-022-03447-9 -
American Journal of Hematology Mar 2021Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include... (Review)
Review
Myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T) - "2021 update on diagnosis, risk-stratification, and management".
DISEASE OVERVIEW
Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include myelodysplastic syndromes with RS (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T).
DIAGNOSIS
MDS-RS is a lower risk MDS, with single or multilineage dysplasia (MDS-RS-SLD/MLD), <5% bone marrow (BM) blasts, <1% peripheral blood blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10 /L and large atypical megakaryocytes.
MUTATIONS AND KARYOTYPE
Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F (50%), DNMT3A, TET2 and ASXL1 mutations. Cytogenetic abnormalities are uncommon in both.
RISK STRATIFICATION
Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia (MPN). Both diseases are associated with a low risk of leukemic transformation.
TREATMENT
Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Luspatercept, a first-in-class erythroid maturation agent is now approved for the management of anemia in patients with MDS-RS and MDS/MPN-RS-T. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains to be defined.
Topics: Allografts; Anemia, Sideroblastic; Bone Marrow; Cell Lineage; Clone Cells; Combined Modality Therapy; DNA Methylation; Disease Management; Erythroblasts; Ferritins; Hematinics; Hematopoietic Stem Cell Transplantation; Humans; Iron Chelating Agents; Mitochondria; Mutation; Myelodysplastic-Myeloproliferative Diseases; Phosphoproteins; Prognosis; RNA Splicing Factors; Risk Assessment; Thrombocytosis
PubMed: 33428785
DOI: 10.1002/ajh.26090 -
Blood Aug 2022Inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterized by BM failure, usually in association with ≥1 extrahematopoietic...
Inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterized by BM failure, usually in association with ≥1 extrahematopoietic abnormalities. BM failure, which can involve ≥1 cell lineages, often presents in the pediatric age group. Furthermore, some children initially labeled as having idiopathic aplastic anemia or myelodysplasia represent cryptic cases of inherited BM failure. Significant advances in the genetics of these syndromes have been made, identifying more than 100 disease genes, giving insights into normal hematopoiesis and how it is disrupted in patients with BM failure. They have also provided important information on fundamental biological pathways, including DNA repair: Fanconi anemia (FA) genes; telomere maintenance: dyskeratosis congenita (DC) genes; and ribosome biogenesis: Shwachman-Diamond syndrome and Diamond-Blackfan anemia genes. In addition, because these disorders are usually associated with extrahematopoietic abnormalities and increased risk of cancer, they have provided insights into human development and cancer. In the clinic, genetic tests stemming from the recent advances facilitate diagnosis, especially when clinical features are insufficient to accurately classify a disorder. Hematopoietic stem cell transplantation using fludarabine-based protocols has significantly improved outcomes, particularly in patients with FA or DC. Management of some other complications, such as cancer, remains a challenge. Recent studies have suggested the possibility of new and potentially more efficacious therapies, including a renewed focus on hematopoietic gene therapy and drugs [transforming growth factor-β inhibitors for FA and PAPD5, a human poly(A) polymerase, inhibitors for DC] that target disease-specific defects.
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Child; Dyskeratosis Congenita; Humans; Neoplasms; Pancytopenia
PubMed: 35605178
DOI: 10.1182/blood.2020006481 -
Toxicologic Pathology Aug 2019The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of...
The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.
Topics: Animals; Animals, Laboratory; Biomedical Research; Bone Marrow; Bone Marrow Diseases; Lymphatic Diseases; Lymphoid Tissue; Mice; Rats; Terminology as Topic
PubMed: 31526133
DOI: 10.1177/0192623319867053 -
Best Practice & Research. Clinical... Jun 2021
Topics: Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Humans; Syndrome
PubMed: 34404531
DOI: 10.1016/j.beha.2021.101288