Congenital Bone Marrow Failure Syndromes
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Deutsches Register für Congenitale Dyserythropoietische Anämien (CDA)
German Registry of Congenital Dyserythopoietic Anemia (CDA)
Congenital dyserythropoietic anaemia (CDA)
Information for health professionals (October 2010)
Congenital dyserythropoietic anaemia is a rare inborn illness, which was first recognized as an independent disease in 1968. At the present time there are more than 600 patients out of 500 families known in Europe, but the true frequency is most probably about two times higher. As for the rarity of this illness it is understood that paediatricians and internists who haven’t specialized in diseases concerning the blood system, are not able to diagnose this ailment. Additionally most haematologists for paediatrics and internal medicine show no experience in diagnosing and treating patients with CDA. Therefore the right diagnosis is often first made when patients reach adulthood. It is necessary that specialists, doctors and patients (including their parents) show a willingness to cooperate closely to guarantee an appropriate treatment.
This information summarizes the most important characteristics in respect of CDAs for doctors dealing with patients suffering from this illness. You will find further information in below-mentioned literature; furthermore an understandable version for patients and relatives is enclosed.
Congenital dyserythropoietic anaemias outline a group of diseases which vary in genetic background and clinical phenotype. Nevertheless similar disturbances and problems are seen in the patient. General differential criteria are:
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Evidence of congenital emergence or heredity through similar occurrences within the family
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Signs of ineffective erythropoiesis, in other words a premature destruction of erythroblasts as the essential mechanism of the anaemia
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Typical morphologic aberrations of the erythroblasts in the bone marrow
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Exclusion of an inherited disorder concerning haemoglobin synthesis or megaloblastic anaemia
The severity of this disorder shows differences within the subtypes. Whereas a few patients require blood transfusions right after birth or during childhood, other patients who haven’t been affected too vigorously show a moderate anaemia and hyperbilirubinaemia accompanied with alternating scleral jaundice. Besides that, physical working capacity is decreased in serious cases. Congenital dysplasia occurs more frequently than by coincidence and preferentially appears in the skeleton.
CDA is classified into three types. Type II is more frequent then type I. Type III hasn’t been described in the German speaking area. Therefore the following illustration is restricted to the most frequent types, I and II. The execution of the principles of clinical diagnostics and therapies are also valid, however, there are individual cases, that can’t be classified as type I or II.
Congenital dyserythropoietic anaemia type II = CDA II is also known as “Hereditary Multinuclearity with a Positive Acid Serum lysis test (HEMPAS)”, because of the positive results of the acidified serum lysis test, which was previously used to diagnose the paroxysmal nocturnal haemoglobinuria. Additionally there are other highly specific and sensitive serological and biochemical testing procedures, especially the varying migration velocity and abnormal configuration of band 3 during the examination of the erythrocyte membrane by polyacrylamide gel electrophoresis (SDS-Page), which is based on a disturbance of glycosylation of some glycoproteins in the red cell membrane. Genetic proof is now possible after having recently identified the mutated gene (SEC23B) on the short arm of chromosome 20. CDA II, an autosomal recessive disorder is more common in Italy than other countries. In the German speaking region it doesn’t show a higher occurrence in respect of people from Greek, Italy, Spain, Turkey and immigrants from other countries. It is also found just as often in German families.
The following notes are characteristic, but not per se specific results:
Amoderate enlargement of the spleen, usually palpable
Mostly a normocytic and normochromic anaemia varying in degree of severity featured by haemoglobin values ranging from 8-12g/dl
An obvious anisocytosis and poikilocytosis of red blood cells recognizable in the blood smear, with basophilic stippled erythrocytes and with seldom seen mono- or binuclear erythroblasts
Normal or inadequately increased absolute and relative reticulocyte counts
An increase of ferritin and a decrease of serum transferrin as a sign for secondary haemochromatosis. These features may possibly be missing through increased demand for iron in the growth period and in premenopausal women.
