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CHAPTER 35 THE CONGENITAL DYSERYTHROPOIETIC ANEMIAS

CHAPTER 35 THE CONGENITAL DYSERYTHROPOIETIC ANEMIAS
Williams Hematology

CHAPTER 35 THE CONGENITAL DYSERYTHROPOIETIC ANEMIAS

ERNEST BEUTLER

Congenital Dyserythropoietic Anemia Type I
Congenital Dyserythropoietic Anemia Type II (Hempas)
Congenital Dyserythropoietic Anemia Type III
Other Forms of Congenital Dyserythropoietic Anemia and Similar Disorders
Enzyme Abnormalities in Congenital Dyserythropoietic Anemia
Differential Diagnosis
Chapter References

The congenital dyserythropoietic anemias are a heterogeneous group of disorders characterized by anemia, the presence of multinuclear erythroid precursors in the marrow, ineffective erythropoeisis, and iron overload. Patients have been classified as type I, II, and III, but there are some patients who appear to fit into the general category of congenital dyserythropoietic anemia but do not fit into any of these three groups. Types I and II congenital dyserythropoietic anemia are inherited as autosomal recessive disorders, and type III disease is dominant. Type II congenital dyserythropoietic anemia is also known by the acronym HEMPAS, which describes characteristic serologic findings that are absent from types I and III congenital dyserythropoietic anemia.

Acronyms and abbreviations that appear in this chapter include: HEMPAS, Hereditary Erythroblastic Multinuclearity associated with a Positive Acidified Serum test; PNH, paroxysmal nocturnal hemoglobinuria.

The term congenital dyserythropoietic anemia applies to a group of hereditary refractory anemias characterized by ineffective erythropoiesis, erythroid multinuclearity, and accumulation of tissue iron. Anemia is characteristically first noted in infancy or childhood. The life span of circulating erythrocytes may be normal to moderately shortened, but dyserythropoiesis with a large component of intramedullary cell death is the dominant factor in pathogenesis. Ineffective erythropoiesis results in increased plasma iron turnover, diminished incorporation of tracer iron into circulating red cells, mild increases in indirect reacting bilirubin, elevated fecal stercobilin level, increased endogenous carbon monoxide production (presumably derived from heme catabolism), intense marrow erythroid hyperplasia, and normal, or at most slightly elevated, absolute reticulocyte counts. Splenomegaly, variably severe anemia, and mild increases in indirect-reacting serum bilirubin are present. Congenital dyserythropoietic anemias have been classified into three types1 (Table 35-1). In addition, a number of cases that do not fit clearly into any of these categories have been described.

