History

Fact Explanation
Features of anemia ( fatigue/ poor exercise tolerance) Seen due to ineffective erythropoiesis and reduced red cell life span, resulting in reduced red cell amount in blood [1].
Jaundice (yellowish discoloration of eyes, skin & mucosal membranes) This is seen as a result of ineffective erythropoiesis and reduced red cell life span [2].
History suggestive of gall stones (cholecystitis/ acute pancreatitis/ biliary colic/ history of cholecystectomy) This is also due to ineffective erythropoiesis and reduced red cell life span [2].
Family history of consanguinity This is commonly seen in congenital dyserythropoietic anemia (CDA) types I & II [2].
Fetal distress (absent/reduced fetal movements) or history of hydrops fetalis This is rarely seen when the affected fetuses suffer from severe anemia [3].
Skin pigmentation This can be seen either due to iron overload or other congenital abnormality associated with CDA type I. When associated with other congenital abnormality, pigmentation is brown and patchy [2].
Respiratory distress Seen very rarely in CDA types II & III, when associated with intra-thoracic paravertebral masses involved with extra-medullary erythropoiesis [4].
Visual disturbances This is seen due to macular degeneration and angioid streaks in CDA [2].
Symptoms related to endocrine dysfunction ( eg: loss of weight, polyuria and polydypsia in diabetes mellitus) Endocrine dysfunction occurs due to deposition of excess iron on endocrine organs. Iron overload occurs as a result of increased iron absorption secondary to erythroid hyperplasia, ineffective erythropoiesis and reduced hepcidin production in CDA [2].
References
  1. BAROSI, G., M. CAZZOLA, M. STEFANELLI, E. ASCARI. Studies of ineffective erythropoiesis and peripheral haemolysis in congenital dyserythropoietic anaemia type II. British Journal of hematology [Online]. Blackwell Scientific Publications. October 1979, 43(2):243-250 [viewed 23 April 2014]. Available from: DOI: 10.1111/j.1365-2141.1979.tb03747.x.
  2. WICKRAMASINGHE, Sunitha N., William G. WOOD. Review: Advances in the understanding of the congenital dyserythropoietic anaemias. British journal of hematology [Online]. Blackwell Publishing Ltd. 2005, 131:431-446 [viewed 23 April 2014]. Available from: doi:10.1111/j.1365-2141.2005.05757.x.
  3. CARTER, C., P.J. DARBYSHIRE. S.N. WICKRAMASINGHE. Congenital dyserythropoietic anaemia variant presenting as hydrops foetalis. British Journal of Haematology [Online]. John Wiley & Sons Ltd. June 1989, 72(2):289-90 [viewed 23 April 2014]. Available from: DOI:10.1111/j.1365-2141.1989.tb07699.x.
  4. KROUWELS, F.H., P. BRESSER, A.E. VON DEM BORNE. Extramedullary hematopoiesis: breathtaking and hair-raising. New England Journal of Medicine [Online]. Massachusetts Medical Society. November 1999, 341:1702–1704. [viewed 23 April 2014]. Available from: DOI: 10.1056/NEJM199911253412219.

Examination

Fact Explanation
Pallor Due to anaemia associated with ineffective erythropoiesis and reduced red cell life span [1].
Icterus Can be present due to jaundice associated with ineffective erythropoiesis and reduced red cell life span [1].
Hepatosplenomegaly Due to compensatory extra medullary erythropoiesis occurring in liver and spleen, as a response to anemia. A palpable spleen is found in 80-90% of CDA type I patients [1].
Frontal & parietal bossing This may be seen in severe erythroid hyperplasia, due to marked widening of the space between the tables of the frontal & parietal bones [1].
Features of iron overload Skin pigmentation, clinical features of endocrine dysfunction & cirrhosis may be seen due to iron overload which occurs as a result of increased iron absorption secondary to erythroid hyperplasia, ineffective erythropoiesis and reduced hepcidin production [1].
Other congenital abnormalities Syndactyly, absent phalanges/nails, pigeon’s chest, short stature, varus deformity of hips, flattened vertebral bodies, hypoplastic ribs, congenital ptosis and deafness are associated with CDA type I [2, 3].
Dysmorphic features Seen in CDA types I & II [4]. However, dysmorphic features are not so common in CDA type II, compared to CDA type 1 [1].
Mental retardation Seen in CDA types II & III [4, 5].
References
  1. WICKRAMASINGHE, Sunitha N., William G. WOOD. Review: Advances in the understanding of the congenital dyserythropoietic anaemias. British journal of hematology [Online]. Blackwell Publishing Ltd. 2005, 131:431-446 [viewed 23 April 2014]. Available from: doi:10.1111/j.1365-2141.2005.05757.x.
  2. HOLMBERG, L., L. JANSSON, A. RAUSING, P. HENRIKSSON. Type I congenital dyserythropoietic anaemia with myelopoietic abnormalities and hand malformations. Scandinavian Journal of Haematology, John Wiley & Sons, Inc. 1978, 21, 72–79. [viewed 23 April 2014]. Available from: DOI: 10.1111/j.1600-0609.1978.tb02496.x.
  3. BRICHARD, B., C. VERMYLEN, J.M. SCHEIFF, J.L. MICHAUX et al. Two cases of congenital dyserythropoietic anaemia type I associated with unusual skeletal abnormalities of the limbs. British Journal of Haematology [Online]. John Wiley & Sons Ltd. January 1994, 86 (1): 201–202. DOI: 10.1111/j.1365-2141.1994.tb03278.x.
  4. VERWILGHEN, R.L., S.M. LEWIS, J.V. DACIE, J.H. CROOKSTON, HEMPAS: congenital dyserythropoietic anaemia (type II). Quarterly Journal of Medicine [Online]. Association of Physicians of Great Britain and Ireland. April 1973, 42(2):257–278 [viewed 23 April 2014]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1146375/pdf/jclinpath00472-0073.pdf
  5. GOUDSMIT, R., D. BECKERS, J.I. DE BRUIJNE, C.P. ENGELFRIET et al. Congenital dyserythropoietic anaemia, type III. British Journal of Haematology [Online]. Blackwell Publishing Ltd. July 1972, 23:97–105. [viewed 23 April 2014]. Available from:DOI: 10.1111/j.1365-2141.1972.tb03463.x.

