Diagnosis Of Hereditary Hemorrhagic Telangiectasia Research Articles

Prevalence of Intracranial Aneurysms in Hereditary Hemorrhagic Telangiectasia: Report from a Single Reference Center.

Neurologic manifestations in hereditary hemorrhagic telangiectasia include an increased incidence of brain abscesses and ischemic strokes due to paradoxic embolization in addition to a wide spectrum of symptoms and complications due to typical brain vascular malformations. Intracranial aneurysms are not part of this brain vascular malformation spectrum. The aim of this study was to determine their prevalence in patients with hereditary hemorrhagic telangiectasia. This was a single-center, retrospective study. Adult patients from the institutional Hereditary Hemorrhagic Telangiectasia registry with a definitive diagnosis of hereditary hemorrhagic telangiectasia and an available report or angiographic imaging study were included and reviewed to determine the intracranial aneurysm prevalence. In addition, the morphologic characteristics of intracranial aneurysms and possible associated risk factors were collected. Two hundred twenty-eight patients were analyzed. Thirty-seven aneurysms in 33 patients (14.5%; 95% CI, 9.9%-19%) were found. The median diameter of intracranial aneurysms was 3.2 mm (interquartile range, 2.6-4.4 mm). No association between intracranial aneurysm and sex, age, or genetic background was noted. There were no subarachnoid hemorrhagic events due to intracranial aneurysm rupture. Due to the high prevalence of intracranial aneurysms in adult patients with hereditary hemorrhagic telangiectasia, further studies regarding bleeding risks and monitoring should be addressed.

EP453: Diagnosis of Hereditary Hemorrhagic Telangiectasia (HHT) in the postpartum period: A case report

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an inherited autosomal dominant disorder characterized by vascular dysplasia. The prevalence is reported to be 1 in 5,000 with higher rates in certain geographically isolated populations such as Afro-Caribbean residents of Curaçao and Bonaire. This is likely an underestimate as often the diagnosis of a proband reveals family members who have epistaxis, stroke, or gastrointestinal (GI) bleeding. The disorder affects males and females in equal numbers.

EP162: Mosaic variant in ENG in infant with pulmonary arteriovenous malformations: Case report and review of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with age-related penetrance and an incidence of 1:10,000 in North America. A clinical diagnosis of HHT requires three of the following criteria: recurrent and spontaneous nosebleeds (epistaxis), mucocutaneous telangiectases, visceral arteriovenous malformations (AVMs), and family history of HHT. Epistaxis occurs in almost all individuals with HHT with average age of onset at 12 years of age and telangiectases usually appear later.

Clinical and Economic Impact of Red Blood Cell Antigen Alloimmunization on Patients with Hereditary Hemorrhagic Telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare autosomal dominant disorder characterized by the presence of arteriovenous malformations which lead to repeated bleeding episodes for which Red Blood Cell (RBC) transfusions may be required. Previous research has shown that this patient population presents with high rates of alloimmunization against RBC antigens (15.29%) (Zheng Transfusion. 2018;58(3):775-780). However, the impact of such complications on clinical and economic outcomes has not been assessed previously. The present study aims to quantify the impact of alloimmunization on clinical outcomes and healthcare costs among HHT patients in a hospital setting.A cross-sectional study of alloimmunized and non-alloimmunized patients using the Premier Hospital chargemaster dataset from January 2015 to June 2019 was performed. Alloimmunization was defined based on the presence of antiglobulin crossmatch and RBC antibody identification laboratory codes in patient medical records. In order to assess the accuracy of this method of identification, the alloimmunization rates among discharges for patients diagnosed with HHT and myelodysplastic syndrome (MDS) for 2018 were extrapolated to the whole country and compared to reports in the literature (Zheng Transfusion. 2018;58(3):775-780, Singhal Haematologica. 2017;102(12):2021-2029). Consistent results were shown, 16.8% vs 15.3% and 11.5% vs. 11% for the HHT and MDS discharges, respectively.Alloimmunized and non-alloimmunized groups were matched for sex, age, admission date, and visit type (outpatient vs. inpatient). Diagnosis of HHT was defined using ICD-10 code I78.0. Cost per discharge for outpatient and inpatient visits, hospital and intensive care unit (ICU) length of stays (LoS), and inpatient mortality were both cases and controls. Bivariate comparisons were performed assuming a two-tailed test of significance and α level of 0.05 and multivariable regression models adjusting for diagnosis-related groups (incidence ≥1%) were performed.A total of 783 alloimmunized HHT cases were matched to 6,744 non-alloimmunized controls. Mean (SD) age was 65.7 (10.9) years for the alloimmunized (cases) and 59.4 (16.3) for the non-alloimmunized (controls), and slightly more than half of the population included in both groups were females (53.0% and 54.0% for the alloimmunized and non-alloimmunized groups, respectively).Outpatient visits were more common than inpatient admissions in both groups (52.6% and 71.4% of cases and controls, respectively albeit inpatient admissions were less common in both control groups (47.4% vs. 28.6%). Most common diagnoses leading to inpatient admission in both groups were disorders of the circulatory system (16.1% and 8.0%, respectively), followed by blood disorders for the alloimmunized group (9.8%) and disorders of the digestive system for the non-alloimmunized group (3.6%).Alloimmunized HHT patients presented with 22% longer hospitalizations (6.1 vs 7.3 days; p=0.0001) and 54% longer ICU stays (4.7 vs 7.2 days; p=0.0146), as well as a 40% increased likelihood of being admitted to the ICU. Inpatient mortality was higher among the alloimmunized population although it did not reach statistical significance (Odds Ratio: 1.53 [0.79; 2.96]; p=0.2092). Overall 12 (3.23%) and 59 (3.1%) deaths were reported for the alloimmunized and non-alloimmunized patient population, respectively. Median costs per discharge were significantly higher both for inpatient ($1,461; p=0.0202) and outpatient ($377; p<0.0001) visits within the alloimmunized population (Table 1).Presence of alloantibodies was associated with significantly worse clinical outcomes, increased healthcare resource use and higher costs within HHT patients. The increased prevalence of alloimmunization within the HHT population is not yet fully understood, and this study was not designed to determine whether prophylactic antigen matching would prevent alloimmunization in the HHT population. Further studies assessing the use of preventive strategies such as prophylactic antigen matching to prevent alloimmunization and its clinical and economic consequences could help determine whether antigen negative RBC units should be preferentially distributed to HHT patients. [Display omitted] DisclosuresGehrie: Grifols SSNA: Consultancy, Honoraria. Viayna: Grifols S.A.: Current Employment. Blanchette: Grifols SSNA: Consultancy; Novo Nordisk Inc.: Current Employment. Meny: Grifols SSNA: Current Employment. Noumsi: Grifols SSNA: Current Employment. Huber: Grifols SSNA: Current Employment. Runken: Grifols SSNA: Current Employment.

