Pediatric alpha-thalassemia

Introduction to Pediatric -thalassemia Alphathalassaemia (referred to as thalassemia), also known as thalassemia, should be called "globin-producing anemia" according to the National Medical Terminology Committee. It is because the synthesis of one or more globin peptide chains is blocked or completely inhibited, resulting in abnormal composition of Hb components, causing chronic hemolytic anemia. According to different types of globin gene deletions or defects, the corresponding inhibition of bead chain synthesis is different, and the thalassemia can be divided into -thalassemia; -thalassemia, -thalassemia, -thalassemia and Rare beta-thalassemia; the previous two types are common, all kinds of thalassemia can be combined with each other, can be combined with various abnormal Hb (such as HbE / beta thalassemia), this group of diseases, also known as thalassemia syndrome , all belong to autosomal incomplete dominant inheritance, -mediterraneananemia (-mediterraneananemia) is a group caused by -globin chain synthesis disorder caused by deletion or functional defect (point mutation) of -globin gene Hemolytic anemia. basic knowledge The proportion of illness: 0.002% Susceptible people: children Mode of infection: non-infectious Complications: hemolytic anemia, jaundice, gallstones, edema

Pediatric -thalassemia etiology

(1) Causes of the disease

It is an autosomal incomplete dominant inheritance. The -globin gene is located on the short arm of chromosome 16 (16P13.33~p13.11~pter), with a total length of about 29kb, and contains seven linked alpha genes or pseudogenes.

1. -gene deletion: Each chromosome has a pair of -genes that control the synthesis of -chain, so there are 4 -genes in each cell, and different degrees (1 to 4) of genetic abnormalities can occur:

(1) +-thalassemia (2 thalassemia): If one -genome is deleted on one of the chromosomes, the synthesis of the controlled -chain is partially inhibited, called +-thalassemia (2 thalassemia) .

(2) -thalassemia (or 1 thalassemia): If two -genes are deleted on one chromosome, the -chain synthesis controlled by the two genes only is completely inhibited, called -thalassaemia (or Alpha 1 thalassemia).

(3) Hb-H disease (or intermediate type -thalassaemia): If three of the four -genes on a pair of chromosomes are deleted (the genotype is o/+poisonous heterozygous), the -chain synthesis is large. Partially suppressed, known as Hb-H disease (or intermediate alpha-thalassemia).

(4) Hb-Barts fetal edema syndrome (Hb Bart's hydrops fetalis): If all four -genes on a pair of chromosomes are deleted (genotype is o/o thalassa homozygous), -chain synthesis is completely inhibited It is called Hb-Barts' fetal edema syndrome (Hb Bart's hydrops fetalis), and the deletion can be divided into left deletion (L type, lack of a 4.2 kb fragment including 2 gene) or right deletion (R type deletion includes a partial 3.7 kb fragment of the 1 and part of the 2 gene).

2. -gene function deficiency: In addition, there are non-deletion -thalassemia, which is due to the "point mutation" of -gene nucleotides, which is caused by three kinds of defects:

(1) Constant Spring (cs): a stop mutation of the 2 gene, which lengthens the chain to 172 amino acids, and the mRNA transcribed by this mutant gene is unstable, resulting in a disorder of chain synthesis.

(2) Quong Sze: mutation of CTG (leucine) of the 125th codon of 2 gene to CCG (valine), which is a highly unstable -globin, which hinders the formation of 11 dimer and thus affects Synthesis of tetramers.

(3) Poly A signal mutation: The addition signal of 3' of 1 gene is mutated from AATAAA to AATAAG, which reduces the mature mRNA and reduces -chain synthesis, and in Guangdong, Guangxi and Sichuan. - In thalassemia, non-deletion accounts for 35% to 60%, and the remainder is missing.

(two) pathogenesis

The normal human chain is involved in the globin peptide chain composition of HbA and F. The -thalassaemia patients have different degrees of -gene defects in -thalassemia, and -chain synthesis is reduced to disappeared, and is not combined with -chain. The excess amount of and chains is different, resulting in different degrees of corresponding tetramers; namely 4 (Hb Bart's) and 4 (Hb-H). These tetramers are unstable Hb and are easily oxidized. , denaturation, precipitation accumulation to form inclusion bodies, attached to the erythrocyte membrane, damage the membrane, plasticity decreased, intravascular or extravascular hemolysis; reduced synthesis of the globin peptide chain, resulting in reduced Hb synthesis, formation of small cells, hypoallergenic anemia (Hb content in each cell is reduced).

