Rogers Syndrome, an Uncommon Cause of Megaloblastic Anemia: A Case Series

Abstract

The present case series describes two male children of 5 months and 11 months old, having diabetes mellitus and megaloblastic anemia, but with no syndromic symptoms or organ involvement. The patient’s clinical history prompted a targeted sequencing of the genes associated with monogenic diabetes. In first case, mutation in SLC19A2 gene (variant – c.391dupT [P.Tyr131leufs*8]), where a homozygous insertion of one base pair (bp) in exon 2 of SLC19A2 gene[c.391dupT] was found, resulted in shift of reading frame and termination of the protein chain downstream to codon 131 [p.Tyr131 LeufsTer8]. In the second case, of mutation in SLC19A2 gene (variant- c. 1002_1004del [p.Gly335del]), a homozygous deletion in exon 3 found. Both the patients were diagnosed with thiamine responsive megaloblastic anemia (TRMA). When patients present with diabetes mellitus, deafness, and megaloblastic anemia, the possibility of TRMA syndrome should be considered. This condition often responds to high-dose thiamine.

INTRODUCTION

A thiamine transporter impacted by the extremely uncommon hereditary condition, known as thiamine-responsive megaloblastic anemia (TRMA) syndrome. The symptoms of TRMA are hearing loss, megaloblastic anemia and diabetes mellitus.[1] Another name for TRMA is Rogers’s syndrome.[1] In this autosomal recessive condition, there is loss of function of the high-affinity thiamine transporter 1 (h-THTR1), which is encoded by SLC19A2 gene located on chromosome 1q23.2–23 and is necessary for thiamine uptake by cells.[2] Out of the two known high-affinity thiamine transporters (THTR), THTR-1 is encoded by SLC19A2 and THTR-2 is encoded by SLC19A3.[1] At low concentrations of extracellular thiamine, THTR-1 mediates the active intracellular thiamine transport.[2] This rare syndrome is often observed in children of consanguineous marriages. A high thiamine intake activates an additional low-affinity route. Reduced nucleic acid production is the primary biochemical disruption in patients with the genetic mutation that affect the bone marrow cells. This mutation causes cell cycle arrest or apoptosis leading to TRMA syndrome presentation.[1,2] The triad of clinical characteristics—megaloblastic anemia, hyperglycemia, and sensorineural deafness—is used to diagnose TRMA syndrome.[2] We are presenting two male children having TRMA with non type 1 diabetes mellitus.

CASE REPORT

Case 1

A five months old male infant, the firstborn of a consanguineous marriage (third degree), was delivered by cesarean section at term with weight at birth of 2500 g. He presented to pediatric outpatient department with fever and cough since last five days. Upon assessment, the whole blood counts showed the following results: 4.1 g/dL of hemoglobin, MCV -82, 4.5 × 10⁹/L of white blood cells (neutrophils: 30%, lymphocytes: 60%, monocytes: 8%, eosinophil’s: 2%), and 179 × 10⁹/L of platelets. On further evaluation, viral serology (hepatitis B and C, human immunodeficiency virus, cytomegalovirus, Epstein Barr Virus, and Parvovirus) was found to be negative. Coomb’s test (direct and indirect) was also negative. Autoimmune screening (ANA, and anti-DS DNA) was negative too. Peripheral blood picture showed normocytic normochromic picture, and retic count of 1.33%. Folic Acid, Vitamin B12 levels, and iron profile were unremarkable. The bone marrow aspiration showed megaloblastic erythroid hyperplasia with iron stores of 4+ [Figure 1]. His blood urea nitrogen was 29 mg/dl, creatinine was 0.24 mg/dl, bilirubin 0.40 mg/dl, and ALT was 22 IU/L. His random blood sugar levels were > 500 mg/dl, urine ketones were 2+, blood pH was 7.31, HCO₃^- 7meq/l, Na⁺ -132meq/l, K⁺-4.4meq/l and HbA1c was found to be 7.8%. Glutamic acid decarboxylase (GAD 65) antibody was negative. However, C-peptide levels revealed a decrease in insulin reserve. We made differential diagnosis of Roger syndrome in the present case. We investigated the case further by doing whole clinical exome sequence and found mutation in SLC19A2 gene (variant – c.391dupT [P.Tyr131leufs*8]), a homozygous insertion of one bp in exon 2 of SLC19A2 gene[c. 391dupT], that results in shift of reading frame and termination of the protein chain downstream to codon 131 [p.Tyr131 LeufsTer8]. A diagnosis of TRMA was established. The patient was treated with Thiamine 50 mg OD and multiple subcutaneous insulin (MSI) regimen. His insulin requirement subsequently decreased and was completely stopped after three months. His whole blood counts after three months of treatment, showed hemoglobin of 10.1 g/dL, MCV -82, 4.5 × 10⁹/L of white blood cells (neutrophils: 40%, lymphocytes: 55%, monocytes: 3%, eosinophil’s: 2%), and 260 × 10⁹/L of platelets. Patient follow up remains satisfactory. His behavioral observation audiometry (BOA) was normal and his ophthalmological examination, 2D echocardiography was also found normal.

