Alternative titles; symbols
SNOMEDCT: 1162828001; ORPHA: 2442, 538931; DO: 0060705;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq25 | Lymphoproliferative syndrome, X-linked, 1 | 308240 | X-linked recessive | 3 | SH2D1A | 300490 |
A number sign (#) is used with this entry because X-linked lymphoproliferative syndrome-1 (XLP1) is caused by mutation in the SH2D1A gene (300490), encoding SLAM-associated protein (SAP), on chromosome Xq25.
X-linked lymphoproliferative syndrome, or Duncan disease, is a primary immunodeficiency characterized by severe immune dysregulation often after viral infection, typically with Epstein-Barr virus (EBV). It is a complex phenotype manifest as severe or fatal mononucleosis, acquired hypogammaglobulinema, hemophagocytic lymphohistiocytosis (HLH), and/or malignant lymphoma. Other features may include aplastic anemia, red cell aplasia, and lymphomatoid granulomatosis (Purtilo et al., 1977; Purtilo, 1981; Purtilo and Grierson, 1991; Coffey et al., 1998; Booth et al., 2011).
Genetic Heterogeneity of X-linked/Autosomal Lymphoproliferative Syndrome
See XLP2 (300635), caused by mutation in the XIAP gene (300079), also on Xq25; LPFS1 (613011), caused by mutation in the ITK gene (186973) on chromosome 5q33; LPFS2 (615122), caused by mutation in the CD27 gene (186711) on chromosome 12p13; and LPFS3 (618261), caused by mutation in the CD70 gene (TNFSF7; 602840) on chromosome 19p13.
Purtilo et al. (1974, 1975) reported a kindred by the name of Duncan in which 6 males died between the ages of 2 and 19 years from a lymphoproliferative disease. The subtle, progressive combined variable immunodeficiency disease was characterized by benign or malignant proliferation of lymphocytes and histiocytosis, as well as alterations in concentrations of serum immunoglobulins. In at least 3 of 6 boys, infectious mononucleosis occurred during or preceding the terminal events. Fever, pharyngitis, lymphadenopathy, hepatosplenomegaly, atypical lymphocytosis, and a spectrum ranging from agammaglobulinemia to polyclonal hypergammaglobulinemia occurred. At necropsy, the thymus glands and thymic-dependent areas in the lymph nodes and spleen were depleted of lymphocytes. Hematopoietic organs, viscera, and central nervous system were diffusely infiltrated by lymphocytes, plasma cells, and histiocytes, some containing erythrocytes. Two of the 6 males, half sibs, had lymphomas of the ileum and central nervous system. The authors raised the possibility that 'the Epstein-Barr virus or other viruses triggered the fatal proliferation of lymphocytes and that progressive attrition of T-cell function allowed uncontrolled lymphoproliferation.' In addition to the kindred described by Purtilo and his colleagues, the kindred in which 4 young male cousins died of infectious mononucleosis, as reported by Bar et al. (1974), and the kindred with agammaglobulinemia developing after infectious mononucleosis in 3 maternal male cousins, as reported by Provisor et al. (1975), may be examples of Duncan disease.
Hamilton et al. (1980) abbreviated the designation of this disease to XLP (X-linked lymphoproliferative) syndrome. They reported studies of 59 affected males in 7 unrelated kindreds ascertained through an XLP registry. Thirty-four patients died of infectious mononucleosis, 8 had fatal infectious mononucleosis with immunoblastic sarcoma, 9 had depressed immunity following Epstein-Barr virus infection, and 8 developed lymphoma.
Purtilo et al. (1982) reviewed 100 cases of XLP in 25 kindreds, and suggested 4 major interrelated phenotypes: infectious mononucleosis (IM), malignant B-cell lymphoma (ML), aplastic anemia (AA), and hypogammaglobulinemia (HGG). Eighty-one of the patients died; 2 were asymptomatic but showed immunodeficiency to EBV; 75 had IM and, concurrently, 17 of this group had AA; all with AA died within a week. On the other hand, AA did not accompany HGG or ML. In 9, IM appeared to evolve into ML; however, most patients with ML showed no obvious antecedent IM. In 1, IM occurred after recurrent ML. Twenty-six of 35 lymphomas were in the terminal ileum. Heterozygous women (mothers of boys with XLP) showed abnormally elevated titers of antibodies to EBV.
