Ask the Hematologist September-October 2009

An eleven-month-old boy with severe macrocytic anemia was referred to a pediatric hematologist. His hemoglobin was 2.1 g/dL, MCV 103 fL; hemoglobin electrophoresis showed an elevated HbF of 9.6 percent. The reticulocyte count was 0.1 percent. B12 and folate were normal and the infant was emergently transfused and observed. A diagnosis of transient erythroblastopenia of childhood was made, but following a third monthly transfusion, the diagnosis was reconsidered and Diamond-Blackfan anemia (DBA) was suspected. A heart murmur was confirmed by echocardiography to be a ventricular septal defect (VSD). A bone marrow aspirate showed erythroid hypoplasia consistent with DBA. At about 14 months of age, the patient was transfused to a hemoglobin level of 8.0 g/dL and placed on oral prednisone, 2mg/kg per day. Within two weeks the reticulocyte count was 6.6 percent and the hemoglobin had risen to 9.0 g/dL. The blood counts of the family revealed the father and nine-year-old sister to have mild macrocytic anemia (hemoglobin 11.5 g/dL, MCV 106 fL (father); hemoglobin 10.2g/dL, 98 fL (sister). Erythrocyte adenosine deaminase (eADA) activity on the family and mutation analysis of the RPS19 gene are pending.

Diamond-Blackfan anemia, first reported in 1936 and more completely described in 1938, is one of a heterogeneous group of disorders characterized by pro-apoptotic hematopoiesis, bone marrow failure, birth defects, and cancer predisposition known as the inherited bone marrow failure syndromes (IBMFS). The IBMFS essentially consist of Fanconi anemia and dyskeratosis congenita, both characterized by pancytopenia, and the predominantly single-cell cytopenias DBA, Kostmann syndrome and Shwachman Diamond Syndrome (neutropenia), and amegakaryocytic thrombocytopenia. The classic diagnostic criteria for DBA are: anemia presenting prior to the first birthday with near normal or slightly decreased neutrophil count, variable platelet counts (often increased), macrocytosis, and normal bone marrow cellularity with a paucity of red cell precursors. With the discovery of the first DBA gene, it has become evident that non-classical cases abound. An index of suspicion for DBA must be maintained in patients presenting beyond the first year of life (even into adulthood), patients with mild or no anemia with consistent congenital anomalies, and completely non-expressing heterozygotes for the dominant mutation in order to avoid delays in diagnosis or misdiagnoses. Awareness of the “non-classical” presentations will lead to an earlier diagnosis

The differential diagnosis of pure red cell aplasia depends upon the presentation and age of the patient. The more common diagnosis for a child with pure red cell aplasia is acquired transient erythroblastopenia of childhood (TEC). Elevated eADA activity is found in about 85 percent of cases of DBA. Other disorders that may present with an aregenerative anemia include Pearson syndrome, parvovirus B19, HIV and other infections, and drug-, toxin-, or immune-mediated disease. The diagnosis of thymoma should be considered in adults, as it rarely occurs in children. DBA is diagnosed in adults more often than previously thought, although other causes of red cell failure are more common. Finally, the other IBMFS should be considered since macrocytic anemia may be an early hematologic manifestation.

Due to the variable penetrance and expressivity of DBA, it has been difficult to ascertain the inheritance pattern for DBA. It seems clear, however, that the vast majority of cases are inherited as an autosomal dominant. However, some multiplex pedigrees suggest possible recessive inheritance, although there is no proof of this and some apparent recessive cases are actually dominant or due to gonadal mosaicism. In the family described above, there is dominant inheritance with weakly expressed phenotypes (mild anemia and macrocytosis). The identification of a mutation in RPS19, described in 25 percent of cases, would confirm the diagnosis of non-classical DBA in the father and sister of this classically affected infant. The failure to recognize “occult” non-classical DBA in the family could result in uninformed reproductive choices and the possibility of using a DBA-affected family member as a stem cell transplant donor.

Although the mechanism of steroid response is not understood, about 80 percent of patients have an initial response, and around half of those can be maintained (prednisone, <0.5 mg/kg/day or <1 mg/kg/every other day) with adequate hemoglobin levels and minimal side effects. For those who do not respond or cannot be maintained on steroids, red cell transfusions with iron chelation are the standard treatment. Although somewhat controversial, allogeneic HLA-matched related stem cell transplant, when available, should be considered. For children under 10 years of age, transplant cure can be achieved in over 90 percent of cases. Alternative donor transplants should be reserved for DBA patients who progress to other significant cytopenias, myelodysplasia, or leukemia.