Pediatric thalassemia

Introduction to pediatric globin-producing anemia Thalassemia (thalassemia), formerly known as mediterraneananemia, is an abnormal hemoglobin disease characterized by resistance or complete inhibition of one or several globin peptide chains in normal hemoglobin. Completely dominant hereditary hemolytic anemia. basic knowledge Sickness ratio: 0.0001% Susceptible people: children Mode of infection: non-infectious Complications: jaundice, neonatal hepatosplenomegaly, gallstone, edema, ascites, pneumonia, liver fibrosis

Pediatric globin-forming anemia

(1) Causes of the disease

The synthesis of human hemoglobin is controlled by its corresponding globin gene specificity. The globin in normal human hemoglobin (Hb) has four peptide chains, namely , , and , according to the globin peptide chain combination. Different kinds of hemoglobin, namely HbA (22), HbA2 (22) and HbF (22), HbA is the main hemoglobin in adult red blood cells, accounting for 95% of Hb, and HbA2 accounts for about 2% of adult Hb. HbF is the main hemoglobin in the fetal and early neonatal period. It accounts for 70% of newborn Hb at birth, 50% after 2 months, and no more than 5% at 1 year old. Normal adult level (0 to 2%), globin-producing anemia, due to genetic defects, globin gene mutation, globin peptide chain synthesis disorder, according to the synthesis of inhibited globin peptide chain, can be divided For several types, the most common is beta-chain synthesis disorder, called -globin-producing anemia, followed by -chain synthesis-reduced -globin-producing anemia, and less common -chain synthesis reduction or or with reduced chain and globin production barrier Globin generated anemia is classified in two ways:

1 According to the defect of globin peptide chain gene, it is divided into , , and , etc. Clinically, and are the most common.

2 According to the severity of the clinical condition, it is divided into static type, light type, intermediate type and heavy type. At present, two classification methods are used in combination.

1. alpha globin-producing anemia

The gene encoding -globin is located at the short arm end of chromosome 16 (16p13.3), and there are two genes 1 and 2 on each chromosome, so there are four genes in diploid cells, which are deleted according to gene. The number and dysfunctions can be divided into five types:

(1) resting globin-producing anemia: also known as 2-globin-producing anemia or -globin-producing anemia, which lacks an gene (-, /, ) on one chromosome; Its clinical features are asymptomatic, normal red blood cell morphology, Hb Bart's (4) 1% to 2% in the blood at birth, disappeared after 3 months, this type of diagnosis is difficult.

(2) 1-globin-producing anemia or 0-globin-producing anemia: This disease is also called standard -globin-producing anemia, which is deleted by two genes on one chromosome (-, - /,) or two -globin-producing anemia genes (-,/-,) lead to -chain synthesis disorder, its clinical features are asymptomatic in patients, mild changes in red blood cell morphology; HbF normal, born At the time, HbBart accounts for 5% to 6%, and disappears after 3 months; this type is more common in the parents of HbBart fetal edema syndrome patients and HbH disease, the disease does not require treatment.

(3) Hemoglobin H disease: an intermediate type of -globin-producing anemia, consisting of a pair of genes on chromosome 16 and an gene on another chromosome 16 with a genotype of (-, //-,-), clinical features of moderate or severe small cell hypochromic anemia, positive inclusion test, HbBart 20% to 30% in the neonatal blood, symptoms appear after infancy, varying degrees Anemia, jaundice, hepatosplenomegaly, aggravation (especially infection and drug as a cause); mature red blood cell morphology changes; older children may appear Hb H (4) 4% to 20%, and HbA2 and HbF content normal,

