Pulmonary arteriovenous malformations in Rendu-Osler-Weber syndrome.

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.

Defective Flow-Migration Coupling Causes Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Activin receptor-like kinase 1 (ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia, a devastating disorder that leads to arteriovenous malformations. Here, we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. METHODS: Using Cre lines that recombine in different subsets of arterial, capillary-venous, or endothelial tip cells, we show that capillary-venous Alk1 deletion was sufficient to induce arteriovenous malformation formation in the postnatal retina. RESULTS: ALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1-deficient cells exhibited increased integrin signaling interaction with vascular endothelial growth factor receptor 2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacologic inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1-deficient mice. CONCLUSIONS: Our study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of arteriovenous malformation formation in hereditary hemorrhagic telangiectasia disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in patients with hereditary hemorrhagic telangiectasia.

Ischemic Stroke in Patients With Pulmonary Arteriovenous Fistulas.

BACKGROUND AND PURPOSE: Pulmonary arteriovenous fistulas (PAVFs) are a treatable cause of acute ischemic stroke (AIS), not mentioned in current American Heart/Stroke Association guidelines. PAVFs are recognized as an important complication of hereditary hemorrhagic telangiectasia. METHODS: The prevalence of PAVF and hereditary hemorrhagic telangiectasia among patients admitted with AIS in the United States (2005-2014) was retrospectively studied, utilizing the Nationwide Inpatient Sample database. Clinical factors, morbidity, mortality, and management were compared in AIS patients with and without PAVF/hereditary hemorrhagic telangiectasia. RESULTS: Of 4 271 910 patients admitted with AIS, 822 (0.02%) were diagnosed with PAVF. Among them, 106 of 822 (12.9%) were diagnosed with hereditary hemorrhagic telangiectasia. The prevalence of PAVF per million AIS admissions rose from 197 in 2005 to 368 in 2014 (Ptrend, 0.026). Patients with PAVF were younger than AIS patients without PAVF (median age, 57.5 versus 72.5 years), had lower age-adjusted inpatient morbidity (defined as any discharge other than home; 39.6% versus 46.9%), and had lower in-hospital case fatality rates (1.8% versus 5.1%). Multivariate analyses identified the following as independent risk markers (odds ratio [95% CI]) for AIS in patients with PAVF: hypoxemia (8.4 [6.3-11.2]), pulmonary hemorrhage (7.9 [4.1-15.1]), pulmonary hypertension (4.3 [4.1-15.1]), patent foramen ovale (4.2 [3.5-5.1]), epistaxis (3.7 [2.1-6.8]), venous thrombosis (2.6 [1.9-3.6]), and iron deficiency anemia (2 [1.5-2.7]). Patients with and without PAVF received intravenous thrombolytics at a similar rate (5.9% versus 5.8%), but those with PAVF did not receive mechanical thrombectomy (0% versus 0.7%). CONCLUSIONS: Pulmonary arteriovenous fistula-related ischemic stroke represents an important younger demographic with a unique set of stroke risk markers, including treatable conditions such as causal PAVFs and iron deficiency anemia.

Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: a proof of concept study.

The inhibiting effects of itraconazole, an antifungal drug on vascular endothelial growth factor (VEGF) have recently been discovered. By inhibiting VEGF, itraconazole has shown potential in clinical trials as anti-cancer treatment. In hereditary hemorrhagic telangiectasia (HHT) patients, VEGF levels are elevated and inhibition of VEGF can decrease bleeding. Itraconazole could potentially serve as anti-angiogenic therapy for HHT-related bleeding. We report a proof of concept study with HHT patients and severe epistaxis. Patients were treated with daily 200 mg orally administered itraconazole for sixteen weeks. Twenty-one HHT patients, 8 females (38%), 13 males (62%), median age of 59 years (interquartile range (IQR) 55-69) were enrolled. Of these patients, 13 (62%) were diagnosed with HHT type 1, seven (33%) with HHT type 2 and in one patient (5%), no pathognomonic HHT mutation was found. Four patients (19%) prematurely terminated the study (3 due to mild or moderate side-effects) resulting in 17 patients included in the analyses. The median epistaxis severity score significantly decreased during treatment from 6.0 (IQR 5.1-7.2) to 3.8 (IQR 3.1-5.2) (p = 0.006). The monthly epistaxis frequency decreased from 56 to 38 epistaxis episodes (p = 0.004) and the monthly duration from 407 to 278 minutes (p = 0.005). Hemoglobin levels did not significantly change. The quality of life showed a small but significant improvement. In conclusion, oral itraconazole significantly improved epistaxis in HHT patients. The potential benefit of itraconazole in HHT should be further investigated.

