What is Diamond Blackfan Anemia (DBA)?

An Overview of Diamond-Blackfan Anemia (DBA)

DBA is a relatively new diagnosis and is considered an extremely rare genetic blood disorder, affecting only 25 babies born worldwide each year. Children are usually diagnosed with DBA within their first year of life. Typically, the baby is brought to a doctor or hospital for lethargy, pallor, weakness, and/or trouble feeding. They are diagnosed with severe anemia and given life-saving blood transfusions. Many lab and imaging tests are done to try to determine the cause of the anemia. When bleeding, internal hemorrhaging, and abnormally formed or faulty RBCs are ruled out (like in sickle-cell anemia), doctors begin looking for destructive or generative causes of anemia. Over the next several months, doctors attempt to rule out destructive causes of red blood cell loss, such as auto-immune disease, problems with the spleen or liver, and viruses.

A bone marrow biopsy is performed, perhaps multiple times, to see what kinds of blood cell precursors are being made in the marrow. If there is also a lack of white blood cells and/or platelets, leukemia is suspected. If the bone marrow shows that those cells are normal or near-normal, but there are only a few red blood cell precursors, doctors suspect the anemia is due to a red blood cell generative dysfunction, and the child is given an umbrella diagnosis of bone marrow failure.

There are many reasons for bone marrow failure. Again, it could be due to a virus. It is most likely, however, that there is something faulty with the mechanism that makes red blood cells. Something in the process is not right. This process is highly complicated and not fully understood. But the likelihood is that there is a genetic component, so the doctors begin to search for a responsible, faulty gene.

The doctors order several genetic tests, as there are many genetic diseases that are linked to the bone marrow’s failure to make healthy RBCs. These tests are expensive and time-intensive. There are several different genes that have been associated DBA. The doctors first check a few genes most commonly associated with DBA. If those are negative for mutation, they search the lesser likely genes, in groups of 3-7. They do the tests in groups because the tests are expensive and require a lot of blood, which is the one thing an anemic child simply cannot spare. The doctors keep checking genes until they run out of ideas, or of genes already associated with DBA. In 40-50% of cases, they do not find a gene with a mutation. In these cases, the children are still diagnosed with DBA, because there is no other explanation for their symptoms.

Many times, DBA is expressed only as a problem making red blood cells. Other times, children with DBA have additional physical challenges, like differently shaped thumbs or short necks (which may create difficulty with achieving a full range of motion in rotation, due to a missing vertebra). Some genetic mutations have more incidence of physical expression than others.

The mutated genes are dominant, meaning that if one parent has a gene mutation associated with DBA and the other parent doesn’t, their children are more likely to inherit the mutated gene. Interestingly, sometimes, neither parent has the mutated gene, and the child is considered to have a spontaneous genetic mutation. Also interestingly, having a genetic mutation associated with DBA does not mean that the child will have any symptoms or problems. In a given family of multiple children, one child could have a genetic mutation associated with DBA and bone marrow failure or other symptoms, and the other children might have the same genetic mutation but express no signs of DBA at all.

The only accepted curative treatment for DBA is a bone marrow transplant. However, this procedure is risky and requires chemotherapy to kill off the child’s own stem cells before replacing them with donor cells. If a child had a sibling bone marrow match, then that transplant has the greatest likelihood of success. If parents hope to conceive a child with a bone narrow match, there is only a 20% likelihood of a sibling having a perfect genetic match, which is necessary for bone marrow transplant.  There is also the chance of the baby is a perfect match, but also has the mutated gene for DBA, which would then disqualify it as a match. The only way to guarantee a viable match is to do in-vitro fertilization and find an embryo that is a perfect match and doesn’t have DBA, and then implant this embryo back into the mother’s womb. The highest likelihood of a successful bone marrow transplant is when the child receives the bone marrow from a sibling, not a stranger, and when the child receives the transplant between 2-5 years old.  Bone marrow transplants are very risky procedures, and can be fatal.

The primary treatment for DBA is a blood transfusion as often as the child requires them.  Typically, this means transfusions are necessary every 2-4 weeks. The problem with transfusion dependence is that transferred red blood cells contain a lot of excess iron, and the body does not have a good mechanism for getting rid of excess iron. Instead of excreting the excess iron, the iron becomes stored in heart, liver, and pancreas tissues. After multiple transfusions, typically somewhere between 10-20, the child may begin to suffer iron overload.  Iron overload is asymptomatic, meaning that there are no observable signs that iron levels are approaching a lethal level.  Iron overload is extremely dangerous, as the excess iron eventually causes organ failure (typically heart or liver failure) and death.

If a child is transfusion dependent and develops iron overload, the iron must be chelated out of the body.  Iron overload is measured via two primary ways:  ferretin and t2* MRI.  Ferretin is an imperfect measurement of iron, as it can also increase when there is inflammation in the body, such as a result of an infection.  Normal ferretin levels are below 200.  Ferretin levels approaching 1000 are considered dangerous and need chelation therapy. Because ferretin levels may be normal, and the body is still accumulating a dangerous level of iron in the heart or liver, doctors will eventually recommend a t2* MRI to check for iron in vital organs.  Young children must be sedated for the MRI, and because sedation is risky in itself (and could cause death), doctors typically do not recommend an MRI until the child is two years old or older.

