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15 p.-5 fig.-3 tab., Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular dysplasia characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM) in the visceral organs. The diagnosis of HHT is based on clinical Curaçao criteria, which show limited sensitivity in children and young patients. Here, we carried out a liquid biopsy by which we isolated total RNA from plasma exosome samples. A cohort of 15 HHT type 1 patients, 15 HHT type 2 patients, and 10 healthy relatives were analyzed. Upon gene expression data processing and normalization, a statistical analysis was performed to explore similarities in microRNA expression patterns among samples and detect differentially expressed microRNAs between HHT samples and the control group. We found a disease-associated molecular fingerprint of 35 miRNAs over-represented in HHT vs. controls, with eight being specific for HHT1 and 11 for HHT2; we also found 30 under-represented, including nine distinct for HHT1 and nine for HHT2. The analysis of the receiver operating characteristic (ROC) curves showed that eight miRNAs had good (AUC > 75%) or excellent (AUC > 90%) diagnosis value for HHT and even for type HHT1 and HHT2. In addition, we identified the cellular origin of these miRNAs among the cell types involved in the vascular malformations. Interestingly, we found that only some of them were incorporated into exosomes, which suggests a key functional role of these exosomal miRNAs in the pathophysiology of HHT., This work was funded by the Spanish Program for Young Investigators of the Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional (grant number SAF2015-74313JIN; MINECO/FEDER, UE) to FJB; and “Programa Operativo FEDER 2014–2020 and Consejería de Economía y Conocimiento de la Junta de Andalucía” (grant number B1-FQM-112-UGR18) to ABJR.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominant disease characterized by pathologic angiogenesis that provokes vascular overgrowth. The evidence about the influence of Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in patients with rare diseases is scarce. We aimed to know the prevalence of coronavirus disease 2019 (COVID-19) in HHT patients. The HHT pathogenic angiogenesis and endothelial injury in COVID-19 are discussed using data from RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry. RiHHTa is an open, multicenter, prospective, observational registry including adult patients with HHT. A 27-item survey that captured clinical data of admitted HHT patients for COVID-19 was distributed to all RiHHTa investigators from June 8th to June 24th 2020. Only one out of 1177 HHT patients was admitted for COVID-19 pneumonia. She is a 74 years-old woman with a pathogenic variant in ACVRL1 gene. Her clinical course did not involve mechanical ventilation or worsening epistaxis, and she was successfully discharged after two weeks. The endothelial damage and the consequent angiogenic process in COVID-19 patients deserve further investigation.

El infarto isquémico cerebral representa la mayoría de los accidentes vasculares cerebrales y se caracteriza por la disminución del flujo sanguíneo cerebral que resulta en muerte celular. El síndrome de Rendu-Osler-Weber o telangiectasia hemorrágica hereditaria, HHT por sus siglas en inglés, es una enfermedad genética de tipo autosómica dominante. Se presenta con malformaciones arteriovenosas por la expresión del gen afectado sobre las células endoteliales. Este reporte describe el caso clínico de una femenina de 44 años con antecedente de cefalea crónica episódica de características migrañosas desde la juventud. Consulta por cuadro de inicio súbito caracterizado por pérdida del equilibrio, cefalea holocraneal y hemiparesia del hemicuerpo izquierdo. Además, se documenta que la paciente realizó un viaje en avión de más de 11 horas de duración, lo cual favorece la enfermedad trombótica. Se realizan distintos estudios radiológicos y se demuestra la oclusión de la arteria cerebral media derecha, la arteria cerebral anterior derecha y de la arteria cerebral posterior izquierda. Además, una resonancia magnética nuclear cardiotorácica pone en evidencia la presencia de una fístula arteriovenosa pulmonar. Se aplica tratamiento fibrinolítico con Alteplase y se realiza una embolización percutánea de la fístula. El estudio genético confirma la presencia de HHT.

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. 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.

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disorder of vascular development. Common manifestations include epistaxis, telangiectasias and arteriovenous malformations (AVMs) in multiple organs. Most patients have deletions or missense mutations in the ENG or ACVRL1 gene respectively, significantly affecting endothelium homeostasis. We analyzed the ENG gene in five members of a Peruvian family affected by HHT. One novel mutation was found in exon four of the ENG gene c.408delA, at aminoacid residue 136. This mutation changes the subsequent reading frame producing an early stop at residue 162, preserving only one fourth of the normal protein of 658 aa. This mutation was found in the four affected members of family.

