Mcph1, mutated in primary microcephaly, is also crucial for erythropoiesis.

Microcephaly is a common feature in inherited bone marrow failure syndromes, prompting investigations into shared pathways between neurogenesis and hematopoiesis. To understand this association, we studied the role of the microcephaly gene Mcph1 in hematological development. Our research revealed that Mcph1-knockout mice exhibited congenital macrocytic anemia due to impaired terminal erythroid differentiation during fetal development. Anemia's cause is a failure to complete cell division, evident from tetraploid erythroid progenitors with DNA content exceeding 4n. Gene expression profiling demonstrated activation of the p53 pathway in Mcph1-deficient erythroid precursors, leading to overexpression of Cdkn1a/p21, a major mediator of p53-dependent cell cycle arrest. Surprisingly, fetal brain analysis revealed hypertrophied binucleated neuroprogenitors overexpressing p21 in Mcph1-knockout mice, indicating a shared pathophysiological mechanism underlying both erythroid and neurological defects. However, inactivating p53 in Mcph1-/- mice failed to reverse anemia and microcephaly, suggesting that p53 activation in Mcph1-deficient cells resulted from their proliferation defect rather than causing it. These findings shed new light on Mcph1's function in fetal hematopoietic development, emphasizing the impact of disrupted cell division on neurogenesis and erythropoiesis - a common limiting pathway.

Macrocytic anemias.

PURPOSE OF REVIEW: Over the last century, the diseases associated with macrocytic anemia have been changing with more patients currently having hematological diseases including malignancies and myelodysplastic syndrome. The intracellular mechanisms underlying the development of anemia with macrocytosis can help in understanding normal erythropoiesis. Adaptations to these diseases involving erythroid progenitor and precursor cells lead to production of fewer but larger red blood cells, and understanding these mechanisms can provide information for possible treatments. RECENT FINDINGS: Both inherited and acquired bone marrow diseases involving primarily impaired or delayed erythroid cell division or secondary adaptions to basic erythroid cellular deficits that results in prolonged cell division frequently present with macrocytic anemia. SUMMARY OF FINDINGS: In marrow failure diseases, large accumulations of iron and heme in early stages of erythroid differentiation make cells in those stages especially susceptible to death, but the erythroid cells that can survive the early stages of terminal differentiation yield fewer but larger erythrocytes that are recognized clinically as macrocytic anemia. Other disorders that limit deoxynucleosides required for DNA synthesis affect a broader range of erythropoietic cells, but they also lead to macrocytic anemia. The source of macrocytosis in other diseases remains uncertain.

[Macrocytic anemia and polychondritis: VEXAS syndrome]. / Makrozytäre Anämie und Polychondritis: VEXAS-Syndrom.

An adult-onset autoinflammatory syndrome caused by somatic mutations in the UBA1 gene on the X chromosome was first reported in 2020. This VEXAS syndrome (acronym for vacuoles, E1 enzyme, X­linked, autoinflammatory, somatic) is characterized by an overlap of rheumatic inflammatory diseases with separate hematologic abnormalities. A substantial number of affected patients suffer from treatment refractory relapsing polychondritis and nearly always show signs of macrocytic anemia. This case report illustrates the diagnostic key points to recognizing patients with VEXAS syndrome.

Anemia: Macrocytic Anemia.

Macrocytic anemia is divided into megaloblastic and nonmegaloblastic causes, with the former being more common. Megaloblastic anemia results from impaired DNA synthesis, leading to release of megaloblasts, which are large nucleated red blood cell precursors with chromatin that is not condensed. Vitamin B12 deficiency is the most common cause for megaloblastic anemia, although folate deficiency also can contribute. Nonmegaloblastic anemia entails normal DNA synthesis and typically is caused by chronic liver dysfunction, hypothyroidism, alcohol use disorder, or myelodysplastic disorders. Macrocytosis also can result from release of reticulocytes in the normal physiologic response to acute anemia. Management of macrocytic anemia is specific to the etiology identified through testing and patient evaluation.

Analysis of Mean Corpuscular Volume and Red Cell Distribution Width in Patients with Aplastic Anemia.

