X-linked lymphoproliferative diseaseIs a lymphatic disease.
Disease alias
X-linked recessive progressive combined immunodeficiency disease, Dunquen disease, X-linked recessive progressive combined variable immune deficiency.
Disease code
ICD: D81.8
Disease classification
Pediatrics
Disease description
X-linked lymphoproliferative disease (XLP) is a combined immunodeficiency disease in which both T and B cells are defective. Epstein-Barr virus (EBV) infection can aggravate the course of the disease.
Symptoms and signs
XLP patients are only particularly sensitive to EBV and have normal immune responses to other herpes viruses such as herpes simplex virus, cytomegalovirus and herpes simplex virus type 6. Clinical manifestations can be grouped into five types:
1. Explosive infectious mononucleosis with virus-associated hematophagocytics yndrome (VAHS) accounted for 58%, the most common. Occurred in 5 to 17 years old. It is characterized by a large proliferation of CD8+ T cells, EBV-infected B cells and macrophages and infiltration in various organs of the body, resulting in fulminant hepatitis and poor myeloproliferative. Other affected tissues have extensive white matter necrosis of the spleen, infiltration of mononuclear cells around the cerebrovascular, mild mononuclear myocarditis, mild interstitial nephritis and thymocyte deficiency and endothelial cell necrosis. Liver failure is a common cause of death. VAHS occurs in 90% of FIM boys and nearly half of XLP children. Tissue cell infiltration, which is extensively engulfed by red blood cells and nuclear debris, is characteristic of VAHS, and most die within 1 month after EBV infection.
2. The abnormality of gamma globulin accounts for 31%. This type is more common. After EBV infection, there are often different degrees of hypoIgGemia, and there may be an increase in IgM. Necrosis, calcification, and loss can occur in lymphoid tissues (lymph nodes, spleen white matter, thymus, bone marrow).
3. Lymphoid malignancies account for 30%. Lymphoma always occurs outside the lymph nodes, most often invading the intestinal ileocecal zone, with less involvement in the central nervous system, liver and kidneys. Pathology is usually Burkitt type, a few are Hodgkin's lymphoma; most are B-celled, and a few are T-cell.
4. Aplastic anemia accounts for 3%. A small number of children develop simple aplastic anemia (complete blood cell anemia or pure red blood cell aplastic anemia) after EBV infection, and their pathogenesis is poorly known.
5. Lymphomatoid granuloma in the blood vessels and lungs accounted for 3%. Development of lymphangiitis caused by aneurysm or arterial wall dilatation damage. It can be expressed as lung T cells and central nervous system lymphomatoid granuloma. Lymphocyte proliferation is primarily a result of CD4+ T cell activation and may not be associated with EBV infection.
Cause of disease
Genetic basis: The mutant gene XLP (LYP) is located at Xq25 and includes four exons. The marking range is DXS982, DXS739, DXS1206, DXS267, DXS6811, DXS75, DXS737 and DXS100. Among them, SH2. Among 16 cases of XLP clinical phenotype, 9 cases found mutations in the SH2 region of XLP (LYP). Its function is related to the signaling lymphocyte-activation molecule (SLAM) of T lymphocytes and B lymphocytes. The protein encoded by XLP (LYP) gene is called SLAM-related protein.
Pathophysiology
EBV infection may only be the cause of XLP in XLP (LYP) gene deletion, and there is immunodeficiency before EBV infection. The pathogenesis of XLP combined with fatal infectious mononucleosis (FIM) is that lymphocyte proliferation is out of control, causing lymphocytes to infiltrate various organs, eventually leading to dysfunction. The function of Th2 cells in XLP patients is hyperactive, while the function of Th1 cells is relatively low, which may be related to XLP combined with lethal FIM.
diagnosis:
1. Confirmation criteria Two or more boys born to the same mother presented with XLP symptoms after EBV infection.
2. Main indicators of suspected criteria: genetic analysis of male children confirmed the presence of XLP site mutation-related markers; or male children with XLP clinical symptoms after EBV infection; secondary indicators: high IgA or IgMemia before EBV infection; Low IgG1 or IgG3, anti-EBNA antibody production was inappropriate after EBV infection; lgM-IgG conversion could not occur after phage φX174 stimulation. Those who meet 2 main indicators or 1 main indicator and 2 secondary indicators can be diagnosed as XLP.
