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Blood Cells, Molecules & Diseases May 2024Diamond-Blackfan anemia (DBA) was the first ribosomopathy described in humans. DBA is a congenital hypoplastic anemia, characterized by macrocytic aregenerative anemia,...
Diamond-Blackfan anemia (DBA) was the first ribosomopathy described in humans. DBA is a congenital hypoplastic anemia, characterized by macrocytic aregenerative anemia, manifesting by differentiation blockage between the BFU-e/CFU-e developmental erythroid progenitor stages. In 50 % of the DBA cases, various malformations are noted. Strikingly, for a hematological disease with a relative erythroid tropism, DBA is due to ribosomal haploinsufficiency in 24 different ribosomal protein (RP) genes. A few other genes have been described in DBA-like disorders, but they do not fit into the classical DBA phenotype (Sankaran et al., 2012; van Dooijeweert et al., 2022; Toki et al., 2018; Kim et al., 2017 [1-4]). Haploinsufficiency in a RP gene leads to defective ribosomal RNA (rRNA) maturation, which is a hallmark of DBA. However, the mechanistic understandings of the erythroid tropism defect in DBA are still to be fully defined. Erythroid defect in DBA has been recently been linked in a non-exclusive manner to a number of mechanisms that include: 1) a defect in translation, in particular for the GATA1 erythroid gene; 2) a deficit of HSP70, the GATA1 chaperone, and 3) free heme toxicity. In addition, p53 activation in response to ribosomal stress is involved in DBA pathophysiology. The DBA phenotype may thus result from the combined contributions of various actors, which may explain the heterogenous phenotypes observed in DBA patients, even within the same family.
Topics: Humans; Anemia, Diamond-Blackfan; Ribosomal Proteins; Anemia, Macrocytic; Erythroid Precursor Cells; Anemia, Dyserythropoietic, Congenital; Mutation
PubMed: 38413287
DOI: 10.1016/j.bcmd.2024.102838 -
American Journal of Clinical Pathology Jun 2024VEXAS syndrome is an adult-onset autoinflammatory disease caused by a somatic pathogenic mutation in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene....
Comprehensive morphologic characterization of bone marrow biopsy findings in a large cohort of patients with VEXAS syndrome: A single-institution longitudinal study of 111 bone marrow samples from 52 patients.
OBJECTIVES
VEXAS syndrome is an adult-onset autoinflammatory disease caused by a somatic pathogenic mutation in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. Patients present with rheumatologic manifestations and cytopenias and may have an increased predisposition to myelodysplastic syndrome (MDS) and plasma cell neoplasms. Prior studies have reported on the peripheral blood and bone marrow findings in patients with VEXAS syndrome. Due to the protean clinical presentation and lack of specificity of morphologic features (eg, vacuoles in early erythroid and granulocytic precursors), an optimal screening methodology to identify these patients in a timely fashion is desirable.
METHODS
To further evaluate and describe the salient diagnostic morphologic features in VEXAS syndrome, we carried out a comprehensive study of the largest single-institution cohort to date. Diagnostic and follow-up bone marrow biopsy specimens from 52 male patients with molecularly identified VEXAS syndrome underwent central review.
RESULTS
Cytopenias were common in all cases, primarily macrocytic anemia, monocytopenia, and thrombocytopenia. Bone marrow aspirate and biopsy were often hypercellular, with an increased myeloid/erythroid ratio, granulocytic hyperplasia with left shift, erythroid left shift, and megakaryocyte hyperplasia, which exhibited a range of striking morphologic findings. Distinctly vacuolated myeloid and erythroid precursors were seen in more than 95% of cases.
CONCLUSIONS
Our data reveal potential novel diagnostic features, such as a high incidence of monocytopenia and distinct patterns of atypical megakaryopoiesis, that appear different from dysmegakaryopoiesis typically associated with MDS. In our experience, those findings are suggestive of VEXAS, in the appropriate clinical context.
Topics: Humans; Male; Middle Aged; Bone Marrow; Adult; Aged; Longitudinal Studies; Biopsy; Ubiquitin-Activating Enzymes; Myelodysplastic Syndromes; Young Adult; Aged, 80 and over; Cohort Studies; Female; Mutation; Thrombocytopenia
PubMed: 38413044
DOI: 10.1093/ajcp/aqad186 -
Journal of Ayub Medical College,... 2023Thiamine-responsive megaloblastic anaemia (TRMA) is characterized by the classic trio of diabetes mellitus, sensorineural hearing loss, and megaloblastic anaemia,...
