Indian Pediatrics 2003; 40:551-555
Congenital Dyserythropoietic Anemia: Clinical and Hematological Profile
From the Division of Pediatric Hematology-Oncology, Advanced Pediatric Center, *Department of Hematology, Postgraduate Institute of Medical Education and Research, and +Department of Hematology and Blood Transfusion, Government Medical College Hospital, Chandigarh, India
Correspondence to: Dr. R. K. Marwaha, Professor of
Pediatrics, Incharge, Division of Pediatric Hematology-Oncology,
Advanced Pediatric Center, PGIMER, Chandigarh 160 012, India.
Abstract: Congenital dyserythropoietic anemia (CDA) is a rare disorder, which manifests clinically with varying degrees of anemia and hepatosplenomegaly. These features are not pathognomic and a diagnosis of CDA is generally considered after other causes of chronic hemolytic anemia have been ruled out. The clinico-hematological profile of 10 patients with CDA is presented in this communication. Six patients had CDA type II and four had CDA type I. Age at onset of pallor ranged from birth to 9 years. Blood transfusion requirements varied from nil to monthly. This is the first report of CDA type I from India.
Key words:Congenital dyserythropoietic anemia (CDA).
Congenital dyserythropoietic anemias (CDA) are familial disorders, characterized by the association of refractory anemia and ineffective erythropoiesis with multi-nuclearity and karyorrhexis(1). CDAs are rare, with only a few hundred cases having been reported worldwide(2). Three types of CDA, designated types I, II and III, have been identified on the basis of morphological and serological characteristics. As the clinical and laboratory findings are not distinctive, it is believed that CDA is often under-diagnosed(3). We share our experience of managing children with CDA through this communique.
Subjects and Methods
Case records of patients diagnosed with CDA were reviewed to determine the clinical manifestations and hematological parameters. The common causes of hemolytic anemia were ruled out in a stepwise manner before undertaking a bone marrow examination. Thalassemia, autoimmune hemolytic anemia, glucose-6-phosphate dehydrogenase defici-ency, hereditary spherocytosis, unstable hemoglobin disorder and pyruvate kinase deficiency were ruled out by hemoglobin electrophoresis, direct Coombs test, methy-lene blue reduction test, osmotic fragility test, heat instability and auto-hemolysis test. A therapeutic trial with folate and vitamin B12 helped to rule out megaloblastic anemia. If the bone marrow aspirate and trephine bone biopsy findings were consistent with a diagnosis of CDA, acidified serum lysis test (Ham’s test) was performed, to identify CDA type II. In patients with positive Ham’s test, paroxysmal nocturnal hemoglobinuria was excluded by performing the Ham’s test with homologous sera and by the sucrose lysis test. Erythrocyte agglutinability and lysis to anti-i and anti-I sera was not tested, due to non-availability of the reagent. Screening for gallstones was done by ultrasonography of the abdomen.
A total of 10 children with CDA were identified in the period from 1991 to 2001. The clinial features and relevant investiga-tions are illustrated in Tables I and II. Based on investigations, six patients were cate-gorized as CDA type II, whilst four patients had CDA type I. The median age at presentation to the institution was 39 months, whilst the first symptom manifested at a median age of three months. The median interval between onset of pallor and presentation was 10 months (range: 1-70). Five (50%) patients belonged to ‘Aggarwal’ caste and two (20%) to ‘Jain’. A history of consanguinity (first cousin) was obtained in two patients, both of whom were Mohammedans. Direct questioning failed to elicit a history of similar manifestations in relatives and family members.
Table I Clinical Features of Patients with Congenital Dyserythropoietic Anemia.
Table II Investigative Profile of Patients with CDA.
All patients had presented with varying degrees of pallor and hepatosplenomegaly. Total and differential leucocyte counts and platelet counts were within the normal ranges in all patients. The peripheral blood smear examination revealed varying degrees of anisocytosis, poikilocytosis, hypochromia and tear drop cells. The cellularity of marrow on trephine biopsy ranged from normo to hyper-cellular. Erythroid hyperplasia was striking. Dyserythropoiesis was evident as multinuclearity, nuclear budding and megalo-blastosis of mature erythroblasts. Giganto-blasts, characteristic of CDA type III, were not observed in our patients. Internuclear bridging of erythroblasts was present in three patients, one of whom was CDA type II. Granulo-poiesis and thrombopoiesis were normal. Prussian blue staining (Perl’s reaction) on aspirated bone marrow particles, revealed iron stores to be normal to increased. Absence of ring sideroblasts excluded sidero-blastic anemia. No skeletal abnormalities of limbs were observed. USG of abdomen did not reveal gallstones. The patients were regularly followed up for a median duration of 20 months (range: 1-120).