Sullivan et al. (1980) found deficient activity of natural killer (NK) cells from patients with XLP. Sullivan et al. (1983) studied 2 males with XLP before and during acute fatal Epstein-Barr virus infection. Before EBV infection, both showed normal cellular and humoral immunity. Death in both cases was caused by liver failure: one developed extensive hepatic necrosis; the other developed massive infiltration of the liver with EBV-infected immunoblasts after aggressive immunosuppressive therapy. Sullivan et al. (1983) proposed that an aberrant immune response triggered by acute EBV infection results in unregulated anomalous killer and natural killer cell activity against EBV infected and uninfected cells. They further suggested that the global cellular immune defects in males with XLP who survive EBV infection represent an epiphenomenon.
Purtilo and Grierson (1991) reported that during the previous decade 240 males with XLP within 59 unrelated kindreds had been identified worldwide. One-half of the patients had developed fatal infectious mononucleosis at an average age of about 2.5 years, and death occurred on average only 33 days following onset of illness. About one-third had acquired hypogammaglobulinemia and another one-fourth had developed malignant lymphoma, most of which were of the Burkitt type involving the ileocecal region. Although hypogammaglobulinemia and malignant lymphoma were associated with longer survivals, no patient had been documented as living into the fifth decade of life.
Seemayer et al. (1995) reviewed XLP 25 years after Purtilo's first observations in 1969. Purtilo established a registry in 1980 to serve as a worldwide resource for the diagnosis, treatment, and research of this condition. After Purtilo's death in late 1992, the registry and research unit continued to function as a worldwide consultative service. By 1995, some 272 affected members of 80 kindreds had been identified. Approximately 10% of the boys who inherited the mutated XLP gene were immunologically abnormal, even before evidence of EBV exposure.
Coffey et al. (1998) noted that the average age of disease onset in XLP is 2.5 years, with 100% mortality by the age of 40 years. Following infection with EBV, patients mount a vigorous, uncontrolled polyclonal expansion of T and B cells. The primary cause of death is hepatic necrosis and bone marrow failure. The extensive tissue destruction of the liver and bone marrow appears to stem from the uncontrolled cytotoxic T-cell response.
Systemic vasculitis is an uncommon manifestation of XLP. Dutz et al. (2001) described a patient who died as a result of chronic systemic vasculitis and fulfilled clinical criteria for the diagnosis of XLP. Sequencing of the SH2D1A gene revealed a novel point mutation affecting the SH2 domain. The patient presented with virus-associated hemophagocytic syndrome, and later chorioretinitis, bronchiectasis, and hypogammaglobulinemia developed. He further developed mononeuritis and fatal respiratory failure. Evidence of widespread small and medium vessel vasculitis was noted at autopsy with involvement of retinal, cerebral, and coronary arteries as well as the segmental vessels of the kidneys, testes, and pancreas. Immunohistochemical analysis showed that the vessel wall infiltrates consisted primarily of CD8+ T cells, implying a cytotoxic T-lymphocyte response to antigen. Epstein-Barr virus DNA was detected by PCR in arterial wall tissue microdissected from infiltrated vessels, suggesting that the CD8+ T cells were targeting EBV antigens within the endothelium. Dutz et al. (2001) proposed that functional inactivation of the SH2D1A gene impairs the immunologic response to EBV, resulting in systemic vasculitis.
