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.