Update on pulmonary arteriovenous malformations / Atualização sobre malformações arteriovenosas pulmonares

ABSTRACT This review aimed to provide an overview of pulmonary arteriovenous malformations, including the major clinical and radiological presentations, investigation, and treatment algorithm of the condition. The primary etiology of pulmonary arteriovenous malformations is hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, with mutations in the ENG gene on chromosome 9 (HHT type 1) or in the ACVRL1/ALK1 complex (HHT type 2). Epistaxis should always be evaluated when repeated, when associated with anemia, and in some cases of hypoxemia. In the investigation, contrast echocardiography and chest CT are essential for evaluating this condition. Embolization is the best treatment choice, especially for correction in cases of hypoxemia or to avoid systemic infections. Finally, disease management was addressed in special conditions such as pregnancy. CT follow-up should be performed every 3-5 years, depending on the size of the afferent and efferent vessels, and antibiotic prophylactic care should always be oriented. Ultimately, knowledge of the disease by health professionals is a crucial point for the early diagnosis of these patients in clinical practice, which can potentially modify the natural course of the disease.

RESUMO Esta revisão teve como objetivo fornecer uma visão geral das malformações arteriovenosas pulmonares, incluindo as principais apresentações clínicas e radiológicas, investigação e algoritmo de tratamento da condição. A principal etiologia das malformações arteriovenosas pulmonares é a telangiectasia hemorrágica hereditária (THH), também conhecida como síndrome de Rendu-Osler-Weber, com mutações no gene ENG no cromossomo 9 (THH tipo 1) ou no complexo ACVRL1/ALK1 (THH tipo 2). A epistaxe sempre deve ser avaliada quando repetida, quando associada à anemia e em alguns casos de hipoxemia. Na investigação, a ecocardiografia e TC de tórax com contraste são essenciais para avaliar essa condição. A embolização é a melhor escolha terapêutica, especialmente para correção em casos de hipoxemia ou para evitar infecções sistêmicas. Por fim, o manejo da doença foi abordado em condições especiais, como a gravidez. O acompanhamento por TC deve ser feito a cada 3-5 anos, dependendo do tamanho dos vasos aferentes e eferentes, e a antibioticoprofilaxia deve sempre ser orientada. Em última análise, o conhecimento da doença pelos profissionais de saúde é um ponto crucial para o diagnóstico precoce desses pacientes na prática clínica, o que pode potencialmente modificar o curso natural da doença.

Cirugía de Young para el tratamiento quirúrgico de la epistaxis en telangiectasia hemorrágica hereditaria: reporte de un caso y revisión de la literatura / Young's procedure for surgical treatment of epistaxis in hereditary hemorrhagic telangiectasia: A case report and literature review

La telangiectasia hemorrágica hereditaria (THH) es una displasia vascular multisistémica, de herencia autosómica dominante, caracterizada por el desarrollo de telangiectasias mucocutáneas y malformaciones arteriovenosas viscerales. El diagnóstico se realiza mediante los criterios de Curasao publicados en el año 2000 y su manejo requiere de un equipo multidisciplinario donde el rol del otorrinolaringólogo(a) es fundamental, puesto que la epistaxis se presenta en un 90%-95% de los pacientes siendo una de las primeras manifestaciones clínicas de la enfermedad y pudiendo amenazar la vida del paciente. En la literatura se describen múltiples alternativas de tratamiento médico y quirúrgico para la epistaxis, sin existir un tratamiento definitivo para la enfermedad. A continuación, presentaremos el caso de una paciente de 56 años con THH y epistaxis recurrentes severas que, tras no responder al tratamiento médico conservador y múltiples procedimientos quirúrgicos, se realizó el cierre nasal mediante el procedimiento de Young, constituyendo el primer caso reportado en nuestro país.

Hereditary hemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia, of autosomal dominant inheritance, characterized by the development of mucocutaneous telangiectasias and visceral arteriovenous malformations. The diagnosis is made using the Curafao criteria published in 2000 and its management requires a multidisciplinary team where the role of the ENTs is fundamental, since epistaxis occurs in 90%-95% of patients, being one of the first clinical manifestations of the disease and may threaten the life of the patient. Multiple medical and surgical treatment alternatives for epistaxis are described in the literature without a definitive treatment for the disease. Here, we present the case of a 56-year-old patient with severe recurrent HHT and epistaxis who, after not responding to the initial conservative and surgical treatments, a nasal closure was performed, using the Young's procedure, constituting the first case reported in our country.

Enfermedad de Rendu-Osler-Weber con presentación inusual / Rendu-Osler-Weber´s disease with unusual presentation

La enfermedad de Rendu-Osler-Weber, también conocido como telangiectasia hemorrágica hereditaria, es una enfermedad genética de herencia autosómica dominante con penetrancia incompleta. Afecta por igual a ambos sexos y los síntomas se inician habitualmente entre los 20 y 40 años, pero se considera que la enfermedad está infradiagnosticada. Típicamente las formas clínicas y el debut de esta enfermedad se asocian a los órganos y tejidos que se afectan con mayor frecuencia: telangiectasias en mucosas y en piel, epistaxis, sangramiento gastrointestinal, pulmonar e intracerebral. En contraste, el caso clínico que se presenta se caracteriza porque las primeras manifestaciones clínicas que motivaron la consulta médica fueron crisis de dolores e inflamación ósea en el miembro superior derecho, lo cual es inusual y se inscribe como un elemento de novedad en la enfermedad. Es el objetivo de esta publicación exponer un caso de telangiectasia hemorrágica hereditaria con una forma de presentación atípica en una adolescente. Al alta hospitalaria, la paciente estaba estable, sin complicaciones. Se recomendó seguimiento hospitalario fundamentalmente por la especialidad de Neumología, por ser los pulmones los órganos más afectados(AU)