To treat iron overload, doctors will recommend using a pharmaceutical chelating agent given orally (or in extreme cases via an overnight IV), that binds to the iron for removal.  The oral chelation agent must be taken daily in order to be effective.  Side effects of the oral chelator include stomach pain, gastrointestinal complaints such as diarrhea, and liver and kidney failure.  Children on oral chelation must be monitored at every tranfusion in order to be sure that their livers and kidneys are still functioning.  They also need monitored yearly to ensure that they do not suffer hearing or vision loss.  If the child develops liver or kidney failure, or loss of vision or hearing, oral chelation is terminated and IV therapy will begin.  IV chelation therapy may be conducted in hospital or at home, depending on the severity of the situation.

Pharmaceutical chelation therapy agents are not ideal, as they can cause a number of undesirable side effects.  In iron overload, however, iron chelation is necessary and life-saving.  Blood transfusions, while risky in their own right, can continue indefinitely as long as iron levels remain low and the child’s body tolerates transfused blood, and does not create antibodies against it.  For this reason, blood is carefully screen and treated so that there is less risk of a transfusion reaction.  When frequent transfusions are required, doctors may recommend placing a port in the body, as continued needlesticks can damage vasculature and make placing an IV difficult. Ports can become infected and must be kept clean. If a child develops a fever while a port is in place, he or she should be taken to the hospital immediately to prevent the infection from spreading through the blood and creating blood sepsis, or toxicity, which can be fatal.

After the child is 9 months to one year old, some doctors recommend a steroid trial. Since DBA is accepted as a genetic disease, there is no rationale behind why steroids help the bone marrow to produce blood.  Yet, in 70-80% of cases, when children take steroids, the bone marrow begins making enough red blood cells for the child to no longer require transfusions. The steroid dosage starts relatively high. For the next 4-6 weeks, the reticulocyte count (baby red blood cells in the blood) is monitored closely.  If it increases, it is a sign that the steroids are working. Once the child no longer requires transfusions, the steroid dosage is very slowly lowered, over a period of months. It is important to lower the dosage slowly, because if done too quickly and the child becomes anemic and requires transfusion again, there is less likelihood that the bone marrow will respond to the steroids a second time.  Steroid-use must also be lowered slowly because if it is done too quickly,  it can cause other serious symptoms of steroid withdrawal.  The lowest dose necessary to sustain stable RBC production is continued indefinitely. In some cases, the eventual dosage necessary to sustain RBC production is so low that it is essentially homeopathic (i.e., the amount of steroids is so small that it is considered medically impossible to have any effect from a physical or chemical perspective, and yet it does.) Some children are able to eventually wean themselves off steroids altogether, and still produce RBCs.

If the child does not seem to respond to steroids within 3-6 months, the trial is ended.  Doctors may advise waiting 3-4 months and then trying the steroid trial again, as some children do not respond the first time but will respond to the second trial.  This cycle could continue indefinitely, until the doctors or parents decide to accept that it is not working.

Short-term use of steroids causes fat to deposit in the body, particularly in the face, and mood disturbances.   Short stature (stunted growth) may result from even a short-term steroid trial.  Long-term use of steroids, especially in children, causes the above side effects and additional ones, and some of them are very serious.  Long-term use of steroids does stunt growth and causes hormonal changes that can manifest as increased hair growth and other secondary sex characteristics.  Growth during the first (and some say second) year of life is extremely important to achieving final adult height, and growth lost during this time due to steroid use cannot be recovered later. (Some doctors will dismiss the fact that steroids stunt growth, claiming that DBA stunts growth anyway.  However, this is not necessarily true. Adahlia, for example, continues to grow normally and is above the 50 percentile for her age in height.)

Steroids decrease the immune system response when taken both short-term and long-term, which can be extremely dangerous if the child is exposed to viral or bacterial pathogens.   Long-term steroid use, even at a low dose, can cause insulin resistance and diabetes in children.  Long-term, low-dose steroid use can also cause other hormone imbalances, such as making the body unable to produce cortisol on its own, which is a vital hormone.  Additionally, the ongoing use of even low-dose steroids can also cause bone density loss in children, leading to increased risk of fractures and other bone problems.

DBA is a mysterious disorder, and it is even more mysterious how it sometimes vanishes. (How does a genetic disorder just suddenly go away on its own?)  Currently, approximately 20% of children diagnosed with DBA will go into what doctors call spontaneous remission. It often happens around 1-2 years, but it has happened to children going through puberty.  Both transfusion-dependent and steroid-dependent children have experienced remission.  It is possible that those in remission will never have anemia again in their lives. However, stressful or hormonal events such as pregnancy has caused patients to relapse and require blood transfusions again.  Those with DBA also have a higher incidence of cancer, particularly leukemia.

Some accounts of spontaneous remission are mysterious because they seem to be tied to medicine therapies other than steroids. One child went into remission after his parents took him to a nutritionist. The nutritionist noted that the boy was very low in certain amino acids, particularly leucine. He was put on high-dose supplements, and since that time, he has not needed blood transfusions. He continues to take high doses of amino acids.  There is currently an in-process scientific study in the USA on the therapeutic use of leucine as a treatment for bone marrow failure.

Another child with DBA was once taken to the hospital with a life-threatening condition unrelated to DBA. Doctors administered valproic acid intravenously, which can be used as an antiviral or anticonvulsant, and is also known to induce fetal hemaglobin. From that point, the child’s symptoms of DBA went into remission.

Another interesting case is that of a man with DBA, now in middle age, that needed to have his spleen removed for reasons not directly attributable to DBA.  Once his spleen was removed, he went into remission for DBA and has not needed a transfusion since.

All scientific journal articles call for further research and investigation of DBA.  They emphasize the importance of finding effective treatments that do not cause harmful side-effects like steroids. Some of the best articles also remind scientists to be mindful of the human aspect of DBA, as new patients are typically very young babies, and their parents are often new parents.

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