What is Diamond Blackfan Anemia?
Anemia is a medical condition where a person has a lower than normal amount of hemoglobin, a component in red blood cells that helps carry oxygen. Anemia can be split into three types depending on the size of the red blood cells. The most common type across all age groups worldwide is iron deficiency anemia. But in this context, we are discussing a less common, genetically-caused anemia.
Diamond Blackfan anemia (DBA) is a rare inherited disorder that results in anemia along with abnormal bone development. It is an ongoing condition, and it causes larger than normal but not overly large red blood cells. Around 40 to 45% of DBA cases are inherited in an “autosomal dominant” pattern, meaning you only need a gene from one parent to get the disease. However, 55 to 60% of cases seem to occur randomly with no obvious pattern of inheritance. There are also some cases, although not as many, that follow an “autosomal recessive” pattern, meaning you need a gene from both parents to get the disease. It is also worth mentioning that while rare, an extreme accumulation of fluid in the body tissues and cavities (known as ‘hydrops’) may also occur as a part of DBA.
What Causes Diamond Blackfan Anemia?
Diamond Blackfan anemia is a condition often caused by a gene mutation. The most commonly seen mutation involves a protein on chromosome 11. But, newer studies have also found mutations of a specific factor known as GATA1.
These mutations involving the ribosomal genes are quite common and occur in about 60 to 70% of Diamond Blackfan anemia cases. They can happen in the gene that is responsible for making both small and large protein units, including RPL5, RPL11, RPS 7, RPS 17, RPS 24, RPS 10, RPS 19, and RPS 26. Also, in some families, mutations have been found in a large number of other genes such as RPL3, RPL7, RPL14, RPL19, RPL26, RPL36, RPL23A, RPL35, RPS 15, RPS 8, RPS27A, RPL35, and RPL18.
However, despite the clear link between gene mutations and the condition, the cause of 30 to 35% of Diamond Blackfan anemia cases remains unknown.
A defect in the creation of the ribosomal protein can cause the death of the cells that produce red blood cells, leading to a failure in the production of these cells. This phenomenon is called ‘ribosomal stress.’ Up to half of Diamond Blackfan anemia cases also have a mutation of the ribosomal gene that results in a loss of function.
Risk Factors and Frequency for Diamond Blackfan Anemia
Diamond Blackfan anemia is a rare disease that mostly begins within a baby’s first year of life. It is an uncommon condition, affecting about 1 in 500,000 newborns. It occurs equally among different ethnic groups and in both males and females.
Signs and Symptoms of Diamond Blackfan Anemia
Diamond Blackfan anemia (DBA) is a medical condition that mostly starts in patients under the age of one year. Approximately half of the cases involve bone deformities at birth and about a third experience slowed growth. The usual symptoms that appear first in children include lethargy and paleness.
When a patient has DBA, they usually experience severe macrocytic and normochromic anemia, which is due to a birth defect causing bone marrow failure. It’s typical for platelet and white blood cell counts to be within normal limits, but some patients have seen low white blood cell counts and high platelet counts. Importantly, patients can have extremely low reticulocyte counts. DBA has also been linked with increased levels of fetal hemoglobin, erythropoietin, and eADA activities.
Diamond Blackfan anemia varies in intensity from mild to severe. Physical abnormalities are found in about half of all cases. The most commonly seen physical abnormalities include deformities of the thumb and upper limbs, abnormalities of the face, and short stature. Some patients may exhibit a pug nose and wide-set eyes. DBA-specific abnormalities often include a particular appearance of the face and a thumb with three phalanges.
There are also links between specific mutations and physical anomalies. For example, PRL5 mutations are associated with a cleft lip or a cleft soft palate. On the other hand, the RPL11 mutation largely aligns with abnormalities of the thumb but can also be found in cases of a cleft lip or palate.
Apart from these, patients can also exhibit urogenital anomalies, atrial septal defects, and ventricular septal defects.
