Abstract

Rogers’ syndrome consisting of thiamine- responsive anaemia, diabetes mellitus and sensorineural deafness is a rare autosomally recessive inherited disorder. This is a case report of a boy with Rogers’ syndrome whose anaemia improved and transfusion dependency stopped after daily intake of large dose of thiamine. This case report is to sensitise towards early diagnosis and treatment with thiamine in patients presenting with anaemia, diabetes and deafness so as to not miss this condition as had happened with elder sibling of our patient.

Introduction

Rogers’ syndrome is a rare syndrome characterized by thiamine responsive anaemia, diabetes mellitus and sensorineural deafness . It is an autosomal recessive disorder resulting from the deficiency of thiamine transporter protein.1 Thiamine responsive anaemia was first described by Rogers’ et al in 19692 responsive only to thiamine. We report a 13 year old boy with Rogers’ syndrome whose transfusion dependency for 1½ year stopped after thiamine therapy. However his diabetes did not show improvement in terms of decreased insulin requirements even on increasing thiamine dosage.

Case Report

A 13 year old boy born out of 3rd degree consanguinity was brought with history of taking blood transfusions regularly every month since last 1½ year. He was deaf and mute since birth. At an age of 3 years he was diagnosed to have insulin dependent diabetes mellitus and was on insulin therapy daily. He had history of pulmonary tuberculosis (primary complex) at 3 years of age for which he was adequately treated. He had normal motor milestones and was going to special school for deafmute. He was the 2nd sibling. His elder brother was also deaf and mute since birth and had insulin-dependent diabetes mellitus since 3½ years of age. He also had transfusion dependent anaemia since 12 years of age and expired at 14 years due to diabetic ketoacidosis.

On examination he had weight of 23 kg (< 3rd centile), height of 131 cm (< 3rd centile and below the mid-parental height range) and severe pallor. Cardiovascular examination revealed soft systolic murmur. Rest of the systemic examination was normal.

Investigations revealed Hb of 5.2 gm%, WBC-1900/cu.mm, P 48, L 46, M 2, E 4, platelets 27000/cu.mm, MCV 89 fl and retic count of 0.3%. His Coomb’s test was negative and PT/aPTT within normal range. On admission he had blood sugar level of 261 mg% and normal blood gas and electrolytes. Serum C-peptide level was below 0.5 ng/ml (Ref. range 0.9-4). Chromosomal analysis did not reveal any chromosomal breakages.

2-D Echo report revealed mild left ventricular dilatation due to anaemia. Bone marrow examination showed sclerotic trabeculae and hypocellularity. There was bilateral sensorineural hearing loss on audiogram. His optic fundi were normal. The parents had normal haemoglobin and blood sugar level.

On the basis of history and investigations he was diagnosed to have thiamine- responsive anaemia with diabetes mellitus and sensorineural deafness (Rogers’ syndrome).

He was treated with 100 mg thiamine orally daily and Inj. insulin split-mixed regimen at 1.3 units/kg/day. A reticulocyte response of 8.3% was seen on day 7 of treatment with thiamine and Hb increased to 11 gm% with normalization of WBC and platelet count by one month. One year later he was maintaining his Hb at 13 gm% on regular thiamine therapy of 100 mg. His thiamine dose was increased to 200 mg and then to 300 mg daily orally to see whether insulin requirements decreased. However even after 5 months of increased thiamine dose insulin requirements remained the same.

Discussion

Thiamine-responsive anaemia syndrome (TRA) consisting of thiamine-responsive anaemia, diabetes and sensorineural deafness is an autosomal recessive disorder with normal thiamine reserve2 which responds to high dose thiamine therapy.