1.2 thalassemia ( thalassemia)

Also known as static -thalassaemia, no clinical and abnormal blood manifestations, often due to family survey of -thalassemia patients or pre-marital, prenatal and neonatal cord blood screening, found in the cord blood Hb Bart's at birth It accounts for 1% to 2% and disappears within 3 months.

2.1 thalassemia (o thalassemia)

Also known as standard alpha-thalassemia, there are two genotypes:

(1) 2 thalassemia homozygote (2 gene/2 gene).

(2) 1 thalassemia heterozygote (1 gene/A gene), no anemia or mild anemia in this disease, anemia increased during infection or pregnancy, mild liver, splenomegaly or no enlargement, mild small cell hypopigmentation Anemia, blood smear red blood cells vary in size, central light staining, abnormal shape, occasional target shape, denatured globin body positive, red blood cell osmotic fragility; cord blood Hb Bart's 3.4% ~ 14.0%, in age Disappear within 6 months, the disease must be distinguished from iron deficiency anemia.

3. Hemoglobin H disease

HbH disease (Hemoglobin H disease) is an intermediate type of thalassemia, and its genotype includes +/o thalassemia double heterozygote (-/-), o/Hb coustant spring (CS) (cs/--), o/ Non-deleted -thalassemia (-/thal) and non-deleted -thalass homozygotes (thal/thal), in China's Hb-H disease, non-deletion genes account for about 50%, and its clinical hematological performance ratio Defective type is severe, the disease is more than 3 years old, the minimum is 40 days, and can be late to adolescence.

Pediatric alpha-thalassemia prevention

Actively carry out prenatal and postnatal work to reduce/control the inheritance of the thalassemia gene.

1. Premarital thalassemia screening to avoid marriage of patients with mild thalassemia can significantly reduce the chances of birth of heavy/intermediate thalassemia patients.

2. Promote prenatal diagnosis technology. For both parents or one of the thalassemia gene carriers, collect fetal villi, amniotic fluid cells or cord blood at 4 months of pregnancy, and obtain genomic DNA by polymerase chain reaction (PCR) technology for high-risk fetuses. For prenatal diagnosis, severe/intermediate children should terminate their pregnancy.

Pediatric alpha-thalassemia complications Complications hemolytic anemia jaundice gallstone edema

Can be complicated by severe chronic hemolytic anemia, can occur hemolytic crisis, severe anemia, bone changes, Kurdish face, splenomegaly, need to rely on blood transfusion to maintain life, jaundice, infection and / or drugs can aggravate hemolysis, can Combined gallstones, high indirect bilirubinemia, severe fetus can die in the uterus or shortly after delivery, severe edema, ascites, growth and development, often accompanied by bronchial or pneumonia, and hemosiderosis , causing organ damage, heart failure, liver fibrosis, liver failure and so on.

Pediatric -thalassemia symptoms common symptoms skin bleeding point jaundice hemolytic jaundice fetal edema splenomegaly physiology anemia hepatomegaly ascites

Hemoglobin H disease

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

(1) Heavy: more than infancy, similar to severe -thalassemia, severe chronic hemolytic anemia, Ku's face, splenomegaly, need to rely on blood transfusion to maintain life, no anemia in neonatal period, Hb Bart's Content 25%, small amount: HbH.

(2) chronic hemolytic jaundice type: this type is rare, mild to moderate anemia, persistent mild to moderate jaundice, mild liver, splenomegaly, infection and / or drug aggravation hemolysis, can be combined with gallstones, high indirect Bilirubinemia, after the spleen, the jaundice does not subside.

(3) Light type: common in this type, childhood or adolescent onset, mild or no anemia, mild or no liver, splenomegaly, infection and / or oxidative drugs can induce or aggravate hemolytic jaundice, or even "hemolysis Crisis, similar to the clinical manifestations of red blood cell G6PD deficiency, should be noted for identification.

2.Hb Bart's fetal edema syndrome

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 Mild jaundice, hepatomegaly is more obvious than splenomegaly, no spleen, visible skin bleeding, placenta is huge and thick, pale, crisp, 3. Hemoglobin Constant Spring (HbCS).

(1) HbCS homozygous state: may have mild hypopigmentation 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, trace Hb Bart's, HbA2 and F are normal, the rest is HbA, this case is rare.

(2) HbCS heterozygous state (ie HbCS characteristics): no hematological abnormalities, or mild anemia, red blood cell abnormalities, small red blood cell disease, etc., HbCS about 0.01, HbA and A2 are normal, HbCS if combined with alpha thalassemia 1 (Genotype CSa/--), its clinical manifestations and blood similar to HbH disease, known as CS-type HbH disease, starch gel electrophoresis using pH 8.6 is easy to distinguish from HbA, HbA2, HbF, etc. Less, easy to ignore.