Thiamine-responsive megaloblastic anaemia (TRMA) is characterized by the classic trio of diabetes mellitus, sensorineural hearing loss, and megaloblastic anaemia, typically emerging subtly between infancy and adolescence. Administration of high-dose thiamine often yields improvements in anaemia and occasionally in diabetes. Uncommon manifestations include optic atrophy, congenital heart defects, short stature, and stroke. In this specific case, a 5-year-old diagnosed with insulin-dependent diabetes mellitus (IDDM) since the age of one presented with symptoms such as polyuria, fever, and vomiting, revealing an HbA1c of 10.64. Further examinations disclosed compromised hearing and vision. A negative antibody workup and a thyroid profile indicating hypothyroidism prompted additional investigations, including Brainstem Evoked Response Audiometry (BERA) and retinal examination, confirming bilateral sensorineural hearing loss and maculopathy, respectively. A comprehensive blood count unveiled megaloblastic anaemia. Genetic profiling confirmed a homozygous mutation in the SLC19A2 gene, thus diagnosing TRMA. An early diagnosis, coupled with genetic confirmation, enables timely intervention, with patients responding positively to high-dose thiamine. Genetic counselling plays a pivotal role in enlightening families about the disease and its inheritance patterns, fostering awareness and understanding.
Topics: Humans; Child, Preschool; Thiamine Deficiency; Thiamine; Anemia, Megaloblastic; Hearing Loss, Sensorineural; Hypothyroidism; Diabetes Mellitus; Membrane Transport Proteins
PubMed: 38406914
DOI: 10.55519/JAMC-S4-12486 -
MedRxiv : the Preprint Server For... Feb 2024encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed...
encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While knockout mice die with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) variant alleles. We characterize an expansive phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis.
PubMed: 38405817
DOI: 10.1101/2024.02.09.24302464 -
Practical Laboratory Medicine Mar 2024To compare the laboratory tests conducted in real-life settings for patients with anemia with the expected prescriptions derived from an optimal checkup.
OBJECTIVE
To compare the laboratory tests conducted in real-life settings for patients with anemia with the expected prescriptions derived from an optimal checkup.
METHODS
A panel of experts formulated an "optimal laboratory test assessment" specific to each anemia profile. A retrospective analysis was done of the laboratory tests conducted according to the type of anemia (microcytic, normocytic or macrocytic). Using an algorithmic system, the laboratory tests performed in real-life practice were compared with the recommendations suggested in the "optimal laboratory test assessment" and with seemingly "unnecessary" laboratory tests.
RESULTS
In the analysis of the "optimal laboratory test assessment", of the 1179 patients with microcytic anemia, 269 (22.8%) had had one of the three tests recommended by the expert system, and only 33 (2.8%) had all three tests. For normocytic anemia, 1054 of 2313 patients (45.6%) had one of the eleven recommended tests, and none had all eleven. Of the 384 patients with macrocytic anemia, 196 (51%) had one of the four recommended tests, and none had all four. In the analysis of "unnecessary laboratory tests", one lab test was unnecessarily done in 727/3876 patients (18.8%), i.e. 339 of 1179 (28.8%) microcytic, 171 of 2313 (7.4%) normocytic, and 217 of 384 (56.5 %) macrocytic anemias.
CONCLUSION
Laboratory investigations of anemia remain imperfect as more than half of the cases did not receive the expected tests. Analyzing other diagnostic domains, the authors are currently developing an artificial intelligence system to assist physicians in enhancing the efficiency of their laboratory test prescriptions.
PubMed: 38404528
DOI: 10.1016/j.plabm.2024.e00357 -
Journal of Clinical Medicine Feb 2024VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently recognized systemic autoinflammatory disease caused by somatic mutations in...
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently recognized systemic autoinflammatory disease caused by somatic mutations in hematopoietic progenitor cells. This case series of four patients with VEXAS syndrome and comorbid myelodysplastic syndrome (MDS) aims to describe clinical, imaging, and hematologic disease presentations as well as response to therapy. Four patients with VEXAS syndrome and MDS are described. A detailed analysis of imaging features, hemato-oncological presentation including bone marrow microscopy and clinical-rheumatological disease features and treatment outcomes is given. All patients were male; ages ranged between 64 and 81 years; all were diagnosed with MDS. CT imaging was available for three patients, all of whom exhibited pulmonary infiltrates of varying severity, resembling COVID-19 or hypersensitivity pneumonitis without traces of scarring. Bone marrow microscopy showed maturation-disordered erythropoiesis and pathognomonic vacuolation. Somatic mutation in the codon 41 were found in all patients by next-generation sequencing. Therapy regimes included glucocorticoids, JAK1/2-inhibitors, nucleoside analogues, as well as IL-1 and IL-6 receptor antagonists. No fatalities occurred (observation period from symptom onset: 18-68 months). Given the potential underreporting of VEXAS syndrome, we highly recommend contemporary screening for mutations in patients presenting with ambiguous signs of systemic autoinflammatory symptoms which persist over 18 months despite treatment. The emergence of cytopenia, especially macrocytic hyperchromic anemia, should prompt early testing for mutations. Notably conspicuous, pulmonary alterations in CT imaging of patients with therapy-resistant systemic autoinflammatory symptoms should be discussed in interdisciplinary medical teams (Rheumatology, Hematology, Radiology and further specialist departments) to facilitate timely diagnosis during the clinical course of the disease.
PubMed: 38398362
DOI: 10.3390/jcm13041049 -
Cureus Jan 2024Vitamin deficiency is common in the geriatric population and is responsible for majorly imbalanced hematological, neurological, and neuropsychiatric functioning....
