A novel missense mutation in tumour necrosis factor receptor superfamily 1A (TNFRSF1A) gene found in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with high serum interleukin (IL)-22

ARTICLE

Auteur(s) : Motonobu Nakamura, Yoshiki Tokura

Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan

Tumour necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS) is a rare autosomal dominant disorder characterized by recurrent episodes of fever, myalgia, abdominal pain, conjunctivitis and skin eruptions [1]. The most common cutaneous manifestation is a centrifugal migratory, erythematous patch overlying the area with myalgia. Less frequently, urticaria-like plaques and generalized serpiginous patches and plaques occur. Mutations in the TNFRSF1A (TNFR superfamily 1A) gene are responsible for TRAPS [2]. To date, over 80 mutations in the gene have been reported, mostly in exons 2-4 and in exon 6. Several cytokines such as IL-1β, IL-6, IL-18 and TNF-α were elevated in the serum of TRAPS patients [3]. Here, we report a case of TRAPS showing a novel mutation in the TNFRSF1A gene and high serum IL-22.

A 29-year-old Japanese female was referred to us due to high fever, arthralgia, myalgia, headache and erythema. For the previous 2 months, she had suffered from periodic high fever up to 40 °C, accompanied by severe headaches, myalgia, arthralgia, splenomegaly and skin eruptions. Her grandmother also had episodes of periodic fever for a long time and died of diabetic mellitus many years before, her son had had fevers, one to three times a month, since he was two months old.

Clinical examination disclosed diffuse erythema on her extremities with underlying harsh myalgia (figures 1A, B). Laboratory examination revealed high serum C-reactive protein 5.30 mg dL-1 (normal, 0.0-0.2), normal white blood cells 6900 mL-1 (normal, 3500-9500) and serum ferritin 59 ng mL-1 (normal, 11-123). Histological examination of an erythematous lesion on the right lower leg disclosed a dense inflammatory infiltrate of lymphocytes intermingled with neutrophils in the deep dermis and subcutaneous fat (figures 1C, D). Enzyme-linked immunosorbent assay (ELISA) with Quantikine immunoassay (R&D Systems, Minneapolis, MN, USA) revealed that serum soluble TNFRSF1A was as low as 328 pg mL-1 (range, 519-1739).

To confirm a diagnosis of TRAPS, we searched for a mutation in the TNFRSF1A gene, after obtaining informed consent. The coding exons and flanking regions of the TNFRSF1A gene were amplified by polymerase chain reaction (PCR) using the specific primers described previously [2]. PCR products were purified and directly sequenced as described [4]. In exon 2 of the TNFRSF1A gene, we identified a c.73A>G (p.N25D) mutation. The mutation in our patient was a novel mutation that has not been reported in the literature or single nucleotide polymorphism database network in Japan (http://snpnet.jst.go.jp/top_e.html). We could not perform genetic evaluation of her family members. She was opposed to taking oral corticosteroids, however, her high fever disappeared without any intervention.

We measured the serum level of serum IL-22 of our case using an enzyme-linked immunosorbent assay kit (R&D Systems). Serum IL-22 was as high as 138 pg mL-1, while we could not detect serum IL-22 in two healthy controls. We could not perform an evaluation of serum IL-22 level of her son.

IL-22 is a T cell-derived cytokine inducing inflammation in the liver, pancreas, intestine and skin [5, 6]. Increased serum levels of IL-22 have been reported in patients affected by psoriasis and pityriasis rosea, and treatment with etanercept, the TNF-α inhibitor, reduced the serum level of IL-22 in psoriatic patients. IL-22 expression was also detected in rheumatoid arthritis synovial tissues. Therefore, in our TRAPS case, the long-lasting activation of TNF-α signals may induce a high IL-22 expression, which may lead to systemic inflammation in the joints, skin and fascias of muscles. Since IL-22 is expressed by Th17 cells and T22 cells [5, 6], our finding also implies that Th17 cells and/or T22 cells are involved in the pathogenesis of TRAPS.

Acknowledgements

References

2 McDermott EM, Aksentijevich I, Galon J, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor (TNFR1) define a family of dominantly inherited auto-inflammatory syndromes. Cell 1999; 97: 133-44.

3 Morbach H, Richl P, Stojanov S, et al. Tumor necrosis factor receptor1-associated periodic syndrome without fever: cytokine profile before and during etanercept treatment. Rheumatol Int 2010; (in press).

4 Nakamura M, Kobayashi M, Tokura Y. A novel missense mutation in tumour necrosis factor receptor superfamily 1A (TNFRSF1A) gene found in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) manifesting adult-onset Still disease-like skin eruptions: report of a case and review of the Japanese patients. Br J Dermatol 2009; 161: 968-70.

5 Eyerich S, Eyerich K, Pennino D, et al. Th22 cells represent a distincthuman T cell subset involved in epidermal immunity and remodeling. J Clin Invest 2009; 119: 3573-85.

6 Kagami S, Rizzo HL, Lee JJ, et al. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 2010; (in press).