X-linked lymphoproliferative syndrome presenting with systemic lymphocytic vasculitis

X-linked lymphoproliferative syndrome (XLP) is a rare, often fatal, primary immunodeficiency disease characterized by an abnormal response to Epstein-Barr virus (EBV) infection. The gene responsible for XLP has been identified as SH2D1A/DSHP/SLAM-associated protein (SAP). The major clinical manifestations include fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia. Affected males uncommonly present with lymphocytic vasculitis in addition to aplastic anemia. In this study, we describe a Japanese XLP patient who presented with hypogammaglobulinemia following acute EBV-induced infectious mononucleosis in the infancy and later had systemic lymphocytic vasculitis and hemophagocytic lymphohistiocytosis in the adulthood, which resolved by steroid pulse therapy. The patient's SAP gene was found to harbor a missense mutation (His8Asp), presumably resulting in defective expression of SAP in T cells. Biopsy specimens of lung and skin disclosed that CD8+ T cells predominantly infiltrated vascular vessels. However, immunohistochemical examination showed that EBV-infected cells were not identifiable in the vessels. We propose that T-cell-mediated immune dysregulation in XLP can cause vasculitis by EBV infection-unrelated mechanism.     

X-Linked Lymphoproliferative Disease in an Adult

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by an extreme susceptibility to Epstein-Barr virus (EBV) infection. Patients with XLP mainly present with the 3 clinical manifestations of fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia and in rare cases have aplastic anemia and lymphocytic vasculitis.The causative gene for XLP was identified as SH2D1A/DSHP/SLAM-associated protein (SAP) in 1998, and genetic analysis has been used for the definite diagnosis of XLP. Diagnosis for most patients occurs at ages younger than 10 years, and there are few adult patients. Here we describe a 23-year-old man with hypogammaglobulinemia and EBV-associated hemophagocytic lymphohistiocytosis and a diagnosis of XLP. In addition, the patient showed type 1 helper T-cell (Th1) skewing, as has been described in Sap knock-out mice. Th1/Th2 imbalance in humans, as well as in mice, may play an important role in the pathogenesis of XLP.     

SH2D1A mutations in Japanese males with severe Epstein-Barr virus--associated illnesses

X-linked lymphoproliferative disease (XLP), a genetic disorder characterized by immunodeficiency to Epstein-Barr virus (EBV) infection, has been linked to mutations in the SH2D1A gene. To search for the occurrence of SH2D1A mutations in Japan, we performed genetic analysis of the SH2D1A gene in 40 males presenting with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and severe chronic active EBV infection. SH2D1A mutations were detected in 10 of these 40 patients. Five of these 10 cases were sporadic. Patients with SH2D1A mutations displayed severe acute infectious mononucleosis with hyperimmunoglobulin M, hypogammaglobulinemia, and B-cell malignant lymphoma. By contrast, chronic active EBV infection was not associated with SH2D1A mutations. XLP survivors exhibited normal levels of circulating EBV-DNA during convalescence, suggesting that SH2D1A protein is not directly responsible for control of EBV replication. Thus, genetic analysis of the SH2D1A gene is particularly useful in the diagnosis of sporadic cases and carriers of XLP. (Blood. 2001;98:1268-1270)     

Allogeneic stem cell transplantation in X-linked lymphoproliferative disease: two cases in one family and review of the literature

X-linked lymphoproliferative disease (XLP) is a rare immunodeficiency caused by mutations in the signaling lymphocyte activating molecule-associated protein/SH2D1A gene and characterized by a dysregulated immune response to Epstein-Barr virus and other pathogens. The clinical presentation is heterogeneous and includes fulminant infectious mononucleosis, lymphoma, hypogammaglobulinemia and aplastic anemia. XLP is associated with a high morbidity and overall outcome is poor. At present, allogeneic stem cell transplantation (alloSCT) is the only curative treatment. XLP patients may be recognized in various stages of disease and even when symptoms are not yet evident. We here present two related XLP patients in different stages of disease that were both treated successfully with alloSCT using a matched unrelated donor. In addition, we have reviewed all reported cases of alloSCTs in XLP patients. Based on these results and in order to improve the final outcome, we conclude that alloSCT should be recommended in both symptomatic and asymptomatic XLP patients.     

