RESUMEN
PURPOSE: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. METHODS: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. RESULTS: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. CONCLUSION: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.
Asunto(s)
Deficiencia GATA2/diagnóstico , Deficiencia GATA2/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Haploinsuficiencia , Penetrancia , Fenotipo , Adolescente , Adulto , Alelos , Línea Celular , Niño , Análisis Mutacional de ADN , Bases de Datos Genéticas , Femenino , Deficiencia GATA2/epidemiología , Genes Dominantes , Estudios de Asociación Genética/métodos , Genotipo , Mutación de Línea Germinal , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/etiología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/etiología , Evaluación de Resultado en la Atención de Salud , Linaje , Secuenciación del Exoma , Adulto JovenRESUMEN
Although current national guidelines suggest combination inhaled corticosteroid/long-acting inhaled beta2-agonist as the preferred treatment in moderate and severe persistent asthma for children, trials aimed at reducing emergency department (ED) visits and hospitalizations in minority inner-city children have not been conducted with the combination product of fluticasone/salmeterol via Diskus (Advair). This study assessed the effect of fluticasone/salmeterol combination via Diskus therapy on hospitalizations and ED visits in children with asthma. We conducted a prospective 1-year study with an intervention group compared with a usual care control group. This study took place at an inner-city university-affiliated children's medical center allergy clinic. Inner-city patients with asthma aged 4-17 years with a history of frequent ED visits and hospitalizations for the 2 previous years were enrolled beginning in July 2001. A control group of inner-city asthmatic patients was identified via hospital medical records. Patients were prescribed fluticasone/salmeterol combination via Diskus (n = 39) for 1 year and were compared with a usual care control group (n = 39). Although the investigators did not intervene in the control patients, review of their records revealed that all control patients had inhaled corticosteroids prescribed during the intervention period. Outcome measures included ED visits and hospitalizations for 1 year after enrollment versus the mean for acute care visits for 2 years before enrollment in the study. The intervention group had a 20% reduction in ED visits, which was significant compared with the control group (p = 0.017); both groups had significant reductions in hospitalizations. The risk of experiencing an asthma exacerbation (ED visit or hospitalization) was reduced by 33% in the intervention group compared with the control group (risk ratio, 0.67; 95% confidence interval, 0.49-0.90; p = 0.005). Our results suggest that fluticasone/salmeterol combination via Diskus is associated with a reduction in risk of acute exacerbations of asthma in inner-city children, including ED visits and hospitalizations.
