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Osler-Weber-Rendu disease (OWRD), also known as hereditary haemorrhagic telangiectasia (HHT), is an autosomal dominant genetic disorder characterised by arteriovenous malformations in several organs. Ischemic cholangitis is a rare life-threatening complication of OWRD, with only a few documented cases in the literature. A liver transplant is the main curative treatment. In this paper, we report a case of a 33-year-old woman with a history of recurrent epistaxis, admitted with abdominal pain and fever, physical examination found multiple cutaneous and mucosal telangiectasias and the biological workup showed cholestasis, abdominal imaging identified arterio-venous shunts and multiple cystic hepatic lesions, one of them seemed to communicate with an intrahepatic biliary duct, finally the diagnosis of ischemic cholangitis due to OWRD was retained and antibiotic treatment has been initiated. We review the various therapeutic options available to improve the management of this fatal complication.
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Abstract Introduction : Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia that might affect 1/5000-10 000 individuals worldwide. It is a rare and underdiagnosed condition. Population-based epidemiological studies are crucial for comprehending and quantifying the impact of this disease. We aim to estimate the prevalence in a Prepaid Health Care System of Buenos Aires, Argentina. Methods : A descriptive cross-sectional study was de signed, which included all patients over 18 years of age affiliated with the Hospital Italiano Medical Care Program (IHMCP), a prepaid health maintenance organization (HMO) of Buenos Aires. For case inclusion, individuals were required to have a clinical diagnosis of HHT. Case detection included the search in our Institutional Registry. The prevalence was calculated by dividing the number of cases of HHT by the total number of all active affiliates at January 2023. Age and gender specific prevalence rates were estimated. Results : 48 cases were reported. The prevalence was 3.2 in 10 000 (IC 95% 2.4-4.2). Specific prevalence in women was 3.9 in 10 000 (IC 95% 2.8-5.5) and in men 2.1 in 10 000 (IC 95% 1.2-3.6). The average age was 54.8 (19), 35 patients were women (72.9%) with an aver age age of 55 (19.9), and 55 (17.2) for men. The most common referrals were physicians (60.4%) followed by family history (18.7%). The 48 patients corresponded to 39 families. Discussion : The prevalence identified in our study is higher than the one documented in other studies.
Resumen Introducción : La telangiectasia hemorrágica heredita ria (HHT) es una displasia vascular que puede afectar a 1 de 5000 a 10 000 personas en el mundo. Es una afección rara y subdiagnosticada. Los estudios epidemiológicos son fundamentales para comprender y cuantificar el im pacto de esta enfermedad. Nuestro objetivo fue estimar la prevalencia en un Sistema Prepago de Atención de la Salud, en Buenos Aires, Argentina. Métodos : Estudio descriptivo transversal en pacientes mayores de 18 años afiliados al Programa de Atención Médica del Hospital Italiano en Buenos Aires (Plan de Sa lud). Para la inclusión de casos, se requería el diagnóstico de HHT. La detección de casos incluyó su búsqueda en nuestro Registro Institucional. La prevalencia se calculó dividiendo el número de casos por el número total de afiliados activos en enero de 2023. Se estimaron tasas específicas por edad y género. Resultados : Se reportaron 48 casos. La prevalencia fue de 3.2 por 10 000 personas (IC 95% 2.4-4.2). La específica en mujeres fue de 3.9 (IC 95% 2.8-5.5) y en hombres de 2.1 por 10 000 (IC 95% 1.2-3.6). La edad promedio fue de 55 años (19), con 35 pacientes mujeres (72.9%) con una edad promedio de 55 años (19.9) y 55 (17.2) para hom bres. La derivación más común fue de médicos (60.4%), seguidas por antecedentes familiares (18.7%). Los 48 pacientes correspondían a 39 familias. Discusión : La prevalencia identificada en nuestro es tudio es más alta que la documentada en otros estudios.