Background Gender differences in organ involvement and clinical severity have been poorly described in hereditary hemorrhagic telangiectasia (HHT). The aim of this study was to describe differences in the severity of HHT manifestations according to gender. Methods Severity was measured according to Epistaxis Severity Score (ESS), Simple Clinical Scoring Index for hepatic involvement, a general HHT-score, needing for invasive treatment (pulmonary or brain arteriovenous malformations -AVMs- embolization, liver transplantation or Young’s surgery) or the presence of adverse outcomes (severe anemia, emergency department -ED- or hospital admissions and mortality). Results One hundred forty-two (58.7%) women and 100 (41.3%) men were included with a mean age of 48.9 ± 16.6 and 49 ± 16.5 years, respectively. Women presented hepatic manifestations (7.1% vs 0%) and hepatic involvement (59.8% vs 47%), hepatic AVMs (28.2% vs 13%) and bile duct dilatation (4.9% vs 0%) at abdominal CT, and pulmonary AVMs at thoracic CT (35.2% vs 23%) more often than men. The Simple Clinical Scoring Index was higher in women (3.38 ± 1.2 vs 2.03 ± 1.2), and more men were considered at low risk of harboring clinically significant liver disease than women (61% vs 25.3%). These differences were mantained when considering HHT1 and HHT2 patients separetely. Duodenal telangiectasia were more frequent in men than women (21% vs 9.8%). Invasive treatments were more frequently needed in women (28.2% vs 16%) but men needed attention at the ED more often than women (48% vs 28.2%), with no differences in ESS, HHT-score, anemia hospital admissions or mortality. Conclusions HHT women showed more severe hepatic involvement than men, also among HHT1 and HHT2 patients. Women had higher prevalence of pulmonary AVMs and needed invasive procedures more frequently, while men needed attention at the ED more often. These data might help physicians to individualize HHT patients follow-up.

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.

Resumo: As malformações arteriovenosas pulmonares são raras e mais de metade dos casos surgem em associação a telangiectasia hemorrágica hereditária.Faz-se uma revisão teórica sobre a apresentação clínica, abordagem diagnóstica, terapêutica e prognóstico destas malformações vasculares. Estão associadas a morbilidade e mortalidade consideráveis, pelo que se preconiza o seu tratamento, assim como o rastreio dos familiares directos quando se identificam malformações arteriovenosas pulmonares num doente com telangiectasia hemorrágica hereditária. Ainda não existem estudos prospectivos que estabeleçam o melhor plano de estudo do doente e seus familiares.Descrevem-se dois casos clínicos de malformações arteriovenosas pulmonares no contexto familiar de telangiectasia hemorrágica hereditária. A identificação das doentes implicou o rastreio familiar que permitiu detectar malformações arteriovenosas pulmonares em dois familiares e excluir o envolvimento pulmonar em quatro familiares com a doença.Rev Port Pneumol 2006; XII (4): 383-399 Abstract: Pulmonary arteriovenous malformations are a rare disorder associated to hereditary hemorrhagic telangiectasia in over50 % of the cases.Clinical presentation, diagnostic work-up, therapeutic options and prognosis are reviewed by the authors. Pulmonary arteriovenous malformations are known to have considerable morbidity and mortality, their treatment being advisable as well as their screening among family members, especially if the index case is diagnosed with both pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. To this moment prospective studies establishing the best diagnostic work-up for the patients and their families are lacking.The authors report two pulmonary arteriovenous malformations cases in a family with hereditary hemorrhagic telangiectasia. Patientâs diagnosis led to family screening which resulted in the identification of pulmonary arteriovenous malformations in two family members and pulmonary disease exclusion in four patients previously known to have hereditary hemorrhagic telangiectasia.Rev Port Pneumol 2006; XII (4): 383-399 Palavras-chave: Malformações arteriovenosas pulmonares, telangiectasia hemorrágica hereditária, embolização, Key-words: Pulmonary arteriovenous malformations, hereditary hemorrhagic telangiectasia, embolization

Pulmonary arteriovenous fistula in hereditary hemorrhagic telangiectasia. Report of one case Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is an autosomal dominant vas- cular disease that can be associated with pulmonary arteriovenous fistulas. We report a 16 years old female with an Osler-Weber-Rendu syndrome and a history of frequent episodes of epistaxis since the age of 10 years. A Chest CAT scan performed on that occasion showed an arteriovenous fistula. The patient presented with progressive dyspnea, low arterial oxygen saturation and clubbing of fingers. An echocardiogram and lung perfusion scintigram confirmed the presence a right to left shunt. The patient was subjected to a lobectomy with a good postoperative evolution.

