Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey

Marie-Olivia Chandesris, Isabelle Melki, Angels Natividad, Anne Puel, Claire Fieschi, Ling Yun, Caroline Thumerelle, Eric Oksenhendler, David Boutboul, Caroline Thomas, Cyrille Hoarau, Yvon Lebranchu, Jean-Louis Stephan, Celine Cazorla, Nathalie Aladjidi, Marguerite Micheau, François Tron, André Baruchel, Vincent Barlogis, Gilles Palenzuela, Catherine Mathey, Stéphane Dominique, Gérard Body, Martine Munzer, Fanny Fouyssac, Rolland Jaussaud, Brigitte Bader-Meunier, Nizar Mahlaoui, Stéphane Blanche, Marianne Debré, Muriel Le Bourgeois, Virginie Gandemer, Nathalie Lambert, Virginie Grandin, Stéphanie Ndaga, Corinne Jacques, Chantal Harre, Monique Forveille, Marie-Alexandra Alyanakian, Anne Durandy, Christine Bodemer, Felipe Suarez, Olivier Hermine, Olivier Lortholary, Jean-Laurent Casanova, Alain Fischer, Capucine Picard
Medicine (Baltimore) 2012, 91 (4): e1-e19
Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.

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