Diagnosis

There are over 800 patients with DBA registered with the DBA Registry (“DBAR”). Each year, approximately 25 to 35 new cases of DBA will be diagnosed in the United States and Canada. DBA is an equal opportunity syndrome, affecting males and females and all ethnicities equally. Most patients are diagnosed with DBA within the first year of life.

According to the DBAR, the average age of presenting with anemia is two months and the average age of diagnosis with DBA is four and a half months. Patients with DBA typically present with common symptoms of anemia, including pale skin, sleepiness, irritability, rapid heartbeat, and heart murmurs.

Diagnostic criteria for Diamond Blackfan Anemia taken from the International Clinical Care Consensus Document (2008):

  • Age less than 1 year
  • Macrocytic anaemia with no other significant cytopenias
  • Reticulocytopenia
  • Normal marrow cellularity with a paucity of red cell precursors
  • Near normal, but variable, neutrophil and/or platelet counts

Supporting criteria:

Major

  • Gene mutation described in “classical” DBA
  • Positive family history

Minor

  • Elevated erythrocyte adenosine deaminase activity
  • Congenital anomalies described in “classical” DBA (Congenital anomalies mainly involve the head, upper limbs, heart, and genitourinary system.)
  • Elevated HbF (fetal hemoglobin)
  • No evidence of another inherited bone marrow failure syndrome

The above diagnostic criteria define what is termed “classical” DBA, but DBA may also present in “nonclassical” ways. For example, individuals may present at an age greater than one year, only with congenital anomalies, without anemia or with a mild hematological phenotype (macrocytosis only). These cases of ‘‘non-classical’’ DBA need to be more carefully identified, particularly when reproductive choices and transplant donor decisions are being made. Furthermore, as the risk of malignancy and other complications of DBA are better defined, the necessity of making a diagnosis in ‘‘asymptomatic’’ individuals will become more important.

There are several tests to aid in diagnosing DBA

Complete Blood Count (CBC): A test that determines the concentration and composition of cellular components of blood. Included in the CBC are values for the number of red blood cells, white blood cells, and platelets in a blood sample. Blood is typically drawn from a vein. In an infant or young child, blood may also be drawn from the heel, a toe, or a finger. A CBC measures many things, including the following values which are generally relevant to the DBA patient:

  • The number of red blood cells
  • The number of white blood cells and the percentage of each type present
  • The number and size of platelets
  • The total amount of hemoglobin in the blood
  • The fraction of the blood composed of red blood cells (“hematocrit”)
  • The size of the red blood cells, referred to as the mean corpuscular volume (“MCV”)
  • A CBC also includes other information about the red blood cells, including the mean corpuscular hemoglobin (“MCH”) and mean corpuscular hemoglobin concentration (“MCHC”)

Reticulocyte Count (Retic): Number of immature or young red blood cells. Immature RBCs/Total RBCs x 100% = retic count. The reticulocyte count is a good measure of bone marrow activity, as it quantifies the production or red blood cells in the past day or two. Without medication or being in remission, DBA patients typically have no or an extremely low reticulocyte count (usually less than 1%). The normal reticulocyte count in healthy individuals is 1 to 2%.

Coombs Test: The Coombs test looks for antibodies that destroy red blood cells. Such antibodies are not typically present in DBA patients. This test is done to rule out the possibility of hemolytic anemia, which is a condition in which the body is destroying red blood cells. This test can be done anytime, including after a transfusion. Virtually all patients with DBA will have a negative Coombs test.

eADA Levels: This test measures the erythrocyte adenosine deaminase activity (“eADA”) in the blood. Elevated eADA levels are present in approximately 80-85% of patients with DBA. This test must be performed on a sample of the patients own blood, so it should not be conducted if the patient has had a transfusion in the previous 3 months.

MCV: The mean corpuscular volume (“MCV”) is a measure of the size of the red blood cells. Patients with DBA tend to have larger than normal red blood cells (macrocystis). The MCV is measured during a standard CBC.

