title: Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.
abstract: Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal hyperinflammatory syndrome characterized by fever, hepatosplenomegaly, cytopenia, and in some cases hemophagocytosis. Here, we describe the mutation analysis, clinical presentation, and functional analysis of natural killer (NK) cells in patients with mutations in STXBP2 encoding Munc18-2, recently associated with familial HLH type 5. The disease severity among 11 persons studied here was highly variable and, accordingly, age at diagnosis ranged from 2 months to 17 years. Remarkably, in addition to typical manifestations of familial HLH (FHL), the clinical findings included colitis, bleeding disorders, and hypogammaglobulinemia in approximately one-third of the patients. Laboratory analysis revealed impairment of NK-cell degranulation and cytotoxic capacity. Interleukin-2 stimulation of lymphocytes in vitro rescued the NK cell-associated functional defects. In conclusion, familial HLH type 5 is associated with a spectrum of clinical symptoms, which may be a reflection of impaired expression and function of Munc18-2 also in cells other than cytotoxic lymphocytes. Mutations in STXBP2 should thus also be considered in patients with clinical manifestations other than those typically associated with HLH.
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Stockholm, Sweden. marie.meeths@ki.se
authors.forename: Marie
authors.initials: M
authors.lastname: Meeths
authors.forename: Miriam
authors.initials: M
authors.lastname: Entesarian
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.forename: Samuel C C
authors.initials: SC
authors.lastname: Chiang
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Wood
authors.forename: Wafa
authors.initials: W
authors.lastname: Al-Ateeqi
authors.forename: Francisco
authors.initials: F
authors.lastname: Almazan
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.forename: Marianne
authors.initials: M
authors.lastname: Ifversen
authors.forename: Bendik
authors.initials: B
authors.lastname: Lund
authors.forename: J Merlijn
authors.initials: JM
authors.lastname: van den Berg
authors.forename: Britt
authors.initials: B
authors.lastname: Gustafsson
authors.forename: Hans
authors.initials: H
authors.lastname: Hjelmqvist
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
mesh_terms: D000293:Adolescent; D000361:Agammaglobulinemia / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic; D004252:DNA Mutational Analysis; D005260:Female; D005767:Gastrointestinal Diseases / Q000235:genetics; D006470:Hemorrhage / Q000235:genetics; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D008297:Male; D051938:Munc18 Proteins / Q000235:genetics*; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics; D010641:Phenotype
chemical_list: D051938:Munc18 Proteins; C497940:STXBP2 protein, human