title: Acquired familial Mediterranean fever associated with a somatic MEFV mutation in a patient with JAK2 associated post-polycythemia myelofibrosis.
abstract: BACKGROUND
  A study was designed to identify the source of fever in a patient with post-polycythemia myelofibrosis, associated with clonal Janus Kinase 2 (JAK2) mutation involving duplication of exon 12. The patient presented with 1-2 day long self-limited periodic episodes of high fever that became more frequent as the hematologic disease progressed.
  
  
  METHODS
  After ruling out other causes for recurrent fever, analysis of the pyrin encoding Mediterranean fever gene (MEFV) was carried out by Sanger sequencing in peripheral blood DNA samples obtained 4 years apart, in buccal cells, laser dissected kidney tubular cells, and FACS-sorted CD3-positive or depleted mononucleated blood cells. Hematopoeitc cells results were validated by targeted deep sequencing. A Sanger sequence based screen for pathogenic variants of the autoinflammatory genes NLRP3, TNFRSF1A and MVK was also performed.
  
  
  RESULTS
  A rare, c.1955G>A, p.Arg652His MEFV gene variant was identified at negligible levels in an early peripheral blood DNA sample, but affected 46 % of the MEFV alleles and was restricted to JAK2-positive, polymorphonuclear and CD3-depleted mononunuclear DNA samples obtained 4 years later, when the patient experienced fever bouts. The patient was also heterozygous for the germ line, non-pathogenic NLRP3 gene variant, p.Q705K. Upon the administration of colchicine, the gold standard treatment for familial Mediterranean fever (FMF), the fever attacks subsided.
  
  
  CONCLUSIONS
  This is the first report of non-transmitted, acquired FMF, associated with a JAK2 driven clonal expansion of a somatic MEFV exon 10 mutation. The non-pathogenic germ line NLRP3 p.Q705K mutation possibly played a modifier role on the disease phenotype.
authors.affiliation: Heller Institute of Medical Research, Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. yshinar@sheba.health.gov.il.
authors.forename: Yael
authors.initials: Y
authors.lastname: Shinar
authors.affiliation: Hematology Laboratory, Sheba Medical Center, Tel Hashomer, Israel. Tali.Tohami@gmail.com.
authors.forename: Tali
authors.initials: T
authors.lastname: Tohami
authors.affiliation: Heller Institute of Medical Research, Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. alivenh@sheba.health.gov.il.
authors.forename: Avi
authors.initials: A
authors.lastname: Livneh
authors.affiliation: Department of Pathology, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Schiby.Ginette@sheba.health.gov.il.
authors.forename: Ginette
authors.initials: G
authors.lastname: Schiby
authors.affiliation: Department of Oral Pathology & Oral Medicine, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel. Abraham.Hirshberg@sheba.health.gov.il.
authors.forename: Abraham
authors.initials: A
authors.lastname: Hirshberg
authors.affiliation: Hematology Laboratory, Sheba Medical Center, Tel Hashomer, Israel. Meital.Nagar@sheba.health.gov.il.
authors.forename: Meital
authors.initials: M
authors.lastname: Nagar
authors.affiliation: Cancer Research Center, Sheba Medical Center, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Itamar.Goldstein@sheba.health.gov.il.
authors.forename: Itamar
authors.initials: I
authors.lastname: Goldstein
authors.affiliation: Heller Institute of Medical Research, Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Rinat.Cohen@sheba.heath.gov.il.
authors.forename: Rinat
authors.initials: R
authors.lastname: Cohen
authors.affiliation: Institute of Nephrology and Hypertension, Sheba Medical Center, Tel Hashomer, Israel. Olga.Kukuy@sheba.health.gov.il.
authors.forename: Olga
authors.initials: O
authors.lastname: Kukuy
authors.affiliation: Maccabi Healthcare Organization, Petach Tikva, Israel. Ora.Shubman@sheba.health.gov.il.
authors.forename: Ora
authors.initials: O
authors.lastname: Shubman
authors.affiliation: Internal Medicine D, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv, Israel. Yehonatan.Sharabi@sheba.health.gov.il.
authors.forename: Yehonatan
authors.initials: Y
authors.lastname: Sharabi
authors.affiliation: Department of Immunology, Hospital Clinic-IDIBAPS, Barcelona, Spain. EVGONZAL@clinic.ub.es.
authors.forename: Eva
authors.initials: E
authors.lastname: Gonzalez-Roca
authors.affiliation: Department of Immunology, Hospital Clinic-IDIBAPS, Barcelona, Spain. JIAROSTE@clinic.ub.es.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Arostegui
authors.affiliation: Cancer Research Center, Sheba Medical Center, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Gidi.Rechavi@sheba.health.gov.il.
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.affiliation: Hematology Laboratory, Sheba Medical Center, Tel Hashomer, Israel. Ninnette.Amariglio@sheba.health.gov.il.
authors.forename: Ninnette
authors.initials: N
authors.lastname: Amariglio
authors.affiliation: Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Ophira.Salomon@sheba.health.gov.il.
authors.forename: Ophira
authors.initials: O
authors.lastname: Salomon
mesh_terms: D001706:Biopsy; D002999:Clone Cells; D003078:Colchicine / Q000627:therapeutic use; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D010505:Familial Mediterranean Fever / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D006074:Gout Suppressants / Q000627:therapeutic use; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011087:Polycythemia Vera / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D055728:Primary Myelofibrosis / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D000071198:Pyrin
chemical_list: D003598:Cytoskeletal Proteins; D006074:Gout Suppressants; C000604192:MEFV protein, human; D000071198:Pyrin; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D003078:Colchicine