Clinical And Laboratory Observations
Congenital dyserythropoietic anemia (CDA) is a rare hematologic disorder characterized by dyserythropoietic features, ineffective erythropoiesis, and secondary hemochromatosis. It is classified into types 1, 2, and 3, along with some variants (1,2). Congenital dyserythropoietic anemia type 1 is characterized by autosomal recessive inheritance and a macrocytic anemia with dyserythropoietic features such as megaloblastoid changes, multinuclearity, and internuclear chromatin bridges (1[ndash]4). On ultrastructural study, the dyserythropoietic cells showed characteristic findings such as spongy chromatin and disruption of the nuclear envelope (1[ndash]4). A recent study has revealed that the gene for CDA type 1 is located on 15q15.1[ndash]q15.3, but no distinct responsible gene has been identified (5). An association with characteristic skeletal anomalies, including anomaly of distal extremities outside the radial ray, has been reported (1,6,7). It has been demonstrated that most patients with CDA type 1 have mild to moderate anemia during the neonatal period (1,6). We present a patient with CDA type 1 who had severe anemia develop during the fetal period resulting in cardiac failure and death.
The patient was born to nonconsanguineous, healthy parents without a family history of anemia. The mother, gravida 3, para 2, had a stillbirth of unknown cause at 38 weeks gestations. The mother's elder brother and elder sister died from congenital heart disease and neuroblastoma at 2 and 7 years old, respectively. The mother was admitted to our hospital at 26 weeks gestation because echography revealed fetal myocardial hypertrophy.
A girl was delivered transvaginally at 34 weeks of gestational age because of premature contraction. The neonate had anemia, asphyxia, and Apgar scores of one at 3 minutes and one at 5 minutes. She weighed 1,572 g ([minus]1.4 standard deviation) and measured 39.0 cm ([minus]2.1 standard deviation). There were multiple anomalies, including nail hypoplasia/aplasia and syndactyly of the feet (Figs. 1A and B). Skeletal radiogram revealed flattened vertebrae, narrow iliac bone, loss of distal phalanges of the right foot, and loss of fourth and fifth distal phalanges of the left foot. Peripheral blood revealed severe anemia with erythroblastemia, macrocytosis, and dyserythropoietic features with internuclear chromatin bridges (hemoglobin[colon] 4.8g/dL, red blood cell count[colon] 1.21 [times] 106/[mgr]L, hematocrit[colon] 15.9[percnt], mean corpuscular hemoglobin concentration[colon] 30.0[percnt], mean corpuscular volume[colon] 131.2 fL, white blood cell count[colon] 30,800/[mgr]L, platelet count[colon] 203 [times] 103/[mgr]L, reticulocyte[colon] 7.4[percnt], reticulocyte absolute count[colon] 89.5 [times] 103/[mgr]L) (Figs. 2A and B). Echocardiography showed severe cardiac dysfunction with myocardial hypertrophy. Although her general condition became stable with intensive care and exchange transfusion, mechanical ventilation and regular transfusions were necessary until the patient's death.
Abnormal erythroblasts gradually decreased in number and completely disappeared from the peripheral blood. Subsequently, her reticulocyte count did not increase (0.2[percnt][ndash]0.7[percnt]) even when her hemoglobin value was at its lowest level. Bone marrow aspiration at age 19 days showed mild dyserythropoietic findings with scattered binuclear erythroblasts (nuclear cell count[colon] 43,500/[mgr]L, myeloblast[colon]erythroblast ratio [equals] 2.06). No ringed sideroblasts or dysplastic features on the granulocytic/megakaryocytic lineage were seen. Mild jaundice was noted (maximum value[colon] 2.7mg/dL). Because anemia was so severe, erythropoietin was administered from day 21. Subsequent bone marrow aspiration at age 32 days and 82 days revealed megaloblastoid erythroblasts with binuclearity or trinuclearity and occasional internuclear chromatin bridges, which were interpreted as an erythropoietin effect. Because erythropoietin administration resulted in no improvement of anemia, it was terminated at age 111 days. Chromosome analysis demonstrated a normal female karyotype. Hemoglobin F level, acidified serum lysis, and osmotic fragility were within normal range. Metabolic disorders and congenital infection were excluded by extensive laboratory examination. Although dysmorphic features suggested anemia associated with a syndrome or CDA type 1, no definite diagnosis was obtained. At age 7 months, the patient had a respiratory infection with subsequent pulmonary hypertension and hemorrhage. The patient died at age 228 days.
