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Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is a rare auto–inflammatory syndrome caused by missense mutations in the proline/serine/threonine phosphate-interacting protein 1 gene, PSTPIP1, which encodes CD2-binding protein (CD2BP)1. This protein has been shown to be a part of an inflammatory pathway.[1]

A 49-year-old man presented with painful ulcerations on his left knees and both lower legs, which had been present for several years. His medical history included recurrent attacks of arthritis on both knees and ankles since young adulthood. Despite several surgical procedures, the patient had a mild limp on his left leg from articular destruction, and he also reported that the surgical wound had not healed readily. There was no other relevant personal or family history.

On physical examination, multiple inflammatory papulonodules were seen on the patient's back and buttocks, and on both lower legs, especially on the bony prominences. The papulonodules had a tendency to progress to ulceration. The patient also had multiple acne scars and persistent papulopustular eruptions on his face (Fig. 1). Routine laboratory tests were within normal limits, aside from raised C-reactive protein (2.08 mg/dL; normal range < 1.0 mg/dL) and erythrocyte sedimentation rate (26 mm/h; < 20 mm/h).

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Figure 1. (a) Multiple acne scars on the face; (b) papulonodules and ulcers on trunk and buttock; (c) odematous and ulcerative plaque with irregular border on the left knee; and (d) linear ulcer with granulation and undermined border on the site of previous surgery on the left ankle.

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On histological examination of a skin biopsy taken from the ulcer, a dense neutrophilic inflammation was seen, compatible with pyoderma gangrenosum. No pathogen was isolated from repeated tissue culture.

We suspected the patient to have PAPA syndrome, and performed gene sequencing on the 15 exons of PSTPIP1, but failed to identify any mutation within this gene. However, using quantitative reverse transcription PCR, we found raised levels of interleukin (IL)-1β, tumour necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 mRNAs (Fig. 2).

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Figure 2. Quantitative reverse transcription PCR showed raised levels of cytokines (tumour necrosis factor (TNF)-α, interleukin (IL)-1β and transforming growth factor (TGF)-β1 mRNAs compared with normal control.

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We treated our patient with various agents including antibiotics and immunosuppressive agents, but these were ineffective. There was some response to prednisone, but the ulcer has not healed completely to date.

The underlying cause of PAPA syndrome is a mutation in the gene encoding CD2BP1. This protein binds to pyrin, which has an inhibitory effect on a pro-inflammatory pathway. Pyrin is expressed on granulocytes and monocytes, but not on T or B cells. The disease pathogenesis of PAPA syndrome may be explained by the altered interaction between pyrin and CD2BP1. The mutated CD2BP1 protein has an increased binding affinity to pyrin, and as a result, pyrin loses its inhibitory effect on the pro-inflammatory signalling pathway that cleaves pro-IL-1β into active IL-1β. Therefore, the mutations predispose to an IL-1β-dependent inflammatory reaction dominated by granulocytes and monocytes. As a result, patients develop recurrent episodes of neutrophilic infiltrative inflammatory disease.[1, 2]

PAPA syndrome has been referred to as an autosomal dominant hereditary disease.[3] The same mutation can result in great variety in expression and in incomplete penetrance. However, sporadic cases of PAPA syndrome are reported regularly.[4] The inflammation cascade is complex, and may be affected by variable factors. Currently, PAPA syndrome is regarded as a pro-inflammatory state with heightened response to triggers. There may be additional factors other than the known mutations in proteins that participate in signalling pathways.

In conclusion, we report a Korean patient with PAPA syndrome, without known mutations in the PSTPIP1 gene. The condition has been reported mainly in the European population, and rarely in East Asian patients[2]; our case is therefore unusual, and may support a further understanding of this disease and inflammatory pathway.

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