Manifestations Of Hereditary Hemorrhagic Telangiectasia Research Articles

Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler’s Disease, Uppsala University Hospital

Aim: The aim of this retrospective single-centre study was to evaluate whether mutations in the ENG, ACVRL1, and SMAD4 genes were associated with different phenotypes in hereditary haemorrhagic telangiectasia (HHT).Methods: The case records of 21 HHT patients with verified mutations in ENG, ACVRL1, or SMAD4 genes were reviewed. The numbers of HHT diagnostic criteria fulfilled for the three genotypes were compared, as was the prevalence of complications such as iron deficiency anaemia, gastrointestinal haemorrhage, stroke, and cerebral abscess.Results: Our results indicate that mutations in the ENG (HHT1), ACVRL1 (HHT2), and SMAD4 genes result in different HHT phenotypes. Epistaxis debuts earlier and may be more severe in HHT1 than in HHT2. The prevalence of pulmonary arteriovenous malformations (AVM) is higher in HHT type 1, whereas hepatic AVMs are more common in HHT2. One patient with mutations in both ENG and ACVRL1 genes was identified, as were two SMAD4-mutated patients suffering from the overlapping juvenile polyposis-HHT syndrome. Nearly one in five patients in our HHT population has been diagnosed with stroke or cerebral abscess, indicating a high prevalence of cerebral complications.Conclusion: Our results showing that ENG and ACVRL1 gene mutations result in different HHT phenotypes confirm the results from other HHT centres worldwide. Cerebral complications of HHT are common, underscoring the importance of regular screening for pulmonary AVMs and early intervention against such AVMs. We have identified an HHT patient with simultaneous mutations in the ENG and ACVRL1 genes. Surprisingly, this patient has had a mild course of the disease.

Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: clinical aspects.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder of blood vessel formation resulting in mucocutaneous telangiectasias and visceral arteriovenous malformations. Nearly half of patients with HHT will have pulmonary arteriovenous malformations (PAVM) that place them at risk for potentially fatal complications that can occur when blood bypasses the pulmonary capillary circulation or as a result of PAVM rupture. Other manifestations of HHT outside the lung may increase the rate and severity of PAVM complications, creating unique clinical challenges. Management hinges on timely screening and diagnosis, followed by treatment of amenable PAVMs with transcatheter embolization in conjunction with medical management and prophylactic measures to treat and prevent complications. The purpose of this review is to highlight the clinical manifestations of PAVMs specific to patients with HHT and to detail screening and treatment strategies that can reduce the risk of developing life-threatening complications.

Клинический случай повторных инфарктов головного мозга у пациента молодого возраста с болезнью Рандю-Ослера-Вебера

Rendu-Osler-Weber disease is a rare inherited disease of the vasculature, characterized by the development of multiple telangiectasias of the skin and mucous membranes, as well as hemorrhagic syndrome of various localization. We present a case report of recurrent acute ischemic strokes in a young patient with Rendu-Osler-Weber disease. In the first part of the article, literature data on the incidence, etiology, pathogenesis, features of clinical manifestations of hereditary hemorrhagic telangiectasia, modern methods of diagnosis and treatment are presented. In the second part of the article, a rare case of recurrent acute ischemic strokes in a young patient with Rendu-Osler-Weber disease, caused by a paradoxical embolism due to pulmonary arteriovenous malformation was demonstrated. The chest CT detected a pulmonary arteriovenous malformation. The data of medical, including anamnesis, a description of the objective and neurological status, the results of laboratory and instrumental methods of examination are presented. The patient was recommended angiopulmonography, during which the pulmonary arteriovenous malformation was successfully embolized. This case indicates the need for targeted examination and monitoring of patients with hereditary hemorrhagic telangiectasia. For the purpose of early detection of vascular malformations in patients with Rendu-Osler-Weber disease and the timely administration of therapy to prevent possible serious cerebrovascular complications, we recommend performing the chest CT.

