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

• Published in: Human immunology 2016-08, Vol.77 (8), p.658-666
• Main Authors: Jin, Ying-Ying, Zhou, Wei, Tian, Zhi-Qing, Chen, Tong-Xin
• Format: Article
• Language: English
• Subjects: Adolescent; Allergy and Immunology; Child; Child, Preschool; China; Epstein-Barr virus; Fatal Outcome; Humans; Infant; Infant, Newborn; Infection - genetics; Infection - physiopathology; Lymphoproliferative Disorders - genetics; Lymphoproliferative Disorders - physiopathology; Male; Meningitis - genetics; Meningitis - physiopathology; Mutation - genetics; Pedigree; Phenotype; Pneumonia - genetics; Pneumonia - physiopathology; SH2D1A mutation; Signaling Lymphocytic Activation Molecule Associated Protein - genetics; X-Linked Inhibitor of Apoptosis Protein - genetics; X-linked lymphoproliferative disease; XIAP mutation
• ISSN: 0198-8859; 1879-1166
• DOI: 10.1016/j.humimm.2016.06.005

Abstract Background X-linked lymphoproliferative disease (XLP) is a rare life-threating syndrome. Rapid recognition and definitive diagnosis are critical to improve the prognosis and survival of patients with XLP. Nowadays, little was 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 viremia 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 viremia were evaluated among 421 PID patients in our center. Four patients had SH2D1A mutations, and one patient had an XIAP mutation. The onset age of the 5 patients range from 1 month to 4 years old which was earlier than that in the western world. The diagnosis age was between 16 months and 9 years with a long diagnosis lag (1-97 months). Two of them had positive family history. The clinical phenotypes varied in different patients among which two patients with FHLH and hypogammaglobulinemia, one with hypogammaglobulinemia, lymphoma and aplastic anaemia(AA) which is the first case with AA in China, one with hypogammaglobulinemia 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, hypogammaglobulinemia, lymphoma and aplastic anaemia, possibility of XLP should be considered and if confirmed, HSCT should be performed as soon as possible.