Diamond-Blackfan anemia is a hereditary form of red cell aplasia with a reliably unexplored type of inheritance (an autosomal dominant type of inheritance is assumed to occur in a quarter of patients). The symptoms of the disease are anemic manifestations that occur, as a rule, during the first year of life – pallor, weakness, increased fatigue, a decrease in the number of red blood cells in the blood. Diagnosis is made on the basis of data from a general blood test, a study of the level of erythropoietins, bone marrow biopsy and microscopy, in a quarter of cases, a genetic study is informative. Treatment is carried out with the help of blood transfusions, glucocorticosteroids.
D61.0 Constitutional aplastic anemia. Blackfan-Diamond syndrome.
Diamond-Blackfan anemia (hereditary partial red cell aplasia) is a genetic lesion of the blood system, in which the formation of red blood cells is disrupted. The name of the pathology was given by the surnames of doctors who in 1938 jointly examined four children with symptoms of severe anemia of a hereditary nature.
This condition is very rare, about 500 cases have been reliably described to date. It is estimated that the incidence of Diamond-Blackfan anemia is about 4-6:1000000, both boys and girls are equally susceptible to it. The discrepancy between the number of proven cases and the calculated occurrence is explained by the fact that a certain part of patients are mistakenly diagnosed with either erythromyeloblastic leukemia or acquired forms of partial red cell aplasia. The most common form of the disease is inherited according to the autosomal dominant principle, however, this explains only 25% of all cases, while there is no data on the remaining variants yet.
Causes of Diamond-Blackfan anemia
The direct cause of a quarter of cases of Diamond-Blackfan anemia is a mutation in the RPS19 gene located on chromosome 19, which encodes the important ribosomal protein S19. The latter is part of the small (40S) subunit of the human ribosome. This mutation is inherited by an autosomal dominant mechanism with a frequency of 6 cases per million people. In other cases, mutations of other genes were found, but they are somehow related to ribosomal proteins – these are the genes RPS7, RPS24, RPL5, RPL32A and a number of others.
The prevalence of such mutations, the nature of their inheritance, the share in the total number of patients with Diamond-Blackfan anemia, their impact on the prognosis and outcome of pathology currently remains the object of study by geneticists. Also of interest is the question of why mutations of ribosomal protein genes have an effect on erythropoiesis and almost do not affect other hematopoiesis sprouts.
There are several theories trying to explain the inhibition of the formation of red blood cells in the red bone marrow. The most common indicate as possible causes of Diamond-Blackfan anemia defects in the microenvironment of erythrocyte progenitor cells, their internal abnormalities, suppression by the immune system or humoral factors that stop the maturation of erythroblasts. None of the theories has received reliable and unambiguous confirmation to date.
With this disease, a steady decrease in erythroid units is observed in the red bone marrow, and in about a third of cases this process begins during intrauterine development, which makes it possible to diagnose Diamond-Blackfan anemia immediately after birth. Accordingly, the number of red blood cells released into the blood begins to decrease, erythroblasts accumulate in the bone marrow, which can be misleading (such changes are characteristic of leukemia). At the same time, fetal hemoglobin levels may not decrease in infants, so this indicator is not considered diagnostic in the case of Diamond-Blackfan anemia. There is a compensatory increase in the level of erythropoietins in the blood, but in this case they are not able to increase the rate of erythrocyte formation. Eventually, severe anemia develops.
Symptoms of of Diamond-Blackfan anemia
Anemic symptoms come to the fore with Diamond-Blackfan syndrome – pallor, weakness of the child, hypotrophy often develops in infants, there is a shortage of weight. Approximately half of the patients, in addition to blood disorders, also have a number of physical abnormalities – microcephaly, hypertelorism, ptosis of the eyelids, micrognathia. Skeletal anomalies are possible – an increase in the size of the shoulder blades and hands, the absence of some fingers, a delay in the growth of bone tissue. In some cases, violations such as “harelip” are possible.
The organs of vision are also affected – strabismus, glaucoma, cataracts develop. Many of these symptoms occur at an early age of the child and are aggravated by severe anemia, so timely treatment can significantly weaken or even eliminate many of them.
Unlike transient and acquired anemia, Diamond-Blackfer syndrome has little effect on the functioning of the liver and spleen – their noticeable increase may occur only in the final stages of the disease or as a result of complications of hemotransfusion therapy.
When examining a child with Diamond-Blackfan anemia, the pallor of the skin, cyanosis of the mucous membranes is determined, venous vessels are visible on the head. There may also be physical abnormalities associated with the disease (microcephaly, hypertelorism, and others), when weighing, a shortage of body weight is often detected. Laboratory diagnostic methods include:
- Blood tests. It shows a picture of normochromic anemia, often macrocytic in nature, a sharp decrease in the number of reticulocytes. In some cases, granulocytopenia and thrombocytopenia are observed, but this cannot serve as a reliable diagnostic criterion for Diamond-Blackfan anemia. A biochemical blood test reveals a sharp increase in the level of erythropoietin.
- Bone marrow biopsy. Microscopic examination of a bone marrow biopsy reveals a generally normocellular type with a marked decrease in erythroid cells. At the same time, with some forms of Diamond-Blackfan anemia, erythroblasts can accumulate in the bone marrow, which often leads to an erroneous diagnosis of acute myeloid leukemia.
- Genodiagnostics. Modern genetics by direct sequence sequencing determines mutations of only one gene associated with Diamond-Blackfan anemia – RPS19. With the help of this diagnostic method, gene mutations are detected only in 25-30% of cases of clinically detected disease.
Treatment of Diamond-Blackfan anemia
With severe anemia, hemotransfusion or transfusion of erythrocyte mass is indicated to make up for a life-threatening deficiency of erythrocytes. In some cases, blood transfusion may be required repeatedly – for example, in the absence of the effect of glucocorticosteroid therapy. In such situations, it is necessary to take measures regarding the prevention of liver and spleen damage by excess iron and other post-transfusion complications – for example, prescribe chelation therapy with deferoxamine.
The main drugs for the treatment of Diamond-Blackfan anemia are glucocorticosteroids (prednisolone, methylprednisolone and others). Therapy begins with increased (shock) dosages of drugs inside, then gradually reducing them to the level of the maintenance dose – at the same time, the hemoglobin level should increase and the blood picture should improve (reticulocytes appear in the bloodstream, the number of macrocytes decreases).
Depending on the dynamics of the disease, glucocorticosteroid therapy is performed using two main schemes – in the pulse therapy mode (up to 7 days of taking increased doses followed by a two- to three-week break) and maintenance therapy with daily intake of small amounts of glucocorticosteroids. The choice of a particular scheme depends on the reaction of the patient’s body to drugs, the presence and severity of side effects, and the effectiveness of treatment. Several cases of Diamond-Blackfan anemia treatment with a positive outcome through bone marrow transplantation from a close relative have been described.
The prognosis of Diamond-Blackfan anemia is largely uncertain due to a poor understanding of the processes that lead to its development. An extensive study, during which the life history of more than 200 patients was studied, revealed that almost a quarter of children who were treated with hemotransfusions and the appointment of glucocorticosteroids had spontaneous remission before adolescence with the restoration of adequate hemoglobin levels. At the same time, more than half of the children remained dependent on both blood transfusions and the use of methylprednisolone even after adolescence. The remaining 25% of patients died in childhood, despite all the therapeutic measures taken.
In many ways, the prognosis is influenced by the presence or absence of concomitant physical abnormalities and the degree of their severity. Treatment with growth factors, iron preparations and other traditional means for anemia is ineffective and can further increase the load on the liver and spleen.