Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases

作者：Rohr Jan; Beutel Karin; Maul Pavicic Andrea; Vraetz Thomas; Thiel Jens; Warnatz Klaus; Bondzio Ilka; Gross Wieltsch Ute; Schuendeln Michael; Schuetz Barbara; Woessmann Wilhelm; Groll Andreas H; Strahm Brigitte; Pagel Julia; Speckmann Carsten; Janka Gritta; Griffiths Gillian; Schwarz Klaus; zur Stadt Udo; Ehl Stephan^*

来源：Haematologica-The Hematology Journal, 2010, 95(12): 2080-2087.

DOI：10.3324/haematol.2010.029389

• familial hemophagocytic lymphohistiocytosis
• mutations
• UNC13D
• STXBP2

Background
Familial hemophagocytic lymphohistiocytosis is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first two years of life and has a poor prognosis unless treated by hematopoietic stem cell transplantation. Atypical courses with later onset and prolonged survival have been described, but no detailed analysis of immunological parameters associated with typical versus atypical forms of familial hemophagocytic lymphohistiocytosis has been performed.
Design and Methods
We analyzed disease manifestations, NK-cell and T-cell cytotoxicity and degranulation, markers of T-cell activation and B-cell differentiation as well as Natural Killer T cells in 8 patients with atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2.
Results
All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. In most patients episodes of hemophagocytic lymphohistiocytosis were preceded or followed by clinical features typically associated with immunodeficiency, such as chronic active Epstein Barr virus infection, increased susceptibility to bacterial infections, granulomatous lung or liver disease, encephalitis or lymphoma. Five of 8 patients had hypogammaglobulinemia and reduced memory B cells. Most patients had a predominance of activated CD8(+) T cells and low numbers of Natural Killer T cells. When compared to patients with typical familial hemophagocytic lymphohistiocytosis, NK-cell cytotoxicity and NK-cell and CTL degranulation were impaired to a similar extent. However, in patients with an atypical course NK-cell degranulation could be partially reconstituted by interleukin-2 and cytotoxic T-cell cytotoxicity in vitro was normal.
Conclusions
Clinical and immunological features of atypical familial hemophagocytic lymphohistiocytosis show an important overlap to primary immunodeficiency diseases (particularly common variable immunodeficiency and X-linked lymphoproliferative syndrome) and must, therefore, be considered in a variety of clinical presentations. We show that degranulation assays are helpful screening tests for the identification of such patients.

• 出版日期2010-12
• 单位河北医科大学