Pediatric X-Linked Lymphoproliferative Disorders

Introduction to X-linked lymphoproliferative disorders in children 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. basic knowledge The proportion of illness: 0.005% Susceptible people: young children Mode of infection: non-infectious Complications: myocarditis, fulminant hepatic failure

Etiology of X-linked lymphoproliferative disorders in children

Cause:

Genetic basis: The mutant gene XLP (LYP) is located in Xq25 and includes four exons with the labeling range of DXS982, DXS739, DXS1206, DXS267, DXS6811, DXS75, DXS737 and DXS100, including SH2, 16 cases of XLP clinical table. Among the 9 cases, there were mutations in the SH2 region of XLP (LYP), and its function was related to T lymphocytes and B lymphocyte surface signaling lymphocyte-activation molecule (SLAM), XLP (LYP) gene. The encoded protein is called a SLAM-related protein.

Pathogenesis

EBV infection may only cause XLP in XLP (LYP) gene deletion, and there is immunodeficiency before EBV infection. The pathogenesis of XLP combined with lethal infectious mononucleosis (FIM) is uncontrolled of lymphocyte proliferation, resulting in Lymphocytes infiltrate various organs and eventually lead to dysfunction. Th2 cells in XLP patients are hyperactive, while Th1 cells are relatively low in function, which may be related to XLP combined with lethal FIM.

Prevention of X-linked lymphoproliferative disorders in children

1. Active prevention and treatment of EB virus infection

Promote breastfeeding and regularly inject immunoglobulins rich in EBV antibodies to prevent the occurrence of FIM. It is not suitable for EBV vaccine.

2. Pregnant women's health

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.

3. 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.

4. 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 no-gammaglobulinemia, severe combined immunodeficiency disease, thereby terminating pregnancy and preventing the birth of children, X-linked lymphoproliferative disease is a relatively rare disease, but early accurate diagnosis, It is important to give specific treatment early and to provide genetic counseling (prenatal diagnosis or even intrauterine treatment).

Pediatric X-linked lymphoproliferative disorders Complications, myocarditis, fulminant hepatic failure

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 .

Symptoms of X-linked lymphoproliferative disorders in children Common symptoms Globulin abnormal herpes granuloma Calcified liver failure

XLP patients are only particularly sensitive to EBV, and the immune response to other herpes viruses such as herpes simplex virus, cytomegalovirus and herpes simplex virus is normal, and the clinical manifestations can be classified into five types:

1. Explosive infectious mononucleosis associated with virus-associated hematophagocytic syndrome (VAHS) accounted for 58%, the most common, occurring in 5 to 17 years old, manifested as CD8 T cells, EBV infection B cells and macrophages proliferate in a large amount and infiltrate all organs in the body, resulting in fulminant hepatitis and myeloproliferative disorders. Other affected tissues have extensive white matter necrosis of the spleen, infiltration of mononuclear cells around the cerebrovascular, mild mononuclear myocarditis, and light rooms. Qualitative 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 children with XLP, systemically massively phagocytic cells of red blood cells and nuclear debris Infiltration is a hallmark of VAHS, and most die within 1 month of EBV infection.

2. Abnormal gamma globulin: 31%, this type is more common, after EBV infection, there are often varying degrees of low IgGemia, there may be increased IgM, lymphoid tissue (lymph nodes, spleen white matter, thymus, bone marrow) Necrosis, calcification and loss occur.

3. Lymphoid malignant tumors: 30%, lymphoma always occurs outside the lymph nodes, most often invade the intestinal ileocecal zone, less invading the central nervous system, liver and kidneys, pathology is usually Burkitt type, a few are Huo Chinchilla lymphoma; most are B-celled and a few are T-cell.

4. Aplastic anemia: 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 its pathogenesis is poorly known.

5. Vascular and pulmonary lymphomatoid granuloma: 3%, developed as lymphangiitis caused by aneurysm or arterial wall dilatation damage, 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.

Examination of X-linked lymphoproliferative disorders in children

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. The diagnosis at this stage should rely on restriction long-term polymorphism analysis to identify the XLP (LYP) gene. defect.

