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Case Reports Indian Pediatrics 1999;36: 1158-1161 |
Congenital Sideroblastic Anemia |
| Reena Das, Amita Trehan,
Neelam, Marwaha and R.K. Marwaha From the Division of
Pediatric Hematology-Oncology, Departments of Pediatrics and *Hematology, Postgraduate
Institute of Medical Education and Research, Chandigarh 160 012, India. The sideroblastic anemias comprise a heterogenous group of acquired primary or secondary and congenital disorders which have in common an anemia, generally refractory to therapy, ineffective erythropoiesis and the presence of large numbers of ring sideroblasts in the marrow(1). Increased levels of tissue iron and varying proportions of hypochromic erythrocytes in the blood are associated features. Inherited sideroblastic anemia is an uncommon condition which can justifiably be regarded as a distinct entity with clinical and genetic heterogeneity(2). Within this category, the severity of anemia, the age of presentation and the response to pyridoxine therapy are variable. Congenital sideroblastic anemia (CSA) is a X-linked recessive disorder which usually affects male sibs. However, about 10 females have been reported to present with CSA where the Lyon's hypothesis of X-chromosome inactivation or an autosomal recessive inheri- tance is used to explain the existence of seriously affected women with CSA(3,4). In view of the rarity of this condition, we present the clinical and hematological profile of two infants with CSA and highlight the features which help in differentiating this rare condition from commoner causes of microcytic, hypochromic anemia, such as iron deficiency anemia (IDA) and thalassemia. Case Reports Case I: A 2-month-old child presented with progressive pallor, which had been first observed at day 15 of life. He received his first blood transfusion when he was 7 weeks old. He was born to non-consanguineous parents at term by normal vaginal delivery. There was no history of neonatal jaundice. Two male siblings had died in infancy. Both had pallor with hepatosplenomegaly but had not been investigated. Physical examination revealed a 3.5 kg male infant with marked pallor. He had hepato-splenomegaly (4 cm and 2 cm, respectively, below the costal margins). Investigations showed a hemoglobin (Hb) of 10.3 g/dl (post transfusional) with a hematocrit (Hct) of 30%. He had hypochromic microcytic red blood cells with a reticulocyte count of 0.1%. The total leucocyte count and platelet counts were normal. Hb electrophoresis, HbF estimation, G-6-PD screening, direct Coomb's test, osmotic fragility and screening for unstable hemoglobin revealed no abnormality. The serum iron was 133 mg/dl (N 60-160 mg/dl) whilst the total iron binding capacity was 141 mg/dl (N 190-400 mg/dl). The hematological parameters, including the red cell indices and red cell distribution width (RDW) of the parents were within the normal range as were quantitative levels of HbA2. The patient was given an empiric trial of hematinics (iron_4 mg/kg/day and folic acid_ 2 mg/day) which did not incite a significant response. At this stage, a bone marrow examination was performed. The bone marrow showed a myeloid : erythroid ratio of 1.3 : 1 with moderate megaloblastosis of the erythroid series. Examination of the iron stained smear showed more than 40% ring sideroblasts. He was given pyridoxine for 5 months in escalating doses of upto120 mg/day with no response. He has since been on periodic packed red cell transfusions and is presently seven years old. He has been started on oral iron chelation therapy about a year ago. Case II: A one-month-old male infant, presented with pallor. He was born by an elective lower segment caesarian section for breech presentation. There was no history of blood loss or any perinatal adverse factors. He was the first born of a non-consanguineous marriage. On examination, apart from marked pallor, there was hepatosplenomegaly of 1 cm each below the costal margins. Investigations revealed a Hb of 5.4 g/dl, Hct of 18% and a reticulocyte count of 0.1%. The total leukocyte count was normal. There was mild thrombocytosis with platelet counts ranging from 500-600 ´ 109/L. Red cells showed hypochromic microcytosis. The Hb electrophoresis was normal and the HbF was 6.5% at the age of 2 months. HbA2 quantitation of the parents showed normal values. G-6-PD screening was normal. He was treated with hematinics which did not result in any improve-ment. Bone marrow examination revealed mild erythroid hyperplasia with normoblastic erythropoiesis. More than 60% ring sideroblasts were observed in the Perl's stained smear (Fig. 1).
