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Pediatric Rheumatology

Open Access

PW02-022 - Recurrent fever syndromes: multiple gene mutations

  • M Bohm1,
  • P Dolezalova1,
  • H Lachmann2,
  • C Modesto3,
  • I Touitou4,
  • P Woo5,
  • M Finetti6,
  • V Hentgen7,
  • L Cantarini8,
  • F De Benedetti9,
  • R Gallizzi10,
  • L Obici11,
  • R Manna12,
  • E Gallo13,
  • N Ruperto6,
  • M Gattorno6 and
Pediatric Rheumatology201311(Suppl 1):A162

Published: 8 November 2013


Familial Mediterranean FeverAutoinflammatory DiseasePeriodic SyndromeMevalonate Kinase DeficiencyPenetrance Mutation


In patients with monogenic autoinflammatory diseases, the majority of detected mutations were found just in a single gene, either in homozygous, heterozygous or compound heterozygous state. However, in some patients mutations in several different genes have been detected. Clinical significance of this finding has yet to be established.


To describe clinical characteristics of patients with rare combinations of genetic mutations.


Seventy-seven centres from 33 countries have been contributing to an international secured web-based registry for autoinflammatory diseases (EUROFEVER), hosted by the PRINTO website (Paediatric Rheumatology International Trial Organisation,

The registry collects anonymised demographic, clinical, laboratory and molecular genetic data on patients with autoinflammatory diseases. Complete clinical information on 1868 consecutive children was available.


In 31 patients (1.7%), the combination of mutations in two different genes, and in one patient in three genes was found with following distribution of clinical diagnoses: Cryopyrin-Associated Periodic Syndromes (CAPS)=9, Tumor necrosis factor (TNF)-Receptor Associated Periodic Syndrome (TRAPS)=7, Familial Mediterranean Fever (FMF)=5, mild Mevalonate Kinase Deficiency (MKD, also known as Hyper IgD Syndrome (HIDS))=2, undefined=9. Out of these patients 18 (56%) carried one high penetrance mutation each. The prevalence of high penetrance mutations among clinically defined groups was most prominent within the CAPS phenotype (8/9) followed by FMF (3/5), MKD (1/2) and TRAPS (3/7). In patients with low penetrance mutations in one of the 4 relevant genes the second mutation was found in one of the remaining 3 genes with the following characteristics: low penetrance (5/14), polymorphisms (3/14), unknown (4/14). In remaining 2 patients the combination of unknown penetrance mutation in one gene and polymorphism in the other was found (both with undefined phenotype).


As the availability of molecular genetic analysis for patients with recurrent fever syndromes increases, the amount of detected mutations in more than one gene will grow. The data currently available suggest that the high prevalence mutations overrule the clinical picture of the disease in majority of patients, though clinical significance of second mutations will have to be evaluated in larger patient series.

Disclosure of interest

None declared.

Authors’ Affiliations

Charles University in Prague, Prague, Czech Republic
University College Medical School, London, UK
Hospital Valle de Hebron, Barcelona, Spain
Hôpital Arnaud de Villeneuve, Montpellier, France
Great Ormond Street Hospital, London, UK
Istituto Giannina Gaslini, Genova, Italy
Centre de reference national des maladies auto-inflammatoires, Paris, France
University of Siena, Siena, Italy
Ospedale Pediatrico Bambin Gesù, Roma, Italy
Università di Messina, Messina, Italy
Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
Policlinico Gemelli, Roma, Italy
Clinica Pediatrica Università di Torino, Torino, Italy


© Bohm et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.