Manifestations Of Hereditary Hemorrhagic Telangiectasia Research Articles

Hepatic manifestations of hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia is a genetic condition of abnormal blood vessel formation resulting from an imbalance of pro- and anti-angiogenic products of the transforming growth factor β/bone morphogenetic protein signalling pathway which contributes to vascular remodelling and maintenance. Hepatic vascular malformations are common although less frequently symptomatic, but may result in high-output cardiac failure, portal hypertension and biliary ischaemia. Whilst the understanding of the genetic and cell signalling pathways that are the hallmark of hereditary haemorrhagic telangiectasia have been clarified, there remain challenges in therapy for these patients. Only patients with symptomatic hepatic vascular malformations require treatment, with most (63%) responding to first-line medical therapy. For non-responders, bevacizumab is effective in reducing cardiac output in those with heart failure secondary to hepatic vascular malformations as well as other manifestations of the disease. Although liver transplantation is the only curative option, optimal timing is critical. Novel anti-angiogenetic drugs and those that target aberrant cell signalling pathway are being explored.

Molecular mechanisms and clinical manifestations of hereditary hemorrhagic telangiectasia

IntroductionHereditary Hemorrhagic Telangiectasia (HHT) is charactered by telangiectasia and arteriovenous malformations (AVMs). Recurrent visceral and mucocutaneous bleeding is frequently reported among HHT patients, while data on the prevalence of thrombosis remains limited. This study aims to describe the clinical manifestations and molecular biological characteristics of HHT patients. MethodsWe conducted a retrospective study at Ruijin Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. A total of 24 HHT patients, observed between January 2019 and December 2023, were included. We recorded the biological, clinical, and therapeutic events, with particular attention to bleeding and thrombotic events. Gene mutation analysis and blood constituent measurements were performed. ResultsThe prevalence of bleeding among all HHT patients was 100 %, while thrombotic events were noted in 41.70 % of cases. Hepatic arteriovenous malformations (HAVMs) were identified in six patients, pulmonary arteriovenous malformations (PAVMs) in five patients, and cerebral arteriovenous malformations (CAVMs) in one patient. For patients with thrombosis, the discontinuation rates were 23.08 % for antiplatelet therapy and 33.33 % for anticoagulant therapy due to the increased risk of bleeding. Genetic mutations related to HHT were present in 16 patients, with ACVRL1 (activin A receptor-like type 1) mutations being the most frequent at 41.67 %, followed by ENG (endoglin) mutations at 20.83 %, and GDF2 (growth differentiation factor 2) mutations at 4.17 %. The incidence of PAVMs was 75.00 % in HHT1 patients with ENG mutations and 20 % in HHT2 patients with ACVRL1 mutations, while HAVMs occurred in 0 % and 40.00 % of these groups, respectively. Patients were divided into non-AVMs and AVMs groups. Compared to normal controls, von Willebrand factor (vWF) activity was significantly increased in all HHT patients (149.10 % vs. 90.65 %, P < 0.001). In the non-AVMs group, the median level of stromal cell-derived factor-1 (SDF-1) was significantly elevated (124.31 pg/mL vs. 2413.57 pg/mL, P < 0.05), while vWF antigen levels were markedly higher in the AVMs group (165.30 % vs. 130.60 %, P = 0.021). Further grouping of HHT patients based on bleeding and thrombosis phenotypes revealed that those with thrombosis had significantly higher median percentages of schistocytes (3.50 % vs. 0 %, P = 0.002), ferritin concentrations (318.50 μg/L vs. 115.50 μg/L, P = 0.001), and lactate dehydrogenase (LDH) levels (437 U/L vs. 105 U/L, P < 0.001). There were no significant differences in the activity of vWF, protein C (PC), protein S (PS), and factor VIII (FVIII) between the two groups. ConclusionThis study highlighted the complex relationship between arteriovenous malformations and genetic mutations in HHT patients. A comprehensive assessment of bleeding and thrombosis risks should be conducted for each HHT patient, additionally, further clinical studies are needed to explore the risk factors for thrombosis and anticoagulant-related bleeding in HHT.

