Congenital dyserythropoietic anemias (CDA) are very rare congenital disorders characterized by ineffective hematopoiesis. The first symptoms of anemia appear in childhood. These diseases can be treated quite well by various therapeutic measures.
What is congenital dyserythropoietic anemia?
Congenital dyserythropoietic anemias belong to a group of rare blood disorders caused by different gene mutations. In the context of these mutations, mostly immature and diseased erythrocytes are formed, which are subject to increased hemolysis. To compensate for this hemolysis, hematopoiesis is further stimulated. Nevertheless, this does not overcome the anemia. Normal erythrocytes mature in the bone marrow and then enter the bloodstream, where they have an average lifespan of about 120 days. In CDA, however, the erythrocytes fail to mature in the bone marrow. In many cases, the immature erythrocytes therefore already die there. Currently, four subtypes of CDA are distinguished, which are based on different mutations. These are the forms type I CDAN1 to type IV CDAN4. Types I and II occur most frequently, with type II still predominating. However, the distinction between the CDA forms is important for the choice of therapy. Currently, the incidence of the disease is thought to be very low. In Europe, two to three people per million are thought to have CDA.
Causes
All forms of CDA are hereditary. Depending on the severity of the condition, the first symptoms often begin shortly after birth. Sometimes they do not appear until adulthood. In most forms of CDA, there is an autosomal recessive inheritance. This means that the disease cannot be transmitted directly from one generation to another. Only when both parents each pass on a defective gene to their offspring does the disease occur. However, since the mutated genes occur very rarely, CDA mainly occurs in children of related parental pairs. Type I CDAN1 is a mutation of the CDAN1 gene, which encodes the protein codanin-1. When this protein is altered, a chromatin bridge is formed between the nuclei of immature erythrocytes. These are small protein and DNA threads that hold the nuclei together. At the same time, the nuclear membranes are permeable to substances from inside the cell. As a result, a disturbed nuclear metabolism develops. In the more common type II CDAN2, a gene on chromosome 20 is affected by a mutation. Here, large immature erythrocytes with multiple nuclei are formed. This multinuclearity causes defects in cell division. Metabolic disorders occur in the cell walls of the red blood cells. Type III CDAN3 is caused by an autosomal dominant mutation in the KIF23 gene on chromosome 15, and type IV CDAN4 is caused by a mutation in the KLF1 gene on chromosome 19.
Symptoms, complaints, and signs
All forms of CDA are characterized by three symptom complexes. These include hemolytic anemia, symptoms of increased hematopoiesis, and signs of iron overload. Hemolytic anemia results from increased breakdown of diseased erythrocytes. It is manifested by rapid fatigue, increasing pallor, headache, difficulty breathing during physical exertion, jaundice, formation of gallstones, and spleen enlargement. Anemia may even worsen in the course of an aplastic crisis. In this case, the formation of new erythrocytes in the bone marrow is temporarily completely interrupted by the influence of parvovirus B19 (the causative agent of ringworm). Only blood degradation takes place. In general, however, anemia provokes increased formation of erythrocytes in the bone marrow. However, since the immature erythrocytes are quickly broken down again, this process is further intensified. The unusually strong new formation of erythrocytes in the bone marrow requires more space and therefore leads to the expansion of the bones. Finally, other organs such as the spleen may be involved in the formation of blood, resulting in their enlargement. Iron overload, which causes the third symptom complex, is caused by increased hematopoietic activity in the bone marrow. The ineffective formation of immature erythrocytes binds more iron, which is deposited in various organs after the breakdown of the blood cells.Heart muscle weakness, liver dysfunction, hypothyroidism and other metabolic disorders occur.
Diagnosis and course of the disease
Diagnosis of CDA includes characterization of erythrocytes and laboratory testing of various blood parameters. Low hemoglobin and haptoglobin levels and elevated levels of bilirubin and ferritin are typical.
Complications
Usually, this disease results in severely decreased hematopoiesis in the patient. This thus has a negative effect on the patient’s entire organism and can greatly reduce his or her ability to cope with stress. Fatigue also occurs and those affected appear pale or suffer from headaches. Respiratory problems or jaundice may also occur and the spleen may enlarge. As a result, pain is not uncommon. If these also occur at night in the form of pain at rest, patients may continue to suffer from sleep problems. Likewise, other organs may also be enlarged due to the decreased blood formation, causing damage to the organs or other discomfort. If necessary, the heart muscle is weakened and liver or thyroid disorders occur. The patient’s quality of life is significantly reduced by this disease. The treatment does not usually lead to complications. Blood loss can be compensated with the help of transfusions. It may also be necessary to remove the spleen. Life expectancy is not reduced with early and proper treatment.
