Diamond-Blackfan anemia.

Diamond-Blackfan anemia is the best-known form of partial red cell aplasia in children. The disease is named after the authors who described four children with characteristic signs of the disease in 1938.

In total, more than 500 cases of Diamond-Blackfan anemia have been registered, the frequency of the syndrome is estimated at 4-10 cases per 1,000,000 births, the ratio of boys to girls is about 1:1. Familial cases account for 10-20% of all cases of Diamond-Blackfan anemia, including the disease has been diagnosed in monozygotic twins. Both autosomal dominant and autosomal recessive inheritance have been proven. 80-90% of cases of Diamond-Blackfan anemia are diagnosed during the first year of life, and in 25% of patients, anemia is detected at birth. The diagnosis of Diamond-Blackfan anemia in older children should be made with caution, after excluding acquired forms of PRCA. Approximately 25-30% of cases of Diamond-Blackfan anemia are associated with a mutation in the gene for ribosomal protein S19, the significance of which for erythropoiesis is unknown. Another chromosomal locus associated with the development of the disease is 8p22-p23.

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Causes and pathogenesis

Diamond-Blackfan anemia is a hereditary disease with a presumably autosomal recessive type of inheritance, with equal frequency among patients boys and girls. Among the mechanisms of disease development indicate an anomaly of erythroid precursor cells, a defect in their microenvironment in the bone marrow, cell-mediated suppression and the presence of humoral inhibitors of erythropoiesis. Constant signs of the disease include a decrease in the number of erythroid units in the bone marrow, an increase in the level of erythropoietins in the blood, a defect in additional bone marrow cells.

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Symptoms of Diamond-Blackfan Anemia

Symptoms are limited to pallor and other symptoms of severe anemia. Enlargement of the liver and spleen is not characteristic of the disease, but later, as a result of the formation of fibrosis and/or cirrhosis of the liver due to iron overload and the course of post-transfusion hepatitis B and C, hepatosplenomegaly becomes a typical symptom.

Patients with Diamond-Blackfan anemia are characterized by congenital developmental anomalies, but their spectrum and severity differ significantly from Fanconi anemia. Chronic course of Diamond-Blackfan anemia is also characteristic; spontaneous remission is noted in some patients, more often during puberty. Diamond-Blackfan anemia is a preleukemic syndrome: AML developed in at least 8 patients.

Diagnostics

Diagnostic criteria for Diamond-Blackfan anemia:

• normochromic, often macrocytic anemia;
• profound reticulocytopenia;
• normocellular bone marrow with isolated decrease in the content of erythroid precursors;
• normal or slightly decreased granulocyte count;
• normal or slightly elevated platelet count.

The fetal hemoglobin level, although it may be elevated, is not a diagnostic sign. Rarely, in patients with Diamond-Blackfan anemia, from the first months of life, the number of primitive erythroblasts in the bone marrow is increased, which can be mistaken for leukemic blasts, which leads to an erroneous diagnosis of leukemia. With age, the cellularity of the bone marrow, determined by trephine biopsy, can significantly decrease, and some patients develop moderate thrombocytopenia. Specialized studies can reveal a sharply reduced number of committed precursors of erythropoiesis - burst-forming units of erythrocytes and colony-forming units of erythrocytes. The level of erythropoietin in patients with Diamond-Blackfan anemia is sharply increased.

Diamond-Blackfan anemia must be differentiated from other forms of PKCA in children, primarily TED. Documentation of normal hemoglobin levels before the clinical manifestation of anemia and spontaneous resolution of the syndrome argue against Diamond-Blackfan anemia.

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Treatment of Diamond-Blackfan anemia

The only effective group of drugs in the treatment of Diamond-Blackfan anemia are glucocorticosteroids. Treatment usually begins with prednisolone orally at a dose of 2 mg / kg per day. A reticulocyte response is expected in 2 weeks, followed by an increase in hemoglobin levels. After hemoglobin values reach a plateau, the dose of prednisolone should be gradually reduced to the minimum that allows maintaining the hemoglobin level above 90 g / l. Often, to maintain a hematological response, it is enough to use doses of about 2.5-5 mg per day or every other day. If there is no response to standard doses of prednisolone, the use of increased doses is justified - 5 mg / kg per day. Increased doses can be used in pulse therapy for 7 days followed by a 2-week break. A total of 3-4 pulse therapies are carried out. Once a response is achieved, the intervals between courses can be increased or the patient can be transferred to daily glucocorticosteroids in standard doses with subsequent reduction to the minimum effective doses. The use of ultra-high doses of methylprednisolone - 30-100 mg/kg, despite its relative popularity, has not proven its high efficiency. In general, about 70% of patients are sensitive to the use of glucocorticosteroids, but 20% of those who responded subsequently become resistant to them. Interestingly, of the patients who initially did not respond to glucocorticosteroids, some respond to subsequent attempts, so trial treatment with glucocorticosteroids must be renewed from time to time (once every 1-2 years).

Treatment of patients with Diamond-Blackfan anemia with growth factors - interleukin-3 and erythropoietin, despite laboratory evidence, has proven to be completely ineffective. The place of cyclosporine, despite several isolated reports of successful treatment, in the therapy of patients with Diamond-Blackfan anemia is questionable. Allogeneic bone marrow transplantation can be offered to patients with an HLA-genoidentical sibling if they are not sensitive to glucocorticosteroid treatment.

Patients in whom glucocorticosteroids are ineffective or effective at doses that cause unacceptable long-term side effects (osteoporosis, growth disorders, diabetes, cataracts, Cushing's syndrome) require competent transfusion and chronic chelation therapy with deferroxamine and/or deferiprone.

Forecast

The literature provides data on the follow-up of 200 children with Diamond-Blackfan anemia: 22.5% had spontaneous remission; 41.8% had corticosteroid-dependent remission; 35.7% had transfusion-dependent remission; 27.6% of the children died.