Introduction to congenital pure red blood cell aplastic anemia

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Overview

Congenital pure red blood cellsAplastic anemiaAlso known as Diamond-Blckfan syndrome (Diamond-Blackfan anemia, DBA) is a rare congenital pure red blood cell regeneration disorder, with anemia as the main clinical manifestations, and involving multiple systemic tissue as the main clinical features of this disease. In 1936, Joseph reported a pure red aplastic anemia in children, considered to be congenital or hereditary. Two years later, Diamond and Blackfan also reported the same case, and the number of cases officially reported so far has exceeded 480.

Epidemiology

Because DBA is quite rare, its exact incidence is difficult to determine. Retrospective studies in Europe have shown that the annual incidence of DBA in children ≤ 15 years old is about 1.5/1 million to 5.0/1 million.

The disease occurs in infants and young children. Most children develop from 2 weeks to 2 years after birth. The vast majority (more than 90%) of the children are diagnosed within 1 year of age. The ratio of male to female patients is about 1.1:1.

Cause

The disease was occasionally seen in siblings, suggesting that the disease is a hereditary disease. Less than 10% of patients have a family history, and most of the patients are sporadic. One third of patients are autosomal dominant, and the rest are recessive. Linkage analysis revealed that there are at least three genetic loci in DBA, two of which have been identified, 19q13.2 and 8p23.3-p22, respectively. The related pathogenic gene has been cloned in the 19q13.2 region, which is the ribosomal protein S19 (RPS19) gene. Sequence analysis revealed that approximately 25% of DBA patients had an RPS19 mutation.

Pathogenesis

The pathogenesis is still not very clear. Conventional colony cultures showed a significant reduction or deficiency in bone marrow erythroid progenitor cells (BFU-E and CFU-E) in DBA patients. The results of previous experimental studies indicate that there is no cell and humoral immune dysfunction associated with erythroid hematopoietic defects in DBA patients, and the bone marrow matrix supports hematopoietic function. At present, a more consistent view is that DBA patients have erythroid progenitor cells with intrinsic qualitative abnormalities, which leads to a decrease in the reactivity of various hematopoietic growth factors (HGFs) that regulate the differentiation and proliferation of erythroid progenitor cells. Since DBA has hematological abnormalities similar to those of W/Wv and sl/sld mice, it is speculated that the pathogenesis of DBA may be related to the c-kit receptor/ligand (KL) system. Another study found that DB34+ cells in DBA patients were stimulated by single or combined EPO, IL-3, IL-6 and GM-CSF, and the BFU-E yield was still low or absent. Adding KL to the above culture system was obvious. Increased BFU-E colony yield and volume suggest that there is no abnormal expression of c-kit receptor in CD34 cells. The occurrence of anemia may be caused by insufficient or lack of KL production in the body. Some people think that most DBA primary defects are not in the c-kit/KL system. Only some patients have some abnormalities in the c-kit/KL system. This reflects the heterogeneity of the disease. These abnormalities explain the development of some patients. The difference in outcome. Fit-3 ligand (FL) did not cooperate with KL to stimulate bone marrow BFU-E growth in DBA patients in vitro, and there was a low level of FL in the same body as normal, suggesting that some DBA erythroid growth is not associated with FL.

The current study confirmed that DBA patients do not have SCL gene and GATA gene expression and protein structure abnormalities, but their E protein expression is significantly lower, and KL can correct this defect in vitro, so it is revealed at the molecular level that KL may promote SCL/ E protein heterodimer formation plays a role in stimulating DBA erythroid hematopoiesis. The relationship between E protein abnormalities and DBA erythroid hematopoietic defects needs further study.

It has been clarified that there is no abnormality in EPO and EPO-R gene expression and protein structure in DBA patients, and there is no anti-EPO-R antibody, but it is not completely excluded from the abnormal signal transmission of EPO and EPO-R in DBA. Compared with other benign anemias (such as iron deficiency anemia) with the same degree of anemia, the serum EPO level of DBA patients is more significant. This change may have the effect of protecting the remaining erythroid progenitor cells from excessive excessive apoptosis. Important physiological significance.

Clinical manifestation

Anemia is the main clinical manifestation of DBA, and approximately 35% of children develop anemia at birth. Another significant clinical manifestation of congenital pure red blood cell aplastic anemia is similar to Fanconi anemia (FA), with a lighter congenital physical developmental malformation. About 1/4 of the children had mild congenital anomalies, such as squinting, nipple retraction, sacral neck, finger or rib abnormalities.

complication

1. Congenital pure red blood cell aplastic anemia patients are more likely to be complicated by multiple malignant tumors. More than 480 patients with congenital pure red cell aplastic anemia reported in the literature, 12 of which were diagnosed with malignant tumors 2 to 43 years after diagnosis. 6 cases of cell leukemia (AML), 1 case of acute lymphoblastic leukemia (ALL), 2 cases of Hodgkin's disease (HD),Myelodysplastic syndrome2 cases (MDS) and 1 case of hepatocellular carcinoma.

