Diamond-Blackfan anemia (DBA) is a congenital pure red blood cell aplastic anemia, named after Diamond and Blackfan, who first reported four cases of this disease in 1938. The disease develops within the first year of life and is characterized only by impaired development of the red lineage, with young red blood cells in the bone marrow stagnating at the directed hematopoietic stem cell and early red blood cell stages, while the granulocyte and megakaryocyte lineages develop normally. Some patients with DBA have short stature or other congenital malformations.
Epidemiology
Because congenital pure red blood cell aplastic anemia is rare, its exact incidence is difficult to determine. A retrospective study in Europe showed that the incidence of DBA is about 15-7. 3/106 live births. Most of the cases are disseminated, and about 10%-25% have a family history.
Etiology and pathogenesis
Erythropoietic hematopoiesis occurs in the following stages: pluripotent hematopoietic stem cells, erythroid-directed hematopoietic stem cells, erythropoietic colonies, erythroid primitive cells, and mature erythrocytes, with erythropoietin (EPO) acting on erythropoietic colonies and subsequent erythrocytes. When stem cell culture was performed, erythropoietic colonies could be formed by pluripotent hematopoietic stem cells from both DBA patients and normal donors, and the number of both was similar, but the former was much smaller than the latter; after adding EPO, erythropoietic colonies from normal donors proliferated and differentiated rapidly to produce mature erythrocytes, while erythropoietic colonies from DBA patients did not respond to EPO. This suggests that erythropoiesis in DBA patients is mainly in the stage of erythropoietic colonies to erythroid primitive cells.
In recent years, a series of ribosomal protein abnormalities have been identified internationally in patients with DBA. Ribosomal protein S19 (RPS19) was the first and most studied ribosomal protein, and animal models of zebrafish with RPS19 mutations have been established to further investigate the pathogenesis of DBA and explore new therapeutic approaches. In addition, DBA is also associated with mutations in RPS24, RPS17, RPL5, RPL11 and RPL35a. These ribosomal protein abnormalities suggest that the nature of DBA may be a ribosomal disease.
In 1999, a case of DBA with t(X;19) was identified and named DBA1 gene; as the study progressed, the transcription product of DBA1 gene was found to be a ribosomal protein, RPS19, instead of the expected regulator of the red lineage hematopoietic process. currently, we found that about 25% of DBA patients have mutations in RPS19 gene.
Patients with DBA with RPS19 mutations develop anemia at a younger age, although there is no statistically significant difference. These patients often have increased levels of erythrocyte adenosine deaminase (eADA), so eADA levels can be measured to identify children with DBA with this mutation. Animal models of zebrafish DBA with RPS19 mutation have been established internationally. When the RPS19 gene is knocked out in embryonic zebrafish, significant hemocytopenia with significant cephalocaudal anomalies can be seen in the early stages of embryonic development. These abnormalities can be restored by injection of zebrafish RPS19 mRNA, whereas injection of mutant RPS19 mRNA from DBA patients is ineffective.
Therapeutically, patients with DBA with RPS19 mutations responded poorly to glucocorticoid therapy, with only 46% of these patients responding to hormone therapy and nearly 70% of DBA patients having an overall hormone efficacy rate. Prognostically, patients with DBA with RPS19 mutation were significantly less sensitive to hormonal therapy (p<0.001) and more likely to become transfusion-dependent and require hla-compatible HSCT (p<0.001).
Clinical presentation
The onset of disease is slow, with significant anemia appearing in the first 2-3 months of life, and the vast majority of patients develop symptoms within the first year of life. About 1/3 of patients have congenital developmental malformations, such as trigeminal thumb malformation, congenital heart disease, urethral malformation, strabismus, or the appearance of Turner syndrome but with normal karyotype or XX/XO chimerism.
