An Italian case series' description of thiamine responsive megaloblastic anemia syndrome: importance of early diagnosis and treatment.

BACKGROUND: Individuals with thiamine-responsive megaloblastic anemia (TRMA) mainly manifest macrocytic anemia, sensorineural deafness, ocular complications, and nonautoimmune diabetes. Macrocytic anemia and diabetes may be responsive to high-dosage thiamine treatment, in contrast to sensorineural deafness. Little is known about the efficacy of thiamine treatment on ocular manifestations. CASES PRESENTATION: Our objective is to report data from four Italian TRMA patients: in Cases 1, 2 and 3, the diagnosis of TRMA was made at 9, 14 and 27 months. In 3 out of 4 subjects, thiamine therapy allowed both normalization of hyperglycemia, with consequent insulin suspension, and macrocytic anemia. In all Cases, thiamine therapy did not resolve the clinical manifestation of deafness. In Cases 2 and 3, follow-up showed no blindness, unlike Case 4, in which treatment was started for megaloblastic anemia at age 7 but was increased to high doses only at age 25, when the genetic diagnosis of TRMA was performed. CONCLUSIONS: Early institution of high-dose thiamine supplementation seems to prevent the development of retinal changes and optic atrophy in TRMA patients. The spectrum of clinical manifestations is broad, and it is important to describe known Cases to gain a better understanding of this rare disease.

A New Case of Association of Megaloblastic Anemia and Pancytopenia of Infants.

BACKGROUND: Vitamin B12, or cobalamin deficiency, an infrequent clinical entity in pediatric age, is found almost solely in breastfed infants whose mothers are purely vegetarian, non-supplemented or with pernicious anemia. Megaloblastic anemia in infants presents with generalized weakness or irritability. METHODS: Diagnosis is usually centered on complete blood count, vitamin dosing, and peripheral smear, which may show macrocytes, hypersegmented neutrophils, reticulocytopenia and a raised mean corpuscular volume (MCV ˃ 100 fL). Pancytopenia has also been noted. RESULTS: We report an exclusive breastfed nine-month-old female child who presented with irritability, developmental delay, and difficulties in introducing new foods. Her initial blood count revealed pancytopenia. Vitamin B12 levels were found to be reduced. Maternal levels of Vitamin B12 were also found to be borderline low. The child was treated as per protocols, and improvement was evidenced with the return of hematological parameters to the regular and gradual advancement of milestones. CONCLUSIONS: We aim to underscore the importance of megaloblastic anemia as an important and rare cause of anemia in infancy.

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.

Clinico-laboratory Profile and Outcomes of Megaloblastic Anemia presenting as Severe Pyrexial Illness mimicking Tropical Infection.

BACKGROUND: Anemia-causing fever has been described in patients with megaloblastic anemia. Although the exact mechanism of this is unknown, high-grade fever is relatively less reported. MATERIALS AND METHODS: This prospective observational study included all new cases of megaloblastic anemia presenting with febrile illness (>101°F) during a 3-year period. Patients with existing anemia, comorbidities, and other causes of macrocytosis were excluded. A detailed evaluation for megaloblastic anemia and workup for excluding tropical infections was done. The patients were treated with parenteral vitamin B12, folic acid, and other hematinics. RESULTS: Around 24 cases of megaloblastic anemia presenting with high-grade fever were included, with 14 (58.3%) males, mean duration of fever 7.7 days (4-18 days), and 09 (37.5%) having temperature >103°F. The mean hemoglobin (Hb) was 8.15 g/dL (3.7-11.1 g/dL), the mean corpuscular volume (MCV) was 111 ± 7.8 fL, 18 (75%) had unconjugated hyperbilirubinemia, the mean lactate dehydrogenase (LDH) was 814 ± 24 IU/L, and 21 (87.5%) had low B12 or folate levels. Most showed good therapeutic response to B12 or folic acid with defervescence in 1-5 days (mean 2.6 days) and improvement in lab parameters in 1 week. The study population was divided into those with temperature ≥103°F, and temperature <103°F it was seen that there was a significant association (p < 0.05) with leucocyte count of ≤3000/cumm, and MCV ≥110 fL, in patients with temperature ≥103°F Conclusion: Megaloblastic anemia should be considered in the differentials of a patient presenting with a febrile illness with no clinical localization and a negative initial fever workup. Early identification and prompt therapy of this easily treatable disorder are very essential.

Effect of megaloblastic anemia on hemoglobin A2 and diagnosis of ß-thalassemia trait.