Differential Diagnoses

Fact Explanation
Folate/ vitamin B12 deficiency Causes megaloblastic anemia with high MCV. A positive hematolohical response is seen with the replenishment of vitamin B12 & folate stores [1]. However, folate deficiency can occur in CDA secondary to severe erythroid hyperplasia [2].
Thalassemia Has clinical features of anemia, hepatosplenomegaly, frontal & parietal bossing and iron overload [3]. High performance liquid chromatography (HPLC) helps to make the diagnosis [4].
Homozygous HbC These patients present with compensated hemolysis or mild to moderate anemia with splenomegaly [5].
Hereditary sideroblastic anemia This also shows clinical features of anemia and iron overload, and erythroid hyperplasia in the bone marrow due to ineffective erythropoiesis [6].
Paroxysmal nocturnal hemoglobinuria Produces a positive Ham test but gives positive results with the patient’s serum as well, and a positive sucrose lysis test, in contrast to CDA type II [2].
Pyruvate kinase deficiency Absence of red cell pyruvate kinase enzyme produces hemolytic anemia and jaundice with splenomegaly [7].
References
  1. SNOW, C.F. Laboratory diagnosis of vitamin B12 and Folate deficiency:A guide for the primary care physician. Archives of internal medicine. American medical association. June 1999, 159:1289-98
  2. WICKRAMASINGHE, Sunitha N., William G. WOOD. Review: Advances in the understanding of the congenital dyserythropoietic anaemias. British journal of hematology [Online]. Blackwell Publishing Ltd. 2005, 131:431-446 [viewed 23 April 2014]. Available from: doi:10.1111/j.1365-2141.2005.05757.x.
  3. KATTAMIS, C., A. METAXOTOU-MAVROMATI, K. KARAMBOULA, E. NASIKA, H. LEHMAN. The Clinical and Haematological Findings in Children Inheriting Two Types of Thalassaemia: High-A, Type P-Thalassaemia, and High-F Type or 6 P-Thalassaemia. British journal of hematology [Online]. 1973,25(3):375-84. [viewed 23 April 2014]. Available from: DOI: 10.1111/j.13652141.1973.tb01748.x.
  4. RYAN, K., B.J.BAIN, D. WORTHINGTON, J. JAMES et al. Significant haemoglobinopathies: guidelines for screening and diagnosis. British journal of hematology [Online]. April 2010, 149(1):35-49. [viewed 23 April 2014]. Available from: DOI: 10.1111/j.1365-2141.2009.08054.x.
  5. BACHIR, D., F. GALACTEROS. Hemoglobin C. Orphanet encyclopedia [Online]. November 2004 , [viewed 26 April 2014]. Available from.
  6. ALCINDOR, T., K. R. BRIDGES. Sideroblastic anemias. British journal of hematology [Online]. Blackwell Publishing Ltd. March 2002, 116(4):733-743 [viewed 23 April 2014]. Available from: DOI: 10.1046/j.0007-1048.2002.03378.x.
  7. ZANELLA, A., E. FERMO, P. BIANCHI,G. VALENTINI. Red cell pyruvate kinase deficiency: molecular and clinical aspects. British journal of hematology [Online]. Blackwell Publishing Ltd. March 2002, 130(1):11-25 [viewed 23 April 2014]. Available from: doi:10.1111/j.1365-2141.2005.05527.x.

