title: Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases.
abstract: 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.
  
  
  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.
authors.affiliation: Centre of Pediatrics and Adolescent Medicine, University Medical Centre, Freiburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rohr
authors.forename: Karin
authors.initials: K
authors.lastname: Beutel
authors.forename: Andrea
authors.initials: A
authors.lastname: Maul-Pavicic
authors.forename: Thomas
authors.initials: T
authors.lastname: Vraetz
authors.forename: Jens
authors.initials: J
authors.lastname: Thiel
authors.forename: Klaus
authors.initials: K
authors.lastname: Warnatz
authors.forename: Ilka
authors.initials: I
authors.lastname: Bondzio
authors.forename: Ute
authors.initials: U
authors.lastname: Gross-Wieltsch
authors.forename: Michael
authors.initials: M
authors.lastname: Schündeln
authors.forename: Barbara
authors.initials: B
authors.lastname: Schütz
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Woessmann
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Groll
authors.forename: Brigitte
authors.initials: B
authors.lastname: Strahm
authors.forename: Julia
authors.initials: J
authors.lastname: Pagel
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.forename: Gritta
authors.initials: G
authors.lastname: Janka
authors.forename: Gillian
authors.initials: G
authors.lastname: Griffiths
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.forename: Udo
authors.initials: U
authors.lastname: zur Stadt
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D005787:Gene Frequency; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007153:Immunologic Deficiency Syndromes / Q000150:complications* / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000502:physiology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000150:complications / Q000235:genetics* / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics*; D051938:Munc18 Proteins / Q000235:genetics*; D009154:Mutation; D022821:RNA Splice Sites / Q000235:genetics
chemical_list: D007074:Immunoglobulin G; D008565:Membrane Proteins; D051938:Munc18 Proteins; D022821:RNA Splice Sites; C497940:STXBP2 protein, human; C507969:UNC13D protein, human
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