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Inherited autosomal‐dominant mutations in the tumour necrosis factor receptor superfamily 1A (TNFRSF1A) gene encoding the tumour necrosis factor receptor p55 (TNF‐R1) are the cause of an auto‐inflammatory syndrome that is characterized by periodic fever attacks, aseptic peritonitis, arthritis, meningitis, conjunctivitis, pleuritis and skin rash (OMIM #142680). The most common TNFR‐associated periodic syndrome (TRAPS)‐like disease that is associated with a R92Q mutation, however, occurs sporadically, with later onset (median 23 years vs 7 years with other mutations) and a milder and often oligosymptomatic course.1,2 Intriguingly, carriers of the R92Q allele bear a slightly increased risk for some other diseases, such as myocardial infarction,3 increased carotid intima‐media thickness,3 thrombotic complications in Behcet's disease4 and early synovitis.1
Due to the low uncertain frequency of the R92Q allele in various ethnic populations (0.5–1%), the available data about multiple sclerosis (MS) patients5,6 do not exclude a possible risk of R92Q mutations being present. Recent case reports on small‐vessel vasculitis in patients with TNFRSF1A mutations (R92Q, T50M)7 and inflammatory manifestations of TNFRSF1A mutations in the central nervous system8 prompted us to investigate a possible mutual relationship between R92Q mutations, MS and Wegener's granulomatosis (WG) in the German population.
A total of 446 MS, 268 WG and 265 control cases (table 11)) were analysed for the presence of the R92Q allele by sequencing and NciI digestion of a PCR‐amplified segment (detailed information on request). Apart from the R92Q heterozygous mutation, we have not found other sequence variations in these patients that affect the extracellular domain of the TNF‐R1 receptor. Dinucleotide repeat length analysis performed in 15 R92Q+ patients from the MS and WG cohorts confirmed the sharing of an identical repeat length haplotype.9
The odds ratios that we obtained (0.64 for MS and 0.91 for WG) do not indicate a significant association of the R92Q allele with these diseases. Although the confidence intervals are relatively large, the data permit us to exclude a more than 2‐fold risk of the R92Q allele in cases of WG and a more than 1.3‐fold risk for MS cases. As both the frequency and the remaining potential risk of the R92Q allele are indeed low, the impact of R92Q mutations on the MS and WG burden in the German population is negligibly small.
Considering the belief that, as yet unknown, susceptibility loci contribute to TRAPS‐like manifestations in R92Q carriers, we wondered if those genes that confer susceptibility to WG and MS convert the low‐penetrance status of the R92Q allele into a high‐penetrance condition. The clinical histories and archival records of those WG and MS patients that carried R92Q, however, did not provide evidence for preceding inflammatory episodes that are typical of TRAPS. Most strikingly, three WG patients suffered from recurrent serositis, which is highly uncommon in WG. Hence, recurrent serositis might be considered to be a manifestation of the R92Q allele on top of an unfolding WG.
With the reasonable assumption that the R92Q allele shows a 1% penetrance rate among the 4% carriers and, in view of the low prevalence of WG (50 per million) in the German population,10 it is extremely unlikely that both clinical phenotypes developed in a single patient just by coincidence. In the case of MS, such a casual coexistence of both clinical phenotypes is more likely as the prevalence of MS is about 30‐fold higher than that of WG.
The authors thank E. Stegmann and W. Essbauer for excellent technical assistance and H. Wekerle for his continuous interest in the project.
MS - multiple sclerosis
TNFRSF1A - tumour necrosis factor receptor superfamily 1A
TRAPS - TNFR‐associated periodic syndrome
WG - Wegener's granulomatosis
Supported by the German Research Council (DEJ, SFB571) and the state of Schleswig‐Holstein (PL, Innovationsfonds).
Competing interests: None declared.