Context: ß-thalassemia trait is usually diagnosed by raised hemoglobin A2 (HbA2). The presence of megaloblastic anemia can cause an increase in HbA2 and create a diagnostic dilemma. Here, we have analyzed the effect of vitamin B12 and folic acid supplementation on HbA2 and diagnosis of ß-thalassemia trait in cases of megaloblastic anemia with raised HbA2. Materials and Methods: Cases of megaloblastic anemia with raised HbA2 on high-performance liquid chromatography (HPLC) were supplemented with vitamin B12 and folic acid. Post-treatment evaluation was done after 2 months. Cases showing adequate hematological response were subjected to statistical analysis. Based on post-treatment HbA2 value, the cases were diagnosed as normal, borderline raised HbA2, or ß-thalassemia trait. Pre- and post-treatment values of red cell parameters and HbA2 were analyzed. Results: There was a significant decrease in HbA2 value after vitamin B12 and folic acid supplementation. The diagnosis was changed in 70.97% of the cases after treatment. The chance of inconclusive diagnosis was decreased from more than 50% to less than 10%. Pre-treatment mean corpuscular volume (MCV) and HbA2% showed a significant difference between the thalassemic and normal groups. Conclusions: Megaloblastic anemia can lead to false-positive diagnosis of ß-thalassemia trait on HPLC. Repeat HPLC should be done after adequate supplementation of vitamin B12 and folic acid in cases of megaloblastic anemia with raised HbA2. Red cell parameters are not helpful to suspect ß-thalassemia trait in presence of megaloblastic anemia. However, HbA2% on HPLC can be a useful parameter to suspect or exclude ß-thalassemia trait in cases of megaloblastic anemia.

Thiamine responsive megaloblastic anaemia complicated with acute Parvovirus infection: A case report.

Thiamine responsive megaloblastic anaemia syndrome also known as Rogers syndrome is a very rare autosomal recessive disorder. The hallmark of the disease is the presence of the classic triad of anaemia, diabetes mellitus, and sensorineural deafness. We report the case of a 14-year-old boy who presented to us with severe megaloblastic anaemia, diabetes mellitus, and sensorineural deafness. The anaemia was further complicated by acute parvovirus infection. He was put on high doses of thiamine (vitamin B1) which led to an improvement.

Thiamine-Responsive Megaloblastic Anaemia With Hypothyroidism, A Puzzling Association.

Background: 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.

Megaloblastic Anemia Masked by an Unrecognized Hemoglobinopathy.

BACKGROUND: Deficiency of vitamin B(12) or folate causes megaloblastic anemia (MA). The disease presents with pancytopenia due to the excessive cellular apoptosis of hematopoietic progenitor. MA is characterized by the presence of high mean corpuscular volume in the blood routine test and hyperlobulation nuclei of the granulocytes in the peripheral blood smears, and megaloblasts in the bone marrow. METHODS: We report a rare case, in which megaloblastic anemia was masked by an unrecognized hemoglobinopathy and presented with normocytic anemia and atypical morphological features of bone marrow. RESULTS: The patient was finally diagnosed with coexistence of MA and a-thalassemia minor due to determination of folate deficiency and genetic mutation for a-thalassemia. CONCLUSIONS: The case focuses on the contribution of the peripheral circulating blood smear examination in the diagnosis of anemia.

Diabetes Out-of-the-Box: Diabetes Mellitus and Impairment in Hearing and Vision.

PURPOSEOF REVIEW: This review aims to provide an update on the etiologies of diabetes that are due to genetic disorders and that co-occur with impaired hearing or vision and to compare them. The potential mechanisms, including novel treatments, will be detailed. RECENT FINDINGS: Wolfram syndrome, Kearns-Sayre syndrome, thiamine-responsive megaloblastic anemia, and maternally inherited diabetes and deafness are genetic disorders characterized by diabetes, impaired hearing, and vision. They differ in mode of inheritance, age at presentation, and the involvement of other organs; they are often misdiagnosed as type 1 or type 2 diabetes. Suspicion of a genetic diabetes syndrome should be raised when pancreatic autoantibodies are negative, other organs are involved, and family history includes diabetes. Correct diagnosis of the various syndromes is important for tailoring the most advanced treatment, preventing disease progression, and enabling proper genetic counseling.

Whole-Exome Sequencing Revealed a Pathogenic Nonsense Variant in the SLC19A2 Gene in an Iranian Family with Thiamine-Responsive Megaloblastic Anemia.

