CPC10: Mediterranean masquerade: clinicopathogenetic analysis of an unusual presentation
L. Kiely,1 C. O’Connor,1,2 C. Heffron,3 D. Costello,2,3J. Ryan2 and M. Bennett1
1South Infirmary Victoria University Hospital; 2University College Cork; and 3Cork University Hospital, Cork, Ireland
A 29-year-old Turkish man, of Kurdish ethnicity, presented with a 5-year history of progressive lower limb weakness, muscle wasting and arthropathy, and a 10-year history of recurrent inflammatory ulceration with extensive scarring and widespread acneiform eruption. He had no history of recurrent fever and no family history of autoimmune disease. Examination revealed muscle wasting of the quadriceps, and knee and ankle arthropathy. There were extensive acneiform changes on the back. Superficial ulcers with an inflammatory edge suggestive of pyoderma gangrenosum were present on the chest. ‘Wrinkled paper’ scarring was present on the upper abdomen. Inflammatory markers were markedly raised. Autoimmune, vasculitic, myositis and infectious screens were negative. Electromyography was consistent with a primary muscle disease rather than denervation. Muscle biopsy showed nonspecific atrophy. Skin biopsy showed extensive scarring and a chronic inflammatory infiltrate of lymphocytes, plasma cells and histiocytes, concerning for an infectious organism. Leishmania polymerase chain reaction was negative. Repeat skin biopsy of a more recent lesion displayed pseudoepitheliomatous hyperplasia with inflammatory infiltrate, consistent with pyoderma gangrenosum. Next-generation sequencing of an autoinflammatory gene panel was performed. A single pathogenic variant was detected in MEFV (c.2080A>G), raising the possibility of a diagnosis of heterozygotic familial Mediterranean fever (FMF). Therapy with the interleukin (IL)-1 receptor antagonist anakinra has been initiated and we are awaiting the response. FMF is characterized by febrile episodes (24–72 h), synovitis, serositis and cutaneous eruptions. Amyloidosis is possible if untreated. FMF is caused by a mutation in MEFV, which encodes pyrin. Previously thought to be inherited in an autosomal recessive manner, up to 20% of patients with FMF are now known to have only one pathogenic MEFV mutation. Our patient’s p.(Met694Val) variant is located in the mutation hotspot in exon 10 and has been associated with more severe disease and higher risk of AA amyloidosis. PAPA syndrome denotes the clinical constellation of pyoderma gangrenosum, acne and pyogenic arthritis. It is a rare IL-1-mediated disease caused by mutations in PSTPIP1. FMF and PAPA are linked by overproduction of IL-1. Proline–serine–threonine phosphatase interacting protein 1 (PSTPIP1) directly interacts with pyrin and PSTPIP1 mutations significantly increase binding of PSTPIP1 to pyrin. Pyrin has anti-inflammatory effects on the inflammasome, and mutations in pyrin lead to uncontrolled activation of this pathway resulting in overwhelming production of IL-1β. The overlap in the pathway between FMF and PAPA syndrome may explain the atypical clinical manifestations in our patient and provides targeted therapeutic options.