To explore the characteristics of hemogram in patients with aplastic anemia (AA), especially mean corpuscular volume (MCV) and red cell distribution width (RDW). We examined the blood routine of 180 new-onset AA patients and used 166 patients with myelodysplastic syndrome (MDS) as controls. Among the 180 AA patients, 105 (58.3%) were diagnosed with severe AA (SAA), while 75 (41.7%) were diagnosed with non-severe AA (NSAA). Compared to MDS, patients with SAA generally had unfavorable hemogram, including significantly lower white blood cell (WBC), absolute neutrophil count (ANC), hemoglobin (Hb), platelet (PLT) and reticulocyte counts (RET). However, WBC, ANC and lymphocyte counts were higher in the NSAA group than in the MDS group; Hb and Ret were comparable between the two groups. 8.5% of SAA patients and 58.1% of NSAA patients presented with macrocytic anemia, whereas 25.7% of SAA and 64.0% of NSAA had a high RDW. In the MDS group, 54.7% of patients presented with macrocytic anemia, and 84.7% had increased RDW. WBC, ANC, PLT, and Ret in a high-RDW group (25.7% of SAA) were significantly higher than in a normal-RDW group (74.3% of SAA). Overall, most SAA patients exhibited normocytic-normochromic anemia, and their hemograms decreased more significantly; more than half of NSAA patients showed macrocytic-heterogeneous anemia, and their hemograms were similar to those of MDS. Patients with elevated RDW may have better residual bone marrow hematopoietic function than those with normal RDW but with more severe anemia.

Association of Serum Ferritin, Folate, Vitamin B12 with Thyroid Hormone Levels in Patients with Thyroid Disorders.

INTRODUCTION: Anemia frequently occurs during course of clinical thyroid diseases. Without proper diagnosis & effective treatment of underlying thyroid disease, it is often difficult to achieve complete correction of anemia. AIM: The present study was conducted to assess prevalence & types of anaemia in patients with thyroid disorders. MATERIALS: A cross sectional study was conducted on 160 patients including both hypothyroid & hyperthyroid patients at OPD/IPD in SRN Hospital affiliated to MLN Medical college Prayagraj between July 2021 & August 2022. Blood samples were taken to estimate CBC, GBP with Retic count, S. ferritin, S. folate, S. Vitamin B12, Thyroid profile. Data was entered in MS Excel Spreadsheet & appropriate statistical package applied. RESULT: Out of 144 hypothyroid patients, 102 (70.83%) were found to be anaemic & out of 16 hyperthyroid patients, 6 (37.5%) were found to be anaemic. In 102 anaemic hypothyroid patients, 56 (54.9%)had normocytic normochromic, 25 (24.5%) had microcytic and 21 (20.5%) had macrocytic anaemia. In 6 anaemic hyperthyroid patients, 3 (50%) had normocytic normochromic, 2(33.33%) had microcytic and 1 (16.67%) had macrocytic anaemia. CONCLUSION: High prevalence of anaemia was found in patients with thyroid disorders. Anaemia is an uncommon finding in hyperthyroidism but when present may be similar to that present in hypothyroidism. The most common type of anaemia in both hyperthyroidism & hypothyroidism was found to be normocytic normochromic, followed by microcytic & least common being macrocytic. References Suhail N, Abu Alsel BT, Batool S. Prevalence and association of thyroid dysfunction with anemia/body iron status among northern border Saudi population. Int J Med Res Health Sci 2020;9(3):1-7. Peraka SA, Karre S, Ravuri S, et al., To evaluate prevalence of anemia in hypothyroid patients. J Diagn Pathol Oncol 2019;4(2):110-113.

Haemoglobin levels and outcomes of subgroups of patients with pre-operative anaemia based on red cell size: A retrospective cohort study.

BACKGROUND: Pre-operative anaemia is common and associated with adverse outcomes. We hypothesised that pre-operative anaemia would be evident more than 1 month pre-operatively, and that peri-operative changes in haemoglobin and post-operative outcomes differed between red cell size-based subsets of anaemia. METHODS: A retrospective single-centre cohort study, including all patients 18 years and older undergoing their first surgery at Landspitali between January 2006 and December 2018 with available measurement of haemoglobin (Hb) within 30 days preceding surgery. Clinical data were compared between patients with subgroups of anaemia classified by mean corpuscular volume (MCV) into microcytic (MCV < 80 fl), normocytic (MCV 80-100 fl), and macrocytic (MCV > 100 fl) anaemia. The development of haemoglobin measurements from a nationwide database was plotted from 1 year pre-operatively to 2 years post-operatively. RESULTS: Of 40,979 patients, 10,505 (25.6%) had pre-operative anaemia, of which 1089 (10.4%) had microcytic anaemia, 9243 (88.0%) had normocytic anaemia, and 173 (1.6%) had macrocytic anaemia. Patients within all subgroups of pre-operative anaemia had a higher degree of comorbidity and frailty burden and a low haemoglobin evident for more than 100 days pre-operatively and similar changes post-operatively. Post-operative prolonged recovery of haemoglobin was slower for macrocytic anaemia than other types of anaemia. All groups of patients with anaemia had a higher incidence of 30-day mortality, acute kidney injury, and rate of readmission compared with patients without anaemia. CONCLUSIONS: Pre-operative anaemia is evident long prior to the procedure and its association with worse outcomes is similar regardless of red cell size.

Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation.

DNA ligase I deficiency is an extremely rare primary immunodeficiency with only 6 patients reported in the literature. Most common manifestations include radiosensitivity, macrocytic anemia, lymphopenia with an increased percentage of gamma-delta T cells, and hypogammaglobulinemia requiring replacement therapy. Two-month-old girl with delayed development, T-B-NK+ SCID, and macrocytic anemia presented features of Omenn syndrome. Whole exome sequencing revealed two novel, heterozygous variants (c.2312 G>A, p.Arg771Gly and c.776+5G>T, p.Pro260*) in the LIG1 gene (NM_000234.1). Hematopoietic stem cell transplantation from a fully matched unrelated donor was performed at the age of 4 months using GEFA03 protocol. Mixed donor-recipient chimerism was observed, with 60-70% chimerism in the mononucleated cell compartment and over 90% in T-lymphocyte compartment, but autologous myeloid recovery. Stable CD4+ and CD8+ T-cell counts above 200/µL were achieved after 2 months, but the patient remained transfusion-dependent. Despite satisfactory immunological reconstitution, the second transplantation due to constitutional hemolytic defect has been considered. In light of possible re-transplantation, an issue of optimal conditioning protocol with sufficient myeloid engraftment is important. For the first time Omenn syndrome is described in a compound heterozygote carrying two the novel variants p.Arg771Gly and p.Pro260* in the LIG1 gene. Patients diagnosed with SCID and Omenn syndrome showing macrocytic anemia, should be screened for DNA ligase I deficiency.

Diagnosis, Treatment and Prevention of Nutritional Anemia in Children: Recommendations of the Joint Committee of Pediatric Hematology-Oncology Chapter and Pediatric and Adolescent Nutrition Society of the Indian Academy of Pediatrics.

JUSTIFICATION: Anemia in children is a significant public health problem in our country. Comprehensive National Nutrition Survey 2016-18 provides evidence that more than 50% of childhood anemia is due to an underlying nutritional deficiency. The National Family Health Survey-5 has reported an increase in the prevalence of anemia in the under-five age group from 59% to 67.1% over the last 5 years. Clearly, the existing public health programs to decrease the prevalence of anemia have not shown the desired results. Hence, there is a need to develop nationally acceptable guidelines for the diagnosis, treatment and prevention of nutritional anemia. OBJECTIVE: To review the available literature and collate evidence-based observations to formulate guidelines for diagnosis, treatment and prevention of nutritional anemia in children. PROCESS: These guidelines have been developed by the experts from the Pediatric Hematology-Oncology Chapter and the Pediatric and Adolescent Nutrition (PAN) Society of the Indian Academy of Pediatrics (IAP). Key areas were identified as: epidemiology, nomenclature and definitions, etiology and diagnosis of iron deficiency anemia (IDA), treatment of IDA, etiology and diagnosis of vitamin B12 and/or folic acid deficiency, treatment of vitamin B12 and/or folic acid deficiency anemia and prevention of nutritional anemia. Each of these key areas were reviewed by at least 2 to 3 experts. Four virtual meetings were held in November, 2021 and all the key issues were deliberated upon. Based on review and inputs received during meetings, draft recommendations were prepared. After this, a writing group was constituted which prepared the draft guidelines. The draft was circulated and approved by all the expert group members. RECOMMENDATIONS: We recommend use of World Health Organization (WHO) cut-off hemoglobin levels to define anemia in children and adolescents. Most cases suspected to have IDA can be started on treatment based on a compatible history, physical examination and hemogram report. Serum ferritin assay is recommended for the confirmation of the diagnosis of IDA. Most cases of IDA can be managed with oral iron therapy using 2-3 mg/kg elemental iron daily. The presence of macro-ovalocytes and hypersegmented neutrophils, along with an elevated mean corpuscular volume (MCV), should raise the suspicion of underlying vitamin B12 (cobalamin) or folic acid deficiency. Estimation of serum vitamin B12 and folate level are advisable in children with macrocytic anemia prior to starting treatment. When serum vitamin B12 and folate levels are unavailable, patients should be treated using both drugs. Vitamin B12 should preferably be started 10-14 days ahead of oral folic acid to avoid precipitating neurological symptoms. Children with macrocytic anemia in whom a quick response to treatment is required, such as those with pancytopenia, severe anemia, developmental delay and infantile tremor syndrome, should be managed using parenteral vitamin B12. Children with vitamin B12 deficiency having mild or moderate anemia may be managed using oral vitamin B12 preparations. After completing therapy for nutritional anemia, all infants and children should be advised to continue prophylactic iron-folic acid (IFA) supplementation as prescribed under Anemia Mukt Bharat guidelines. For prevention of anemia, in addition to age-appropriate IFA prophylaxis, routine screening of infants for anemia at 9 months during immunization visit is recommended.

