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

• Published in: Medicine (Baltimore) Vol. 91; no. 4; pp. e1 - e19
• Main Authors: Chandesris, Marie-Olivia, Melki, Isabelle, Natividad, Angels, Puel, Anne, Fieschi, Claire, Yun, Ling, Thumerelle, Caroline, Oksenhendler, Eric, Boutboul, David, Thomas, Caroline, Hoarau, Cyrille, Lebranchu, Yvon, Stephan, Jean-Louis, Cazorla, Celine, Aladjidi, Nathalie, Micheau, Marguerite, Tron, François, Baruchel, André, Barlogis, Vincent, Palenzuela, Gilles, Mathey, Catherine, Dominique, Stéphane, Body, Gérard, Munzer, Martine, Fouyssac, Fanny, Jaussaud, Rolland, Bader-Meunier, Brigitte, Mahlaoui, Nizar, Blanche, Stéphane, Debré, Marianne, Le Bourgeois, Muriel, Gandemer, Virginie, Lambert, Nathalie, Grandin, Virginie, Ndaga, Stéphanie, Jacques, Corinne, Harre, Chantal, Forveille, Monique, Alyanakian, Marie-Alexandra, Durandy, Anne, Bodemer, Christine, Suarez, Felipe, Hermine, Olivier, Lortholary, Olivier, Casanova, Jean-Laurent, Fischer, Alain, Picard, Capucine
• Format: Journal Article
• Language: English
• Published: United States Lippincott, Williams & Wilkins 01.07.2012
• Subjects: Adolescent; Adult; Age Distribution; Child; Child, Preschool; Cross-Sectional Studies; Databases, Factual; DNA Mutational Analysis; Eczema - epidemiology; Eczema - etiology; Female; France - epidemiology; Genetic Predisposition to Disease - epidemiology; Genetics; Heterozygote; Humans; Immunocompromised Host - genetics; Immunology; Incidence; Infant; Infant, Newborn; Job Syndrome - complications; Job Syndrome - epidemiology; Job Syndrome - genetics; Job Syndrome - immunology; Life Sciences; Male; Middle Aged; Phosphorylation; Pneumonia, Bacterial - epidemiology; Pneumonia, Bacterial - etiology; Respiratory Tract Infections - epidemiology; Respiratory Tract Infections - etiology; Risk Assessment; Severity of Illness Index; Sex Distribution; Signal Transduction; Skin Diseases, Bacterial - epidemiology; Skin Diseases, Bacterial - etiology; Staphylococcal Infections - epidemiology; Staphylococcal Infections - etiology; STAT3 Transcription Factor - deficiency; STAT3 Transcription Factor - genetics; Survival Analysis; Young Adult; France
• ISSN: 0025-7974; 1536-5964
• DOI: 10.1097/MD.0b013e31825f95b9

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.