The triad of thiamine-responsive anaemia, diabetes mellitus and sensorineural deafness, which is inherited as an autosomal recessive syndrome, has been reported in a total of 15 patients ( Abboud et al, 1985 ; Borgna-Pignatti et al, 1989 ; Esposito et al, 1985 ; Haworth et al, 1982 ; La Grutta et al, 1980 ; Mandel et al, 1984 ; Poggi et al, 1984 ; Rogers et al, 1969 ; Rosskamp, 1985; Viana & Carvalho, 1978). The classic haematological picture in this syndrome is that of macrocytic anaemia, sometimes associated with a moderate thrombocytopenia and neutropenia. The bone marrow aspirate usually shows a megaloblastic bone marrow, dyserythropoietic changes and many ringed sideroblasts. However, a typical picture of myelodysplasia has never been reported. We describe two patients who presented with diabetes, deafness and thiamine-responsive pancytopenia. Bone marrow aspirate and trephine biopsy were typical of tri-lineage myelodysplasia with evidence of dyserythropoiesis, dysgranulopoiesis and dysmegakaryopoiesis. We propose the term ‘thiamine-responsive myelodysplasia’ rather than that of thiamine-responsive anaemia.
The triad of thiamine-responsive anaemia, diabetes mellitus and deafness has been reported in 15 patients with macrocytic anaemia, sometimes associated with moderate thrombocytopenia. The bone marrow aspirate usually shows megaloblastic changes and ringed sideroblasts. However, tri-lineage myelodysplasia has never been reported. We describe two patients who presented with diabetes, deafness and thiamine-responsive pancytopenia. Bone marrow aspirate and biopsy were typical of tri-lineage myelodysplasia. These findings suggest that thiamine may have a role in the regulation of haemopoiesis at the stem cell level. We propose the term ‘thiamine-responsive myelodysplasia’ rather than that of thiamine-responsive anaemia.
The patient, an 8-year-old Lebanese girl, was born on 22 February 1989, following an apparently normal gestation. Growth and development during infancy was normal. The family history revealed no deafness, diabetes or haematological disorder. At 1 year of age a hearing deficit was first noticed and she was found to have incomplete sensorineural deafness. At 6 years of age the patient developed insulin-dependent diabetes mellitus.
Two episodes of anaemia requiring blood transfusion had occurred at the age of 2 years. Pancytopenia was observed in January 1996, with a haemoglobin level of 5.2 g/dl (MCV 90; reticulocyte count 0.2%), a WBC count of 3.1 × 109/l (14% neutrophils and 66% lymphocytes) and a platelet count of 88 × 109/l. Physical examination was normal except for anaemia symptoms. The biological data revealed normal serum iron and total binding capacity, normal urea and creatinine, normal liver function tests and LDH level and a negative Coombs test. G6PD level and haemoglobin electrophoresis was normal.
The bone marrow aspirate was hypercellular showing tri-lineage haemopoiesis with a myeloid:erythroid ratio of 2:1. Megakaryopoiesis was moderately decreased with hypolobulation, multinucleation and minimal platelet production ( Figs 1D and 1E). Granulopoiesis was moderately left shifted, was hypogranular mainly in the mature component, and hypolobulated with pseudo-Pelger Huet changes (Fig 1C). Erythropoiesis was decreased and megaloblastoid with karyorrhectic nuclei and irregular cytoplasm ( Figs 1A and 1B). Iron stain was positive with only few sideroblasts and ring sideroblasts. The myeloperoxidase reaction was positive in granulocytes with weak positivity in the mature cells. These findings were consistent with a myelodysplastic syndrome, refractory anaemia (FAB: MDS-RA).
The diagnosis of myelodysplasia was confirmed by thin sections of a bone marrow trephine biopsy showing hypercellular bone marrow (80–90% cellularity) predominant in the granulocytic lineage. Megakaryopoiesis was decreased with predominance of small megakaryocytes. Granulopoiesis was dysplastic with clustering of immature-looking precursor cells, mainly located in the central areas of the bone marrow constituting an abnormal localization of immature precursors (ALIP). Erythropoiesis was decreased and megaloblastoid. The silver stain showed no increase in reticulin.
Oral iron, vitamin B6, folic acid and parenteral vitamin B12 were administered without haematological response. The patient required blood transfusion support (pheno-identical packed red cells with leucocyte filtration), at an average of 1 unit/month.
After 6 months of transfusions, the bone marrow aspirate was repeated. At that time the iron stain showed markedly increased iron stores with numerous ringed sideroblasts. Late normoblasts, intermediate normoblasts and even basophilic normoblasts manifested perinuclear accumulation of haemosiderin. The diagnosis was that of myelodysplasia (ringed sideroblastic anaemia). Cytogenetic analysis was performed on the bone marrow aspirate. 20 cells were examined and showed a female karyotype with no apparent abnormality. Chromosome breakage studies showed no evidence of Fanconi's anaemia.
Multiple profiles of bone marrow normoblasts were examined by transmission electron microscopy, which revealed almost universal dyserythropoietic cells with large intramitochondrial inclusions of haemosiderin. The nuclear features also showed dyserythropoietic changes with large nuclear membrane pores and abnormal distribution of heterochromatin. There was also an increase in cytoplasmic vacuoles containing scanty amounts of electron-dense material. These findings confirmed the light-microscopic observations of dyserythropoiesis and ringed sideroblasts.