Angiopoietin-2 Inhibition Rescues Arteriovenous Malformation in a Smad4 Hereditary Hemorrhagic Telangiectasia Mouse Model.

BACKGROUND: Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular disorder caused by heterozygous, loss-of-function mutations in 4 transforming growth factor beta (TGFß) pathway members, including the central transcriptional mediator of the TGFß pathway, Smad4. Loss of Smad4 causes the formation of inappropriate, fragile connections between arteries and veins called arteriovenous malformations (AVMs), which can hemorrhage leading to stroke, aneurysm, or death. Unfortunately, the molecular mechanisms underlying AVM pathogenesis remain poorly understood, and the TGFß downstream effectors responsible for hereditary hemorrhagic telangiectasia-associated AVM formation are currently unknown. METHODS: To identify potential biological targets of the TGFß pathway involved in AVM formation, we performed RNA- and chromatin immunoprecipitation-sequencing experiments on BMP9 (bone morphogenetic protein 9)-stimulated endothelial cells (ECs) and isolated ECs from a Smad4-inducible, EC-specific knockout ( Smad4-iECKO) mouse model that develops retinal AVMs. These sequencing studies identified the angiopoietin-Tek signaling pathway as a downstream target of SMAD4. We used monoclonal blocking antibodies to target a specific component in this pathway and assess its effects on AVM development. RESULTS: Sequencing studies uncovered 212 potential biological targets involved in AVM formation, including the EC surface receptor, TEK (TEK receptor tyrosine kinase) and its antagonistic ligand, ANGPT2 (angiopoietin-2). In Smad4-iECKO mice, Angpt2 expression is robustly increased, whereas Tek levels are decreased, resulting in an overall reduction in angiopoietin-Tek signaling. We provide evidence that SMAD4 directly represses Angpt2 transcription in ECs. Inhibition of ANGPT2 function in Smad4-deficient mice, either before or after AVMs form, prevents and alleviates AVM formation and normalizes vessel diameters. These rescue effects are attributed to a reversion in EC morphological changes, such as cell size and shape that are altered in the absence of Smad4. CONCLUSIONS: Our studies provide a novel mechanism whereby the loss of Smad4 causes increased Angpt2 transcription in ECs leading to AVM formation, increased blood vessel calibers, and changes in EC morphology in the retina. Blockade of ANGPT2 function in an in vivo Smad4 model of hereditary hemorrhagic telangiectasia alleviated these vascular phenotypes, further implicating ANGPT2 as an important TGFß downstream mediator of AVM formation. Therefore, alternative approaches that target ANGPT2 function may have therapeutic value for the alleviation of hereditary hemorrhagic telangiectasia symptoms, such as AVMs.

SMAD4 Prevents Flow Induced Arteriovenous Malformations by Inhibiting Casein Kinase 2.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder that causes arteriovenous malformations (AVMs). Mutations in the genes encoding Endoglin ( ENG) and activin-receptor-like kinase 1 ( AVCRL1 encoding ALK1) cause HHT type 1 and 2, respectively. Mutations in the SMAD4 gene are present in families with juvenile polyposis-HHT syndrome that involves AVMs. SMAD4 is a downstream effector of transforming growth factor-ß (TGFß)/bone morphogenetic protein (BMP) family ligands that signal via activin-like kinase receptors (ALKs). Ligand-neutralizing antibodies or inducible, endothelial-specific Alk1 deletion induce AVMs in mouse models as a result of increased PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) signaling. Here we addressed if SMAD4 was required for BMP9-ALK1 effects on PI3K/AKT pathway activation. METHODS: The authors generated tamoxifen-inducible, postnatal, endothelial-specific Smad4 mutant mice ( Smad4iΔEC). RESULTS: We found that loss of endothelial Smad4 resulted in AVM formation and lethality. AVMs formed in regions with high blood flow in developing retinas and other tissues. Mechanistically, BMP9 signaling antagonized flow-induced AKT activation in an ALK1- and SMAD4-dependent manner. Smad4iΔEC endothelial cells in AVMs displayed increased PI3K/AKT signaling, and pharmacological PI3K inhibitors or endothelial Akt1 deletion both rescued AVM formation in Smad4iΔEC mice. BMP9-induced SMAD4 inhibited casein kinase 2 ( CK2) transcription, in turn limiting PTEN phosphorylation and AKT activation. Consequently, CK2 inhibition prevented AVM formation in Smad4iΔEC mice. CONCLUSIONS: Our study reveals SMAD4 as an essential effector of BMP9-10/ALK1 signaling that affects AVM pathogenesis via regulation of CK2 expression and PI3K/AKT1 activation.

