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: 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
• Journal: Orphanet journal of rare diseases (Orphanet J Rare Dis) Vol. 10 Pg. 86 (Jun 30 2015) ISSN: 1750-1172 [Electronic] England
• PMID: 26123310 (Publication Type: Case Reports, Journal Article)

Chemical References

• Cytoskeletal Proteins
• Gout Suppressants
• MEFV protein, human
• Pyrin
• JAK2 protein, human
• Janus Kinase 2
• Colchicine

Topics

• Biopsy
• Clone Cells
• Colchicine (therapeutic use)
• Cytoskeletal Proteins (genetics)
• Exons (genetics)
• Familial Mediterranean Fever (diagnosis, drug therapy, genetics)
• Female
• Gout Suppressants (therapeutic use)
• Humans
• Janus Kinase 2 (genetics)
• Middle Aged
• Mutation
• Polycythemia Vera (diagnosis, drug therapy, genetics)
• Polymorphism, Restriction Fragment Length
• Primary Myelofibrosis (diagnosis, drug therapy, genetics)
• Pyrin