OBJECTIVE: Solute carrier family 19 member 2 (SLC19A2, OMIM *603941) encodes thiamine human transporter 1 (THTR-1), which contributes to bringing thiamine (vitamin B1) into cells. Mutations in SLC19A2 lead to a rare recessive genetic disorder termed thiamine-responsive megaloblastic anemia (TRMA) syndrome. METHODS: An Iranian family with TRMA was investigated by whole-exome sequencing (WES) to determine the genetic cause(s) of the disease. Accordingly, SLC19A2 genetic variants were gathered through literature analysis. RESULTS: WES recognized a known pathogenic variant, c.697C > T (p. Q233X), within exon 2 of SLC19A2 (NM_006996). Subsequently, the proband's parents and sister were confirmed as heterozygous carriers of the identified variant. CONCLUSION: The diagnostic utility and affordability of WES were confirmed as the first approach for the genetic testing of TRMA to verify the diagnosis. This analysis can be used to guide future prenatal diagnoses and determine the consequences in the other family members.

How I investigate acquired megaloblastic anemia.

In this review of megaloblastic anemia (MA), an overview of vitamin B12 and folate body requirements, biochemical pathways, and laboratory testing strategies will be provided. However, the focus of this review is the classic and unique features of MA in blood and bone marrow. Acquired MA is a benign disorder for many, but can be detrimental for some. The clinical presentation can vary considerably, and the spectrum of symptoms and signs is diverse and quite broad. Prompt recognition and therapy are critical to prevent potential irreversible damage and clinical sequelae, especially in patients with vitamin B12 deficiency. A delay in diagnosis of vitamin B12 deficiency can result in significant neurologic sequelae that may not fully resolve with treatment, including in neonates and young infants. The blood and bone marrow features in MA can closely mimic thrombocytopenic purpura, myelodysplasia, and other myeloid neoplasms. Both pancytopenia and normal MCV at presentation are common in MA and raise unique challenges for the diagnostician. Partially treated MA is also a significant diagnostic "trap". MA is highly responsive to treatment, and patients tend to improve rapidly upon treatment initiation. However, the broad range of clinical and hematologic features makes the rapid, successful diagnosis of MA a unique challenge for the hematopathologist. Even in the era of state-of-the-art laboratory testing, a high suspicion is required.

Pancitopènia en un lactant secundària a anèmia perniciosa materna / Pancitopenia en un lactante secundaria a anemia perniciosa materna / Pancytopenia secondary to maternal pernicious anemia in an infant

Introducció. L’anèmia megaloblàstica és una causa poc freqüent de pancitopènia en lactants. La seva principal etiologia és el dèficit matern de vitamina B12 en recent nascuts alimentats exclusivament amb lactància materna, toti que en alguns casos aquest déficit pot ser secundari auna anèmia perniciosa materna.Cas clínic. Lactant de 3 mesos que va consultar a urgènciesper vòmits i estancament ponderal de 3 setmanesd’evolució. En l’analítica sanguínia destacava anèmia (hemoglobina 6,5 g/dL), trombocitopènia (12 x10E9/L) i leucopènia (5,5 x10E9/L) amb neutropènia severa (0,11x10E9/L). Els nivells de vitamina B12 van resultar ser de60 pg/mL. Davant la confirmació d’anèmia megaloblàstica,es completà l’estudi amb una analítica sanguínia i gastroscòpia materna que mostraren una anèmia perniciosa, prèviament desconeguda, causant del dèficit de cobalamina ala pacient. Es va iniciar suplementació amb vitamina B12endovenosa, comprovant-se bona resposta reticulocitària,augment de leucòcits i manteniment de xifra normal deplaquetes i hemoglobina.Comentaris. Les alteracions neurològiques secundàries aldéficit de vitamina B12 poden arribar a ser severes, i enalgunes ocasions fins i tot irreversibles. La importància delseu diagnòstic és la instauració de suplementació precoçper a corregir el dèficit i així millorar el pronòstic. (AU)

