Pediatric X-linked agammaglobulinemia

Introduction to X-linked no-gammaglobulinemia in children X-linkedagammaglobulinemia (XLA) is a primary immunodeficiency disease caused by a developmental disorder of the human B cell line and is a typical representative of primary B cell defects. Also known as congenital hypogammaglobulinemia. Only boys develop the disease, with repeated bacterial infection as the main clinical feature. basic knowledge Sickness ratio: 0.0004% Susceptible people: children Mode of infection: non-infectious Complications: anemia, dermatomyositis

The cause of X-linked no-gammaglobulinemia in children

(1) Causes of the disease

Shanghai Xinhua Hospital confirmed that one of the children was a Bruton tyrosine kinase (Btk) gene mutation.

The Btk gene is located at Xq21.3~22, including 19 exons. The encoded protein product belongs to the cytoplasmic tyrosine kinase family (Btk) and can be divided into PH (pleckstrin homology), TH (Techomology), SH2. (Src homology 2), five functional regions including SH3 and kinase domain (also known as SH1), Btk's Src kinase family (Lyn, Fyn, Blk, Hck) and B cell receptor (BCR) hinges are activated and further Activation of Syk leads to phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM) and related receptors of Ig and Ig components. Calcium induced by PLC phosphorylation and activation is known. The inflow depends on Btk.

The Btk gene mutations in children with XLA were followed by missense point mutation, nonsense point mutation, deletion frame shift, Splice-site frameshift, Insertion frameshift, and complete deletion. The frame is missing, the splice-site in-frame and the splicing-site in frame shift. The above-mentioned molecular defects lead to the further maturation of the pre-B cells in XLA disease to B cell dysfunction. There is not necessarily a consistent relationship between type and clinical phenotype, and environmental factors also play a role.

(two) pathogenesis

There are pre-B cells in the bone marrow of the patients, and there are almost no plasma cells and mature B lymphocytes in the peripheral blood and lymph nodes. Immature B cells and pre-B cells are seen in the peripheral blood. The thymus tissue and cellular immune function of the children are all Normally, considering the existence of the intrinsic differentiation abnormality of the B cell system in this disease, that is, there are obstacles in the differentiation stage of the development of the pre-B cells to the mature B cells, resulting in insufficient synthesis of all types of Ig, and no specific antibody response to many antigens, in recent years. Molecular biological studies on the pathogenesis of this disease show that the pre-B cells of XIA patients have lower DNA synthesis than normal people, and immunoglobulin gene analysis found that patients with this disease lack normal pre-B cells to form the chain. The structure of VH/DH/JH, while the DH/JH structure lacking VH is the majority. The study also found the gene Btk (Bruton tyrosine kinase) related to B cell differentiation, but what kind of gene abnormality is common in this disease? And the method used to effectively detect it is still a problem.

Prevention of X-linked agammaglobulinemia in children

Pay attention to the prevention of genetic diseases. Pregnant women with family history should undergo prenatal examination and detection of mutated gene carriers. After the amniotic fluid test proves to be a boy, further determination of whether the Btk gene is mutated for early diagnosis and correct treatment.

Pregnant woman health care

It is known that the occurrence of some immunodeficiency diseases is closely related to embryonic dysplasia. If pregnant women are exposed to radiation, receive certain chemical treatments or develop viral infections (especially rubella virus infections), they can damage the fetal immune system. Especially in the early pregnancy, it can affect multiple systems including the immune system. Therefore, it is very important to strengthen the health care of pregnant women, especially in the early pregnancy. Pregnant women should avoid receiving radiation, use some chemical drugs with caution, and inject rubella vaccine to prevent as much as possible. Virus infection, but also to strengthen the nutrition of pregnant women, timely treatment of some chronic diseases.

2. Genetic counseling and family survey

Although most diseases cannot determine the genetic pattern, genetic counseling for diseases with defined genetic patterns is valuable if genetically immunodeficiency in adults will provide the developmental risk of their children; if a child has autosomals Recessive genetic or sexually linked immunodeficiency disease, it is necessary to tell parents that their next child is likely to be sick, for patients with antibodies or complement deficiency patients should check the antibody and complement levels to determine the family disease For some diseases that can be genetically mapped, such as chronic granulomatosis, parents, siblings and their children should be genetically tested. If a patient is found, it should also be performed among his or her family members. Check that the child's child should be carefully observed at the beginning of the birth for any disease.

3. Prenatal diagnosis

Some immunodeficiency diseases can be prenatally diagnosed, such as cultured amniotic fluid cell enzymology can diagnose adenosine deaminase deficiency, nucleoside phosphorylase deficiency and some combined immunodeficiency diseases; fetal blood cell immunological test can be Diagnosis of CGD, X-linked agammaglobulinemia, severe combined immunodeficiency disease, thereby terminating pregnancy and preventing the birth of children. In recent years, X-linked agammaglobulinemia has been reported in various parts of China, and early diagnosis is possible. It is important to give specific treatment early and to provide genetic counseling (prenatal diagnosis or even intrauterine treatment).

Children with X-linked agammaglobulinemia complications Complications anemia dermatomyositis

Often complicated by repeated serious infections, anemia; oral polio vaccine can cause limb paralysis; combined with viral infection, dermatomyositis-like syndrome can also occur; Pneumocystis carinii infection, autoimmune hemolytic Anemia, rheumatoid arthritis, malabsorption syndrome and amyloidosis.

Symptoms of X-linked agammaglobulinemia in children Common symptoms Repeated infection of malabsorption syndrome Amyloid granulocytes reduce tonsil small or absent hair loss

The disease is only seen in boys. About half of the sick children can ask about family history. Since the mother IgG can enter the fetal blood circulation through the placenta, the child usually does not have any symptoms within a few months after birth, along with the maternal IgG. The catabolism gradually decreases, and the sickness begins to appear more than 4 to 12 months after birth.