Identifying PTPN14-dependent mechanisms that influence clinical manifestations of Hereditary Hemorrhagic Telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder caused predominantly by loss of a single allele of ENG (HHT1) or ACVRL1 (HHT2). Global incidence is about 1 in 5,000. Clinical manifestations includecutaneous, mucosal and /or gastrointestinal (GI) tract telangiectases that can cause severe epistaxis or Gl bleeding. Some patients (10–50%) develop arteriovenous malformations (AVMs) in the lung, brain or liver. We previously showed that genetic variants of PTPN14 (Phospho-Tyrosine Phosphatase Non-Receptor Type 14) genetically associate with the presence of lung AVMs. Homozygous loss of PTPN14 has also been reported to cause lymphedema due to lymph EC hyperplasia.Other studies, in tumor epithelial cells, show that PTPN14 can dephosphor-ylate b- catenin, modulate HIPPO signaling and regulate tyrosine kinase receptor turnover through endosomal pathways.To investigate its role in ECs and its interactions with the endoglin/ACVRL1 axis, we studied the effect of PTPN14 knock down on differential expression of components of BMP9 and TGF-b signaling pathways in primary human umbilical artery ECs (HUAEC). PTPN14 expression had no effect on pSmad2/3 or pSmad1/5/8 activation but affected protein levels of VEGFR2 and EphrinB2. PTPN14 may thus act on a network of interacting signaling pathways, including endoglin and ACVRL1, by regulating cell surface receptor presentation and endocytic turnover.Studies are ongoing to address this issue in greater molecular detail. Elucidating the molecular mechanisms involved should contribute to a better understanding of the molecular pathology of HHT, and the regulation of angiogenesis versus stabilization of the vascular bed.

59-Year-Old Woman With Fatigue, Dyspnea, and Lower Extremity Edema

59-Year-Old Woman With Fatigue, Dyspnea, and Lower Extremity Edema

Gastrointestinal Manifestations of Hereditary Hemorrhagic Telangiectasia (HHT): A Systematic Review of the Literature.

Hereditary hemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disease that affects the vasculature of numerous organs. The prevalence of HHT is estimated to be between 1.5 and 2 persons per 10,000. While there is still much to learn about this condition, there is an increasing understanding its underlying pathophysiology, genetic basis, presentations, and management. Recognizing that the clinical manifestations of HHT can involve a number of organ systems will provide clinicians with a higher index of suspicion for the disease. This early diagnosis and genotyping can greatly reduce mortality for a patient with HHT through appropriate screening for complications. This review will focus on the gastrointestinal manifestations of HHT and how these can dictate treatment and prognosis.

Abstract 330: MicroRNA Dysregulation in Patients with Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is a rare, understudied, autosomal dominant disorder that is characterized by angiogenic abnormalities. Gene mutations in HHT involve key angiogenic factors. Clinical manifestations of HHT include benign telangiectasias and potentially life threatening arteriovenous malformations (AVMs) that can occur in the pulmonary and cerebral circulation. Currently, there is no effective treatment for HHT. PBMCs have been implicated in the pathogenesis of HHT and the goal of this study was to profile and characterize PBMC microRNAs, to determine whether they had a role in the observed angiogenic abnormalities. A total of 28 HHT patients with confirmed mutations in either ENG , ACVRL1 or SMAD4 , and 25 controls were recruited. PBMCs were isolated from 16 ml of peripheral blood and total RNA was obtained. PBMC expression profiling was conducted with a human miR array analysis. Dysregulated miRs identified from the analysis were then validated with RT-qPCR. Significant differences were determined using a two-tailed t- test. Of the 800 miRs screened, 167 dysregulated miRs were identified in PBMCs. Selected PBMC miRs (MiRs-28-5p, -30b-5p, -361-3p and -374a-5p) were validated with RT-qPCR. PBMC miR-361-3p ( p =0.025) known to target IGF1, was found to be significantly decreased compared to controls. IGF1 messenger RNA (mRNA) levels in PBMCS of HHT patients was significantly elevated (p=0.005) compared to controls. Our results show dysregulation of select miRs in PBMCs from HHT patients. We also show an increase in IGF1 mRNA, an important angiogenic factor, in PBMCs that may be related to the downregulation of miR-361-3p in HHT patients. This may represent an important pathogenic mechanism that is involved in the angiogenic dysfunction observed in HHT and may provide for a unique miR therapeutic target.

