Variable clinical phenotypes of X-linked lymphoproliferative syndrome in China: Report of five cases with three novel mutations and review of the literature.

Background: X-linked lymphoproliferative disease (XLP) is a rare life-threatening syndrome. Rapid recognition and definitive diagnosis are critical to improve the prognosis and survival of patients with XLP. Nowadays, little is known about patients with XLP in China.

Methods: We report the characterization of five Chinese XLP patients with three novel mutations and review the literature related to this syndrome. Male patients with fulminant infectious mononucleosis (FIM), Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) or persistent EBV viraemia were enrolled in this study. The patients' clinical features were assessed by retrieval of data from medical records. Immunological function included analysis of lymphocyte subsets and the detection of immunoglobulins G, A, M and/or E were evaluated by flow cytometry and nephelometry. Direct sequencing was used to detect SH2D1A/XIAP gene mutations.

Results: Twenty-two male patients with FIM, EBV-associated HLH or persistent EBV viraemia were evaluated among 421 PID patients in our centre. Four patients had SH2D1A mutations, and one patient had an XIAP mutation. The onset age of the 5 patients range from 1month to 4years which was earlier than that in the western world. The diagnosis age was between 16months and 9years with a long diagnosis lag (1-97months). Two of them had positive family history. The clinical phenotypes varied in different patients among which two patients with FHLH and hypogammaglobulinaemia, one with hypogammaglobulinaemia, lymphoma and aplastic anaemia (AA) which is the first case with AA in China, one with hypogammaglobulinaemia only and the other one with FHLH. For immunological function, three exhibited reduced CD4/CD8 ratios. Arg55stop mutations as well as splice mutation in intron 1 were most frequently found and exon 2 was the hottest exon in China. Two patients died at the time of diagnosis for severe infection or hepatic coma. Three were alive and waiting for haematopoietic stem cell transplantation (HSCT).

Conclusion: For patients with severe EBV-associated HLH, hypogammaglobulinaemia, lymphoma and aplastic anaemia, possibility of XLP should be considered and if confirmed, HSCT should be performed as soon as possible.