chronic granulomatous disease in children
Introduction
Introduction to chronic granulomatosis in children Pediatric chronic granulomatosis (pediatric chronic granulomatous disease) is a fatal hereditary leukocyte dysfunction, the incidence of more than 2 years old, a few can be as late as 10 years old. The main clinical feature is that, for some reason, the lack of NADPH oxidase in phagocytic cells leads to the decrease of reactive oxygen species and H2O2 production, and the bactericidal function is defective. The patient is responsible for various catalase-positive bacteria such as Staphylococcus, Serratia, and Kosher. The genus is highly sensitive, and chronic bacterial infection occurs repeatedly, and the infection locally forms chronic granuloma. basic knowledge The proportion of illness: 0.034% Susceptible people: children Mode of infection: non-infectious Complications: pneumonia, empyema, lung abscess
Cause
Causes of chronic granulomatosis in children
(1) Causes of the disease
Normal human phagocytic cells have two sterilization systems that are independent of oxygen sterilization and oxygen-dependent sterilization. In general, the oxygen-dependent sterilization system is more important. The phagocytic NADPH oxidase activity of CGD patients is significantly reduced or even deficient. NADPH oxidase is phagocytosis. The important enzyme that triggers the "breathing burst" during phagocytosis, the activity of NADPH oxidase is reduced or lacked, the "breathing burst" is impaired, and a sufficient amount of reactive oxygen species, hydrogen peroxide, and phagocytic cells are reduced in dependence on oxygen sterilization. The phagocytic cells can not effectively kill the microorganisms after phagocytizing the microorganisms, resulting in increased susceptibility to bacteria and fungi, and repeated chronic infection. The phagocytic NADPH oxidase consists of two cytochrome b membrane subunits (h subunit, 22kDa and subunit). Unit, 91kDa) and two cytosolic soluble synergistic factors (67kDa, 47kDa), the 91kDa subunit is encoded by the sex chromosome CGD gene, 80% to 90% of cytochrome b is stored in neutrophil-specific particles, molecular biology Studies have found that NADPH oxidase deficiency in the different cases of the molecular defects of the enzyme, and the genetic side of the disease Related.
(two) pathogenesis
Normal granulocytes phagocytose bacteria, degranulate to produce hydrogen peroxide, and release new ecological oxygen after phagocytosis, oxidize iodine and chlorine compounds into free iodine and chlorine to form complete hydrogen peroxide-peroxidase-iodine Ion sterilization system, this disease is due to the lack of glucose oxidase, can not produce hydrogen peroxide, so that bacteria that can not produce hydrogen peroxide, such as Staphylococcus aureus, Candida albicans, Klebsiella, E group Escherichia coli, sticky The bactericidal function of Serratia marcescens, but the Streptococcus pneumoniae that can produce hydrogen peroxide still has a killing effect. In short, there is a disease caused by the lack of bactericidal activity of granulocyte peroxides. Each subtype of hereditary chronic granulomatous disease is caused by a mutation in the qp91-phox subunit gene encoding cytochrome b, which is named CYBB (MIM306400) and contains 13 exons located on the X chromosome xp211.1 About 30kb, according to the analysis of 261 cases of children with conjoined CGD according to the multi-center international database, the gene mutation has obvious heterogeneity, and there are many family-specific, gene-deficient, staggered mutations and The incidence of sense mutations is close to 20% of all mutations; shear to point mutations (16%) and insertions (10%) account for the majority of the remaining mutations. Two regulatory mutations, CyBB gene mutations, are also found. The distribution has no obvious mutation hotspots and seems to have some randomness.
In conclusion, most of the cross-linked CGD is caused by mutations in the coding region and splicing region of CyBB, but not by the deletion of the emptying region of the gene. Most mutations affect the stability of mRNA and/or the protein, and the mutation of qp91-phox gene The diversity was parallel to the clinical heterogeneity of the CGD. The neutrophil respiratory burst activity was normal in 5% of patients with O2 production using the tetrazolium blue test (NBT) and flow cytometry; 95% The granulocyte lacks respiratory burst activity, and the total amount of cytochrome b is about 5% of normal. It is speculated that only a small number of cell clones have normal cytochrome b levels, and the respiratory burst activity is complete. The mutation in the emptying zone will be detrimental to the expression of cytochrome b. .
Prevention
Prevention of chronic granulomatosis in children
CGD is a kind of hereditary disease, and genetic disease prevention and control measures should be taken. Prevention should be carried out from pre-pregnancy to prenatal: pre-marital physical examination plays an active role in preventing birth defects. The size depends on the examination items and contents, including serological examination. (such as hepatitis B virus, Treponema pallidum, HIV), reproductive system examination (such as screening for cervical inflammation), general physical examination (such as blood pressure, electrocardiogram), and asking about the family history of the disease, personal medical history, etc., doing genetic disease counseling, pregnant women Avoid hazards as much as possible, including away from smog, alcohol, drugs, radiation, pesticides, noise, volatile harmful gases, toxic and harmful heavy metals, etc. During the antenatal care of pregnancy, systematic screening of birth defects is required, including regular Ultrasound examination, serological screening, etc., if necessary, chromosomal examination, if abnormal results occur, it is necessary to determine whether to terminate the pregnancy; the safety of the fetus in the uterus; whether there is sequelae after birth, whether it can be treated, how to prognosis, etc. Wait, take practical measures for diagnosis and treatment.