Surgical treatment of brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia: a single-center experience

OBJECTIVE Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant disorder characterized by multiple vascular malformations. Brain arteriovenous malformations (bAVMs) are a significant manifestation of HHT. The surgical management of these lesions in patients with HHT remains debated, with limited literature on postoperative outcomes. The goal of this study was to evaluate the safety and efficacy of surgical treatment for bAVMs in patients with HHT and propose a treatment rationale based on a single-center experience. METHODS This retrospective review included 20 patients diagnosed with HHT who underwent resection of 23 bAVMs at the Stanford University Medical Center between January 2007 and September 2023. Data were also collected on bAVMs treated conservatively, with embolization, or with radiosurgery at the authors’ institution, for comparison. RESULTS There were 16 Spetzler-Martin (SM) grade I, 6 SM grade II, and 1 SM grade IV bAVM. Six of the bAVMs presented with neurological symptoms (3 with hemorrhage and 3 with focal neurological deficits), while the rest were detected on routine screening. Complete excision was angiographically confirmed in all patients, with a mean overall hospital stay of 2.1 days and a mean follow-up of 36 months. Postoperative complications were limited to transient mild weakness in 2 patients, 1 of whom also had transient speech deficits, and visual field deficits in 3 patients, 2 of whom improved on long-term follow-up. CONCLUSIONS In this most extensive surgical series published to date, resection of bAVMs in patients with HHT showed favorable outcomes with a low complication rate, suggesting that the benefits of surgery outweigh the risks, especially considering the potential cumulative lifetime risk of hemorrhage. MR arterial spin labeling was found to be the most sensitive noninvasive measure of detecting bAVMs in patients with HHT.

A rare cause of stroke at a young age: ischemic stroke by the mechanism of paradoxical embolism in a patient with hereditary hemorrhagic telangiectasia

Clarification of the aetiology of ischemic stroke (IS) in young adults (aged between 18 and 45 years) is an extremely difficult task, as rare causes that are hardly known to neurologists are very common. One of these causes is paradoxical embolism due to pulmonary arteriovenous malformation (AVM), one of the manifestations of hereditary hemorrhagic telangiectasia (HHT). The diagnosis of HHT-associated pulmonary AVMs and IS is a multistep task that requires a personalized multidisciplinary approach using high-tech ultrasound, tomographic and genetic examination methods. This article discusses the clinical case of a young patient with HHT and recurrent IS through the mechanism of paradoxical embolism from pulmonary AVMs; issues of diagnosis, treatment and prevention of both the underlying disease and recurrent vascular events are discussed.

Multidisciplinary coordinated care of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease).

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is a rare disorder with a case prevalence as high as one in 5000, causing arteriovenous malformations in multiple organ systems. HHT is familial with autosomal dominant inheritance, with genetic testing allowing confirmation of the diagnosis in asymptomatic kindreds. Common clinical manifestations are epistaxis and intestinal lesions causing anemia and requiring transfusions. Pulmonary vascular malformations predispose to ischemic stroke and brain abscess and may cause dyspnea and cardiac failure. Brain vascular malformations can cause hemorrhagic stroke and seizures. Rarely, liver arteriovenous malformations can cause hepatic failure. A form of HHT can cause juvenile polyposis syndrome and colon cancer. Specialists in multiple fields may be called to care for one or more aspects of HHT, but few are familiar with evidence-based guidelines for HHT management or see a sufficient number of patients to gain experience with the unique characteristics of the disease. Primary care physicians and specialists are often unaware of the important manifestations of HHT in multiple systems and the thresholds for their screening and appropriate management. To improve familiarity, experience, and coordinated multisystem care for patients with HHT, the Cure HHT Foundation, which advocates for patients and families with this disease, has accredited 29 centers in North America with designated specialists for the evaluation and care of patients with HHT. Team assembly and current screening and management protocols are described as a model for evidence-based, multidisciplinary care in this disease.

Spontaneous haemothorax caused by a ruptured pulmonary arterio-venous malformation: A manifestation of hereditary haemorrhagic telangiectasia in pregnancy.

