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.

Clinical features and gene mutation analysis of 4 Chinese children with X-linked lymphoproliferative disease / 中华实用儿科临床杂志

Objective To summarize clinical,gene mutation and their families of 4 Chinese children with X-linked lymphoproliferative (XLP) disease.Methods The clinical records and 6 genes of immunodeficiency associated with Epstein-Barr(EBV) infection were summarized and the literatures were reviewed.Results The four cases were all boys younger than 3 years old,who had onset with fever.They were all treated with ganciclovir,plasma,intravenous immunoglobulin and methylprednisolone after hospitalization,but 3 cases had the features of fulminant or fatal infectious mononucleosis (FIM),whose progression of disease was getting worse and died of second hemophagocytic lymphohistiocytosis (HLH) in the end.The survival time after onset was about 20 days.One boy had the complications of HLH associated with EBV infection and drug-induced hypersensitivity syndrome,who was improved and discharged from hospital.Two cases had adverse family history in which brothers or cousins died at younger ages.EBV-CAIgM and EBV-DNA of the 4 cases were all positive,with the copy of EBV DNA ＞ 108 copies/L.The results of the 6 genes of immunodeficiency associated with EBV infection of the 4 boys showed SH2D1A mutation.Mothers of 3 cases separately had the same SH2D1A mutation as her boy,while 1 mother refused to have the genes detected.Conclusions Patients who had the XLP were all male.Infants and young children under 5 years old usually had the features of FIM,with the complication of EBV associated HLH.Patients with XLP showed SH2D1A mutation.For male patients with FIM,especially those under 5 years,it is important to perform genetic detection early and to receive therapy as early as possible.