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Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French
Marie-Olivia Chandesris1, Isabelle Melki, Angels Natividad
1From the Hematology Department (MOC, FS, OH), Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris; University Paris Descartes (MOC, IM, AN, AP, LY, SB, AD, CB, FS, OH, OL, JLC, AF, CP), Necker Medical School, Paris; Laboratory of Human Genetics of Infectious Diseases (IM, AN, AP, LY, JLC, CP), Necker Branch, INSERM U980, Paris; Clinical Immunology Department (CF, EO), Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris; EA 3963 (CF, DB), Saint-Louis Hospital, University Paris 7, Paris; Pediatric Pulmonary Department (C. Thumerelle), Jeanne de Flandres Hospital, Lille; Pediatric Hemato-Oncology Department (C. Thomas), Nantes Hospital, Nantes; Immunology Unit (C. Hoarau, YL), Tours Hospital, Tours; Pediatric Hemato-Oncology Department (JLS), Saint-Etienne Hospital, Saint-Etienne; Department of Infectious Diseases (CC), Saint-Etienne Hospital, Saint-Etienne; Pediatric Hemato-Oncology Department (NA, M. Micheau), Pellegrin Hospital, Bordeaux; Immunology Unit (FT), Rouen Hospital, Rouen; Pediatric Hemato-Oncology Department (AB),Robert Debré Hospital, Assistance Publique Hôpitaux de Paris, Paris; Pediatric Hemato-Oncology Department (VB), Timone Hospital, Marseille; PediatricDepartment (GP), Béziers Hospital, Béziers; Pediatric Department(CM), Aix-en-Provence Hospital, Aix-en-Provence; Pulmonary Department (SD), Rouen Hospital, Rouen; Pediatric Pulmonary Department (GB), Châlons-en-Champagne Hospital, Châlons-en-Champagne; Pediatric Hemato-Oncology Department (M. Munzer), Reims Hospital, Reims; Pediatric Hemato-Oncology Department (FF), Nancy Hospital, Nancy; Internal Medicine, Infectious Diseases, Immunology Clinic (RJ), Hôpital Robert Debré, Reims Hospital, Reims; Pediatric Immuno-Hematology Unit (BBM, NM, SB, MD, JLC, AF, CP), Necker Children's Hospital, Assistance Publique Hôpitaux de Paris, Paris; Centre de Référence des Déficits Immunitaires Héréditaires (CEREDIH) (MOC, NM, AD, FS, OH, OL, AF, CP), Necker-Enfants Malades Hospital, Paris; Pediatric Pulmonary Department (MLB), Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris; Pediatric Hemato-Oncology Department (V. Gandemer), Rennes Hospital, Rennes; Study Center for Primary Immunodeficiencies (NL, V. Grandin, SN, CJ, C. Harre, MF, AD, CP), Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris; Immunology Laboratory (MAA), Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris; INSERM U768 (AD, AF), Necker-Enfants Malades Hospital, Paris; Pediatric Dermatology Department (CB), Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris, Paris; Department of Infectious Diseases and Tropical Medicine (OL), Assistance Publique Hôpitaux de Paris, Necker-Enfants Malades Hospital and Pasteur Institut, Paris, France; and St. Giles Laboratory of Human Genetics of Infectious Diseases (JLC), Rockefeller Branch, The Rockefeller University, New York, New York, United States.
Abstract:
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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