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Rendu-Osler-Weber syndrome, also known as hereditary hemorrhagic telangiectasia, is an autosomal dominant hereditary disorder. It is characterized by presence of multiple arteriovenous malformations (AVMs) and telangiectasias. This article reports two cases of patients with Rendu-Osler-Weber syndrome who had pulmonary AVMs and underwent successful endovascular treatment. A brief review of the literature shows that up to 50% of patients with the syndrome have pulmonary AVMs and there is usually a positive family history in these patients. These pulmonary AVMs are multiple in 30% of cases and are associated with the most severe disease complications. Most patients are asymptomatic, even in the presence of AVMs with right-left shunts. When these shunts exceed 25% of the total blood volume, dyspnea, cyanosis, digital clubbing, and extracardiac murmurs may occur. Endovascular treatment is safe and offers control of complications from hereditary hemorrhagic telangiectasia and is currently the treatment of choice for these lesions.
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BACKGROUND: Renal arteriovenous malformation (AVM) in Hereditary Hemorrhagic Telangiectasia (HHT) is uncommon and only few cases have been described, mainly with surgical management because of uncontrolled hematuria. CASE PRESENTATION: We managed a 70-year-old patient with HHT who presented with hematuria and left flank pain. Computed Tomography and ultrasound showed left renal AVM of 18 mm with clotting in the urinary tract. An external ureteral catheter was placed during 3 days to allow rinsing and facilitate elimination of clots. Given the patient's hemodynamic stability, a non-surgical management was chosen. Treatment of the AVM was performed by trans-arterial embolization using micro-coils and ethylene-vinyl alcohol copolymer. CONCLUSIONS: Our case study shows a conservative management by embolization of ruptured left renal AVM revealed by hematuria in a 70-year-old patient with HHT.
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In October 2021, a 51-year-old woman developed a skin rash. Abdominal computed tomography revealed a large splenic artery aneurysm and an intrahepatic portovenous shunt. As her splenic artery aneurysm was at risk of rupture, she was referred to the Kindai University Hospital and underwent coiling surgery. In October 2023, approximately two years after she had been initially referred, contrast-enhanced ultrasound revealed findings suggestive of focal nodular hyperplasia. No reports have confirmed the occurrence of liver masses in patients with hereditary hemorrhagic telangiectasia, which is considered to be an interesting finding when investigating the mechanism of tumor development.
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Resumo A síndrome de Rendu-Osler-Weber, também conhecida como telangiectasia hemorrágica hereditária, é uma doença hereditária autossômica dominante. Ela é caracterizada pela presença de múltiplas malformações arteriovenosas e telangiectasias. Este artigo relata dois casos de pacientes com síndrome de Rendu-Osler-Weber que apresentaram malformações arteriovenosas pulmonares e foram submetidos a tratamento endovascular com sucesso. Uma breve revisão da literatura mostra que até 50% dos pacientes com a síndrome têm malformações arteriovenosas pulmonares e geralmente há um histórico familiar positivo nesses pacientes. Em 30% dos casos, elas são múltiplas e estão associadas a complicações mais graves da doença. A maioria dos pacientes é assintomática, mesmo na presença de malformações arteriovenosas com shunt direito-esquerdo. Quando esses shunts excedem 25% do volume total de sangue, podem surgir dispneia, cianose, baqueteamento digital e sopros extracardíacos. O tratamento endovascular oferece segurança e controle das complicações da telangiectasia hemorrágica hereditária, sendo atualmente o tratamento de escolha para essas lesões.
Abstract Rendu-Osler-Weber syndrome, also known as hereditary hemorrhagic telangiectasia, is an autosomal dominant hereditary disorder. It is characterized by presence of multiple arteriovenous malformations (AVMs) and telangiectasias. This article reports two cases of patients with Rendu-Osler-Weber syndrome who had pulmonary AVMs and underwent successful endovascular treatment. A brief review of the literature shows that up to 50% of patients with the syndrome have pulmonary AVMs and there is usually a positive family history in these patients. These pulmonary AVMs are multiple in 30% of cases and are associated with the most severe disease complications. Most patients are asymptomatic, even in the presence of AVMs with right-left shunts. When these shunts exceed 25% of the total blood volume, dyspnea, cyanosis, digital clubbing, and extracardiac murmurs may occur. Endovascular treatment is safe and offers control of complications from hereditary hemorrhagic telangiectasia and is currently the treatment of choice for these lesions.