The gene for TRA is located to chromosome 1q23.2-1q23.3.3 This gene designated as “SLC19A2”, a member of the solute carrier gene super family is mutated in all TRA kindreds. The product of the gene is a membrane protein which transports thiamine with sub-micromolar affinity.4 It is presumed that deficiency of gene product- thiamine transporter protein (TTP)- may play a crucial role in facilitating the transport of thiamine not only in haemopoietic tissues but also into pancreatic islet cells, cochlear cells and many other cells and tissues in the body.1,3,5 Even heterozygous parents may show some manifestations like diabetes mellitus, deafness or megaloblastic anaemia, raising the possibility that mutations at this locus predispose carriers to these manifestations. Recent advances in molecular biology suggests critical role of human thiamine transporter-1 (hTHTR1) structure integrity and microtubules in intracellular trafficking of hTHTR1.5

Various varieties of anaemias are found in thiamine-responsive anaemia syndrome- megaloblastic, sideroblastic or aplastic—all of which respond to thiamine therapy. This suggests role of thiamine at various levels- DNA metabolism (megaloblastic changes), heme synthesis (ringed sideroblastic changes) and regulation at stem cell level.2

Diabetes is mild to moderate, insulin secretion may improve with thiamine therapy. The response to thiamine therapy in 17 patients with TRA over period of last 30 years has been reviewed.3 The response in majority was either absent or partial in terms of insulin requirement. Two out of 17 patients responded completely to thiamine therapy. However even thiamine responders had deterioration of metabolic control especially at onset of puberty, requiring reinstitution of insulin therapy.3 The reason for metabolic deterioration in initial thiamine responders may be slow islet cell apoptosis due to intracellular thiamine deficiency.6 Literature has shown that higher doses of thiamine could improve metabolic control leading to discontinuation of insulin.1 The variable response to thiamine in TRA may depend on the degree of TTP deficiency or to some yet unknown factors.1 The authors (Bappal et al) have recommended a trial of 200 mg or even higher dose in all cases of TRA before declaring ineffectiveness of thiamine in controlling diabetes.1 Our patient showed improvement in haematological parameters, however there was no decrease in insulin requirements even on increasing thiamine dose.

Thiamine is not effective in progression of sensorineural deafness.1 In addition to the cardinal clinical manifestations of the syndrome some patients may show congenital heart disease and/or arrhythmias, situs viscerum inversus and abnormalities of the retina and optic nerve.3 The wide spectrum of derangements seen in TRA-metabolic, cardiovascular, haematologic, neurologic-responding to vit. B1 therapy indicates that thiamine has a role in major physiologic processes.

Due to rarity of this syndrome, it may go unrecognized as it happened in the patient’s elder sibling. Hence this case report is to sensitise towards early diagnosis and treatment with high dose thiamine in patients presenting with anaemia, diabetes and deafness. The role of thiamine in pathogenesis and treatment of diabetes in this syndrome may help in future to know implications of therapy with this vitamin in patients with type 1 diabetes.

Acknowledgement

We are grateful to The Dean of B.J.Wadia hospital for Children, Dr U.S. Ali for allowing us to publish this case report.

References

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2. Mandel H, Berant M, hazani A, Naveh Y. Thiamine-dependent beriberi in the “thiamine –responsive anemia syndrome”. N E J Med 1984; 311 : 836-8.
3. Valeria V, Angela R, Di Sallee F, Ciro I, Vincenzo P, Brunella C. Acute ischemic stroke in a young woman with the thiamine-responsive megaloblastic anemia syndrome. J Clin Endoc Metab 2000; 85 : 947-9.
4. Neufeld EJ, Fleming JC, Tartaglini E, Steinkamp MP. Thiamine-responsive megaloblastic anemia syndrome: a disorder of high-affinity thiamine transport. Blood Cells Mol Dis 2001; 27 (1) : 135-8.
5. Subramanian VS, Marchant JS, Parker I, Said HM. Cell biology of the human thiamine transporter-1 (hTHTR1). Intracellular trafficking and membrane targeting mechanisms. J Biol Chem 2003; 278 (6) : 3976-84.
6. Stagg AR, Fleming JC, Baker MA, Sakamoto M, Cohen N, Neufeld EJ. Defective high affinity thiamine transporter leads to cell death in thiamine- responsive megaloblastic anemia syndrome fibroblasts. J Clin Invest 1999; 103 : 723-29.

*Associate Professor; **Consultant, Division of Hemato-oncology; ***Asso.Professor, Department of Paediatrics, B.J.Wadia Hospital for children Parel, Mumbai 400 012, India.