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.