Figure 1.

Picture showing megaloblast in the bone marrow aspirate (Leishman stain, 1000×)

Case 2

A 11 months old male infant, an offspring of consanguineous marriage presented to pediatric outpatient department with irritability and refusal to feed since last three days. Upon assessment, the whole blood counts showed the following results: 6.1 g/dL of hemoglobin, MCV -82, 6.5 × 10⁹/L of white blood cells (neutrophils: 40%, lymphocytes: 50%, monocytes: 8%, eosinophil’s: 2%), and 165 × 10⁹/L of platelets. His random blood sugar levels were >500 mg/dl, urine ketones 3+, and blood pH: 7.31, HCO₃^- was 7meq/l, Na⁺ was 130 meq/l, K⁺ was 4.5 meq/l and HbA1c was 7.8%. Glutamic acid decarboxylase (GAD 65) antibody was found negative. However, C-peptide levels revealed a decrease in insulin reserve. The patient was managed for diabetic ketoacidosis with regular insulin 2 IU and long-acting insulin 2 IU. The patient was referred to clinical hematology outpatient department for comprehensive assessment of anemia. On further evaluation, viral serology (hepatitis B and C, human immunodeficiency virus, cytomegalovirus, Epstein Barr Virus, and Parvovirus) was found to be negative. Coomb’s test (direct and indirect) was negative. Autoimmune screening (ANA, and anti-DS DNA) was also negative. Peripheral blood picture showed normocytic normochromic picture, and retic count of 1.10%. Folic Acid, Vitamin B12 levels and iron profile was unremarkable. The bone marrow aspiration showed megaloblastic erythroid hyperplasia with iron stores of 3+. His blood urea nitrogen was 13 mg/dl, creatinine was 0.34 mg/dl, bilirubin 0.50 mg/dl, and ALT was 21 IU/L. We made differential diagnosis of roger syndrome in the present case. We investigated the case further by doing whole clinical exome sequence and found mutation in SLC19A2 gene (variant- c.1002_1004del [p.Gly335del]), a homozygous deletion in exon 3. A TRMA was diagnosed. The patient was treated with Thiamine 50 mg OD and MSI. His insulin requirement subsequently decreased and insulin completely stopped after three months. His whole blood counts after three months of treatment showed hemoglobin of 11.1 g/dL, MCV 82, 4.5 × 10⁹/L of white blood cells (neutrophils: 40%, lymphocytes: 55%, monocytes: 3%, eosinophil’s: 2%), and 180 × 10⁹/L of platelets. His BOA was normal and his ophthalmological examination, 2D echocardiography was normal too. Hence, patient follow up remained satisfactory.

DISCUSSION

The autosomal recessive condition TRMA is characterised by diabetes mellitus, megaloblastic anemia, and sensorineural hearing loss. It is commonly seen in consanguineous marriages. The cases that have been documented, come from Brazilian, Japanese, Italian, Iranian, Pakistani, Russian, Israeli, Arab, and Lebanese people.[2]

