Clinical features and studies of erythropoiesis in Israeli Bedouins with congenital dyserythropoietic anemia type I

Congenital dyserythropoietic anemia (CDA) type I is a rare macrocytic anemia of unknown etiology. In the present study, we redefined the clinical and laboratory picture of CDA type 1, some of its pathogenic aspects, and the association with thalassemia-like features in 20 patients, all of whom belong to one Bedouin tribal group and are probably descended from a common ancestor. In each case ultrastructural studies of bone marrow (BM) erythroblasts showed the classic morphological findings of CDA type 1. Serological tests for CDA type II were negative. The clinical picture was variable, but mostly benign. Some patients displayed elevated hemoglobin A2 levels or a high ratio of a-to non-a ONGENITAL dyserythropoietic anemias (CDAs) are a C rare group of red blood cell (RBC) disorders of unknown etiology characterized by ineffective erythropoiesis, pathognomonic cytopathology of the nucleated RBCs in the bone marrow (BM) and secondary hemochromatosis. In 1968, Heimpel and Wendtl classified these disorders into three types, which were later confirmed by electron microscopy and serological findings.' Type I is characterized by congenital macrocytic anemia, megaloblastoid erythroid hyperplasia, and the presence of nuclear chromatin bridges between erythroblasts. More than 60 sporadic cases of CDA type I have been reported in the literat~re.~" The typical morphological ultrastructural studies accompanied by negative acidified serum lysis and adult i/l agglutination test constitute the major diagnostic features. The more common type 11, also known as hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS): is characterized by normocytosis or macrocytosis with binucleated and multinucleated marrow erythroblasts and karyorrhexis. Type 111 is manifested by macrocytosis and erythroblastic multinuclearity with prominent gigantoblask3 More than 30 documented cases could not be clearly assigned to type I, 11, or III.3 Type IV was the classification used in four reports in which BM morphology resembling that in type I1 was accompanied by negative acid serum tests5 CDA in association with thalassemia has been described in 17 patients.'.' Members of more than a dozen other families had CDAs that were even more difficult to cla~sify.~ Anselstetter et a19 in 1977 were the first to report that band 3 glycoproteins from HEMPAS erythrocyte membranes migrate faster than those obtained from normal erythrocyte membranes. Reduced levels of N-glycans in HEMPAS erythrocyte membranes with low N-acetylglucosaminyltransferase I1 activity have been documented in some patients," and a defect in the a-mannosidase I1 gene was reported in one patient." Faulty glycosylation of transfemn, a glycoprotein produced in the liver, has also been described.I2 The molecular basis for the defects in other CDAs is not known. In the following study, we describe 20 patients with CDA type I who belong to seven Bedouin families living in the Negev (the southern part of Israel). The aim of the study was to redefine the clinical and laboratory characteristics of globin. However, neither family studies nor complete sequence analysis of the p-globin was compatible with pthalassemia. Increased erythropoiesis was manifested by a high number of BM erythroid burst-forming units. Serum erythropoietin was also elevated. BM flow cytometry studies demonstrated arrest of erythroid precursors in the S phase of the cell cycle. The ultrastructural morphological features of the erythroid precursors, showing peripheral chromatin condensation, suggest apoptosis. AddiCional studies are indicated to define the molecular basis of this disease. 0 1996 by The American Society of Hematology. CDA type I in this homogeneous population in an attempt to clarify the pathogenesis of the disorder and its association with thalassemia. MATERIALS AND METHODS Twenty patients (14 men, 6 women), aged 1 to 23 years (median, 10 years) from seven families were evaluated. Three patients were originally diagnosed and followed at our center, and the medical records of the 11 patients followed for anemia at the Soroka Medical Center in Beersheva were reviewed. Six additional patients were identified in the course of family studies. Each of the 20 patients underwent a complete physical examination. Bone age was determined in six patients. Control BM samples for culture studies and flow cytometry studies were obtained from healthy children who were donors for BM transplant. &thalassemia major BM samples were obtained at diagnosis. The following blood and BM examinations were performed for each patient.