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Rendu-Osler-Weber disease or hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease. It is characterized by vascular dysplasia with the formation of telangiectasias on the skin, mucous membranes of the respiratory and digestive tracts, arteriovenous malformations (AVMs) in the internal organs, which is manifested by bleeding. Diagnosis is based on Curacao criteria: recurrent and spontaneous nosebleeds, multiple telangiectases on the characteristic localizations, AVMs in one or more of the internal organs, a family history of HHT (i.e. first-degree relative who meets these same criteria for definite HHT). Therapy is aimed at preventing and stopping gastrointestinal, nosebleeds, correction of iron deficiency anemia. A promising method of therapy is the use of angiogenesis inhibitors, in particular bevacizumab. The article presents a description of a clinical case of HHT in a 49-year-old woman with telangiectisia on the mucous membrane of the tongue, gastrointestinal tract and liver AVMs.
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Anemia Ferropriva , Telangiectasia Hemorrágica Hereditária , Feminino , Humanos , Pessoa de Meia-Idade , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/tratamento farmacológico , Anemia Ferropriva/tratamento farmacológico , Epistaxe/complicações , Epistaxe/tratamento farmacológico , Bevacizumab/uso terapêutico , Inibidores da AngiogêneseRESUMO
BACKGROUND: Rendu-Osler-Weber disease (Osler's disease) is the most common cause of pulmonary arteriovenous fistula. We report a case of pulmonary arteriovenous fistula associated with Osler's disease that was treated by lobectomy. CASE REPORT: A 44-year-old man with Osler's disease presented with respiratory distress. Computed tomography showed a pulmonary arteriovenous fistula, which had a 26-mm-long diameter in S6 of the left lung. Transcatheter treatment had a high risk of recurrence, and surgery was indicated. The pulmonary arteriovenous fistula was found at the beginning of A6. A6 and the basilar artery were cut together with a stapler. The postoperative course was uneventful, and respiratory distress symptoms improved with no recurrence. CONCLUSION: We report a case of pulmonary arteriovenous fistula caused by Osler's disease treated by lobectomy. Although transcatheter treatment is the mainstream treatment for pulmonary arteriovenous fistulas, surgical resection may be effective depending on the size of the lesion.
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Fístula Arteriovenosa , Veias Pulmonares , Síndrome do Desconforto Respiratório , Telangiectasia Hemorrágica Hereditária , Masculino , Humanos , Adulto , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Telangiectasia Hemorrágica Hereditária/cirurgia , Fístula Arteriovenosa/complicações , Fístula Arteriovenosa/diagnóstico , Veias Pulmonares/cirurgia , Dispneia/complicaçõesRESUMO
Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare autosomal dominant multisystem disorder. It is a mucocutaneous and fibrovascular dysplasia, the diagnosis of which is based on the fulfillment of the four Curaçao criteria: 1) recurrent epistaxis; 2) dermatovascular mucosal telangiectasias at characteristic sites: skin of the face, ears, fingertips, lips, tongue, and oral and nasal cavity; 3) arteriovenous malformations (AVMs) of visceral organs and central nervous system; and 4) family history: diagnosis of HHT in a first-degree relative. We describe a case of a 76-year-old patient who presented to our department with clinical manifestations of HHT in the skin (face, fingertips), lips, hard palate, tongue, ears, and nasal cavities. Individual and family history was obtained, as well as clinical laboratory examination, pan-endoscopy of the ear, nose, and throat (ENT) systems, and treatment of active foci of bleeding from the above areas. The otolaryngologist may be the first doctor to suspect Rendu-Osler-Weber syndrome and the one responsible for treating patients with HHT since recurrent epistaxis is the most frequent (90-96% of patients) and the earlier manifestation of the disease and the main reason for the arrival of these patients in the Emergency Department. The purpose of this study is to present a clinical case of Rendu-Osler-Weber syndrome with multiple ENT manifestations, as well as a review of the literature on their management and treatment.
