title: Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations.
abstract: BACKGROUND
  Perforin, encoded by PRF1, is a pore-forming protein crucial for lymphocyte cytotoxicity. Biallelic PRF1 nonsense mutations invariably result in early-onset hemophagocytic lymphohistiocytosis (HLH), termed familial HLH type 2 (FHL2). In contrast, biallelic PRF1 missense mutations may give rise to later-onset disease and more variable manifestations.
  
  
  METHODS
  We retrospectively searched our database for patients from families with siblings carrying biallelic PRF1 missense mutations where at least one sibling did not develop HLH, and for patients with biallelic PRF1 missense mutations and an atypical presentation of disease. We reviewed their clinical, genetic, and immunological characteristics.
  
  
  RESULTS
  In all, we identified 10 such patients, including three sibling pairs with discordant manifestations. Interestingly, in two families, siblings of late-onset HLH patients developed Hodgkin lymphoma but no HLH. In a third family, one sibling presented with recurrent HLH episodes, whereas the other remains healthy. Of note, the affected sibling also suffered from systemic lupus erythematosus. Additional unrelated patients with biallelic PRF1 missense mutations were affected by neurological disease without classical signs of HLH, gastrointestinal inflammation as initial presentation of disease, as well as a hematological malignancy. Compared to early-onset FHL2 patients, the patients with an atypical presentation displayed a partial recovery of NK cell cytotoxicity upon IL-2 stimulation in vitro.
  
  
  CONCLUSIONS
  Our findings substantiate and expand the spectrum of clinical presentations of perforin deficiency, linking PRF1 missense mutations to lymphoma susceptibility and highlighting clinical variability within families. PRF1 mutations should, therefore, be considered as a cause of several diseases disparate to HLH.
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.|Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Bianca
authors.initials: B
authors.lastname: Tesi
authors.affiliation: Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Samuel C C
authors.initials: SC
authors.lastname: Chiang
authors.affiliation: Pediatric Allergy and Immunology Unit, Children's Hospital, Ain Shams University, Cairo, Egypt.
authors.forename: Dalia
authors.initials: D
authors.lastname: El-Ghoneimy
authors.affiliation: Bone Marrow and Stem Cell Transplantation Program, King Hussein Cancer Center, Amman, Jordan.
authors.forename: Ayad Ahmed
authors.initials: AA
authors.lastname: Hussein
authors.affiliation: Department of Women's and Children's Health, Queen Silviás Childreńs Hospital, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Langenskiöld
authors.affiliation: Shaukat Khanum Memorial Cancer Hospital & Research Center, Lahore, Pakistan.
authors.forename: Rabia
authors.initials: R
authors.lastname: Wali
authors.affiliation: Department of Oncology and Pediatrics, Aga Khan University, Karachi, Pakistan.
authors.forename: Zehra
authors.initials: Z
authors.lastname: Fadoo
authors.affiliation: Institute for Research and Innovation on Health and Center for Predictive and Preventive Genetics of the IBMC-Institute for Cell and Molecular Biology, University of Porto, Portugal.
authors.forename: João Pinho
authors.initials: JP
authors.lastname: Silva
authors.affiliation: Hematology Service, University Clinic of Navarra, Pamplona, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Lecumberri
authors.affiliation: Division of Pediatric Hematology, Hacettepe University, Ankara, Turkey.
authors.forename: Sule
authors.initials: S
authors.lastname: Unal
authors.affiliation: Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.affiliation: Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.|Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Meeths
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D006689:Hodgkin Disease / Q000235:genetics*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009422:Nervous System Diseases / Q000235:genetics*; D054353:Perforin / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: C510468:PRF1 protein, human; D054353:Perforin
keywords: hemophagocytic lymphohistiocytosis; lymphocyte cytotoxicity; lymphoma; missense mutation; perforin