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Traballo Fin de Grao en Medicina. Curso 2021-2022 INTRODUCCIÓN: La capilaroscopia periungueal, técnica sencilla, barata y no invasiva, permite el estudio de la microcirculación in vivo, estando indicada principalmente en el estudio del Fenómeno de Raynaud y de la Esclerosis Sistémica. La Telangiectasia Hemorrágica Hereditaria (THH), debida a mutaciones en diferentes genes de la vía del TGF-β, se caracteriza por la presencia de múltiples malformaciones capilares en toda la biología que pueden condicionar epistaxis, sangrados digestivos, hemorragias pulmonares o cerebrales. A pesar de esta afectación microvascular característica, la capilaroscopia no se ha utilizado de rutina en esta entidad. OBJETIVOS: Realizar una revisión sistemática de la literatura, añadiendo nuestra propia serie, buscando los datos existentes sobre los hallazgos capilaroscópicos más frecuentes en pacientes con THH y su correlación con los subtipos genéticos o las distintas manifestaciones clínicas. RESULTADOS: Se seleccionaron 6 artículos, en los cuales se observó una prevalencia de alteraciones capilaroscópicas entre 7-100% de los pacientes. La más frecuente fue la presencia de megacapilares (7-100%), relacionados con en el subtipo genético THH1 en un estudio (81.33%, p

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.

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. 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.

La Telangiectasia Hemorrágica Hereditaria o Enfermedad de Rendu-Osler- Weber, es una entidad infradiagnosticada y el retraso diagnóstico es fre- cuente, lo que va a difi el screening y tratamiento preventivo de los pacientes y de sus familiares afectos. Presentamos el caso de una paciente que debutó con una complicación grave de la enfermedad, a pesar de lo cual el diagnóstico de la enfermedad no se realizó hasta pasados 10 años

Orientador: Carmen Sílvia Bertuzzo Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: A Telangiectasia Hemorrágica Hereditária (THH) é uma desordem autossômica dominante caracterizada por epistaxe recorrente, telangiectases mucocutânea, hemorragia gastrointestinal, e malformação arteriovenosa pulmonar (PAVM), cerebral e hepática. A prevalência da doença é de 1/5000 e a mortalidade relatada da doença entre pacientes jovens quando comparado com aqueles com mais de 60 anos é de 36%. Dois genes da superfamília de receptores para TGF-? têm sido relacionados com THH, o gene da endoglina e o gene da activina (activin receptor-like-kinase). Estes genes são altamente expressos em células endoteliais e outros tecidos altamente vascularizados como pulmão e placenta. Mutações no gene da endoglina causam a THH tipo 1 que é caracterizada pela alta incidência de malformação arteriovenosa pulmonar sintomática (PAVMs). Mutações no gene da activina levam a THH tipo 2 caracterizada por epistaxe recorrente e malformação arteriovenosa gastrointestinal. Foi objetivo deste trabalho realizar uma triagem de mutações na região codificadora dos genes ALK-1 e endoglina em doze pacientes portadores de THH atendidos no Hemocentro da Unicamp. A abordagem metodológica incluiu a amplificação dos exóns dos genes da activina e endoglina seguida pela técnica de PCR/CSGE, clonagem e sequenciamento. Dos doze pacientes estudados, sete apresentaram alguma alteração molecular, destes três pacientes apresentaram uma deleção de um nucleotídeo T na posição 913 no exon 7, um paciente apresentou uma inserção de um nucleotídeo G na posição 204-205 no exon 3 e três pacientes apresentavam uma mutação misense nos exons 7 e 8 na posição 976 e 1204 respectivamente. Nossos resultados mostraram que a THH tipo 1 e tipo 2 são raras no Brasil e todas as mutações citadas na tabela IV e Figura 10 são novas, somente a mutação ocorrida no exon 8 foi previamente descrita na literatura Abstract: Background: Hereditary hemorrhagic telangiectasia in humans, also known as HHT or Osler-Rendu-Weber syndrome, is an autosomal dominant vascular disorder characterizes by recurrent epistaxis, mucocutaneous telangiectases, gastrointestinal, pulmonary, cerebral and hepatic arteriovenous malformations (HAVM). The prevalence of the illness is of 1/5000 and the reported mortality of the illness among young patients when compared with those with more than 60 years is 36%. Two genes of the receptors superfamily for TGF-? have been related with THH, the gene of the endoglin (ENG) in the chromosome 9q33-34 and the gene of the activin (receptor-like-kinase 1 ALK-1), in the chromosome 12q11q14. These genes are highly express in endothelial cells and other tissue highly vascularized as lung and placenta. Mutations in the gene of the endoglin cause the HHT type 1 which is characterized by the high incidence of symptomatic pulmonary arteriovenous malformation (PAVM). Mutations in the activin gene cause HHT were described among patients in whom the linking with HHT in the chromosome 9q33 or mutation in the endoglin gene was excluded. It was the objective of this work to carry through a selection of mutations in the coding region of gene ALK-1 and endoglin in 12 patients carrying HHT whose are treated in the Blood Center at Unicamp. Methods: Twelve patients were analyzed. Diagnosis of HHT was carried out by means of clinical history of recurrent bleeding, heredity studies, and the presence of multiple telangiectases lesions. PCR products with consistent abnormal migration patterns were cloned into the SureCloneTM ligation kit vector system and sequenced using the DYEnamic TM ET dye terminator cycle sequencing Kit, and analyzed by the MegaBace 1000 DNA automated analyzer. A panel of 252 chromosomes from unrelated individuals without the disease was used to evaluate the frequency of each mutation in the general population. Results: In six patients three novel mutations were identified in the coding sequence of the ALK-1 gene in their families, which demonstrated clinical manifestations of HHT type 2. These mutations included an insertion a deletion of single base pairs in éxons 3 (c.204-205insG) and 7 (c.913del T), as well as missense mutations in éxons 7 (c.976A>G) and 8 (c.1204G>A) of the ALK-1 gene. The mutations identified in éxons 7 and 8 affect the kinase domain and the mutation identified in éxon 3 affect the extracellular domain. These data indicate that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity. Conclusion: We suggest the high rate of mutation detection and the small size of the ALK-1 gene make genomic sequencing a viable diagnostic test for HHT2. This was the only research about this subject made in Brazil so far Doutorado Genética Animal e Evolução Doutora em Genética e Biologia Molecular