Rendu-Osler-Weber´s disease, also known as hereditary hemorrhagic telangiectasia, is a genetic disease of autosomal dominant inheritance with incomplete penetrance. It affects both sexes equally and symptoms usually begin between the ages of 20 and 40, but it is considered that the disease is underdiagnosed. Typically, the clinical forms and the onset of this disease are associated with the organs and tissues that are most frequently affected: mucosal and skin telangiectasias, epistaxis, gastrointestinal, pulmonary and intracerebral bleeding. In contrast, the clinical case that is presented is characterized because the first clinical manifestations that motivated the medical consultation were crises of pain and bone inflammation in the right upper limb, which is unusual and is inscribed as an element of novelty in the disease. The objective of this publication is to present a case of hereditary hemorrhagic telangiectasia with an atypical presentation in a female teenager(AU)

Hereditary hemorrhagic telangiectasia complicated by aortic sinus aneurysm caused by a pathogenic mutation in the ACVRL1 gene: a family survey / 中华皮肤科杂志

Objective:To investigate clinical and genetic characteristics of a family with hereditary hemorrhagic telangiectasia complicated by aortic sinus aneurysm, and to analyze causative genes.Methods:Clinical data and peripheral blood samples were collected from the proband and her relatives, and genomic DNA was extracted. Causative genes were screened by whole-exome sequencing, and then verified by Sanger sequencing.Results:A heterozygous mutation c.137G>A was identified at position 137 in exon 3 of the ACVRL1 gene in the proband, her daughter, grandson and granddaughter, which led to the substitution of cysteine by tyrosine at amino acid position 46 (p.C46Y) . The mutation was not found in any of the other 5 family members without clinical symptoms.Conclusion:A causative mutation c.137G>A (p.C46Y) in the ACVRL1 gene was identified in the family with hereditary hemorrhagic telangiectasia type 2 complicated by aortic sinus aneurysm, which had not been previously reported in Asian populations.

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.

Sangramento gastrointestinal em paciente portador de síndrome de Rendu-Osler-Weber: relato de caso / Gastrointestinal bleeding in a patient with Osler-Weber-Rendu syndrome: a case report / Sangrado gastrointestinal en paciente con síndrome de Rendu-Osler-Weber: reporte de caso

A síndrome de Rendu-Osler-Weber, ou telangiectasia hemorrágica hereditária (THH), é uma doença autossômica dominante de penetrância variável que altera a camada muscular e elástica da parede dos vasos sanguíneos, causando neles grande fragilidade e dilatação e tornando-os suscetíveis a sangramentos secundários, a traumatismos e malformações arteriovenosas (MAV) ­ sendo elas as mais comuns no cérebro, nos pulmões e no trato gastrointestinal e hepático. Este relato de caso tem como objetivo realizar uma revisão sobre essa síndrome, bem como a respeito da melhor terapia e do melhor manejo para sangramentos gastrointestinais por angiectasias. Trata-se de uma paciente de 62 anos de idade, com episódio de hematêmese e melena recorrentes, que foi admitida instável hemodinamicamente e com queda importante dos níveis de hemoglobina, necessitando de múltiplas transfusões sanguíneas. Após entrevista clínica, que chamou a atenção para o histórico familiar de quadros similares, epistaxes recorrentes associados ao exame físico e angiectasias gástricas à endoscopia digestiva alta, foi atribuído o diagnóstico de síndrome de Rendu-Osler-Weber. Angiectasias foram erradicadas com terapia endoscópica usando plasma de argônio. A THH é uma doença subdiagnosticada que merece atenção especial por conta do seu risco de causar hemorragias graves com expressão fenotípica mais aflorada com o avançar da idade. Por seu cunho hereditário, faz-se necessário um acompanhamento médico linear com a família para evitar complicações secundárias da doença, bem como para o manejo adequado de suas apresentações.

Osler-Weber-Rendu syndrome or hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease that changes the muscular and elastic layer of the blood vessel wall, making them fragile and more susceptible to bleeding secondary to trauma and arteriovenous malformations (AVM) ­ a condition that commonly affects the brain, lungs, gastrointestinal tract, and liver. This study aims to perform a literature review on this syndrome, as well as on the best treatment and management for gastrointestinal bleeding from angioctasia. To this end, it reports the case of a 62-year-old female patient with recurrent episodes of hematemesis and melena, who was admitted to hospital with hemodynamic instability and low hemoglobin levels, requiring multiple blood transfusions. After clinical interview, which indicated family history of recurrent epistaxis, physical examination, and upper digestive endoscopy showing gastric angiectasias, the patient was diagnosed with Osler-Weber-Rendu syndrome. Angiectasias were treated with endoscopic argon plasma. Considering the risk of severe hemorrhages and its more pronounced phenotypic expression with advancing age, HHT is an underdiagnosed disease that deserves special attention. Due to its hereditary nature, a linear medical follow-up with the family is necessary to avoid secondary complications of the disease, as well as the proper management of its presentations.

