Overview of X-linked dysgammaglobulinemia (XLA)
X-linked dysgammaglobulinemia (XLA), also known as Bruton’s disease, is a primary immunodeficiency disease caused by a developmental disorder of the human B-cell family, and is a typical representative of primary B-cell defects, also known as congenital hypogammaglobulinemia, which occurs only in boys, with a prevalence rate of about (6~10)/million. It is characterized by recurrent bacterial infections, markedly reduced or absent immunoglobulins in the serum, inability to produce antibody response to antigenic stimuli, reduced B lymphocytes in the blood circulation, lack of germinal centers and lymphoid follicles in lymph nodes and lymphoid tissues, absence of plasma cells in the bone marrow, but with a normal number of pre-B lymphocytes, and a normal number of T lymphocytes and their function.
Etiology
Mutations in the Bruton’s tyrosine kinase (Btk) gene.
The Btk gene is located in Xq21.3-22, including 19 exons, and encodes a protein product belonging to the family of cytoplasmic tyrosine kinases, which can be divided into five functional regions, including PH, TH, SH2, SH3, and the kinase region.The Src kinase family of Btk (Lyn, Fyn, Blk, and Hck) hinges on the B cell receptor (BCR) and is activated, and further activates Syk, resulting in the activation of the Igα and Igβ kinases. phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) and related receptors of the Igα and Igβ components. Calcium efflux due to PLCγ phosphorylation and activation is known to be dependent on Btk, and mutations in the Btk gene in children with XLA are, in order, missense point mutations, nonsense point mutations, shifted deletions, splice site shifted deletions, insertion shifted deletions, complete deletions, deletions in frames, and intraframe splicing and splicing shifted deletions, and the above molecular defects result in impaired further maturation of pre-B cells into B cells in children with XLA. There is not always a consistent relationship between the genotype and the clinical phenotype of the disease, and environmental factors also play a role.
Symptoms
The disease is seen only in boys, and a family history can be inquired about in about nearly half of the children with the disease. Because maternal IgG passes through the placenta and enters the fetal circulation, children usually do not show any symptoms for several months after birth. With the continuous decomposition and metabolism of maternal IgG, it gradually decreases, and most of the children start to show symptoms of infection from 4 to 12 months after birth.
1. Recurrent infections
The most prominent clinical manifestation is recurrent severe bacterial infections, especially podococcal purulent bacteria, such as hemolytic streptococcus, hemophilic influenza bacillus, staphylococcus aureus and pseudomonas spp. are the most common infections. Susceptibility to gram-negative bacilli such as pathogenic Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, and Serratia marcescens is also significantly increased.
Children with XLA have fair resistance to viruses in general, but poor resistance to certain enteroviruses, such as echovirus, coxsackievirus, and poliovirus. It should be noted that live oral polio vaccine can cause paralysis of the limbs, and dermatomyositis-like syndrome may occur in children with XLA in combination with these viral infections. Pneumocystis carinii infection has also been reported.
2. Other manifestations
The disease is prone to allergic and autoimmune disorders. Including autoimmune hemolytic anemia, rheumatoid arthritis, immune neutropenia, alopecia, protein-losing enteropathy, malabsorption syndrome and amyloidosis. Arthritis tends to involve the larger joints, such as the knee and elbow joints, with swelling of the affected area, limitation of movement, and insignificant bone destruction of the articular surfaces. Blood sedimentation is normal, rheumatoid factor and antinuclear antibody are negative.
3. Physical examination
Repeated infections cause chronic consumptive constitution, pallor, anemia, mental depression. Tonsils and adenoids are small or absent, superficial lymph nodes and spleen are not palpable, and adenoid shadows are absent or small on lateral X-ray examination of the nasopharynx.
Examination
Lack of B cells in the peripheral blood and marked decrease in serum immunoglobulins (including IgG, IgA, IgM and IgE) are the main laboratory features of the disease.
1. Serum
Total Ig usually does not exceed 200-250mg/dl; IgG may be completely undetectable, and in a few cases may reach 200-300mg/dl, but usually below 100mg/dl; IgM and IgA are trace or undetectable.
2. Antibody reaction
The absence of homologous erythrocyte agglutinins (anti-A and anti-B blood group antibodies), even if the diphtheria toxoid injection is performed several times, the Sick’s test can not be converted to negative. Lack of specific antibody response (both T-cell-dependent and T-cell-independent antigens).
3. B-cell count and function
The total number of peripheral blood leukocytes may be in the normal range, the lymphocyte count is normal or mildly decreased, and mature B cells are absent. Bone marrow B cells and plasma cells are absent, and a small number of pre-B cells are seen.
4. Prenatal testing and mutation carrier testing
Women with a positive family history of XLA should undergo prenatal testing to determine whether the fetus has XLA. amniotic fluid cells can be examined to determine the sex of the fetus, and if the fetus is a male, amniotic fluid or umbilical cord blood should be examined to determine the number of B-cells. The diagnosis can also be confirmed by DNA sequencing to find out if a mutation in the Btk gene is present or to discover the presence of a complex gene fragment (DXS178) that is tightly linked to Btk. The latter two methods can also be used to identify carriers of the mutated gene.
5. Other auxiliary tests
X-ray chest radiographs and ultrasound are routinely performed. Repeated lung infections can be seen as bronchial dilatation, joint cavity effusion, and lack of or small adenoid shadows on lateral X-ray of the nasopharynx.