Hepatic angiodynamic profile in paediatric patients with hereditary haemorrhagic telangiectasia type 1 and type 2.

Liver involvement is a common manifestation of hereditary haemorrhagic telangiectasia (HHT). Although a number of studies have been carried out in adult patients, no study has ever been focused on investigating HHT-related hepatic involvement in paediatric patients. The present study aimed for the first time to systematically estimate the prevalence of HHT-associated liver involvement and to characterize HHT-associated hepatic angiodynamic features in paediatric age. The study was designed as a cross-sectional survey in an HHT paediatric cohort, subclassified as HHT1 and HHT2 according to the mutated gene. The evaluation of the angiodynamic profile was performed by duplex ultrasound examination. Investigation by multi-slice computed tomography (MSCT) or magnetic resonance angiography (MRA) was performed in patients >12 years. MSCT/MRA examination disclosed silent hepatic involvement in 7/20 (35.0 %) children, and nodular regenerative hyperplasia in two cases. Diameter of common hepatic artery was significantly larger in HHT2 (0.45 ± 0.15 cm) compared to HHT1 (0.33 ± 0.09, p < 0.01) and control children (0.32 ± 0.08, p < 0.05). None of the patients had clinical manifestations of liver involvement. Angiodynamic profiles were different between paediatric and adult HHT patients. Liver involvement can be detected in paediatric HHT patients, albeit with a lower frequency compared to adults. Paediatric HHT2 children show a higher frequency of liver involvement and a trend to hepatic artery dilation when compared to HHT1 children.

Sinonasal quality of life outcomes following laser treatment of epistaxis related to hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder which manifests as recurrent, episodic, and potentially debilitating epistaxis. In this study, we aim to (1) characterize baseline sinonasal symptoms for HHT patients and to (2) analyze changes in sinonasal symptoms before and after laser surgical treatment for HHT. We performed a retrospective chart review of sinonasal outcome test-22 (SNOT-22) scores before and after one or more laser surgical treatments for HHT-related epistaxis between January 1, 2010 and December 1, 2015 at a tertiary academic medical center with an HHT Foundation-approved Center of Excellence. Preoperative and all subsequent postoperative SNOT-22 scores (short-term, <45days and long-term, ≥45days) were compared. Twenty consecutive HHT patients underwent 51 laser surgeries for recurrent epistaxis. Mean preoperative, short-term postoperative, and long-term postoperative SNOT-22 scores were 34.6 ± 5.4, 33.9 ± 5.5, and 18.8 ± 4.6, respectively. When analyzing subcategory scores, there was a significant improvement in the rhinologic domain from short-term to long-term postoperatively (13.5 vs. 7.3; p = 0.004), in the non-rhinologic otolaryngic domain from short-term to long-term postoperatively (2.8 vs. 1.7; p = 0.014), and in the psychological domain from preoperative and short-term postoperative to long-term postoperatively (12.2 and 10.0 vs. 6.0; p = 0.015 and 0.01, respectively). Following laser surgery for HHT-related epistaxis, patients' rhinologic symptoms worsened on the short run postoperatively but improved over time. The main benefit of laser treatment appears to be long-term improvement in psychological factors. This study once again underscores the important role of the otolaryngologist in managing sinonasal manifestations of HHT.

RENDU-OSLER-WEBER DISEASE AT 75 YEARS OLD WOMAN

The publication presents a clinical case of hereditary hemorrhagic telangiectasia in a woman of 75 years. In the first part of the article, literature data on the incidence and features of Rundu-Osler-Weber disease are presented, modern diagnostic principles based on the Curacao criteria (1999) are reviewed, which allow to define the diagnosis as “reliable”, with three criteria, “probable” — with Two criteria (most often the family nature of the disease and spontaneous nasal bleeding) and “doubtful”, with one criterion of the above. Methods of treating hereditary hemorrhagic telangiectasia are considered, the authors draw attention to the fact that the choice of the method of therapy depends on the degree of damage to the target organ. Symptomatic methods of treatment suggest slight relief for patients, but hereditary hemorrhagic telangiectasia remains a progressive, severe and potentially life-threatening pathology. The second part of the article presents a clinical observation with late verification of the patient’s P., 75 years of age. The data of medical history, including anamnesis, catamnesis, photographs of macro- and micro-preparations are given. The presented observation illustrates the severe course of hereditary hemorrhagic telangiectasia, manifested by severe hemorrhagic syndrome, due to vascular malformations, the gradual involvement of internal organs in the pathological process with the formation of arteriovenous shunts, aneurysms. The manifestation of hereditary hemorrhagic telangiectasia in the described clinical case was manifested as abundant nasal, uterine bleeding, skin telangiectasias, followed by involvement in the pathological process of the lungs, organs of the gastrointestinal tract. The authors were able to observe a variant of the course and manifestation of visceral vascular anomalies. This clinical case illustrates the need to take into account the totality of all the symptoms of the disease in hereditary hemorrhagic telangiectasia for early detection of the disease, dynamic observation of the patient and the timely administration of therapy