El síndrome de Rendu-Osler-Weber o telangiectasia hemorrágica hereditaria (THH) es una enfermedad autosómica dominante de penetrancia variable, que modifica la capa muscular y elástica de la pared de los vasos sanguíneos, provocando una gran fragilidad y dilatación de estas, haciéndolas susceptibles a hemorragias secundarias a trauma y malformaciones arteriovenosas (MAV), que son las más comunes en el cerebro, pulmones, tracto gastrointestinal e hígado. Este estudio tiene como objetivo realizar una revisión de este síndrome, así como la mejor terapia y manejo del sangrado gastrointestinal por angioctasia en esta patología. Se trata de un paciente de 62 años, con episodio de hematemesis recurrente y melena, que ingresa hemodinámicamente inestable y con descenso significativo de los niveles de hemoglobina, requiriendo múltiples transfusiones sanguíneas. Tras entrevista clínica, destacando los antecedentes familiares de patologías similares, epistaxis recurrente, exploración física y angiectasias gástricas a endoscopia digestiva alta, se asignó el diagnóstico de síndrome de Rendu-Osler-Weber. Las angiectasias se erradicaron con terapia endoscópica con plasma de argón. La HHT es una enfermedad infradiagnosticada que merece una atención especial por su riesgo de hemorragias severas, con una expresión fenotípica más pronunciada con el avance de la edad. Además de su carácter hereditario, es necesario un seguimiento médico lineal con la familia para evitar complicaciones secundarias de la enfermedad, así como el adecuado manejo de sus presentaciones.

Epistaxis: aspectos nuevos a considerar / Epistaxis: new aspects to consider

La epistaxis es una de las urgencias otorrinolaringológicas más frecuentes, y se estima que un 6% requerirá algún tipo de intervención. Según la localización del sitio de sangrado puede clasificarse en anterior, posterior o superior. A lo largo de la historia su manejo ha seguido ciertos ejes que se mantienen vigentes, como son la compresión nasal, posicionamiento de la cabeza, taponamiento nasal, entre otros. Tras la implementación de la evaluación endoscópica sistemática del sitio de sangrado, estudios han descrito un nuevo punto de sangrado denominado S-point, que debiese ser especialmente considerado en epistaxis severa. Además, durante los últimos años la evidencia ha revelado ciertos aspectos especiales y relevantes en torno a la evaluación y/o manejo de pacientes con epistaxis y condiciones asociadas, como el uso de terapia antitrombótica, telangiectasia hemorrágica hereditaria o con hipertensión arterial. El objetivo de esta revisión es resumir aspectos novedosos en la evaluación, estudio y manejo de la epistaxis, donde se incluirán el uso de ácido tranexámico y de nuevos dispositivos intranasales.

Epistaxis is one of the most frequent otorhinolaryngological emergencies, and it is estimated that 6% require some type of intervention. Depending on the location of the bleeding site, it may be classified as anterior, posterior or superior. Throughout history, its treatment has remained the same, including nasal compression, head positioning, nasal packing, among others. After the implementation of the systematic endoscopic assessment of the bleeding site, studies have described a new point of bleeding called S-point, which should be especially considered in severe epistaxis. In addition, during the last years the evidence has revealed certain special and relevant aspects regarding the evaluation and/or management of patients with epistaxis and associated conditions, such as the use of antithrombotic therapy, hereditary hemorrhagic telangiectasia or arterial hypertension. The objective of this review is to summarize novel aspects in the evaluation, study and management of epistaxis, which include the use of tranexamic acid and new intranasal devices.

Chronic postoperative orofacial pain. Case reports / Dor orofacial pós-operatória crônica. Relato de casos

ABSTRACT BACKGROUND AND OBJECTIVES: The presence of neoplasms, chronic and oral diseases may require surgical treatment for its resolution, although it may consequently cause chronic pain. Chronic postoperative orofacial pain remains even after tissue healing and its causes are not defined. Although neuropathic etiology is the most reported, it represents 30% of cases; the other 70% are still unclear and the main risk factors involved in the development of this chronic pain condition remains on discussion. The aim of the study was to report three clinical cases of different postoperative orofacial pain etiologies. CASE REPORTS: Case 1: Female patient, 39-year-old, history of osteoblastoma exeresis in the mandibular body, presenting continuous postoperative shock pain, with intra and extraoral allodynia in the area. Diagnosis: post-traumatic trigeminal neuropathic pain. Case 2: Female patient, 30-year-old, diagnosed with refractory epilepsy and neurocysticercosis, complained of orofacial pain and bitemporal headache worse after craniotomy that treated the reported diseases. Diagnosis: post-craniotomy headache and orofacial pain. Case 3: Female patient, 49-year-old, with hereditary hemorrhagic telangiectasia, complained of pulsing in the alveolar ridge after extraction of three teeth, performed at different times. Diagnosis: Perception of orofacial pain secondary to systemic vascular disease. CONCLUSION: Different surgical procedures, intra and extraoral, led to the development of orofacial postoperative pain in the reported cases, whose etiology is not only neuropathic. Prospective multidisciplinary studies are necessary in order to clarify the causes of orofacial postoperative pain.

