The clinical diagnosis for XLP is often difficult, especially in sporadic cases, because of the diverse presentation and the lack of unique findings in XLP. For example, fatal IM in XLP can be indistinguishable clinically and histologically from sporadic forms of virus-associated hemophagocytic syndrome. 7 Sumegi et al 6 reported that no SH2D1A mutations were detected in 25 males who manifested an XLP phenotype without a family history of XLP. Thus, it is not currently clear whether molecular diagnosis of XLP is applicable to patients with a sporadic XLP phenotype.XLP patients have been reported from North America, Europe, the Middle East, and South America but, except for one recent case report, 8 not from the highly populated countries of Asia. 2 To search for the possible presence of XLP in Japan, we systematically screened 40 Japanese males with severe EBV-associated illnesses.The SH2D1A mutations were detected in 10 cases. Notably, 5 of these 10 cases had no family history of XLP.
Study design PatientsForty Japanese boys with severe EBV-associated illnesses were studied. All patients, except for 2 brothers, were unrelated. Five patients, including the 2 brothers, had a family history supporting an X-linked inheritance for the XLP phenotype. The study population included 3 groups: (group 1) 18 patients who had experienced severe acute IM (ages 0-17 years); (group 2) 5 patients with EBV genome-positive lymphoma (ages 0-8 years); and (group 3) 17 patients with severe chronic active EBV infection (CAEBV) (ages 1-12 years). The cases in group 1 met the diagnostic criteria for hemophagocytic lymphohistiocytosis 9 or died immediately following an acute IM-like illness. All of these patients harbored the EBV genome in tissue specimens or displayed a serologic response suggestive of primary EBV infection: antibody positive for viral capsid antigen without detectable antibodies to EBV nuclear antigen. Lymphomas were defined as EBVpositive when the tissue harbored EBV genome detected by polymerase chain reaction or by in situ hybridization for EBV-encoded small RNAs. 10 This group consisted of 3 B-cell lymphomas, including one Burkitt lymphoma, one Hodgkin disease, and one nasal lymphoma. CAEBV was diagnosed according to the previously described criteria. 11-13 Briefly, these patients were characterized by prolonged or recurrent IM-like symptoms For personal use only. on March 24, 2019. by guest www.bloodjournal.org From for more than one year, with hepatosplenomegaly, lymphoadenopathy, anemia, or cytopenia and with an unusual pattern of anti-EBV antibodies: high anti-viral capsid antigen and/or anti-early antigen, and low or absent anti-EBV nuclear antigen titers. None of these patients had an overt immunodeficient condition.
SH2DIA mutation analysisMutation analysis of the coding region in the SH2DIA gene was conducted on both complementary DNAs and genomic DNAs. Polymerase chain reaction conditions and primer sequences for amplifying the complementary DNA and the 4 exons of SH2DIA were as previously reported. 4
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