A 16-year-old adolescent white girl presented to the hematology clinic with a 4-year history of pallor and anemia. Her medical history was otherwise unremarkable. Her family was of European origin, with no consanguinity. Neither her parents nor her 2 siblings had ever been diagnosed with anemia or other hematologic disorders. On physical examination, the patient was found to have a soft cardiac murmur and mild splenomegaly; hepatomegaly was absent. A complete blood count revealed a red blood cell count of 3.7 × 106/μL, a hemoglobin level of 7.7 g/dL, a leukocyte count of 4100/μL, a platelet count of 226 × 103/μL, and a reticulocyte count of 140.4 × 103/ μL. Her mean corpuscular volume was 64.8 μm3 (normal range, 80–94 μm3), her mean corpuscular hemoglobin was 20.6 pg (normal range, 24.0–31.0 pg), and her mean corpuscular hemoglobin concentration was 31.7 g/dL (normal range, 32.0–36.0 g/dL). Results of her iron studies were as follows: serum iron, 172 μg/dL (30.8 μmol/L) (normal range, 50–150 μg/dL [9.0–26.9 μmol/L]); ferritin, 391.5 ng/mL (normal range, 22–400 ng/mL); transferrin, 161 mg/dL (normal range, 185–370 mg/dL); and free erythrocyte protoporphyrin, 37 μg/dL (normal range, 0– 78 μg/dL). Assays for her serum lead and copper levels were within normal ranges. Hemoglobin electrophoresis revealed mildly increased hemoglobin F (5.6%) and normal hemoglobin A2 (2.3%). She had a normal karyotype on cytogenetic studies.
Microscopic examination of her peripheral blood smear revealed a dual population of microcytic and normocytic red blood cells, hypochromia, and marked poikilocytosis (Figure 1). Several red blood cells displayed coarse basophilic stippling. Evaluation of her bone marrow aspirate demonstrated significant hypercellularity associated with marked erythroid hyperplasia. Many erythrocytic precursors exhibited megaloblastoid maturation or nucleocytoplasmic asynchrony (Figure 2). The myeloid-erythroid ratio was 0.1:1.0 (normal ratio, 2.5:1.0). Stainable iron stores were increased. A striking feature was the presence of numerous ringed sideroblasts, in which the perinuclear iron granules encircled more than one third of the nuclear circumference (Figure 3, arrows). These cells made up 50% to 60% of the total erythroid precursors. Megakaryopoiesis was adequate and unremarkable, as was granulopoiesis. There was no apparent increase in blast cells. The ringed sideroblasts were further viewed on transmission electron microscopy, using the deparaffinized bone marrow biopsy tissue. Nonspecific siderosomes (Figure 4, black arrow) and pathognomonic iron-laden mitochondria (Figure 4, white arrow) were seen in the perinuclear zones. The mitochondria appeared edematous and distorted, with iron clusters deposited in the spaces between the cristae (Figure 4, inset and arrowheads). The patient was treated with pyridoxine hydrochloride and folic acid and was followed up routinely. Eleven months after she started the therapy, her red cell indices were unchanged, but the hemoglobin level was higher (9.1 g/dL).
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Pathologic Diagnosis: Pediatric Idiopathic Acquired Sideroblastic Anemia
Abstract
Idiopathic acquired sideroblastic anemia, also known as refractory anemia with ringed sideroblasts, primarily occurs in older adults. The disorder is rare in children. In this case, a 16-year-old adolescent girl with chronic hypochromic microcytic anemia was found to have a dual population of red blood cells in her blood smear. Her bone marrow was characterized by marked erythroid hyperplasia. Numerous ringed sideroblasts that exhibited pathognomonic ultrastructural features were seen in the bone marrow aspirate. The patient's family history was negative for sideroblastic anemia. Further patient investigation revealed no evidence of lead poisoning or any other type of intoxication. This case emphasizes that, despite its rarity in children, idiopathic acquired sideroblastic anemia is an important entity that should be considered in the differential diagnosis of pediatric hypochromic microcytic anemia.
Broadly categorized as hypochromic microcytic anemia, sideroblastic anemia may be hereditary or acquired. The hereditary forms comprise a heterogeneous group of defects of the heme synthesis and mitochondrial disorders. Of these, X-linked δ-aminolevulinic acid synthetase deficiency is the best defined. The other known forms are inherited by an X-linked or autosomal dominant pattern.1,2 Acquired sideroblastic anemia is further divided into idiopathic and toxic forms. The latter form is associated with lead poisoning, alcoholism, or use of certain therapeutic drugs. Our patient was a girl with no family history of sideroblastic anemia and without clinical or laboratory evidence of lead poisoning or any other type of chemical intoxication. This case was therefore classified as idiopathic acquired sideroblastic anemia, also known as refractory anemia with ringed sideroblasts, according to the latest World Health Organization classification of myelodysplastic syndromes.3 Occurring primarily in older adults, this disorder accounts for approximately 10% to 12% of cases of myelodysplastic syndromes.3 Idiopathic acquired sideroblastic anemia, or refractory anemia with ringed sideroblasts, is a rare disorder in children.4
The pathologic hallmark of all forms of sideroblastic anemia is ineffective bone marrow erythropoiesis, with erythroid hyperplasia, increased iron stores, and excess ringed sideroblasts that constitute more than 15% of the total erythrocytic precursors.3 The peripheral blood is characterized by a dual red blood cell population with significant anisopoikilocytosis, and coarse basophilic stippling is often identifiable. Serum iron is usually increased, whereas total iron binding capacity is decreased, which often results in an increase in percentage of transferrin saturation. Free erythrocyte protoporphyrin is typically elevated in the acquired form, with the highest level seen with lead poisoning. Our patient, with a normal free erythrocyte protoporphyrin level and clinical responses to pyridoxine hydrochloride treatment, appeared to fall into the subgroup of idiopathic acquired sideroblastic anemia, as suggested by Takeda et al.5 These cases overlap with the hereditary form clinically and pathologically, and at least 1 such case was found to have a novel missense mutation of the erythroid-specific δ-aminolevulinate synthase gene.6 Electron microscopy is not a routine procedure for the diagnosis. In this case, however, we performed electron microscopy on the material retrieved from the paraffin block to demonstrate to trainees the ultrastructural alterations associated with the disorder. Sideroblastic anemia, regardless of its types, is attributed to the failed insertion of iron into the porphyrin ring during the intramitochondrial heme biosynthesis. The siderotic granules are therefore sequestered in the developing erythrocyte mitochondria, which have a perinuclear distribution in humans. Unincorporated iron deposited between the cristae may damage the mitochondria further, leading to their swelling and distortion.7
The pathogenesis of idiopathic acquired sideroblastic anemia, or refractory anemia with ringed sideroblasts, remains poorly understood. A bone marrow stem cell disorder has been postulated. Clonal chromosomal abnormalities are seen in fewer than 10% of the cases.3 In animal studies, the novel transmembrane protein sideroflexin, thought to facilitate the intramitochondrial use of iron, is mutated in mice with sideroblastic anemia. Zheng et al8 recently reported the cloning of a human gene, mapped to chromosome 10 (q25–26), that is homologous to the mouse gene encoding for sideroflexin. Mutation of the erythroid-specific δ-aminolevulinate synthase gene may partially explain why some acquired cases have a low free erythrocyte protoporphyrin level and respond to pyridoxine therapy.
Acknowledgments
We thank Howard Rosenberg, BSc, MLT, and Mike Starr, RBP, for preparing the photomicrographs.
References
The authors have no relevant financial interest in the products or companies described in this article.