Telangiectasia hemorrágica hereditaria durante el embarazo: Reporte de caso / Hereditary hemorrhagic telangiectasia during pregnancy: Case report

Resumen ANTECEDENTES: La telangiectasia hemorrágica hereditaria, o síndrome de Rendu-Osler-Weber, es una enfermedad vascular, hereditaria y autosómica caracterizada por telangiectasias mucocutáneas y malformaciones arteriovenosas en el pulmón, el cerebro e hígado. La prevalencia estimada es de 1.5 a 2 personas afectadas por cada 10,000 habitantes. El 90% de los casos se debe a una mutación en el gen endoglina y en el de la cinasa 1 similar al receptor de activina (ACVRL1). En la mujer embarazada, la telangiectasia hemorrágica hereditaria es de alto riesgo, sobre todo durante el segundo y tercer trimestre. OBJETIVO: Reportar un caso de telangiectasia hemorrágica hereditaria y exponer las complicaciones que pueden registrarse durante el embarazo. CASO CLÍNICO: Paciente de 23 años, con antecedente heredofamiliar de madre con diagnóstico de telangiectasia hemorrágica hereditaria (síndrome de Osler-Weber-Rendu) que falleció a los 38 años. Antecedente personal patológico de telangiectasia hemorrágica hereditaria, con diagnóstico a los 12 años luego de múltiples episodios de epistaxis. Recibió tratamiento con transfusiones sanguíneas en múltiples ocasiones y 200 mg de sulfato ferroso cada 24 horas. CONCLUSIÓN: La telangiectasia hemorrágica hereditaria condiciona, en la mujer embarazada, la aparición de complicaciones que pueden poner en riesgo la vida de la madre y el feto. Las mujeres con antecedente conocido deben valorarse antes de la concepción con el propósito de conocer el estado de la enfermedad.

Abstract BACKGROUND: Hereditary hemorrhagic telangiectasia, or Rendu-Osler-Weber syndrome, is an autosomal inherited vascular disease characterized by mucocutaneous telangiectasias and arteriovenous malformations in the lung, brain and liver. The estimated prevalence is 1.5 to 2 affected persons per 10,000 population. Ninety percent of cases are due to a mutation in the endoglin gene and in the activin receptor-like kinase 1 gene (ACVRL1). In pregnant women, hereditary hemorrhagic telangiectasia is high risk, especially during the second and third trimester. OBJECTIVE: To report a case of hereditary hemorrhagic telangiectasia and to expose the complications that can occur during pregnancy. CLINICAL CASE: 23-year-old patient, with hereditary family history of mother diagnosed with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) who died at 38 years of age. Personal pathological history of hereditary hemorrhagic telangiectasia, diagnosed at the age of 12 years after multiple episodes of epistaxis. She was treated with multiple blood transfusions and 200 mg of ferrous sulfate every 24 hours. CONCLUSION: Hereditary hemorrhagic telangiectasia conditions, in pregnant women, the appearance of complications that can put the life of the mother and fetus at risk. Women with a known history should be evaluated before conception in order to know the status of the disease.

Descrição da frequência de variantes genéticas no gene da endoglina em uma população do Nordeste do Brasil / Description of the frequency of genetic variants in the endoglin gene in a population of Northeast Brazil

Introdução: a endoglina (ENG, CD105) é um co-receptor da família transforming growth factor-beta e participa da regulação de processos celulares como proliferação, diferenciação, migração e apoptose. ENG é mais conhecida por sua expressão em células endoteliais, desempenhando papel importante na angiogênese e vasculogênese, porém sua expressão já foi associada a diferentes desfechos patogênicos, inclusive devido a mutações no gene ENG. Objetivos: descrever a frequência de variantes genéticas no gene ENG, comparar com populações ancestrais e analisar as variantes genéticas que possam estar envolvidas em processos patogênicos em outras populações. Metodologia: foi utilizado o banco de dados do programa SCAALA (Social Change Asthma and Allergy in Latin America) para a população do estudo, sendo genotipado 1309 indivíduos usando o chip Illumina 2.5 Human Omni Bead e feitas análises in silico utilizando plataformas on-line. Resultados: as variantes genéticas rs10987746, rs10121110, rs11792480 e rs16930129 apresentaram frequência de menor alelo entre 16 a 48% na população estudada, as quais foram mais reiteradamente próximas do padrão africano que do europeu. Os SNVs foram relacionados aos mecanismos regulatórios genéticos conhecidos, pressupondo que essas variantes não estejam envolvidas diretamente em processos funcionais. Conclusão: são necessárias maiores investigações referentes aos mecanismos funcionais deste gene, visto que a endoglina participa de uma gama de processos celulares importantes e mais esforços devem ser feitos para estudos genéticos na população brasileira, considerando a mistura de populações.