RESUMO JUSTIFICATIVA E OBJETIVOS: A presença de neoplasias, doenças crônicas e doenças bucais pode exigir tratamento cirúrgico para sua resolução, embora possa ocasionar dor crônica. A dor orofacial pós-operatória crônica permanece mesmo após a cicatrização tecidual e suas causas não estão claramente descritas. A etiologia neuropática, embora seja a mais relatada, representa 30% dos casos; os outros 70% não estão elucidados e ainda são discutidos quais os principais fatores de risco envolvidos no desenvolvimento desta condição de dor crônica. O objetivo deste estudo foi relatar três casos clínicos de indivíduos com diferentes etiologias de dor orofacial pós-operatória crônica. RELATO DOS CASOS: Caso 1: Paciente do sexo feminino, 39 anos, com histórico de exérese de osteoblastoma em corpo mandibular, apresentou dor pós-operatória em choque, contínua, com alodínia intra e extraoral na área abordada. Diagnóstico: dor neuropática trigeminal pós-traumática. Caso 2: Paciente do sexo feminino, 30 anos, com diagnóstico de epilepsia refratária e neurocisticercose, queixou-se de dor orofacial e cefaleia bitemporal com piora após craniotomia para tratamento das doenças relatadas. Diagnóstico: cefaleia e dor orofacial pós-craniotomia. Caso 3: Paciente do sexo feminino, 49 anos, com telangiectasia hemorrágica hereditária, queixou-se de pulsar em rebordo alveolar após exodontia de três dentes, realizada em momentos distintos. Diagnóstico: percepção de dor orofacial secundária à doença vascular sistêmica. CONCLUSÃO: Diferentes procedimentos cirúrgicos, intra e extraorais, levaram ao desenvolvimento da dor orofacial pós-operatória crônica nos casos relatados, de etiologia não apenas neuropática. Estudos prospectivos multidisciplinares serão necessários para esclarecer as causas desse quadro doloroso.

Síndrome de Osler-Weber-Rendu: presentación de un caso clínico y revisión de la literatura / Osler-Weber-Rendu syndrome: a case report and literature review

El síndrome de Osler-Weber-Rendu, también conocido como telangiectasia hemorrágica hereditaria, es una enfermedad de herencia autosómica dominante de baja prevalencia, que se caracteriza por unas paredes delgadas de los vasos sanguíneos que conducen a malformaciones arteriovenosas, principalmente en cerebro, pulmón e hígado, pero que pueden potencialmente afectar cualquier otro órgano. La principal manifestación clínica son las epistaxis recurrentes; sin embargo, también pueden aparecer otras manifestaciones como hemoptisis o sangrado gastrointestinal, y telangiectasias mucocutáneas, entre otras. Su expresión clínica varía de un paciente a otro y el diagnóstico usualmente se basa en los criterios de Curazao. Se describe el caso de una paciente con historia de 12 años de epistaxis recurrente, a quien se le diagnosticó síndrome de Osler-Weber-Rendu hace dos años. Fue referida al servicio de Hepatología por presentar compromiso hepático, además de malformaciones arteriovenosas cerebrales y pulmonares. El manejo óptimo de la telangiectasia hemorrágica en esta paciente por parte de los diferentes especialistas, apoyado en los estudios de imagenología, ha permitido que la paciente tenga una buena calidad de vida hasta el momento. Se presenta el caso de esta paciente de 46 años y se realiza una revisión corta de la literatura.

Osler-Weber-Rendu syndrome, also known as hereditary hemorrhagic telangiectasia, is an autosomal dominant low-prevalence disease, characterized by thin blood vessel walls, leading to arteriovenous malformations, mainly in the brain, lung and liver, but can potentially affect any other organ. The main clinical manifestation is recurrent epistaxis; however, other manifestations may also appear, such as hemoptysis or gastrointestinal bleeding, and mucocutaneous telangiectasias, among others. Its clinical expression varies from patient to patient and the diagnosis is usually based on Curacao criteria. We present the case of a patient with a 12-year history of recurrent epistaxis, who was diagnosed with Osler-Weber-Rendu syndrome two years ago. She was referred to the Hepatology service due to liver findings, in addition to brain and pulmonary arteriovenous malformations. The optimal management of hemorrhagic telangiectasia in this patient by the different specialists, supported by imaging studies, has allowed the patient to have a good quality of life. The case of this 46-year-old patient is presented, and a brief literature review is also provided.

Bevacizumab as a treatment option in gastrointestinal bleeding associated to hereditary hemorrhagic telangiectasia. Case Report / Bevacizumab como opción terapéutica en sangrado gastrointestinal asociado a telangiectasia hemorrágica hereditaria. Reporte de caso

Abstract Introduction: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disease characterized by the presence of arteriovenous malformations in the nasal mucosa, the tips of fingers, and sometimes in the lungs, the gastrointestinal tract, the liver, the pancreas, the marrow and the brain. Its treatment is based on symptomatic control measures, but recently, the administration of anti-vascular endothelial growth factor (VEGF) molecules has been proposed as a treatment alternative, especially in patients with recurrent bleeding. Case presentation: The case of a 67-year-old man diagnosed with HHT and suffering from potentially life-threatening gastrointestinal GI bleeding is presented. The patient underwent several esophagogastric cauterization procedures but not positive outcomes were obtained, so he had to go to the Emergency Service of the hospital multiple times due to having low levels of hemoglobin (as low as 3.5g/dL). A bevacizumab based treatment was started by using a novel dosage regimen consisting of the administration of 6 5mg/kg bevacizumab dosages every 14 days. During the first week of treatment, hemoglobin levels increased to 14g/dL and the condition was stabilized. Conclusions: The findings reported here suggest that bevacizumab may be a therapeutic choice to be considered when treating patients with recurrent and refractory GI bleeding caused by HHT. However, a larger sample is required to determine if administering this medication is safe for these patients, as well as the appropriate dosage.