We report our experience of managing a massive haemothorax caused by a ruptured, previously unknown, pulmonary arteriovenous malformation (pAVM) at 34 + 5 weeks of gestation, which proved to be a manifestation of hereditary haemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome. The patient underwent an emergency caesarean section under general anaesthesia after placement of a chest tube and gave birth to a healthy infant. A postoperative thoracic computed tomography angiography highlighted the presence of the large pAVM. Transcatheter embolization was performed right after the delivery. Subsequent patient's anamnesis, family history and genetic analysis finally revealed the presence of the syndrome. The aim of our report is to create awareness of this serious condition with potential life-threatening complications, especially in pregnancy. Simple criteria have been published and allow to easily consider HHT and the presence of potential AVM during anamnesis, ideally even before pregnancy.

UNTREATED PULMONARY ARTERIOVENOUS MALFORMATIONS IN A CARDIORESPIRATORY STORM

UNTREATED PULMONARY ARTERIOVENOUS MALFORMATIONS IN A CARDIORESPIRATORY STORM

Hereditary hemorrhagic telangiectasia with bilateral pulmonary vascular malformations and a cerebral abscess as a complication: A case report

Introduction: Hereditary hemorrhagic telangiectasia (HHT) also known as Osler–Weber–Rendu syndrome is a relatively common, under-recognized autosomal-dominant disorder that results from multisystem vascular dysplasia. It is characterized by telangiectasis and arteriovenous malformations of skin, mucosa, and viscera. Case Report: A 26-year-old man presented with an 8-day history of headache, fever, cough, right hemiparesis, motor dysphasia, and dysgraphia. The urgent brain computed tomography (CT) scan revealed a bulky rounded left frontal lobe lesion, with peripheral contrast enhancement and marked perilesional edema, indicating a brain abscess or metastasis. A brain magnetic resonance imaging showed an intra-axial hypovascular round enhancing left frontal lobe lesion, with pronounced perilesional edema. Laboratory findings discovered severe polycythemia with normal level of erythropoietin and gas analysis of blood revealed hypoxemia of secondary cause. Computed tomography of the lungs suggested pulmonary arteriovenous malformations (AVMs) in the right and left lung. Contrast-enhanced chest CT scan confirmed AVM of the lungs, while abdominal CT scan ruled out AVM of the liver. The brain abscess was treated neurosurgically. The patient reported positive family history of epistaxis. Conclusion: Brain abscess may be the first manifestation of HHT and early clinical recognition of HHT in patients with positive family history of epistaxis may help to prevent complications. Keywords: Arteriovenous malformations, Brain abscess, Hereditary hemorrhagic telangiectasia, Hypoxemia, Polycythemia

Dental manifestations of hereditary hemorrhagic telangiectasia: a clinical case

A rare disorder that changes the blood vessels of many organs and causes bleeding. The disease affects the lungs, liver, central nervous system, gastrointestinal tract, skin and mucous membranes. The degree of incidence of Randu-Weber-Osler disease is not high and ranges from 1 detected case per 50 thousand – per 100 thousand population. The scientific article presents a clinical case with dental manifestations of Randu-Weber-Osler disease and indicates the important role of the dentist in monitoring such patients. The red border of the lips is dry, pale, with pronounced multiple punctate telangiectasias of red-violet color. In the area of the lower lip, brightly colored round nodules with a diameter of about 5 mm are found, protruding above the surface, painless on palpation. On the dorsal and lateral surfaces, there are papular formations of a red-violet color, with a diameter of 5 to 7 mm, protruding above the surface. The gums are hyperemic, edematous, loose, bleeds on probing, periodontal pockets with exudative contents. On examination, attention was drawn to an insufficient amount of saliva, which was located mainly in the retromolar region; it was frothy. The salivation rate is reduced (0.1 ml per minute). It is assumed that before and during invasive dental procedures, antibiotic therapy is necessary, especially when working in infected areas (500 mg of amoxicillin) every 8 hours starting 12 hours before the procedure for 7 days. Given that hypoxia and cerebral embolism are frequent complications, the dental chair should be in an upright position throughout the patient's appointment. Treatment of this disorder is only supportive in nature, its goals are to relieve symptoms, treat complications and prevent progression of the disease. Early definition of the manifestations of this disease and careful observation of the patient gives a favorable prognosis of the course and prevents the development of severe complications. Keywords: hereditary hemorrhagic telangiectasia, periodontitis, xerostomia.