Verhelst et al. (2007) reported a boy with SAP deficiency who developed limbic encephalitis. He was diagnosed and treated for cervical B-cell non-Hodgkin lymphoma at age 9 years. At age 15, during hospitalization for pneumonia, blood tests revealed hypogammaglobulinemia for the first time. At age 16, he presented with seizures, decreased alertness, short-term memory loss, and hemiparesis. MRI and cerebral biopsy showed vasculitis with infiltration of T lymphocytes and granulomas. Despite aggressive treatment, he showed further deterioration and died 10 months later. There was absence of SAP protein on immunostaining of the patient's lymphocytes, but no mutation was identified in the SH2D1A gene. There was no family history of a similar disorder.
Booth et al. (2011) performed a retrospective analysis of 91 patients with genetically confirmed XLP1 ascertained worldwide, including 43 who had hematopoietic stem cell transplant (HSCT) and 48 without transplant. The most common presenting feature was hemophagocytic lymphohistiocytosis (HLH), which occurred in 39.6% of patients, and the most common overall feature was dysgammaglobulinemia, which occurred in 50% of patients at some point during the illness. Twenty-two patients had malignant lymphoproliferative disease, including 18 with B-cell non-Hodgkin lymphoma. Fifty-one (64.6%) of 79 patients tested were EBV-positive. There was no significant difference in mortality between those with and without documented EBV infection, but those with EBV infection had a higher frequency of HLH. The mortality for patients presenting with HLH was 65.6%, with a median age at presentation of 3 years, 2 months. Overall survival after transplant was 81.4%; however, survival fell to 50% in patients with HLH as a feature of disease. Untransplanted patients had an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH was extremely poor, at only 18.8%. Overall, the study indicated that hematopoietic stem cell transplant should be undertaken in all XLP1 patients with HLH, because outcome without transplant is extremely poor, whereas the outcome of HSCT for other manifestations of XLP1 is very good.
Purtilo and Grierson (1991) concluded that the diagnosis of XLP in affected males and female carriers was 99% accurate based on results of linkage to DXS42 RFLPs (lod = 19.4) and 95% accurate with RFLP probes to DXS37 (lod = 11.8). By linkage analysis, they detected males with the XLP gene before EBV infection occurred.
Using RFLP analysis, Grierson et al. (1993) evaluated 10 families in which a single male had died of infectious mononucleosis. The authors suggested that, in such families, Epstein-Barr virus-seronegative males must be considered at risk for XLP and should be identified pre-EBV infection in order to maximize survival. One family in the study was determined to have XLP; 3 other families in the study had carriers of XLP, and 3 families were determined not to have XLP.
Prenatal Diagnosis
Skare et al. (1992) made the diagnosis of XLP prenatally by analyzing closely linked RFLP markers of cells obtained at amniocentesis at 15 weeks' gestation. By use of DNA markers applied to chorionic villus sampling (CVS) material, Mulley et al. (1992) identified with high reliability an unaffected male fetus, brother of an affected male. By HLA-DR typing of the CVS, they also showed that the fetus was DR-identical to the affected sib.
Williams et al. (1993) reported successful bone marrow transplantation in an 11-year-old boy with Duncan syndrome, with restoration of an apparently normal host immune response to EBV. They presented this as evidence that the primary abnormality in this disorder resides in bone marrow-derived cells.
Vowels et al. (1993) described a boy with this disorder in whom transplantation of cord-blood stem cells from an HLA-identical sib resulted in correction of the genetic defect and the hypogammaglobulinemia. Cord blood collected at birth contains 5 to 10 times more marrow progenitor cells than the peripheral blood of older infants or children, and the volume of blood and nucleated cells that can be collected is substantial. The authors noted that cord blood had successfully been transplanted into patients with aplastic anemia and leukemia, resulting in repopulation of the bone marrow and immune systems.
