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Pediatrics International : Official... Jan 2022Since the first report in 2009, whole exome sequencing has become the most effective and efficient research tool in human genetics. MIRAGE syndrome is a novel... (Review)
Review
Since the first report in 2009, whole exome sequencing has become the most effective and efficient research tool in human genetics. MIRAGE syndrome is a novel single-gene disorder discovered through whole-exome sequencing for pediatric patients with adrenal insufficiency of unknown etiology, and is caused by de novo heterozygous variants in SAMD9. MIRAGE syndrome was initially discovered as a systemic disease affecting multiple systems, including hematopoietic, immune, endocrine, and gastrointestinal systems but later studies revealed a subset of patients with myelodysplastic syndrome as the sole manifestation. In addition, pathogenic variants in SAMD9L, a paralog gene of SAMD9, were reported to cause an inherited disorder of the hematopoietic system and central nervous system, called ataxia-pancytopenia syndrome. This article reviews the history of MIRAGE syndrome from its discovery to the proposal of SAMD9/SAMD9L syndromes, and discusses directions for future research.
Topics: Adrenal Insufficiency; Child; Heterozygote; Humans; Intracellular Signaling Peptides and Proteins; Myelodysplastic Syndromes; Pancytopenia; Exome Sequencing
PubMed: 35972063
DOI: 10.1111/ped.15283 -
Blood Oct 2023Mechanistic studies of immune bone marrow failure are difficult because of the scarcity of residual cells, the involvement of multiple cell types, and the inherent... (Review)
Review
Mechanistic studies of immune bone marrow failure are difficult because of the scarcity of residual cells, the involvement of multiple cell types, and the inherent complexities of hematopoiesis and immunity. Single-cell genomic technologies and bioinformatics allow extensive, multidimensional analysis of a very limited number of cells. We review emerging applications of single-cell techniques, and early results related to disease pathogenesis: effector and target cell populations and relationships, cell-autonomous and nonautonomous phenotypes in clonal hematopoiesis, transcript splicing, chromosomal abnormalities, and T-cell receptor usage and clonality. Dense and complex data from single-cell techniques provide insights into pathophysiology, natural history, and therapeutic drug effects.
Topics: Humans; Pancytopenia; Anemia, Aplastic; Bone Marrow Failure Disorders; Hematopoiesis; Syndrome; Genomics
PubMed: 37478398
DOI: 10.1182/blood.2022018581 -
The American Journal of Emergency... Jul 2021Neutropenic enterocolitis is also known as typhlitis, is characterized by severe inflammation in the bowel loops. It is often seen in immunosuppressed patients, and it...
Neutropenic enterocolitis is also known as typhlitis, is characterized by severe inflammation in the bowel loops. It is often seen in immunosuppressed patients, and it has high morbidity and mortality. Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the respiratory system and causes COVID-19 (Coronavirus Disease 2019), it may affect hematopoietic and gastrointestinal systems. Herein, we present a rare case of COVID-19-associated pancytopenia and typhlitis in a 60-year-old female who presented with abdominal pain. Contrast-enhanced abdominal computed tomography (CT) demonstrated the bowel wall thickening in the cecum and ascending colon compatible with enterocolitis. Moreover, the chest CT showed bilateral, peripheral, and multifocal ground-glass opacities, consistent with COVID-19 pneumonia. We also aimed to emphasize the laboratory, clinical, and CT findings of the patient.
Topics: COVID-19; Colon; Female; Humans; Lung; Middle Aged; Pancytopenia; Pandemics; SARS-CoV-2; Tomography, X-Ray Computed; Typhlitis
PubMed: 33446380
DOI: 10.1016/j.ajem.2020.12.049 -
Blood Jun 2023
Topics: Humans; Bone Marrow Failure Disorders; Bone Marrow Diseases; Pancytopenia; Clone Cells; Leukemia; Tumor Suppressor Protein p53; DNA Helicases
PubMed: 37289478
DOI: 10.1182/blood.2023020394 -
International Journal of Hematology Mar 2024Acquired aplastic anemia is an immune-mediated disease that targets hematopoietic stem cells, which is diagnosed by findings of peripheral blood pancytopenia and...