Cardiac and Hemodynamic Manifestations of Hereditary Hemorrhagic Telangiectasia.

The autosomal dominant trait hereditary hemorrhagic telangiectasia (HHT) causes multiorgan dysplastic lesions of the vasculature that can activate multiple physiological cascades leading to a broad array of cardiovascular diseases. Up to 78% of patients with HHT develop hepatic arteriovenous malformations (AVMs), which cause a hyperdynamic circulatory state secondary to hepatic/portal shunting. This condition can eventually progress to high-output cardiac failure (HOCF) with continued peripheral tissue hypoxemia. Treatment for HOCF is often limited to supportive measures (diuretics and treatment of anemia); however, recent studies using systemic bevacizumab have shown promise by substantially reducing the cardiac index. In the context of liver AVMs and high cardiac output, the pulmonary vasculature can also experience high flow. Without adequate dilation of pulmonary vessels, post-capillary pulmonary hypertension can develop. Another form of pulmonary hypertension observed in HHT, pulmonary arterial hypertension, is caused by HHT-related mutations in ENG and ACVRL1 causing congestive arteriopathy. Post-capillary pathogenesis is addressed by reducing the high-output state, whereas the pre-capillary state is treated with supportive mechanisms (diuretics, oxygen) and agents targeting pulmonary vasoreactivity: endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors. If either form of pulmonary hypertension is left untreated or proves refractory and progresses, the common hemodynamic complication is right heart failure. Targeted right heart therapies involve similar strategies to those of pulmonary arterial hypertension, with several experimental approaches under study. In this review, we describe in detail the mechanisms of pathogenesis, diagnosis, and treatment of the hemodynamic complications and associated cardiovascular diseases that may arise in patients with HHT.

Recognition and management of vascular lesions in von Willebrand disease

Recognition and management of vascular lesions in von Willebrand disease

Classification of endonasal HHT lesions using digital microscopy

BackgroundRecurrent spontaneous epistaxis is the most common clinical manifestation and the most debilitating symptom in hereditary haemorrhagic telangiectasia (HHT) patients. To this date, there exist only a classification of HHT patients by different genetic mutations. There is no standard classification for the mucocutaneous endonasal manifestations of HHT. The aim of the present study was to document the variety of endonasal HHT lesions using digital microscopy and to propose a clinical classification.MethodsWe recorded the endonasal HHT lesions of 28 patients using a digital microscope. We reconstructed the 3D images und videos recorded by digital microscope afterwards and classified the endonasal lesions of HHT in two classes: Grade A, presence of only flat telangiectasias in the mucosa level and Grade B, (additional) presence of raised berry or wart-like telangiectasia spots. We investigated also Haemoglobin level by routine laboratory procedures, plasma VEGF level by ELISA, Severity of epistaxis by epistaxis severity score (ESS) and quality of life by a linear visual analogue scale (VAS).ResultsWe found a higher quality of life and a lower severity of epistaxis in Grade A patients in comparison to Grade B patients. No difference in plasma VEGF level and in Haemoglobin between Grad A patients and Grade B patients could be detected. Plasma VEGF levels showed no gender specific differences. It could also not be correlated to the extranasal manifestation.ConclusionThe classification for endonasal manifestation of HHT proposed in this study indicates severity of epistaxis und quality of life. Digital microscopy with the ability of 3D reconstruction of images presents a useful tool for such classifications. The classification of endonasal HHT lesions using digital microscopy allows to evaluate the dynamic of HHT lesions in the course of time independent of examiner. This allows also to evaluate the efficacy of the different treatment modalities by dynamic of HHT lesions. Moreover digital microscopy is very beneficial in academic teaching of rare diseases.

