Haematologica Journal of Hematology volume 85 – number 7 – July 2000

Haematologica 2000; 85:673-674 Editorial and Views

ditions characterized by dyserythropoiesis. In general Congenital dyserythropoietic the features of dyserythropoiesis, in terms of ineffec- anemias: a still unsolved puzzle tive erythropoiesis, should be demonstrated by sever- al criteria: bone marrow examination by light Dyserythropoiesis was the term used, for the first microscopy, ultrastructural features, assessment of time by Crookston et al. in 19661 and later by Heim- erythropoietic production and destruction, etc. Cer- pel and Wendt,2 to indicate a congenital defect in ery- tainly the main assessment method, and one which is thropoiesis. However this term now refers to any alter- easy to perform, is light microscopy. Morphologic ation of the normal differentiation-proliferation path- abnormalities include binuclearity and multinuclear- way of the erythroid lineage. It incorporates both mor- ity, internuclear bridging, asynchrony between nuclear phologic and kinetic aspects of erythropoiesis (ery- and cytoplasmic maturation and premature nuclear throid lineage failure) and recognizes that even when extrusion, nuclear budding, fragmentation and degen- erythroblasts are functionally abnormal some survive eration (karyorrhexis) and various abnormalities of and mature although their descendent erythrocytes mitosis. There are intercellular cytoplasmic connec- are likely to have a shortened life-span (hemolytic tions and abnormalities of the cytoplasm itself such aspects).3,4 Dyserythropoiesis appears to be a quali- as vacuolation, basophilic stippling and an excessive tative and a quantitative defect of erythropoiesis and amount of siderotic granules. Even normal erythro- occurs in a wide range of diseases embracing a num- poiesis when stressed in hemolytic anemias results in ber of conditions which primarily affect the nucleus or minor morphologic and other features of dyserythro- the cytoplasm of the erythroblasts or the environment poiesis. The use of the term should be restricted to in which erythropoiesis takes place. This could be a those conditions in which the features of dyserythro- physiologic condition (e.g. during the neonatal peri- poiesis are dominant or at least apparent and readi- od) or a disease (nutritional anemias, myelodysplas- ly demonstrable. tic syndromes, liver disease, paroxysmal nocturnal The first classification of CDA was revelaed to have hemoglobinuria, AIDS and malaria, post bone mar- limited applicability and in fact there were some cas- row transplantation and chemotherapy). The latter es of dyserythropoiesis which did not fulfill the strict could be the principal (congenital dyserythropoietic diagnostic criteria and thus new groups (groups IV- anemias, CDA) or a secondary characteristic (tha- VII) were defined. In the Wickramasinghe studies4 lassemia syndromes; unstable hemoglobins or thia- approximately one third of dyserythropoietic ane- mine-responsive anemias).3,4 mias are types other than I-III. Recently Wickramas- CDA comprise a group of hereditary disorders of inghe identifies four additional groups. However, it erythropoiesis characterized by ineffective erythro- is notewortly that each group may be genetically het- poiesis as the predominant mechanism of anemia erogeneous and that the group is proposed on the and distinct morphologic abnormalities of the basis of the common phenotypic appearance. majority of erythroblasts in the bone marrow. Heim- The three classical congenital forms of dyserythro- pel proposed classifying these disorders into three poiesis appear very different from each other, types.2 These first classical types (I-III) differ in bone although all having the unifying feature of morpho- marrow erythroid morphology as well in their inher- logically abnormal erythroblasts. In general they are itance pattern. This issue contains a complete review rare diseases: there were 126 cases of CDA-I, 179 of of the clinical and molecular aspects of CDA-III was CDA-II and 65 of CDA-III reported in the literature published by Sandstrom and Wahlin.5 in the period 1951 to 1999. Anemia is not usually One of the main problems of the CDAs was their severe enough to need intervention. However, during heterogeneity, both at clinical and genetic levels. This the first year of life or pregnancy, or in the case of is the consequence of the very large number of con- coinheritance of another congenital defect of ery-

Table 1. Classification and distinguishing features of congenital dyserythropoietic anemias (CDAs).

