Thiamine-Responsive Megaloblastic Anemia Syndrome Mimicking Myelodysplastic Neoplasm

Thiamine-responsive megaloblastic anemia syndrome (TRMA) is a rare autosomal recessive disease with a homozygous or compound-heterozygous variants in SLC19A2 gene. It was first described by Porter et al. [1] in 1969 with only around 200 cases described worldwide until now [2].

SLC19A2 encodes for the high affinity thiamine transporter [3]. Disruption of this gene by biallelic variants leads to a deficiency of thiamine, resulting in impaired cell metabolism [4, 5]. The main clinical signs of TRMA are megaloblastic anemia occurring in childhood or adolescence with normal laboratory values for folic acid and vitamin B12, diabetes mellitus (DM), and progressive irreversible sensorineural hearing loss [6]. In addition, thrombocytopenia, or pancytopenia, heart anomalies, such as cardiomyopathy or coronary vascular disease, as well as optic atrophy and retinal degeneration can occur [7].

The patients require multidisciplinary management, with treatment consisting of lifelong oral thiamine supplementation. The treatment goal is the resolution of anemia, but unfortunately it has no effects on hearing loss or DM [8]. Here, we report on a 38-year-old male Caucasian patient diagnosed with TRMA with a long history of unexplained anemia.

The 38-year-old patient first presented in our department with symptoms of fatigue and reported about a 12-year history of macrocytic and hyperchromic anemia. At the age of 26 years, he was diagnosed with myelodysplastic neoplasm (MDS) with low blast count, and initially did not require specific treatment. During subsequent follow-ups, he developed symptomatic anemia, became transfusion dependent and received two units of red blood cells twice. Additionally, he was suffering on DM type 1, diagnosed at the age of one and had an optic neuropathy and cataract with choroidal coloboma since early childhood. DM was treated with subcutaneous long- and short-term insulin. Three years prior to presentation, a drug-eluted stent was placed due to coronary single-vessel disease. He received oral acetylsalicylic acid and atorvastatin.

At presentation his physical examination revealed no relevant findings, his complete blood counts showed megaloblastic anemia with a hemoglobin (Hb) concentration of 5.4 mmol/L (reference: 8.4–10.9 mmol/L) and a mean corpuscular volume (MCV) of 97.3 fL (reference: 80–98 fL). White blood cell and platelet counts were normal, as well as folic acid, vitamin B12 and ferritin levels, lactate dehydrogenase, erythropoietin, inflammation markers, and liver and renal function tests. The blood count and laboratory parameters values at the age of 26 and 38 years are presented in Table 1.

The bone marrow smears from both time points showed dysplastic erythropoiesis with megaloblastic changes and normal megakaryopoiesis. Myeloblast count was 5% (Fig. 1a). Cytogenetic evaluation showed a normal male karyotype. Molecular genetic analysis by targeted next-generation sequencing revealed no somatic variants associated with MDS.

Due to multiple clinical comorbidities and the absence of typical MDS variants, the patient was referred for human genetic examination. Whole-exome sequencing using TWIST Human Core Exome Kit (TWIST Bioscience, San Francisco, USA) on an Illumina NovaSeq6000 sequencer was performed and analysis using the browser-based genomics software Varvis (Limbus 117 Medical Technologies GmbH, Rostock, Germany). Variant nomenclature was according to HGVS, genomic positions based on human genome assembly hg38. Data analysis revealed a heterozygous missense variant (NM_006996.3: c.1001G>A, p.(Gly334Asp)) in SLC19A2, which results in an amino acid change from glycine to aspartic acid at codon 334. According to American College of Medical Genetics and Genomics (ACMG) classification [9], the variant was classified as pathogenic (criteria PS3, PM3_STR, PM2_SUP, PP3, PP4). The missense variant had already been described in association with TRMA in multiple unrelated individuals who were compound heterozygous for pathogenic SLC19A2 variants including p.(Gly334Asp) [10‒13].

Analysis of the whole genome data using the browser-based genomics software Emedgene (Illumina, San Diego, USA) additionally detected a 3.4 Mb inversion in the chromosomal region 1q24.2 (NC_000001.11: g.166068365_169484680inv) with breaking points in FAM78B and SLC19A2. Due to this structural variant, exons 2-6 of SLC19A2 are inverted and located at the 3′ end of FAM78B, most probably leading to a premature truncation and a functionally null allele. Based on ACMG Classification, this variant was also classified as pathogenic (criteria PVS1, PM2_SUP, PP4). Segregation analysis by Sanger sequencing showed that the missense variant p.(Gly334Asp) was inherited from the healthy mother, whereas amplification with differential annealing-mediated racket PCR and oxford nanopore technologies based sequencing [14] revealed that the structural variant was inherited from the healthy father (Fig. 1c). Thus, both compound heterozygosity and the diagnosis of TRMA were confirmed in our patient.