Arkwright et al. (1998) reported a sibship of 4 males born to unrelated parents, 3 of whom had X-linked lymphoproliferative disease. The proband was born at 33 weeks' gestation and developed neonatal varicella zoster infection complicated by tibial osteomyelitis. At 18 months of age, he developed infectious mononucleosis complicated by hepatitis and aplastic anemia. The latter responded well to oral corticosteroids, broad-spectrum antibiotics, and acyclovir. He later developed hypoglobulinemia and required regular intravenous infusions of immunoglobulin. An older brother was healthy until the age of 7, when he developed a fulminant cytomegalovirus infection (hemophagocytic lymphohistiocytosis). This responded to etoposide-based chemotherapy and a successful allogenic bone marrow transplant from his normal sib. At 4 months of age, another brother was shown by RFLP and microsatellite markers flanking the XLP locus to have inherited the high-risk haplotype. Although healthy, he was receiving prophylactic intravenous immunoglobulin infusions. This sibship demonstrated the varied clinical manifestations of X-linked lymphoproliferative disease.
Schuster and Kreth (1999) stated that the only means available to prevent EBV- and non-EBV-related complications in later life is early transplantation of allogeneic hematopoietic stem cells, i.e., cord blood or bone marrow (Vowels et al., 1993; Williams et al., 1993). The age of the patient at the time of transplantation appeared to be critical. Whereas 4 of 8 XLPD patients who underwent stem cell transplantation before the age of 15 years were alive and well for more than 2 years posttransplantation, all 4 boys older than 15 years of age at the time of transplantation died within 90 days of complications.
Skare et al. (1987, 1987) demonstrated linkage of XLP with marker DXS42, which maps to Xq24-q27 (lod score of 5.26). Haplotype analysis refined the XLP locus distal to DXS42 and proximal to DXS99. Skare et al. (1989) extended the linkage information on the family they reported in 1987 and studied 6 additional families, all of which corroborated the close linkage to DXS42 (1% recombination; lod = 17.5) and DXS37 (maximum lod = 13.3 at theta = 0.0.)
Hayoz et al. (1988) identified a large, extensively affected Swiss family with XLP, ascertained through a patient with acquired hypogammaglobulinemia associated with a mononucleosis syndrome at the age of 18 years; the patient died at 19. In this family, a new mutation in the F8 gene (300841) causing hemophilia A (306700) had occurred, resulting in a woman who was a carrier of both genes. She had a son with hemophilia, a daughter who was a carrier of both disorders, and a son who was free of both disorders. The doubly-heterozygous daughter had 1 son with XLPD and 1 son who was doubly affected. The observations suggested that the hemophilia A locus and the XLPD locus are far apart, a conclusion that was supported by other mapping data.
Harris et al. (1988) excluded linkage of XLP to 28 X-linked probes. Harris and Docherty (1988) found no particular chromosomal abnormalities in this disorder. One of their patients was found to have the Klinefelter syndrome, having inherited 2 copies of his maternal XLPD-carrying X chromosome. Wyandt et al. (1989) found deletion of part of band Xq25 in a male with this disorder; others found the same deletion in the mother and a sister. Skare et al. (1989) reported family linkage studies of the XLP-causing gene with several Xq DNA markers. They also reported 1 male of 14 unrelated affected persons who had a deletion in Xq which was thought to involve about one-half of Xq25. This male retained sequences at all 5 loci that had been found to be closely linked to XLP, but lacked DXS6 which by somatic hybrid mapping had been assigned to Xq26-qter. In a large Swiss family with XLP, Sylla et al. (1989) demonstrated linkage of XLP to marker DXS37, which is located in Xq25-q26. Multipoint linkage analysis showed that the XLP locus is distal to DXS11 but proximal to HPRT (308000). Sanger et al. (1990) demonstrated an interstitial deletion involving a portion of Xq25 in an affected male as well as in 1 sister and their mother. Using blot hybridization, Skare et al. (1993) identified 3 XLP males with deletions of Xq25 encompassing marker DXS739.
In 9 unrelated patients with X-linked lymphoproliferative syndrome, Coffey et al. (1998) identified mutations in the SH2D1A gene (300490.0001-300490.0009).