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.

[ES]Introducción: el Síndrome Telangiectasia Hemorrágica Hereditaria (STHH) o Rendu-Osler-Weber es una enfermedad rara debida a la alteración en la vía de señalización molecular de las células endoteliales que cursa con malformaciones arteriovenosas viscerales, epistaxis recurrente y múltiples telangiectasias mucocutáneas. Las lesiones mucocutáneas suponen más que un problema estético aislado, llegando a perjudicar gravemente la calidad de vida de los pacientes, a pesar de lo cual, apenas existen estudios hasta el momento que valoren el impacto del tratamiento de estas lesiones. Objetivo: determinar el impacto del tratamiento con láser en la calidad de vida de los pacientes diagnosticados de STHH. Métodos: 45 pacientes diagnosticados de STHH fueron tratados con láser vascular Nd:YAG percutáneo (Cynosure Cynergy 585/1064 nm) en el Servicio de Dermatología del Hospital Universitario de Cruces. Se valoró el impacto del tratamiento mediante cuestionarios específicos sobre la calidad de vida previa y posterior al tratamiento con láser, el grado de remisión percibido por el paciente y el dolor percibido durante el tratamiento. Resultados: la mediana de afectación basal de la calidad de vida de los pacientes fue de 11,5 (rango intercuartílico [RIQ] 8, 14) sobre 15, lo que equivale a un score de “afectación severa”. El 78,80% de los pacientes percibió una remisión total de las lesiones tratadas y hasta el 97% de los pacientes refirió algún tipo de remisión tras una media de 2,08 ± 1,55 (rango 1-6) sesiones. La mediana de mejoría global en la calidad de vida gracias al tratamiento fue de 10 (RIQ 8, 10) sobre 10. Finalmente, la mediana de dolor en la mucosa fue de 5 (RIQ 2, 6) sobre 10 y de 4 (RIQ 1, 5) sobre 10 en la cara, mayor en mujeres para ambas localizaciones. Conclusiones: el tratamiento con láser vascular Nd:YAG mejora globalmente la calidad de vida de los pacientes afectos de STHH con telangiectasias mucocutáneas. [EN]Introduction: Hereditary Hemorrhagic Telangiectasia Syndrome (HHTS), also known as Rendu-Osler-Weber, is a rare disease due to the mutation of the molecular signaling pathway of the endothelial cells, which causes visceral arteriovenous malformations, recurring epistaxis and multiple mucocutaneous telangiectasias. Mucocutaneous telangiectasias cause more than banal cosmetic issues, also markedly damaging the quality of life of HHTS-diagnosed patients. Nevertheless, there are few studies, which assess the impact, that the treatment of these lesions may cause. Objective: determine the impact of laser treatment in the improvement of the quality of life of patients diagnosed with HHTS. Methods: 45 patients diagnosed with HHTS were treated with percutaneous Nd:YAG vascular laser (Cynosure Cynergy 585/1064 nm) in the Dermatology Department of the Cruces University Hospital. The impact of the laser treatment was assessed by specific questionnaires about the patients’ quality of life before and after laser treatment, the perceived clearance of the lesions and a numerical pain-scale during treatment. Results: the median of base worsening of the quality of life was 11,5 (interquartile range [IQR] 8, 14) out of 15, which translates into a “severe worsening of quality of life”. 78.8% of the patients reported total clearance of the treated lesions, whilst up to 97% of the patients reported some clearance, after an average of 2.08 ± 1.55 laser sessions (range 1-6). The median of overall improvement in the quality of life was 10 (IQR 8, 10) out of 10. Finally, the median of pain perceived for mucous lesions was 5 (IQR 2, 6) out of 10 and 4 (IQR 1, 5) out of 10 for facial lesions, both greater in women. Conclusions: Nd:YAG vascular laser improves the quality of life overall in HHTS-diagnosed patients with mucocutaneous telangiectasias.

