Etiology

The primary defect in DBA is intrinsic to the erythroid progenitor cell and results in increased apoptosis (programmed cell death). High levels of erythropoietin (EPO) are present in serum and urine, although mutations in the EPO receptor gene have not been identified. In about 25% of cases, mutations are seen in the gene RPS19, which codes for a ribosomal protein mapped to chromosome 19q13.2. De novo mutations have also been found in the genes RPS24 and RPS17, located at chromosome 10q22-q23 and 15q25.2, respectively, and also coding for ribosomal proteins. Mutations have also been found in large ribosomal subunit proteins.

Epidemiology

Approximately 40-45% of cases of DBA are familial, with an autosomal dominant pattern of inheritance. The others are either sporadic or familial, with varying inheritance patterns.

Clinical Manifestations

Although hematopoiesis is usually adequate in fetal life, some affected infants appear pale at birth or in the first days after birth; rarely, hydrops fetalis occurs. Profound anemia usually becomes evident by 2-6 mo of age, occasionally somewhat later. Growth retardation (short stature) is recognized in about 30% of children, and congenital malformations are noted in about 35-45%. Craniofacial abnormalities are the most common anomalies and include hypertelorism and snub nose. Thumb abnormalities, including flattening of the thenar eminence and triphalangeal thumb, may be bilateral or unilateral. The radial pulse may be absent. Ophthalmologic, urogenital, cardiac, musculoskeletal, and neuromotor anomalies have also been identified. Overall, the abnormalities are diverse, with no specific pattern emerging among most of those affected.

Laboratory Findings

The RBCs are usually macrocytic for age, but no hypersegmented neutrophils or other characteristics of megaloblastic anemia are appreciated on the peripheral blood smear. Chemical evaluation of the RBCs reveals an enzyme pattern similar to that of a “fetal” RBC population with increased expression of “i” antigen and elevated fetal hemoglobin (HbF). Erythrocyte adenosine deaminase (ADA) activity is increased in most patients with this disorder, a finding that helps distinguish congenital RBC aplasia from acquired transient erythroblastopenia of childhood (Chapter 444). Because elevated ADA activity is not a fetal RBC feature, measurement of this enzyme may be particularly helpful when diagnosing DBA in very young infants. Thrombocytosis or rarely thrombocytopenia and occasionally neutropenia also may be present. Reticulocyte percentages are characteristically very low despite severe anemia. RBC precursors in the marrow are markedly reduced in most patients; other marrow elements are usually normal. Serum iron levels are elevated. Bone marrow chromosome studies are normal and, unlike in Fanconi anemia, there is no increase in chromosomal breaks when lymphocytes are exposed to alkylating agents.

Differential Diagnosis

DBA must be differentiated from other anemias with low reticulocyte counts. The syndrome of transient erythroblastopenia of childhood (TEC) is often the primary alternative diagnosis. Table 444-1 in Chapter 444 shows a useful comparison of findings in these two disorders. TEC often is differentiated from DBA by its relatively late onset, although it occasionally develops in infants <6 mo of age (Chapter 444). Macrocytosis, congenital anomalies, fetal red cell characteristics, and elevated erythrocyte ADA are generally associated with DBA and not with TEC.

Hemolytic disease of the newborn can have a protracted course, and the associated anemia is occasionally coupled with markedly reduced erythropoiesis; the anemia usually resolves spontaneously at 5-8 wk of age. Aplastic anemic crisis characterized by reticulocytopenia and by decreased numbers of RBC precursors, often caused by parvovirus B19 infection, can complicate various types of chronic hemolytic disease but usually occurs after the first several months of life (Chapter 444). Infection with parvovirus B19 (Chapter 243) in utero can also cause pure RBC aplasia in infancy, even with hydrops fetalis at birth. The absence of parvovirus B19 detected by polymerase chain reaction (PCR) is an essential feature in establishing the diagnosis of DBA in young infants. Other inherited macrocytic bone marrow failure syndromes should be considered, particularly Fanconi anemia and Schwachman-Diamond syndrome. Other infections, including HIV, as well as drugs, immune processes, and Pearson syndrome (Chapter 443) should also be ruled out.

Treatment

Corticosteroids are the mainstay of therapy, and about 80% of patients respond initially. The mechanism of the effect remains unknown. Owing to concerns regarding possible detrimental properties and the lack of evidence that a delay of corticosteroids is associated with poor response, this therapy is generally not recommended for children <6 mo of age. Many hematologists recommend not beginning corticosteroids before age 1 yr. Prednisone or prednisolone in doses totaling 2 mg/kg/24 hr is used as an initial trial. An increase in RBC precursors is usually seen in the bone marrow 1-3 wk after therapy is begun and is followed by peripheral reticulocytosis. The hemoglobin can reach normal levels in 4-6 wk, although the rate of response is quite variable. Once it is established that the hemoglobin concentration is increasing, the dose of corticosteroid may be reduced gradually by tapering and then by eliminating all except a single, lowest effective daily dose. This dose may then be doubled, used on alternate days, and tapered still further while maintaining the hemoglobin level at ≥9 g/dL. In some patients, very small amounts of prednisone, as low as 2.5 mg twice a week, may be sufficient to sustain adequate erythropoiesis. Many children with DBA who are initially started on corticosteroids stop taking the drug, usually because of unacceptable side effects or the evolution of corticosteroid refractoriness at acceptable doses. In as many as 20% of cases, there is spontaneous remission of anemia with independence from steroid or red cell transfusion therapy.

In patients who do not respond to corticosteroid therapy, transfusions at intervals of 4-8 wk are necessary to sustain normal growth and activities. Chelation therapy needs to be instituted as excess iron accumulates. Other therapies, including androgens, cyclosporine, cyclophosphamide, antithymocyte globulin (ATG), high-dose intravenous immunoglobulin, high-dose methylprednisolone, EPO, and interleukin-3 have not had consistent beneficial effects and can have a high incidence of side effects.

Hematopoietic stem cell transplantation can be curative but remains a controversial treatment option for DBA. Transfusion dependence is the most common indication, although some practitioners would consider this alternative for any young child with DBA who has an HLA-matched related donor. When allogeneic sibling and alternative donor transplants are compared, survival is 72% vs. 17% at ≥5 yr from transplant. Survival for patients <10 yr of age who received transplants from HLA matched siblings is 92%.

Prognosis

Among patients with DBA approximately 40% are transfusion dependent, 40% are steroid dependent, and 20% require neither therapy to maintain an acceptable hemoglobin level. Most remissions occur in the first decade. The Diamond-Blackfan Anemia Registry (DBAR) is accumulating data to ascertain responses to therapy and survival (www.dbar.org/). An analysis of North American DBAR data revealed an overall actuarial survival at >40 years to be 75.1%. About 70% of deaths were treatment related (opportunistic infection secondary to corticosteroid therapy, iron overload, transplant complications, etc.) and about 30% were disease related (aplastic anemia and malignancy). DBA may be a premalignant syndrome, with acute leukemia (usually myeloid) and myelodysplasia occurring in a small proportion (∼5%) of patients. Solid tumor malignancies are also reported, especially osteosarcoma.