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

• Published in: Haematologica (Roma) Vol. 95; no. 12; pp. 2080 - 2087
• Main Authors: ROHR, Jan, BEUTEL, Karin, WOESSMANN, Wilhelm, GROLL, Andreas H, STRAHM, Brigitte, PAGEL, Julia, SPECKMANN, Carsten, JANKA, Gritta, GRIFFITHS, Gillian, SCHWARZ, Klaus, ZUR STADT, Udo, EHL, Stephan, MAUL-PAVICIC, Andrea, VRAETZ, Thomas, THIEL, Jens, WARNATZ, Klaus, BONDZIO, Ilka, GROSS-WIELTSCH, Ute, SCHÜNDELN, Michael, SCHÜTZ, Barbara
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01.12.2010
• Subjects: Adolescent; Adult; Alleles; B-Lymphocytes - immunology; Biological and medical sciences; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell Degranulation - immunology; Cell Line, Tumor; Cells, Cultured; Child; Child, Preschool; Chronic infection; Common variable immunodeficiency; Cytotoxicity; Cytotoxicity, Immunologic - immunology; Degranulation; Differentiation; Encephalitis; Epstein-Barr virus; Flow Cytometry; Gene Frequency; Hematologic and hematopoietic diseases; Histiocytosis; Humans; Hypogammaglobulinemia; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunodeficiency; Immunoglobulin G - blood; Immunologic Deficiency Syndromes - complications; Immunologic Deficiency Syndromes - immunology; Immunological memory; Immunopathology; Interleukin 2; K562 Cells; Killer Cells, Natural - immunology; Killer Cells, Natural - physiology; Liver diseases; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphocytosis; Lymphohistiocytosis, Hemophagocytic - complications; Lymphohistiocytosis, Hemophagocytic - genetics; Lymphohistiocytosis, Hemophagocytic - immunology; Lymphoma; Medical sciences; Membrane Proteins - genetics; Memory cells; Munc18 Proteins - genetics; Mutation; Natural killer cells; Obstructive lung disease; Original; Other diseases. Hematologic involvement in other diseases; Prognosis; RNA Splice Sites - genetics; stem cell transplantation; X chromosome; Immunopathology; Familial hemophagocytic lymphohistiocytosis; mutations; Hematology; Primary; STXBP2; Genetics; Atypical; Mutation; Immune deficiency; UNC13D
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2010.029389

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. 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. 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. 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.