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.

RESUMEN Objetivo Conocer la mortalidad directamente atribuida a la telangiectasia hemorrágica hereditaria (THH) en España, su tendencia temporal y la posible variabilidad geográfica. Método El total de los fallecidos por THH de base poblacional se obtuvo del Instituto Nacional de Estadística, seleccionando los códigos 448.0 (CIE 9-MC, 1981-1998) y I78.0 (CIE 10, 1999-2016) como causa básica de defunción. Se calcularon las tasas de mortalidad específicas y ajustadas por edad para cada sexo, las razones de mortalidad estandarizadas (RME) por provincia y comarca, y las RME suavizadas. Resultados Se identificaron 327 fallecimientos por THH (el 49,5% eran mujeres), siendo la mortalidad más alta a los 80-84 años en los hombres (0,220 por 100.000 habitantes) y a los 75-79 años en las mujeres (0,147 por 100.000 habitantes). No se detectaron cambios temporales entre 1981 y 2016. Las provincias de Navarra, Cantabria, Guipúzcoa, Pontevedra y Las Palmas presentaron un riesgo significativamente superior con respecto a lo esperado para el total nacional, así como las comarcas de Monte Sur (Ciudad Real) y Ripollès (Girona). Conclusiones Este trabajo ha permitido identificar algunas regiones con mayor riesgo de defunción por THH, si bien se desconoce si estas diferencias se asocian a la distribución de los tipos THH1 y THH2, por lo que son necesarios estudios posteriores para profundizar en las causas de la variabilidad geográfica. Estos hallazgos complementan la información proporcionada por otros estudios y registros, además de ser útiles para la planificación sanitaria. ABSTRACT Objective To identify the mortality directly attributed to hereditary haemorrhagic telangiectasia (HHT) in Spain, and to analyze its time trends and geographic variability. Method Population-based deaths due to HHT were selected from the Spanish National Statistics Institute: codes 448.0 (ICD-9, 1981-1998) and I78.0 (ICD-10, 1999-2016) as the basic cause of death. Specific and age-adjusted mortality rates were calculated by sex, as well as standardized mortality ratios (SMR) by province and district, and smoothed SMR. Results We identified 327 deaths attributed to HHT (49.5% women), with the highest mortality at 80-84 years in men (0.220 per 100,000 inhabitants) and at 75-79 years in women (0.147 per 100,000 inhabitants). Age-adjusted mortality rates did not show any significant time trend between 1981 and 2016 in Spain. The provinces of Navarra, Cantabria, Guipúzcoa, Pontevedra and Las Palmas had higher than expected mortality, as well as the regions of Monte Sur (Ciudad Real) and Ripollès (Girona). Conclusions This study has identified some regions with higher risk of death due to HHT in Spain. It is unknown whether these differences are associated with the distribution of types HHT1 and HHT2, and further studies will be necessary to know the determinants of this geographical variability. These findings are useful to complement the information provided by other studies and registries, and for health planning.

