TRMA syndrome (thiamine-responsive megaloblastic anemia): a case report and review of the literature

Abstract: Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder with features that include megaloblastic anemia, mild thrombocytopenia and leukopenia, sensorineural deafness and diabetes mellitus. In this disease, the active thiamine uptake into cells is disturbed. Treatment with pharmacological doses of thiamine ameliorates the megaloblastic anemia and diabetes mellitus. Previous studies have demonstrated that the disease is caused by mutations in the SLC19A2 gene encoding a high-affinity thiamine transporter. We present a 5-yr-old-boy with TRMA and, because of its rarity, we review the literature.     

Thiamine responsive megaloblastic anemia syndrome

Thiamine responsive megaloblastic anemia syndrome (TRMA) is a clinical triad characterized by thiamine-responsive anemia, diabetes mellitus and sensorineural deafness. We report a 4-year-old girl with TRMA whose anemia improved following administration of thiamine and this case report sensitizes the early diagnosis and treatment with thiamine in children presenting with anemia, diabetes and deafness.     

A novel mutation in the SLC19A2 gene in a Turkish female with thiamine-responsive megaloblastic anemia syndrome

Reported here is a 2-year-old girl who was diagnosed to have thiamine-responsive megaloblastic anemia during evaluations for her bilateral neurosensorial deafness. Besides reporting a new mutation on the gene SLC19A2 for the first time in the literature, we highlight the recognition of this syndrome--when megaloblastic anemia and diabetes mellitus coexists--and the role of thiamine replacement for the treatment of both disorders.     

Thiamine-responsive megaloblastic anemia with diabetes mellitus and sensorineural deafness

This study introduces a patient who has thiamine and thiamine pyrophosphokinase (TPKase) enzyme deficiency associated with diabetes mellitus, sensorineural deafness and thiamine-responsive megaloblastic anemia. Diabetes mellitus was diagnosed when she was 20 months old. After 1 year, macrocytic anemia developed and the thiamine therapy was started at 75 mg/day. During the follow-up, the insulin requirement decreased and even ceased, and macrocytic anemia improved with thiamine treatment. After thiamine therapy was ceased an increase in insulin requirement was observed and macrocytic anemia developed again.     

Cardiac Manifestations in Thiamine-Responsive Megaloblastic Anemia Syndrome

Thiamine-responsive megaloblastic anemia (TRMA) syndrome is a rare autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. Other features of this syndrome gradually develop. We describe three TRMA patients with heart rhythm abnormalities and structural cardiac anomalies. Eight other reported TRMA patients also had cardiac anomalies. Recently, the TRMA gene, SLC19A2, was identified, encoding a functional thiamine transporter. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine in common cardiac abnormalities.     

Thiamine withdrawal can lead to diabetic ketoacidosis in thiamine responsive megaloblastic anemia: report of two siblings

Thiamine responsive megaloblastic anemia syndrome (TRMA), an autosomal recessive disorder caused by the deficiency of thiamine transporter protein, is the association of diabetes mellitus, anemia and deafness. Pharmacological dose thiamine normalizes hematological abnormalities and their effects on the course of diabetes mellitus. We report on 8 years follow up of two siblings with TRMA. They presented in the prepubertal period with diabetic ketoacidosis due to lack of thiamine supplementation for 2 months. Their insulin requirements fell rapidly and disappeared with thiamine therapy. Hematological parameters normalized within 30 days. The diabetic picture is responsive to thiamine treatment in patients with TRMA. Insulin dependent diabetes may occur throughout the pubertal period. If thiamine supplementation is not sufficient, ketoacidosis may develop in patients during the prepubertal period.     

Thiamine-responsive megaloblastic anemia syndrome with atrial standstill: a case report

Thiamine-responsive megaloblastic anemia (TRMA) syndrome is an uncommon autosomal recessive disorder. The disease is caused by mutations in the gene, SLC19A2, encoding a high-affinity thiamine transporter, which disturbs the active thiamine uptake into cells. Major features include megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Cardiac malformations with conduction defects and/or dysrhythmias, have also been described in some patients. To our knowledge, only 13 TRMA patients with cardiac defects have been reported. Here, we describe the first case of TRMA syndrome with atrial standstill, probably caused by a 2 base-pair deletion in exon 4 (1147delGT) of the gene SLC19A2.     

Monogenic diabetes: A single center experience from South India

Monogenic forms of diabetes in children are frequently misclassified as either type 1 diabetes or young‐onset type 2 diabetes. There is a paucity of literature regarding pediatric monogenic diabetes in the Indian population. A retrospective analysis of case records of 37 children with monogenic diabetes who were diagnosed between 2008 and 2019 in a South Indian tertiary care center was performed. The write‐up describes the clinical, biochemical, and genetic characterization of these patients with the diagnoses of neonatal diabetes mellitus (15 patients), MODY (five patients), and various forms of syndromic diabetes (13 with Wolfram syndrome, two with H syndrome, one with mitochondrial diabetes, and one with thiamine responsive megaloblastic anemia).     