Due to the association of sideroblastic anaemia, diabetes mellitus and hypoacousia, the patient was started on high doses of vitamin B1 (100 mg/d p.o.) + folic acid (5 mg/d p.o.). A rapid haematological response was observed after 1 month of therapy; her blood count showed a haemoglobin level of 10.8 g/dl, a WBC 7.3 × 109/l with 47% neutrophils and 38% monocytes, and a platelet count of 295 × 109/l. Following 1 year of the same therapy, the patient's CBC remained normal (Hb 12.2 g/dl; WBC 8.4 × 109/l (55% neutrophils, 33% lymphocytes); platelets 304 × 109/l). The patient continues to receive vitamin therapy without any further complications. A bone marrow aspirate was not repeated, and no significant improvement in either deafness or diabetes states has been observed.
The patient, a 5-year-old Lebanese boy was born in 1992 following an apparently normal gestation. The child was on the fifth centile for height and weight. His parents are first-degree relatives and his father and a brother have insulin-dependent diabetes mellitus (IDDM). At 2 years of age he developed diabetes mellitus and has been on insulin since then. He was reported by his mother to have impaired hearing and no speech development. An audiogram revealed sensorineural hearing loss.
Anaemia requiring blood transfusion (three packed cells over a period of 4 months) was diagnosed at the age of 5 years. CBC revealed haemoglobin 6.5 g/dl (MCV 86; reticulocyte count 0.1%), a WBC count of 2.8 × 109/l (38% neutrophils, 52% lymphocytes) and a platelet count of 41 × 109/l. The blood smear showed anisopoikilocytosis and oval macrocytic red blood cells. Physical examination was normal except for pallor. Haemoglobin electrophoresis was normal, and the serum iron level, total iron binding capacity, ferritin, vitamin B12 and folic acid levels were within the normal ranges. Coombs test was negative and G6PD level was normal.
Bone marrow aspirate was hypercellular showing dysplastic tri-lineage haemopoiesis, with a myeloid:erythroid ratio of 3:1. Megakaryocytes were hypolobulated, and multinucleated with minimal platelet production. Granulopoiesis was hypolobulated with rounded nuclei and irregular granulation. Erythropoiesis showed megaloblastoid features and nuclear karyorrhexis.
Considering that many of the patients diagnosed with diabetes mellitus, thiamine-dependent megaloblastic anaemia and sensorineural deafness are of Lebanese origin, this child was started on thiamine 100 mg p.o. once daily. After 1 month of therapy with thiamine his haemoglobin level improved and he did not require further transfusions. 2 months later his haemoglobin was 12 mg/dl and platelet count 180 × 109/l. His blood count on follow-up 1 month later remained within normal. No significant improvement in either deafness or diabetes states has been observed.
The clinical picture of the two patients is consistent with the so-called thiamine-responsive anaemia syndrome, of which 15 cases have been reported ( Abboud et al, 1985 ; Borgna-Pignatti et al, 1989 ; Esposito et al, 1985 ; Haworth et al, 1982 ; La Grutta et al, 1980 ; Mandel et al, 1984 ; Poggi et al, 1984 ; Rogers et al, 1969 ; Rosskamp, 1985; Viana & Carvalho, 1978). All the previously reported cases are children who presented with megaloblastic or sideroblastic anaemia, diabetes and hearing loss, and their anaemia invariably responded to high-dose thiamine treatment although their thiamine level, when evaluated, was normal.
Thiamine-related enzymes measurements were performed in 7/15 patients reported to date. A low level of thiamine pyrophosphokinase (TPKase), the enzyme that phosphorylates thiamine to its active form (thiamine pyrophosphate), was reported in the only three patients in whom TPKase activity was studied ( Borgna-Pignatti et al, 1989 ; Poggi et al, 1984 ). It was suggested that this decrease in TPKase activity was responsible for the suboptimal availability of thiamine pyrophosphate, leading to defective erythropoiesis ( Borgna-Pignatti et al, 1989 ). The ringed sideroblasts reported in the bone marrow of some, but not all, cases may be due to a deficiency of α-ketoglutarate dehydrogenase, which is required for haem synthesis, leading to ineffective erythropoiesis of the sideroblastic type ( Abboud et al, 1985 ). However, no alteration of the nucleic acid synthesis in the bone marrow cells or of the methylation of deoxyuridilate was reported ( Mandel et al, 1984 ) and the megaloblastic changes remain unexplained. Moreover, BFU-E growth in vitro is not restored by the addition of thiamine ( Rotoli et al, 1986 ).
The tri-lineage myelodysplastic changes described in the bone marrow aspirate and trephine biopsy of our patients have not been reported before and suggest that thiamine may have a role not only in erythropoiesis and haem synthesis (megaloblastic and ringed sideroblastic changes) but also in the regulation of haemopoiesis at the stem cell level.
Out of the 17 patients reported, five are of Lebanese origin, suggesting the existence of a relatively endemic region ( Abboud et al, 1985 ). Identification of additional cases, especially familial ones, may enable the cloning of the defective gene responsible for this metabolic genetic disease. This putative gene may play a critical role in the regulation of haemopoiesis.
Finally, although we have not demonstrated clonality of this dysplastic haemopoiesis, some unexplained myelodysplasia (refractory anaemia or ringed sideroblastic anaemia type) in adults may be due to a similar, but aquired, genetic defect. We therefore suggest a trial of thiamine therapy in adult myelodysplasia.