Acquired aplastic anemia is an immune-mediated disease that targets hematopoietic stem cells, which is diagnosed by findings of peripheral blood pancytopenia and hypocellular bone marrow. Although the diagnostic definition is simple, differential diagnosis from other overlapping hematopoietic disorders such as hypoplastic myelodysplastic syndrome and inherited bone marrow failure syndrome is not easy. Immune suppressive therapy and allogeneic hematopoietic stem cell transplantation are important treatment approaches for aplastic anemia, and both have advanced in recent years. This issue of Progress in Hematology covers four topics related to aplastic anemia: (1) laboratory markers to identify immune pathophysiology and their role on differential diagnosis and prognosis, (2) the path to combination therapy with horse anti-thymocyte globulin, cyclosporine A, and eltrombopag, (3) more than 60 years of history and recent trends in allogeneic HSCT, and (4) genetic testing for differential diagnosis from IBMFS and novel approaches to transplantation for children including fludarabine/melphalan-based conditioning.
Topics: Child; Humans; Anemia, Aplastic; Pancytopenia; Hematopoietic Stem Cell Transplantation; Cyclosporine; Antilymphocyte Serum
PubMed: 38310173
DOI: 10.1007/s12185-024-03715-1 -
Clinical Chemistry Aug 2019
Topics: Female; Humans; Liver Function Tests; Pancytopenia; Peripheral Nervous System Diseases
PubMed: 31358501
DOI: 10.1373/clinchem.2019.302919 -
Blood Mar 2023
Topics: Humans; Anemia, Refractory; Osteochondrodysplasias; Pancytopenia; Anti-Inflammatory Agents, Non-Steroidal; Bone Marrow Failure Disorders
PubMed: 36995703
DOI: 10.1182/blood.2022019351 -
The Journal of Allergy and Clinical... Nov 2023Genetic defects in components of inflammasomes can cause autoinflammation. Biallelic loss-of-function mutations in dipeptidyl peptidase 9 (DPP9), a negative regulator of...
BACKGROUND
Genetic defects in components of inflammasomes can cause autoinflammation. Biallelic loss-of-function mutations in dipeptidyl peptidase 9 (DPP9), a negative regulator of the NLRP1 and CARD8 inflammasomes, have recently been shown to cause an inborn error of immunity characterized by pancytopenia, skin manifestations, and increased susceptibility to infections.
OBJECTIVE
We sought to study the molecular basis of autoinflammation in a patient with severe infancy-onset hyperinflammation associated with signs of fulminant hemophagocytic lymphohistiocytosis.
METHODS
Using heterologous cell models as well as patient cells, we performed genetic, immunologic, and molecular investigations to identify the genetic cause and to assess the impact of the identified mutation on inflammasome activation.
RESULTS
The patient exhibited pancytopenia with decreased neutrophils and T, B, and natural killer cells, and markedly elevated levels of lactate dehydrogenase, ferritin, soluble IL-2 receptor, and triglycerides. In addition, serum levels of IL-1β and IL-18 were massively increased, consistent with inflammasome activation. Genetic analysis revealed a previously undescribed de novo mutation in DPP9 (c.755G>C, p.Arg252Pro) affecting a highly conserved amino acid residue. The mutation led to destabilization of the DPP9 protein as shown in transiently transfected HEK293T cells and in patient-derived induced pluripotent stem cells. Using functional inflammasome assays in HEK293T cells, we demonstrated that mutant DPP9 failed to restrain the NLRP1 and CARD8 inflammasomes, resulting in constitutive inflammasome activation. These findings suggest that the Arg252Pro DPP9 mutation acts in a dominant-negative manner.
CONCLUSIONS
A de novo mutation in DPP9 leads to severe infancy-onset autoinflammation because of unleashed inflammasome activation.
