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Autoinflammation due to homozygous S208 MEFV mutation
  1. Ying Hong1,
  2. Ariane S I Standing1,
  3. Sira Nanthapisal1,
  4. Neil Sebire2,
  5. Stephen Jolles3,
  6. Ebun Omoyinmi1,
  7. Ruud HJ Verstegen4,
  8. Paul A Brogan1,
  9. Despina Eleftheriou1,5
  1. 1 Infection, Inflammation and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, London, UK
  2. 2 Histopathology Department, UCL Great Ormond Street Institute of Child Health, London, UK
  3. 3 Immunology Department, Immunodeficiency Centre for Wales, University Hospital of Wales, Wales, Cardiff
  4. 4 Department of Paediatric Rheumatology, Sheffield Children’s Hospital, Sheffield, UK
  5. 5 ARUK Centre for Adolescent Rheumatology, UCL, London, UK
  1. Correspondence to Dr Despina Eleftheriou, Infection, Inflammation and Rheumatology Section, UCL Great Ormond Street Institute of Child Health, London, UK; d.eleftheriou{at}ucl.ac.uk

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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.

Figure 1

Family tree, genetic sequencing results, proinflammatory cytokines and pyrin inflammasome activation in patients with homozygous p.S208T MEFV mutation. (A) The family tree shows the two affected male siblings and their unaffected sibling from the consanguineous marriage of first cousins; segregation of the p.S208T MEFV variant is also shown. (B) Sanger sequencing chromatogram of …

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