DBA is characterized by macrocytic anemia, reticulocytopenia, and normal bone marrow cellularity with a paucity of erythroid precursors. DBA is caused by a defect in which erythroid progenitors and precursors are highly sensitive to death by apoptosis, leading to erythropoietic failure [4
As in this study, routine cytogenetic analysis of patients with DBA is normal. However, a balanced reciprocal translocation t(X;19) was discovered in a DBA patient [6
], revealing the first DBA gene (DBA1
) that encodes a ribosomal protein S19 (RPS19
) that is essential for the maturation of the 40S ribosomal subunit [14
]. The identification of subsequent DBA genes has established DBA as a ribosomal disorder, because the affected gene encodes ribosomal proteins [8
protein haploinsufficiency is not sufficient to produce normal function. Recently, de novo
mutations have been identified in ribosomal proteins RPS24 [8
], RPS17, RPL5, RPL11, and RPL35a. To date, approximately 50% of DBA patients have a single mutation in a gene encoding a ribosomal protein. These findings implicate DBA as a disorder of ribosome biogenesis and/or function.
The diagnostic criteria for "classical" DBA, presented in 1976 [2
], include the followings: anemia, usually presenting prior to the first birthday, with near normal, but variable, neutrophil and/or platelet counts; reticulocytopenia; macrocytosis; and normal marrow cellularity with a paucity of red cell precursors. "Non-classical" DBA is characterized by presentation at an age >1 year, with congenital anomalies, no anemia, a mild hematological phenotype (macrocytosis only), or the presence of a mutation shared by affected family members.
Although all immediate family members should be evaluated with a thorough relevant history, and a complete blood count, including red cell indices, erythrocyte adenosine deaminase (eADA) activity, and HbF, these were not completely performed in our study. This may be the reason why only 3 cases in our study revealed a family history. Generally, 40-45% of DBA cases are familial with autosomal dominant inheritance [15
], and the remainder is sporadic or familial with seemingly different patterns of inheritance.
In a study of 80 DBA patients in the United Kingdom [16
], 35% of classical DBA patients were found to have one or more unequivocal congenital anomalies, not including growth retardation. A similar proportion has been described in the French, Italian, and North American registries (40%, 46%, and 47%, respectively) [3
]. More than one anomaly was found in up to 25% of individuals. In this study, 21 cases (38.2%) showed congenital defects, with more than one anomaly in 21.2%. Renal anomalies have not been seen. However, in the North American Diamond Blackfan Anemia Registry (DBAR), where the majority of patients undergo formal genitourinary and cardiac imaging, the prevalence is 19%.
The incidence of DBA is estimated to be between 1 in 100,000 and 1 in 200,000 without ethnic predilection, and both sexes are reported to be equally affected [3
]. In our study, the prevalence of DBA was similar to these statistics (6.6 cases per million), but with a male predilection (M:F=1.67:1).
The reported proportion of cancer is 4% (29/700) in patients with DBA, which is higher than the expected 0.5% for a cohort less than 30 years of age [20
]. The median age for cancer in these reports was 15 years, much younger than the median of 68 years in the general population [22
]. The crude frequency reported from Boston Children's Hospital was 6.6% [23
], the French series 3.8% [18
], and the DBAR 1.9% (8/420) [3
]. In this study, 2 cases (3.6%) with DBA developed cancer: osteogenic sarcoma and diffuse large cell lymphoma, respectively.
Corticosteroids remain the mainstay of DBA treatment. The therapeutic mechanism of corticosteroids in DBA may involve increased sensitivity to erythropoietin (Epo) [4
]. Remission occurred in 48.9%. The initial recommended starting dose was 2 mg/kg prednisone or the glucocorticoid equivalent. Most patients are controlled with the recommended maximum maintenance dose (≤1 mg/kg every other day or ≤0.5 mg/kg daily). Seventy percent of those who achieved remission did so within the first decade of life.
Complications due to steroid therapy were noted in 20% of patients on long-term steroid therapy [18
], and 22% of those in the DBAR [3
]. In our study, growth retardation was most common, followed by moon face, hirsutism, impaired glucose tolerance, and diabetes mellitus. Growth hormone therapy has been used successfully to increase growth velocity [25
]. In our study, 1 patient who had been diagnosed with growth hormone deficiency showed good response to recombinant growth hormone therapy for 1.5 yrs (height increased from less than the 3rd percentile to the 10th percentile), without bone age advancement.
Addition of iron-chelating therapy is recommended in transfusion-dependent patients, because prolonged iron acquisition from transfusion can cause a potentially fatal iron overload in the liver, heart, or pancreas. Iron chelation was initiated when a ferritin level was 1,000 ng/mL or more instead of the hepatic iron concentration reaching 6-7 mg/g dry weight. Chelation by subcutaneous deferoxamine (Desferal, Novartis) was switched in 2007 to oral deferasirox (ICL670, Exjade, Novartis), which is now approved in Korea as the first-line therapy for transfusional iron overload [26
Hematopoietic stem cell transplantation (HSCT) is the curative treatment for DBA [3
]. According to the DBAR [3
], where the major indication for HSCT was transfusion dependence, the bone marrow was the most common source of stem cells. The survival rate for allogeneic sibling versus alternative donor transplant was 72.7% vs. 17.1% at >5 years following SCT. The survival for patients <10 years of age who underwent transplantation from human leukocyte antigen (HLA)-matched allogeneic siblings was 92.3% [19
]. More recently, successful related umbilical cord blood and unrelated donor transplants have been reported to the DBAR, but it is too early for a meaningful analysis of the data.
In conclusion, the incidence of DBA is similar to data already published, but there was a male predilection in our study. Although all patients responded to initial treatment with steroids, about half needed further steroids after remission. It is necessary to collect further data, including information on management pathways, from nationwide DBA registries, in addition to molecular analyses. Since DBA patients need lifetime care, they should be managed by a multidisciplinary team involving pediatric and adult hematologists, internists, and subspecialists.