Thiamine-responsive anemia in DIDMOAD syndrome

Two children with the DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) developed a megaloblastic and sideroblastic anemia, neutropenia, and borderline thrombocytopenia. Plasma thiamine concentration was low in one patient and normal in the other; in both children, thiamine pyrophosphate in erythrocytes and thiamine pyrophosphokinase activity were lower than the lowest values observed in control subjects. A month after institution of treatment with thiamine, the hematologic findings had returned to normal and the insulin requirements had decreased. Withdrawal of thiamine repeatedly induced relapse of the anemia and an increase in insulin requirements. We propose that an inherited abnormality of thiamine metabolism is responsible for the multisystem degenerative disorder known as DIDMOAD syndrome.     

Imerslund syndrome with dolichocephaly

Imerslund syndrome is a rare autosomal recessive disorder of megaloblastic anemia as a result of selective vitamin B12 malabsorption associated with proteinuria. An Arabic Muslim family is described, with three children who had inherited selective vitamin B12 malabsorption with proteinuria. Dolichocephaly was noted in all the male children of this family in association with congenital megaloblastic anemia and proteinuria. The findings of this anemia are compatible with Imerslund-Gr?sbeck syndrome, and coexistence of this syndrome with dolichocephaly in a single family has not been previously reported.     

Megaloblastic Anemia—A Rare Cause

A 2- year- old boy presented with non responsive megaloblastic anemia, growth failure and developmental delay. Blood levels of B₁₂, folic acid and iron were normal. Tandem mass spectroscopy for common inborn errors of metabolism did not reveal any abnormality. There was an increased excretion of orotic acid in urine. The authors report this as a rare cause of megaloblastic anemia.     

Homocystinuria: a rare cause of megaloblastic anemia

We present an eight-year-old boy who initially presented to us with megaloblastic anemia and subsequently developed dislocation of lens. The child had a positive sodium nitroprusside test and homocystinuria. He was diagnosed to have homocystinuria type 1. His anemia improved on oral pyridoxine and folic acid therapy. Homocystinuria should be remembered as a cause of megaloblastic anemia.     

Refractory pancytopenia and megaloblastic anemia due to falciparum malaria

Anemia is a common complication in malarial infection. Direct destruction and ineffective erythropoesis does not adequately explain the cause of anemia in malaria. We present a case with refractory megaloblastic anemia with asymptomatic falciparum malaria. We hypothesize that promoter variants in the inducible nitric oxide synthase gene might be the cause of severe refractory megaloblastic anemia and pancytopenia in our patient. Malaria should always be kept in mind as a cause of anemia especially in endemic areas even if the child is asymptomatic or there is no demonstrable parasite on routine smear examination.     

Refractory iron deficiency anemia as the primary clinical manifestation of celiac disease

In the absence of dietary insufficiency, iron deficiency is usually caused by chronic blood loss or intestinal malabsorption. Celiac disease is one of the most common causes of intestinal malabsorption during childhood, and its association with insulin-dependent diabetes mellitus has been previously reported. Here the authors describe an otherwise asymptomatic diabetic adolescent boy with iron deficiency anemia that was not responsive to oral iron therapy. A diagnosis of celiac disease was made based on both anti-endomysial antibody titers and small intestinal biopsy. Institution of a gluten-free diet resulted in correction of the anemia. These observations emphasize the importance of considering a diagnosis of celiac disease in patients with nonresponsive iron deficiency anemia, particularly in the setting of insulin-dependent diabetes mellitus.     

Thiamine responsive megaloblastic anemia: a novel SLC19A2 compound heterozygous mutation in two siblings

Thiamine responsive megaloblastic anemia (TRMA) is an autosomal recessive disease caused by loss of function mutations in the SLC19A2 gene. TRMA is characterized by anemia, deafness, and diabetes. In some cases, optic atrophy or more rarely retinitis pigmentosa is noted. We now report two sisters, the eldest of which presented to a different hospital during childhood with sensorineural deafness, which was treated with a hearing prosthesis, insulin requiring diabetes, retinitis pigmentosa, optic atrophy, and macrocytic anemia. These features initially suggested a clinical diagnosis of Wolfram syndrome (WS). Therapy with thiamine was initiated which resulted in the resolution of the anemia. The younger sister, who was affected with sensorineural deafness, was referred to our hospital for non‐autoimmune diabetes. She was found to have macrocytosis and ocular abnormalities. Because a diagnosis of TRMA was suspected, therapy with insulin and thiamine was started. Sequencing analysis of the SLC19A2 gene identified a compound heterozygous mutation p.Y81X/p.L457X (c.242insA/c.1370delT) in both sisters. Non‐autoimmune diabetes associated with deafness and macrocytosis, without anemia, suggests a diagnosis of TRMA. Patients clinically diagnosed with WS with anemia and/or macrocytosis should be reevaluated for TRMA.     