The Prevalence of Malformations of Cortical Development in a Pediatric Hereditary Hemorrhagic Telangiectasia Population.

Brain AVM, cerebral abscess, and ischemic stroke are among the well known neurologic manifestations of hereditary hemorrhagic telangiectasia. However, recently reported data suggest an additional association with malformations of cortical development. The purpose of this study was to determine the prevalence of malformations of cortical development in a population of pediatric patients with hereditary hemorrhagic telangiectasia. A retrospective review of brain MRIs from 116 pediatric patients was performed. Each patient was referred from our institution's Hereditary Hemorrhagic Telangiectasia Clinic. Each MRI included a 3D sequence, most frequently MPRAGE. The 3D sequence was evaluated by a neuroradiology fellow, with specific attention to the presence or absence of malformations of cortical development. Positive studies were subsequently reviewed by 2 attending neuroradiologists, who rendered a final diagnosis. Fourteen of 116 (12.1%) patients were found to have a malformation of cortical development. Among these 14, there were 12 cases of polymicrogyria and 2 cases of bifrontal periventricular nodular heterotopia. Pediatric patients with hereditary hemorrhagic telangiectasia have a relatively high prevalence of malformations of cortical development, typically perisylvian polymicrogyria.

Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia: A Randomized Clinical Trial.

Epistaxis is the most frequent and disabling manifestation of hereditary hemorrhagic telangiectasia (HHT). The efficacy of intravenous bevacizumab (an anti-vascular endothelial growth factor monoclonal antibody) for epistaxis has been shown. However, the efficacy of intranasal bevacizumab has yet to be evaluated. To evaluate the efficacy of 3 different doses of bevacizumab administered as a nasal spray in a repeated manner for the duration of nosebleeds in patients with HHT. Randomized, multicenter, placebo-controlled, phase 2/3 clinical trial with dose selection at an intermediate analysis and prespecified stopping rules (nonbinding stopping for futility). Patients aged 18 years or older with a diagnosis of HHT were recruited from 5 French centers from April 2014 to January 2015 with a 6-month follow-up after the end of treatment. Participants had a history of self-reported nosebleeds with a monthly duration of more than 20 minutes in at least the 3 months prior to inclusion corroborated by epistaxis grids completed during the same preinclusion period. Eighty consecutive HHT patients were randomized and treated in the phase 2 study, with 4 parallel groups in a 1:1:1:1 ratio. One group received placebo (n = 21); the other 3 received bevacizumab nasal spray. Each bevacizumab group received a different dose of the drug (25 mg [n = 20], 50 mg [n = 20], or 75 mg [n = 19] per treatment) in 3 doses 14 days apart for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, and 225 mg in each treatment group. Mean monthly epistaxis duration for 3 consecutive months immediately after the end of the treatment. Of the 80 patients who were randomized (mean age, 60.47 [SD, 10.61] years; 37 women [46.25%]), 75 completed the study. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 59 patients receiving bevacizumab in comparison with the placebo group (P = .57) or between the bevacizumab groups. The mean monthly epistaxis duration was 259.2 minutes (95% CI, 82.1-436.3 minutes) in the 25-mg group, 244.0 minutes (95% CI, 81.8-406.2 minutes) in the 50-mg group, 215.0 minutes (95% CI, 102.8-327.2 minutes) in the 75-mg group, and 200.4 minutes (95% CI, 109.3-291.5 minutes) in the placebo group. Toxicity was low and no severe adverse events were reported. This study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee. In patients with HHT, a bevacizumab nasal spray treatment of 3 administrations at 14-day intervals with doses of 25 mg, 50 mg, or 75 mg per spray, compared with a placebo, did not reduce monthly epistaxis duration in the 3 consecutive months immediately after the end of treatment. clinicaltrials.gov Identifier: NCT02106520.