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.

Resumen: Objetivo: Conocer la mortalidad directamente atribuida a la telangiectasia hemorrágica hereditaria (THH) en España, su tendencia temporal y la posible variabilidad geográfica. Método: El total de los fallecidos por THH de base poblacional se obtuvo del Instituto Nacional de Estadística, seleccionando los códigos 448.0 (CIE 9-MC, 1981-1998) y I78.0 (CIE 10, 1999-2016) como causa básica de defunción. Se calcularon las tasas de mortalidad específicas y ajustadas por edad para cada sexo, las razones de mortalidad estandarizadas (RME) por provincia y comarca, y las RME suavizadas. Resultados: Se identificaron 327 fallecimientos por THH (el 49,5% eran mujeres), siendo la mortalidad más alta a los 80-84 años en los hombres (0,220 por 100.000 habitantes) y a los 75-79 años en las mujeres (0,147 por 100.000 habitantes). No se detectaron cambios temporales entre 1981 y 2016. Las provincias de Navarra, Cantabria, Guipúzcoa, Pontevedra y Las Palmas presentaron un riesgo significativamente superior con respecto a lo esperado para el total nacional, así como las comarcas de Monte Sur (Ciudad Real) y Ripollès (Girona). Conclusiones: Este trabajo ha permitido identificar algunas regiones con mayor riesgo de defunción por THH, si bien se desconoce si estas diferencias se asocian a la distribución de los tipos THH1 y THH2, por lo que son necesarios estudios posteriores para profundizar en las causas de la variabilidad geográfica. Estos hallazgos complementan la información proporcionada por otros estudios y registros, además de ser útiles para la planificación sanitaria. Abstract: Objective: To identify the mortality directly attributed to hereditary haemorrhagic telangiectasia (HHT) in Spain, and to analyze its time trends and geographic variability. Method: Population-based deaths due to HHT were selected from the Spanish National Statistics Institute: codes 448.0 (ICD-9, 1981-1998) and I78.0 (ICD-10, 1999-2016) as the basic cause of death. Specific and age-adjusted mortality rates were calculated by sex, as well as standardized mortality ratios (SMR) by province and district, and smoothed SMR. Results: We identified 327 deaths attributed to HHT (49.5% women), with the highest mortality at 80-84 years in men (0.220 per 100,000 inhabitants) and at 75-79 years in women (0.147 per 100,000 inhabitants). Age-adjusted mortality rates did not show any significant time trend between 1981 and 2016 in Spain. The provinces of Navarra, Cantabria, Guipúzcoa, Pontevedra and Las Palmas had higher than expected mortality, as well as the regions of Monte Sur (Ciudad Real) and Ripollès (Girona). Conclusions: This study has identified some regions with higher risk of death due to HHT in Spain. It is unknown whether these differences are associated with the distribution of types HHT1 and HHT2, and further studies will be necessary to know the determinants of this geographical variability. These findings are useful to complement the information provided by other studies and registries, and for health planning. Palabras clave: Telangiectasia hemorrágica hereditaria, Análisis espacio-temporal, Sistemas de información geográfica, Mortalidad, Salud poblacional, Registros, Keywords: Hereditary hemorrhagic telangiectasia, Spatio-temporal analysis, Geographic information systems, Mortality, Population health, Registries

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.

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.