Thiamine-responsive megaloblastic anaemia syndrome: long-term follow-up and mutation analysis of seven families

Aim: Thiamine-responsive megaloblastic anaemia syndrome (TRMA) is the association of diabetes mellitus, anaemia and deafness, due to mutations in SLC19A2, encoding a thiamine transporter protein. This is a unique monogenic form of vitamin-dependent diabetes for which there is limited long-term data. We aimed to study genotype-phenotype relationships and long-term follow-up in our cohort. Methods: We have studied 13 patients from seven families and have follow-up data for a median of 9 y (2-30 y). Results: All patients originated from Kashmir or Punjab, and presented with non-immune, insulin-deficient diabetes mellitus, sensorineural deafness and a variable anaemia in the first 5 y of life, the anaemia progressing to megaloblastic and sideroblastic changes in the bone marrow. The anaemia and diabetes mellitus responded to oral thiamine hydrochloride 25 mg/d, but during puberty thiamine supplements became ineffective, and almost all patients require insulin therapy and regular blood transfusions in adulthood. All patients are homozygous for mutations in the SLC19A2 gene. We have identified a novel missense mutation (T158R) that was excluded in 100 control alleles.

Conclusion: Diabetes in this syndrome is due to an insulin insufficiency that initially responds to thiamine supplements; however, most patients become fully insulin dependent after puberty. A mutation screening strategy is feasible and likely to identify mutations in almost all cases.     

Thiamine-responsive megaloblastic anaemia: a cause of syndromic diabetes in childhood

Thiamine-responsive megaloblastic anaemia (TRMA) is a rare autosomal recessive condition, characterized by megaloblastic anaemia, non-autoimmune diabetes mellitus, and sensorineural hearing loss. We describe three infants with TRMA from two consanguineous Pakistani families, who were not known to be related but originated from the same area in Pakistan. All children were homozygous, and the parents were heterozygous for a c.196G>T mutation in the SLC19A2 gene on chromosome 1q23.3, which encodes a high-affinity thiamine transporter. The result is an abnormal thiamine transportation and vitamin deficiency in the cells. Thiamine in high doses (100-200 mg/d) reversed the anaemia in all our patients. Two patients discontinued insulin treatment successfully after a short period, while the third patient had to continue with insulin. The hearing loss persisted in all three children. The diagnosis of TRMA should be suspected in patients with syndromic diabetes including hearing loss and anaemia, even if the latter is only very mild and, particularly, in the case of consanguinity.     

Megaloblastic anaemia in infancy or early childhood and diabetes as leading symptoms of the TRMA syndrome

Diabetes mellitus may occur in children and adolescents as an independent disease, most frequently as autoimmune type 1 diabetes, or can coexist with other abnormalities. If diabetes coincides with other disorders occurring sequentially, a syndromic form of monogenic diabetes should be suspected. Thiamine-responsive megaloblastic anaemia (TRMA) syndrome is an example of a rare form of monogenic diabetes coexisting with anaemia and deafness. In the paper, we discuss clinical features and treatment of TRMA syndrome - a unique syndromic form of vitamin-dependent monogenic diabetes. The review might be useful in establishing a prompt diagnosis and initiating optimal management in children and adolescents with the disease.     

Thiamine-dependent anemia and thrombocytopenia, insulin-dependent diabetes mellitus and sensorineural deafness--case report and review

Report of an 3 1/2 year old girl who because of resistant anemia and thrombocytopenia received blood transfusions since her third month of life. 15 months later she developed diabetes mellitus. Sensorineural deafness was noticed since her third year of life. Daily 25 mg thiamine prevented anemia and thrombocytopenia. The syndrome is compared with the 5 published cases of world literature.     

Imerslund-Gräsbeck syndrome: report of two cases

INTRODUCTION: The Imerslund-Gr?sbeck syndrome is a rare hereditary autosomal recessive disease, characterized by the onset of megaloblastic anemia and asymptomatic proteinuria during the first 2 years of life. OBJECTIVE: To emphasize the importance of early detection of this disorder, due to high morbidity when not correctly treated, in addition to the necessity of screening and genetic counseling of the asymptomatic family members. METHODS: The authors report two patients, male and female, 8 and 10 years old, respectively. Their past history revealed anemia and multiple blood transfusions since their infancy. They evolved with pancytopenia during childhood and diagnosis of Severe Aplastic Anemia or Fanconi Syndrome was suspected. They were referred to the Bone Marrow Transplantation Section -HC- UFPR. RESULTS: Laboratory investigations revealed pancytopenia in peripheral blood. Bone marrow aspiration showed a marked megaloblastic erythropoiesis. Twenty-four-hour urine collection revealed proteinuria (3.0 and 5.8 g/dl respectively). Cytogenetic analysis was normal. Resolution of symptoms followed replacement therapy with parenteral vitamin B12. CONCLUSIONS: The presence of megaloblastic anemia in children should be followed by investigation of proteinuria, due to the existence of this rare disorder, that has a simple diagnosis and an effective treatment.