Diagnosis

The following two criteria are considered diagnostic for DBA syndrome:

1. Pathogenic or likely pathogenic mutation in a gene known to cause DBA syndrome

• There are 27 confirmed and 7 suspected gene mutations that can cause DBA syndrome with the majority occurring in ribosomal protein (RP) genes.
• Non-ribosomal protein gene mutations that are confirmed to cause DBA syndrome are located in GATA1, TSR2, and HEATR3 genes
  

OR

2. Clinical hematologic features of DBA syndrome

• Macrocytic anemia – low hemoglobin with larger than normal mean cell volume (MCV) for age
• Reticulocytopenia – low number of reticulocytes (early red blood cells)
• Low number of red blood cell precursors in the bone marrow as found on a bone marrow aspirate and/or biopsy

Other Common Features of DBA Syndrome

• Onset of anemia at less than 1 year of age
• Elevated erythrocyte adenosine deaminase (eADA), drawn prior to transfusion, found in approximately 80-85% of DBA syndrome patients
• Elevated fetal hemoglobin (HbF) in patients over 6 months of age
• Congenital anomalies, which are seen in 50% of cases, commonly involve the head, upper limbs, heart, and genitourinary system
• Positive family history of DBA syndrome or anemia in infancy or childhood (not iron deficiency anemia)
• No evidence of another inherited bone marrow failure syndrome

Awareness of common and unique presentations of DBA syndrome is important for proper and timely diagnosis. It is important to identify these less common cases particularly when reproductive choices and transplant donor decisions are being made. Furthermore, as the risk of malignancy and other complications of DBA syndrome are better defined, the necessity of making a diagnosis in these “asymptomatic” individuals has become increasingly important. Cancer screening and surveillance at younger ages need to be considered, regardless of hematologic status.

Classic Presentation:

Most DBA syndrome patients present with macrocytic anemia and low reticulocyte counts during the first year of life. Other blood counts, such as white blood cells and platelets, are usually normal; however, some individuals present with neutropenia (low neutrophils) and thrombocytopenia (low platelets). Genetic mutations in RPL35A more often present with neutropenia and immunodeficiency, whereas GATA1 mutations may be accompanied by neutropenia and/or thrombocytopenia. Individuals with DBA syndrome do not typically present with destruction of red blood cells (hemolysis), enlarged liver (hepatomegaly), or enlarged spleen (splenomegaly).

Frequent Congenital Abnormalities:

Congenital abnormalities, or birth defects, occur in 40-50% of patients with DBA syndrome with ~25% of patients presenting with more than one anomaly. Individuals with large deletions tend to have complex anomalies and developmental delay. The most frequently observed abnormalities include cleft lip and/or palate, eye-related defects, thumb irregularities or missing thumbs, heart defects, and urogenital malformations. Short stature is common in DBA syndrome; however, chronic anemia, steroid treatment, and iron overload may also contribute to this finding. Due to the frequency of congenital anomalies in patients with DBA syndrome, careful physical examination by specialists and imaging studies (i.e., echocardiograph) are highly recommended.

Common Congenital Abnormalities:

• Short stature
• Face and head abnormalities (50% of patients)
  • Small head (microcephaly)
  • Cleft lip and/or palate
  • Low set and/or prominent ears
  • Drooped eyelids (ptosis)
• Abnormalities of the upper arm and hand (38% of patients)
• Heart defects (30% of patients)
  • Ventricular (VSD) or atrial septal defect (ASD)
  • Tetralogy of Fallot
  • Coarctation of the aorta
• Kidney defects (39% of patients)
  • Absent or horseshoe kidney
• Inguinal hernias
• Urogenital malformations
• Congenital glaucoma or cataracts
• Café-au-lait spots
• Learning difficulties
• Developmental delay

Unique Presentations:

Although less common, DBA syndrome may present at an age greater than 1 year, with only congenital anomalies, without anemia, or with only a mild hematological phenotype (i.e., macrocytosis only). With the advancement of genetic testing and clinical knowledge, an increasing number of adults are being diagnosed with DBA syndrome. Other less frequent presentations include:

• Mild anemia initially that becomes more severe later in life.
• A parent may be diagnosed after his/her child is diagnosed with DBA syndrome and the gene is found in both the parent and the child.
• Family members without anemia may have congenital anomalies and then found to have a DBA syndrome genetic mutation once their relative is diagnosed with DBA syndrome.