In 2 brothers with early-onset non-Hodgkin lymphoma, but no clinical or laboratory evidence of EBV infection, Brandau et al. (1999) identified a deletion of exon 1 of the SH2D1A gene (300490.0010). Other SH2D1A mutations were identified in 2 additional unrelated patients without evidence of EBV infection; 1 had non-Hodgkin lymphoma and 1 had signs of dysgammaglobulinemia. Development of dysgammaglobulinemia and lymphoma without evidence of prior EBV infection in 4 patients suggested that EBV is unrelated to these particular phenotypes, in contrast to fulminant or fatal infectious mononucleosis. No SH2D1A mutations were found in 3 families in which clinical features were suggestive of XLP.
Sumegi et al. (1999) reviewed the molecular basis of Duncan disease. They tabulated 15 mutations in the SH2D1A gene.
Rigaud et al. (2006) studied a cohort of 18 families with an inherited disease diagnosed as X-linked lymphoproliferative syndrome. Among them, 15 were found to harbor mutations in the SH2D1A gene. However, in affected individuals from 3 families, Rigaud et al. (2006) failed to detect mutations in the SH2D1A gene or any of its regulatory regions. Unlike SAP-deficient patients with XLP, these patients often had splenomegaly, noticed as their first clinical manifestation of this condition. Further investigations demonstrated that in these 3 families, XLP was caused by insufficiency of XIAP (300079).
Nichols et al. (2005) observed that Sh2d1a -/- mice lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell-autonomous and could be rescued by reconstitution of Sh2d1a expression within Sh2d1a -/- bone marrow cells. Nichols et al. (2005) also studied 17 individuals with XLP and differing SH2D1A genotypes. All 17 lacked NKT cells, and a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Nichols et al. (2005) concluded that SH2D1A is a crucial regulator of NKT cell ontogeny, and that the absence of NKT cells may contribute to the XLP phenotype, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.
Ma et al. (2005) analyzed 14 XLP patients from 9 families and found normal B-cell development but a marked reduction in the number of memory B cells; the few detected were IgM+, revealing deficient isotype switching in vivo. However, XLP B cells underwent proliferation and differentiation in vitro as efficiently as control B cells, indicating that the block in differentiation in vivo is B-cell extrinsic. XLP CD4+ (186940) T cells did not efficiently differentiate into IL10+ (124092) effector cells or provide optimal B-cell help in vitro; provision of exogenous IL10 or ectopic expression of SH2D1A, which increased IL10 production by T cells, improved the B-cell help. Ma et al. (2005) suggested that insufficient IL10 production may contribute to hypogammaglobulinemia in XLP.
Using immunohistochemistry and flow cytometric analysis, Ma et al. (2006) found that IgM-positive/CD27 (TNFRSF7; 186711)-positive B cells from XLP patients were morphologically and functionally similar to those from normal donors. The authors suggested that production of affinity-matured IgM by these cells may protect against pathogens to which a normal immune response is elicited in XLP patients.
By studying T-cell receptor (TCR; see 186740) restimulation of preactivated T cells from EBV-naive XLP patients after prolonged exposure to IL2 (147680), Snow et al. (2009) found that activated T cells from these patients were specifically and substantially less sensitive to restimulation-induced cell death (RICD). Silencing SAP or NTBA (SLAMF6; 606446) expression recapitulated resistance to RICD in normal T cells, indicating that both molecules are necessary for optimal TCR-induced apoptosis. TCR restimulation triggered increased recruitment of SAP to NTBA, and these proteins functioned to augment TCR-induced signal strength and induction of downstream proapoptotic target genes, including FASL (TNFSF6; 134638) and BIM (BCL2L11; 603827). Snow et al. (2009) proposed that XLP patients are inherently susceptible to antigen-induced lymphoproliferative disease and fulminant infectious mononucleosis due to compromised RICD.
Schuster and Kreth (1999) attributed the first report of a family with XLP to Hambleton and Cottom (1969), who described a family in which 2 brothers suffered from hypogammaglobulinemia and malignant lymphoma following infectious mononucleosis.
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