(4) HbBart fetal edema syndrome: is a severe -globin-producing anemia, which is a homozygous state of 1, and all genes on chromosome 16 are defective, and its genotype is (-, -/- ,-), because the four genes controlling -chain synthesis are deleted, there is no -chain synthesis, so it is impossible to synthesize HbA, HbA2 and HbF containing chains. In the late fetal period, and chains each form a large amount of 4 (HbBart). And 4 (HbH), at the same time, the embryonic early chain synthesis compensatory increase and lasts until the entire fetal period, and with alpha composition HbPortland, HbBart with high oxygen affinity and very unstable, leading to severe chronic hemolysis and severe tissue in the intrauterine fetus Hypoxia, heart failure, edema, causing miscarriage, stillbirth, most of the fetuses die in the uterus during the 30-40 weeks of gestation or die shortly after delivery. Once the fetus is lucky, the whole body is severely edematous, ascites, severe anemia, Mild jaundice, liver; HbBart content 70% ~ 100%, can be a small amount of HbH (4), the parents of this disease is 1 globin heterozygous anemia, the incidence rate in siblings is about 1/4.

(5) Non-deletion -globin production anemia: the gene structure is not deleted, but its dysfunction, expression level is reduced, and clinical manifestations similar to -globin-producing anemia, the genotype is (a, aThal/a, aA) or non-deletion double heterozygote (a, aThal/a, aThal).

2. Beta globin-producing anemia

The -globin gene is located in the short arm 1 region 2 band (11p1.2) of chromosome 11 and most of the disease is caused by point mutations except for a few nucleotide deletions. There are dozens of mutations. The -chain synthesis is partially inhibited as -globin-producing anemia. The -chain synthesis is completely blocked. It is called 0 globin-producing anemia. The inhibition of peptide-chain synthesis involves -chain. The globin-producing anemia or 0, the two allele mutations on the chromosome are the same as homozygous; the homologous chromosome has only one mutation point called heterozygote; the allele has different mutation points. Known as double heterozygote, the incidence of -globin-producing anemia in China is 0.67%, which is high in Guangdong, Guangxi, Yunnan, Guizhou and other provinces.

(two) pathogenesis

Thalassemia

HbBart fetal edema syndrome lacks 4 -peptide chain genes, and no -peptide chain is formed at all. The chain synthesized in the fetal phase can be polymerized into Hb Bart (4), and HbBart has high oxygen affinity, resulting in severe hypoxia and edema of tissues. There are three -peptide chain gene deletions or defects in HbH disease, and only a small amount of -peptide chain is formed. In the fetal period, the peptide chain and the -peptide chain are combined into a small amount of Hb F (22), so they can survive to birth, with age after birth. Growth, synthesis of -peptide chain is converted to -peptide chain synthesis, -peptide chain that fails to bind to -peptide chain is polymerized into HbH(4), HbH has high oxygen affinity, loses oxygen transport function, and free -peptide chain The erythrocyte variability forms Hb H inclusion bodies, which damages the erythrocyte membrane. The standard alpha thalassemia and the static alpha thalassemia, respectively, lack two and one alpha peptide chain genes, and the peptide chain formation is slightly reduced.

2. Beta thalassemia

Beta thalassemia is a disorder of -peptide synthesis, but the synthesis of -peptide is normal, so that the production of Hb A(22) is reduced, although the relatively increased -peptide chain can be combined with the production of more delta peptides and -peptide chains. Hb A2 (22) and Hb F (22) can be increased, but a large amount of excess free -peptide chains are precipitated in the red blood cells to form inclusion bodies, which damage the erythrocyte membrane and cause premature destruction of the young red blood cells in the bone marrow. "Invalid red blood cell production"; young red blood cells flowing into the blood circulation are destroyed prematurely in the spleen and liver, causing hemolytic anemia, followed by hyperfunction of bone marrow and extramedullary hematopoiesis, active bone marrow hyperplasia, hepatosplenomegaly, long-term bone marrow hyperplasia, causing bone marrow The cavity is enlarged, causing bone growth malformation and developmental disorders. In addition, severe hemolytic anemia requires repeated blood transfusions, and there may be excessive accumulation of hemoglobin and iron, and hemosiderinosis.