TABLE 35-1 CONGENITAL DYSERYTHROPOIETIC ANEMIA, TYPES I, II, III—MARROW AND SEROLOGIC FEATURES

These disorders are quite uncommon. In a survey of the United Kingdom between 1994 and 1996, 47 cases were identified. Twelve had type I, 13 type II, 2 type III, and 20 had types that did not fit into this classification.2
CONGENITAL DYSERYTHROPOIETIC ANEMIA TYPE I
Type I dyserythropoietic anemia generally first becomes manifest in infancy, childhood, or adolescence, and is characterized by slight hyperbilirubinemia, moderate anemia (hematocrit usually 25 to 36 percent), and commonly, splenomegaly.3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24 The mode of genetic transmission is autosomal recessive and the disorder has been documented in identical twins.25 Linkage analysis has narrowed localization of the gene responsible for this disorder to a 0.5 centimorgan interval in the q15.1 to q15.3 region.24 The level of serum haptoglobin is low; that of serum iron is normal or high. The red cell morphologic picture is characterized by well-marked aniso- and poikilocytosis and slight to moderate macrocytosis. The intensely cellular erythroid marrow shows megaloblastoid features.3,4 and 5 By light microscopy, the majority of erythroblasts have varying degrees of abnormality. In particular, three morphologic aberrations are regarded as typical: (1) very large cells containing an irregularly shaped nuclear mass with two nuclear segments suggesting incomplete nuclear division (1 to 2 percent of erythroblasts), (2) double nucleated cells in which the two nuclei differ in size, structure, and stainability (0.3 to 0.8 percent of erythroblasts), and (3) pairs of erythroblasts connected by thin chromatin bridges of different lengths (0.8 to 2.3 percent of erythroblasts).5 Only the erythroid series shows significant abnormalities by electron and light microscopy. The pores of the nuclear envelope of the erythroid cells become abnormally numerous and wide with progressive maturation. Later the cytoplasm has invaded between the nuclear chromatin strands of many cells and there is intense clumping of the dense chromatin. In even more severely affected cells, the cytoplasm separates the chromatin fragments and gives the nucleus a spongy appearance.5,6,7 and 8,10,11,13,17,21,26 The persistence of cytoplasmic microtubules has also been demonstrated.10 Some mitochondria show deposition of ferruginous micelles, causing a loss of normal structure, but these changes are quantitatively much less severe than in the sideroblastic anemias (Chap. 63). In other studies, hypertetraploid DNA values were found in a high proportion of erythroblasts, and RNA synthesis was markedly reduced, leading to impaired hemoglobin synthesis.11,12 Serologic abnormalities, such as occur in congenital dyserythropoietic anemia type II, have usually not been present. An increase in the a/b globin chain synthetic ratio has been reported.13,27 An animal model of the disease has been described.28
No effective treatment is available, but although anemic, most subjects do not require transfusion. The latter is to be avoided if at all possible, since iron overload is often present.14,20,29 The cautious use of phlebotomy or administration of iron-chelating agents to help prevent tissue siderosis has been suggested.20 In one case splenectomy was noted to decrease the transfusion requirement16 but not in two others.14,18
CONGENITAL DYSERYTHROPOIETIC ANEMIA TYPE II (HEMPAS)
Most commonly known as HEMPAS, a somewhat whimsical acronym for Hereditary Erythroblastic Multinuclearity associated with a Positive Acidified Serum test, type II congenital dyserythropoietic anemia was first described in 1962.30,31 The unusual serologic abnormalities characterizing this disorder were defined in the late 1960s.32 By 1975, the clinical and hematologic features of 84 patients in 55 families had been described and were reviewed.33 A considerable number of additional patients with HEMPAS have been reported since.27,34,35,36,37,38,39,40,41,42 and 43 The geographic distribution of affected patients suggests a higher frequency of the HEMPAS gene in Northwest Europe, Italy, and North Africa. Both sexes are affected; the mode of genetic transmission is autosomal recessive.44 The gene has been localized to chromosome 20q11.2 by linkage analysis.45
The red cell membrane of HEMPAS patients characteristically contains abnormal complex carbohydrate patterns (Fig. 35-1). Presumably as a consequence of the abnormality in glycosylation, the electrophoretic mobilities of membrane proteins of the red cells from patients with HEMPAS deviates markedly from normal, and this could occur as a result of either a genetic defect in N-acetylglucosaminyltransferase II or a-mannosidase II.28,49,50 Targeted disruption of the a-mannosidase II gene of the mouse produces mild anemia with HEMPAS-like changes in erythrocytes.50 On the other hand, mapping of the gene to 20q11.2 in Italian families45,51 ruled out both of these candidate genes as the primary defect. It is possible that in these cases, at least, the abnormality might be caused by a defect in a gene encoding a transcription factor that controls expression of both of these enzymes.

FIGURE 35-1 Schematic models for erythrocyte glycoproteins and glycolipids of normal, HEMPAS, and variant G.K. Band 3 glycoproteins in normal erythrocyte membranes are glycosylated by large carbohydrate chains—polyactosaminoglycans. Most glycolipids have short carbohydrate chains but have small amounts of polyactosaminylceramide. In HEMPAS erythrocytes, band 3 has truncated hybrid-type oligosaccharides and most polylactosamines shift to lipid acceptors. In variant G.K., band 3 has high mannose-type oligosaccharides and polyactosamines are not present in glycolipids either. Incompletely glycosylated band 3s in HEMPAS and variant G.K. appear to be clustered in the membranes. (Reprinted from Fukuda MN: Congenital dyserythropoietic anaemia type II (HEMPAS) and its molecular basis. Balliere’s Clinical Haematology, Vol 6, pp 493–511, 1993. By permission of the publisher, WB Saunders Company Limited, London.49)

