Introduction
Chronic granulomatosis(CGD) is a hereditary granulocyte bactericidal defect characterized by extensive granulomatous lesions in the skin, lungs and lymph nodes. Most patients are male. X-linked recessive inheritance; a few are autosomal recessive inheritance. Both sexes can be affected. The main drawback is that the hydrogen peroxide produced by the host phagocytic system is insufficient to kill the catalase-positive bacteria, causing widespread spread of infection. Granuloma is a response to contrast-induced purulent infections, often with pigmented lipid tissue cells infiltrating and wrapping. Clinical manifestations are characterized by repeated severe infections and the formation of pigmented granuloma at sites of repeated infection.
Cause
(1) Causes of the disease
When a foreign body such as bacteria enters the body, the initial defense mechanism is non-specific immunity. After normal phagocytic cells are subjected to physiological stimulation (ie, phagocytosis), the intracellular reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex transfers electrons from NADPH to molecules. Oxygen, which rapidly produces superoxide anion, causes a "breathing burst." However, due to the absence or reduction of certain components of NADPH oxidase in children with CGD, it is not effective to produce bactericidal superoxide anion and its metabolites such as hydrogen peroxide, hydroxide ions and hypochlorous acid. Thus, phagocytic cells cannot produce a "breathing outbreak."
1. CYBB gene CYBB gene encodes the gp91phox subunit gene of cytochrome b558, located in the short arm of X chromosome (Xp21.1), contains 13 exons, the extracellular region of p91phox can bind to heme and interact with p22phox In effect, the intracellular hydrophilic region contains a NAPDH binding site. IFN-γ promotes transcription of the CYBB gene.
Expressed in the myeloid system, there is also low expression in mesangial cells and B cells. Mutations in the CYBB gene cause 65% of CGD. In addition to gene conversion, other mutations include deletions (from a single nucleotide to 500 nucleotides), insertions (often small fragment insertions), single nucleotide substitutions, including splicing sites. Mutations result in termination of mRNA transcription, single amino acid substitutions due to missense mutations, and nonsense mutations (CpG→TG) cause CGA→TGA, leading to premature termination of transcription. Mutations in the CYBB gene are usually heterozygous.
2. The CYBA gene CYBA gene encodes p22phox, which is located at 16q24 and contains six exons. Its helicoidal hydrophobic region may be located in the transmembrane region, where the proline-rich region binds to the p22phox molecule. The CYBA gene mRNA is expressed in all cells, but the p22phox protein is expressed only in the myeloid system. Mutations in the CYBA gene cause the p22phox subunit of cytochrome b558 to be inactive, including deletions, insertions, splicing site mutations and missense mutations, accounting for 5% of CGD. Children with CYBA gene mutation CGD are all mutated homozygous.
3. The NCF1 gene NCF1 gene encodes the p47phox molecule, which is located at 7q11.23 and contains 11 exons, 9 serine phosphorylation sites, an SH3 functional region and a proline rich region. IFN-γ promotes transcription of the NCF1 gene. Expressed in the myeloid system and B cells. 25% of CGD is a mutation in the NCF1 gene, which makes p47phox absent. Mainly for CT dinucleotide deletion, hot spots are 73-74 and 75-76. There are also 502 cases of G-deletion. The level of p22phox mRNA was normal in 20 children with CGD, but p22phox protein could not be detected.
4. NCF2 gene NCF2 gene encoding p67phox molecule located in 1q25, length 40kb, contains 16 exons, a SH3 functional area. Expressed in the myeloid system and other hematopoietic cells. 5% of CGD is a mutation in the NCF2 gene, resulting in a defect in p67phox. Mutations include deletions (from 3 nucleotides to 10 nucleotides), missense mutations (233 G→A and 1183 C→T substitutions), nonsense mutations (304 C→T substitutions), splicing sites Mutations (introns 3, 4, 9gt → at / ac) and insertions ( inserts AG after 397 A or 399 G).
(two) pathogenesis
Normal granulocytes phagocytose bacteria, degranulate to produce hydrogen peroxide, and release new ecological oxygen after phagocytosis, oxidize iodine and chlorine compounds to free iodine and chlorine to form complete hydrogen peroxide-peroxidase-iodine Ion sterilization system. Due to the lack of NAPDH oxidase, this disease cannot produce hydrogen peroxide, so that bacteria that cannot produce hydrogen peroxide, such as Staphylococcus aureus, Candida albicans, Klebsiella, E. coli, Serratia marcescens, etc. The bactericidal function, but still has a killing effect on streptococcus and pneumococci which can produce hydrogen peroxide. In short, there is a disease caused by a lack of bactericidal power of granulocyte.
The NAPDH oxidase consists of four subunits, the cytochrome b558 on the cell membrane of the two subunits, 91kD and 22kD, respectively, called gp91phox and p22phox. The other two subunits are cytoplasmic proteins with molecular weights of 47kD and 67kD, termed p47phox and p67phox.
The cytochrome b558 subunits of NADPH, gp91phox and p22phox, are segregated by 20 amino acid residues of gp91phox such that NADPH oxidase cannot be contacted with its substrate NADPH. When the cells are activated, the intracellular cytosolic NADPH oxidase component p47phox/P67 is transferred to the cytochrome b558 subunits gp91phox and p22phox, which changes the conformation of gp91phox and removes 20 amino acid residues, allowing NADPH to bind to gp91phox. The electrons are released and oxidation occurs.