Large deletion of the X-linked lymphoproliferative disease gene detected by fluorescence in situ hybridization

The X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by an abnormal responses to infection with Epstein-Barr virus (EBV), resulting in fatal infectious mononucleosis, hypogammaglobulinemia, virus-associated hemophagocytic syndrome, and malignant lymphoma. Mutations in the gene coding for a T cell-specific SLAM-associated protein (SAP) have been recently identified in XLP patients. We report on a 1-year-old boy representing fulminant hemophagocytic syndrome. He developed high fever, lymphadenopathy, hepatosplenomegaly with liver dysfunction, and pancytopenia with marrow hemophagocytosis. EBV DNA was abnormally increased in the blood. Polymerase chain reaction failed to amplify SAP mRNA and genomic DNA products from the patient' As peripheral blood. A large deletion of the SAP gene was confirmed by fluorescence in situ hybridization (FISH). FISH analysis also disclosed that the patient's mother was a carrier. We conclude that FISH can be useful in the diagnosis of XLP with large deletions of the SAP gene and its carrier state.     

Epstein-Barr virus infections in males with the X-linked lymphoproliferative syndrome

A registry of persons with the X-linked lymphoproliferative syndrome, which is characterized by marked susceptibility to diseases induced by the Epstein-Barr virus, has enrolled 161 patients within 44 kindreds. Fifty-seven percent of the males died of infectious mononucleosis, 29% developed acquired hypogammaglobulinemia, and 24% had malignant lymphoma. The mortality rate was 80%; 70% died by 10 years of age and 100% by 40 years. Thirty-two boys survive, most with malignant lymphoma, acquired hypogammaglobulinemia, or both. We hypothesized that the defective lymphoproliferative control locus on the X chromosome results in unregulated cytotoxic lymphocytic responses to the Epstein-Barr virus; hence, severe hepatitis and virus-associated hemophagocytic syndrome occur with the infectious mononucleosis phenotype. T-cell suppression of immunoglobulin secretion by B cells is responsible for acquired hypogammaglobulinemia. A sustained polyclonal B-cell proliferation probably converts to a monoclonal B-cell malignancy as a result of molecular alterations.     

A boy with fatal infectious mononucleosis suspected as the first Japanese case of X-linked lymphoproliferative syndrome

We report a case of a 10-month-old boy who died of severe hepatic failure after a prolonged course of infectious mononucleosis. He also presented interstitial pneumonitis, meningoencephalitis and aplastic anaemia. Epstein-Barr virus (EBV)-specific cytotoxic T lymphocyte (CTL) activity had not been detected in his peripheral blood during the course of the illness. Studies of his mother revealed a severe reactivation pattern of anti-EBV antibodies and decreased EBV-specific CTL activity. An X-linked familial susceptibility to EBV infection such as X-linked lymphoproliferative syndrome (XLP) might be associated with his fatal EBV infection.     

Primary Immunodeficiencies Inducing EBV-Associated Severe Illnesses

Epstein-Barr virus (EBV) is a ubiquitous human gamma-herpesvirus that infects about 95% of the adult population. The majority of primary infections occurs in early childhood and is generally subclinical; it can cause infectious mononucleosis (IM), which is usually a self-limiting lymphoproliferative disorder. However, infection of EBV occasionally results in severe, often lethal diseases, which include fatal IM, hemophagocytic syndrome, polyclonal lymphoproliferative disorders, and malignant lymphoma. These severe EBV-related illnesses occur secondary to some primary immunodeficiency diseases showing inefficient immune reaction to EBV. One example is X-linked lymphoproliferative disease (XLP), which is caused by mutations in the SLAM-associated protein (SAP) gene. The major clinical manifestations of XLP are fulminant IM, malignant lymphoma and dysgammaglobulinemia. Aplastic anemia, virus-associated hemophagocytic syndrome, and vasculitis have also been reported in XLP. We have developed a flow cytometric method using the anti-SAP monoclonal antibody to search for XLP. This clinically useful assay has successfully been used to identify XLP patients in Japan. In this review, clinical and mutational characteristics of XLP in Japan are mainly described. In addition, it is shown that the similar situations to XLP can occur in other primary immunodeficiencies involving T-cell killing function, such as autoimmune lymphoproliferative syndrome caused by Fas gene mutations or familial hemophagocytic lymphohistiocytosis caused by perforin gene mutations. Finally, the EBV-related terrible disease condition, namely chronic active EBV infection, which is common in Asian areas but its genetic background remains to be elucidated, will be touched on.     

Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome

X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency caused by a defect in the SH2D1A gene. At least 3 major manifestations characterize its clinical presentation: fatal infectious mononucleosis (FIM), lymphomas, and immunoglobulin deficiencies. Common variable immunodeficiency (CVID) is a syndrome characterized by immunoglobulin deficiency leading to susceptibility to infection. In some patients with CVID, a defective btk or CD40-L gene has been found, but most often there is no clearly identified etiology. Here, 2 unrelated families in whom male members were affected by CVID were examined for a defect in the XLP gene. In one family previously reported in the literature as having progressive immunoglobulin deficiencies, 3 brothers were examined for recurrent respiratory infections, whereas female family members showed only elevated serum immunoglobulin A levels. A grandson of one of the brothers died of a severe Aspergillus infection secondary to progressive immunoglobulin deficiency, FIM, aplastic anemia, and B-cell lymphoma. In the second family, 2 brothers had B lymphocytopenia and immunoglobulin deficiencies. X-linked agammaglobulinemia syndrome was excluded genetically, and they were classified as having CVID. The occurrence of FIM in a male cousin of the brothers led to the XLP diagnosis. Because the SH2D1A gene was found altered in both families, these findings indicate that XLP must be considered when more than one male patient with CVID is encountered in the same family, and SH2D1A must be analyzed in all male patients with CVID. Moreover, these data link defects in the SH2D1A gene to abnormal B-lymphocyte development and to dysgammaglobulinemia in female members of families with XLP disease.     

Hematopathology and pathogenesis of the X-linked recessive lymphoproliferative syndrome

Subtle immunodeficiency to infectious agents including measles virus and the Epstein-Barr virus (EBV) has been described in the X-linked recessive lymphoproliferative syndrome. This syndrome has affected six male cousins and possibly another boy. Three brothers died of an infectious mononucleosis syndrome, in a maternal cousin agammaglobulinemia developed three years after infectious mononucleosis, and two half-brothers of the Duncan kindred died of lymphoma of the brain and intestinal tract, respectively. In three of the boys, unusual measles viral infections had developed. Paramyxovirus-like particles suggestive of measles virus were seen at necropsy in the atrophic lymphoid tissue of two boys. Also, numerous plasma cells were seen in the brains, visceral organs and the thymus glands, and thymic-dependent lymphocytes were sparse in lymph nodes and spleen. The abnormal lymphopoiesis in the syndrome probably results from a subtle immunodeficiency, and concurrent measles and EB virus infections.     

X-linked lymphoproliferative disease: genetic lesions and clinical consequences

X-linked lymphoproliferative disorder (XLP) was first described almost 30 years ago; remarkably, the three major manifestations of XLP, fulminant infectious mononucleosis (FIM), lymphoma, and dysgammaglobulinemia, are all described in the report of the initial kindred. Subsequent establishment of an XLP registry has led to recognition of more unusual phenotypes in affected males; concurrently, much progress has been made in caring for boys with XLP, including treatment for the three major phenotypes, and curative bone marrow transplantation (BMT). The immunologic and genetic mechanisms resulting in XLP have also been intensively studied. Several years ago, the gene defective in XLP was identified as SAP (SLAM-associated protein), and recent data suggest that SAP plays a broad role in immune signaling. Here, we review the clinical manifestations and therapy of XLP, and briefly summarize recent research into the structure and function of SAP.     

Loss of circulating CD27+ memory B cells and CCR4+ T cells occurring in association with elevated EBV loads in XLP patients surviving primary EBV infection

Detailed longitudinal studies of patients with X-linked lymphoproliferative disease (XLP) may increase our understanding of the immunologic defects that contribute to the development of lymphoma and hypogammaglobulinemia in XLP. We describe progressive changes observed in immunoglobulin concentrations, lymphocyte subsets, and Epstein-Barr virus (EBV) loads occurring in a 2-year period in a newly infected, but otherwise healthy, carrier (patient 9). We compare these findings with those observed in the patient's brother, who had hypogammaglobulinemia and XLP (patient 4). Immunoglobulin G (IgG), IgM, and IgA concentrations increased in patient 9 during acute EBV infection, but thereafter they decreased steadily to concentrations consistent with hypogammaglobulinemia, reaching a plateau 5 months after infection. In both patients, CD19+ B-lymphocyte rates remained lower than 3%, with a contraction of the B-cell memory compartment (CD27+ CD19+/CD19+) to 20% (normal range, 32%-56%). T-lymphocyte subpopulations showed a reduction in CD4+ T-cell counts and a permanent CD8+ T-cell expansion. Interestingly, CXCR3 memory TH1 cells were expanded and CCR4+ TH2 lymphocytes were reduced, suggesting that abnormal skewing of memory T-cell subsets might contribute to reduced antibody synthesis. Despite an expanded number of CD3+CD8+ lymphocytes, increased EBV loads occurred in both patients without overt clinical symptoms of mononucleosis, lymphoproliferative disease, or lymphoma.     

Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease

The purposes of this study were to determine the frequency of mutations in SH2D1A in X-linked lymphoproliferative disease (XLP) and the role of SH2D1A mutations and Epstein-Barr virus (EBV) infection in determining the phenotype and outcome of patients with XLP. Analysis of 35 families from the XLP Registry revealed 28 different mutations in 34 families-large genomic deletions (n = 3), small intragenic deletions (n = 10), splice-site (n = 3), nonsense (n = 3), and missense (n = 9) mutations. No mutations were found in 25 males, so-called sporadic XLP (males with an XLP phenotype after EBV infection but no family history of XLP) or in 9 patients with chronic active EBV syndrome. Of 304 symptomatic males in the XLP Registry, 38 had no evidence of EBV infection at first clinical manifestation. When fulminant infectious mononucleosis (FIM) was excluded, there was no statistical difference in the frequency of EBV infectivity in the other XLP phenotypes. Furthermore, there was no difference at age of first clinical manifestation between EBV(+) and EBV(-) males or in survival when patients with FIM were excluded. In conclusion, it was found that mutations in the SH2D1A gene are responsible for XLP but that there is no correlation between genotype and phenotype or outcome. It was also found that though EBV infection often results in FIM, it is unnecessary for the expression of other manifestations of XLP, and it correlates poorly with outcome. These results suggest that unidentified factors, either environmental or genetic (eg, modifier genes), contribute to the pathogenesis of XLP.     

Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy

X-linked lymphoproliferative disease (XLP) is a congenital immunodeficiency that is characterized by an abnormal immune response to primary Epstein-Barr virus (EBV) infection. After EBV exposure, affected patients often develop fulminant infectious mononucleosis (FIM), a life-threatening condition marked by the uncontrolled expansion and activation of T and B lymphocytes and macrophages. We hypothesized that the rapid elimination of B cells immediately following EBV exposure might reduce the severity of primary EBV infection in patients with XLP. To test this possibility, we administered the anti-CD20 antibody rituximab to 2 patients who presented with acute infection. Following treatment, both patients exhibited a complete resolution of symptoms and no longer demonstrated detectable EBV DNA within circulating lymphocytes. Moreover, neither patient has developed FIM or lymphoma in more than 2 years of follow-up. These data suggest that the pre-emptive use of B-cell-directed therapy may reduce the morbidity and mortality of primary EBV infection in XLP-affected individuals.     

Epstein–Barr Virus Infection Masquerading as Acute Leukemia: A Report of Two Cases and Review of Literature

Epstein–Barr virus (EBV) is the first herpes virus to be completely sequenced. It is implicated in diseases from the benign infectious mononucleosis to malignant nasopharyngeal carcinoma, Burkitt’s lymphoma and primary CNS lymphoma in AIDS patients. It has also been found to be associated with some miscellaneous diseases like chronic fatigue syndrome, multiple sclerosis etc. however causality still remains an issue of debate. As the virus mainly targets the lymphomonuclear cells and the reticuloendothelial system of the body, it’s various manifestations are often mistaken as leukemic malignancies. We report two such cases of young adults who had been diagnosed as having acute leukemia on the basis of atypical cells in the peripheral blood. One patient later turned out to be a classical infectious mononucleosis and second patient had EBV associated hemophagocytic lymphohistiocytosis syndrome.     

Histological and immunopathological studies in a case of chronic Epstein-Barr virus infection terminating in a Burkitt-like lymphoma

A 6-year-old boy suffered from a severe lymphadenopathy, characterized histologically by a fulminant polyclonal immunoblast proliferation simulating malignant lymphoma with many immunoblasts resembling Reed-Sternberg cells. He had no history of infectious mononucleosis but Epstein-Barr virus (EBV) infection was evident from serological findings, and EBV-associated nuclear antigen (EBNA) was demonstrated in a high percentage of lymphocytes of blood and lymph nodes. An adequate humoral response to EBV ruled out the possibility of an X-linked recessive lymphoproliferative syndrome as the underlying cause of chronic EBV infection. A chromosomal defect in a subpopulation of lymphocytes was induced by interferon and might somehow be associated with a subtle immunodeficiency of our patient. After exacerbation of the disease chemotherapy was included in the treatment but the patient died 9 months after the onset of the disease. At autopsy the lymphoblastic cell proliferation had changed from that of immunoblasts to cells resembling the Burkitt's lymphoma cells. A change of the proliferating cell type was supported by means of cytochemical and immunological cell markers. The presence of EBV in these cells was demonstrated with the EBNA technique. It is concluded that our case may well support the hypothesis, that EBV may induce lymphoma-like polyclonal immunoblast proliferation in immunodeficient individuals, and that occasionally a monoclonal proliferation of the Burkitt's lymphoma type may supervene.     

Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene

The hemophagocytic lymphohistiocytoses (HLH) comprise a heterogeneous group of disorders characterized by dysregulated activation of T cells and macrophages. Although some patients with HLH harbor perforin gene mutations, the cause of the remaining cases is not known. The phenotype of HLH bears a strong resemblance to X-linked lymphoproliferative disease (XLP), an Epstein-Barr virus (EBV)-associated immunodeficiency resulting from defects in SH2D1A, a small SH2 domain-containing protein expressed in T lymphocytes and natural killer cells. Here it is shown that 4 of 25 male patients with HLH who were examined harbored germline SH2D1A mutations. Among these 4 patients, only 2 had family histories consistent with XLP. On the basis of these findings, it is suggested that all male patients with EBV-associated hemophagocytosis be screened for mutations in SH2D1A. Patients identified as having XLP should undergo genetic counseling, and be followed long-term for development of lymphoma and hypogammaglobulinemia.     

Histological and Immunopathological Studies in a Case of Chronic Epstein-Barr Virus Infection Terminating in a Burkitt-Like Lymphoma

A 6-year-old boy suffered from a severe lymphadenopathy, characterized histologically by a fulminant polyclonal immunoblast proliferation simulating malignant lymphoma with many immunoblasts resembling Reed-Sternberg cells. He had no history of infectious mononucleosis but Epstein-Barr virus (EBV) infection was evident from serological findings, and EBV-associated nuclear antigen (EBNA) was demonstrated in a high percentage of lymphocytes of blood and lymph nodes. An adequate humoral response to EBV ruled out the possibility of an X-linked recessive lymphoproliferative syndrome as the underlying cause of chronic EBV infection. A chromosomal defect in a subpopulation of lymphocytes was induced by interferon and might somehow be associated with a subtle immunodeficiency of our patient. After exacerbation of the disease chemotherapy was included in the treatment but the patient died 9 months after the onset of the disease. At autopsy the lymphoblastic cell proliferation had changed from that of immunoblasts to cells resembling the Burkitt's lymphoma cells. A change of the proliferating cell type was supported by means of cytochemical and immunological cell markers. The presence of EBV in these cells was demonstrated with the EBNA technique. It is concluded that our case may well support the hypothesis, that EBV may induce lymphoma-like polyclonal immunoblast proliferation in immunodeficient individuals, and that occasionally a monoclonal proliferation of the Burkitt's lymphoma type may supervene.     

Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus-associated T/NK-cell lymphoproliferative disease

Epstein-Barr virus (EBV) is implicated in a variety of human diseases, some of which have fatal outcomes. Some EBV related diseases are considered to be candidates for the treatment of hematopoietic stem cell transplantation (HSCT). X-linked lymphoproliferative (XLP) syndrome is one of the representative diseases in which more than half of affected males die of infectious mononucleosis (IM) within a few weeks of primary infection, whereas the minority who survive have an increased risk of acquired hypogammaglobulinemia and lymphoma. Patients with XLP usually die by the age 40. Similarly, the majority of patients with chronic active EBV infection develop hemophagocytic syndrome, organ failure, opportunistic infection, and/or lymphoma and die within 5-10 years from onset. Recently, HSCT has provided successful outcomes in these patients. In this review, progress in the new therapeutic strategy is summarized, focusing on EBV-associated T/NK-cell lymphoproliferative disease (LPD), which is one of the heterogeneous EBV-associated disorder.     

Acute Epstein-Barr virus infection and diffuse large-cell lymphoma

The antibody response to Epstein-Barr virus (EBV) has not been fully investigated in previous cases of diffuse large-cell lymphoma associated with infectious mononucleosis. It is not clear, therefore, whether acute EBV infection is related to this malignant condition. In this paper, a case of diffuse large-cell lymphoma accompanied by acute EBV infection is described.