Neurovascular Manifestations of Hereditary Hemorrhagic Telangiectasia: A Consecutive Series of 376 Patients during 15 Years.

Hereditary hemorrhagic telangiectasia is associated with a wide range of neurovascular abnormalities. The aim of this study was to characterize the spectrum of cerebrovascular lesions, including brain arteriovenous malformations, in patients with hereditary hemorrhagic telangiectasia and to study associations between brain arteriovenous malformations and demographic variables, genetic mutations, and the presence of AVMs in other organs. Consecutive patients with definite hereditary hemorrhagic telangiectasia who underwent brain MR imaging/MRA, CTA, or DSA at our institution from 2001 to 2015 were included. All studies were re-evaluated by 2 senior neuroradiologists for the presence, characteristics, location, and number of brain arteriovenous malformations, intracranial aneurysms, and nonshunting lesions. Brain arteriovenous malformations were categorized as high-flow pial fistulas, nidus-type brain AVMs, and capillary vascular malformations and were assigned a Spetzler-Martin score. We examined the association between baseline clinical and genetic mutational status and the presence/multiplicity of brain arteriovenous malformations. Three hundred seventy-six patients with definite hereditary hemorrhagic telangiectasia were included. One hundred ten brain arteriovenous malformations were noted in 48 patients (12.8%), with multiple brain arteriovenous malformations in 26 patients. These included 51 nidal brain arteriovenous malformations (46.4%), 58 capillary vascular malformations (52.7%), and 1 pial arteriovenous fistula (0.9%). Five patients (10.4%) with single nidal brain arteriovenous malformation presented with hemorrhage. Of brain arteriovenous malformations, 88.9% (88/99) had a Spetzler-Martin score of ≤2. Patients with brain arteriovenous malformations were more likely to be female (75.0% versus 57.6%, P = .01) and have a family history of hereditary hemorrhagic telangiectasia (95.8% versus 84.8%, P = .04). The prevalence of brain arteriovenous malformation was 19.7% in endoglin (ENG) mutations and 12.5% in activin receptor-like kinase (1ACVRL1) mutations. Our study of 376 patients with hereditary hemorrhagic telangiectasia demonstrated a high prevalence of brain arteriovenous malformations. Nidal brain arteriovenous malformations and capillary vascular malformations occurred in roughly equal numbers.

Splenic Involvement in Hereditary Hemorrhagic Telangiectasia.

A 33-year-old man who presented with prolonged epigastric pain was referred to our hospital. He had experienced recurrent epistaxis and had a family history of hereditary hemorrhagic telangiectasia. Computed tomography and magnetic resonance imaging revealed splenomegaly and a 9 cm hypervascular mass in his spleen. Computed tomography also showed a pulmonary arteriovenous malformation and heterogeneous enhancement of the liver parenchyma, suggesting the presence of arteriosystemic shunts and telangiectases. Based on these findings, the patient was definitely diagnosed with hereditary hemorrhagic telangiectasia according to Curaçao criteria. He underwent splenectomy, and his symptoms disappeared after surgery. Pathological examination of the resected specimen revealed that the hypervascular lesion of the spleen was not a tumor but was composed of abnormal vessels associated with hereditary hemorrhagic telangiectasia. Symptomatic splenic involvement may be a rare manifestation of hereditary hemorrhagic telangiectasia but can be revealed by imaging modalities.