The diagnostic criteria for Diamond Blackfan anemia include:
- Onset of the illness before the age of 12 months
- Macrocytic anemia without other significant blood cell deficiencies
- Reticulocytopenia, which means having lower than normal levels of young red blood cells
- Normal bone marrow cellularity but a lack of early red blood cell
Other factors that support a diagnosis of Diamond Blackfan anemia include:
- A gene mutation that has been described in DBA
- A positive family history
- Increased ADA activity
- Birth anomalies described in classical DBA
- Increased HbF (fetal hemoglobin)
- No evidence of another inherited bone marrow failure syndrome
Testing for Diamond Blackfan Anemia
After observing symptoms that suggest Diamond Blackfan Anemia (DBA), doctors need to carry out specific lab tests to make a final diagnosis.
One test measures erythropoietin (a hormone that regulates red blood cell production) levels. In DBA, these levels are unusually high. This happens because the body lacks enough EPO receptors. Other crucial tests include immune phenotyping (which studies the various immune cells in your body) and IgG/IgA (types of antibodies) agglutinin titer to support the diagnosis.
Additionally, a process named molecular diagnosis is essential. It starts with a bone marrow evaluation that helps describe the disease’s nature. After that, molecular tests are conducted to identify any gene mutations typically associated with DBA.
There are three main types of these molecular tests, which include serial single-gene testing and multigene panel. These tests aim to find out if there’s a ‘heterozygous pathogenic variant’, which means a certain kind of abnormal gene often found in DBA patients.
Also, because the Parvovirus B19 is commonly associated with bone marrow failure, it is crucial to rule out its presence. Tests for this include blood serology or a blood Parvovirus B19 PCR examination.
Lastly, a common blood tests series is conducted. This includes a complete blood count, a hemoglobin F test, an ADA (Adenosine Deaminase) test, an erythropoietin level measure, a reticulocyte count (young red blood cells), and an examination of a peripheral blood smear (a drop of blood observed under a microscope).
Treatment Options for Diamond Blackfan Anemia
Corticosteroids are the main treatment used for Diamond Blackfan anemia, a rare blood disorder. However, as these have long-term side effects, patients often need regular blood transfusions and therapy to get rid of excess iron in their bodies.
If a patient reacts positively to the steroid treatment but experiences too many side effects, they may need regular blood transfusions instead. The aim is to maintain a level of hemoglobin, an iron-rich protein in the blood, of 8 grams per deciliter and they would need a transfusion approximately every 35 weeks. Regular checks on the patient’s ferritin levels, which show the amount of iron in the body, determine if therapy is needed to remove excess iron. Typically, iron removal therapy is initiated after 12 to 15 units of blood transfusions if the concentration of ferritin increases in the serum, or if the amount of iron in the liver expands.
When iron removal is necessary, the treatments used are deferasirox and desferrioxamine. Deferiprone, however, is not recommended due to its harmful effect of reducing white blood cells.
The exact way corticosteroids work to treat Diamond Blackfan anemia is not fully understood, but it is believed to protect blood-making cells from dying. Metoclopramide, a medication used to treat nausea, can be added to the steroid treatment to decrease the steroid dose and manage the side effects. Trials also suggest leucine, an amino acid, as a reinforcement treatment to steroids.
Treatment can also include a procedure known as hematopoietic stem cell transplantation (HSCT), where healthy blood-making stem cells are introduced to replace the diseased cells. This treatment is the only one that can potentially “cure” the blood disorder symptoms of Diamond Blackfan anemia, but it carries risks particularly if a compatible donor, like a sibling, does not exist. This therapy works successfully in younger patients treated with stem cells that match perfectly. It is suggested as an option if the patient does not respond to regular blood transfusions or if they experience side effects due to excess iron. However, HSCT also has its own drawbacks, such as infection and a condition where the donated cells attack the patient’s body.
Newer treatments such as gene therapy and gene editing show promise in future treatments for Diamond Blackfan anemia. The difference between these and HSCT is in the source of the stem cells used. Ingene therapy, the patient’s own normal stem cells are used, and a correct version of the faulty gene is inserted. In HSCT, the stem cells come from a donor.
About 25% of Diamond Blackfan anemia cases involve a mutation in the RPS19 gene. Therefore, gene therapy that replaces a normal RPS19 gene might help these patients by getting rid of the symptoms. Viral vector systems are commonly used in gene therapy and show high success rates and acceptable safety profiles.