Fetal hemoglobin levels: In utero, the fetus makes two kinds of hemoglobin: fetal hemoglobin (sometimes called Hemoglobin F) and adult hemoglobin (sometimes called Hemoglobin A). At birth, the majority of the hemoglobin present is fetal hemoglobin. During the first year of life, the percentage of fetal hemoglobin drops to 0 less than 5% in most healthy individuals and the percent of adult hemoglobin rises to 95-100%. However, many patients with DBA maintain an increased level of fetal hemoglobin. The fetal hemoglobin test can be confusing after a patient has had a transfusion, but it still may be possible to run this test.

Bone Marrow Aspiration or Bone Marrow Biopsy: A bone marrow biopsy is a test whereby a small amount of bone and bone marrow are removed usually from the hip bone. A bone marrow aspiration removes only the marrow; a bone marrow biopsy also removes a very small piece of the bone. A patient typically receives sedation or anesthesia during this procedure. The marrow is then analyzed to determine how many blood cells of each type (red blood cells, white blood cells and platelets) are being produced by the bone marrow, as well how healthy they are. The genetic makeup of the bone marrow and the physical architecture of the bone marrow can also be determined. The bone marrow in a patient with DBA typically reveals that very few new red blood cells are being created.

Genetic Testing: To date, approximately 65% of DBA patients have a single mutation in a gene encoding a ribosomal protein. Recent discoveries have identified non-ribosomal protein gene mutations, including GATA1 mutations. A genetic mutation has not yet been found for approximately 35% of patients with DBA. Genetic testing is conducted through a blood test, which typically analyzes the white blood cells. Therefore, even if a DBA patient has recently had a red blood cell transfusion, the patient’s blood will contain the patient’s own white blood cell, which can be tested. The most common gene mutation seen in DBA patients is found on the RPS19 gene, which is seen in 25% of patients registered with DBAR. The following genetic mutations are known to be associated with DBA:

  • RPS19: seen in ~25% of patients
  • RPL5: seen in ~7% of patients
  • RPL11: seen in ~5% of patients
  • RPL35a: seen in ~3% of patients
  • RPS26: seen in ~3-6% of patients
  • RPS24: seen in ~2% of patients
  • RPS17: seen in ~1% of patients
  • RPS7: seen in ~1% of patients
  • RPS10: seen in ~3-6% of patients
  • RPL19: unknown
  • RPL26: unknown
  • RPS29: unknown
  • RPL31: unknown
  • RPS 28: unknown
  • RPS20: unknown
  • RPL15: unknown
  • RPL17: unknown
  • GATA1: unknown
  • TSR2: unknown

Research is on-going here in the United States and around the world to identify additional genes that might be associated with DBA.

Other potential diagnoses

When a physician is trying to determine the cause of anemia, other diagnoses may also be considered. The following list contains some other conditions which may cause anemia that is similar to the anemia associated with DBA.

Transient Erythroblastopenia of Childhood (“TEC”): TEC is a slow developing anemia that occurs when the bone marrow temporarily stops making red blood cells.This most often occurs following a viral infection. TEC usually occurs early in childhood, typically around the age of two. As the name suggests, TEC is a short-term form anemia, from which all patients completely recover.

Fifth Disease or Parvovirus: This virus can also cause the bone marrow to temporarily stop producing red blood cells, resulting in a dramatic drop in the patient’s hemoglobin level. As the patient’s body recovers from the virus, the bone marrow will start making red blood cells again, and the hemoglobin will return to normal levels. Parvovirus in humans is a very different condition than the parvovirus seen in pets.

Auto-immune Hemolytic Anemia: Auto-immune hemolytic anemia is a condition in which antibodies attack and destroy red blood cells. This is a treatable condition which is diagnosed by a Coombs test.

Other Inherited Bone Marrow Failure Syndromes: There are other inherited bone marrow failure syndromes which may present similarly to DBA, including Shwachman Diamond syndrome and Fanconi anemia, and myelodysplastic syndrome.

5q- Syndrome: 5q- is a subtype of a myelodysplastic syndrome, which affects adults of an advanced age, not children. Patients with this disorder require blood transfusion therapy.