3. The suspected population has a confirmed XLP patient on the maternal side, and any male who is related to the maternal line is a suspicious group.
Laboratory inspection:
1. Laboratory examination before EBV infection In general, the disease does not have any laboratory abnormalities before EBV infection, and only some of the children present different degrees of immunoglobulin abnormalities. Confirmation at this stage should rely on a restricted long-term polymorphism analysis to identify XLP (LYP) gene defects.
2. Laboratory examination after EBV infection
(1) Hematological changes: Peripheral blood and bone marrow behave differently at different times after EBV infection:
1 early (1 to 2 weeks): peripheral blood leukocytes increased, a large number of variant lymphocytes, mainly activated T cells. Myeloid myeloid hyperplasia is active with a left shift of the nucleus.
2 Interim: Peripheral blood complete blood loss. The bone marrow lymphoid cells are extensively infiltrated, mainly activated T cells and plasma cells, accompanied by cell necrosis and tissue cell phagocytosis (VAHS).
3 late: a large number of bone marrow necrosis, VAHS is more prominent.
(2) Immunological examination: In the early stage of EBV infection, the number of peripheral blood T cells and B cells is normal, but the lymphocyte proliferative response of some children is decreased. The number of CD8 cells is increased in most children, the ratio of CD4/CD8 cells is decreased, and low Ig blood is low. Symptoms and antibody response are low.
The ability of T cells to secrete IFN-γ is decreased, while the function of synthetic IL-2 is normal. NK cell function is normal before EBV infection, increased at the time of infection, and decreased after infection. The skin was delayed in response to late reaction.
3. Virological examination The abnormal response of primary EBV infection in patients with XLP includes decreased or absent anti-EBV nuclear antigen (EBNA) antibody titer, anti-EBV shell antigen (VCA) antibody titer varies, PCR detection of EBV genome or histochemistry Staining revealed the presence of EBNA in lymphoid tissue to identify EBV infection (positive rate up to 100%).
4. Other examinations of acute FIM, liver function abnormalities including elevated serum transaminases, lactate dehydrogenase and bilirubin. The phagocytic agglutination reaction was positive.
Other auxiliary examinations: X-ray examination, B-ultrasound examination, brain CT examination, etc. should be routinely performed to understand the lesions of heart, liver, spleen, kidney, brain and intestine (the ileocecal area).
Differential diagnosis
The clinical manifestations of XLP are complex and should be differentiated from the following diseases. These include sporadic cfadalinfective mononucleosis (SFIM), non-X-linked syndrome with susceptibility to singular EBV infections, XLA, X-linked high IgMemia, Fas deficiency, and CVID.
Treatment programs
1. Pre-treatment of EBV infection, regular injection of EBV-rich antibodiesImmunoglobulinTo prevent the occurrence of FIM, but its effect is not reliable. It is not advisable to vaccinate the EBV to prevent the spread of systemic vaccines. Allogeneic hematopoietic stem cell transplantation is an effective treatment, but it should be done before the age of 15.
2. The treatment of FIM has not been effectively treated until now.Etoposide(Ghost scorpion) has inhibitory macrophage activity and can be used in VAHS and bone marrow regeneration crisis. Cyclosporine has been successfully used in the treatment of severe acute FIM/VAHS or XLP aplastic anemia.
