Acquired familial Mediterranean fever associated with a somatic MEFV mutation in a patient with JAK2 associated post-polycythemia myelofibrosis

Yael Shinar, Tali Tohami, Avi Livneh, Ginette Schiby, Abraham Hirshberg, Meital Nagar, Itamar Goldstein, Rinat Cohen, Olga Kukuy, Ora Shubman, Yehonatan Sharabi, Eva Gonzalez-Roca, Juan I. Arostegui, Gideon Rechavi, Ninnette Amariglio, Ophira Salomon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number86
JournalOrphanet Journal of Rare Diseases
Volume10
Issue number1
DOIs
StatePublished - 30 Jun 2015

Keywords

  • Autoinflammatory
  • FMF
  • Fever
  • JAK2
  • MEFV
  • Mosaicism
  • Myelofibrosis
  • Polycythemia vera
  • Somatic mutation

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