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Heterozygous mutations in the MEFV gene disrupting the Serine-242 residue in the 14-3-3 binding motif of pyrin cause Pyrin-AssociatedAutoinflammation with Neutrophilic Dermatosis (PAAND).1–5 We now describe familial autoinflammation associated with homozygous Serine-208 mutations in MEFV, the second crucial phosphorylation site of the pyrin 14-3-3 binding domain.
Two Pakistani boys (IV-1 and IV-2; figure 1A) born of consanguineous parents presented aged 12 and 9 years old, respectively, with a systemic autoinflammatory disease characterised by a remitting relapsing course over time. Both had recurrent fevers with elevated acute phase responses: C-reactive protein >100 mg/L (reference range (RR)<20); serum-amyloid-A >200 mg/L (RR <10); leucocytosis 92×109/L (RR 4–11; eosinophils 82.4×109/L) and normalisation of these parameters in between fever attacks. Both had recurrent oral ulceration, intestinal inflammation, transient purpuric rashes (leucocytoclastic vasculitis on biopsy), lymphadenopathy (biopsy showed mixed lymphocytic, eosinophil infiltrate), hepatosplemonegaly, arthralgia and failure to thrive. Patient IV-2 developed pulmonary nodular changes and had a history of sterile cutaneous neck abscess at age 5. They had normal complement function studies, immunoglobulin levels and negative autoantibodies. Bone marrow aspirate for IV-2 showed marked eosinophilia (81%) with normal morphology and no malignancy; lymphocyte clonality studies were normal. Digital subtraction angiography and echocardiography were normal. Routine genetic screening for TNFRSF1A, MVK, NLRP3, MEFV exon 10 was wild type. Both patients partially responded to corticosteroids, but subsequently received treatment with cyclophosphamide, mycophenolate mofetil, methotrexate, azathioprine and antitumour necrosis factor alpha therapy. Inflammatory attacks persisted despite these therapies.
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