SMAD4 mutation and the combined juvenile polyposis and hereditary hemorrhage telangiectasia syndrome: a single center experience.

Mutations of the SMAD4 gene can result in a distinct syndrome with combined clinical features of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT). Even though it is known that patients with the overlap syndrome are at increased risk for colorectal malignancies and bleeding, the outcomes of this patient population have not been extensively studied. Retrospective study aiming to describe the phenotype and clinical outcomes of patients with genetically confirmed JP-HHT combined syndrome in a single large tertiary center in North America. A total of 22 patients were identified, the majority females (59%) with a median age diagnosis at 24years. Polyps were more commonly seen in the lower gastrointestinal (GI) tract, and tubular adenomas were seen in 50%. Epistaxis and pulmonary arteriovenous malformations (AVM) were the most common manifestations of HHT, with a median Curacao score of 3 [1-4]. Hospitalization for gastrointestinal bleeding and cerebrovascular events occurred at a rate of 28% and 4%, respectively. Two patients had GI malignancies, one rectal and one small bowel adenocarcinoma. Overall mortality was 14%. Patients with the combined JP-HHT syndrome remain at risk for life-threatening vascular complications and gastrointestinal malignancies; close follow-up is necessary to minimize morbidity and mortality in this patient population.

HEREDITARY HEMORRHAGIC TELANGIECTASIA: A CASE REPORT

Hereditary hemorrhagic telangiectasia (HHT) is a rare mucocutaneous disease, inherited by autosomal dominant trait. Its diagnosis can be established by the identification of 3 of the following criteria: (1) frequent episodes of epistaxis; (2) telangiectasias of the skin and mucosa; (3) arteriovenous malformations involving lungs, liver, or central nervous system; and (4) family history of HHT. The purpose of this study is to perform a case report of HHT, attended at a stomatology service. The patient was a 70-year-old female, with numerous vascular lesions affecting the oral mucosa, hands, and feet. Endoscopic analysis also showed telangiectasias in the gastric mucosa. The patient had anemia and frequent episodes of epistaxis, and also reported a family history of these manifestations, involving her father, sister, and children. The diagnosis was defined as HHT. The dentist should be aware of the different manifestations of HHT and consider it as a possible diagnosis for patients with various vascular lesions.

Gene diagnosis and treatment of hereditary hemorrhagic telangiectasia with epistaxis as its main symptom

Objective:The aim of this study is to investigate the gene diagnosis and the treatment of hereditary hemorrhagic telangiectasia (HHT) with epistaxis as the main symptom, and to analyze the mutation of ACVRL1 gene in the family. Method:Detailed pedigree investigation was carried out on the proband.Sixtynine genes related to coagulation disorder were sequenced and analyzed by high throughput sequencing for the father and son of the proband. Result:Four generations of the family consisted of 30 probands, including 11 patients. A pathogenic mutation ACVRL1_ex9 c.1313T > C (p.M438T) was detected in both patient and his father. Conclusion:Recurrent epistaxis is the main manifestation of hereditary hemorrhagic telangiectasia in this family. The mutation of ACVRL1 gene is the pathogenic gene of this family, which can be treated by surgery and medicine.

Assessing the Hereditary Hemorrhagic Telangiectasia Algorithms in a Community-Based Patient Population.

Hereditary hemorrhagic telangiectasia (HHT) is a rare, genetic, and underdiagnosed disease that causes vascular malformations throughout the body. Two specific combinations of International Classification of Diseases, Ninth Revision-Clinical Modification diagnosis codes, the "HHT Algorithms" (HHTAs), were developed previously from a derivation cohort to help identify undiagnosed HHT cases. To test these 2 algorithms, and a third, newly designed HHTA, in an independent population with available clinical records and thus identify people who might have undiagnosed HHT. The HHTAs were applied to the patient population of Kaiser Permanente Northern California. The HHTAs produced 3 groups (A, B, and C) using different combinations of diagnosis codes reflecting clinical manifestations of HHT. First, the number of Kaiser Permanente Northern California patients with each code was determined by database programming. Next, detailed chart review was performed, and patients with a Curaçao score of 2 or higher were considered to have possible HHT. Of 3,065,210 records queried, 163 patients met HHTA criteria. After chart review, the study identified 113 patients with possible undiagnosed HHT (Group A: n = 3, Group B: n = 3, Group C: n = 107). Employing the HHTAs in this community-based population resulted in a modest yield of patients with possible HHT. Further research is required to assess the utility of the HHTAs in identifying patients with actual HHT.