Vitamin deficiency is common in the geriatric population and is responsible for majorly imbalanced hematological, neurological, and neuropsychiatric functioning. Methylcobalamin deficiency or vitamin B deficiency can be underestimated in some cases and be misdiagnosed as other illnesses, such as thalamic syndrome. Timely diagnosis of this deficiency is essential, especially in the geriatric population, as it might cause irreversible structural brain damage. This is also presented as elevated levels of homocysteine and methylmalonic acid. Clinically, it presents with the following symptoms: lower sensitivity levels to touch and light, psychosis, paresthesia, anemia, imbalance, fatigue, cognitive disturbances, difficulty remembering, and confusion. Symptoms are usually progressive and worsen over a period of time. In this case report, we present the case of a 62-year-old male with clinical symptoms of numbness and tingling in the right side of the body. The neurological presentations resembled left thalamic infarct, but the underlying reason was methylcobalamin deficiency.
PubMed: 38389590
DOI: 10.7759/cureus.52761 -
Respirology Case Reports Feb 2024In cases of Sweet's syndrome with pulmonary involvement, fever of unknown origin, and macrocytic anaemia, VEXAS syndrome can be considered in the differential diagnosis....
Steroid reduction-resistant pulmonary involvement with Sweet's syndrome suspected of being vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome: A case report.
In cases of Sweet's syndrome with pulmonary involvement, fever of unknown origin, and macrocytic anaemia, VEXAS syndrome can be considered in the differential diagnosis. A 67-year-old man who was taking prednisolone for a fever of unknown origin and Sweet's syndrome was referred to us because of an abnormal chest shadow. Computed tomography revealed a nonfibrotic hypersensitivity pneumonitis-like opacity, and blood test results indicated macrocytic anaemia. His pulmonary symptoms spontaneously improved but again exacerbated approximately 1 month later. Methylprednisolone pulse therapy improved his condition, but he had recurring fever flare and pulmonary involvement post-treatment. A peripheral blood gene test planned at a specialized institution was not performed, making the diagnosis difficult. We attempted careful tapering of methylprednisolone, but his macrocytic anaemia led to pancytopenia and he unfortunately died of sepsis due to neutropenia.
PubMed: 38384745
DOI: 10.1002/rcr2.1288 -
Pathologie (Heidelberg, Germany) Mar 2024Besides microscopic evaluation of smears, flow cytometric analysis, chromosomal and molecular studies, histological analysis of bone marrow biopsies (BMbx) is...
Besides microscopic evaluation of smears, flow cytometric analysis, chromosomal and molecular studies, histological analysis of bone marrow biopsies (BMbx) is an important component of multiparameter diagnostics of cytopenias in hematology. More than in other fields of histopathology, correct interpretation of BMbx requires correlation with the results of these further studies and other clinical findings. Microcytic, normocytic and macrocytic anemia, isolated granulocytopenia and thromobocytopenia as well as pancytopenia represent frequent and recurrent diseases. With regard to aetiology, reactive and neoplastic causes must be differentiated. Reactive causes of cytopenia include substrate deficiencies, enhanced turn over and loss, and inflammatory processes. Neoplastic disorders with the exception of myeloproliferative neoplasms generally manifest as cytopenia and comprise myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and lymphoma.
Topics: Humans; Bone Marrow; Cytopenia; Diagnosis, Differential; Myelodysplastic Syndromes; Hematology
PubMed: 38381371
DOI: 10.1007/s00292-024-01302-z -
Scientific Reports Feb 2024We investigated the clinical implications of the mean corpuscular volume (MCV) in patients with major trauma. This single-center retrospective review included 2021...
We investigated the clinical implications of the mean corpuscular volume (MCV) in patients with major trauma. This single-center retrospective review included 2021 trauma patients admitted to the intensive care unit between January 2016 and June 2020. We included 1218 patients aged [Formula: see text] 18 years with an injury severity score [Formula: see text] 16 in the final analysis. The clinical and laboratory variables were compared between macrocytosis (defined as MCV [Formula: see text] 100 fL) and non-macrocytosis groups. Cox regression analysis was performed to calculate the hazard ratios (HRs) of variables for 30-day mortality, with adjustment for other potential confounding factors. The initial mean value of MCV was 102.7 fL in the macrocytosis group (n = 199) and 93.7 fL in the non-macrocytosis group (n = 1019). The macrocytosis group showed a significantly higher proportion of initial hypotension, transfusion within 4 and 24 h, and 30-day mortality than the non-macrocytosis group. Age ([Formula: see text] 65 years), hypotension (systolic blood pressure [Formula: see text] 90 mmHg), transfusion (within 4 h), anemia (Hb < 12 g/day in women, < 13 g/day in men), and macrocytosis were significantly associated with 30-day mortality (adjusted HR = 1.4; 95% confidence interval 1.01-1.94; p = 0.046) in major trauma patients. Thus, initial macrocytosis independently predicted 30-day mortality in patients with major trauma at a Level I trauma center.
Topics: Male; Humans; Female; Aged; Erythrocyte Indices; Retrospective Studies; Prognosis; Anemia; Anemia, Macrocytic; Folic Acid Deficiency; Hypotension
PubMed: 38365858
DOI: 10.1038/s41598-024-54057-1