In both the cases, patient presented with hyperglycemia and pallor. Given the findings of hyperglycemia and megaloblastic anemia, TRMA was considered as potential diagnosis. Although TRMA is a kind of sideroblastic anemia, it differs from other sideroblastic anemia because of its megaloblastic characteristics.[2,3] Megaloblastic anemia usually begins in early childhood, though some patients may present later. TRMA is diagnosed based on megaloblastic alterations with sideroblasts constituting more than 10% of cells in the bone marrow aspiration. The characteristic hematological profile of TRMA includes macrocytic anemia with ringed sideroblasts. In the current cases, we observed a megaloblastic picture without ringed sideroblasts [Figure 1]. The clinical symptoms of TRMA are caused by a mutation in the SLC19A2 gene, located on long arm of chromosome 1q23.3. Amino acids 69-269 are included in the SLC19A2 gene’s exon 2.[3] Out of the two known high-affinity thiamine transporters (THTR), THTR-1 is encoded by SLC19A2 and THTR-2 is encoded by SLC19A3. At low concentrations of extracellular thiamine, THTR-1 mediates the active transport of intracellular thiamine. Certain mutations cause THTR-1 to be unusually short and non-functional, while other mutations cause the protein to fold incorrectly, and prevents it from reaching the cell surface. All of these mutations impair THTR-1’s ability to transport thiamine into the cell. Other tissues in body with two high–affinity thiamine transporters can compensate for this deficiency. However, pancreatic beta cells, bone marrow and cochlear cells have single transporter, THTR1, explaining the cause of anemia, diabetes, and hearing loss in patient with TRMA.

The normal shape of the pancreatic islets found in SLC19A2 knockout animals suggests that, the diabetes resulting from SLC19A2 loss was likely caused by impaired insulin production and secretion rather than an developmental defect in the islet., This implies that thiamine therapy may enhance pancreatic beta cell activity in people with SLC19A2 defects.[2,3]

In the first case, the mutation in SLC19A2 gene (variant – c.391dupT [P.Tyr131leufs*8]), a homozygous insertion of one bp in exon 2 of SLC19A2 gene[c. 391dupT] was identified. This results in shift of reading frame and termination of the protein chain downstream to codon 131 [p.Tyr131 LeufsTer8]. In the second case, mutation in SLC19A2 gene (variant- c. 1002_1004del [p.Gly335del]), a homozygous deletion in exon 3 was found.

The pharmacologic dosages of thiamine can cure megaloblastic anemia in TRMA syndrome. For treating TRMA, the goal is to get affected people on pharmacologic dosages of thiamine (25–75 mg/day) as early as possible. In the present case series after receiving thiamine 50 mg/day, the child’s severe anemia and megaloblastic picture improved drastically. Additionally, the patient was able to discontinue insulin therapy after three months of treatment. Thiamine at high doses increase the intracellular concentration by passive diffusion and improvement in anemia, blood sugar levels.

A prior report by Beshlawi et al.[4] described six patients from the same family had a 5224 base pair deletion in the SLC19A2 gene and resulted deletion in exons 4, 5, and 6.[4] They also reported variable response to thiamine. After one month of thiamine treatment (100 mg/day), the haemoglobin reached to normal range, and insulin requirement also decreased.

Similarly, Alzahrani et al.[5] showed that high –dose thiamine treatment in TRMA patient can improve the symptoms, increase the haemoglobin level and reduce the requirement of insulin.[6,7]

In the present case, both patients did not have sensory deafness. This can be explained because hearing loss in TRMA is progressive in nature, and early treatment could prevent the development and progression of deafness. It also depends upon the type of mutation. The amount of inner hair cell loss is the cause of sensory deafness in TRMA and it depends on the length and severity of thiamine deficiency.[8]

Onal et al.[9] in their study showed that with thiamine supplementation as early as at 1.5 months of age, and patients at 30 months follow up resulted normal hearing. Similarly Bergmann et al.[10] showed that early treatment with thiamine resulted in normal hearing at the ages of 15 and 30 years. So, early detection and appropriate therapy before 2 months of age could be effective in hearing loss prevention.

However, Potter et al.[11] in their study of three affected sibling., reported that although two among the three initiated thiamine therapy at an early age of 3.6 and 0.6 months, on subsequent follow up both developed sensorineural hearing loss by ages 2 and 3.9 years, respectively. So they concluded that thiamine treatment does not necessarily prevent hearing loss but only delays its onset.[11,12] In the present case, preserved hearing could be due to early initiation of thiamine treatment. There is scarcity of data of long term follow up in TRMA patients. So, further research is needed to see the long-term effect of thiamine in TRMA patients.

CONCLUSION

When an infant or adolescent presents with triad of megaloblastic anemia, diabetes mellitus and deafness, a differential diagnosis of thiamine responsive megaloblastic anemia should be considered. The early treatment with high dose of thiamine improves the anemia, glycaemic control and prevents the hearing loss even if genetic testing is still pending or has not been conducted.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.