Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ Congenital dyserythropoietic anemias (CDA) are a heterogeneous group of disorders characterized by anemia, the presence of multinuclear erythroid precursors in the marrow, ineffective erythropoiesis, and iron overload. Although rare, uncovering the molecular basis of CDA has helped unravel novel aspects of the cell biology of erythropoiesis. Three types of CDA have been distinguished. In addition, a number of patients with forms of congenital dyserythropoietic anemia that do not fit these categories have been described. + CDA TYPE I Download Section PDF Listen +++ +++ Clinical and Laboratory Features ++ Presents in infancy or adolescence. Autosomal recessive inheritance, caused by mutations of the CDAN1 gene (codanin-1), encoding a cell-cycle-regulated protein of yet unknown function; homozygosity is often associated with consanguinity. In a number of patients, only one CDAN1 allele is identified with a mutation; other causative genes suspected because in rare CDA I families, no mutations of the CDAN1 gene found. Moderately severe macrocytic anemia (approximately 9.0 g/dL). Hepatomegaly and cholelithiasis are common. Splenomegaly increases with age. Specific morphologic findings of CDA type I are summarized in Table 7–1 and exemplified in Fig. 7–1. Dysmorphologic features may be present, the most common involve the bones of the hand and the foot. Other, less common features are small stature, almond-shaped blue eyes, hypertelorism (increased distance between two body parts or organs), and micrognathism. ++Table Graphic Jump LocationTABLE 7–1MAIN FEATURES OF TYPES I, II, AND III CONGENITAL DYSERYTHROPOIETIC ANEMIASView Table||Download (.pdf) TABLE 7–1 MAIN FEATURES OF TYPES I, II, AND III CONGENITAL DYSERYTHROPOIETIC ANEMIAS CDA Type Light Microscopy Electron Microscopy Serology Inheritance I Most erythroid cells abnormal: double nuclei, internuclear chromatin bridges (Fig. 7–1) Widened nuclear pores, spongy appearance of the heterochromatin, invasion by the cytoplasm containing various organelles No serologic abnormalities Autosomal recessive II Mature stage erythroblasts with two or more nuclei, lobulated nuclei, karyorrhexis, pseudo-Gaucher cells (Fig. 7–1) Endoplasmic reticulum cisternae lining the inner surface of the red cell plasma membrane Cells containing the HEMPAS antigen are lysed by 30% of acidified normal sera; strong reactivity with anti-"i" autoantibodies Autosomal recessive III Giant erythroblasts, up to 50 μm in diameter, with up to 12 nuclei, basophilic stippling Clefts and blebs within nuclear areas, some iron-filled mitochondria, autophagic vacuoles and myelin figures in the cytoplasm No clearly defined abnormalities Autosomal dominant (not all cases) Source: Williams Hematology, 8th ed, Chap. 39, Table 39–1, p. 514. ++ FIGURE 7–1 Light microscopy of marrow. A. Congenital dyserythropietic anemia type I. Note the intranuclear chromatin bridge marked by an arrow. This bridge is unusually long. B. Congenital dyserythropietic anemia type II. The two arrows point to binucleate erythroblasts, characteristic of this type. (Used with permission from Dr. Odile Fenneteau.) (Source: Williams Hematology, 8th ed, Chap. 39, Fig. 39–2, p. 515.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ Differential Diagnosis ++ May be confused with the thalassemia syndromes because of similar blood findings and evidence of ineffective erythropoiesis. Megaloblastoid marrow findings may suggest folic acid or vitamin B12 deficiency. +++ Treatment ++ Severe forms may present with hydrops fetalis. In some cases, intrauterine red cell transfusions are warranted by the severity of the anemia. Red cell transfusions for long-term therapy should be avoided whenever possible because of the risk of iron overload. In compensated moderate anemia, small volume, regular phlebotomies, if tolerable, or chelating agents may be beneficial for iron overload. + CDA TYPE II (HEMPAS) Download Section PDF Listen +++ ++ Type II CDA is also known by its acronym HEMPAS for Hereditary Erythroblastic Multinuclearity associated with a Positive Acidified Serum test. +++ Clinical and Laboratory Features ++ Autosomal recessive inheritance, due to mutations in SEC23B, the gene encoding a protein component of the coat protein complex II (COPII). COPII is responsible for the biogenesis of endoplasmic reticulum-derived vesicles destined for the cis-Golgi compartment. These protein complexes are thought to be the primary determinants underlying deformation of membranes into vesicles. Anemia varies from mild to severe. Moderate-to-marked anisocytosis and poikilocytosis, anisochromia, and contracted spherocytes are present in the blood film. Gaucher-like cells and ring sideroblasts may be present in the marrow (Table 7–1). Multinuclearity of red cell precursors is a morphologic hallmark (Fig. 7–1). Body iron stores are increased and frank hemochromatosis may occur even in the absence of transfusions. +++ Treatment ++ Red cell transfusions may be necessary; iron chelation should be instituted when the ferritin level exceeds 500 to 1000 μg/L. Partial benefit may be obtained with splenectomy. Marrow transplantation has been used in few patients. + CDA TYPE III Download Section PDF Listen +++ +++ Clinical and Laboratory Features ++ Autosomal dominant inheritance due to an as yet unidentified mutation that maps to chromosome 15q22-25. Most patients are asymptomatic with mild to moderate anemia, mild jaundice and, commonly, cholelithiasis. Some macrocytes may be extremely large ("gigantocytes"), and poikilocytes are present; the marrow has marked erythroid hyperplasia, with large multinucleate erythroblasts with big lobulated nuclei, and giant multinucleate erythroblasts (Table 7–1). +++ Treatment ++ Generally, none is needed. One symptomatic patient benefited from splenectomy. ++ For a more detailed discussion, see Jean Delaunay: The Congenital Dyserythropoietic Anemias. Chap. 39, p. 513 in Williams Hematology, 8th ed.