OVERVIEW
X-linked lymphocyte hyperplasia (XLP) is a rare combined immunodeficiency disease with defects in both T and B lymphocytes, in which the patient is highly susceptible to Epstein-Barr virus (EBV).Clinical symptoms prior to EBV infection are mild and early diagnosis is difficult.EBV infection leads to alterations in the function of various immune cells, especially the cytotoxicity of CD8+ T lymphocytes, NK cells and NKT cells, thereby inducing lethal hemophagocytic lymphohistiocytosis (HIH) or fulminant infectious mononucleosis (FIM). EBV infection can lead to changes in the function of various immune cells, especially the cytotoxicity of CD8+ T lymphocytes, NK cells and NKT cells, leading to lethal hemophagocytic lymphohistiocytosis (HIH) or fulminant infectious mononucleosis (FIM), which is associated with a very high mortality rate.
Etiology
The cause of the disease is a mutation in the SH2D1A gene on the X chromosome. The mutant gene is localized to Xq25 and includes four exons. Its markers range from DXS982, DXS739, DXS1206, DXS267, DXS6811, DXS75, DXS737 and DXS100.
Symptoms.
Patients with XLP are particularly susceptible only to EBV, with normal immune responses to other herpesviruses such as herpes simplex virus, cytomegalovirus, and herpesvirus type 6. The clinical manifestations can be categorized into 5 types:
1. fulminant infectious mononucleosis with virus-associated hemophagic syndrome (VAHS)
VAHS occurs in 90% of boys with FIM and nearly half of children with XLP. Overall it accounts for approximately 58% of all patients and is the most common type. It occurs between the ages of 5 and 17 years (mean age 2.5 years), with a mean survival time of 32 days after an episode, with most dying within 1 month of EBV infection. It manifests as a massive proliferation of CD8+ T cells, EBV-infected B cells and macrophages and infiltration in all organs of the body, resulting in fulminant hepatitis and myelodysplasia. Other tissues involved were extensive white matter necrosis of the spleen, perivascular mononuclear cell infiltration of the brain, mild mononuclear cell myocarditis, mild interstitial nephritis and thymocyte deficiency and endothelial cell necrosis. Systemic massive infiltration of histiocytes engulfed with erythrocytes and nuclear debris is characteristic of VAHS. Liver failure occurs in approximately 89% of infected boys, anemia in 81% of patients, and platelet insufficiency in 93%. Hepatic failure leading to hepatic encephalopathy or hemorrhage of the central nervous system, gastrointestinal tract, or lungs is a common cause of death.
2. Abnormal Gammaglobulinemia
This type is more common, with a prevalence of 31% in males carrying the XLP gene, and usually develops between 7 and 9 years of age. After EBV infection, there are often varying degrees of hypoimmunoglobulin G (IgG) anemia, and there may also be increased immunoglobulin M (IgM). Lymphoid tissues (lymph nodes, splenic white matter, thymus, bone marrow) may be necrotic, calcified and absent. Symptoms in such patients may be ameliorated by intravenous infusion of gammaglobulin.
3. Malignant lymphoma
Malignant lymphomas are found in 30% of men who carry the XLP gene. Patients often have a combination of abnormal gammaglobulinemia and/or FIM, and the disease usually begins at 4 to 6 years of age. Lymphomas always occur outside the lymph nodes, with approximately 75% located in the ileocecal region of the intestines and a small percentage invading the central nervous system, liver, and kidneys. About 90% are of B-cell origin, predominantly Burkitt lymphomas, and a few are of T-cell origin (about 6%).
4. Aplastic anemia
About 3% of cases. A small percentage of children develop simple aplastic anemia (periplasmic anemia or pure red blood cell remyelination) after EBV infection, the pathogenesis of which is not clear.
5. Lymphangiomatoid granuloma of blood vessels and lungs
It accounts for about 3% of cases. It develops as lymphomatoid vasculitis leading to aneurysm or dilatational damage to the arterial wall. It may present as pulmonary T-cell and CNS lymphomatoid granulomas. Lymphocyte proliferation is primarily the result of CD4+ T-cell activation and may not be associated with EBV infection.
Examination
1. Laboratory tests before EBV infection
In general, there are no laboratory abnormalities prior to EBV infection, and only some children present with varying degrees of immunoglobulin abnormalities. Confirmation of the diagnosis at this stage depends on mutation analysis of the main causative gene: SH2D1A.
2. Laboratory tests after EBV infection
(1) Hematologic changes Peripheral blood and bone marrow show different manifestations at different times after EBV infection.
(2) Immunological examination In the early stage of EBV infection, the number of peripheral blood T cells and B cells is normal, but the proliferative response of lymphocytes decreases in some children, the number of CD8+ T cells increases in the majority of children, and the ratio of CD4+/CD8+ T cells decreases, with hypoimmunoglobulinemia and a low antibody response.The ability of T cells to secrete interferon-gamma (IFN-γ) decreases, whereas the function of synthesizing IL-2 is normal. Normal. Natural killer cell (NK cell) function was normal before EBV infection, increased during infection, and decreased after infection. The skin delayed reaction is negative.
3. Virology
Abnormal reactions to initial EBV infection in patients with XLP include a decrease or lack of anti-EBV nuclear antigen (EBNA) antibody titer, and variable anti-EBV shell antigen (VCA) antibody titer. PCR testing of the EBV genome or histochemical staining reveals the presence of EBNA in lymphoid tissues, which can definitively identify EBV infection (the positivity rate can be up to 100%).
4.Other examinations
In the acute phase of FIM, liver function abnormalities include elevated serum transaminases, lactate dehydrogenase and bilirubin. Phagocytic heteroagglutination reaction is positive.
X-rays, ultrasound, and brain CT should be routinely done for lesions of the heart, liver, spleen, kidneys, brain, and intestines (ileocecal region).
Diagnosis
1. Diagnostic criteria
Male patients with 2 or more sororal relationships presenting with any of the clinical phenotypes of XLP after EBV infection.
2. Diagnostic criteria
(1) Primary criteria: Genetic analysis of the male child confirms the presence of markers associated with mutations at the XLP locus; or the male child develops clinical symptoms of XLP after EBV infection;
(2) Secondary indicators Hyper IgA or IgM anemia and low IgG1 or IgG3 before EBV infection; weak or absent anti-EBNA antibodies after EBV infection; inability to undergo lgM-IgG conversion after a second contact with phage φX174. The diagnosis of XLP is confirmed when a single patient meets 2 major indicators or 1 major and 2 minor indicators.
3. Suspect population
Any male who is related to a patient with XLP by an aunt’s cousin is a high-risk group.
Treatment
1. Preventive treatment before EBV infection
Immunoglobulin rich in EBV antibodies can be injected regularly to prevent FIM, but its effectiveness is unreliable. EBV vaccination is contraindicated to prevent systemic vaccine spread. Allogeneic hematopoietic stem cell transplantation is the only cure for XLP, but it is advisable to perform it before the age of 15 years. Therefore, early diagnosis and early transplantation is the key to improving the prognosis of patients.
2.Treatment of FIM
The application of high-dose gammaglobulin and antiviral drugs is not effective. In recent years, etoposide has been found to inhibit macrophage activity, which 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 reentry crisis.
3. Treatment of Hypoglycemia
Standardized IVIG replacement therapy is given to prevent recurrent bacterial and viral infections, but does not prevent later development of aplastic anemia and lymphoma.