When should you see a doctor?
Parents who notice rapid fatigability and exhaustion in their child, possibly associated with headaches, difficulty breathing, and other symptoms, should involve the pediatrician. Congenital dyserythropetic anemia must be treated early to rule out health complications and long-term sequelae. Therefore, medical advice should be sought at the first sign of a serious condition. If the child is already showing signs of jaundice or gallstones, parents should take him or her to a hospital. If there are signs of an aplastic crisis, manifested by pallor, lassitude and dizziness, the emergency physician must be called. CDA is hereditary and can be detected by genetic testing. If there are cases of the disease in the family, a test should be arranged at an early stage. This way, CDA can be detected and treated in time before serious complications develop. Parents can consult the pediatrician or an internist. Further treatment usually takes place in a specialist center for hereditary diseases.
Treatment and therapy
Therapy for CDA includes regular blood transfusions, administration of hematopoietic substances, removal of the spleen if necessary, stem cell transplants, and administration of drugs to remove excess iron. Administration of hematopoietic agents such as alpha-interferon is appropriate in type I CDA CDAN1. Removal of the spleen can prolong the life of the erythrocytes. However, because of the potential complications, this surgery is performed only in very severe cases. In very severe courses, stem cell transplantation may also be considered. For this, however, the blood characteristics of the donor and recipient must essentially match. Medication for iron overload must always be given to patients with CDA. Iron overload occurs both with increased red blood cell production and as a result of frequent blood transfusions. Medications used to remove excess iron are called iron chelators.
Outlook and prognosis
Congenital dyserythropoietic anemia (CDA) occurs very rarely. With early diagnosis and treatment, the outlook for most newborns with congenital dyserythropoietic anemia is quite good to have a normal life expectancy. However, it is important that those affected and their relatives cooperate optimally. Impaired hematopoiesis has consequences that last a lifetime. If possible, treatment should be carried out by a team of specialized doctors. The cooperation of family doctors or pediatricians with specialists in blood disorders improves the statistical chances of those affected to have a halfway normal life. However, it is problematic that even specialists cannot make predictions about the course of congenital dyserythropoietic anemia (CDA).Many factors can affect survival with a blood disorder. CDA can only be cured by stem cell transplantation. However, the majority of doctors are concerned with alleviating the symptoms and sequelae of congenital dyserythropoietic anemia. Under optimal cooperation of patient and family, a high life expectancy can be assumed, at least in countries with high medical standards. In other countries, where such conditions do not exist, the survival prognosis looks worse. It should be noted, however, that a positive prognosis can prove deceptive even in this country. CDA can take an unfavorable course due to many circumstances.
Prevention
Prevention from CDA is not possible because it is very rare as a hereditary disease. Moreover, the corresponding mutations are usually also inherited in an autosomal recessive manner. Therefore, there is only an increased risk for this disease in descendants of related individuals.
Follow-up
In this disease, the measures and options for aftercare are significantly limited in most cases. First and foremost, the disease should be detected early by a physician to prevent further worsening of symptoms. In the case of a desire to have children, genetic counseling may also be useful to prevent the recurrence of the disease in the children. Self-cure will not usually occur. The treatment itself is carried out by taking various medications, whereby here the affected person should pay attention to a regular intake and also to a correct dosage of the medication. In case of any uncertainties or questions, a doctor should always be consulted first. Regular blood transfusions are also necessary, so that many patients are dependent on the help and care of family, friends and acquaintances in their lives due to the disease. Loving conversations also have a positive effect on the further course of the disease, as in many cases depression and other psychological upsets can be prevented. Possibly, the disease also reduces the life expectancy of the affected person.
What you can do yourself
Patients with congenital dyserythropoietic anemia are able to take certain steps to improve their quality of life and contribute to the success of therapy. Affected individuals suffer from decreased exercise capacity and tire quickly. Accordingly, patients refrain from overworking themselves psychologically. Instead, together with the doctor and physiotherapist, the patients choose sports and exercises that are appropriate for their performance level. In this way, there is no overloading and the patients still train their muscles and condition. Patients regularly visit their doctor for various examinations and therapeutic measures. Hospital stays may be necessary, for example if the spleen has to be removed due to enlargement. The nursing staff and the physicians give important instructions on resting, taking medications and diet, which must be followed by the patient. With adequate therapy of the disease, patients are able to participate in social life and attend normal school. However, it is possible that the affected children do not participate in physical education. For adequate care of patients, it is important that the social environment is informed about the existence of the disease and intervenes in case of medical complications.