Repeated infection

The most prominent clinical manifestations are repeated serious bacterial infections, especially capsular purulent bacteria such as hemolytic streptococcus, haemophilic influenza bacilli, Staphylococcus aureus and Pseudomonas infections, most negative for Gram. The susceptibility of bacilli such as pathogenic Escherichia coli, Pseudomonas aeruginosa, Proteus, Serratia, etc. is also significantly increased.

Children with XLA have good resistance to general viruses, but they have poor resistance to certain enteroviruses such as Echo, Coxsackie and Poliovirus. It should be noted that oral polio vaccine can cause illness. In children with XL, children with XLA combined with the above-mentioned virus infection can also develop dermatomyositis-like syndrome, and there are also reports of Pneumocystis carinii infection.

2. Other performance

Prone to allergic and autoimmune diseases, including autoimmune hemolytic anemia, rheumatoid arthritis, immune neutropenia, alopecia, protein-losing enteropathy, malabsorption syndrome and amyloidosis, arthritis Most of the joints are larger, such as the knee and elbow joints, the affected part is swollen, the movement is limited, the joint surface bone destruction is not obvious, the erythrocyte sedimentation rate is normal, and the rheumatoid factor and anti-nuclear antibody are negative.

3. Physical examination

Repeated infection causes chronic consumptive constitution, pale, anemia, wilting, tonsils and adenoids are small or absent, superficial lymph nodes and spleen can not be touched, lateral sinus X-ray examination can be seen a lack of adenoid shadow or Become smaller.

Examination of X-linked no-gammaglobulinemia in children

A significant decrease in peripheral blood-deficient B cells and serum immunoglobulins (including IgG, IgA, IgM, and IgE) is a major laboratory feature of the disease.

Sick serum

The total Ig is generally not more than 200 ~ 250mg / dl; IgG may not be completely detected, a small number of cases can reach 200 ~ 300mg / dl, but generally less than 100mg / dl; IgM and IgA trace or can not be measured.

2. Antibody reaction

The same family of hemagglutinin (anti-A and anti-B blood group antibodies) is absent, even if multiple diphtheria toxoid injections, the Sikh test can not be negative, specific antibody response is lacking (including T cell-dependent and T cell-independent antigen).

3. B cell number and function

The total number of peripheral white blood cells can be in the normal range, the number of lymphocytes is normal or slightly decreased, mature B cells (CDL9+, CD20+, membrane surface Ig+) are absent, bone marrow B cells and plasma cells are absent, and a small amount of pre-B cells are seen.

4. Prenatal testing and detection of mutant gene carriers

Women with a positive family history should have an antenatal checkup during pregnancy to determine if the fetus is suffering from XLA. The amniotic fluid cells can be examined first to determine their gender. For males (XY), the number of B cells in amniotic fluid or cord blood should be further examined. DNA sequence analysis can also be used to determine whether a Btk gene mutation or a complex gene fragment (DXS178) that is tightly linked to Btk is present, and the latter two methods can also be used to find a mutant gene carrier.

Conventional X-ray chest X-ray, B-ultrasound and other examinations, repeated pulmonary infection can be seen in bronchiectasis, joint cavity effusion, lateral sinus X-ray examination showed a lack of adenoid shadow or smaller.

Diagnosis and differential diagnosis of X-linked no-gammaglobulinemia in children

diagnosis

According to repeated purulent infections after 4 months of birth, the incidence of boys, the reduction of serum Ig and circulating B lymphocytes, and the male patients with similar manifestations in the maternal family, it is not difficult to make a diagnosis, the lateral position of the nasopharynx X The line examination showed a lack of adenoid tissue, but chest X-ray showed thymography. After local antigen stimulation, there was still no plasma cells in the lymph nodes of the drainage area. The baby rectal mucosal biopsy was very meaningful. The healthy infant had a rectal mucosa 1 month after birth. There are a lot of plasma cells, and patients lack plasma cells.

Differential diagnosis

According to clinical manifestations and laboratory results, it is not difficult to diagnose XLA, but should be differentiated from hypogammaglobulinemia caused by other causes. In 2 years old, it should be differentiated from temporary hypogammaglobulinemia in infants. The latter's blood circulation B lymphocyte count is normal, the disease itself is self-limiting, and gradually returns to normal after 2 years of age, patients with childhood onset need to be identified with common variant immunodeficiency disease, the latter can Involved in both sexes, the number of B lymphocytes in the blood circulation is normal or reduced, and the degree of Ig in serum is reduced to a lesser extent.

1. Infant physiological hypogamma globulin status: In general, serum IgG is not less than 350mg/dl, IgM and IgA content exceeds 20mg/dl, so it can be differentiated from XLA, individual suspicious cases, serum IgG after 3 months If IgM and IgA increase significantly, XLA can be ruled out.

2. Infant temporary gamma globulin deficiency: The total serum Ig level of the disease is not less than 300mg/dl, IgG is not less than 200mg/dl, and generally returns to normal after 18 to 30 months after birth.

3. Severe combined immunodeficiency disease (SCID): The age of onset is earlier than XLA, more than soon after birth, the disease is severe, the number of peripheral blood T cells and B cells are significantly reduced, and the three Ig are very low or detect Less than, T cell function is seriously deficient, systemic lymphoid tissue dysplasia, thymus is very small, more than 2g, and lack of thymus corpuscle, the prognosis is worse than XLA.

4. Chronic malabsorption syndrome and severe malnutrition: Children with both plasma hypoproteinemia and hypoalbuminemia, and the degree of hypo-immunoglobulinemia is relatively light, not reaching the level of XLA, so it is easier Different from each other.

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