Correction

HomeStrokeVol. 46, No. 11Correction Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection Originally published1 Nov 2015https://doi.org/10.1161/STR.0000000000000082Stroke. 2015;46:e247This article corrects the followingCerebrovascular Manifestations of Hereditary Hemorrhagic TelangiectasiaIn the article by Brinjikji et al (Brinjikji W, Iyer VN, Sorenson T, Lanzino G. Cerebrovascular manifestations of hemorrhagic hereditary telangiectasia. Stroke. 2015;46:3329−3337. DOI: 10.1161/STROKEAHA.115.010984.), which published online ahead of print on September 24, 2015, and appears in the November 2015 issue of the journal, a correction was needed.The title, “Cerebrovascular manifestations of hemorrhagic hereditary telangiectasia,” has been changed to read, “Cerebrovascular manifestations of hereditary hemorrhagic telangiectasia.”The authors regret the error.This correction has been made to the online and print version of the article, which is available at http://stroke.ahajournals.org/content/46/11/3329. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesCerebrovascular Manifestations of Hereditary Hemorrhagic TelangiectasiaWaleed Brinjikji, et al. Stroke. 2015;46:3329-3337 November 2015Vol 46, Issue 11 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/STR.0000000000000082PMID: 26504191 Originally publishedNovember 1, 2015 PDF download Advertisement

Cerebrovascular Manifestations of Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu–Osler–Weber disease, is an autosomal-dominant genetic disorder affecting the vasculature in multiple organ systems. The first reports of the disease were published by several English physicians in the 19th century, including Henry Sutton, Benjamin Babington, and John Legg who described families of patients with recurrent nosebleeds. Between 1896 and 1907, Marie Rendu, William Osler, and Frederick Parkes Weber further described the disease by demonstrating the association between epistaxis, mucocutaneous lesions, and visceral arteriovenous malformations (AVMs). In 1909, Frederic Hanes was the first to coin the term HHT; however, the eponym lives on as a tribute to Rendu, Osler, and Weber.1 The pathognomic vascular lesions in HHT are telangiectasias and AVMs. These are frequently seen on the skin and mucus membranes and also in internal organs, such as the liver, lung, gastrointestinal track, and brain. Patients with HHT often present with a wide range of serious neurological, pulmonary, and gastrointestinal complications, such as cerebral and spinal AVMs, cerebral abscess, stroke, epistaxis, pulmonary AVMs (PAVMs), liver AVMs, and gastrointestinal bleeding.2–8 HHT is diagnosed clinically using the Curacao criteria.9 The 4 Curacao criteria are (1) spontaneous and recurrent epistaxis, (2) mucocutaneous telangiectasias (lips, oral cavity, face, and fingers) (3) visceral AVMs (brain, liver, lung, etc.), and (4) diagnosis of HHT in a first degree relative using the same criteria. Patients who meet ≥3 of the 4 criteria are labeled as definite HHT, whereas those with 2 of the 4 criteria are labeled as possible or suspected HHT.10 Patients with 0 or 1 criterion are considered unlikely to have HHT. Patients with HHT present a unique challenge to physicians because of the multisystemic nature of the disease. Because of the higher prevalence of cerebral and spinal vascular manifestations and associated complications, …

Brain Abscess as a Manifestation of Hereditary Hemorrhagic Telangiectasia in a Pediatric Patient

Brain Abscess as a Manifestation of Hereditary Hemorrhagic Telangiectasia in a Pediatric Patient

Global gene expression profiling of telangiectasial tissue from patients with hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, is predominantly caused by mutations in ENG and ACVRL1, which are part of the transforming growth factor beta (TGF-β) signaling pathway. HHT is characterized by the presence of mucocutaneous telangiectases and arteriovenous malformations in visceral organs, primarily the lungs, brain and liver. The most common symptom in HHT is epistaxis originating from nasal telangiectasia, which can be difficult to prevent and can lead to severe anemia. The clinical manifestations of HHT are extremely variable, even within family members, and the exact mechanism of how endoglin and ALK1 haploinsufficiency leads to HHT manifestations remains to be identified. ObjectivesThe purpose of this study was to detect significantly differentially regulated genes in HHT, and try to elucidate the pathways and regulatory mechanisms occurring in the affected tissue of HHT patients, in order to further characterize this disorder and hypothesize on how telangiectases develop.By microarray technology (Agilent G3 Human GE 8x60), we performed global gene expression profiling of mRNA transcripts from HHT nasal telangiectasial (n=40) and non-telangiectasial (n=40) tissue using a paired design. Comparing HHT telangiectasial and non-telangiectasial tissue, significantly differentially expressed genes were detected using a paired t-test. Gene set analysis was performed using GSA-SNP.In the group of ENG mutation carriers, we detected 67 differentially expressed mRNAs, of which 62 were down-regulated in the telangiectasial tissue. Gene set analysis identified the gene ontology (GO) terms vasculogenesis, TGF-β signaling, and Wnt signaling as differentially expressed in HHT1. Altered Wnt signaling might be related to HHT pathogenesis and a greater understanding of this may lead to the discovery of therapeutic targets in HHT.