[VEXAS gene variants explain previously unrecognized clinical syndrome].

This review aims to make clinicians aware of the newly described syndrome, VEXAS. VEXAS should become an obvious differential diagnosis in cases of unexplained inflammation, anemia, and rheumatological and/or hematological manifestations. Patients with VEXAS are typically male aged > 60, with inflammation, and macrocytic anaemia. On suspicion of cancer or infections patients have frequently been exposed to extensive diagnostic procedures and hospital admissions. In this review, we summarise the current knowledge of VEXAS regarding pathogenesis, symptoms, diagnosis, and treatment.

Quantitative evaluation of treatment response to lenalidomide by applying fluorescence in situ hybridization for peripheral blood granulocytes in a patient with 5q- syndrome.

The introduction of lenalidomide has significantly improved clinical outcomes in myelodysplastic syndrome (MDS) with isolated interstitial deletion of the long arm of chromosome 5 (del(5q)) (5q- syndrome). These days, MDS with isolated del(5q) includes cases with one additional chromosome abnormality other than monosomy 7 or del(7q), and so we need a better way to monitor tumor cells in each patient than the clinical parameters used to date. An 82-year-old woman with MDS with isolated del(5q) was treated with lenalidomide daily for 21 days in a 4-week cycle. Fluorescence in situ hybridization with CSF1R located at 5q was applied to the peripheral blood samples. Because mature lymphocytes are not involved in the MDS clone, based on the nuclear morphology, polymorphonuclear cells (PMNs) and round-shaped nuclear cells (RSNs) were separately evaluated during treatment. After a single course of treatment, the number of PMNs with del(5q) decreased; by the end of the second course of treatment, both PMNs and RSNs with del(5q) had disappeared. The dynamics of 5q- PMNs is a simple but rapid and reliable indicator to confirm the effect of lenalidomide in MDS with del(5q).

Alterações no VCM e suas correlações com os valores de RDW-SD e RDW-CV em caninos e felinos / Variation in MCV and its correlation with RDW-SD and RDW-CV values in dogs and cats

A anemia é uma síndrome caracterizada pela diminuição do número de hemácias, hematócrito e/ou concentração de hemoglobina. Conforme o Volume Corpuscular Médio (VCM), as anemias podem ser classificadas em microcíticas, normocíticas ou macrocíticas. O RDW (Amplitude de Distribuição dos Eritrócitos) também é utilizado para ajudar na classificação das anemias, refletindo a anisocitose da população eritrocitária. Neste estudo retrospectivo objetivou-se determinar a correlação entre o RDW-SD (Desvio Padrão), RDW-CV (Coeficiente de Variação), macrocitose e microcitose em caninos e felinos atendidos na rotina clínica do Hospital Veterinário da Universidade Luterana do Brasil. Para a realização deste estudo, selecionou-se 662 laudos de hemogramas realizados (434 caninos e 228 felinos), com faixa etária de seis meses até 10 anos, foram divididos em dois grupos: Grupo 1 ­ Anemia microcítica (255 caninos e 61 felinos); Grupo 2 ­ Anemia macrocítica (179 caninos e 167 felinos). Posteriormente, correlacionou-se os grupos com os valores de RDW-SD e RDW-CV. As análises de correlação foram realizadas utilizando o teste Spearman, para a análise de significância foi utilizado o T Student, no programa IBM SPSS®Statistics. Na análise estatística do grupo canino, não houve correlação da microcitose com o RDW-SD, enquanto o RDW-CV apresentou uma correlação inversamente proporcional, razoável. No grupo macrocítico canino, a análise de correlação com o RDW-SD foi moderada e diretamente proporcional, e com o RDW-CV foi moderada e diretamente proporcional. No grupo felino, não houve correlação entre microcitose e RDW-SD, e com o RDW-CV houve uma correlação razoável e inversamente proporcional. Entre macrocitose em felinos e o RDW-SD houve uma correlação moderada e diretamente proporcional, já o RDW-CV apresentou uma correlação razoável e diretamente proporcional. Conclui-se que os caninos e felinos do grupo microcítico apresentam uma correlação com o RDW-CV. Contudo, os caninos com macrocitose apresentaram correlação tanto para o RDW-CV quanto para o RDW-SD, e os felinos apresentaram uma maior correlação com o RDW-SD.

