title: Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey.
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.
authors: From 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.
authors: Marie-Olivia
authors: MO
authors: Chandesris
authors: Isabelle
authors: I
authors: Melki
authors: Angels
authors: A
authors: Natividad
authors: Anne
authors: A
authors: Puel
authors: Claire
authors: C
authors: Fieschi
authors: Ling
authors: L
authors: Yun
authors: Caroline
authors: C
authors: Thumerelle
authors: Eric
authors: E
authors: Oksenhendler
authors: David
authors: D
authors: Boutboul
authors: Caroline
authors: C
authors: Thomas
authors: Cyrille
authors: C
authors: Hoarau
authors: Yvon
authors: Y
authors: Lebranchu
authors: Jean-Louis
authors: JL
authors: Stephan
authors: Celine
authors: C
authors: Cazorla
authors: Nathalie
authors: N
authors: Aladjidi
authors: Marguerite
authors: M
authors: Micheau
authors: François
authors: F
authors: Tron
authors: André
authors: A
authors: Baruchel
authors: Vincent
authors: V
authors: Barlogis
authors: Gilles
authors: G
authors: Palenzuela
authors: Catherine
authors: C
authors: Mathey
authors: Stéphane
authors: S
authors: Dominique
authors: Gérard
authors: G
authors: Body
authors: Martine
authors: M
authors: Munzer
authors: Fanny
authors: F
authors: Fouyssac
authors: Rolland
authors: R
authors: Jaussaud
authors: Brigitte
authors: B
authors: Bader-Meunier
authors: Nizar
authors: N
authors: Mahlaoui
authors: Stéphane
authors: S
authors: Blanche
authors: Marianne
authors: M
authors: Debré
authors: Muriel
authors: M
authors: Le Bourgeois
authors: Virginie
authors: V
authors: Gandemer
authors: Nathalie
authors: N
authors: Lambert
authors: Virginie
authors: V
authors: Grandin
authors: Stéphanie
authors: S
authors: Ndaga
authors: Corinne
authors: C
authors: Jacques
authors: Chantal
authors: C
authors: Harre
authors: Monique
authors: M
authors: Forveille
authors: Marie-Alexandra
authors: MA
authors: Alyanakian
authors: Anne
authors: A
authors: Durandy
authors: Christine
authors: C
authors: Bodemer
authors: Felipe
authors: F
authors: Suarez
authors: Olivier
authors: O
authors: Hermine
authors: Olivier
authors: O
authors: Lortholary
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: Alain
authors: A
authors: Fischer
authors: Capucine
authors: C
authors: Picard
mesh_terms: D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D016208:Databases, Factual; D004485:Eczema / Q000453:epidemiology / Q000209:etiology; D005260:Female; D005602:France / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006579:Heterozygote; D006801:Humans; D016867:Immunocompromised Host / Q000235:genetics*; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D007589:Job Syndrome / Q000150:complications / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D018410:Pneumonia, Bacterial / Q000453:epidemiology / Q000209:etiology; D012141:Respiratory Tract Infections / Q000453:epidemiology / Q000209:etiology; D018570:Risk Assessment; D050796:STAT3 Transcription Factor / Q000172:deficiency* / Q000235:genetics*; D012720:Severity of Illness Index; D017678:Sex Distribution; D015398:Signal Transduction; D017192:Skin Diseases, Bacterial / Q000453:epidemiology / Q000209:etiology; D013203:Staphylococcal Infections / Q000453:epidemiology / Q000209:etiology; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D050796:STAT3 Transcription Factor