2. Long-term application of hormone therapy can be combined with developmental disorders and secondary infections.

3. Progression of the disease can lead to heart failure, and advanced blood transfusion can be secondary to hemorrhagic disease, or cardiogenic cirrhosis.

Laboratory inspection

1. Peripheral blood is positive cell positive anemia, hemoglobin 10 ~ 90g / L, the absolute value of reticulocytes is reduced, infants and young children are generally not associated with peripheral blood leukocytes and thrombocytopenia. Secondary spleen hyperfunction can lead to a reduction in whole blood cells, and there are giant changes.

2. Bone marrow hyperplasia is good, but the red line is significantly reduced, and other bone marrow cells are normal.

3. Red blood cell survival time is normal.

4. Serum iron and serum iron saturation increase, fetal hemoglobin increases, i antigen persists.

5. Blood bilirubin and fecal gallbladder excretion are normal.

Other auxiliary inspection

According to the condition, clinical manifestations, symptoms and signs, choose ECG, B-ultrasound, X-ray and other tests.

diagnosis

According to comprehensive literature reports, some scholars have proposed the following diagnostic criteria:

1 large cell (or positive cell) positive pigmented anemia occurs within 1 year of birth;

2 the number of reticulocytes is reduced;

3 myeloid hyperplasia is active, with selective red lineage precursor cells significantly reduced;

4 the number of white blood cells is normal or slightly lower;

5 The number of platelets is normal or slightly increased. Typical cases are not difficult to diagnose.

Differential diagnosis

Should be noted with Fanconi anemia, children with transient erythrocytosis (TEC), chronic hemolytic anemia with B19 parvovirus infection, Pearson syndrome and cartilage dysplasia syndrome, including congenital pure red cell aplastic anemia Differential diagnosis with FA is especially important.

treatment

Red blood cells and adrenocortical hormones are effective treatments that keep children healthy. However, due to the long course of disease, long-term red blood cells can be secondary to hemochromatosis, which requires special attention. The main comorbidities of adrenocortical hormone drugs are developmental disorders and secondary infections.

1. About 75% of patients with adrenocortical hormones respond to adrenocortical hormone therapy, but only a small number of patients can achieve sustained remission, and more than 80% of patients with effective corticosteroid dependence. ClinicallyPrednisoneThe recommended dose for the treatment of congenital pure red blood cell aplastic anemia is 2mg/(kg·d) for more than 1 month. After that, the prednisone dose and course of treatment can be adjusted according to the therapeutic response. Ineffective patients can use large doses experimentally.Methylprednisolone(HDMP), 100mg / (kg · d), intravenous infusion, for 3 consecutive days, gradually reduced afterwards. It has been reported that 9 of 17 patients with congenital pure red blood cell aplastic anemia have long-term efficacy without maintenance dose of prednisone after treatment with methylprednisolone (HDMP). However, in view of the obvious side effects of methylprednisolone (HDMP), clinically, this therapy should be cautious. Some scholars have reported that switching to oral methylprednisolone (HDMP) can reduce its side effects.

2. HGFs have erythropoietin (rhEPO), rhIL-3 and rh Morastin (GM-CSF) alone, combined or sequential treatment of congenital pure red blood cell aplastic anemia, only rhIL-3 for some patients effective. Bastion et al used rhIL-3 in the treatment of 25 patients with congenital pure red blood cell aplastic anemia. The dose was gradually increased from 2.5μg / (kg · d) to 10μg / (kg · d) for 8 to 12 weeks, 13 patients Obtain a lasting effect.

3. Allogeneic bone marrow transplantation (allo-BMT) In recent years, allo-BMT has been successfully used in the treatment of patients with refractory congenital pure red blood cell aplastic anemia. Greinix et al. performed Alla-BMT with HLA-matched sibling donors in 4 patients with congenital pure red blood cell aplastic anemia, except for one patient who died of lung complications in the early stage, and the other 3 patients survived 3.0 after allo-BMT. In 7.4 and 10.6, the Kamofsky behavioral score showed that the 3 patients had good quality of life. The International Bone Marrow Transplant Registry (IBMTR) reported 10 cases of allo-BMT in patients with congenital pure red blood cell aplastic anemia, and 8 cases received HIL-matched sibling donor allo-BMT, of which 6 had survived for 5 to 87 months, 2 years. Survival rates were as high as 72.0%; the other 2 patients who received non-HLA matched donors died within 2 weeks after allo-BMT. It has recently been reported that cord blood hematopoietic stem cell transplantation has been successful in the treatment of patients with congenital pure red blood cell aplastic anemia.