A characteristic feature of HEMPAS is the behavior of the patient’s cells in serologic tests. HEMPAS cells are lysed by certain group-compatible sera at pH 6.8, resembling in this respect cells of paroxysmal nocturnal hemoglobinuria (PNH) (see Chap. 26). However, HEMPAS cells differ from those in PNH in several important respects.44,52 The sucrose hemolysis test (see Chap. 36) is negative,44 and the cells are not lysed by their own acidified serum. Only about 30 percent of group-compatible sera lyse HEMPAS cells. Unlike PNH cells, HEMPAS cells behave as a single population in quantitative lysis tests. The lysis of HEMPAS cells appears to be due to a naturally occurring IgM complement-binding antibody that can be removed by absorption with HEMPAS but not with normal or PNH cells. The antigen recognized by the antibody is unknown. A constant finding in HEMPAS is the strong reactivity of the red cells with anti-i autoantibodies. In this respect the red cells resemble those of newborn infants.32,34,52 HEMPAS cells are agglutinated and lysed more readily than normal cells by coldreacting agglutinins (anti-I and anti-i). It appears that this is largely explained by increased antibody binding rather than by increased sensitivity to complement.53
Multinuclearity and karyorrhexis are present in 15 to 20 percent of late erythroblasts from patients with HEMPAS, and autoradiography indicates that these cells are no longer synthesizing DNA.
The extent of anemia in different patients with HEMPAS varies widely, ranging from mild to severe. The circulating red cells exhibit moderate to marked aniso- and poikilocytosis and anisochromia. There are also a few irregularly contracted spherocytes. Ferrokinetic studies document the ineffective erythropoiesis.32,44 Reticulocyte counts are normal or slightly elevated. Body iron stores and serum iron levels are usually increased, and the occurrence of frank hemochromatosis has been observed.36 From 10 to 30 percent of the erythroblasts, chiefly the more mature stages, have two or more nuclei or lobulated nuclei (Fig. 35-2). Gaucher-like cells may develop due to phagocytosis of erythroblasts by macrophages. Ringed sideroblasts are not conspicuous. No satisfactory treatment is available, but partial benefit has been reported with splenectomy.44 One patient was successfully phlebotomized, removing 1.2 g of iron, in spite of an initial hemoglobin of 7 g/dl, a level that improved in the course of phlebotomy.43

FIGURE 35-2 Multinuclearity of the erythroblasts in the marrow of a patient with HEMPAS.