Introduction: the endoglin (ENG, CD105) is a coreceptor of the family transforming growth factor-beta and participates in the regulation of cellular processes such as proliferation, differentiation, migration and apoptosis. ENG She is best known for your expression in endothelial cells, playing an important role in angiogenesis and vasculogenesis, but its expression has already been associated with different pathogenic outcomes, including due to mutations in the ENG gene. Objectives: describe the frequency of genetic variants in the ENG gene in the population of northeastern Brazil, compare with ancestral populations and analyze genetic variants that may be involved in pathogenic processes in other populations. Methodology: we used the SCAALA program database (Social Change Asthma and Allergy in Latin America) for the population of the study, and the DNA of 1309 individuals were genotyped using the Illumina chip 2.5 Human Omni Bead and made in silico analysis. Results: the SNVs rs10987746, rs10121110, rs11792480 and rs16930129 presented lower allele frequency between 16 to 48% in the population studied, which were more consistently next African European standard. The SNVs were related to known genetic regulatory mechanisms assuming that these variants are not directly involved in functional processes. Conclusion: further investigation regarding the functional mechanisms of this gene are necessary, since the endoglin participates in a range of important cellular processes and more efforts should be made for genetic studies in the Brazilian population, considering the mixture of populations.

Significancia del desbalance de los factores angiogénicos en preeclampsia

La participación de los factores antiangiogénicos, la forma soluble de la fms-semejante a la tirosina quinasa (Flt-1s) y la endoglina soluble (Engs), en el desarrollo de la preeclampsia (PE) se ha demostrado en múltiples estudios clínicos y experimentales. Estos estudios están complementados por estudios en animales, en los cuales la sobreexpresión de estos factores antiangiogénicos origina manifestaciones clínicas muy similares a la PE. El origen de esta enfermedad permanece desconocido. Sin embargo, factores genéticos, ambientales e inmunológicos parecen alterar el desarrollo normal de la placenta, lo cual conduce últimamente a la PE. Flt-1s y Engs inhiben la producción y las propiedades proangiogénicas del factor de crecimiento vascular endotelial (FCVE) y del factor de crecimiento placentario (FCP), necesarios para el desarrollo normal vascular de la placenta y las adaptaciones vasculares fisiológicas del embarazo. Cantidades exageradas de Flt-1s y Engs se producen en la placenta disfuncional y se liberan en la circulación materna. Altas concentraciones de Flt-1s y Engs se encuentran en la circulación materna semanas antes de que la enfermedad sea detectada clínicamente. Las capacidades de los factores angiogénicos para predecir PE en embarazos asintomáticos de riesgo bajo y alto son inconsistentes y no útiles para el uso clínico. Por otro lado, proporciones de los factores Flt-1s/FCP, FCP/Flt-1s, y FCP/Eng poseen valores predictivos más altos para diagnosticar PE y predecir sus complicaciones en mujeres con sintomatología de PE. En estas condiciones, el uso clínico de estos marcadores biológicos podría ser implementado en un futuro cercano. Las propiedades biológicas y farmacocinéticas de las estatinas las convierten en uno de los medicamentos con más potencial preventivo para la PE. Otros opciones terapéuticas que se están estudiando son medicamentos que directamente inhiban los factores antiangiogénicos circulantes. Estudios in vitro y estudios pilotos clínicos se están realizando actualmente examinando la seguridad materno-fetal, la transferencia placentaria y la efectividad de estas terapias.

The role of the antiangiogenic factors, the soluble form of the fms-like tyrosine kinase receptor 1 (sFlt1) and the soluble endoglin (sEng), in the development of preeclampsia (PE) has been demonstrated in multiple clinical and experimental studies. These studies are complemented by animal studies, in which overexpression of these antiangiogenic factors leads to clinical manifestations similar to PE. Although, the origin of this disease remains unknown, genetic, environmental, and immunological factors appear to affect the normal placental development, resulting ultimately in PE. sFlt-1 and sEng inhibit the proangiogenic properties of the vascular endothelial growth factor (VEGF) and the placental growth factor (PlGF), affecting the normal vascular development in the placenta and the physiological vascular adaptations that occur in pregnancy. Exaggerated amounts of sFlt-1 and sEng, produced in the dysfunctional placenta, are released into the maternal circulation and elevated circulating concentrations of these antiangiogenic factors are found several weeks prior to the clinical manifestations of the disease. Multiple studies have reported the capacity of circulating antiangiogenic factor concentrations to predict PE in asymptomatic low and high risk pregnancies. The reported predictive values of sFlt-1 and sEng are inconsistent across these studies and therefore their clinical use in this population is not recommended. On the other hand, maternal plasma concentrations of these factors appear to have a better performance in women with symptoms of PE. Among the possible combinations, the ratios of sFlt-1/PlGF, PlGF/sFlt-1, and PlGF/Engs seem to have the highest sensitivities and specificities to diagnose PE as well as the highest predictive values for PE-related adverse outcomes. These properties support their clinical use in this setting and it is likely those ancillary tests will be incorporated to the clinical practice in the near future. The participation of antiangiogenic factors in the pathogenesis of PE, also have stimulated investigation of new targeted therapies. The biological and pharmacokinetic properties of statins have converted them in one of the most promising preventive therapies for this disease. Others are investigating agents that directly inhibit the circulating antiangiogenic factors. In-vitro and pilot clinical studies are currently evaluating the effectiveness, maternal-fetal safety, and placental transference of these therapies.