Resumen Introducción. La telangiectasia hemorrágica hereditaria (HHT) es una enfermedad genética autosómica dominante que se caracteriza por la presencia de malformaciones arteriovenosas en mucosa nasal, dedos y, algunas veces, pulmones, tracto gastrointestinal, hígado, páncreas, médula ósea y cerebro. El tratamiento se basa en el control sintomático, pero recientemente se ha propuesto la administración de moléculas anti-factor de crecimiento de endotelio vascular (VEGF), en especial en pacientes que presentan sangrado recurrente. Presentación del caso. Paciente masculino de 67 años con diagnóstico de telangiectasia hemorrágica hereditaria (HHT) y hemorragia gastrointestinal severa potencialmente mortal. El paciente recibió múltiples cauterizaciones esofagogástricas sin obtener respuesta, por lo que ingresó en múltiples oportunidades al servicio de urgencias con niveles de hemoglobina incluso tan bajos como 3.5g/dL. Se inició tratamiento con bevacizumab con un novedoso esquema de 6 dosis de 5mg/k cada 14 días, lográndose aumentar los niveles de hemoglobina a 14g/dL durante la primera semana de tratamiento y estabilizando la enfermedad. Conclusiones. Los hallazgos sugieren que el bevacizumab puede ser una opción terapéutica en sangrado gastrointestinal recurrente y refractario secundario a HHT. Sin embargo, se requiere incluir una cohorte de pacientes más amplia para establecer la seguridad del medicamento y la dosificación apropiada para este tipo de pacientes.

Diagnóstico y tratamiento de pacientes con telangiectasia hemorrágica hereditaria (síndrome de Rendu-Osler-Weber) en un hospital universitario en Colombia / Diagnosis and treatment of patients with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome) at a university hospital in Colombia

Resumen Introducción: la telangiectasia hemorrágica hereditaria (THH) es una enfermedad vascular hereditaria caracterizada por epistaxis, sangrado digestivo y anemia crónica; en muchos casos hay malformaciones arteriovenosas de órganos sólidos. El diagnóstico se realiza con base en datos clínicos, hallazgos endoscópicos e imagenológicos. La detección temprana con enfoque multidisciplinario y tratamiento de las complicaciones impacta en morbimortalidad de la enfermedad. Objetivos: describir las características demográficas, clínicas y desenlaces de pacientes con diagnóstico de THH en un hospital universitario. Métodos: estudio tipo serie de casos en pacientes evaluados entre 2012 hasta el 2017. Resultados: se obtuvieron registros de 18 casos, 11 (61,1 %) hombres, con edad mediana de 56 años (rango intercuartílico [IQR]: 52-64). Los casos son provenientes de Colombia y algunos países caribeños. En todos los pacientes el diagnóstico se estableció mediante los criterios de Curazao. El número de ingresos hospitalarios tuvo una mediana de 6 días (IQR: 2,5-20,5). Los ingresos fueron en relación a sangrado en todos los casos, 61 % de los pacientes requirió transfusión de hemoderivados. En el 61 % de los pacientes se identificó compromiso en el órgano sólido mediante imágenes. Conclusiones: la THH es una enfermedad de expresión clínica variable. En nuestro estudio las manifestaciones gastrointestinales fueron las causas de ingreso más frecuentes. Se requirió con frecuencia transfusión de hemoderivados. Los pacientes requirieron múltiples estudios para identificar la extensión de la enfermedad y el compromiso de órgano sólido. El tratamiento se basó en el manejo endoscópico y médico, especialmente a base de bevacizumab y octreotida.

Abstract Introduction: Hereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu syndrome) is a hereditary vascular disease characterized by recurrent epistaxis, gastrointestinal bleeding and chronic anemia. Many cases have arteriovenous malformations of solid organs. Diagnosis is based on clinical data, endoscopy and imaging. Early detection and treatment of complications with a multidisciplinary approach impacts the disease's morbidity and mortality. Objectives: The objective of this study was to describe the demographic, clinical and outcome characteristics of patients diagnosed with HHT at a university hospital. Methods: This is a case series of patients evaluated between 2012 and 2017. Results: Records of 18 cases were obtained. The patients were from Colombia and other Caribbean countries. All diagnoses were established using the Curaçao criteria. Eleven patients 11 (61.1%) were men, and the median patient age was 56 years (IQR 52-64). The median number of hospital admissions was 6 (33.3%) (IQR 2.5-20.5), and all admissions were related to bleeding. Sixty-one percent of patients required transfusion of blood products, and the compromises of solid organs were found in the same number of patients by imaging studies. Conclusions: The clinical expression of THH varies, but in our study gastrointestinal manifestations were the most frequent causes of hospital admission. They frequently required transfusion of blood products and patients required multiple studies to identify the extent of the disease, and solid organ compromise. Treatment was based on endoscopic and medical management, especially administration of bevacizumab and octreotide.

