|Note|| XLP is estimated to affect 1-3 per million male individuals, although the incidence may be higher as the condition may go undetected. Nonetheless, any male individual presenting with severe or fatal EBV infection, or HLH as a result of EBV exposure should be evaluated for XLP, especially if there is a family history of maternally related males with dysgammaglobulinemia, lymphoma or EBV-induced HLH. Early diagnosis of XLP is paramount, as the mean ages of death of individuals with XLP1 and XLP2 are 11 and 16 years, respectively (Pachlopnik Schmid et al., 2011).|
|Phenotype and clinics|| XLP1 patients usually present with fulminant FIM (a hyperinflammatory condition resembling HLH that is induced by EBV infection and typified by the dysregulated expansion of EBV-infected B cells and cytotoxic T cells, and the abnormal activation of macrophages), dysgammaglobulinemia and B cell lymphoma. Less commonly, XLP1 manifests as lymphocytic vasculitis (usually involving the lungs or central nervous sytem [CNS]), aplastic anemia or lymphatoid granulomatosis (Gaspar et al., 2002). The manifestations of XLP1 can occur in the absence of EBV infection.|
XLP2 commonly presents with splenomegaly and recurrent episodes of HLH, often in response to EBV infection. XLP2 patients also display dysgammaglobulinemias, and a proportion of affected individuals develop hepatitis and/or colitis.
There is no known correlation between SH2D1A or XIAP genotype and phenotype in XLP1 or XLP2. Affected members of the same family may exhibit significant variability in presentation.
Diagnosis is generally suspected based on clinical history. Screening tests can be performed to assess for protein levels of SAP or XIAP in lymphocytes via flow cytometry, and the diagnosis confirmed by genetic analysis of the associated genes. In rare instances, genetic analysis fails to identify an abnormality in SH2D1A or XIAP in a host presenting with signs and symptoms consistent with XLP.
|Neoplastic risk|| The risk for development of lymphomas in XLP1 approaches 25-30%, with a mortality rate of 9% (Booth et al., 2011). The lymphomas are typically high grade non-Hodgkins type B cell lymphomas. Lymphomas tend to be extranodal and involve the intestines, although they can also be found in liver, kidneys and CNS. Histologically, they are classified as Burkitt's, immunoblastic, small cleaved B cell lymphomas or mixed cell lymphomas. Not all lymphomas carry evidence of EBV genome. It remains poorly understood why patients with XLP1 develop lymphoma; however, absence of invariant natural killer T (NKT) cells and defects in T and NK cell cytotoxic function may contribute to lymphoma formation.|
|Treatment|| The therapy of choice for XLP patients is hematopoietic cell transplantation (HCT). HCT is the only known curative treatment and has the best chance of success if performed as early as possible - before the onset of other disease manifestations. Other therapies directed at treating the manifestations of XLP may be necessary before HCT is attempted. Although HCT carries its own risk of complications and mortality, without it only 50% of XLP1 patients reach adulthood. The majority perish secondary to HLH (70%), lymphoma (12%) or myelodysplasia (6%) (Booth et al., 2011; Pachlopnik Schmid et al., 2011). The prognosis is similarly poor for XLP2 without HCT, in which mortality is attributed to HLH (30%), colitis (23%), liver failure (8%), and infectious causes (8%) (Pachlopnik Schmid et al., 2011).|
HLH is generally treated with corticosteroids, cyclosporine, and etoposide. Rituximab has been used successfully to prevent EBV-induced FIM in XLP1 (Milone et al., 2005), and should be considered in any XLP1 or -2 patient who experiences primary EBV infection.
Lymphomas can be effectively treated with standard chemotherpateutic regimens; however, patients should be carefully monitored for the development of EBV and other infections, which can be difficult to manage due to underlying immune defects.
Patients with hypogammaglobulinemia are treated with monthly immunoglobulin replacement.
Asymptomatic patients with XLP should be periodically monitored for immunoglobulin levels, evidence for EBV exposure, and signs of development of other manifestations of disease.
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