Evidence- based proof through distinctive changes of erythroblasts in the bone marrow is accomplished by the above mentioned serological and biochemical tests. A recent investigation, together with different European laboratories, has shown that the examination of erythrocyte membranes via SDS-Page is the most sensitive and specific method, as individual patients may possibly show a negative acid serum test. A SEC23B mutation evaluation supplements the proof. Electron microscopy also shows specific modifications; however this method is no longer necessary for diagnostic proof.
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Blood smear of congenital dyserythropoietic anaemia type II, after splenectomy. Left image shows erythrocytes with Jolly-bodies, right image a basophilic cell with high magnification |
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The appearance of CDA in affected families is usually restricted to siblings, not to parents or children of affected people. This disease will affect one person or several in a row of siblings. We are often asked whether people with CDA are able to have healthy children. As for the rareness of this hereditary disposition it is assumed that the disposition may be inherited by patients children, however they and their descendants are healthy. Although affected women are able to get pregnant and give birth without complications, it is necessary for them to organize cooperation between haematologist and gynaecologists precociously, preferably in the planning of the pregnancy. The same applies for parents who already have an affected child. To prevent congenital malformations of the neural tube it is advised to ingest 1mg folic acid per day as a periconceptional prophylactic measure.
Congenital dyserythropoietic anaemia type I = CDA I
By looking at the mentioned results from CDA type II, type I is also a suspected diagnosis. However a macrocytic anaemia is mostly present here, therefore it is not surprising that initially high MCV-values (up to 120fl) rush the doctor into making a diagnosis of megaloblastic anaemia. Treatments with vitamin B12 and folic acid are without effect. On average the anaemia is more pronounced and likewise shows highly variable haemoglobin values in the range of 7-12g/dl. The diagnostic proof is given through significant changes in the blood smear and by high specific modifications of erythroblasts in the bone marrow using optical and electron microscopic images. Furthermore, various mutations on chromosome 15q15 were identified in almost all CDA I- families. The affected gene, CDAN-I gene, encodes for the codanin-I-protein, which has no completely known function in erythropoiesis at present. It is neither clear whether these mutations underlie every family with phenotopic severity nor how their position influences the ineffectivity of erythropoiesis. Because of this, evidence-based proof relies on morphologic changes via electron microscopy in the case of ambiguous molecular-genetic results. Beyond that CDA II specific non- morphological tests show a negative outcome when used on CDA I.
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Left image shows a blood smear from a CDA II patient Right image shows typical binucleated erythroblasts in the bone marrow. |
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Peripheral blood smear of a patient with CDA I. Single target cells may be present, in addition to red cells showing gross basophilic stippling |
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Bone marrow smear of a patient with CDA I. Nuclear bridge (left) and partly washed-out nuclear structure (right, lower right corner of the image) |
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Apart from these three classical types, other inconclusive varieties exist, which show morphological similarities, however, they have a more severe clinical course. It is unclear to what extent therapeutic advice should be followed in these cases.
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Blood smear from a patient affected with a CDA II like variant, after splenectomy. Numerous mature erythroblasts with atypical nucleus. |
In all CDA-forms, the correct clinical diagnosis is partly made in adulthood, especially concerning patients who are only slightly affected. Most frequent misdiagnosises are of different varieties of haemolytic anaemia such as hereditary spherocytosis regarding to CDA II and of megaloblastic anaemia as to CDA I.
Most patients with CDA have a normal life expectancy, even so they are at high risk of suffering from consequences directly associated with their disease, for example:
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A very common formation of biliary concrements, most notably in CDA II.
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Sudden reinforcement of the anaemia through exacerbating viral infections (e.g. parvovirus B19).In the case of such a unique, however dangerous aplastic crisis, it’s usually necessary to treat the patient with erythrocyte transfusions.
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Secondary haemochromatosis, mostly defined as a constant increased iron resorption, potentially accelerated via erythrocyte transfusions. Depending on the severe ness of iron overload in the body, liver, heart and endocrine gland damages are possible.
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In a few cases extramedullary tumour- like haematopoiesis paravertebral or in the lungs
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In elderly people poorly healing of lower thigh ulcers especially those localized in the paramalleolar region.