Type Clinical features Morphology Inheritance

I Anemia on neonatal onset; jaundice; splenomegaly; Megaloblastoid erythroid hyperplasia; nuclear bridges. Autosomal recessive rare syndactyly; common complication: hemochromatosis ME: spongy-appearing nuclei and invagination Locus: 15q15.1-15.3 of the cytoplasm in the nucleus

II Anemia; jaundice; splenomegaly; hemochromatosis; 2-4 nucleated late erythroblasts; Autosomal recessive gallstones karyorrhexis 20q11.2

III Anemia (mild to moderate); jaundice; gammapathy Giant multinucleated erythroblasts Dominant 15q22

Haematologica vol. 85(7):July 2000 674 editorials and views thropoiesis (such as β-thalassemia) the anemia may worsen and require transfusions. References Iron overload appears to be a very frequent compli- cation in CDA-I and II, but not in CDA-III. However 1. Crookston JH, Shalmon L, Wightman KJR. Congeni- generalizations on this last condition should be made tal dyserythropoietic anemia. Sydney: Abstract from XI with caution since they are heavily reliant on observa- Congress of the International Society of Hematology, tion made on the Vasterbotten family, in which dysery- 1966, p. 18. 2. Heimpel H, Wendt F. Congenital dyserythropoietic thropoiesis appeared as a part of a more general syn- anemia with karyorrhexis and multinuclearity of ery- drome (myeloma or monoclonal gammapathy; throblasts. Helv Med Acta 1968, 34:103-15. angioid streaks). Interestingly, involvement of other 3. Delaunay J, Iolascon A. Congenital dyserythropoietic tissues was also signaled in CDA-I: syndactyly in hands anemias. Clinics Hematol 2000 (in press). and/or feet; absence of the distal phalanges and nails. 4. Wickramasinghe, S. N. Congenital dyserythropoietic The serum thymidine kinase levels are greatly increased anaemias: clinical features, haematological morphol- in CDA-I as well as in CDA-III; these high values pre- ogy and new biochemical data. Blood Rev 1998; 12: sumably result from the intramedullary destruction of 178-200. erythroblats. 5. Sandström H, Wahlin A. Congenital dyserythropoiet- ic anemia type III. Haematologica 2000; 85:753-7. The last consideration is related to the problem of 6. Tamary H, Shalev H, Luria D, et al. Clinical features splenectomy in CDAs. Many cases are reported in lit- and studies of erythropoiesis in Israeli Bedouins with erature which suggested an improvement of Hb lev- congenital dyserythropoietic anemia type I. Blood el following splenectomy. But it appears, particular- 1996; 87:1763-70. ly in CDA-II, that the spleen plays a pivotal role; in 7. De Franceschi L, Turrini F, Miraglia del Giudice E, et fact due to the underglycosylation of band 3 there is al. Decreased band 3 anion transport activity and clusterization of these molecules and the appearance band 3 clusterization in congenital dyserythropoietic of auto-antibodies, whereas the ribs appear to be anemia type II. Exp Hematol 1998; 26:869-73. selectively removed by the spleen. Interestingly three 8. Tamary H, Shalmon L, Shalev H, et al. Localization of the gene for congenital dyserythropoietic anemia type patients with CDA type I have shown a partial I to a <1-cM interval on chromosome 15q15.1-15.3. response to subcutaneously-administred recombi- Am J Hum Genet 1998; 62:1062-9. nant interferon α, with an elevation of Hb levels and 9. Fukuda MN, Gaetani GF, Izzo P, Scartezzini P, Dell A. a reduction of jaundice. This partial remission of clin- Incompletely processed N-glycans of serum glycopro- ical findings further supports the idea that the three teins in congenital dyserythropeitic anaemia type II forms of classical congenital dyserythropoiesis are (HEMPAS). Brit J Haematol 1992; 82:745-52. very different from each other. 10. Sandström H, Wahlin A, Eriksson M, Bergström I. Serum thymidine kinase in congenital dyserythropoi- Achille Iolascon etic anaemia type III. Br J Haematol 1994; 87:653-4. Dept. of Biomedicine of Evolutive Age – CISME, University of Bari, Bari, Italy [email protected]

Haematologica vol. 85(7):July 2000