Additionally, around 20 – 25% of patients with Diamond Blackfan anemia spontaneously get better without treatment.
What else can Diamond Blackfan Anemia be?
Diamond Blackfan Anemia is a unique blood-related disorder in which the body fails to produce enough red blood cells, unlike other disorders that cause overall bone marrow failure (BMF). Other BMF conditions could include Fanconi Anemia, Shwachman Bodian Diamond Syndrome, Cartilage-hair Dysplasia, and Dyskeratosis Congenita.
Here are a few examples of conditions that cause bone marrow failure:
- Transient Erythroblastopenia of Childhood (TEC) – This is a rare condition that affects red blood cells. It typically occurs in children around the age of one. Unlike Diamond Blackfan Anemia, only 10% of affected individuals have high levels of eADA, and the anemia is normocytic.
- Fanconi Anemia – This BMF disorder results in a low count of all types of blood cells and typically results in physical abnormalities during early childhood.
- Shwachman-Diamond Syndrome – This condition is usually characterized by digestive problems, blood cell issues, slow growth, bone irregularities and higher risk of blood cancer.
Some other genetic conditions like Pearson Syndrome, Dyskeratosis Congenita, Cartilage-hair Hyperplasia, Thrombocytopenia Absent Radii Syndrome, and Congenital Amegakaryocytic Thrombocytopenia also cause bone marrow failure. Each of these conditions comes with a unique set of symptoms and usually manifest during infancy or childhood. For instance, Pearson Syndrome causes anemia in children, liver failure, and kidney defects; it’s generally fatal in infancy.
Furthermore, bone marrow failure can be caused by certain acquired conditions. These may include certain viral infections and autoimmune diseases or be a side-effect of certain medications.
What to expect with Diamond Blackfan Anemia
The outlook for patients is generally good, but complications arising from treatment may have an impact on their quality of life. Serious complications due to treatment or the onset of cancer may shorten their life expectancy. The severity of the disease is assessed based on the quality of life and response to treatment.
Possible Complications When Diagnosed with Diamond Blackfan Anemia
Those suffering from Diamond Blackfan anemia are often likely to develop a blood complication within their first year of life. This condition brings a high risk of developing illnesses like AML, MDS, and certain forms of cancer.
Other complications can also occur, which are often connected to an overload of iron due to blood transfusion, the chronic use of steroids, and hematopoietic stem cell transplantation (HSCT). Such complications can include growth failure, organ failure, and infection.
Common Complications:
- Development of blood complications
- Acute Myeloid Leukemia (AML)
- Myelodysplastic Syndromes (MDS)
- Solid tumors
- Growth failure
- Organ failure
- Infections
Preventing Diamond Blackfan Anemia
Patients with the condition known as DBA often need to have regular full blood count tests. Occasionally, a procedure where a small sample of bone marrow is taken may be necessary, as this can help to identify any new blood disorders or a failure of the bone marrow to work properly. It’s also important to closely monitor those who need steroids or blood transfusions, as these individuals are at an increased risk of their organs not working correctly. Sometimes, these patients might need to see a specialist in hormone disorders (an endocrinologist). Even patients with DBA who are in good health should have a check-up, including a blood test, every 4 to 6 months to ensure there aren’t any signs of cancer. A quick drop in any type of blood cell could mean bone marrow failure, and a bone marrow sample along with genetic tests may be needed to look for any unusual changes in the chromosomes that might indicate cancer.”
Family members of someone with DBA are also at risk of developing the condition. This is because around 40 to 45% of patients with DBA inherit a genetic variant from a parent which is associated with the condition. And in some cases, the DBA is linked to the X chromosome. If it is known that someone has a genetic variant linked to DBA, then it might be a good idea for them to have genetic testing. This could mean other blood tests could be done earlier to check for DBA and any signs of cancer.”
About 55 to 60% of people with the DBA condition have a brand-new genetic variant that is not inherited from a parent. This could be because of different biological parents, such as through assisted reproduction treatments or adoption.”