RESUMEN
X-linked inhibitor of apoptosis (XIAP) deficiency, caused by mutations in BIRC4, is an immunodeficiency associated with immune dysregulation and a highly variable clinical presentation. Current diagnostic screening tests such as flow cytometry for XIAP expression or lymphocyte apoptosis assays have significant limitations. Based on recent evidence that XIAP is essential for nucleotide-binding and oligomerization domains (NOD)1/2 signalling, we evaluated the use of a simple flow cytometric assay assessing tumour necrosis factor (TNF) production of monocytes in response to NOD2 stimulation by muramyl dipeptides (L18-MDP) for the functional diagnosis of XIAP deficiency. We investigated 12 patients with XIAP deficiency, six female carriers and relevant disease controls. Irrespective of the diverse clinical phenotype, the extent of residual protein expression or the nature of the mutation, the TNF response was severely reduced in all patients. On average, L18-MDP induced TNF production in 25% of monocytes from healthy donors or female carriers, while fewer than 6% of monocytes responded in affected patients. Notably, the assay clearly discriminated affected patients from disease controls with other immunodeficiencies accompanied by lymphoproliferation, hypogammaglobulinaemia or inflammatory bowel disease. Functional testing of the NOD2 signalling pathway is an easy, fast and reliable assay in the diagnostic evaluation of patients with suspected XIAP deficiency.
Asunto(s)
Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Proteína Inhibidora de la Apoptosis Ligada a X/deficiencia , Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Acetilmuramil-Alanil-Isoglutamina/farmacología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Lactante , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Proteína Adaptadora de Señalización NOD2/metabolismo , Fenotipo , Linfocitos T/metabolismo , Factores de Necrosis Tumoral/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Adulto JovenRESUMEN
X-linked lymphoproliferative syndromes (XLP) are rare primary immunodeficiencies. Mutations within the XIAP/BIRC4 gene characterize XLP type 2 and cause XIAP deficiency. We present the case of a 5-year-old boy with a novel mutation of the XIAP/BIRC4 gene and describe the immunological phenotype for the first time. We characterized the distinct immunological phenotype and evaluated the family history accordingly.
Asunto(s)
Análisis Mutacional de ADN , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Linfohistiocitosis Hemofagocítica/genética , Trastornos Linfoproliferativos/genética , Fenotipo , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Muerte Celular/genética , Muerte Celular/inmunología , Preescolar , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/inmunología , Expresión Génica/genética , Tamización de Portadores Genéticos , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Humanos , Células Asesinas Naturales/inmunología , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/inmunología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/inmunología , Masculino , Linaje , Perforina/genética , Pronóstico , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Approximate entropy (ApEn) of blood pressure (BP) can be easily measured based on software analysing 24-h ambulatory BP monitoring (ABPM), but the clinical value of this measure is unknown. In a prospective study we investigated whether ApEn of BP predicts, in addition to average and variability of BP, the risk of hypertensive crisis. In 57 patients with known hypertension we measured ApEn, average and variability of systolic and diastolic BP based on 24-h ABPM. Eight of these fifty-seven patients developed hypertensive crisis during follow-up (mean follow-up duration 726 days). In bivariate regression analysis, ApEn of systolic BP (P<0.01), average of systolic BP (P=0.02) and average of diastolic BP (P=0.03) were significant predictors of hypertensive crisis. The incidence rate ratio of hypertensive crisis was 14.0 (95% confidence interval (CI) 1.8, 631.5; P<0.01) for high ApEn of systolic BP as compared to low values. In multivariable regression analysis, ApEn of systolic (P=0.01) and average of diastolic BP (P<0.01) were independent predictors of hypertensive crisis. A combination of these two measures had a positive predictive value of 75%, and a negative predictive value of 91%, respectively. ApEn, combined with other measures of 24-h ABPM, is a potentially powerful predictor of hypertensive crisis. If confirmed in independent samples, these findings have major clinical implications since measures predicting the risk of hypertensive crisis define patients requiring intensive follow-up and intensified therapy.
Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial , Hipertensión Maligna/diagnóstico , Adulto , Anciano , Monitoreo Ambulatorio de la Presión Arterial/métodos , Monitoreo Ambulatorio de la Presión Arterial/estadística & datos numéricos , Diagnóstico por Computador , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Dinámicas no Lineales , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
BACKGROUND: There are few families with the diagnosis of ascending aortic aneurysm and acute type-A aortic dissection inherited as an autosomal-dominant disorder in the absence of a known genetic syndrome. METHODS: We investigated a family with 26 members in whom ascending aortic aneurysms and acute type-A aortic dissections occurred over three generations. Examinations were performed to identify family members at specific risk. RESULTS: Six members presented with acute type-A aortic dissections and three relatives had ascending aortic aneurysms. Clinical examinations showed no characteristics of a known genetic syndrome. Molecular genetic analysis revealed no mutations known to cause a form of autosomal-dominant inherited aortic disease. CONCLUSION: Adequate diagnostic measures are mandatory in families with ascending aortic aneurysms or type-A aortic dissections to identify or exclude family members at risk for aortic diseases. Even in the absence of identifiable mutations causing isolated aortic aneurysms or aortic dissections, we recommend standardised examinations of all first-degree relatives of affected families. An indication for prophylactic aortic root replacement should be considered for patients at risk.