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

TY - JOUR

T1 - Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases

AU - Rohr, Jan

AU - Beutel, Karin

AU - Maul-Pavicic, Andrea

AU - Vraetz, Thomas

AU - Thiel, Jens

AU - Warnatz, Klaus

AU - Bondzio, Ilka

AU - Gross-Wieltsch, Ute

AU - Schündeln, Michael

AU - Schütz, Barbara

AU - Woessmann, Wilhelm

AU - Groll, Andreas H

AU - Strahm, Brigitte

AU - Pagel, Julia

AU - Speckmann, Carsten

AU - Janka-Schaub, Gritta

AU - Griffiths, Gillian

AU - Schwarz, Klaus

AU - Zur Stadt, Udo

AU - Ehl, Stephan

PY - 2010/12

Y1 - 2010/12

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Alleles

KW - B-Lymphocytes/immunology

KW - CD8-Positive T-Lymphocytes/immunology

KW - Cell Degranulation/immunology

KW - Cell Line, Tumor

KW - Cells, Cultured

KW - Child

KW - Child, Preschool

KW - Cytotoxicity, Immunologic/immunology

KW - Flow Cytometry

KW - Gene Frequency

KW - Humans

KW - Immunoglobulin G/blood

KW - Immunologic Deficiency Syndromes/complications

KW - K562 Cells

KW - Killer Cells, Natural/immunology

KW - Lymphohistiocytosis, Hemophagocytic/complications

KW - Membrane Proteins/genetics

KW - Munc18 Proteins/genetics

KW - Mutation

KW - RNA Splice Sites/genetics

U2 - 10.3324/haematol.2010.029389

DO - 10.3324/haematol.2010.029389

M3 - SCORING: Journal article

C2 - 20823128

VL - 95

SP - 2080

EP - 2087

JO - HAEMATOLOGICA

JF - HAEMATOLOGICA

SN - 0390-6078

IS - 12

ER -