Congenital dyserythropoietic anemia type I: First report from the Congenital Dyserythropoietic Anemia Registry of North America (CDAR)

Abstract

Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and distinctive erythroblast abnormalities; the diagnosis is often missed or delayed due to significant phenotypic heterogeneity. We established the CDA Registry of North America (CDAR) to study the natural history of CDA and create a biorepository to investigate the pathobiology of this heterogeneous disease. Seven of 47 patients enrolled so far in CDAR have CDA-I due to biallelic CDAN1 mutations. They all presented with perinatal anemia and required transfusions during infancy. Anemia spontaneously improved during infancy in three patients; two became transfusion-independent rapidly after starting interferon-α₂; and two remain transfusion-dependent at last follow-up at ages 5 and 30 y.o. One of the transfusion-dependent patients underwent splenectomy at 11 y.o due to misdiagnosis and returned to medical attention at 27 y.o with severe hemolytic anemia and pulmonary hypertension. All patients developed iron overload even without transfusions; four were treated with chelation. Genetic testing allowed for more rapid and accurate diagnosis; the median age of confirmed diagnosis in our cohort was 3 y.o compared to 17.3 y.o historically. In conclusion, CDAR provides an organized research network for multidisciplinary clinical and research collaboration to conduct natural history and biologic studies in CDA.

Keywords: Anemia; CDAN1; Congenital dyserythropoietic anemia; Erythropoiesis; Rare disease registry.

Figure 1.. The general characteristics of CDAR participants.

(A) Cumulative enrollment on CDAR by year. The proportion of affected individuals, family members, and misdiagnosed participants is shown in each year. (B) The distribution of CDA subtypes based on genetic results in the 38 affected individuals with CDA in CDAR.

Figure 2.. Peripheral blood and bone marrow abnormalities in CDA-I.

(A) Peripheral blood smear of CDA-I patient showing marked anisopoikilocytosis, RBC fragmentation and basophilic stippling (inset). (B) Bone marrow biopsy (H&E, 400x) showing erythroid hyperplasia in a patient with CDA-I. (C) Bone marrow aspirate (100x) demonstrating binucleated erythroblast (arrow). The lower inset shows erythroid cells with a chromatin bridge, and the upper inset showing nuclear lobation. (D) Electron microscopy image of erythroblasts in CDA-I showing the characteristic “spongy” or “swiss cheese” appearance of nuclear heterochromatin and widened pore membrane dilations (arrow in inset).