Year : 2009 | Volume
: 52 | Issue : 3 | Page : 424--426
Congenital sideroblastic anemia: A report of two cases
Sanjeev Kumar Gupta, Seema Rao, Rakhee Kar, Seema Tyagi, Hara Prasad Pati
Department of Hematology, IRCH, All India Institute of Medical Sciences, Ansari Nagar, New Delhi -110 029, India
Sanjeev Kumar Gupta
B-1/226, Yamuna Vihar, Delhi - 110 053
Sideroblastic anemia, comprising of acquired and congenital forms, is a heterogeneous group of disorders characterized by the presence of ring sideroblasts in the bone marrow. Congenital sideroblastic anemia is a rare condition which is mostly X-linked, caused by mutations of delta-aminolevulinic acid synthase 2. We describe two cases of congenital sideroblastic anemia, one of them indicating an autosomal recessive inheritance, with their clinico-hematological profile. It is important to recognize this entity early in life as a significant percentage of cases respond to pyridoxine thus avoiding any long-term complications.
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Gupta SK, Rao S, Kar R, Tyagi S, Pati HP. Congenital sideroblastic anemia: A report of two cases.Indian J Pathol Microbiol 2009;52:424-426
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Gupta SK, Rao S, Kar R, Tyagi S, Pati HP. Congenital sideroblastic anemia: A report of two cases. Indian J Pathol Microbiol [serial online] 2009 [cited 2019 Sep 18 ];52:424-426
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Sideroblastic anemia is a heterogeneous group of disorders characterized by the presence of ring sideroblasts in the bone marrow.  It comprises of acquired and congenital forms. Acquired type has been further classified into idiopathic, secondary, and reversible groups. Congenital sideroblastic anemia is a rare condition with clinical and genetic heterogeneity. The most frequent form is X-linked, caused by mutations of delta-aminolevulinic acid synthase 2 (ALAS2).  However, autosomal recessive, dominant, and mitochondrial pattern of inheritance have also been documented. It is important to recognize this entity early in life as around 75% cases may respond to pyridoxine thus avoiding any long-term complications. We present two cases of congenital sideroblastic anemia with their clinico-hematological profile.
A 1.5 year-old-male child presented in the outpatient department of hematology with complaints of pallor since birth. The child required frequent hospital admissions due to severe pallor and had been receiving blood transfusions every two to three months starting since two months of age. There was no history of jaundice, fever, bleeding episodes or swelling anywhere in his body. There was no history of any drug intake. The patient belonged to a Punjabi family and ancestors of both parents had migrated from Pakistan. However, the parents, elder sister and brother were normal. There was no history of consanguinity. On examination, severe pallor and frontal bossing were noted. There was no icterus, cyanosis, clubbing or lymphadenopathy. Liver was palpable 4 cm below costal margin and spleen was not palpable. The milestones were normal for age. There was no ataxia. The respiratory and cardiovascular system examination was normal. Previous record of investigations revealed the lowest documented hemoglobin (Hb) to be 2.4 g/dl. The results of hemogram at presentation and other investigations have been summarized in [Table 1].
On the basis of history of transfusion dependent anemia and geographical origin, possibility of thalassemia major was considered although spleen was not palpable. A pre-transfusion high performance liquid chromatography (HPLC) revealed normal results with no fetal hemoglobin (HbF). HPLC of both parents was also normal. The family screening for silent b-thalassemia mutations by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and common alpha thalassemia mutations (α -3.7 , α-4.2 deletions) by Gap-PCR was negative. The various other possibilities then considered were pure red cell aplasia (PRCA), congenital dyserythropoietic anemia (CDA), and enzymopathies.
Bone marrow examination showed normal cellularity, myeloid to erythroid ratio (M:E ratio) of 1:1 with normoblastic erythroid maturation [Figure 1]. There was no significant dyserythropoiesis. Myeloid and megakaryocytic series were within normal limits. Prussian blue staining (Perl's stain) showed increased iron stores (Grade IV) with presence of ring sideroblasts in 80% of erythroid precursors [[Figure 1], inset]. A molecular analysis or enzyme levels of ALA synthase could not be done. A final diagnosis of congenital sideroblastic anemia was suggested and the patient was started on 40 mg oral pyridoxine per day. There was a rise in hemoglobin level from 5.7 to 6.7 g/dl in first three weeks of treatment and the patient is still under follow up.
A 2 year-old-male child presented with complaints of progressive pallor since birth. He had received multiple blood transfusions in last 1.5 years. There was no history of fever or bleeding episodes. There was no jaundice or swelling anywhere in the body. The twin sister of the patient also had similar problem of transfusion dependent anemia, however, the elder brother and parents were normal. One fetal loss had been documented previously. There was no history of consanguinity in the family. On examination, severe pallor was noted. There was no icterus, cyanosis, clubbing or lymphadenopathy. Liver was palpable 3 cm below costal margin and spleen was not palpable. The respiratory and nervous system examination were normal and cardiovascular system examination revealed the presence of ejection systolic murmur. There was a developmental delay with absence of new milestones after one year of age.