With the intention to improve the symptoms of anemia, the treatment with oral thiamine 100 mg daily was initiated. The patient reported that the therapy was well tolerated, without any significant side effects. Nine months after the induction of treatment, his physical condition showed marked improvement, without symptoms of fatigue reported. Laboratory results indicated normalization of Hb and MCV (Hb 10.1 mmol/L, MCV 90.4 fL). The subsequent bone marrow smear (Fig. 1b) showed completely normalized hematopoesis, without any signs of dysplasia or an increase of myeloid blasts.

We report a case of an adult patient diagnosed with TRMA at the age of 38 years caused by a previously described missense variant and a novel structural variant involving SLC19A2. The patient was diagnosed with TRMA after 12 years history of anemia, misinterpreted as MDS.

Distinguishing MDS from megalobastic anemia due to TRMA can be challenging, as bone marrow smears frequently show ring sideroblasts [15]. In contrast to TRMA, MDS usually presents at advanced age and is characterized by dysplastic features affecting at least 10% cells of one hematopoietic lineage [16]. Hematopoietic cells of patients with MDS, by definition, harbor at least one somatic genetic alteration (when analyzing all protein-coding genes) or recurrent chromosomal abnormality [17]. However, no somatic genetic alteration associated with MDS was detected in our case using a targeted sequencing approach. Approximately 10% of patients diagnosed with MDS show no genetic changes when analyzed by targeted NGS and conventional cytogenetics. Due to the presence of erythroid dysplasia and 5% myeloblasts, the bone marrow smear of our patient was initially interpreted as MDS.

Another relevant common finding for both MDS and TRMA is transfusion dependency. As there is a risk of overtreatment if misdiagnosed as MDS, we consider it extremely important to perform genetic diagnostics including whole exome or whole genome sequencing, especially in pediatric and young adult patients with further clinical stigmata. Interestingly, even though 90% of described TRMA cases suffer from hearing loss [18], our patient had no auditory impairment.

Our patient diagnosed at the age of 38 years with a delay of 12 years from the onset of megaloblastic anemia. This is in line with published case series of 7 TRMA patients with median time to diagnose of 8 years [10]. Kutlucan [15] also reported an adult female patient diagnosed with TRMA at 32 years of age. Besides megaloblastic anemia, DM and hearing loss, the patient presented with autoimmune thyroiditis, cardiomegaly as well as second-degree atrio-venticular dissociation. Similar to our patient, she was also mistakenly interpreted as MDS and the treatment with darbepoetin and filgrastim showed no effects. Also here, the blood counts normalized 4 months after the initiation of treatment with thiamine [15]. We assume that due to dysplastic changes in bone marrow smears of TRMA patients, a relevant number of patients is being underdiagnosed and falsely referred as MDS thus receiving potentially unnecessary and inefficient therapy.

With only 200 described cases, TRMA is an extremely rare disease [2] but should be considered as a differential diagnosis in pediatric but also in adult patients with blood anomalies or clinical features of MDS and indicative comorbidities such as DM, sensorineural hearing-loss but also cardiovascular abnormalities, optic atrophy, or retinal degeneration. Therefore, we highly recommend genetic diagnostics in these patients. Furthermore, TRMA should not be excluded if only one potentially causative variant is detected, as uncommon variants may not be detected by standard genetic diagnostic methods.

We would like to thank to Christel Müller and Daniela Bretschneider for performing cytogenetic analysis. We also would like to thank the patient and his parents for participating in the study.

Written informed consent was obtained from the patient and his parents for the publication of any potentially identifiable images or data included in this article. Ethical approval is not required for this study in accordance with local or national guidelines.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

C.K., F.S., V.V., and U.P. wrote the manuscript, A.-S.K., M.J., G.-N.F., J.U., K.H.M., H.F., R.-T.J., H.O., D.P., and J.R.L. provided administrational support. All authors contributed to the interpretation of the results and editing of the manuscript and agreed on the final version.

Christina Klötzer and Franziska Schnabel contributed equally and share the first authorship.Vladan Vučinić and Uwe Platzbecker contributed equally and share the senior authorship.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.