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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Iolascon, A. Articles by Camaschella, C. Search for Related Content PubMed PubMed Citation Articles by Iolascon, A. Articles by Camaschella, C. Related Collections Red Cells Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 August 2001, Vol. 98, No. 4, pp. 1258-1260 BRIEF REPORT Natural history of congenital dyserythropoietic anemia type II Achille Iolascon, Jean Delaunay, Sunitha N. Wickramasinghe, Silverio Perrotta, Maddalena Gigante, and Clara Camaschella From the Istituto di Pediatria, Università di Foggia e CISME-Dipartimento di Biomedicina dell'Età Evolutiva, Università di Bari, Italy; Service d'Hématologie, d'Immunologie et de Cytogénétique, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, and INSERM U 473, Le Kremlin-Bicêtre, France; Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; Dipartimento di Pediatria, Seconda Università degli Studi di Napoli, Napoli, Italy; and Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Italy.     Abstract Top Abstract Introduction Study design Results and discussion References Congenital dyserythropoietic anemia type II (CDA-II) is an autosomal recessive disease characterized by anemia, jaundice, splenomegaly, and erythroblast multinuclearity. The natural history of the disease is unknown. The frequency, the relevance of complications, and the use of splenectomy are poorly defined. This study examined 98 patients from unrelated families enrolled in the International Registry of CDA-II. Retrospective data were obtained using an appropriate questionnaire. The mean age at presentation was 5.2 ± 6.1 years. Anemia was present in 66% and jaundice in 53.4% of cases. The mean age at correct diagnosis was 15.9 ± 11.8 years. Twenty-three percent of patients for whom data were available developed anemia during the neonatal period, and 10 of these individuals required transfusions. Splenectomy produced an increased hemoglobin (P < .001) and a reduced bilirubin level (P = .007) in comparison with values before splenectomy. Preliminary data indicate that iron overload occurs irrespective of the hemochromatosis genotype. (Blood. 2001;98:1258-1260) © 2001 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Congenital dyserythropoietic anemia type II (CDA-II) is an autosomal recessive disorder affecting the normal differentiation-proliferation pathway of the erythroid lineage.1-4 It comprises an anemia of variable severity, jaundice, and variable splenomegaly. Erythroid hyperplasia with binuclearity or multinuclearity involving late erythroblasts in the bone marrow (BM) is a key feature of the diagnosis. In addition, on electron microscopy, vesicles of endoplasmic reticulum (ER) appear to be running beneath the plasma membrane in this disorder.5 Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS-PAGE) of erythrocyte membrane proteins shows that band 3, the anion exchanger, is narrower and has an accelerated migration rate,6,7 because of abnormal glycosylation. Underglycosylated band 3 aggregates in solution and clusters in membranes, resulting in membrane disorganization.8,9 Western blotting following SDS-PAGE shows the presence of calreticulin, the glucose-regulated protein 78 (GRP 78) and the protein disulfide isomerase,5 which belongs in the ER and corresponds to the above-mentioned vesicles. The view of CDA-II as a primary genetic defect of glycosylation8 has been discounted because of the lack of linkage with the genes encoding N-acetylglucosaminyltransferaseII or -mannosidaseII,10 2 enzymes deficient in CDA-II. We obtained evidence for linkage of CDA-II to the long arm of chromosome 20,11 but at least 5% to 10% of cases failed to map to 20q,12 stressing genetic heterogeneity. Despite the progress in genetics and pathophysiology, the primary molecular lesion remains speculative. No information exists on the frequency and the clinical relevance of complications. Treatment is largely supportive and the benefit of splenectomy is uncertain. Based on long-term follow-up of a large group of patients, we here report the natural history of CDA-II.     