Pediatric globin-producing anemia prevention

The disease is a hereditary disease, conducting a population survey, genetic counseling, and doing pre-marital guidance work. Avoiding marriage between patients is important for preventing this disease. In recent years, neonatal cord blood was used as a pH 8.34 discontinuous vinegar fiber membrane. Electrophoresis can be used as an early screening method for -globin-producing anemia. In particular, it can detect non-clinical static and standard -globin-producing anemia, conduct prenatal diagnosis, and measure with fetal blood. The ratio of / chain or DNA extracted from fetal white blood cells or villous cells can be used to diagnose the disease early and terminate the pregnancy in time, which can reduce the burden on families and society and improve the national quality.

Pediatric globin-producing anemia complications Complications, jaundice, neonatal hepatosplenomegaly, cholelithiasis, ascites, pneumonia, liver fibrosis

Can be complicated by jaundice, hepatosplenomegaly, gallstone, can be complicated by hemolytic crisis, edema, ascites, anemia, bone changes, stagnant growth and development, often complicated by bronchial or pneumonia, complicated with hemosiderosis, causing organ damage, concurrent Heart failure, liver fibrosis, liver failure and so on.

Pediatric globin-producing anemia symptoms Common symptoms Skin pale hemolytic anemia Hemolytic jaundice Skin bleeding Point nose low ascites Edema Splenomegaly Hepatomegaly Large frog-shaped belly

1.-globin-producing anemia

Infection and/or oxidative drugs can induce or aggravate hemolytic jaundice, even "hemolytic crisis", similar to the clinical manifestations of erythrocyte G6PD deficiency, attention should be paid to early identification, -globin-producing anemia and its clinical features.

2. Beta thalassemia

The vast majority of gestation period 30 to 40 weeks (average 34 weeks), the fetus died in the uterus or died shortly after delivery, systemic severe edema, ascites, frog belly, a few cases of edema and ascites, severe anemia, pale There may be mild jaundice, hepatomegaly is more obvious than splenomegaly, but no splenomegaly, visible skin bleeding, placenta is huge and thick, pale, crisp.

HbCS homozygous state: may have mild hypochromic anemia, sometimes jaundice, mild swelling of liver and spleen, red blood cell size, target cells, low MCH, increased reticular red blood cell count, HbCS 0.05 ~ 0.06 The traces of HbBart's, HbA2 and F are normal, and the rest are HbA. This case is rare.

HbCS heterozygous state (ie HbCS characteristics): no hematologic abnormalities, or mild anemia, red blood cell abnormalities, small red blood cell disease, etc., HbCS about 0.01, HbA and A2 are normal.

If HbCS is combined with alpha thalassemia 1 (genotype is CS/--), its clinical manifestations and blood picture are similar to HbH disease, which is called CS-type HbH disease. It is easy to use HbA, HbA2 with starch gel electrophoresis at pH 8.6. HbF and other distinctions can come, and because of the small amount, it is easy to ignore.

According to the degree of deletion of the -peptide chain gene and the degree of inhibition (partial or complete inhibition) of -chain synthesis, it can be classified into the following types:

According to the age of onset of thalassemia, the severity of the disease can be divided into the following three types:

(1) Light type: It is a heterozygous state of normal gene and globin-producing anemia o, , gene, which is common in this type, childhood or adolescent, mild or no anemia (Hb 100120g/L), Mild or no liver, splenomegaly, mild jaundice and splenomegaly in infancy, good prognosis; more commonly found in heavy family surveys.

(2) Heavy: also known as Cooley's anemia, which is a homozygous or double heterozygous state of o, gene. Its clinical features are mostly infancy, and 50% occur within 6 months after birth. Occasionally In the neonatal period, the earlier the onset age, the heavier the disease, the severe chronic hemolytic anemia, the need to rely on blood transfusion to maintain life, no anemia in the neonatal period, HbBart's content of 25%, a small amount of HbH, a serious chronic progressive anemia, Hemoglobin often <30g / L; special face, the performance of the head is large, the tibia is slightly higher, the bridge of the nose is depressed, the eye distance is widened, the expression is dull; the liver and spleen are gradually enlarged, mainly splenomegaly, up to the pelvis , often complicated by infection, poor prognosis, died of heart failure and infection before the age of 5, the treatment often died before the age of 20 arrhythmia or heart failure.