Introducción. La anemia megaloblástica es una causa poco frecuente de pancitopenia en lactantes. Su principal etiología es eldéficit materno de vitamina B12 en recién nacidos alimentadosexclusivamente con lactancia materna, aunque en algunos casospuede ser secundario a una anemia perniciosa materna.Caso clínico. Lactante de 3 meses que consultó a urgencias porvómitos y estancamiento ponderal de 3 semanas de evolución. Enla analítica sanguínea destacaba anemia (hemoglobina 6,5 g/dL), trombocitopenia (12 x10E9/L) y leucopenia (5,5 x10E9/L) con neutropenia severa (0,11 x10E9/L). Los niveles de vitamina B12 resultaron ser de 60 pg/mL. Ante la confirmación de anemia megaloblástica, se completó el estudio con una analítica sanguínea ygastroscopia materna que mostraron una anemia perniciosa, previamente desconocida, causante del déficit de cobalamina a la paciente. Se inició suplementación con vitamina B12 endovenosa,comprobándose buena respuesta reticulocitaria, aumento de leucocitos y mantenimiento de cifra normal de plaquetas y hemoglobina.Comentarios. Las alteraciones neurológicas secundarias al déficitpueden llegar a ser severas, y en algunas ocasiones incluso irreversibles. La importancia de su diagnóstico es la instauración de suplementación precoz para corregir el déficit y así mejorar el pronóstico. (AU)

Introduction. Megaloblastic anemia is a rare cause of pancytopeniain infants. Its main etiology is maternal vitamin B12 deficiency inexclusively breastfed newborns, although in some cases it may besecondary to maternal pernicious anemia.Case report. Three-month-old infant who consulted the emergencydepartment for vomiting and a three-week failure to thrive. Laboratory evaluation was significant for anemia (hemoglobin 6,5 g/dL),thrombocytopenia (12 x109/L) and leukopenia (5,5 x109/L) withsevere neutropenia (0,11 x109/L). Vitamin B12 levels were foundto be 60 pg/mL. Upon confirmation of megaloblastic anemia, thestudy was completed with a blood test and maternal gastroscopythat showed a previously unknown pernicious anemia causingthe patient's cobalamin deficit. Vitamin B12 supplementationwas started intravenously, proving good reticulocyte response,increase of leukocytes and normalization of platelet and hemoglobin values.Comments. Neurological alterations secondary to vitamin B12 deficit can be severe, and sometimes even irreversible. The importance of its diagnosis is the establishment of early supplementation to correct the deficit and thus improve the prognosis. (AU)

Leber congenital amaurosis as an initial manifestation in a Chinese patient with thiamine-responsive megaloblastic anemia syndrome.

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder, inherited by the defective SLC19A2 gene that encodes a high-affinity thiamine transporter (THTR-1). TRMA is characterized by the occurrence of classical triad manifestations including megaloblastic anemia, diabetes mellitus, and sensorineural deafness. In addition to the systemic manifestations, ophthalmic features can be present and include retinitis pigmentosa, optic atrophy, cone-rod dystrophy, maculopathy, and Leber congenital amaurosis. Here we report a 6-year-old boy presenting severe early-onset retinal dystrophy with the initial diagnosis of Leber congenital amaurosis, which followed for 12 years. Diabetes mellitus occurred 3 years after vision problem. Eosinophilic granuloma of the left scapula was confirmed at 13 years old. Whole-exome sequencing was performed to identify two novel compound heterozygous variants c.725dupC (p.Ala243Serfs*3) and c.121G>A (p.Gly41Ser) in SLC19A2 gene (NM_006996.3). Oral thiamine supplementation treatment was initiated at 13 years. This case demonstrates Leber congenital amaurosis can present as the first clinical feature before systemic manifestations. Phenotypic variety should be aware and multidisciplinary teamwork and regular follow-up are important for TRMA patient care.

A Brief Review on Vitamin B12 Deficiency Looking at Some Case Study Reports in Adults.

In the era of evidence-based medicine, the randomized clinical trial corresponds to the top step in the qualitative scale of the evidence available in the literature, while small series of cases or the description of individual cases occupy the last place. However, the latter represent an important part of clinical practice and have significantly influenced the evolution of medicine, contributing significantly to the advancement of scientific knowledge. Vitamin B12 deficiency shares several common symptoms that affect several tissues and organs with health aliments, so its diagnosis could be unobvious for the broad array of its effects and investigation methods used. In this review, we focused our attention on some case reports related to the vitamin B12 deficiency associated to anemia, neurologic disorders, and hyperhomocysteinemia. B12 deficiency reversal is simply achieved by prompt therapy, even though it is not the same for several disorders.

Megaloblastic anemia-related iron overload and erythroid regulators: a case report.

BACKGROUND: In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload. CASE PRESENTATION: An 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15. CONCLUSIONS: This case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.