Study design Top Abstract Introduction Study design Results and discussion References We investigated 98 CDA-II patients (39 males and 59 females; mean age, 17.6 years; range 1 month to 67 years) from 78 unrelated families enrolled in the CDA-II International Registry, which has been collecting all newly notified cases since 1996. Patients originated predominantly from Italy or from other European countries.13 The enrollment questionnaire contained information on age and symptoms at discovery, age at diagnosis, diagnostic criteria, complications, and therapy. The tests concerning erythrocyte membrane protein analysis used to confirm the diagnosis in some cases were performed as reported1,3 and are shown in Figure 1. C282Y and H63D mutations in the hemochromatosis (HFE) gene were analyzed as described.14 View larger version (109K): [in this window] [in a new window]   Figure 1. Diagnostic criteria for patients enrolled in the International Registry of CDA-II. Overall determinations: bone marrow (BM), 98; electronic microscopy (EM), 30; Ham-test (Ha), 48; Ag-i (Ai), 22; SDS-PAGE (SDS), 58; Western blots for ER proteins (We), 15. Approval for these studies was obtained from the University of Bari Institutional Review Board. Informed consent was provided according to the Declaration of Helsinki.     Results and discussion Top Abstract Introduction Study design Results and discussion References Of the 98 patients enrolled in the registry, 88 questionnaires were fully evaluable. Diagnostic criteria were based on BM examination and on further tests (Figure 1). Age at presentation The age at presentation ranged from 1 month to 25 years (mean, 5.2 ± 6.1 years). The symptoms included anemia (66%) and jaundice (53.4%). The age at diagnosis ranged from 4 months to 65 years (mean, 15.9 ± 11.8 years). Extent of anemia By the time of diagnosis, the basic parameters were hemoglobin (Hb), 8.3 ± 1.2 g/dL; mean corpuscular volume (MCV), 86 ± 10 fL; reticulocytes, 103.5 ± 45.6 × 109/L; total biliribin, 4.6 ± 2.3 mg/dL. In the 26 patients who were diagnosed after the age of 16, Hb level was 10.1 ± 1.8 g/dL. Clinical course during infancy Information on neonatal period was available for 64 subjects. Fifteen had a Hb level less than 8.0 g/dL on the third postpartum day, with 10 requiring transfusions. Seven of these subjects had transfusions in adult life and 5 became dependent on transfusions. Sixteen had jaundice that required phototherapy and 10 underwent exchange transfusion. A 2-month-old anemic girl died of pulmonary complications. Considering both newborns and infants, 66% of patients were anemic (Hb level 7.9 ± 1.4 g/dL). During infancy spleen enlargement was documented in 68 of 88 cases, jaundice in 48, and gallstones in 14 cases. Transfusion requirements Thirty-three of 88 patients with a Hb value below 6 g/dL had transfusions during the first year of life. In the following years the transfusion requirements decreased; only 5 subjects (3 with associated -thalassemia trait) remained dependent on transfusions during adulthood. A patient aged 15 received a BM transplant from an identical sibling and was disease-free after 2 years.15 Splenomegaly and effect of splenectomy Splenectomy was performed in 26 patients at a mean age of 12.6 years (range, 3.5-40 years). In 4 cases it was performed prior to the diagnosis of CDA-II. In 19 patients, the Hb level was 8.05 ± 1.62 g/dL before and 9.75 ± 1.03 g/dL after splenectomy (P < .001) and the serum bilirubin level was 5.07 ± 1.22 mg/dL before and 2.50 ± 1.42 mg/dL after splenectomy (P = .007). Three transfusion-dependent patients became transfusion-independent after splenectomy. Twenty subjects had cholecystectomy, usually at the time of splenectomy. Iron overload Forty-seven transfusion-independent patients were evaluable for iron studies. One died from severe heart failure at age 15. No other clinical complications related to iron overload were recorded. Serum ferritin level gradually increased from the time of diagnosis onward. There were no significant differences between patients with or without H63D mutation. Both subgroups showed an age-dependent increase in ferritin (Table 1). In 21 splenectomized patients ferritin levels were 299 ± 219 µg/L versus 220 ± 114 µg/L in 39 nonsplenectomized subjects, matched for age (P = .070).                                