Topics: Humans; CARD Signaling Adaptor Proteins; Inflammasomes; Lymphohistiocytosis, Hemophagocytic; Pancytopenia; HEK293 Cells; Apoptosis Regulatory Proteins; Mutation; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Neoplasm Proteins
PubMed: 37544411
DOI: 10.1016/j.jaci.2023.07.013 -
Journal of Clinical Immunology Aug 2023MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic... (Review)
Review
MECOM deficiency is a recently identified inborn error of immunity and inherited bone marrow failure syndrome caused by haploinsufficiency of the hematopoietic transcription factor MECOM. It is unique among inherited bone marrow failure syndromes, many of which present during later childhood or adolescence, because of the early age of onset and severity of the pancytopenia, emphasizing the importance and gene dose dependency of MECOM during hematopoiesis. B-cell lymphopenia and hypogammaglobulinemia have been described in a subset of patients with MECOM deficiency. While the mechanisms underlying the B-cell deficiency are currently unknown, recent work has provided mechanistic insights into the function of MECOM in hematopoietic stem cell (HSC) maintenance. MECOM binds to regulatory enhancers that control the expression of a network of genes essential for HSC maintenance and self-renewal. Heterozygous mutations, as seen in MECOM-deficient bone marrow failure, lead to dysregulated MECOM network expression. Extra-hematopoietic manifestations of MECOM deficiency, including renal and cardiac anomalies, radioulnar synostosis, clinodactyly, and hearing loss, have been reported. Individuals with specific genotypes have some of the systemic manifestations with isolated mild thrombocytopenia or without hematologic abnormalities, highlighting the tissue specificity of mutations in some MECOM domains. Those infants with MECOM-associated bone marrow failure require HSC transplantation for survival. Here, we review the expanding cohort of patient phenotypes and accompanying genotypes resulting in MECOM deficiency, and the proposed mechanisms underlying MECOM regulation of human HSC maintenance and B-cell development.
Topics: Humans; Child; Pancytopenia; Transcription Factors; Bone Marrow Failure Disorders; Hematopoietic Stem Cells; Gene Expression Regulation; Congenital Bone Marrow Failure Syndromes; Thrombocytopenia; Hematopoiesis; MDS1 and EVI1 Complex Locus Protein
PubMed: 37407873
DOI: 10.1007/s10875-023-01545-0 -
Recent Advances in Inflammation &... 2023SARS-CoV-2 infection has mild and asymptomatic to critical clinical course affecting mainly the lungs. Few case reports of COVID-19-associated pancytopenia are reported,... (Observational Study)
Observational Study
BACKGROUND
SARS-CoV-2 infection has mild and asymptomatic to critical clinical course affecting mainly the lungs. Few case reports of COVID-19-associated pancytopenia are reported, but a series of 18 cases is not described in the literature to date.
AIMS AND OBJECTIVES
This study aimed to investigate pancytopenia in COVID-19 and its correlation with severity and to explore the detailed clinical and biochemical information in COVID-19- associated pancytopenia. This study also highlights pancytopenia's rarity and prognostic value among COVID-19 patients.
MATERIALS AND METHODS
This was a retrospective observational study conducted in a tertiary care centre at a level 3 COVID care facility that included adults of either sex having positive RT PCR for COVID-19 from October 2020 to May 2021. Data were collected from the online outpatient department and hospitalized patients.
RESULTS
A total of 18 cases were included in the study; 13 were males (72.2%). The mean age was calculated as 48.56 years. Cases were categorized as severe 13 (72.2%) and non-severe 5 (27.8%) disease on the first day of pancytopenia. The most common presentations were fever 18 (100%) and cough 18 (100%), followed by generalized weakness 16 (88.9%), breathlessness 15 (83.3%), and diarrhoea 10 (55.6%). One case died in the severe disease group. The mean of haemoglobin, leukocyte count, and platelets in severe vs non-severe disease were calculated as 8.59 vs 8.74, 2339 vs 2578, and 77769 vs 88600, respectively.
CONCLUSION
Pancytopenia was more prevalent in severe disease and age group 40-60 years. CAP was most likely due to secondary bone marrow suppression. It has no prognostic value for disease outcomes.
Topics: Adult; Male; Humans; Middle Aged; Female; COVID-19; Pancytopenia; SARS-CoV-2; Retrospective Studies; Bone Marrow Diseases
PubMed: 36475340
DOI: 10.2174/2772270817666221207094122