Complication
Complications of chronic granulomatosis in children Complications, pneumonia, empyema, lung abscess
Repeatedly complicated with various serious infections, such as pneumonia, empyema, lung abscess, enteritis and colitis, can go to the anal fistula, common in the liver, spleen, lung and bone abscess, the occurrence of Aspergillus abscess in the brain, esophagus, small intestine and ureter can occur Obstruction, often resulting in short stature, with lupus erythematosus, juvenile rheumatoid arthritis, etc.
Symptom
Symptoms of chronic granulomatosis in children Common symptoms Repeated infection of pulmonary infections Granuloma Liver splenomegaly Eczema Gingivitis Gastric sinus stenosis Brain abscess
1. Infection usually occurs clinically in the first few months after birth. Most children with CGD will have at least one serious infection in the first year after birth. The diagnosis of CGD may be delayed until puberty or adulthood, or even 60 years old. It is an eczema-like change in the skin around the ear and nose, which gradually progresses to suppurative dermatitis, which forms scar with local lymphadenopathy, recurrent infection, and granuloma formation. It is characterized by the formation of brown granules and foam in phagocytic cells, and pulmonary infection. (including recurrent pneumonia, hilar lymphadenopathy, empyema, and lung abscess) are most common, others have digestive tract infections (ulcerative stomatitis, gingivitis, enteritis and colitis, even with anal fistula), chronic rhinitis and Conjunctivitis also occurs frequently. Abscess formation is an important manifestation of CGD. It can occur in any part of the body, especially in the liver, spleen, lungs and bones. Aspergillus pneumonia is quite common. Aspergillus-induced brain abscess is often fatal. The pathogen of infection in children with CGD is a catalase-positive bacterium, which persists in children with CGD because it can inactivate peroxide. Within the granulocytes, which become the source of chronic inflammation and granuloma formation, the most common are Staphylococcus aureus, Salmonella, Escherichia coli, Pseudomonas and Aspergillus, in addition, the genus Uncommon bacteria such as Mycobacterium and Actinomycetes are also pathogenic bacteria of the disease.
2. Other manifestations of sinus stenosis caused by obstruction is quite common, granuloma spread can also cause obstruction of esophagus, small intestine and ureter, children with short stature, become an important complaint, have reported systemic or discoid lupus erythematosus, and juvenile Type of rheumatoid arthritis, infants and young children repeatedly skin, suppurative infection of the organs, with hepatosplenomegaly, should be done tetrazolium blue test, screening for white blood cell function, and then combined with the corresponding X-ray examination to confirm the diagnosis.
Examine
Examination of chronic granulomatosis in children
The number of white blood cells is often increased, oxidase abnormalities and granulocyte dysfunction can be confirmed by the following experiments:
1. The bactericidal defect of neutrophils in the incubation of white blood cells and Staphylococcus aureus, only 10% of the bacteria in the cells after 1 hour of normal leukocyte culture, and 80% of the bacteria in the patients were not eliminated.
2. The abnormality of oxidative metabolism after phagocytosis, namely the qualitative and content of tetrazolium blue: normal neutrophils can phagocytize this dye to reduce it to form a black precipitate, while the patient's neutrophils have no such function, suspicious carrying Chemical extraction of tetrazolium blue can also be used for quantitative detection of photoelectric colorimetry. Complex methods can be used to determine the oxygen consumption of neutrophils after phagocytosis by oxygen electrode or Warburgs apparatus. The child is not obvious, the determination of cytochrome b content in patients with neutrophils can be used as the basis for CGD typing, and sometimes the neutrophil membrane and cytoplasmic granule free cell oxidase activity should be determined, once suspected cytoplasmic particle defects The free cell system can be subjected to immunoblot analysis or compensation studies using known p47-phox or p67-phox deficient cytoplasmic particles to determine which component is defective.
3. Molecular genetic analysis of myeloid cDNA or genomic DNA can assist in diagnosis and typing, and can identify the site of mutation. DNA can be extracted from fetal chorionic or amniotic cells for prenatal diagnosis. In the absence of the above methods, NBT can be used and taken. Placental blood analysis, X-ray photograph shows that 90% of patients have abnormal lungs, pulmonary chronic granuloma early manifested as pulmonary lymphadenopathy, inflammation around the hilar, lung field visible clear circular shadow, can develop into wrap Pneumonia, lung abscess, and later manifested as patchy shadows, with a tendency to merge with each other, but less affected the entire lobe.
Diagnosis
Diagnosis and diagnosis of chronic granulomatosis in children
Diagnosis is based on clinical performance and examination.
Differential diagnosis
1. G6-PD deficiency: The patient's leukocyte G6-PD activity is also reduced, generally about 80% of normal. This patient is prone to hemolytic anemia and repeated infection. Due to lack of enzyme, no monophosphate has been detected in white blood cells. The metabolic activity of the sugar bypass, which cannot be corrected for methylene blue, is distinguished from CGD.
2. Leukocyte glutathione peroxidase deficiency: The condition is milder than CGD, and there are no heterozygous patients in the family.
3. Family lipoprotein histiocytosis: Late onset, only female onset, its granulocyte defects are similar to CGD.