View this table: [in this window] [in a new window]   Table 1. Iron parameters (±1 SD) in 47 transfusion-independent patients Discussion The remarkable difference between age at presentation and age at diagnosis points to the difficulty in recognizing CDA-II. Because of hemolytic symptoms, CDA-II is not infrequently misdiagnosed as hereditary spherocytosis (HS). Only a suboptimal reticulocyte count for the degree of anemia may hint at dyserythropoietic anemia. BM examination remains the "gold standard" for diagnosis (Figure 1). SDS-PAGE and Western blotting are straightforward and reliable and should gain wider use in the future. The other investigations are either less sensitive or not widely available. No information was previously available on neonatal CDA-II. We show that 25% of affected newborns were anemic, that transfusions were required in two thirds of them, and that jaundice was common and required treatment. Neonatal CDA-II appears less severe than HS, in which up to 65% of newborns have disease-related symptoms.16 However, whereas clinical symptoms during the neonatal period are not predictive of the outcome in HS,16 they may anticipate the disease evolution in CDA-II. Anemia, jaundice, and splenomegaly were present in 66% of patients during infancy and childhood. Although CDA-II is considered a benign condition, 2 patients died and 33 required transfusions during the first year of life. Anemia during this period has been attributed to a low physiologic reserve of the BM with a weak response to erythropoietin.16,17 Ten patients required transfusions after the first year and only 5 became dependent on transfusions. A small percentage of cases had late diagnosis, reflecting a milder disorder. The phenotypic heterogeneity could reflect both heterogeneous molecular lesions and different acquired factors. In our experience 20q unlinked disorders seem to be more severe (data not shown). Other modifier genes may play a role; -thalassemia, adding a further cause (globin chain imbalance) of ineffective erythropoiesis, aggravates the severity of the anemia.18 Although splenomegaly is common, the recommendation regarding splenectomy is not uniform among hematologists. Thirty percent of the patients had splenectomy when last observed. From our analysis, splenectomy is sometimes of benefit because anemia improves and hemolysis decreases. One complication of dyserythropoiesis is iron overload, because iron absorption increases secondary to expanded erythropoiesis. In a limited follow-up, serum ferritin level increases with age, irrespective of the HFE H63D genotype, suggesting that the erythropoietic expansion is the major determinant of iron loading. Because our series did not include any C282Y mutations, no conclusions could be drawn on the effect of C282Y heterozygosity. A single case of iron loading due to C282Y homozygosity is known in CDA-II.19 Prolonged follow-up of patients in the registry will provide additional data on the evolution of iron overload.     Acknowledgments The authors thank all the colleagues for referring the investigated families. The authors are particularly grateful to the chairmen of the centers participating in the recruitment of patients: U. Ramenghi (Torino), M. D. Cappellini (Milano), P. Scartezzini (Genova), G. Barosi (Pavia), R. Galanello (Cagliari), D. Gallisai (Sassari), P. Rigano (Palermo), L. Felici (Pesaro), P. Izzo (Bari), G. Schilirò (Catania), P. Sticca (Como), B. Nobili and E. Miraglia del Giudice (Napoli), J. Vives-Corrons (Barcelona), G. Tchernia (Paris), S. Eber (Zurich), F. Gilsanz (Madrid), V. Premetis (Athens), A. Colita (Bucharest), H. Toriello and S. Mckanzie (United States), S. Aftimos (New Zealand), and H. Heimpel (Germany). The authors also thank the pediatricians affiliated with the AIEOP and ESPHI.     Footnotes Submitted January 18, 2001; accepted April 12, 2001. Supported by grants from the Italian Ministry of Health (A.I.), MURST 40% and 60% University of Bari (A.I.), and Telethon project E-645 (A.I.). The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Achille Iolascon, Dipartimento di Biomedicina dell'Età Evolutiva, Piazza G. Cesare 11, 70124 Bari, Italy; e-mail: a.iolascon{at}bioetaev.uniba.it.     References Top Abstract Introduction Study design Results and discussion References 1. Delaunay J, Iolascon A. The congenital dyserythropoietic anemias. Bailleres Clin Hematol. 1999;12:691-705. 2. Heimpel H, Wendt F. Congenital dyserythropoietic anemia with karyorhexis and multinuclearity of erythroblasts. Helv Med Acta. 1968;34:103-112[Medline] [Order article via Infotrieve]. 3. Wickramasinghe SN. Congenital dyserythropoietic anaemias: clinical features, haematological morphology and new biochemical data. Blood Rev. 1998;12:178-200[CrossRef][Medline] [Order article via Infotrieve]. 4. Crookston JH, Crookston MC, Burnie KL, Francombe WH, Dacie JV, Lewis SM. Hereditary erythroblastic multinuclearity associated with a positive acidified-serum test: a type of congenital dyserythropoietic anaemia. Br J Haematol. 1969;17:11-23[Medline] [Order article via Infotrieve]. 