@article{Jan Rohr_Karin Beutel_Andrea Maul-Pavicic_Thomas Vraetz_Jens Thiel_Klaus Warnatz_Ilka Bondzio_Ute Gross-Wieltsch_Michael Schündeln_Barbara Schütz_Wilhelm Woessmann_Andreas H. Groll_Brigitte Strahm_Julia Pagel_Carsten Speckmann_Gritta Janka_Gillian Griffiths_Klaus Schwarz_Udo zur Stadt_Stephan Ehl_2010, place={Pavia, Italy}, title={Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases}, volume={95}, url={https://haematologica.org/article/view/5816}, DOI={10.3324/haematol.2010.029389}, abstractNote={<strong>Background</strong> 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 <em>versus</em> atypical forms of familial hemophagocytic lymphohistiocytosis has been performed.<strong>Design and Methods</strong> 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 <em>UNC13D</em> and <em>STXBP2</em>.<strong>Results</strong> All but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in <em>UNC13D</em> or <em>STXBP2</em>. 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<sup>+</sup> 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 <em>in vitro</em> was normal.<strong>Conclusions</strong&gt; 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.}, number={12}, journal={Haematologica}, author={Jan Rohr and Karin Beutel and Andrea Maul-Pavicic and Thomas Vraetz and Jens Thiel and Klaus Warnatz and Ilka Bondzio and Ute Gross-Wieltsch and Michael Schündeln and Barbara Schütz and Wilhelm Woessmann and Andreas H. Groll and Brigitte Strahm and Julia Pagel and Carsten Speckmann and Gritta Janka and Gillian Griffiths and Klaus Schwarz and Udo zur Stadt and Stephan Ehl}, year={2010}, month={Dec.}, pages={2080-2087} }