Abstract T MP46: Stroke Occurrence in Hereditary Hemorrhagic Telangiectasia

Purpose: Stroke is an important manifestation of Hereditary Hemorrhagic Telangiectasia (HHT). Many individuals may be unaware they have HHT, even after a stroke, due to its rarity. Our goal was to assess the occurrence of stroke among patients with HHT compared to the general population. Methods: Population-based administrative health data on inpatient and ambulatory admissions were extracted for the period 1997 to 2012 in Alberta using ICD-9 and ICD-10 codes. We observed overall occurrence of strokes in the HHT population and subsequently analyzed the data by gender, specific age groups, and stroke subtypes. Then we compared our findings to stroke occurrence among the general population. Results: The age-standardized occurrence rate of stroke in HHT was about 450 [95% CI 276.4, 622.6] per 100,000 PY compared to 260 [95% CI 259.3, 262.1] per 100,000 PY in the general population. Less than 3% of strokes occurred under 30 years old in both groups. Although the majority of strokes occurred after 60 years of age, 23% of strokes in the general population occurred in the middle-aged group (31-60). The prevalence of HHT in Alberta is 1 in 3,800 and three times as many women were diagnosed with HHT than men by 2012. Conclusion: The prevalence of HHT in Alberta was considerably higher than the North American estimate (1 in 5,000). Individuals diagnosed with HHT were 1.73 times more likely to have a stroke than average, a statistically significant difference. Among the general population, a substantial number of strokes occurred in the middle-aged group. There is a higher probability of an underlying genetic component in strokes occurring before 60 years. For patients who have a stroke before 60 without a clear etiology, clinicians should consider evaluation for genetic disorders such as HHT. This is particularly true for males in whom there may be underdiagnosis of HHT.

Neuroradiological Manifestations of Hereditary Hemorrhagic Telangiectasia in 139 Japanese Patients.

The purpose of this study is to report the neuroradiological manifestations of hereditary hemorrhagic telangiectasia (HHT). One hundred and thirty-nine Japanese HHT patients (73 men and 66 women, aged 2–78 years) were included in this study. Diagnosis of HHT was based on genetic analysis and/or clinical diagnosis of Curaçao. They included 68 HHT1 and 37 HHT2 patients. Essentially, all patients underwent brain magnetic resonance imaging (MRI) and pulmonary computed tomography (CT). Contrast enhanced studies of brain MRI and hepatic CT were performed in a subset of patients. Catheter cerebral angiography was performed when indicated. Their neuroradiological features were reviewed retrospectively. Various imaging abnormalities were found. Brain arteriovenous malformations (AVMs) were observed in 27/136 patients (19.9%, 21 patients with HHT1 and 1 patient with HHT2). Pulmonary arteriovenous fistulas (AVFs) were found in 73/137 patients (65.2%, 45 patients with HHT1 and 6 patients with HHT2). Cerebral infarction and brain abscess were found in 17 patients and 3 patients with pulmonary AVFs, respectively. T1 high lesions in the basal ganglia suggestive of porto-venous shunts were observed in 51/136 patients (37.5%, 9 patients with HHT1 and 28 patients with HHT2). Hepatic AVMs were observed in 61/136 patients (44.9%, 15 patients in HHT1 and 29 patients in HHT2). Brain AVMs and pulmonary AVFs were more common in HHT1 than in HHT2 (both p < 0.01), but hepatic AVMs were conversely more common in HHT2 than in HHT1 (p < 0.01). In conclusion, HHT patients present with a variety of neuroradiological manifestations, which are related to substantial causes of morbid-mortality in HHT.