Congenital dyserythropoietic anemia (CDA)

Congenital dyserythropoietic anemia (CDA) is a rare group of inherited blood disorders. In CDA, young red blood cells in the bone marrow (erythroblasts) are oddly shaped and do not mature normally. Many are destroyed before they can work. The result is too few healthy red blood cells (anemia).

There are several types. Type II is the most common, followed by type I. The other types are rarer. Some centers now describe a fifth type, and up to half of all cases cannot be classified. Each type has a different genetic cause, but the signs overlap.

Most people with CDA have mild to moderate anemia. Some have severe anemia that needs frequent blood transfusions.

CDA is caused by changes (variants) in genes that guide red blood cell development. Type I is linked to the CDAN1 or CDIN1 gene, type II to SEC23B, type III to KIF23 or RACGAP1, and type IV to KLF1. In at least 10 in 100 people with type I, the cause is not known.

Types I and II are autosomal recessive. A child is affected when both copies of the gene have a change, one from each parent. Parents usually have no symptoms. Type IV, and type III caused by KIF23, are autosomal dominant. One changed copy is enough, and usually a parent is also affected.

Signs can include tiredness, weakness, yellow skin and eyes (jaundice), and a large liver and spleen. Gallstones are common in type II. Some people with type I have short stature or differences in the fingers or toes.

CDA makes the body absorb too much iron from food, even without transfusions. Over time, extra iron can damage the liver, heart and hormone glands. Transfusions add more iron.

Timing varies by type. Type I often shows in childhood or the teen years, and type II in the teen or young adult years. Type I and type IV are sometimes found before birth, and type IV can cause fluid build-up before birth (hydrops fetalis). Some people with type III develop a blood protein change called monoclonal gammopathy, which can lead to multiple myeloma.

Doctors think of CDA when someone has long-term anemia, jaundice or a large spleen and more common causes have been ruled out. First tests include a complete blood count, a reticulocyte (young red cell) count, bilirubin and iron tests. Other conditions, such as vitamin B12 or folate deficiency, hemoglobin disorders and immune causes, need to be ruled out.

A bone marrow test has long been the key step. Under the microscope, erythroblasts in CDA have typical shapes, such as two nuclei in type II. Electron microscopy can show a “Swiss cheese” pattern in type I.

Gene testing, using a panel of red cell genes from a blood sample, can confirm the type. It can sometimes avoid the need for a bone marrow test. In a North American registry, people with type I found by gene testing were diagnosed at a median age of 3.

Care depends on the type and how severe the anemia is. Some people need transfusions only as newborns or during infections or pregnancy. A small number need regular transfusions. Iron levels are checked over time, and iron-removal medicine (chelation) is used when iron builds up.

For type I, interferon alpha can raise hemoglobin and lower iron in some people. It is the only specific treatment for type I and is not used for the other types.

Removing the spleen (splenectomy) can modestly raise hemoglobin in type II. European experts suggest it for people with type II who have severe anemia or a troublesome large spleen. In type I, responses have been inconsistent. The same experts said it should probably be kept for worsening anemia, low platelet or white cell counts, or a very large, painful spleen. They made no formal recommendation. A North American registry team says it should not be done in type I. Some people also need their gallbladder removed.

A donor stem cell transplant is the only cure. It is used for people with very severe, transfusion-dependent CDA. In the largest study, from Europe, results were better with a matched brother or sister and without iron overload before transplant.

Because CDA is rare and looks like more common anemias, the diagnosis is often missed or delayed. In earlier reports, people with type I were diagnosed at a median age of about 17. Genetic testing now helps many people get a clear answer sooner.

Long-term care usually includes regular blood tests, iron checks and follow-up of the liver, heart and hormone glands. Problems in these organs become more important with age. In type I, thin bones (osteoporosis) are common, so bone health is checked too.

For the few people who consider a transplant, the decision weighs a possible cure against serious risks. These include graft failure, graft-versus-host disease and death from complications.

Most people with CDA never need a donor. For the few with severe, transfusion-dependent disease, a transplant gives them blood-forming stem cells from a donor, most often from bone marrow.

In a European registry study, 44 in 100 of the people transplanted had an unrelated donor. Survival was higher with a matched brother or sister than with an unrelated donor. The authors said this should be discussed with families when no family donor is available.

An unrelated volunteer can still make a transplant possible when no family member matches. In a series of 18 children from a pediatric transplant group, 13 had unrelated donors.

For most people, the outlook for CDA is good. Most have mild to moderate anemia and are not transfusion-dependent. Long-term health depends a lot on finding and treating iron overload, because iron can build up even without transfusions.

Iron overload can harm the liver, heart and hormone glands over time. In type I, thin bones are common. Some people with type III develop a blood protein change that can lead to multiple myeloma, which is one reason for regular follow-up.

For people with severe, transfusion-dependent CDA, a donor transplant can cure the anemia, but results are mixed. In the largest study, from Europe, survival was lower with an unrelated donor and with iron overload before transplant. A smaller study of children found no clear factor linked to results. None of these numbers can predict one person’s course.