Diagnosis
The diagnosis is not difficult to make based on recurrent purulent infections after 4 months of life, onset in boys, significant reduction in serum Ig of all types and circulating B lymphocytes, and a male patient with similar presentation in the maternal family, Lateral nasopharyngeal X-ray shows lack of adenoidal tissue but thymic shadows are seen in the chest X-ray, and lack of plasma cells in the lymph nodes in the drainage area even after localized antigenic stimulation, and the infant’s rectal mucosa Biopsy of the rectal mucosa of infants is of great interest, as healthy infants have large numbers of plasma cells in the rectal mucosa at 1 month after birth, whereas affected infants lack plasma cells.
Differential diagnosis
Based on clinical manifestations and laboratory findings, it is not difficult to make a diagnosis of XLA, but it should be differentiated from other causes of hypogammaglobulinemia.
1. Physiologic hypogammaglobulinemia in infants
In general, serum IgG is not less than 350mg/dl, and IgM and IgA content is more than 20mg/dl, so it can be differentiated from XLA. In individual suspected cases, XLA can be ruled out if there is a clear rising trend of serum IgG, IgM and IgA after 3 months.
2. Infantile transient gammaglobulin deficiency
In this disease, the serum total Ig level is not less than 300mg/dl, and IgG is not less than 200mg/dl, and it usually returns to normal naturally at 18-30 months after birth.
3. Severe combined immunodeficiency disease
The age of onset is earlier than that of XLA, and the onset of the disease starts soon after birth. The condition is serious, the number of T cells and B cells in peripheral blood is significantly reduced, the three kinds of Ig are very low or undetectable, the function of T cells is seriously defective, and the whole body of lymphoid tissue is underdeveloped, and the thymus gland is very small, mostly less than 2g, and lacks thymus gland microsomes, and the prognosis is even worse than that of XLA.
4. Chronic malabsorption syndrome and severe malnutrition
Children with both plasma hypoproteinemia and hypoalbuminemia, but the degree of hypoimmunoglobulinemia is less severe than that of XLA, so it is easier to distinguish between them.
Complications
Recurrent severe infections, anemia; oral polio vaccine can cause limb paralysis; combined with viral infections, dermatomyositis-like syndrome can also occur; complicated by Pneumocystis carinii infection, autoimmune hemolytic anemia, rheumatoid arthritis, malabsorption syndrome and amyloidosis.
Treatment
Intravenous immunoglobulin (IVIG) replacement therapy controls the symptoms of infection in the majority of children with XLA, and the general condition improves rapidly, with significant relief of joint pain, malabsorption, and anemia.IVIG therapy is particularly important in the prevention and treatment of acute, or chronic, infections with enteroviruses such as coxsackie and echovirus.
IVIG therapy should be started early, and high dose is significantly better than low dose therapy; however, the dosage should be individualized to the extent that the serum IgG concentration rises to 1000mg/dl. In a few cases, the effect of IVIG therapy is very unsatisfactory, which may be due to: too late treatment, insufficient dosage, IVIG can not replace the secretory IgA. Various supportive therapies, including nutrition, living and hygienic conditions, prevention of infections, appropriate physical exercise, and maintenance of a good psychological state have a positive effect.
Prognosis
In recent years, early diagnosis and routine use of IVIG replacement therapy have greatly improved the prognosis of the disease. More than 50% of those who do not receive regular IVIG therapy have chronic lung infections and often have obstructive lung disease or pulmonary heart disease, and few children survive early childhood. Concomitant chronic disseminated enteroviral infections are also not uncommon. In about 2% of cases, death occurs as a result of malignant tumors of the lymphoreticular tissue.
Prevention
The prevention of genetic diseases should be emphasized. Pregnant women with family history should undergo prenatal checkups and testing for mutation gene carriers, and after the amniotic fluid test proves that the child is a boy, further determination of whether there is any mutation in the Btk gene should be carried out, so as to facilitate early diagnosis and correct treatment.
1. Health care for pregnant women
It is known that the occurrence of some immunodeficiency diseases is closely related to embryonic dysplasia, so it is very important to strengthen the health care of pregnant women, especially in early pregnancy. Pregnant women should avoid accepting radiation, be careful in using some chemical drugs, rubella vaccine, etc., and prevent viral infections as far as possible, but also to make the pregnant women to strengthen the nutrition, and timely treatment of some chronic diseases.
2. Genetic counseling and family survey
Although most of the diseases can not determine the mode of inheritance, but to determine the mode of inheritance of the disease of genetic counseling is very valuable, for the antibody or complement defects in patients’ immediate family members should be examined for antibody and complement levels to determine the family mode of disease, for some of the diseases that have been able to carry out the gene localization of the disease, the patient’s parents, siblings and their children should be done to locate the gene test, if found to have a patient, the same should be carried out among his or her If a patient is found, the patient’s family members should also be examined, and the patient’s children should be carefully monitored from birth for the presence of the disease.
3. Prenatal diagnosis
Certain immunodeficiency diseases can be diagnosed prenatally, and when immunodeficiency is found, pregnancy can be terminated to prevent the birth of the affected child. Early and accurate diagnosis, early specific treatment and genetic counseling are very important.