Investigations - for Diagnosis

Fact Explanation
Full blood count Shows lower than normal hemoglobin level with normal platelet and neutrophil counts. The mean corpuscular volume (MCV) is usually normal [1].
Blood picture Macrocytes are seen in types I & III while normocytes are seen in type II. Additionally in CDA type I, poikilocytes and red cells with basophilic stippling are seen, while in type II anisochromasia and poikilocytosis, spherocytes and stippled cells are seen. In CDA type III, anisopoikilocytosis, basophilic stippling and very large red cells are seen in the blood film. About 7% of red cells in CDA type I are bi-nucleate [1].
Bone marrow examination Inter-nuclear chromatin bridges between erythroblasts are diagnostic of CDA type I [2]. However, as this is present in only 1.6% of erythroblasts, a large portion should be examined before the diagnosis is excluded [3]. Important: inter-nuclear chromatin strands may also be seen in other congenital/acquired dyserythropoietic states, so other investigations are important for diagnosis [1]. Also, spongy ‘swiss-cheese’ appearance of 60% of intermediate & late erythroblasts on electron microscopy is a characteristic feature of CDA type I [1]. 10-35% of late erythroblasts in CDA type II are binucleate and light microscopy on bone marrow in CDA type III shows giant multinucleate & mononucleate erythroblasts, with upto 12 nuclei seen in a single multinucleate erythroblast [1].
Acidified serum lysis test (Ham test) Gives negative results in CDA types I & III [4, 1], and usually positive in CDA type II, with fresh ABO compatible donor sera but not with patient’s own serum [5].
Hemoglobin electrophoresis Shows increased HbA2 level in some cases of CDA type I [1].
Chromosomal studies Mutations in CDAN1 gene in chromosome 15q15.1-15.3 [6], CDAN2 gene in chromosome 20q11.2 [1], and CDAN3 gene in 15q22 [7] are found in CDA types I, II & III respectively.
References
  1. WICKRAMASINGHE, Sunitha N., William G. WOOD. Review: Advances in the understanding of the congenital dyserythropoietic anaemias. British journal of hematology [Online]. Blackwell Publishing Ltd. 2005, 131:431-446 [viewed 23 April 2014]. Available from: doi:10.1111/j.1365-2141.2005.05757.x.
  2. HEIMPEL, H., J. FORTEZA-VILA, W. QUEISSER, E. SPIERTZ. Electron and light microscopic study of the erythroblasts of patients with congenital dyserythropoietic anemia. Blood [Online]. March 1971, 37:299–310 [viewed 23 April 2014]. Available from: http://bloodjournal.hematologylibrary.org/content/37/3/299.full.pdf
  3. WICKRAMASINGHE, S.N. Dyserythropoiesis and congenital dyserythropoietic anaemias. British Journal of Haematology [Online]. Blackwell Publishing Ltd. September 1997, 98(4):785–797 [viewed 23 April 2014]. Available from:. DOI: 10.1046/j.1365-2141.1997.2513065.x.
  4. LEWIS, S.M., R. L. VERWILGHEN. Annotation: Dyserythropoiesis and dyserythropoietic anaemia. British Journal of Hematolog y [Online]. John Wiley & Sons Ltd. July 1972, 23(1): 1-4 [viewed 23 April 2014]. Available from: DOI: 10.1111/j.1365-2141.1972.tb03452.x.
  5. CROOKSTON, J.H., M.C. CROOKSTON, K.L. BRUNIE, W.H. FRANCOMBE et al. Hereditary erythroblastic multinuclearity associated with a positive acidified-serum test: a type of congenital dyserythropoietic anaemia. British Journal of Haematology [Online]. John Wiley & Sons Ltd. July 1969, 17(1):11-26 [viewed 23 April 2014]. Available from: DOI: 10.1111/j.1365-2141.1969.tb05660.x.
  6. DGANY, O.,N. AVIDAN, J. DELAUNAY, T. KRASNOV et al. Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. American Journal of Human Genetics[Online]. The American Society of Human Genetics. December 2002, 71(6):1467–1474 [viewed 23 April 2014]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC378595/
  7. LIND, L., H. SANDSTRO¨M, A. WAHLIN, M. ERIKSSON et al. Localization of the gene for congenital dyserythropoietic anemia type III, CDAN3, to chromosome 15q21–q25. Human Molecular Genetics [Online] . Oxford University Press. January 1995, 4:109–112 [viewed 23 April 2014]. Available from: doi:10.1093/hmg/4.1.109.