CONGENITAL DYSERYTHROPOIETIC ANEMIA TYPE III
A third type of congenital dyserythropoietic anemia was first described in a woman and all three of her children, in whom 16 to 22.7 percent of marrow erythroblasts were multinucleated.54 Giant-sized erythrocytes were present in the blood, and giant erythroblasts with coarse basophilic stippling and up to 12 nuclei were present in the marrow. All patients were asymptomatic, with absent or minimal anemia. The reticulocyte count was below 3 percent. A similar, dominantly transmitted disorder has also been described in 15 members of a large Swedish family55 under the name of hereditary benign erythro-reticulosis, and other cases have been reported subsequently.
Precipitation of b chains has been observed within the abnormal erythroblasts.66 The defect in the erythrocyte precursors is intrinsic to the stem cell: it can be reproduced in tissue culture, in which both morphologically normal and giant multinuclear erythroblasts are found.
OTHER FORMS OF CONGENITAL DYSERYTHROPOIETIC ANEMIA AND SIMILAR DISORDERS
A number of cases of congenital dyserythropoietic anemia that do not have the features of types I, II, and III have been reported,68,69,70,71,72,73,74,75,76,77,78,79 and 80 and it has been suggested that one of these be designated as type IV.74 The salient features of some of the earlier cases of atypical congenital dyserythropoietic anemia have been reviewed.71 In two kindreds, congenital dyserythropoietic anemia was inherited in a dominant fashion. In some, marrow erythroid multinuclearity resembled that of HEMPAS, but the acidified serum lysis test was negative.73,74 Long-lasting erythroblastosis occurring after splenectomy of such patients has been attributed to impairment of the denucleation of erythroblasts.73 Un-balanced globin-chain synthesis with excess production of a chains was documented in several patients. In one such kindred, a disorder with features of both thalassemia and hereditary erythroid multinuclearity was dominantly transmitted.70 In variant syndromes, there were also differences in the degree of agglutination by anti-i antibodies and in the concentrations of Hb F and A2. In one case of congenital dyserythropoietic anemia, the acidified serum lysis test was positive, but erythroid multinuclearity was absent.
Still other ill-defined forms of congenital dyserythropoietic anemia undoubtedly exist. Several cases of apparently lifelong anemia, thought to be hereditary, have been described.72 These are characterized by marked aniso- and poikilocytosis and occasional teardrop and fragmented erythrocytes in the blood. Hyperplastic marrows showed megaloblastoid features without multinuclearity or ringed sideroblasts,72 but a case with prominent ringed sideroblasts has also been described.77 Neutropenia is commonly present, and thrombocytopenia has been observed in some patients. Cytogenetic studies of marrow revealed no chromosomal abnormalities. The reticulocyte response to anemia was absent or inappropriately low in all. In most cases studies of parents failed to reveal abnormalities, suggesting an autosomal recessive mode of transmission. High-dose androgen therapy appeared partially to benefit two subjects.72
ENZYME ABNORMALITIES IN CONGENITAL DYSERYTHROPOIETIC ANEMIA
In both congenital dyserythropoietic anemia types I and II, as well as in certain less well-defined but apparently hereditary dyserythropoietic anemias, a diversity of abnormalities of individual red cell enzyme activities and of activity ratios have been identified.72,81 Enzyme patterns differ strikingly from those of either normal red cells or reticulocyte-rich blood. They resemble closely, however, patterns observed in a variety of disorders characterized by ineffective erythropoiesis, including certain acquired and congenital sideroblastic anemias, certain preleukemic states, and certain refractory, nonsideroblastic anemias with cellular marrow.72
DIFFERENTIAL DIAGNOSIS
Congenital dyserythropoietic anemia may be confused with the thalassemic syndromes because of the frequent presence of marked aniso- and poikilocytosis, hypochromia, and evidence of ineffective erythropoiesis. The readily evident erythroid multinuclearity of congenital dyserythropoietic anemia type II and the marrow gigantocytes of the rarer congenital dyserythropoietic anemia type III point toward the correct diagnosis in these conditions. The marrow changes in congenital dyserythropoietic anemia type I are, however, more subtle and more easily missed. Family studies and evaluation of hemoglobin A2 levels indicate that thalassemia is not present. The megaloblastoid marrow structure may cause some confusion with other disorders associated with abnormalities of vitamin B12, folic acid, and nucleic acid metabolism. Some forms of congenital dyserythropoietic anemia also resemble some of the acquired or hereditary sideroblastic anemias, but sideroblastosis is usually not prominent and the other marrow features described earlier point to the correct diagnosis. The abnormal serologic tests observed with HEMPAS are of obvious major diagnostic importance. Otherwise, indirect hyperbilirubinemia and splenomegaly may suggest a hemolytic process, but low reticulocyte counts, the marrow features, and findings of ineffective erythropoiesis should point to the correct diagnosis.
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Ohisalo JJ, Viitala J, Lintula R, Ruutu T: A new congenital dyserythropoietic anaemia. Br J Haematol 68:111, 1988.

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Pothier B, Morle L, Alloisio N, et al.: Aberrant pattern of red cell membrane and cytosolic proteins in a case of congenital dyserythropoietic anaemia. Br J Haematol 66:393, 1987.

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Brien WF, Mant MJ, Etches WS: Variant congenital dyserythropoietic anaemia with ringed sideroblasts. Clin Lab Haematol 7:231, 1985.

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Wickramasinghe SN, Illum N, Wimberley PD: Congenital dyserythropoietic anaemia with novel intra-erythroblastic and intra-erythrocytic inclusions. Br J Haematol 79:322, 1991.

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Sansone G, Masera G, Cantu-Rajnoldi A, Terzoli S: An unclassified case of congenital dyserythropoietic anaemia with a severe neonatal onset. Acta Haematol (Basel) 88:41, 1992.

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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12 comments on “CHAPTER 35 THE CONGENITAL DYSERYTHROPOIETIC ANEMIAS

  1. […] CHAPTER 35 THE CONGENITAL DYSERYTHROPOIETIC … […]