The results of hemogram and other investigations have been summarized in [Table 1]. The bone marrow revealed normoblastic erythroid hyperplasia (M: E ratio 1:4) with prominent cytoplasmic fraying and deep basophilic cytoplasm of late normoblasts. Perl's staining revealed increased iron stores and presence of ring sideroblasts in 50% of erythroid precursors. So, a diagnosis of congenital sideroblastic anemia was suggested. The patient has been put on 40 mg oral pyridoxine per day and is under follow up. The marrow examination of affected twin sister was also advised as her hemolytic work-up including HPLC, glucose-6-phosphate dehydrogenase (G6PD) assay, Coombs test, and incubated osmotic fragility test (OFT) was normal.
Congenital sideroblastic anemia is characterized by the presence of ringed sideroblasts in erythroid precursors, usually hypochromic erythrocytes and variable degrees of iron overload.  The severity of anemia, age of presentation, and the response to high dose pyridoxine are variable.
Congenital sideroblastic anemia was first described by Cooley  in 1945. It is rare and characterized by heterogeneous patterns of inheritance. The most frequent form is X-linked sideroblastic anemia (XLSA), caused by mutations of ALAS2. It may rarely show autosomal dominant, recessive or mitochondrial pattern of inheritance.  The anemia occurs primarily in males, however, sporadic and familial cases have been described that affect only females, possibly due to skewed X-chromosome inactivation affecting the normal allele for the ALAS2 gene.  Our second case and his twin sister had a history of transfusion dependent anemia since birth, however, other siblings and parents were normal indicating an autosomal recessive inheritance. Previously, only two case reports of congenital sideroblastic anemia have been described from India, however all three patients (one female and two male patients) described were isolated sporadic cases. ,
ALAS2 catalyses the first and regulatory step of haem synthesis in erythroid precursors. Impaired haem production due to ALAS2 deficiency results in variable degrees of microcytic hypochromic anemia and excess mitochondrial iron manifests as ringed sideroblasts. The excess non-haem iron deposited in the cell may act as a toxin resulting in ineffective erythropoiesis. The heterogeneity and complexity of sideroblastic anemia is explained by an increasing number of recognized molecular defects like mitochondrial proteins involved in iron-sulphur cluster biogenesis, such as ABCB7 (ATP-binding cassette, sub-family B, member 7) and GLRX5 (Glutaredoxin 5). 
Bone marrow examination shows erythroid hyperplasia with poorly developed cytoplasm in erythroid cells and fraying of cytoplasmic margins as found in our cases also. At times, it may result in morphological resemblance to lymphoid cells. We also faced this diagnostic confusion in one of our case but examination of more marrow slides and the iron stain helped in delineating the erythroid cells properly as well as revealed the presence of many ringed sideroblasts. This emphasizes the role of a thorough morphological evaluation of the slides along with the importance of a simple procedure like Iron stain which may be very useful in clinching the correct diagnosis. Local mitochondrial iron overload is present in all sideroblastic anemias, whereas systemic iron overload occurs only in primary or secondary deficiency of ALAS2. 
In many families, co-inheritance of other X-linked traits (e.g., G6PD deficiency, ataxia with sideroblastic anemia) has been described. Rarely, patients may present as an autosomal recessive disorder having a triad of thiamine dependent megaloblastic anemia, diabetes mellitus, and neural deafness. Another rare congenital mitochondrial disorder is Pearson's syndrome in which the bone marrow shows prominent vacuolization of precursor cells. In our patients, there was no ataxia, diabetes mellitus or sensorineural deafness. G6PD assay was normal and bone marrow did not show any vacuolization of marrow cells ruling out the associations described above.
Anemia may respond to oral pyridoxine to variable degree in around 75% cases of congenital sideroblastic anemia due to ALAS2 defects,  hence the name 'pyridoxine-responsive anemia' was used previously. In comparison, pyridoxine response is uncommon in acquired cases. We had earlier reported two cases of pyridoxine responsive sideroblastic anemia; one acquired idiopathic type and the other secondary to alcohol.  Pyridoxine (pyridoxal phosphate) is an essential cofactor for ALAS. In addition, it has been shown to enhance ALAS activity by stabilizing ALAS during folding of the mutant enzyme after its synthesis.  The standard treatment consists of 50-100 mg/d with use of higher doses occasionally. Maintenance therapy with low dose pyridoxine is advocated for the responders to maintain an adequate pool of pyridoxal phosphate and prevent recurrence of anemia. Regular blood transfusion support may be required by those patients having partial response or not responding at all to pyridoxine. Bone marrow transplantation has also been tried in few cases of severe sideroblastic anemia in children not responding to pyridoxine.
Ringed sideroblasts have also been described in cases of myelodysplastic syndromes (MDS) where the porphyrin ring synthesis is unaffected unlike congenital sideroblastic anemias. The possible mechanism offered in cases of MDS is mitochondrial respiratory chain defect rather than ALAS which results in unavailability of iron in ferrous form for haem synthesis. [9,10] So, MDS cases with ring sideroblasts like refractory anemia with ring sideroblasts (RARS) are unlikely to respond to pyridoxine therapy.
The differentiation of congenital sideroblastic anemia from other causes of microcytic hypochromic anemia in this age group like thalassemia and iron deficiency anemia is based on Hb-HPLC or Hb electrophoresis, serum iron studies, and bone marrow examination. A simple bone marrow iron stain (Perl's stain) should be done and screened for ring sideroblasts in all such cases with non contributory HPLC or Hb electrophoresis and serum iron studies. The early detection of these cases may lead to early institution of pyridoxine which may be therapeutic in many cases of congenital sideroblastic anemia and prevent long-term complications of anemia.
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