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Hereditary hemorrhagic teleangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is the most common cause of hepatic vascular malformations in adults. Different vascular shunts (arteriovenous, arterioportal or portovenous) lead to different clinical manifestations. Even though no hepatic-related symptoms are reported in the majority of cases, the severity of liver disease could lead to refractory medical conditions, in some cases requiring liver transplantation. The aim of this manuscript is to provide an updated overview of the current evidence regarding the diagnosis and treatment of HHT liver involvement and liver-related complications.
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OBJECTIVE: Osteomalacia is an uncommon, overlooked and debilitating metabolic bone disease with numerous aetiologies. Herein, we report an atypical cause of osteomalacia - intravenous iron therapy. METHODS: Description of a case report of hypophophatemic osteomalacia induced by ferric carboxymaltose infusions. RESULTS: A 70-year-old male with Rendu-Osler-Weber syndrome requiring repeated infusions of ferric carboxymaltose was admitted for disabling lower limb pain associated with persistent hypophosphatemia (1.6mg/dL) and increased urinary fractional excretion of phosphate (43%, UP04=118.3mg/dL), serum fibroblast growth factor 23 (324UA/mL), intact parathyroid hormone (110pg/mL) and bone alkaline phosphatase (40.1mcg/L). X-ray and CT of the feet showed severe diffuse bone demineralization. Feet MRI displayed a subchondral fracture of the cuneiform-navicular joints. Spine X-ray revealed dorsolumbar vertebral flattening. Somatostatin receptor PET scan excluded an occult tumor. Bone biopsy with histomorphometry confirmed the presence of osteomalacia. After excluding other causes, a diagnosis of hypophosphatemic osteomalacia induced by frequent ferric carboxymaltose infusions was made. The iron formulation was replaced by saccharated ferric oxide infusions and progressive titration of calcitriol up to 1.5mg/day and oral disodium phosphate up to 5740mg/day was started. After 6 months, there was a clear clinical and analytical improvement. CONCLUSION: Osteomalacia may be a consequence of prolonged hypophosphatemia induced by recurrent ferric infusions, which is an uncommon and neglected bone adverse event of this therapy. Phosphate levels and bone symptoms should be monitored during repetitive iron infusions, maintaining a high level of suspicion for osteomalacia as it is important to identify and treat it in a timely manner, minimizing its severe morbidity.
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Hipofosfatemia , Osteomalacia , Masculino , Humanos , Idoso , Osteomalacia/induzido quimicamente , Osteomalacia/diagnóstico , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/diagnóstico , Fosfatos/uso terapêutico , Ferro/efeitos adversosRESUMO
A Telangiectasia Hemorrágica Hereditária ou Síndrome de Rendu-Osler-Weber é uma displasia fibrovascular sistêmica de herança autossômica dominante caracterizada por epistaxes de repetição, telangiectasias mucocutâneas e malformações arteriovenosas (MAVs) que frequentemente acometem as circulações pulmonar, hepática e cerebral. Tratamentos sistêmicos podem ser necessários para aqueles com sangramento refratário geralmente manifestados por necessidade de múltiplas transfusões sanguíneas e reposição de ferro. Com o avançar dos estudos, em 2020, houve a incorporação de terapias antiangiogênicas sistêmicas nos algoritmos para epistaxe, sangramentos de trato gastrointestinal e MAVs hepáticas graves. Neste estudo, trazemos o relato de uma paciente com a síndrome atendida no Hospital Municipal Moysés Deutsch localizado em São Paulo-SP no mês de maio de 2022. Além disso, faz-se uma revisão bibliográfica de sua etiopatogenia, manifestações clínicas e terapêutica com ênfase no que temos de mais novo em relação às terapias sistêmicas antiangiogênicas, ainda com necessidade de estudos controlados randomizados em busca de evidências mais consolidadas em relação à eficácia, perfis de segurança e eventos adversos.
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Humanos , Masculino , FemininoRESUMO
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.