  2. […] CONGENITAL DYSERYTHROPOIETIC ANEMIA TYPE III A third type of congenital dyserythropoietic anemia was first described in a woman and all three of her children, in whom 16 to 22.7 percent of marrow erythroblasts were multinucleated.54 Giant-sized erythrocytes were present in the blood, and giant erythroblasts with coarse basophilic stippling and up to 12 nuclei were present in the marrow. All patients were asymptomatic, with absent or minimal anemia. The reticulocyte count was below 3 percent. A similar, dominantly transmitted disorder has also been described in 15 members of a large Swedish family55 under the name of hereditary benign erythro-reticulosis, and other cases have been reported subsequently. Precipitation of b chains has been observed within the abnormal erythroblasts.66 The defect in the erythrocyte precursors is intrinsic to the stem cell: it can be reproduced in tissue culture, in which both morphologically normal and giant multinuclear erythroblasts are found. OTHER FORMS OF CONGENITAL DYSERYTHROPOIETIC ANEMIA AND SIMILAR DISORDERS A number of cases of congenital dyserythropoietic anemia that do not have the features of types I, II, and III have been reported,68,69,70,71,72,73,74,75,76,77,78,79 and 80 and it has been suggested that one of these be designated as type IV.74 The salient features of some of the earlier cases of atypical congenital dyserythropoietic anemia have been reviewed.71 In two kindreds, congenital dyserythropoietic anemia was inherited in a dominant fashion. In some, marrow erythroid multinuclearity resembled that of HEMPAS, but the acidified serum lysis test was negative.73,74 Long-lasting erythroblastosis occurring after splenectomy of such patients has been attributed to impairment of the denucleation of erythroblasts.73 Un-balanced globin-chain synthesis with excess production of a chains was documented in several patients. In one such kindred, a disorder with features of both thalassemia and hereditary erythroid multinuclearity was dominantly transmitted.70 In variant syndromes, there were also differences in the degree of agglutination by anti-i antibodies and in the concentrations of Hb F and A2. In one case of congenital dyserythropoietic anemia, the acidified serum lysis test was positive, but erythroid multinuclearity was absent. Still other ill-defined forms of congenital dyserythropoietic anemia undoubtedly exist. Several cases of apparently lifelong anemia, thought to be hereditary, have been described.72 These are characterized by marked aniso- and poikilocytosis and occasional teardrop and fragmented erythrocytes in the blood. Hyperplastic marrows showed megaloblastoid features without multinuclearity or ringed sideroblasts,72 but a case with prominent ringed sideroblasts has also been described.77 Neutropenia is commonly present, and thrombocytopenia has been observed in some patients. Cytogenetic studies of marrow revealed no chromosomal abnormalities. The reticulocyte response to anemia was absent or inappropriately low in all. In most cases studies of parents failed to reveal abnormalities, suggesting an autosomal recessive mode of transmission. High-dose androgen therapy appeared partially to benefit two subjects.72 ENZYME ABNORMALITIES IN CONGENITAL DYSERYTHROPOIETIC ANEMIA In both congenital dyserythropoietic anemia types I and II, as well as in certain less well-defined but apparently hereditary dyserythropoietic anemias, a diversity of abnormalities of individual red cell enzyme activities and of activity ratios have been identified.72,81 Enzyme patterns differ strikingly from those of either normal red cells or reticulocyte-rich blood. They resemble closely, however, patterns observed in a variety of disorders characterized by ineffective erythropoiesis, including certain acquired and congenital sideroblastic anemias, certain preleukemic states, and certain refractory, nonsideroblastic anemias with cellular marrow.72 DIFFERENTIAL DIAGNOSIS Congenital dyserythropoietic anemia may be confused with the thalassemic syndromes because of the frequent presence of marked aniso- and poikilocytosis, hypochromia, and evidence of ineffective erythropoiesis. The readily evident erythroid multinuclearity of congenital dyserythropoietic anemia type II and the marrow gigantocytes of the rarer congenital dyserythropoietic anemia type III point toward the correct diagnosis in these conditions. The marrow changes in congenital dyserythropoietic anemia type I are, however, more subtle and more easily missed. Family studies and evaluation of hemoglobin A2 levels indicate that thalassemia is not present. The megaloblastoid marrow structure may cause some confusion with other disorders associated with abnormalities of vitamin B12, folic acid, and nucleic acid metabolism. Some forms of congenital dyserythropoietic anemia also resemble some of the acquired or hereditary sideroblastic anemias, but sideroblastosis is usually not prominent and the other marrow features described earlier point to the correct diagnosis. The abnormal serologic tests observed with HEMPAS are of obvious major diagnostic importance. Otherwise, indirect hyperbilirubinemia and splenomegaly may suggest a hemolytic process, but low reticulocyte counts, the marrow features, and findings of ineffective erythropoiesis should point to the correct diagnosis. CHAPTER REFERENCESSource: wordpress.com […]

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