Laboratory tests
Hematology generally shows severe macrocytic orthochromic anemia with reticulocyte percentage <2%, white blood cells and platelets may be normal or mildly elevated. Hemoglobin f is higher than the normal value for the same age. Erythropoietin is elevated. Bone marrow picture: erythroid lineage <5% with maturation arrest, granulocyte and megakaryocyte lineage development is normal, and lymphocyte proportion may be increased. Stem cell culture shows a lack of red lineage progenitor cells in culture. Some patients have karyotype abnormalities. < p="">
Diagnostic criteria
Large cell (orthocytic) orthochromic anemia occurring within the first 12 months of life; marked reduction in reticulocytes; active bone marrow proliferation with marked reduction in selective erythroid precursor cells; increased erythropoietin levels; normal or slightly reduced white blood cells; normal or slightly increased platelet count.
Differential diagnosis
The clinical differentiation is from transient hypoerythropoietic hypogammaglobulinemia. The disease is usually seen in children aged 1-4 years, often with a history of viral infection, and is relatively mild in anemia, with no increase in hemoglobin F. It may resolve on its own.
Hemolysis causing “remitting crisis” may also have similar bone marrow pattern, but more often have symptoms associated with hemolysis. In addition, some patients with DBA have an increased percentage of lymphocytes in the bone marrow, which should be differentiated from acute lymphoblastic leukemia.
Treatment
Adrenocorticotropic hormone About 70% of patients respond to initial treatment; the earlier the treatment is started, the more effective it is. If treatment is started within 3 months of onset, almost 100% of children respond to treatment. If prednisone is started after 3 years of onset, it is less effective. The initial dose of prednisone is usually 2.0 mg/kg/d. In those who respond, an increase in reticulocytes is seen in 2-4 weeks, followed by an increase in hemoglobin. Long-term remission can be achieved in 20% of patients with DBA after receiving hormone therapy.
2, blood transfusion Those who are not sensitive to prednisone often rely on regular red blood cell transfusion to maintain hemoglobin around 80g/L. Long-term transfusion can cause iron-containing hemoglobinosis, hemochromatosis and hepatomegaly. In severe cases, continuous infusion of desferrioxamine can improve and delay the effect of iron accumulation.
3, Immunosuppressants Cyclophosphamide (CTX), cyclosporine A (CSA), 6-mercaptopurine (6-MP), vincristine (VCR), etc.. If CTX 3mg/kg /d or 6-MP 2mg/kg /d for 2 months, after the symptoms improve, gradually reduce the dose to a small maintenance treatment for 2-3 years, can be used in combination with corticosteroids.
4, bone marrow transplantation Those who are insensitive to adrenocorticotropic hormone and need blood transfusion to maintain and have complications can be given bone marrow transplantation. According to statistics, the 3-year survival rate after allogeneic bone marrow transplantation is 85%, but screening is required before transplantation to exclude RPS19 mutant donors.
5, Gene therapy Hamaguchi et al. used a viral vector containing RPS19 to transfer RPS19 into bone marrow CD34+ cells of DBA patients with RPS19 mutation, and overexpression of the transgenic RPS19 increased erythroid colonies almost 3-fold without adverse effects on granulocyte-macrophage colony formation. This suggests that gene therapy using a viral vector to transfer RPS19 into RPS19-deficient DBA patients is feasible.
Lactogenic receptors are structurally and functionally similar to erythropoietin receptors. Lactogenic receptors can increase erythropoiesis in vitro, probably by increasing erythropoietin receptor expression. Abkowitz et al. administered metoclopramide 600-900 μg/kg/d intramuscularly to 15 patients with DBA who were maintained by blood transfusion and had developed hemochromatosis, and 9 cases were cured or remitted.
7. Other successful treatment of DBA has been reported with androgens, antithymocyte globulin, antilymphocyte globulin, valproic acid, leucine and interleukin 3.
Prognosis
10%-20% of patients can go into spontaneous remission; about 70% can achieve complete remission or cure with treatment, but some patients still relapse and can still achieve complete remission with treatment; some patients are poorly treated and mainly rely on blood transfusion to improve symptoms, so it is easy to cause hemochromatosis and hepatomegaly; some patients die of congestive heart failure, myelodysplastic syndrome, leukemia, malignant lymphoma and various solid tumors. The median survival time is 38 years.