3. Treatment of hypo- IgG is given a standardized IVIG replacement therapy to prevent repeated bacterial and viral infections, but does not prevent aplastic anemia and lymphoma in the future.
complication
Explosive infectious mononucleosis accompanied by virus-related hemophagocytic syndrome can cause fulminant hepatitis, poor myeloproliferative, spleen extensive white matter necrosis, myocarditis, nephritis, liver failure, etc.; abnormal gamma globulin can be lymphatic Tissue necrosis, calcification and loss; lymphoid tissue malignant tumor type can occur in a variety of lymphoma; aplastic anemia can occur; aneurysm or arterial wall dilatation damage occurs, lung T cells and central nervous system lymphomatoid granuloma occur .
Prognosis and prevention
Prognosis: The mortality rate of 236 cases of XLP was 75%, 70% of which died before the age of 10, and only 2 cases survived to 40 years old. 157 cases of XLP developed into FIM and VAHS. The survival rates of FIM/VAHS, lymphoproliferative abnormalities, abnormal immunoglobulinemia, and aplastic anemia were 4%, 35%, 55%, and 50%, respectively.
prevention:
1. Active prevention and treatment of EB virus infection to promote breastfeeding, regular injection of immunoglobulin rich in EBV antibodies to prevent the occurrence of FIM, should not be vaccinated with EBV.
2. Maternal health care It is known that the occurrence of some immunodeficiency diseases is closely related to embryonic dysplasia. If a pregnant woman is exposed to radiation, is treated with certain chemicals, or has a viral infection (especially a rubella virus infection), it can damage the fetal immune system, especially in the early pregnancy, and can include multiple systems including the immune system. Affected. Therefore, it is very important to strengthen the health care of pregnant women, especially in the early pregnancy. Pregnant women should avoid radiation, use some chemical drugs with caution, and inject rubella vaccine to prevent viral infections. It is also necessary to strengthen the nutrition of pregnant women and treat some chronic diseases in time.
3. Genetic counseling and family surveys Although most diseases cannot determine the genetic pattern, genetic counseling for diseases with defined genetic patterns is valuable. If an adult has a hereditary immunodeficiency disease, it will provide the developmental risk of their child; if a child has an autosomal recessive or sexually linked immunodeficiency disease, tell the parents that their next child has the possibility of illness. How big is it. Immediate family members of patients with antibodies or complement deficiency should be examined for antibody and complement levels to determine the mode of family disease. For some diseases that can be genetically mapped, such as chronic granulomatosis, the patient's parents, siblings and their children should be tested for localization. If a patient is found, it should also be checked among his or her family members. The child's child should be carefully observed at the beginning of the birth for any disease.
4. Prenatal diagnosis Some immunodeficiency diseases can be used for prenatal diagnosis. For example, cultured amniotic fluid cell enzymology can diagnose adenosine deaminase deficiency, nucleoside phosphorylase deficiency and some combined immunodeficiency diseases; Blood cell immunological tests can diagnose CGD, X-linked agammaglobulinemia, and severe combined immunodeficiency disease, thereby terminating pregnancy and preventing the birth of the child. X-linked lymphoproliferative disorders are a relatively rare disease, but early accurate diagnosis, early administration of specific treatment and provision of genetic counseling (prenatal diagnosis or even intrauterine treatment) are very important.
Epidemiology
The disease was first reported in 1969. In 1975, several male children in the Duncan family were found to have died of severe outbreaks of infectious mononucleosis, or later evolved into hypogammaglobulinemia, intracranial lymphoma. And ileocecal lymphoma, named Duncan disease and X-linked recessive progressive combined immunodeficiency disease (X-linked recessive progressive combined variant immunodeficiency). In 1976, it was renamed XLP. By 1995, there were 272 registered patients worldwide, and the male incidence rate was 1:10 to 3:1 million.
Special Note
It is important to strengthen maternal health care, especially early pregnancy care. Pregnant women should avoid radiation, use some chemical drugs with caution, and inject rubella vaccine to prevent viral infections. It is also necessary to strengthen the nutrition of pregnant women and treat some chronic diseases in time.
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