Of the three types, CDA type II is the commonest, identfied by positive Ham’s test and multinucleated erythroblasts. CDA type I is characterized by binuclearity and inter-nuclear chromatin bridging of erythroblasts. CDA type III is the rarest, and is identified by giant erythroblasts, with up to 12 nuclei-the gigantoblasts(1). Few rarer type of CDA have also been identified, which do not fit into the common three types(1). The pathogenesis of CDA is more clearly known for type II than for others. There is a defect in the enzymatic glycosylation of membrane proteins. Band 3 glycoprotein, which plays an important role in the organization of cytoskeleton, is abnormal. This in part accounts for the disrupted membrane structure of erythroblasts; a feature characteristic of the disease(1,4). The end result is an increased rate of phagocytosis of abnormal erythroblasts by bone marrow macrophages.
The diagnosis of CDA is often made during childhood, though there is no age limit. It can have an intra-uterine onset with severe anemia, resulting in cardiac failure or the disease may remain undiscovered until late adult life(5,6). The patients in our study had a wide range in the age at first presentation. Anemia in CDA is often mild to moderate; 15% of patients with CDA type I and II are reported to be transfusion dependent(7). Blood transfusion requirements of our patients varied from none to once in 4 weeks.
CDA I and II are autosomal recessive disorders and family members of affected children should ideally be screened. However family history suggestive of anemia was stoutly denied. Inspite of active motivation, relatives and family members failed to report for investigations, possibly because they were asymptomatic. Significantly, our cases appeared to belong to two particular castes. Originally thought to be concentrated in the Baltic and Mediterranean basin region, CDA’a have now been diagnosed in patients of diverse ethnicity in America, Africa, Australia and Asia(2). Whether CDA is more commonly found in the ‘Baniya’ and ‘Jain’ community in India can only be known when more such cases are reported.
The principal clinical manifestations include hepatosplenomegaly, variable degree of jaundice and hemolytic facies. These features are common to a number of hemolytic and dyserythropoietic anemias. A diagnosis of CDA is considered only after exclusion of these(3). There are reports of dysmorphic features, patches of brown skin pigmentation, syndactyly and abnormality of nails and ribs in patients with CDA type I(8). None of our patients with CDA type I had somatic malformations.
The mean reticulocyte count was 2.3%. Reticulocyte counts in CDA are typically normal to slightly increased(3). In fact, dyserythropoiesis is suspected when there is sub-optimal reticulocyte response for the degree of anemia, in the face of erythroid hyperplasia in the marrow. The erythrocytes of patients with CDA type II are lysed in the acidified serum lysis test (Ham’s test) by about 30% of fresh ABO-compatible normal sera, but not the patient’s serum. Conse-quently, CDA type II is also described as hereditary erythroblastic multinuclearity with a positive acidified serum lysis test (HEMPAS)(9). Ham’s test was positive in six (60%) of our patients. To obtain a statistically reliable result, Boogaert et al.(10) have recommended that the patient’s red cells must be reacted against 30 normal sera. The number of sera used in the index study was four. Reclassification of patients to CDA type II is known, due to insufficient number of sera being used in the initial Ham’s test(11). Internuclear chromatin bridges, which connect partially separated erythroblasts are characteristic of CDA type I, though they rarely may be found in other CDA types(3). One patient with CDA type II had internuclear chromatin bridges in our study.
Serum ferritin levels were high in all the three patients tested for it; two of them had received blood transfusions occasionally while one had never received a transfusion. Secondary hemochromatosis is a known late complication of the illness(12). Even in the absence of blood transfusions, hyper-absorption of iron from the gastrointestinal tract leads to iron over load. Chelation therapy forms an important part of management of patients with CDA(3).
In the first report of patients with CDA from India, Pati et al. described six patients with CDA type II(13). Prasher et al.(14) have reported a 30-year-old female with CDA type II, who had onset of symptoms at nine years of age. To the best of our knowledge, CDA type I has not been reported from India so far.
Treatment consists of blood transfusion, tailored to individual needs. Folate is prescribed to support increased requirements, secondary to erythroid hyperplasia. Iron therapy is almost always contraindicated, because of the strong predisposition of patients to iron overload. A proportion of patients with CDA type II have benefited from splenectomy. Recently, interferon therapy has shown promise in CDA type I(6,15). Bone marrow transplantation is a potential option for transfusion dependent patients; there is at least one report of successful bone marrow transplant in a patient with CDA(16).
The considerable time gap between the onset of symptoms and reporting to a tertiary care center indicates that the disease is often suspected and diagnosed late. There is obviously a need for enhancing awareness of CDA amongst the pediatricians, physicians and pathologists, so that a larger number of cases of ‘difficult anemias’ are investigated for it. Establishing a diagnosis early will help in enhancing the quality of life. Moreover, diagnosing CDA is no longer an exercise in futility because besides transfusion and iron-chelation, bone marrow transplant, interferon therapy and splenectomy could be suggested, as these have been reported to be beneficial.
Contributors: RKM, AT and DB participated in the hematology clinic. DB collected the data and drafted the paper. GG and NM reported the hematological investigations. RKM will act as guarantor for the paper. All contributed in the review of the manuscript.
Competing interests: None stated.