Spectrum of Novel Hereditary Hemorrhagic Telangiectasia Variants in an Austrian Patient Cohort

OBJECTIVES: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disorder characterized by pathogenic blood vessel development and maintenance. HHT type 1 (HHT1) and type 2 (HHT2) are caused by variants in endoglin (ENG) and activin receptor-like kinase-1 (ACVRL1), respectively. The aim of this study was to identify the spectrum of pathogenic variants in ENG and ACVRL1 in Austrian HHT families. METHODS: In this prospective study, eight Austrian HHT families were screened for variants in ENG and ACVRL1 by polymerase chain reaction amplification and sequencing of DNA isolated from peripheral blood. RESULTS: Heterozygous variants were identified in all families under study. HHT1 was caused by a novel c.816+1G>A splice donor variant, a novel c.1479C>A nonsense (p.Cys493X) variant and a published c.1306C>T nonsense (p.Gln436X) variant in ENG. Variants found in ACVRL1 were novel c.200G>C (p.Arg67Pro) and known c.772G>A (p.Gly258Ser) missense variants in highly conserved residues, a known heterozygous c.100dupT frameshift (p.Cys34Leufs*4) and the known c.1204G>A missense (p.Gly402Ser) and c.1435C>T nonsense (p.Arg479X) variants as causes of HHT2. CONCLUSION: Novel and published variants in ENG (37.5%) and ACVRL1 (62.5%) were exclusively identified as the cause of HHT in an Austrian patient cohort. Identification of novel causative genetics variants should facilitate the development of tailored therapeutical applications in the future treatment of autosomal dominant HHT.

Pulmonary arteriovenous malformations: diagnostic and treatment characteristics / Malformações arteriovenosas pulmonares: características diagnósticas e de tratamento

ABSTRACT Objective: To present a case series of pulmonary arteriovenous malformations (PAVMs), describing the main clinical findings, the number/location of pulmonary vascular abnormalities, the clinical complications, and the treatment administered. Methods: This was a retrospective observational study evaluating patients with PAVM divided into two groups: hereditary hemorrhagic telangiectasia (HHT); and idiopathic PAVM (iPAVM). Results: A total of 41 patients were selected for inclusion, but only 33 had PAVMs. After clinical evaluation, 27 and 6 were diagnosed with HHT and iPAVM, respectively. In the HHT group, the mean age was 49.6 years and 88.9% were female. In that group, 4 patients had an SpO2 of < 90% and the most common clinical finding was epistaxis. In the iPAVM group, the mean age was 48.1 years and 83.3% were female. In that group, 3 patients had an SpO2 of < 90%. Computed tomographic pulmonary angiography showed that most of the PAVMs were in the lower lobes: 56.4% in the HHT group and 85.7% in the iPAVM group. Embolization was performed in 23 patients (in both groups). At this writing, 10 patients are scheduled to undergo the procedure. One of the patients who underwent embolization was subsequently referred for pulmonary resection. Conclusions: In both of the PAVM groups, there was a predominance of women and of fistulas located in the lower lobes. Few of the patients had respiratory symptoms, and most had an SpO2 > 90%. The treatment chosen for all patients was percutaneous transcatheter embolization.

RESUMO Objetivo: Apresentar uma série de casos de malformações arteriovenosas pulmonares (MAVP) e descrever os principais achados clínicos, a quantidade e localização das MAVP, as complicações clínicas e os tratamentos realizados. Métodos: Estudo retrospectivo observacional que avaliou pacientes com MAVP divididos em dois grupos: telangiectasia hemorrágica hereditária (THH) e MAVP idiopática (MAVPi). Resultados: Foram avaliados 41 pacientes, sendo 33 pacientes portadores de MAVP. Após a avaliação clínica, 27 e 6 foram diagnosticados com THH e MAVPi, respectivamente. No grupo THH a média de idade foi de 49,6 anos e 88,9% eram do sexo feminino. Desses pacientes, 4 tinham SpO2 < 90% e o achado clínico mais frequente era epistaxe. No grupo MAVPi a média de idade foi de 48,1 anos, sendo que 83,3% eram do sexo feminino. Desses, 3 tinham SpO2 < 90%. Após a realização de angiotomografia de tórax observou-se que a maior parte das MAVP se situava nos lobos inferiores, totalizando 56,4% e 85,7% nos grupos THH e MAVPi, respectivamente. O tratamento por embolização foi realizado em 23 pacientes nos dois grupos, enquanto 10 aguardavam o procedimento até o momento da escrita deste estudo. Um paciente submetido à embolização foi encaminhado para ressecção pulmonar. Conclusões: Em ambos os grupos de pacientes com MAVP observou-se uma predominância de mulheres e de fístulas localizadas nos lobos inferiores. A maioria era assintomático respiratório com SpO2 > 90%. O tratamento de escolha para todos foi a embolização percutânea por cateter.