4. Others have tried androgen, but more attention should be paid to the development of the child. Some people try cyclosporine (cyclosporine A) to increase hematocrit, but not lasting.

Recently reported a case of congenital pure red blood cell aplastic anemia in patients with hemochromatosis caused by long-term blood transfusionRecombinant human growth hormoneAfter (rhGH) treatment, its growth rate was significantly accelerated.

Prognosis

Different genetic modes, variable clinical manifestations, and various in vitro biological responses suggest that the disease may be a heterogeneous disorder caused by different causes. The survival period and quality of life of patients depend on their clinical response. In order to find more effective treatments (such as gene therapy), the molecular biological and pathological mechanisms of this disease should be further studied.

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Introduction About the relationship between aplastic anemia and pregnancy, most scholars believe that pregnancy is not the cause of aplastic anemia, does not induce or promote the occurrence of aplastic anemia, pregnancy with aplastic anemia is often the two in pregnancy The coupling, or some patients have already developed before pregnancy, and the disease is aggravated after pregnancy. Therefore, not all patients with aplastic anemia must terminate their pregnancy. However, a large number of clinical data indicate that aplastic anemia can cause adverse effects on pregnancy; pregnancy with aplastic anemia, high incidence of hypertensive disorder complicating pregnancy and early onset, serious illness, prone to heart failure and placental abruption , prone to miscarriage, premature delivery, fetal death, fetal growth restriction. The high incidence of postpartum hemorrhage and infection rate is the main cause of maternal mortality in pregnancy with aplastic anemia. If hemoglobin is <60g/L after pregnancy, abortion should be hospitalized in the early stages of pregnancy. If you have reached the second trimester, the risk of bleeding and infection due to induction of labor is greater than that of natural childbirth, and termination of pregnancy does not reduce maternal mortality in aplastic anemia, so you can continue your pregnancy while actively supporting the therapy. However, the treatment of acute aplastic anemia is not effective, especially the severe reduction of hematopoietic cells, the occurrence of maternal and child complications, and serious threat to the mother and child, should also consider termination of pregnancy. Patients who continue to have a pregnancy should work closely with the hematologist. Develop a careful treatment plan. Detailed observation and treatment of hospitalization if necessary. Accept a strict system of perinatal care. Active prevention and treatment of pregnancy complications. After full-term pregnancy, if there is no indication of obstetrics, vaginal delivery should be done as much as possible to reduce the surgical output. It is best to carry out planned delivery; after the cervical ripening, after transfusion of whole blood or blood, hemoglobin reaches 80g/L, and platelets reach 20×. 109/L (20,000) or more, in the case of preparing enough fresh blood to promote childbirth. Try to avoid tissue damage during childbirth, carefully check and improve the suture wound. The uterine contraction agent is used in time after delivery to accelerate the exfoliation and discharge of the placenta. Effectively promote uterine contractions and reduce postpartum hemorrhage. Antibiotics are routinely used in clinical postpartum to prevent infection. In the puerperium period, the clinical manifestations of infection should be closely observed, and antibiotics should be continued, supplemented by appropriate Chinese medicine treatment to promote uterine involution. It has been argued that if cesarean section is required for obstetric indications, the uterus can be removed to avoid severe bleeding and infection after surgery. Wu Jing et al (1996) reported that in patients with pregnancy and aplastic anemia, strict perinatal care, pregnancy and childbirth and neonatal care can significantly improve the prognosis of mother and child. It is generally believed that hemoglobin >60g/L during pregnancy has little effect on the fetus. Newborns who can survive after childbirth generally have normal blood and rarely have aplastic anemia. Hemoglobin ≤ 60g / L can lead to miscarriage, premature delivery, fetal growth restriction, stillbirth and stillbirth. The prognosis of aplastic anemia is related to its type. Severe and very severe AA treatment is difficult, mortality is high, acute aplastic anemia is more than one year of onset, and intracranial hemorrhage and severe infection are the most common causes of death. 30% to 50% of patients with chronic aplastic anemia can be cured after active treatment. Although aplastic anemia is not a contraindication to pregnancy, the risk at pregnancy is much greater than during non-pregnancy. Pregnancy and childbirth in patients with aplastic anemia must be given sufficient attention and serious consideration. It is generally believed that patients with aplastic anemia should have strict contraception and should not be pregnant.

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