Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Impact of MEFV Mutations in Caucasian Children with Periodic Fevers: Clinical Evidence for a Gain of Function Effect.
Federici1, Silvia, Calcagno2, Giuseppina, Finetti3, Martina, Gallizzi4, Romina, Meini5, Antonella, Vitale2, Agata, Caroli1, Francesco
G. Gaslini Institute, Genova, Italy
Ospedale Galliera, Genova, Italy
Sezione di Reumatologia Pediatrica, Università di Messina, Messina, Italy
IRCCS G Gaslini, Pediatria II, Reumatologia, Genova, Italy
Sezione di Immunologia e Reumatologia Pediatrica, Università di Messina, Messina, Italy
Dipartimento di Pediatria, University of Brescia, Brescia, Italy
University of Padua, Padova, Italy
Dipartimento di Pediatria, Univerity of Trieste, Trieste, Italy
Divisione di Reumatologia, Ospedale Pediatrico Bambino Gesù, Roma, Italy
Unità di Biostatistica, DISSAL, University of Genoa, Genova, Italy
despite FMF is considered an autosomal recessive disease caused by mutations of MEFV, one third of patients carry one mutation only. Aim of the present study was to analyze the clinical manifestation associated with periodic fever in a set of Caucasian children with periodic fever to evaluate the actual impact of MEFV mutations on the phenotype.
113 Caucasian patients carrying MEFV mutations (46 with mutations in two alleles, 67 heterozygous) and 205 genetically negative patients for MEFV, TNFSF1A and MEFV (70% with a PFAPA phenotype) were analyzed. The extracellular region of the p55 TNF receptor (from exon 1 to exon 6) of the TNFRSF1A gene, the 10 coding exons (from 2 to 11) of the MVK gene and exons 2, 3, 5 and 10 of the MEFV gene were analyzed by means of denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing. For each patient detailed clinical information about family and personal history, prevalence and frequency (sometimes, often, always) of the clinical manifestations associated with fever episodes had been collected by means of a standardized questionnaire. The following groups were considered: patients with: i) 2 high penetrance mutations (M694V, M694I, M680I), ii) 1 high, 1 low penetrance mutation, iii) 2 low penetrance mutations, iv) 1 high penetrance mutation, v) one low penetrance mutation, vi) genetically negative.
Patients with two MEFV mutations displayed higher prevalence of chest pain (p = 0.001, Fisher's Exact Test), pleurisy (p = 0.003) and severe abdominal pain (p = 0.002). In contrast, patients carrying one mutation displayed an higher prevalence of erythematous (p = 0.01) and exudative ( p = 0.009) pharyngitis, enlarged cervical lymph nodes (p = 0.002) and skin rash (p= 0.007). Moreover, patients with 2 MEFV mutations displayed also a later disease onset (mean 47 ± 40 months) and a shorter duration of fever episodes (2.9 ± 1.6 days) in respect to heterozygous patients (mean 30 ± 36.9 months, p = 0.02; and 5.1 ± 6.9 days, p = 0.03, respectively).The frequency of "FMF-like symptoms" decreases from patients carrying two high penetrance mutations towards patients with a single low penetrance mutation with a opposite behavior for "PFAPA-like symptoms" (Figure).
the present study shows a dosage effect of MEFV mutations not consistent with a pure autosomal recessive disorder. A dominant negative or gain of function effects or variants of still unidentified modifier genes may influence the presence of a FMF phenotype in heterozygous patients.
To cite this abstract, please use the following information:
Federici, Silvia, Calcagno, Giuseppina, Finetti, Martina, Gallizzi, Romina, Meini, Antonella, Vitale, Agata, et al; Impact of MEFV Mutations in Caucasian Children with Periodic Fevers: Clinical Evidence for a Gain of Function Effect. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2452