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1.
Medicine (Baltimore) ; 91(4): e1-e19, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22751495

RESUMO

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.


Assuntos
Hospedeiro Imunocomprometido/genética , Síndrome de Job/epidemiologia , Síndrome de Job/genética , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Estudos Transversais , Análise Mutacional de DNA , Bases de Dados Factuais , Eczema/epidemiologia , Eczema/etiologia , Feminino , França/epidemiologia , Predisposição Genética para Doença/epidemiologia , Heterozigoto , Humanos , Incidência , Lactente , Recém-Nascido , Síndrome de Job/complicações , Síndrome de Job/imunologia , Masculino , Pessoa de Meia-Idade , Fosforilação , Pneumonia Bacteriana/epidemiologia , Pneumonia Bacteriana/etiologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/etiologia , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Transdução de Sinais , Dermatopatias Bacterianas/epidemiologia , Dermatopatias Bacterianas/etiologia , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/etiologia , Análise de Sobrevida , Adulto Jovem
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