ALK1 Loss Results in Vascular Hyperplasia in Mice and Humans Through PI3K Activation.

OBJECTIVE: ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-ß (transforming growth factor-ß) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia-a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia. APPROACH AND RESULTS: In this work, we report that a reduction in ALK1 gene dosage (heterozygous ALK1+/- mice) results in enhanced retinal endothelial cell proliferation and vascular hyperplasia at the sprouting front. We found that BMP9/ALK1 represses VEGF (vascular endothelial growth factor)-mediated PI3K (phosphatidylinositol 3-kinase) by promoting the activity of the PTEN (phosphatase and tensin homolog). Consequently, loss of ALK1 function in endothelial cells results in increased activity of the PI3K pathway. These results were confirmed in cutaneous telangiectasia biopsies of patients with hereditary hemorrhagic telangiectasia 2, in which we also detected an increase in endothelial cell proliferation linked to an increase on the PI3K pathway. In mice, genetic and pharmacological inhibition of PI3K is sufficient to abolish the vascular hyperplasia of ALK1+/- retinas and in turn normalize the vasculature. CONCLUSIONS: Overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia.

[Diagnosis and treatment of Osler's disease]. / Diagnostik und Therapie des M. Osler.

Osler's disease is an autosomal dominant hereditary syndrome which belongs to the group of orphan diseases. Affected patients suffer primarily from severe epistaxis. Diagnosis is based on the Curaçao criteria and molecular genetic tests. Organ manifestations can be found in the form of arteriovenous shunts in the lung, liver, and gastrointestinal tract; more rarely also in the central nervous system (CNS) and other parts of the body. Many patients with gastrointestinal and other organ manifestations are frequently clinically asymptomatic; therefore, organ screening is essential to avoid later complications and should be performed in centers with particular expertise. No curative therapy currently exists. From the otolaryngologist's perspective, nasal mucosa treatments and endonasal laser applications are important and effective therapeutic approaches to epistaxis. Pharmacological interventions are focused on compensation of haploinsufficiency as well as antiangiogenetic approaches. Severe side effects have to be considered.

[Rendu-Osler-Weber disease : More than just a nosebleed]. / Morbus Osler : Mehr als nur Nasenbluten.

A 72-year-old female patient presented with increasing dyspnea of unclear origin classified as New York Heart Association stage III (NYHA III). Using transesophageal echocardiography a patent foramen ovale (PFO) and right heart failure could be diagnosed. Right heart catheterization revealed a large left to right shunt due to an arteriovenous malformation in the liver. Because of additional telangiectasia of the lips the presumptive diagnosis was Rendu-Osler-Weber disease. Typical nosebleeds and other symptoms of the disease were lacking and only two out of four Curaçao criteria were positive; therefore, genetic testing was performed, which verified the clinical diagnosis. Off-label use of the angiogenesis inhibitor bevacizumab was initiated as the therapeutic strategy and led to an improvement in the symptomatic dyspnea.

Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND AND PURPOSE: Hereditary hemorrhagic telangiectasia (HHT) is a systemic disease characterized by mucocutaneous telangiectasias, epistaxis, and arteriovenous malformations (AVMs). Intracranial hemorrhage (ICH) rates in this population are not well described. We report ICH rates and characteristics in HHT patients with brain AVMs (HHT-BAVMs). METHODS: We studied the first 153 HHT-BAVM patients with follow-up data enrolled in the Brain Vascular Malformation Consortium HHT Project. We estimated ICH rates after BAVM diagnosis. RESULTS: The majority of patients were women (58%) and white (98%). The mean age at BAVM diagnosis was 31±19 years (range, 0-70), with 61% of cases diagnosed on asymptomatic screening. Overall, 14% presented with ICH; among symptomatic cases, 37% presented ruptured. During 493 patient-years of follow-up, 5 ICH events occurred yielding a rate of 1.02% per year (95% confidence interval, 0.42-2.44%). ICH-free survival differed significantly by ICH presentation (P=0.003); ruptured cases had a higher ICH rate (10.07%; 95% confidence interval, 3.25-31.21%) than unruptured cases (0.43%; 95% confidence interval, 0.11-1.73%). CONCLUSIONS: Patients with HHT-BAVM who present with hemorrhage are at a higher risk for rehemorrhage compared with patients with BAVM detected presymptomatically.

Common and distinctive pathogenetic features of arteriovenous malformations in hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 animal models--brief report.

OBJECTIVE: Hereditary hemorrhagic telangiectasia is a genetic disorder characterized by visceral and mucocutaneous arteriovenous malformations (AVMs). Clinically indistinguishable hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 are caused by mutations in ENG and ALK1, respectively. In this study, we have compared the development of visceral and mucocutaneous AVMs in adult stages between Eng- and Alk1-inducible knockout (iKO) models. APPROACH AND RESULTS: Eng or Alk1 were deleted from either vascular endothelial cells (ECs) or smooth muscle cells in adult stages using Scl-CreER and Myh11-CreER lines, respectively. Latex perfusion and intravital spectral imaging in a dorsal skinfold window chamber system were used to visualize remodeling vasculature during AVM formation. Global Eng deletion resulted in lethality with visceral AVMs and wound-induced skin AVMs. Deletion of Alk1 or Eng in ECs, but not in smooth muscle cells, resulted in wound-induced skin AVMs. Visceral AVMs were observed in EC-specific Alk1-iKO but not in Eng-iKO. Intravital spectral imaging revealed that Eng-iKO model exhibited more dynamic processes for AVM development when compared with Alk1-iKO model. CONCLUSIONS: Both Alk1- and Eng-deficient models require a secondary insult, such as wounding, and ECs are the primary cell type responsible for the pathogenesis. However, Alk1 but not Eng deletion in ECs results in visceral AVMs.

Endoglin deficiency impairs stroke recovery.

BACKGROUND AND PURPOSE: Endoglin deficiency causes hereditary hemorrhagic telangiectasia-1 and impairs myocardial repair. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia-1 are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that endoglin deficiency impairs stroke recovery. METHODS: Eng heterozygous (Eng+/-) and wild-type mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Pial collateral vessels were quantified before pMCAO. Infarct/atrophic volume, vascular density, and macrophages were quantified in various days after pMCAO, and behavioral function was assessed using corner and adhesive removal tests on days 3, 15, 30, and 60 after pMCAO. The association between ENG 207G>A polymorphism and brain arteriovenous malformation rupture and surgery outcome was analyzed using logistic regression analysis in 256 ruptured and 157 unruptured patients. RESULTS: After pMCAO, Eng+/- mice showed larger infarct/atrophic volumes at all time points (P<0.05) and showed worse behavior performance (P<0.05) at 15, 30, and 60 days when compared with wild-type mice. Eng+/- mice had fewer macrophages on day 3 (P=0.009) and more macrophages on day 60 (P=0.02) in the peri-infarct region. Although Eng+/- and wild-type mice had similar numbers of pial collateral vessels before pMCAO, Eng+/- mice had lower vascular density in the peri-infarct region (P=0.05) on day 60 after pMCAO. In humans, ENG 207A allele has been associated with worse outcomes after arteriovenous malformation rupture or surgery of patients with unruptured arteriovenous malformation. CONCLUSIONS: Endoglin deficiency impairs brain injury recovery. Reduced angiogenesis, impaired macrophage homing, and delayed inflammation resolution could be the underlying mechanism.

De novo cerebrovascular malformation in the adult mouse after endothelial Alk1 deletion and angiogenic stimulation.