Sclerotherapy and Topical Nasal Propranolol: An Effective and Safe Therapy for HHT-Epistaxis.

Epistaxis is the most frequent clinical manifestation of hereditary hemorrhagic telangiectasia (HHT). Several topical, systemic, and surgical treatments have been tried, but none have been completely effective. The aim of the present study is to evaluate whether a combined treatment sclerotherapy and topical therapy with propranolol 0.5% nasal formulation would reduce the epistaxis due to HHT and improve patient's quality of life. An observational cross-sectional study was carried out. The primary outcome measure was frequency and severity of epistaxis as measured by the epistaxis severity score (ESS) at baseline (4 weeks before therapy) and at least 4 weeks after the treatment was implemented. Quality of life was analyzed using EuroQol-5D (EQ-5D) scale and visual analogue (VAS) scale before and after treatment. A total of 38 consecutive patients subjected to the combined treatment were evaluated (mean age: 57.2 years, standard deviation [SD] = 13.9; 60.5% women). The mean time of treatment was 37.1 weeks (SD = 14.9). Combined therapy significantly reduces frequency and severity of epistaxis, with an ESS improvement of 5 points from 6.9 ± 2.6 to 1.9 ± 1.3 (P < 0.05); however, the EQ-5D scale increased from 0.66 ± 0.27 to 0.93 ± 0.12 (P < 0.05). The difference in VAS means showed an increase from 44.6 ± 28.3 to 82.5 ± 12.5 (P < 0.05). The increases in quality of life are in line with the drop in ESS. The study demonstrated that combined therapy (sclerotherapy and topical nasal propranolol) significantly reduced the epistaxis due to HHT and increased patients' quality of life. 2c Laryngoscope, 129:2216-2223, 2019.

Abdominal manifestations of hereditary hemorrhagic telangiectasia: a series of 333 patients over 15years.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multi-organ vascular disorder that commonly affects the gastrointestinal tract and the liver resulting in telangiectasias and arteriovenous malformations (AVMs). Previous studies looking at the prevalence of liver and abdominal organ involvement in HHT have been limited by differing imaging techniques and sample size limitations. We sought to define the prevalence of HHT related abdominal vascular abnormalities using optimized multiphasic contrast-enhanced abdominal computed tomography (CT) exams in a large cohort of HHT patients. Between January 2001 and May 2015; we identified a total of 333 consecutive HHT patients who had undergone a dedicated HHT protocol multiphase abdominal CT at our institution. The CT exams were reviewed by three board certified abdominal radiologists for the presence of vascular abnormalities involving the liver, pancreas, spleen, and other abdominal organs. Vascular abnormalities involving the liver were further categorized as telangiectasias, large confluent vascular masses, perfusion abnormalities, or hepatic shunts. In patients with abdominal vascular abnormalities, the liver was the most commonly involved organ, with 180 out of 333 (54.1%) patients demonstrating at least one hepatic vascular abnormality (telangiectasia, confluent vascular mass, transient perfusion abnormalities, and hepatic shunts), with most (70.0%) demonstrating multiple hepatic vascular abnormalities. The other most common organs involved included the pancreas (18.0%), spleen (6.3%), and small bowel (4.5%). In patients with the clinical diagnosis of HHT, greater than half demonstrate an abdominal vascular abnormality, with the most commonly involved organ being the liver. These may be under recognized on routine or single phase contrast-enhanced CT of the abdomen. This supports the use of optimized multiphasic abdominal CT exams as an important tool for the evaluation and screening of patients with HHT.