Mutations in the CYBB, CYBA, NCF2 and NCF1 genes deficient the gp91phox, p22phox, p67phox and p47phox subunits of NAPDH oxidase, respectively. Any defect in these four components can cause NADPH. Oxidase activity is deficient and cannot produce superoxide and other reactive oxygen ions. The ability to kill microorganisms engulfed by phagocytic cells is severely impaired, and the clinical manifestations of CGD appear.
Female heterozygous carriers can produce moderate amounts of cytochrome b558 and superoxide, and the tetrazolium blue (NBT) test is 50% positive. The clinical manifestations of the p47phox mutation were lighter than those of the gp91phox and p22phox/p67phox mutations, and the age of onset was later. The NAPDH oxidase activity of the sick children ranged from 5% to 25% of normal, and a few were only normal 2% to 5%. Neutrophils produced only a small amount of superoxide and weakly positive in the NBT test.
symptom
It usually occurs in childhood. It is characterized by repeated infections of the skin, lungs and lymph nodes. Pathogenic bacteria are often caused by catalase-producing bacteria such as Staphylococcus aureus, Serratia, Escherichia coli and Pseudomonas, causing purulent lymphadenitis, rhinitis, conjunctivitis, and lung Chronic dermatitis, liver abscess and osteomyelitis are also common. Localized granuloma of the stomach wall can cause sinus narrowing. In addition, it can cause retinal damage, chronic diarrhea, perianal abscess and brain abscess. May have skin granuloma, eczema dermatitis, liver and spleen. In each affected organ, granuloma formed by tissue cells containing pigment lipids can be seen. The sick child is generally delayed in development.
diagnosis
According to the repeated occurrence of skin, organ purulent infection, and hepatosplenomegaly. Granulocyte enlargement, reduced NBT function, can be diagnosed.
Molecular genetic analysis of myeloid cDNA or genomic DNA can aid in diagnosis and typing, and can identify mutation sites. DNA can be extracted from fetal chorionic or amniotic cells for prenatal diagnosis. In the absence of the above means available. Tetrazolium blue test and placental blood analysis.
Identification
Mainly differentiated from those with repeated infections with hepatosplenomegaly. The tetrazolium blue assay should be performed to screen for leukocyte function. It should also be identified with the following diseases:
1. G-6-PD activity of leukocytes in patients with G-6-PD deficiency is also reduced, generally about 80% of normal. This type of patient is prone to hemolytic anemia and repeated infections. Due to the lack of enzymes, the metabolic activity of the monophosphate hexose bypass was not detected in leukocytes. It cannot be corrected for methylene blue, which is different from CGD.
2. Leukocyte glutathione peroxidase deficiency is milder than CGD, and there are no heterozygous patients in the family.
3. Familial lipodystrophy histiocytosis is late onset, only in females. Its granulocyte defects are similar to CGD.
4. Chronic granuloma around the appendix should be distinguished from ascending colon cancer: located in the retroperitoneal appendix, due to long-term chronic inflammation of the appendix, appendix exudation, peritoneal tissue wrapping, repeated exudation and gradually increase, absorption The process of chronic granuloma formed around the appendix. From the appearance and texture, it is difficult for the naked eye to distinguish from malignant tumors. However, reviewing the history of fever, right lower quadrant pain and diarrhea is consistent with the clinical manifestations of chronic granuloma around the appendix.
complication
Complications of the disease:
1. Repeated infections such as pneumonia, empyema, lung abscess, enteritis and colitis, can go to anal fistula. Abscesses are common in the liver, spleen, lungs, and bones, and Aspergillus abscesses in the brain occur. The esophagus, small intestine and ureter can be blocked.
2. rhinitis;
3. Gastric sinus stricture;
3. Chronic diarrhea;
4. Delayed development of sick children. Often caused by short stature, with lupus erythematosus, juvenile rheumatoid arthritis.
treatment
Focus on preventing and treating infections. Once an infection has occurred, a broad-spectrum antibiotic should be used, with diclocillin (dichloropenicillin), cephalosporin andRifampinMore effective. Recently, it has been found that sulfamethoxazole can promote the bactericidal ability of phagocytic cells in children. Interleukin-α can also enhance neutrophil bactericidal power. In addition, infusion of white blood cells and bone marrow transplantation is beneficial to this disease.
Granulocyte colony-stimulating factor (G-Csf) can reduce infection or shorten the course of disease, and it will not be applied for a long time.Adrenocorticotropic hormoneNot suitable for use, it can aggravate granulocyte function defects. Infection usually requires a large amount of antibiotics to be administered intermittently or continuously, and sulfisoxazole is also effective. The use of hydrogen peroxide generating agents such as methylene blue and benzodiazepines has little effect. Abscess requires surgical drainage. In the past, CGD was considered to have a poor prognosis, but some patients were healthy and survived to young adults. Severe cases can be transplanted into the bone marrow.
prevention
1. Avoid marriage by close relatives, pregnant women with a family history, can be given early intervention. It is recommended to do prenatal examination.
2. Strengthen care and nutrition to improve patient resistance and immunity.
3. Prevention of infection should pay attention to isolation and minimize contact with pathogens.
Prognosis
The course of the disease is generally 5 to 7 years, and the prognosis of women is good. In the past 30 years, the quality of life of patients with CGD has been greatly improved, but serious bacterial and fungal infections remain a major problem in patients with CGD.
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