Essential Diagnostic Tests:

• Complete blood count (CBC) with differential, red cell indices, and reticulocyte count
• Erythrocyte adenosine deaminase (eADA)
• Fetal hemoglobin (HbF)
• Bone marrow aspiration and biopsy (morphology and cellularity)
• Parvovirus B19 PCR and/or serology
• DBA genetic workup/panel
• Imaging for congenital abnormalities: echocardiograph and full abdominal ultrasound

Test Details: 

Complete Blood Count (CBC): This test determines the concentration and composition of cellular components of blood. Values for the number of red blood cells, white blood cells, and platelets in a blood sample are included in the CBC. A CBC may be ordered with “differential” which measures the number of each type of white blood cell, such as neutrophils (ANC). Blood is typically drawn from a vein. In an infant or young child, blood may also be taken from the heel, toe, or finger. A CBC measures many things, including the following values which are generally relevant to the DBA patient:

• Number of red blood cells
• Total amount of hemoglobin in the blood
• Fraction of the blood composed of red blood cells (hematocrit)
• Size of the red blood cells, referred to as the mean corpuscular volume (MCV)
• Number of white blood cells and the percentage of each cell type present (percentage included in CBC with differential only)
• Number and size of platelets
• Other information about the red blood cells, including the mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC)

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 (macrocytosis). The MCV is measured during a standard CBC.

Reticulocyte Count (Retic): The retic count is the number of immature or young red blood cells. In mathematic terms, immature RBCs/Total RBCs x 100% = retic % count. The reticulocyte % count is a good measure of bone marrow activity, as it quantifies the production of red blood cells within the past 1-2 days. Without medication or being in remission, DBA patients typically have no or extremely low reticulocyte counts (less than 1%). The normal reticulocyte count in healthy individuals, with a normal number of RBCs, is 1 to 2%.

eADA Levels: This test measures the erythrocyte adenosine deaminase (eADA) activity 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 patient’s own blood, meaning it should not be conducted if the patient has had a transfusion in the previous 3 months.

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 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 and/or Bone Marrow Biopsy: A bone marrow examination is a test in which a small amount of bone marrow is removed, usually from the hip bone. A bone marrow aspiration removes only the liquid marrow, whereas a bone marrow biopsy also removes a very small piece of the bone. Pediatric patients typically receives sedation or anesthesia during this procedure. Once removed, the sample 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 as the health of the cells. The genetic makeup and physical architecture of the bone marrow can also be determined. The bone marrow in a patient with DBA typically reveals very few early red blood cells (reticulocytes). This test is typically recommended at the time of diagnosis, except for infants who may delay this test to just prior to starting steroids.

Genetic Testing: To date, approximately 70% of DBA patients have a single mutation or deletion in a gene encoding a ribosomal protein. A small percentage of patients have been identified with non-ribosomal protein gene mutations in GATA1, TSR2, and HEATR3. A genetic mutation has not yet been found for approximately 20-25% of patients with DBA. Genetic testing is conducted through a blood test, which typically analyzes DNA found in white blood cells. Therefore, even if a DBA patient has recently had a red blood cell transfusion, the patient’s DNA will be in the patient’s own white blood cells, which can be tested. See the Genetics section for more information on the genetic mutations which are known and suspected to be associated with DBA.

When a physician is trying to determine the cause of anemia or other symptoms, additional diagnoses may be considered. The following list contains other conditions which may present with 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, around the age of two years. As the name suggests, TEC is a transient form of anemia, from which patients completely recover.
• Parvovirus B19 (Fifth Disease): Parvovirus B19 is a virus that can 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 usually in days to weeks. Parvovirus in humans is a very different condition than the parvovirus seen in pets.
• Autoimmune Hemolytic Anemia: This is a condition in which antibodies attack and destroy red blood cells. This anemia is a treatable condition which is diagnosed by a Coombs or direct antiglobulin test.
• Other Inherited Bone Marrow Failure Syndromes (IBMFS): There are other inherited bone marrow failure syndromes which may present similarly to DBA, such as Shwachman Diamond syndrome, Fanconi anemia, and Dyskeratosis Congenita.
• Myelodysplastic Syndrome: This is often a pre-leukemic condition where the blood cells become abnormal and patients may present with anemia. This usually occurs in adulthood, but can be seen in childhood and adolescence in rare instances.
• 5q- Syndrome: 5q- syndrome is a subtype of myelodysplastic syndrome, which usually affects adults of an advanced age, not children. Most patients with this disorder present with anemia and require blood transfusion therapy.

Other less commonly encountered conditions resembling DBA syndrome that may be considered include Pearson syndrome, congenital sideroblastic anemia, ADA2 deficiency, other viruses (EBV, CMV, HIV), medications, autoimmune diseases, and some cancers.

If a genetic diagnosis is not found, a workup to rule out these and other conditions that may mimic DBA syndrome should be performed. The following tests are recommended in those without a confirmed diagnosis of DBA, but with similar symptoms:

• Bone marrow cytogenetics and biopsy
• Chromosome breakage
• Telomere length
• Fecal elastase
• Mitochondrial DNA genetics
• ADA2
• TP53 genetics
• Genetic workup/panel for other inherited bone marrow failure syndromes