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Humanos , Feminino , Pessoa de Meia-Idade , Telangiectasia Hemorrágica Hereditária/cirurgia , Telangiectasia Hemorrágica Hereditária/complicações , Epistaxe/cirurgia , Resultado do Tratamento , Procedimentos Cirúrgicos Nasais/métodosRESUMO
BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome is a bleeding disorder that can affect all parts of the body including the eyes. Different ocular abnormalities have been described in relation to HHT, but the pathogenesis of retinal involvement is still unknown. A few cases have described chorioretinal abnormalities primarily occurring in elderly patients. In this study, we present a unique case of a young female with known HHT and a series of retinal fundus images including optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) with macular telangiectasia-like lesions. CASE PRESENTATION: A young female genetically diagnosed with hereditary hemorrhagic telangiectasia (HHT), is regularly attending retinal screening since she is diagnosed with Type 1 diabetes. At one visit, abnormal retinal telangiectasia-like lesions in the macula, are observed. These abnormalities are monitored over an extended period of time with fundus imaging, and further investigated with OCT and OCTA. The patient has no visual complaints at any time and best-corrected visual acuity is 20/20 Snellen equivalent in both eyes. CONCLUSIONS: To the best of our knowledge, this is the first case to describe the occurrence of telangiectasia-like lesions in macula with secondary choriocapillaris atrophy in a patient diagnosed with HHT in such a young age.
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Retinopatia Diabética , Telangiectasia Hemorrágica Hereditária , Humanos , Feminino , Idoso , Adolescente , Telangiectasia Hemorrágica Hereditária/complicações , Telangiectasia Hemorrágica Hereditária/diagnóstico , Tomografia de Coerência Óptica , Acuidade Visual , Fundo de Olho , Retinopatia Diabética/complicaçõesRESUMO
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)
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Humanos , Feminino , Adolescente , Doenças Genéticas Inatas/prevenção & controle , Telangiectasia Hemorrágica Hereditária/diagnósticoRESUMO
OBJECTIVES: To evaluate short- and long-term safety and efficacy of embolization with Onyx® for recurrent pulmonary arteriovenous malformations (PAVMs) in hereditary hemorrhagic telangiectasia (HHT). METHODS: In total, 45 consecutive patients (51% women, mean (SD) age 53 (18) years) with HHT referred to a reference center for treatment of recurrent PAVM were retrospectively included from April 2014 to July 2021. Inclusion criteria included evidence of PAVM recurrence on CT or angiography, embolization using Onyx® and a minimal 1-year-follow-up CT or angiography. Success was defined based on the standard of reference criteria on unenhanced CT or pulmonary angiography if a recurrence was suspected. PAVMs were analyzed in consensus by two radiologists. The absence of safety distance, as defined by a too-short distance for coil/plug deployment, i.e., between 0.5 and 1 cm, between the proximal extremity of the primary embolic material used and a healthy upstream artery branch, was reported. RESULTS: In total, 70 PAVM were analyzed. Mean (SD) follow-up was 3 (1.3) years. Safety distance criteria were missing in 33 (47%) PAVMs. All procedures were technically successful, with a short-term occlusion rate of 100% using a mean (SD) of 0.6 (0.5) mL of Onyx®. The long-term occlusion rate was 60%. No immediate complication directly related to embolization was reported, nor was any severe long-term complication such as strokes or cerebral abscesses. CONCLUSIONS: In HHT, treatment of recurrent PAVM with Onyx® showed satisfactory safety and efficacy, with an immediate occlusion rate of 100% and a long-term rate of 60%.
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(1) Background: Genetic hereditary hemorrhagic telangiectasia (HHT) is clinically diagnosed. The clinical manifestations and lack of curative therapeutic interventions may lead to mental illnesses, mainly from the depression-anxiety spectrum. (2) Methods: We report the case of a 69-year-old patient diagnosed with HHT and associated psychiatric disorders; a comprehensive literature review was performed based on relevant keywords. (3) Results: Curaçao diagnostic criteria based the HHT diagnosis in our patient case at 63 years old around the surgical interventions for a basal cell carcinoma, after multiple episodes of epistaxis beginning in childhood, but with a long symptom-free period between 20 and 45 years of age. The anxiety-depressive disorder associated with nosocomephobia resulted in a delayed diagnosis and low adherence to medical monitoring. A comprehensive literature review revealed the scarcity of publications analyzing the impact of psychiatric disorders linked to this rare condition, frequently associating behavioral disengagement as a coping strategy, psychological distress, anxiety, depression, and hopelessness. (4) Conclusions: As patients with HHT face traumatic experiences from disease-related causes as well as recurring emergency hospital visits, active monitoring for mental illnesses and psychological support should be considered as part of the initial medical approach and throughout the continuum of care.