(3) Intermediate type: chronic hemolytic jaundice type, which is a homozygous state of gene (high F) or o globin-producing anemia. Its clinical manifestation is between severe and light, this type is rare, and the clinical features are the onset. Late age (usually 4 to 5 years old); moderate anemia; mild hepatic spleen, mild to moderate spleen, often persistent mild to moderate jaundice; red blood cell morphology similar to heavy; HbF content 40 % ~ 70%, HbA2 content is normal or reduced; no treatment, can live to adulthood, infection and / or drug aggravation hemolysis, can be combined with gallstones, high indirect bilirubinemia, after spleen and jaundice does not subsided.

Examination of pediatric globin-producing anemia

Blood picture

Due to the decrease of Hb synthesis, it is a small cell hypochromic anemia. The peripheral blood samples show different red blood cell sizes, the central light-stained area is enlarged, the red blood cell morphology is obviously changed, and the shape is abnormal (pear shape, teardrop shape, small spherical shape, triangle shape or target shape). ), debris red blood cells and nucleated red blood cells, basophilic stippling, etc., polychromatic red blood cells, Hao-Chou body, etc., reticulocytes are normal or increased, usually 10%.

2. Red blood cell osmotic fragility test

Decreased, 0.40% ~ 0.38% NaCl solution began to hemolyze, completely hemolyzed in 0.20% or lower hypotonic saline, light cases can be normal.

3.HbF determination

This is an important basis for the diagnosis of severe -globin-producing anemia. HbF content is slightly elevated (<5%) or significantly increased (20% to 99.6%); HbA2 is often decreased, normal or moderately elevated, HbA2 3.5% ~8.0%.

4. Hemoglobin electrophoresis

Isolation of HbH or Hb Bart is an important basis for the diagnosis of alpha-producing anemia.

5. Peptide chain analysis

The content of , , , peptide chains can be determined by high performance liquid chromatography, and the ratio of / is <0.1 (normal value is 1.0 to 1.1) in Cooley anemia.

6. Isopropanol test

Positive, like the thermal instability test, can identify unstable Hb and alpha-marine anemia.

7. Inclusion body formation test

Red blood cell inclusions and Heinz bodies can be positive.

8. Bone marrow

The erythroid hyperplasia is obviously active. In the middle, the young red blood cells are the majority, and the mature red blood cell morphology is the same as that of the peripheral blood, but the -globin-producing anemia static type bone marrow can be normal.

9. Nucleic acid analysis

Determination of the mRNA content of the Hb peptide bond or the identification of the globin gene of the patient by DNA hybridization and restriction endonuclease technology. In recent years, continuous fragment length polymorphism (RFLP) analysis, synthetic oligonucleosides Acid probe hybridization and gene in vitro amplification (PCR) technology indirectly or directly for genetic diagnosis, can detect and identify mutant genes, routine X-ray, B-ultrasound, electrocardiogram, bone X-ray examination, bone marrow cavity widening, cortex Thinning and osteoporosis, the inner and outer plates of the skull are thinned, the bone marrow cavity of the skull is enlarged, the barrier is widened, the intermedullary cortex has vertical stripes, and the hair is short-haired, and the short bone is thinned by the trabecular bone. Or inlay pattern spacing, the phalanx and metacarpal bone appear earlier, the long bone is thinner and the medullary cavity is wider, and the femur is more endless.

Diagnosis and diagnosis of pediatric globin-producing anemia

diagnosis

According to the beginning of infancy, chronic progressive anemia, splenomegaly and special face, peripheral blood red blood cell morphology, red blood cell osmotic fragility and/or positive family history, should be highly suspected, further hemoglobin electrophoresis, genetic analysis, etc. Can be diagnosed.

Differential diagnosis

Must be associated with iron deficiency anemia, hereditary spherocytosis, viral hepatitis or cirrhosis, G-6-PD deficiency, neonatal homologous immune hemolytic disease.

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