Pediatric alpha-thalassemia check

Hemoglobin H disease

(1) Peripheral blood: severity of anaemia, red blood cells (0.4l ~ 4.06) × 10 ¹² / L, Hb18 ~ 110g / L, reticulocytes increased, range 0.004 ~ 0.22 (average 0.046), occasionally, late Red blood cells, peripheral blood smear showed obvious red blood cell size, light stain, shaped, target shape and debris, generally white blood cells and platelets normal.

(2) HbH inclusion body and Heinz body formation test: HbH inclusion body and Heinz body formation test were positive, the positive rate of HbH inclusion body red blood cells was 3.0%-100.0%, and Heinz body positive cells were 30.0%-100%.

(3) Isopropanol test: strong positive.

(4) Red blood cell osmotic fragility: reduced.

(5) Hemoglobin electrophoresis: visible HbH, content 1.5% ~ 44.3%, about 76% composite Hb Bart's content (anti-alkali ratio) 0.12% ~ 19.5% (average 4.6% ± 3.3%); about 13% composite HbCS The content is 0.82% to 6.80%.

(6) Bone marrow: The red blood cell line is obviously proliferating, mainly in the middle and late red blood cells.

(7) -thalassemia gene diagnosis: There are four main methods: 1 restriction enzyme digestion direct analysis, 2 restriction fragment length polymorphism (RLFP) indirect analysis, 3 oligonucleotide probe (ASO) Analytical method, 4 polymerase chain reaction (PCR) gene diagnosis method: At present, PCR is used for the deletion of HbH disease genes; PCR plus allele-specific oligonucleotide probes are commonly used for non-deletion types. Dot blot hybridization (ASO), which is still unknown, is confirmed by sequencing. There are 16 non-deletion mutation points discovered so far, and the 2 gene CDL24 (CG) mutation has been reported recently.

2.Hb Bart's fetal edema syndrome

(1) Peripheral blood: severe to moderate anemia, Hb 30 ~ 110g / L (mean 49 ~ 70g / L), red blood cells (2.1 ~ 4.8) × 10 ¹² / L, reticulocytes 0.038 ~ 0.48, increased nucleated red blood cells Up to 76 ~ 522 / 100 white blood cells, peripheral blood smear red blood cells are obviously different in size, shaped, target shape, with characteristic hypochromic giant red blood cells.

(2) The red blood cell HbH inclusion body and Heinz body formation test can be positive.

(3) Red blood cell osmotic fragility decreased, and the isopropanol test was positive.

(4) The serum unbound bilirubin can be slightly increased (85 mmol/L).

(5) Hemoglobin analysis: Hb Bart's content 70% ~ 100%, Hb Portland 7.0% ~ 25%, there is still a small amount of HbH, no HbAl, HbA2 and HbF, anti-alkali Hb 32% ~ 76% (Hb Bart's weak anti-alkaline ).

(6) Peptide chain analysis: High-performance liquid chromatography (HPLC) was used to detect the biosynthesis level of micro-globin peptide chain, and it was confirmed that there was no -chain in this disease. The gene diagnosis confirmed that there was no -chain gene, and X-ray and B-ultrasound were routinely performed. Electrocardiogram and other examinations, bone X-ray examination, bone marrow cavity widening, cortical thinning and osteoporosis, thinning of the inner and outer plates of the skull, enlargement of the skull and bone marrow cavity, widening of the barrier, and vertical streaks of the intermedullary cortex Short hair changes, short bone due to thinning of the trabecular bone to form a lace or inlay pattern interval, the phalanx and metacarpal bone appear earlier, the long bone is thinner and the medullary cavity is widened, and the femur is more endless.

Diagnosis and diagnosis of -thalassemia in children

Diagnostic identification

Hemoglobin H disease

According to the clinical characteristics and Hb electrophoresis, HbH can be diagnosed, and the conditional unit can be further diagnosed.

2.Hb Bart's fetal edema syndrome

According to the clinical features of this disease, hepatomegaly is more obvious than splenomegaly. The characteristic red blood cell morphology and Hb electrophoresis main Hb is Hb Bart's can be diagnosed.

Differential diagnosis

Hemoglobin H disease

The disease must be differentiated from beta-thalassaemia, erythrocyte GbPD deficiency, jaundice-type viral hepatitis, HS, and iron deficiency anemia.

2.Hb Bart's fetal edema syndrome

The identification of fetal edema caused by immunological hemolysis in neonates with neonates is clinically characterized by hepatomegaly greater than splenomegaly. The characteristic red blood cell morphology and Hb electrophoresis main Hb is Hb Bart's, which can be identified.

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