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Hereditary hemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber disease, is a dominant autosomal disease characterized by the presence of multiple telangiectasia in skin and mucus, associated with arteriovenous malformations (AVM) of various organs, including the lungs, gastrointestinal system and brain. HHT is presented most frequently as recurrent, spontaneous epistaxis. Patients may also present digestive, pulmonary and intracranial hemorrhage, as well as secondary anemia. This article reports the case of a female patient, 62 years old, with multiple episodes of epistaxis and vaginal bleeding, with diagnosis of complex HHT, which was managed with multiple embolizations, which improved symptoms and survival. In this kind of patient, it is possible, with timely diagnosis and treatment, to obtain a greater quality and expectation of life. Due to the fact that the severity and alterations in each patient are so variable, management should be individualized.
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BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder, affecting 1:5000 individuals worldwide. All the genes associated to the disease (ENG, ACVRL1, SMAD4, GDF2) belong to the TGF-ß/BMPs signaling pathway. We found 19 HHT unrelated families, coming from a Northern Italy region and sharing the ACVRL1 in-frame deletion c.289_294del (p.H97_N98). METHODS: To test the hypothesis of a founder effect, we analyzed 88 subjects from 19 families (66 variant carriers, showing clinical signs of HHT, and 22 non-carriers, unaffected) using eight microsatellite markers within 3.7 Mb around the ACVRL1 locus. After the haplotype reconstruction, age estimation of the variant was carried out. RESULTS: We observed a common disease haplotype in 16/19 families, while three families showed evidence of recombination around the ACVRL1 locus. The subsequent age estimation analyses suggested that the mutation occurred about 8 generations ago, corresponding to about 200 years ago. We also present novel in silico and modeling data supporting the variant pathogenicity: the deletion alters the protein stability and removes the unique extracellular glycosylation site. CONCLUSION: We have demonstrated, for the first time, a "founder effect" for a HHT pathogenic variant in Italy.
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Receptores de Activinas Tipo II , Telangiectasia Hemorrágica Hereditária , Receptores de Activinas Tipo II/genética , Endoglina/genética , Efeito Fundador , Heterozigoto , Humanos , Itália , Mutação , Telangiectasia Hemorrágica Hereditária/diagnósticoRESUMO
Objective: To study the genotypes and phenotypes of cerebral arteriovenous fistulas that drain or do not drain through the vein of Galen, and true vein of Galen aneurysmal malformations, in order to determine whether genotyping could help improve classification of these malformations and their management. Methods: We carried out a retrospective review of genetic and phenotypic data in databases of four centers. All children with cerebral arteriovenous fistula or vein of Galen aneurysmal malformations aged below 18 years at onset were included. We recorded the nature of the genetic variant or absence of variant, age at onset, type of malformation, symptoms at onset (hemorrhage, neurological deficit, hydrocephalus, incidental, and heart failure), type of venous drainage and the long-term outcome. Results: One hundred and fifteen children were included. Autosomal dominant variants were identified in 39% of patients. The most frequent variant affected was the RASA1 gene (25%) followed by EPHB4 (8%) and the HHT-associated genes (5%). HHT gene variants were only observed in pial arteriovenous fistula not draining into the vein of Galen; on the contrary, EPHB4 variants were only seen in genuine vein of Galen aneurysmal malformation. RASA1 variants were identified in all types of shunts. Conclusions: EPHB4 variants seem specific to the vein of Galen aneurysmal malformation, RASA1 variants are associated with either pial arteriovenous fistulas or with genuine VGAM and HHT gene variants seem specific to pial arteriovenous fistulas. The genetic data helps to classify these malformations and to guide treatment toward lowest risk of post-operative cerebral ischemic-hemorrhagic complications.