5. Alloisio N, Texier P, Denoroy L, et al. The cisternae decorating the red blood cell membrane in congenital dyserythropoietic anemia (type II) originate from the endoplasmic reticulum. Blood. 1996;87:4433-4439[Abstract/Free Full Text]. 6. Anselstetter V, Horstmann HJ, Heimpel H. Congenital dyserythropoietic anaemia, type I and II: aberrant pattern of erythrocyte membrane proteins in CDA II, as revealed by two-dimensional polyacrylamide gel electrophoresis. Br J. Haematol. 1977;35:209-217[Medline] [Order article via Infotrieve]. 7. Baines AJ, Banga JP, Gratzer WB, Linch DC, Huehns ER. Red cell membrane protein abnormalities in congenital dyserythropoietic anemias type II (HEMPAS). Br J Haematol. 1982;50:563-574[Medline] [Order article via Infotrieve]. 8. Fukuda MN. HEMPAS disease: genetic defect of glycosylation. Glycobiology. 1990;1:9-15[Abstract/Free Full Text]. 9. De Franceschi L, Turrini F, Miraglia del Giudice E, et al. Decreased band 3 anion transport activity and band 3 clusterization in congenital dyserythropoietic anemia type II. Exp Hematol. 1998;26:869-873[Medline] [Order article via Infotrieve]. 10. Iolascon A, Miraglia del Giudice E, Perrotta S, Granatiero M, Zelante L, Gasparini P. Exclusion of three candidate genes as determinants of congenital dyserithropoietic anemia type II (CDA II). Blood. 1997;10:4197-4200. 11. Gasparini P, Miraglia del Giudice E, Delaunay J, et al. Localization of the congenital dyserythropoietic anemia II locus to chromosome 20q11.2 by genomewide search. Am J Hum Genet. 1997;61:1112-1116[CrossRef][Medline] [Order article via Infotrieve]. 12. Iolascon A, Perrotta S, Carella M, Lambertenghi Deliliers G, De Mattia D, Gasparini P. Genetic heterogeneity of congenital dyserythropoietic anemia II (CDA II). Blood. 1998;92:2593-2594[Free Full Text]. 13. Iolascon A, Servedio V, Carbone R, et al. Geographic distribution of CDA-II: did a founder effect operate in Southern Italy. Haematologica. 2000;85:504-508. 14. Carella M, D'Ambrosio L, Totaro A, et al. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet. 1997;60:828-832[Medline] [Order article via Infotrieve]. 15. Iolascon A, Sabato V, De Mattia D, Locatelli F. Bone marrow transplantation in a case of severe congenital dyserythropoietic anemia type II. Bone Marrow Transplant. 2001;27:213-215[CrossRef][Medline] [Order article via Infotrieve]. 16. Delhommeau F, Cynober T, Schischmanoff PO, et al. Natural history of hereditary spherocytosis during the first year of life. Blood. 2000;95:393-397[Abstract/Free Full Text]. 17. Tchernia G, Delhommeau F, Perrotta S. et al. Recombinant erythropoietin therapy as an alternative to blood transfusions in infants with hereditary spherocytosis. Hematol J. 2000;1:146-152[CrossRef][Medline] [Order article via Infotrieve]. 18. Perrotta S, Miraglia del Giudice E, Carbone R, et al. Gilbert's syndrome accounts for the phenotypic variability of congenital dyserythropoietic anemia type II (CDA-II). J Pediatr. 2000;136:556-559[CrossRef][Medline] [Order article via Infotrieve]. 19. Fargion S, Valenti L, Fracanzani AL, et al. Hereditary hemochromatosis in a patient with congenital dyserythropoietic anemia. Blood. 2000;96:3653-3655[Abstract/Free Full Text]. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Iolascon and J. Delaunay Close to unraveling the secrets of congenital dyserythropoietic anemia types I and II Haematologica, May 1, 2009; 94(5): 599 - 602. [Full Text] [PDF] H. Heimpel, V. Anselstetter, L. Chrobak, J. Denecke, B. Einsiedler, K. Gallmeier, A. Griesshammer, T. Marquardt, G. Janka-Schaub, M. Kron, et al. Congenital dyserythropoietic anemia type II: epidemiology, clinical appearance, and prognosis based on long-term observation Blood, December 15, 2003; 102(13): 4576 - 4581. [Abstract] [Full Text] [PDF] S. Perrotta, L. Luzzatto, M. Carella, and A. Iolascon Congenital dyserythropoietic anemia type II in human patients is not due to mutations in the erythroid anion exchanger 1 Blood, October 1, 2003; 102(7): 2704 - 2705. [Full Text] [PDF] J. Milledge, P. J. Shaw, A. Mansour, S. Williamson, B. Bennetts, T. Roscioli, J. Curtin, and J. Christodoulou Allogeneic bone marrow transplantation: cure for familial Mediterranean fever Blood, July 18, 2002; 100(3): 774 - 777. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Iolascon, A. Articles by Camaschella, C. Search for Related Content PubMed PubMed Citation Articles by Iolascon, A. Articles by Camaschella, C. Related Collections Red Cells Brief Reports Social Bookmarking                   What's this?

	Copyright © 2001 by American Society of Hematology         Online ISSN: 1528-0020