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, bone marrow myeloid hyperplasia, with nuclear left shift.

2 Interim: Peripheral blood complete blood loss, extensive infiltration of bone marrow lymphoid cells, mainly activated T cells and plasma cells, accompanied by cell necrosis and tissue cell phagocytic blood cell phenomenon (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- decreased, while the function of synthetic IL-2 was normal. The function of NK cells was normal before EBV infection, and it increased when infected, but decreased after infection, and the skin delayed reaction was negative.

3. Virological examination

Abnormal responses to primary EBV infection in patients with XLP include decreased or absent anti-EBV nuclear antigen (EBNA) antibody titers, and varying concentrations of anti-EBV shell antigen (VCA) antibody titers, PCR detection of EBV genome or histochemical staining found in lymphoid tissues The presence of EBNA can identify EBV infection (positive rate up to 100%),

4. Other inspections

  In the acute phase of FIM, abnormal liver function includes elevated serum transaminase, lactate dehydrogenase and bilirubin, and positive for phagocytic agglutination.

X-ray examination, B-ultrasound examination, brain CT examination, etc. should be routinely performed to understand the lesions of the heart, liver, spleen, kidney, brain and intestine (the ileocecal area).

Diagnosis and diagnosis of X-linked lymphoid tissue proliferative diseases in children

diagnosis

Diagnose based on

1. Diagnostic criteria

Two or more boys born to the same mother presented with XLP symptoms after EBV infection.

2. The standard of doubt

MAIN OUTCOME MEASURES: Genetic analysis of male children confirmed the presence of markers associated with XLP locus mutations; or male patients with XLP clinical signs after EBV infection; secondary indicators: high IgA or IgMemia before EBV infection; low IgG1 or IgG3, Anti-EBNA antibody is not produced properly after EBV infection; IgG-IgG conversion can not occur after phage X174 stimulation, and it can be diagnosed as XLP if it meets 2 main indicators or 1 main indicator and 2 secondary indicators.

3. Suspicious people

One of the maternal patients has a confirmed XLP patient, and any male who is related to the maternal line is a suspicious group.

Differential diagnosis

The clinical manifestations of XLP are complex and should be differentiated from the following diseases, including sporadic fatal infectious mononucleosis (SFIM), non-X-linked severe EBV infection syndrome (non-X-linked syndrome). With susceptibility to severe EBV infections), XLA, X-linked high IgMemia, Fas deficiency and CVID.

1. Sporadic fatal infectious mononucleosis (SFIM) Of the approximately 3,000 IM patients, 1 is fatal, with an average age of 5.5 years, and XLP with lethal IM The average age of onset is 2.5 years old. The disease is not X-linked, so there is no gender difference. The acute phase is similar to XLP combined with IM, but low immunoglobulinemia and lymphoma do not occur.

2. Non-X-linked syndrome with susceptibility to severe EBV infections. The disease is rare, NK cell activity declines and repeated bacterial infections before EBV infection, its autosomal inheritance Helps identify with XLP.

3. X-linked agammaglobulinemia (XLA) deficiency of peripheral blood B cells in children, low or absent immunoglobulins, repeated bacterial infections due to defective antibody response, but sensitivity to EBV infection There is no enhancement, DNA analysis found that Btk mutation can confirm the disease.

4. X-linked hyper-IgM syndrome (XHIM) Serum IgM is normal or elevated, other immunoglobulin classes are decreased, bacterial or opportunistic infections occur repeatedly, but sensitivity to EBV infection is not increased. Genetic analysis revealed mutations in the CD40 ligand gene.

5.Fas deficiency is a rare disease. Due to the mutation of Fas gene, lymphocytes proliferate, non-malignant lymphadenopathy, hepatosplenomegaly, hyperimmune globulinemia and autoimmune phenomenon, and increased CD3 CD4- in peripheral blood. CD8-lymphocytes, clinical manifestations appear in infancy.

6. Common variable immunodeficiency (CVID) serum partial or total immunoglobulin class levels decreased, antibody response is poor, most patients B cells are normal, but can not differentiate into antibody-producing plasma cells, EBV infection The sensitivity is not increased, nor is it X-linked inheritance, easy to identify.

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