Fig. 1. Bone marrow aspirate smear from Case II showing a ring sideroblast Perl's stain ´ 1375. He was started on 30 mg pyridoxine daily which was increased to 90 mg/day. However, his anemia failed to respond. He has been receiving periodic packed red cell trans-fusions for over a year, with pre-transfusion hemoglobin being maintained at over 9 g/dl. Discussion Congenital sideroblastic anemia is a rare disorder which is characterised by mild to moderate anemia with a dimorphic blood picture showing normal red cells and a variable number of microcytes. In the bone marrow, ring sideroblasts are present as a sign of disturbed iron metabolism at a mitochondrial level(3). The excess intracellular non-heme iron may result from a diversion of iron which was intended, but not utilized for hemoglobin synthesis. Alternately, excess amounts of iron may be absorbed by the cell because of a failure of normal regulation of iron transfer into the cell. With either event, the excess non-heme iron deposited in the cell may act as a toxin which either initiates or aggravates intracellular organelle damage finally resulting in ineffective erythropoiesis. Congenital sideroblastic anemia (CSA) is usually a X-linked recessive disorder. The first family with this disorder was described by Cooley in 1945(5) and subsequently this entity became well recognized. However, there is a relative paucity of reports on CSA from India(6). Earlier Agarwal(6) had described an Indian female child who presented with pallor and required regular blood transfusions wherein the diagnosis of CSA was made after bone marrow examination. To the best of our knowledge, no other case of CSA has been described from India. Patients of CSA presents with hereditary hypochromic anemia which is apparently not due to iron deficiency or thalassemia. The two infants in this report presented at an early age with pallor and hepatospleno-megaly. Since both were males and the first case gave a positive family history of two male sibs having died of similar complaints, an X-linked mode of inheritance can be speculated. In the classical form, females are unaffected and have no anemia. However, a careful examination of the blood smear may reveal two populations of erythrocytes in some females. RDW has been used to screen for affected family members, who may demonstrate increased RDW bases on automated red cell indices(4). The minor population of microcytes would result in tailing or even shouldering to the left of the RDW-CV (coefficient of variation). In case I, the mother showed normal indices with the RDW being 13.3%. Mild thrombocytosis, observed in the second case, was probably a secondary finding which has been recorded earlier(5-7). Both the patients failed to show any satisfactory response to pyridoxine. Due to the rarity of CSA and the fact that thalassemia major and IDA are common in our region, these individuals may be erroneously treated with iron, which may consequently lead to iron overload. All the three disorders in their severe form show reduced MCV, MCH and MCHC. The RDW is also wide. RDW has a discriminant role in milder forms of sideroblastic anemia, IDA and thalassemia minor. However, peripheral blood film examination in thalassemia major often shows many nucleated red cells and marked basophilic stippling, features usually not seen in severe iron deficiency anemia or sideroblastic anemia. Elevated HbF levels, alongwith presence of thalassemia trait in both parents, establish the diagnosis of thalassemia major. Parental screening is essential, not only because thalassemia major is a genetic disorder, but also because high levels of HbF may occur in some parents whose infants have CSA. Serum iron parameters distinguish IDA from CSA; in the former, serum iron, tansferrin saturation and ferritin are markedly reduced. CSA, congenital form of pure red cell aplasia and congenital dyserythropoietic anemia form the main differential diagnosis, after thalassemia and IDA are ruled out as diagnostic possibilities in a given case. Bone marrow examination, a simple test, is diagnostic in all these conditions. CSA must be suspected especially in infants who present before the age of 2 months with pallor, hepatosplenomegaly and a microcytic, hypochromic blood picture. Since the mainstay for therapy is repeated blood transfusions, such children need assessment for iron overload. Iron chelation therapy needs to be instituted at an early age to prevent damage to vital organs. References 1. Hines JD, Grosso JA. The sideroblastic anemias. Semin Hematol 1970; 7: 86-106. 2. Nusbaum NJ. Concise review. Genetic basis for sideroblastic anemias. Am J Hematol 1991; 37: 41-44. 3. Bottomless SS. Sideroblastic anemias. In: Clinical Hematology. Eds. Lee GR, Bithell Tc, Foerster J, Athens JW, Lukens JN. Philadelphia Lea and Febiger, Philadelphia, 1994; pp 852-871. 4. Van Waveren Hogervorst GD, Van Roermund HPC, Snijders PJ. Hereditary sideroblastic anemia and autosomal inheritance of erythrocyte dimorphism in a Dutch family. Eur J Hematol 1987; 38: 405-409. 5. Looby TB. A severe type of hereditary anemia with elliptocytosis. Interesting sequence of splenectomy. Am J Med Sci 1945; 209: 561-562. 6. Agarwal MB. Congenital sideroblastic anemia in a female. Indian Pediatr 1988; 25: 685- 688. 7. Streeter RR, Presant CA, Reinhard E. Prognostic significance of thrombocytosis in idiopathic sideroblastic anemia. Blood 1997; 50: 427-430. |