Regular controls are required during the entire lifetime, especially in childhood, less frequent in adulthood. Time between check-ups is set individually depending on severity and risk of complications. In the case of an adult, examinations once a year are often adequate. Apart from medical history and a physical examination it is important to do a sonography of the upper abdomen, a blood count, check indirect and direct serum bilirubin, serum ferritin level, blood glucose (Hb-A1c is not useful to demonstrate or to exclude diabetes mellitus) and TSH to detect a latent hypothyroidism early enough. If an iron overload (increase of serum ferritin value above 1000ng/ml or higher) is displayed or noticeable signs of disturbed organ functions are shown further tests to the detection of damaged organs through secondary haemochromatosis are recommended. If possible it is necessary to identify the hepatic and cardiac iron concentration via non-invasive methods before starting with an iron depletion therapy. This permits a safe assessment towards treatment success.
Assurance of the medical diagnosis and establishment of the CDA-type serve as the basis for therapy and are assessed through specific inquiries carried out in clinical institutions which are familiar with this disease and work in close cooperation with specialists for paediatric and adult haematology. Merely depending on the establishment of the subtype and the assessment of physical ability as well as of the quality of living due to illness, it is possible or necessary to give specific therapy advice:
In the case of CDA II a splenectomy is the next thing to consider after having done the conventional infection prophylaxis. Splenectomy achieves a steady improvement of the anaemia, however the tendency towards iron overload is not eradicated. Furthermore booster injections of polyvalent pneumococcal vaccines are administered every 5 years and an antibiotic therapy is indicated when a bacterial infection seems likely.
CDA I is treated with interferon-α which also improves the anaemia and reduces the iron overload.
All patients suffering from an iron overload which may possibly cause organ damages are treated with depletion therapy via bloodletting in minor cases of anaemia and/or iron chelating agents as Deferoxamine (Desferal®), Deferiprone (Ferriprox®) or Deferasirox (Exjade®). The latter compounds are not licensed to treat non-transfusion-related haemochromatosis. If the insurance company does not approve, further queries to the Ulm Registry are possible. Desferal® is supposed to be administered as a continuous subcutaneous infusion whereas the others are ingested orally. Ferriprox® and Exjade® are newer compounds without long-term experiences towards CDA. It is necessary to consider undesirable side effects and dose adjustment, as mentioned in the information for professional circles.
Because of the increased endogenous erythropoietin production it is neither appropriate performing an erythropoietin therapy nor is it worth considering under economic aspects. Even vitamin supplements are unnecessary, if there are no signs of deficiency. Besides that ferric compounds are contraindicated.
Patients with CDA are advised to carry a patient pass with them mentioning the diagnosis, the treating doctor and, if applicable, the execution of a splenectomy!
Literatur
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Heimpel H, Anselstetter V, Chrobak L, Denecke J, Einsiedler B, Gallmeier K et al. Congenital dyserythropoietic anemia type II: epidemiology, clinical appearance, and prognosis based on long-term observation. Blood 2003; 102(13):4576-4581.
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Heimpel H, Schwarz K, Ebnöther M, Goede J, Heydrich D, Kamp T et al. Congenital dyserythropoietic anemia type I (CDA I): Molecular genetics, clinical appearance and prognosis based on long-term observation. Blood 2006; 107(1):334-340.
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Heimpel H, Iolascon A. Congenital dyserythropoietic anemia. In: Beaumont C, Beris Ph, Beuzard Y, Brugnara C, editors. Disorders of homeostasis, erythrocytes, erythropoiesis. Paris: European School of Haematology, 2009: 120-142.
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Schwarz K, Iolascon A, Verissimo F, Trede NS, Horsley W, Chen W, et al. Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. Nat Genet 2009 Jun 28;41(8):936-40.
Prof. emerit. Dr. med. Hermann Heimpel |
Prof. Dr. med. Elisabeth Kohne |
Prof. Dr. med. Hubert Schrezenmeier |
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Deutsches Register für
kongenitale dyserythropoetische Anämien |
Universitätsklinik für Kinder-und Jugendmedizin |
Universitätsklinik Ulm |
aktualisiert am 02.02.2011