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Blood, 1 November 2000, Vol. 96, No. 9, pp. 3118-3125
IMMUNOBIOLOGY
Correlation of mutations of the SH2D1A gene and
Epstein-Barr virus infection with clinical phenotype and outcome in
X-linked lymphoproliferative disease
Janos Sumegi,
Dali Huang,
Arpad Lanyi,
Jack D. Davis,
Thomas A. Seemayer,
Akihiko Maeda,
George Klein,
Marco Seri,
Hiroshi Wakiguchi,
David T. Purtilo, and
Thomas G. Gross
From the Department of Pathology and Microbiology,
Center for Human Molecular Genetics, Eppley Institute for Research in
Cancer and Allied Diseases; the Departments of Pathology and
Microbiology and Pediatrics, University of Nebraska Medical Center,
Omaha, NE; the Center for Microbiology and Tumorbiology, Karolinska
Institute, Stockholm, Sweden; the Laboratorio di Genetica Molecolare,
Instituto Giannina Gaslini, Genoa, Italy; the Department of Pediatrics,
Kochi Medical School, Nankoku, Japan; and the Division of Hematology
and Oncology, Children's Hospital Medical Center, Cincinnati, OH.
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.
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