Current Status of Clinical Diagnosis and Genetic Analysis of Hereditary Hemorrhagic Telangiectasia in South Korea: Multicenter Case Series and a Systematic Review / 신경중재치료의학

PURPOSE: Hereditary hemorrhagic telangiectasia (HHT), a rare genetic vascular disorder, has been rarely reported in South Korea. We investigated the current prevalence and presenting patterns of genetically confirmed HHT in South Korea. MATERIALS AND METHODS: We defined HHT patients as those with proven mutations on known HHT-related genes (ENG, ACVRL1, SMAD4, and GDF2) or those fulfilling 3 or 4 of the Curaçao criteria. A computerized systematic search was performed in PubMed and KoreaMed using the following search term: (“hereditary hemorrhagic telangiectasia” AND “Korea”) OR (“Osler-Weber-Rendu” AND “Korea”). We also collected government health insurance data. HHT genetic testing results were collected from three tertiary hospitals in which the genetic tests were performed. We integrated patient data by analyzing each case to obtain the prevalence and presenting pattern of HHT in South Korea. RESULTS: We extracted 90 cases from 52 relevant articles from PubMed and KoreaMed. An additional 22 cases were identified from the three Korean tertiary hospitals after excluding seven cases that overlapped with those in the published articles. Finally, 112 HHT patients were identified (41 males and 71 females, aged 4–82 years [mean±standard deviation, 45.3±20.6 years]). The prevalence of HHT in South Korea is about 1 in 500,000, with an almost equal prevalence among men and women. Forty-nine patients underwent genetic testing, of whom 28 had HHT1 (ENG mutation) and 19 had HHT2 (ACVRL1 mutation); the other two patients were negative for ENG, ACVRL1, and SMAD4 mutations. CONCLUSION: The prevalence of HHT is underestimated in Korea. The rate of phenotypic presentation seems to be similar to that found worldwide. Korean health insurance coverage is limited to representative genetic analysis to detect ENG and ACVRL1 mutations. Further genetic analyses to detect HHT3, HHT4, and other forms of HHT should be implemented.

Telangiectasia hemorrágica hereditaria: a propósito de un caso clínico / Hereditary hemorrhagic telangiectasia: on the subject of a clinical case

La epistaxis, es un síntoma frecuente en la consulta de otorrinolaringología. Dentro de las causas posibles encontramos la telangiectasia hemorrágica hereditaria (síndrome de Rendu Osler Weber), que corresponde a un desorden autosómico dominante caracterizado por sangrados nasales y gastrointestinales asociados a malformaciones arteriovenosas sistémicas. Su manifestación más frecuente es la epistaxis, presentándose más frecuentemente en personas mayores de 40 años, sin predilección por género. Se presenta el caso de un paciente de sexo masculino de 46 años quien consulta por epistaxis a repetición y severa. Durante la hospitalización se efectúa el tratamiento convencional de la epistaxis, diagnóstico retroactivo del síndrome de Rendu Osler Weber y manejo multidisciplinario de la patología. Se realiza revisión de la literatura y discusión del manejo del paciente que cursa con esta enfermedad.

Epistaxis is a common symptom in the otorhinolaryngology consultation. Among the possible causes are hereditary hemorrhagic telangiectasia (Rendu Osler Weber syndrome), which corresponds to an autosomal dominant disorder characterized by nasal and gastrointestinal bleeding associated with systemic arteriovenous malformations. Its most frequent manifestation is epistaxis, presenting more frequently in people over 40 years of age, without gender preference. We present the case of a male patient of 46 years old who consults for recurrence and severe epistaxis. During hospitalization, conventional treatment of epistaxis, retroactive diagnosis of Rendu Osler Weber syndrome and multidisciplinary management of pathology are performed. We review the literature and discuss the management of patients with this disease.

Síndrome de rendu osler weber en una adolescente en colombia. reporte de un caso de autopsia / Rendu osler weber syndrome in an adolescent in colombia. an autopsy case report

RESUMEN La telangiectasia hemorrágica hereditaria es una enfermedad genética rara, perteneciente al grupo de púrpuras angiopáticas de tipo congénito, caracterizada por lesiones vasculares, encontrando frecuentemente telangiectasias en piel y mucosa del tracto gastrointestinal, fístulas arteriovenosas pulmonares y malformaciones vasculares en sistema nervioso central. Su manifestación clínica más frecuente son las hemorragias del tracto respiratorio superior. Este es el caso de una adolescente de 13 años con hallazgos de hepatopatía crónica, esplenomegalia difusa, pancitopenia, fístulas arteriovenosas pulmonares, deterioro neurológico progresivo secundario a hemorragia subaracnoidea con posterior defunción. Se realizó autopsia médicocientífica que reveló múltiples telangiectasias en mucosas, cirrosis de Osler, malformaciones arteriovenosas en polígono encefálico, hemorragia intraventricular con extensión subaracnoidea y bronconeumonía bibasal con pleuritis secundaria.

ABSTRACT Hereditary hemorrhagic telangiectasia is a rare genetic disease, belonging to the group of congenital angiopathic purpuras. Vascular injuries characterize it, being the most frequent telangiectasia on the skin and the gastrointestinal tract mucosa, pulmonary arteriovenous fistulas and vascular malformations in the central nervous system. The most frequent clinical manifestations are hemorrhages from the upper respiratory tract. It is presented the case of a 13-year-old girl with findings of chronic liver disease, diffuse splenomegaly, pancytopenia, pulmonary arteriovenous fistulas, progressive neurological deterioration secondary to subarachnoid hemorrhage with subsequent death. A medical-scientific autopsy was carried out that revealed multiple telangiectasias in mucous membranes, Osler's cirrhosis, arteriovenous malformations in the brain polygon, intraventricular hemorrhage with subarachnoid extension, and bibasal bronchopneumonia with secondary pleuritis.

