Asunto(s)
Deficiencia GATA2 , Hipersensibilidad Inmediata , Inmunoglobulina E/inmunología , Femenino , Deficiencia GATA2/genética , Deficiencia GATA2/inmunología , Deficiencia GATA2/patología , Humanos , Hipersensibilidad Inmediata/genética , Hipersensibilidad Inmediata/inmunología , Hipersensibilidad Inmediata/patología , MasculinoAsunto(s)
Mutación con Ganancia de Función , Mutación con Pérdida de Función , Factor de Transcripción STAT3/genética , Sustitución de Aminoácidos , Animales , Células COS , Línea Celular , Chlorocebus aethiops , Humanos , Síndrome de Job/genética , Trastornos Linfoproliferativos/genética , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Factor de Transcripción STAT3/química , Factor de Transcripción STAT3/inmunología , Electricidad Estática , Dominios Homologos src/genéticaRESUMEN
PURPOSE: Autosomal Dominant Hyper IgE Recurrent Infection Syndrome (AD-HIES) is caused by mutations in STAT3 and characterized by eczema, recurrent bacterial infections, and skeletal and connective tissue abnormalities. To further understand the minimal trauma fractures of AD-HIES, we examined bone mineral density (BMD) and laboratory markers of bone turnover. METHODS: Patients with AD-HIES enrolled in a prospective natural history study were examined with dual x-ray absorptiometry (DEXA) scans and laboratory studies of bone metabolism. The number of fractures was recorded as well as clinical features of AD-HIES including scoliosis and retained primary teeth. Patients on medications with skeletal effects, including bisphosphonates, were examined separately. RESULTS: Twenty-three AD-HIES children (6-18 years) and 33 AD-HIES adults (21-50 years) not receiving bone-active drugs were studied. Fourteen of the 23 children (61%) had histories of minimal trauma fractures, as did 26 of the 33 adults (79%). Osteopenia or osteoporosis was found in 79% of children and adults. Only radial BMD correlated with the qualitative occurrence of fractures but it did not correlate with the numbers of fractures. Markers of bone metabolism did not correlate with minimal trauma fractures or BMD. Patients on bone-active medications had improved BMD, but still sustained fractures. CONCLUSIONS: Minimal trauma fractures and decreased BMD are common in AD-HIES. Low radial BMD is associated with fractures, but hip and spine BMD are not. Treatment with bisphosphonates increased BMD but its role in fracture prevention remains undefined.
Asunto(s)
Densidad Ósea , Fracturas Óseas/etiología , Síndrome de Job/complicaciones , Síndrome de Job/patología , Factor de Transcripción STAT3/deficiencia , Absorciometría de Fotón , Adolescente , Adulto , Conservadores de la Densidad Ósea/uso terapéutico , Niño , Femenino , Humanos , Síndrome de Job/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). We describe 2 subjects in whom somatic mosaicism was associated with intermediate phenotypes. OBJECTIVE: Somatic mosaics might shed light on the pathogenesis of dominant STAT3 mutations and the mechanisms behind the immunologic and nonimmunologic features of the disease. METHODS: Clinical evaluations were conducted. Mutant STAT3 was amplified from different tissues and sequenced, and the percentage of mosaicism in various cell types was calculated. Flow cytometry was performed to determine percentages of IL-17(+) cells, IL-22(+) cells, or both. Suction blisters were induced in 1 subject, and exudate fluid was analyzed for whether emigrating neutrophils were STAT3 mutant or wild-type; neutrophils from peripheral blood were simultaneously examined. RESULTS: The 2 subjects with STAT3 somatic mosaicism had intermediate phenotypes and were found to have preserved TH17 cell compartments and apparently normal CD8 cells. However, they still had infections, including mucocutaneous candidiasis. The percentage of STAT3 mutant neutrophils migrating into blisters at 16 hours was the same as in peripheral blood, suggesting normal chemotaxis. CONCLUSION: STAT3 mosaicism accounts for a milder phenotype and allows for further investigation into the pathogenesis of AD-HIES. Despite having a preserved TH17 cell compartment, both subjects with mosaicism had chronic mucocutaneous candidiasis, suggesting that candidiasis in subjects with AD-HIES is not driven solely by low TH17 cell numbers. The percentage of STAT3 mutant neutrophils emigrating into a suction blister at 16 hours was the same as the percentage in peripheral blood, suggesting that early chemotaxis of STAT3 neutrophils is normal in vivo.
Asunto(s)
Síndrome de Job/diagnóstico , Síndrome de Job/genética , Mosaicismo , Fenotipo , Adulto , Alelos , Secuencia de Bases , Exones , Humanos , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Factor de Transcripción STAT3/genética , Células Th17/metabolismoRESUMEN
Autosomal dominant hyper-IgE syndrome (AD-HIES) or Job's syndrome is a primary immunodeficiency with a wide array of clinical features caused by dominant negative mutations in STAT3. In recent years, not only the clinical phenotype of the disease has been expanded with recognition of features such as arterial aneurysms, but also our understanding of the pathogenesis of the disease has greatly improved.