AUTOPSY AND PLACENTAL FINDINGS
Autopsy was performed approximately 12 hours after death. The anemic body was small for age (weight 4,700 g), and had multiple anomalies as mentioned previously. The heart was hypertrophic (53.7 g, standard value for weight[colon] 42 g) and the lung was solid, congestive, and partially hemorrhagic. Histologically, the lung demonstrated diffuse congestion, hemorrhage, and bronchopneumonia. The heart showed nonspecific myocardial hypertrophy. Extramedullary hematopoiesis was observed in the liver and spleen. Iron staining revealed mild hemosiderosis in the liver and the pancreas. The bone marrow was hypercellular and showed mild erythroblastic hyperplasia with megaloblastoid changes, and 4[percnt] to 5[percnt] of the entire erythroblasts demonstrated binuclearity with rare trinuclearity or tetranuclearity. No giant erythroblasts were present. Electron microscopy showed disruption of the nuclear envelope, cytoplasmic indentation within the nuclear area, and spongy appearance of the chromatin in the erythroblasts of the bone marrow (Figs. 3A and B). No dysplastic features were observed in the granulocytic/megakaryocytic lineage by light or electron microscopy. These findings and characteristic dysmorphic features were consistent with CDA type 1 (1,3,4,7). Review of the placental histology showed aggregates of binuclear erythroblasts in the villous capillaries, suggesting fetal onset of the disease (8).
This patient with CDA type 1 had severe anemia during the fetal period, accompanied by fetal cardiomegaly and heart failure. Antenatal onset of the disease was also confirmed by histology of the placenta that showed nuclear erythroblasts with dysplastic features in the villous capillaries (8). Recent surveys reveal that symptoms of CDA type 1 cases often developed in the neonatal period, but they improved during the patient's first year of life (1,6). Manifestation of congestive heart failure is rare (1,6). Antenatal onset and early neonatal presentation of cardiac insufficiency associated with severe anemia has not been reported in CDA type 1, although stillbirth or neonatal death has been described in other types of CDA (9[ndash]11). The stillborn infants or neonates who died from unspecified CDA manifested severe anemia and myocardial hypertrophy, similar to the case described in this article. Further investigation is required to clarify the clinical course of CDA type 1.
Differential diagnosis included thalassemia, some hemoglobinopathies, hereditary sideroblastic anemia, congenital myelodysplasia, and other forms of CDA (1). Congenital anemia such as Blackfan[ndash]Diamond anemia and Fanconi anemia also should be considered. Our patient showed prominent macrocytosis with dyserythropoiesis, commonly not observed in a case of thalassemia or hemoglobinopathy. No ringed sideroblasts or dysplastic features on the granulocytic/megakaryocytic lineage were seen. Acidified serum lysis was normal. Peripheral blood smears at initial presentation and the bone marrow histology at autopsy revealed internuclear chromatin bridges and erythroid hyperplasia with megaloblastoid changes and multinuclearity. No giant erythroblasts were observed. These findings all favored a diagnosis of CDA type 1 (1[ndash]4,7).
Furthermore, the skeletal anomalies supported the diagnosis. Although skeletal limb defects (radial ray deficiency or dysplasia) may occur in patients with Fanconi anemia and Blackfan[ndash]Diamond anemia (12[ndash]13), congenital dyserythropoietic anemia type 1 involves, if any, skeletons outside the radial ray (7), as seen in our patient. Finally, the ultrastructural findings of the erythroblasts were mostly diagnostic and confirmed the diagnosis of CDA type 1 (1[ndash]4,7).
Our patient had an unusual clinical course that made definite diagnosis difficult. Dyserythropoietic features were noted in the peripheral blood at birth, but the features disappeared gradually from the peripheral blood. Examination of bone marrow at age 19 days showed minimal dyserythropoietic features in contrast to the severity of the anemia. But after the administration of erythropoietin, dyserythropoietic features became prominent with no effect on anemia. It is difficult to completely explain these clinical findings.
Gradual disappearance of dyserythropoiesis in the neonatal period may be caused by transient suppression of erythropoiesis resulting from transfusion. It has been suggested that dysplastic erythroblasts demonstrate arrest of DNA synthesis and apoptotic features, indicating defects in proliferation and/or differentiation (14). Therefore, patients with severe disease may have relatively mild dysplastic features resulting from cell death. Furthermore, administration of erythropoietin, which induced proliferation/differentiation of erythroblasts (15), seemed to result in no improvement of anemia but instead possibly made dyserythropoietic features more prominent.
The final diagnosis of CDA type 1 was made by postmortem pathologic examination. Because the mother had had the stillbirth of unknown cause and CDA type 1 has autosomal recessive inheritance, it was necessary to confirm the diagnosis and to evaluate the risk for recurrence through genetic counseling. Histologic examinations, including electron microscopic study, of the peripheral blood, bone marrow, and placenta are desirable for differential diagnosis in a patient suspected of having congenital anemia (1,3,4).
We express great thanks to Professor Wickramasinghe and Dr. Yawata who reviewed the slides and gave us detailed comments on this case.
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Keywords:© 2001 Lippincott Williams & Wilkins, Inc.
Congenital dyserythropoietic anemia; Fetal onset; Congenital heart failure