Decreased levels of miR-28-5p and miR-361-3p and increased levels of insulin-like growth factor 1 mRNA in mononuclear cells from patients with hereditary hemorrhagic telangiectasia 1.

Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disorder inherited in an autosomal dominant manner. Patients with HHT can develop vascular dysplasias called telangiectasias and arteriovenous malformations (AVMs). Our objective was to profile and characterize micro-RNAs (miRNAs), short noncoding RNAs that regulate gene expression posttranscriptionally, in HHT patient-derived peripheral blood mononuclear cells (PBMCs). PBMCs, comprised mostly of lymphocytes and monocytes, have been reported to be dysfunctional in HHT. A total of 40 clinically confirmed HHT patients and 22 controls were enrolled in this study. PBMCs were isolated from 16 mL of peripheral blood and purified for total RNA. MiRNA expression profiling was conducted with a human miRNA array analysis. Select dysregulated miRNAs and miRNA targets were validated with reverse transcription-quantitative polymerase chain reaction. Of the 377 miRNAs screened, 41 dysregulated miRNAs were identified. Both miR-28-5p and miR-361-3p, known to target insulin-like growth factor 1 (IGF1), a potent angiogenic growth factor, were found to be significantly downregulated in HHT patients. Consequently, IGF1 mRNA levels were found to be significantly elevated. Our research successfully identified miRNA dysregulation and elevated IGF1 mRNA levels in PBMCs from HHT patients. This novel discovery represents a potential pathogenic mechanism that could be targeted to alleviate clinical manifestations of HHT.

SMAD4 Mutation and the Combined Juvenile Polyposis and Hereditary Hemorrhage Telangiectasia Syndrome: A Single Center Experience

Introduction: Juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT) are autosomal dominant disorders with characteristic clinical phenotypes. Mutations of the SMAD4 gene can result in a distinct syndrome with combined clinical features of both HHT and JPS. We aimed to describe the clinical phenotype of patients with the SMAD4 mutations seen at Mayo Clinic Rochester. Methods: Retrospective review of patients with genetically confirmed diagnosis of combined JP-HHT syndrome between January 1998 and January 2018. HHT phenotype was assessed using the Curacao criteria. JPS features were determined by review of endoscopy and pathology reports. Additional outcomes included: incidence of gastrointestinal (GI) malignancies, vascular events, hospitalization for gastrointestinal bleeding (GIB) and overall mortality. Results: A total of 22 patients were identified. Median age was 34 years (1-67) and 41% were males. Median age diagnosis and time of follow-up were 24 (1-66) and 6.5 (0-58) years, respectively. Median Curacao score was 3 (1-4). Seventy-seven percent of patients had a prior episode of epistaxis, 56% skin telangiectasias and 60% visceral arteriovenous malformations (AVM). Common sites for visceral AMV were lower respiratory (45%), liver (27%), GI (10%) and central nervous system (10%). Eighty two percent of patients had family history of HHT. Lower GI polyps (LGP) were found in 86% of patients, most commonly located in the right side of the colon. Upper GI polyps (UGP) were seen in 68% of patients, mainly in the stomach (10/15) and duodenum (5/15). Forty percent of LGP were found to be tubular adenomas compared to 20% of UGP. Family history of polyps and colorectal cancer were present in 91% and 54% of patients, respectively. Two patients had GI malignancies, one rectal and one small bowel adenocarcinoma. One patient had an ischemic cerebellar stroke at age 24 years. A third of the cohort (6/16) had a history of hospitalization for GIB. Overall mortality was 14% with average age of death at 66 years. Conclusion: In our cohort, patients with the combined JP-HHT syndrome had epistaxis and pulmonary AVMs as common manifestations of HHT. Hospitalization for GIB and cerebrovascular events occurred at a rate of 28% and 4%, respectively. Polyps were more commonly seen in the lower GI tract and tubular adenomas were seen in 50%. GI adenocarcinoma occurred at a rate of 10% and overall mortality was 14% within the observed follow-up period.