Anemia is a syndrome characterized by a low red blood cell count, hematocrit and/or hemoglobin concentration. According to the Mean Corpuscular Volume (MCV), anemias can be classified as microcytic, normocytic or macrocytic. The RDW (Red Cell Distribution Width) is also used to help classify anemias, reflecting the anisocytosis of the erythrocyte population. This retrospective study aimed to determine the correlation between RDW-SD (Standard Deviation), RDW-CV (Coefficient of Variation), macrocytosis and microcytosis in canines and felines treated in the clinical routine of the Veterinary Hospital of Universidade Luterana do Brasil. To carry out this study, 662 blood count reports were selected (434 canines and 228 felines), aged between six months and 10 years, divided into two groups: Group 1 ­ Microcytic anemia (255 canines and 61 felines); Group 2 ­ Macrocytic anemia (179 canines and 167 felines). Subsequently, the groups were correlated with the values of RDW-SD and RDW-CV. Correlation analyzes were performed using the Spearman test, for the analysis of significance the T Student was used, in the IBM SPSS® Statistics program. In the statistical analysis of the canine group, there was no correlation between microcytosis and the RDW-SD, while the RDW-CV showed a reasonable, inversely proportional correlation. In the canine macrocytic group, correlation analysis with RDW-SD was moderate and directly proportional, and with RDW-CV it was moderate and directly proportional. In the feline group, there was no correlation between microcytosis and RDW-SD, and with RDW-CV there was a reasonable and inversely proportional correlation. There was a moderate and directly proportional correlation between macrocytosis in felines and RDW-SD, whereas RDW-CV presented a reasonable and directly proportional correlation. It is concluded that the canines and felines of the microcytic group present a correlation with the RDW-CV. However, canines with macrocytosis showed a correlation for both RDW-CV and RDW-SD, and felines showed a greater correlation with RDW-SD.

Clonal cytopenia of undetermined significance and atypical Behçet's: the importance of zinc.

Atypical Behçet's is recognised in myelodysplastic syndrome (MDS) cases and is associated with trisomy 8. Clonal cytopenia of undetermined significance (CCUS) is recognised as a precursor to MDS. Our case describes the presentation of atypical Behçet's, in association with CCUS, post a Streptococcal infection. A mutation of a zinc finger RNA spliceosome, ZRSR2, is also described. Our patient initially presented with macrocytic anaemia, together with neutropenia and lymphocytopenia on routine monitoring. Later gastrointestinal symptoms together with oral and anal ulcerations developed. He was treated with oral zinc therapy and had resolution of recurrent oral ulcerations and significant reduction in severity of anal ulcerations. The functional impact of ZRSR2 mutation on spliceosome assembly is yet to be defined, but has been previously reported in CCUS with a clinical phenotype of macrocytic anaemia.

Is 5q deletion in de novo Acute Myelogenous Leukemia (AML) with excess blasts a surrogate marker for the cryptic t(7;21)(p22;q22)? A case report and review of literature.

Although the 5q- syndrome is common in both de novo and treatment related myelodysplastic syndrome (MDS) and the World Health Organization defined 5q- syndrome as a specific type of MDS, it is less common in acute myelogenous leukemia (AML). Recently, it was suggested that AML with diploidy/tetraploidy and/or 5q alterations may be associated with the cryptic translocation, t(7;21)(p22;q22) resulting in RUNX1-USP42 gene fusion and this association may have been underestimated. Here, we report another case of de novo AML with cryptic t(7;21)(p22;q22) associated with a 5q deletion.

Hyperregenerative macrocytic anaemia: the role of copper and zinc.

In a patient with a history of bariatric surgery, severe copper deficiency presenting with macrocytic hyperregenerative anaemia was diagnosed. Besides the impaired intestinal absorption due to a short bowel syndrome, the enteral zinc supplementation competitively decreased the intestinal copper uptake. Once the zinc supplementation was stopped, enteral copper replacement ensued and normalised haemoglobin levels with decreasing median corpuscular volume were observed during follow-up visits.