Gene identification in a family of hereditary hemorrhagic telangiectasia / 中华血液学杂志

Objective@#To study the mutation of ENG, ACVRL1, and SMAD4 genes in one of a family of hereditary hemorrhagic telangiectasia (HHT) and explore its molecular pathogenesis. @*Methods@#A family spectrum of a patient with a clinical diagnosis of HHT was surveyed. Peripheral blood samples from proband and their eldest were collected, and ENG, ACVRL1 and SMAD4 gene analysis was performed by chip capture high-throughput sequencing. The mutation detected was verified by Sanger. @*Results@#9 of the 71 family members were diagnosed with HHT with the main manifestation of recurrent nasal bleeding. Genetic analysis showed that the proband and the eldest son of ENG gene exon 9 frameshift mutation: c.1502-1503insGG (p.Gly501GlyfsX18) , and mutations in ACVRL1 and SMAD4 genes were not detected. @*Conclusion@#The frameshift mutation c.1502-1503insGG (p.Gly501GlyfsX18) of the ENG gene is the genetic basis for the pathogenesis of this HHT family.

Gene identification in a family of hereditary hemorrhagic telangiectasia / 中华血液学杂志

Objective: To study the mutation of ENG, ACVRL1, and SMAD4 genes in one of a family of hereditary hemorrhagic telangiectasia (HHT) and explore its molecular pathogenesis. Methods: A family spectrum of a patient with a clinical diagnosis of HHT was surveyed. Peripheral blood samples from proband and their eldest were collected, and ENG, ACVRL1 and SMAD4 gene analysis was performed by chip capture high-throughput sequencing. The mutation detected was verified by Sanger. Results: 9 of the 71 family members were diagnosed with HHT with the main manifestation of recurrent nasal bleeding. Genetic analysis showed that the proband and the eldest son of ENG gene exon 9 frameshift mutation: c.1502-1503insGG (p.Gly501GlyfsX18) , and mutations in ACVRL1 and SMAD4 genes were not detected. Conclusion: The frameshift mutation c.1502-1503insGG (p.Gly501GlyfsX18) of the ENG gene is the genetic basis for the pathogenesis of this HHT family.

Diagnóstico y tratamiento endovascular de las malformaciones arteriovenosas pulmonares y hepáticas en pacientes adultos con telangiectasia hemorrágica hereditaria / Diagnosis and Endovascular Treatment of Pulmonary and Hepatic Arteriovenous Malformations in Adult Patients with Hereditary Hemorrhagic Telangiectasia

La telangiectasia hemorrágica hereditaria (THH) o síndrome de Rendu-Osler-Weber (SROW) es una displasia vascular autosómica dominante con penetrancia variable, caracterizada por malformaciones arteriovenosas y telangiectasias mucocutáneas. Actualmente, el diagnóstico y pronóstico está orientado a la identificación temprana de factores de riesgo, signos y síntomas, así como en el reconocimiento e identificación de las malformaciones vasculares en los diferentes órganos que se ven afectados por la enfermedad. La aplicación de técnicas percutáneas, por parte de un equipo de radiología intervencionista, hace parte del abordaje en el tratamiento de los pacientes a quienes se les han confirmado malformaciones arteriovenosas en pulmón e hígado, como en los casos que se expondrán en esta revisión. Con estas técnicas de tratamiento se ha logrado curar o paliar las complicaciones que se pudieran generar por las diferentes malformaciones.

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber syndrome (ROWS) is an autosomal dominant vascular dysplasia with variable penetrance, characterized by arteriovenous malformations and mucocutaneous telangiectasias. The current diagnosis and prognosis is oriented to the early identification of risk factors, signs and symptoms, as well as in the recognition and characterization of vascular malformations in the different organs that are involved by the disease. The application of percutaneous techniques by an interventional radiology team is part of the approach in the treatment of patients with confirmation of arteriovenous malformations in lung and liver, such as in the cases that will be exposed in this revision. These treatment techniques have achieved the curative or palliative control of the different complications that could be generated by the different malformations.

Current understanding of the genetics of extracranial arteriovenous malformation / 中华整形外科杂志

Arteriovenous malformation (AVM) is defined as a congenital vascular anomaly that shunts blood from arteries to veins with no capillary perfusion. In some rare hereditary diseases, including capillary malformation-arteriovenous malformation (CM-AVM), hereditary hemorrhagic telangiectasia (HHT), PTEN hamartoma-tumor syndrome (PHTS), AVM is generally considered the characteristic clinic presentation. This review primarily focused on the mechanisms of genetic regulation during embryonic vasculature development, genetic mutations in TGF-beta signaling pathway of HHT, PTEN mutations in PHTS and genetic screening of CM-AVM. In addition, current findings in somatic mutations of extracranial AVM were discussed as well. This review aimed to provide insight into the etiology to help the diagnosis and treatment of extracranial AVM in clinic.