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Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population
  1. Silvia Federici1,
  2. Giuseppina Calcagno2,
  3. Martina Finetti1,
  4. Romina Gallizzi3,
  5. Antonella Meini4,
  6. Agata Vitale2,
  7. Francesco Caroli5,
  8. Marco Cattalini4,
  9. Roberta Caorsi1,
  10. Francesco Zulian6,
  11. Alberto Tommasini7,
  12. Antonella Insalaco8,
  13. Maria Pia Sormani9,
  14. Maurizia Baldi10,
  15. Isabella Ceccherini5,
  16. Alberto Martini1,11,
  17. Marco Gattorno1
  1. 1UO Pediatria II Reumatologia, Istituto G Gaslini, Genova, Italy
  2. 2Sezione di Reumatologia Pediatrica, Dipartimento di Scienze Pediatriche Mediche e Chirurgiche, AOU ‘G Martino’, Messina, Italy
  3. 3Sezione di Immunologia e Reumatologia Pediatrica dell'UOC di Genetica e Immunologia Pediatrica, Università di Messina, Messina, Italy
  4. 4Dipartimento di Pediatria, Unità di Immunologia e Reumatologia Pediatrica, Spedali Civili e University of Brescia, Brescia, Italy
  5. 5Laboratorio di Genetica Molecolare, Istituto G Gaslini, Genoa, Italy
  6. 6Dipartimento AI di Pediatria, University of Padua, Padova, Italy
  7. 7IRCCS Burlo Garofolo, Dipartimento di Pediatria, University of Trieste, Trieste, Italy
  8. 8Divisione di Reumatologia, Ospedale Pediatrico Bambino Gesù, IRCCS, Roma, Italy
  9. 9Unità di Biostatistica, DISSAL, University of Genoa, Genova, Italy
  10. 10Dipartmento di Genetica Umana, Ospedale Galliera, Genoa, Italy
  11. 11Dipartmento di Pediatria, University of Genoa, Genova, Italy
  1. Correspondence to Marco Gattorno, UO Pediatria II, Reumatologia, Istituto G Gaslini, Largo G Gaslini 5, 16147, Genova, Italy; marcogattorno{at}


Objective To evaluate the actual impact of MEFV mutations on clinical manifestations associated with fever attacks in Caucasian children with periodic fever.

Methods 113 children carrying MEFV mutations (44 with mutations in two alleles, 69 heterozygous) and 205 children negative for mutations in genes associated with periodic fevers were analysed. The following groups of patients were considered: patients carrying two high penetrance mutations (M694V, M694I, M680I); one high, one low penetrance mutation; two low penetrance mutations; one high penetrance mutation; one low penetrance mutation; genetically negative patients.

Results Patients with two MEFV mutations displayed a shorter duration of fever attacks and higher prevalence of a positive family history than patients carrying one MEFV mutation and genetically negative patients. Severe abdominal pain, chest pain and pleurisy were also more frequent in patients with two MEFV mutations compared with children with one MEFV mutation and genetically negative patients. Conversely, a higher frequency of exudative and erythematous pharyngitis, enlargement of cervical lymph nodes, aphthous stomatitis and non-specific skin rash was observed in genetically negative patients and, to a lesser extent, in patients with one MEFV mutation. The frequency of ‘familial Mediterranean fever (FMF)-like symptoms’ decreases from patients carrying two high penetrance mutations towards patients with a single low penetrance mutation with an opposite trend for ‘periodic fever, aphthous stomatitis, pharyngitis, adenitis-like symptoms’.

Conclusions This clinical observation supports recent findings contrasting the notion of FMF being a pure autosomal recessive disorder associated with recurrence of mutations leading to loss of protein function. A dosage effect could be invoked, giving rise to symptom onset even in the presence of one wild-type allele.

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  • Funding This work was partially supported by Ricerca Corrente Ministeriale (Istituto di Sanità).

  • Competing interests None.

  • Ethics approval The study was approved by the ethical board of G Gaslini Institute.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The research has not been published elsewhere.