BACKGROUND AND PURPOSE: In humans, activin receptor-like kinase 1 (Alk1) deficiency causes arteriovenous malformations (AVMs) in multiple organs, including the brain. Focal Alk1 pan-cellular deletion plus vascular endothelial growth factor stimulation induces brain AVMs in the adult mouse. We hypothesized that deletion of Alk1 in endothelial cell (EC) alone plus focal vascular endothelial growth factor stimulation is sufficient to induce brain AVM in the adult mouse. METHODS: Focal angiogenesis was induced in the brain of 8-week-old Pdgfb-iCreER;Alk1(2f/2f) mice by injection of adeno-associated viral vectors expressing vascular endothelial growth factor. Two weeks later, EC-Alk1 deletion was induced by tamoxifen treatment. Vascular morphology was analyzed, and EC proliferation and dysplasia index (number of vessels with diameter>15 µm per 200 vessels) were quantified 10 days after tamoxifen administration. RESULTS: Tangles of enlarged vessels resembling AVMs were present in the brain angiogenic region of tamoxifen-treated Pdgfb-iCreER;Alk1(2f/2f) mice. Induced brain AVMs were marked by increased dysplasia index (P<0.001) and EC proliferation clustered within the dysplastic vessels. AVMs were also detected around the ear tag-wound and in other organs. CONCLUSIONS: Deletion of Alk1 in EC in adult mice leads to an increased local EC proliferation during brain angiogenesis and de novo brain AVM.

North American Study for the Treatment of Recurrent Epistaxis with Doxycycline: The NOSTRIL trial.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a vascular bleeding disorder characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. A frequently debilitating symptom is spontaneous recurrent epistaxis. OBJECTIVE: To evaluate whether doxycycline therapy improves epistaxis in HHT by using a prospective, randomized, placebo-controlled crossover study design. PATIENTS/METHODS: Twenty-two eligible patients between December 2017 and July 2020 at a single center were randomized to one of two study arms: doxycycline treatment followed by placebo, or vice versa. Primary outcomes measured differences in epistaxis severity between treatments. Changes in quality of life, laboratory markers of bleeding, and number of monthly blood transfusions or iron infusions were assessed as secondary endpoints. Additional post hoc endpoints included frequency and duration of dripping epistaxis and gushing epistaxis. A post hoc longitudinal analysis assessed effects of doxycycline over time. RESULTS/CONCLUSIONS: Doxycycline was safe and well tolerated. However, there was no reduction in the three primary outcome measures, nosebleed frequency (p = .16), nosebleed duration (p = .05), and Epistaxis Severity Score (p = .19). Quality of life, hemoglobin level, and number of blood transfusions and iron infusions did not differ between groups. Post hoc analysis demonstrated reduction in instances of gushing (p = .02) with doxycycline, although this finding is of unclear clinical significance. Post hoc longitudinal analysis showed reduction in frequency (mean estimate of coefficient = -0.19, standard error = 0.07, p = .01) and duration (mean estimate of coefficient = -2.33, standard error = 1.08, p = .03) of epistaxis over time. Post hoc findings suggest possible benefit of doxycycline but should be interpreted with caution given the overall negative study. Further investigation is needed with a larger sample size and a longer treatment duration.

Integration of clinical parameters, genotype and epistaxis severity score to guide treatment for hereditary hemorrhagic telangiectasia associated bleeding.

