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Changing concepts in familial Mediterranean fever: is it possible to have an autosomal-recessive disease with only one mutation?

Familial Mediterranean fever (FMF) is the most common of the autoinflammatory syndromes (1). The typical features are recurrent attacks of fever and serositis with significant acute-phase inflammation. The disease is associated with mutations in the Mediterranean fever (MEFV) gene that codes for pyrin and is transmitted in an autosomal-recessive manner. Thus, a heterozygote is expected to be a carrier and lack the clinical phenotype. However, carriers have been shown to have higher levels of acute-phase reactants (2), a tendency to develop excessive febrile episodes (3), and more rheumatic diseases than the healthy population (4). These findings have been mainly explained by the robust inflammatory milieu due to the enhanced innate immune response in the presence of even 1 MEFV mutation (4). In those who develop rheumatic conditions, one may wonder where the borderline of inflammation is set in their system and which additional factors are involved. Since the identification of the MEFV gene, the mutations have been studied extensively in affected people. Surprisingly, it has become evident that the mutation in the second allele cannot be demonstrated in 20–26% of the patients who have FMF (5–7). The phenotype of these patients is confirmed by the presence of typical attacks of FMF symptoms and by the response to colchicine therapy. So, how can a person carrying only 1 MEFV mutation present with this autosomal-recessive disease? Two articles published elsewhere in this issue of Arthritis & Rheumatism address some of the questions in this context (6,8). The easiest explanation would be the presence of less common mutations that are missed by routine techniques; hence, a lack of sensitivity of screening techniques. However, studies in a substantial number of cases fail to show a second mutation, even when the gene and promoter region are fully sequenced. Thus, sequencing seems unlikely to yield a second mutation, and indeed, the authors of one of the relevant papers in this issue (8) suggest that our routine screening for the common mutations is adequate in the clinical setting. This is an important comment, since screening requires a considerably higher amount of time and money. Subsequent to standard sequencing, Booty et al (8) performed sophisticated sequencing in DNA samples from 10 patients, and they failed to define any intragenic genomic deletions. Marek-Yagel et al (6) sequenced complementary DNA to rule out further mutations or abnormal methylation, and their findings excluded these possibilities. Another approach to the investigation of a possible mutation on the second allele is to perform haplotype analysis. Both studies failed to show a common haplotype within the families of the patients with 1-mutation disease (6,8). Marek-Yagel et al (6) performed haplotype analysis in 2 families in which more than 1 sibling was diagnosed as having FMF (with a single mutation): the affected siblings inherited different alleles of the MEFV gene from the parent who did not have the MEFV mutation. If this parent had had an “unidentified mutation” in the MEFV gene, one would have expected the children to inherit the same allele. Other autoinflammatory diseases have to be carefully excluded in these patients. These would include the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumor necrosis factor receptor– associated periodic syndrome (TRAPS), and the cryopyrin-associated periodic syndromes (CAPS) (1,7). Some of these patients may lack the typical features at presentation, and thus, specific mutation analysis may need to be considered. In contrast, there are examples of digenic inheritance of autoinflammatory diseases. Digenic inheritance refers to the interaction of 2 genes resulting in the expression of a phenotype. FMF patients with only 1 MEFV mutation may produce a disease Seza Özen, MD: Hacettepe University, Ankara, Turkey. Address correspondence and reprint requests to Seza Özen, MD, Department of Pediatrics, Hacettepe University, Ankara 06100, Turkey. E-mail: sezaozen@hacettepe.edu.tr. Submitted for publication June 16, 2008; accepted in revised form March 9, 2009.