espanolCaso clinico: Mujer de 45 anos con episodios recurrentes de epifora hematica espontanea. La paciente presentaba epistaxis de repeticion no filiadas y, tenia antecedentes familiares de hemorragia digestiva, ademas una de sus hijas sufria de epistaxis. Discusion: El diagnostico de telangiectasia hemorragica hereditaria por oftalmologos es un hecho infrecuente. La presencia de lagrimas con sangre o epifora hematica espontanea, en un paciente con historia de hemorragias de repeticion en forma de epistaxis o hemorragia digestiva, nos tiene que hacer sospechar y buscar la presencia de esta enfermedad. La historia y exploracion clinica son fundamentales en el diagnostico de dicha enfermedad. EnglishCase report: Our patient was a 45-year-old woman who had recurrent episodes of hematic epiphora, repeated epistaxes for which no cause was found and a family history of gastric hemorrhage. One of her daughters also suffered from spontaneous hemorrhages. Discussion: Hereditary hemorrhagic telangiectasia is rarely diagnosed by an ophthalmologist; however the occurrence of bloody tears occurring spontaneously in a patient with epistaxis or gastric hemorrhage should lead to suspicion of hereditary hemorrhagic telangiectasia or Rendu-Osler-Weber disease. It should never be forgotten that clinical examination and appropriate investigations are basic components of disease diagnosis.

4 páginas, 3 tablas -- PAGS nros. 129-132, [EN]Objective: Recurrent epistaxis is the most frequent clinical manifestation of hereditary haemorrhagic telangiectasia (HHT). Its treatment occasionally presents difficulties as there is no consensus on the appropriate therapeutic protocol. Our objective was to explore the utility of oral tranexamic acid for the treatment of epistaxes in HHT patients. Patients and method: A 3-year prospective study was carried on HHT patients with epistaxis treated with oral tranexamic acid in the HHT unit at our hospital. Results: Ten patients with HHT were treated with oral tranexamic acid during the study. Most of them improved both the frequency and severity of their epistaxis and were satisfied with the treatment. No treatment-related complications were recorded. Two patients needed more aggressive treatments to control epistaxis. Conclusions: Oral tranexamic acid is useful for achieving significant reductions in epistaxis frequency and intensity in selected patients with HHT. In those presenting severe epistaxis, however, it may need to be combined with more aggressive therapies, [ES]Introducción: Las epistaxis son la manifestación clínica más frecuente en los enfermos con telangiectasia hemorrágica hereditaria (HHT). Su tratamiento es en ocasiones muy complejo, y no hay consenso sobre el protocolo terapéutico que se ha de aplicar. El objetivo de nuestro estudio fue valorar la utilidad del ácido tranexámico oral en las epistaxis secundarias a HHT. Pacientes y método: Se realizó un estudio prospectivo de pacientes con HHT tratados por epistaxis en la unidad de HHT de nuestro hospital mediante ácido tranexámico durante 3 años. Resultados: Se trató a 10 pacientes con HHT mediante ácido tranexámico oral durante el período de estudio. Todos ellos presentaron una disminución tanto en la intensidad como la frecuencia de las epistaxis. En su mayoría estaban satisfechos con los resultados del tratamiento. Ninguno presentó complicaciones relacionadas con él y 2 pacientes siguieron precisando otros tratamientos para control de las epistaxis. Conclusiones: El ácido tranexámico oral es útil en el tratamiento de las epistaxis en algunos pacientes con HHT,pues reduce de forma significativa tanto la intensidad como la frecuencia. Sin embargo, en los que presentan epistaxis severas no impide la necesidad de seguir realizando Ç otros tratamientos agresivos.

Relato de um caso de úlcera plantar por fístula arteriovenosa em paciente portador de telangiectasia hemorrágica hereditária ou doença de Rendu-Osler-Weber tratado com ácido tranexâmico. Este fármaco é utilizado para tratamento de epistaxe, referindo-se o principal achado deste artigo ao uso eficaz desse medicamento na terapia de úlceras plantares hemorrágicas. São descritos os aspectos fisiopatológicos e clínicos da doença e as propriedades antifibrinolíticas do ácido tranexâmico. Este foi bem tolerado e apresentou evidências de eficácia na utilização para controle do sangramento e cicatrização da úlcera. Case report of one patient with Hereditary Hemorrhagic Telangiectasia, also known as Rendu-Osler-Weber syndrome, treated with Tranexamic Acid for arteriovenous plantar ulcer. This drug has proved effective in controlling epistaxis, but the main point of this report is to expose the success use of this medication in the therapy of skin bleeding ulcer. The pathophysiologic and clinical features of the disease are reviewed and also the pharmacological aspects of the antifibrinolytic drugs. This drug was well tolerated by the patient and show evidence of good activity in the bleeding and healed the ulcer.