Investigations - Followup

Fact Explanation
Serum Ferritin There is an increase in iron deposition throughout life and about 20% of CDA type II develop cirrhosis of the liver from iron deposition. Therefore serum ferritin should be monitored at least once a year in every patient [1].
Full blood count This is useful in monitoring the degree of anemia and deciding the need for blood transfusion.
References
  1. HEIMPEL, H., V. ANSELSTETTER, L. CHROBAK, J. DENECKE et al. Congenital dyserythropoietic anemia type II: epidemiology, clinical appearance, and prognosis based on long-term observation. Blood [Online]. American society of hematology. December 2003, 102, 4576–4581. [viewed 23 April 2014]. Available from: doi:10.1182/blood-2003-02-0613.

Management - General Measures

Fact Explanation
Screening of affected patients’ family members. This is crucial in identifying asymptomatic CDA patients who are at risk of developing iron overload [1].
References
  1. WICKRAMASINGHE, Sunitha N., William G. WOOD. Review: Advances in the understanding of the congenital dyserythropoietic anaemias. British journal of hematology [Online]. Blackwell Publishing Ltd. 2005, 131:431-446 [viewed 23 April 2014]. Available from: doi:10.1111/j.1365-2141.2005.05757.x.

Management - Specific Treatments

Fact Explanation
Blood transfusions This is not routinely recommended in mild to moderate anemia unless hemoglobin level falls below the base-line level in inter-current illness/ pregnancy [1].
Prevention of iron overload Iron chelation therapy: Subcutaneous infusion of desferrioxamine is given to transfusion dependent patients [1]. It is recommended to start chelation therapy at a ferritin level of 1500 µg/L [2]. Regular venesection: This is shown to be effective in reducing iron storage upto 500 µg/L, in mild anemia[3].
Interferon therapy Recombinant alpha-interferon therapy 2-3 times weekly has shown to increase the Hb level, reduce the MCV, red cell distribution width, serum bilirubin level and improve the erythroblast morphology [4]. Also, prolonged treatment with interferon has shown to reduce iron overload is reported one patient [4], thus it is recommended to start therapy with interferon in transfusion dependent patients and those with moderate anemia who are about to undergo venesection as they cannot tolerate iron chelation therapy [5].
Splenectomy This is known to cause a significant increase in Hb in CDA type II [6].
Stem cell transplantation Human leukocyte antigen (HLA) matched allogenic stem cell transplantation in severely affected CDA has been tried with successful outcome [1].
References
  1. WICKRAMASINGHE, Sunitha N., William G. WOOD. Review: Advances in the understanding of the congenital dyserythropoietic anaemias. British journal of hematology [Online]. Blackwell Publishing Ltd. 2005, 131:431-446 [ viewed 23 April 2014]. Available from: doi:10.1111/j.1365-2141.2005.05757.x.
  2. WICKRAMASINGHE, S.N. Dyserythropoiesis and congenital dyserythropoietic anaemias. British Journal of Haematology [Online]. Blackwell Publishing Ltd. September 1997, 98(4):785–797 [viewed 23 April 2014]. Available from:. DOI: 10.1046/j.1365-2141.1997.2513065.x.
  3. WICKRAMASINGHE, S.N., M.J. PIPPARD. Studies of erythroblast function in congenital dyserythropoietic anaemia, type I: evidence of impaired DNA, RNA, and protein synthesis and unbalanced globin chain synthesis in ultrastructurally abnormal cells. Journal of Clinical Pathology [Online]. BMJ Publishing Group Ltd & Association of Clinical Pathologists. August 1986, 39(8):881–890. [viewed 23 April 2014]. Available from:DOI: 10.1136/jcp.39.8.881.
  4. LAVABRE-BERTRAND, T., P. BLANC, R. NAVARRO, M. SAGHROUN et al. Alpha-interferon therapy for congenital dyserythropoiesis type I. British Journal of Haematology [Online]. John Wiley & Sons Ltd.April 1995, 89(4):929–932. [viewed 23 April 2014]. Available from:DOI: 10.1111/j.1365-2141.1995.tb08442.x.
  5. WICKRAMASINGHE, S.N. Response of CDA type I to alphainterferon. European Journal of Haematology [Online]. John Wiley & Sons Ltd. February 1997, 58(2):121–123 [viewed 23 April 2014]. Available from:DOI:10.1111/j.1600-0609.1997.tb00935.x.
  6. VERWILGHEN, R.L., S.M. LEWIS, J.V. DACIE, J.H. CROOKSTON, HEMPAS: congenital dyserythropoietic anaemia (type II). Quarterly Journal of Medicine [Online]. Association of Physicians of Great Britain and Ireland. April 1973, 42(2):257–278 [viewed 23 April 2014]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC378595/