BACKGROUND: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare inherited disorder characterized by development of mucocutaneous telangiectases and visceral organ arteriovenous malformations, which can lead to recurrent, spontaneous bleeding and development of iron deficiency anemia. The primary objective of this study was to ascertain the relationship between epistaxis severity scores (ESS), laboratory values, genotype, and phenotype in HHT. Our secondary objective was to assess efficacy of systemic antifibrinolytic therapy in reducing ESS in HHT. METHODOLOGY: We conducted a retrospective review of patients seen at the UNC HHT Center from January 1, 2009 to February 28, 2015. ESS, demographics, and results of genetic testing were abstracted from the medical record. Response to antifibrinolytic therapy was evaluated by comparing pre-post ESS. RESULTS: One hundred and forty nine patients were eligible with 116 having genetic testing and 33 without. Age, hemoglobin and ferritin levels were predictive of ESS. Of the 116 patients that underwent genetic testing: 63 had an ACVRL1 mutation, 40 had an ENG mutation, 2 had a SMAD4 mutation, and 11 patients had no pathologic HHT genetic variation detected. Compared to patients without a detectable HHT-associated genetic variation, patients with a HHT-associated genetic variation had higher ESS scores (p < 0.05). Neither ESS nor genotype was predictive of pulmonary or brain AVMs. Twenty-four HHT patients with ESS > 4 were started on antifibrinolytic therapy (tranexamic acid or aminocaproic acid) and had a post-treatment ESS recorded. All patients had a decrease in ESS of > 0.71 (minimal meaningful difference), but patients taking antifibrinolytics displayed larger decreases. No patients on antifibrinolytics experienced a VTE with median follow up of 13 months. CONCLUSIONS: We demonstrate that the ESS correlates with age, hemoglobin and ferritin. Additionally, we demonstrate that HHT patients with genetic mutations have higher ESS scores. Our data demonstrate that antifibrinolytics are effective in decreasing epistaxis severity and safe with long-term use in HHT patients.

CT dose optimization for the detection of pulmonary arteriovenous malformation (PAVM): A phantom study.

PURPOSE: To determine the lowest suitable dose level for the detection of pulmonary arteriovenous malformation (PAVM) using a task-based image quality assessment. MATERIAL AND METHODS: A phantom was scanned using the standard chest protocol (STD) and 4 other ultra-low dose protocols (ULD) using various kVp. Raw data were reconstructed using level 5 of the hybrid iterative reconstruction algorithm (iDose4) for the STD protocol, and level 6 of iDose4 and levels 1 to 3 of model-based iterative reconstruction (IMR) for the ULD protocols. Both quantitative criteria and qualitative analysis were used to compare protocols. Noise-power-spectrum and Task-based transfer function were computed using imQuest software. The detectability-index (d') was computed for the detection of PAVM. A subjective analysis was performed by 2 chest radiologists to validate the image-quality obtained on the anthropomorphic phantom for all protocols. RESULTS: Similar d' values were found for ULD-140 using iDose4 6 compared to STD protocol. Greater d' values were found for all ULD protocols using IMR compared to STD. Subjective image quality was rated as acceptable to excellent for ULD-140 and ULD-120 for all reconstruction types, for ULD-100 and ULD-80 using IMR2, and for ULD-100 using IMR1. Image smoothing was poor for IMR3 for ULD-100 and ULD-80. Finally, the ULD-80 protocol reconstructed with IMR2 was chosen for the detection of PAVM. With this protocol, the dose (CTDIvol of 0.3mGy) was reduced by 91% compared with the STD protocol. CONCLUSION: A dose level as low as 0.3mGy reconstructed with IMR2 provides an image quality suitable for the detection of PAVM.

Clinical features and mutations in the ENG, ACVRL1, and SMAD4 genes in Korean patients with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder that is characterized by abnormal communication between the arteries and veins in the skin, mucosa, and various organs. HHT has been reported to show significant phenotypic variability and genetic heterogeneity with wide ethnic and geographic variations. Although mutations in the endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes have been known to cause HHT for more than 10 yr, little is known about the clinical features or genetic background of Korean patients with HHT. In addition, mutations in mothers against decapentaplegic homolog 4 (SMAD4) are also seen in patients with the combined syndrome of juvenile polyposis and HHT. This study examined five Korean patients with the typical manifestations of HHT such as frequent epistaxis and pulmonary arteriovenous malformations. Direct sequencing of the ENG and ACVRL1 genes revealed one known mutation, ENG c.277C>T, in one patient and two novel mutations, ENG c.992-1G>C and ACVRL1 c.81dupT in two patients, respectively. The remaining two patients with negative results were screened for SMAD4 mutations as well as gross deletions of ENG and ACVRL1 using multiple ligation-dependent probe amplification, but none was detected. Despite the small number of patients investigated, we firstly report Korean patients with genetically confirmed HHT, and show the genetic and allelic heterogeneity underlying HHT.

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

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

Malformações arteriovenosas pulmonares na síndrome de Rendu-Osler-Weber / Pulmonary arteriovenous malformations in Rendu-Osler-Weber syndrome

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.