Hereditary haemorrhagic telangiectasia: an overview from an ear, nose and throat perspective.

Patients with hereditary haemorrhagic telangiectasia can present with a multitude of symptoms caused by telangiectasia and arteriovenous malformations in the nose, brain, gastrointestinal tract, liver and spinal cord. Clinicians should be aware of the potential diagnosis of hereditary haemorrhagic telangiectasia and how to manage these patients both in the acute and chronic setting. Identifying these patients and optimising their management can help reverse the reduced life expectancy back to that of the normal population. The management of these patients is complex and often requires a multidisciplinary approach, with difficult discussions to be had around screening for arteriovenous malformations and genetic testing. The stepwise management ladder can be used in both the medical and surgical strategies; there are multiple pharmacological and surgical options available, all with their own side effects and risks. Patient education is key to help informed decision making. This article outlines the clinical characteristics of the disease and management options available.

Cyanosis in a Previously Well Child.

Cyanosis in a Previously Well Child.

S2747 Hereditary Hemorrhagic Telangiectasia: A Rare Disease Diagnosed From Incidental Liver Lesions

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant syndrome characterized by mucocutaneous telangiectasias and AVMs. Epistaxis and GI bleeding are the most common presenting features. HHT-related visceral AVMs have also been well-described and when identified without a prior diagnosis of HHT can present a significant diagnostic challenge. Case Description/Methods: A 60-year-old male with prior history of prior tobacco and alcohol use was referred to GI clinic for two years of chronic diarrhea and dyspepsia. No unintentional weight loss although he reported intermittent episodes of epistaxis every 2-3 months for past 40 years. Physical examination and family history was unremarkable. CT A/P showed a heterogeneous liver with innumerable liver lesions. (Figure 1) An EGD was performed for dyspepsia which revealed an 8mm gastric body ulcer and biopsy negative for H.pylori. The patient’s diarrhea resolved with probiotics and changes to diet. Hepatology recommended a liver biopsy which was suggestive of an arteriovenous or vascular malformation with scarring. Follow up EGD revealed a healed stomach ulcer and a 5mm gastric AVM. Chart review revealed a prior CT chest with a small pulmonary vascular malformation. The patient was referred to genetics for evaluation of HHT. A HHT genetic panel was positive for a pathogenic heterozygous variant in the ACVRL1 gene and the diagnosis of HHT was confirmed. Discussion: HHT is a clinically heterogenous disorder and diagnosis requires at least three of the following Curaçao criteria: epistaxis, mucocutaneous telangiectasias, visceral AVMs and family history of HHT. HHT-related AVMs can involve the brain, lung or liver. Hepatic involvement is common ranging from 32% up to 95%. Hepatic AVMs, are rarely symptomatic and routine screening is not recommended. Symptomatic hepatic AVMs can present with three distinct clinical presentations – high output heart failure from AV shunting, portal hypertension from arterioportal shunting and biliary disease from chronic ischemia. In the absence of routine screening, follow-up of these patients requires close attention to the development of these complications. In these cases, multi-phasic CT may be the preferred imaging modality. In conclusion, hepatic AVMs should be included in the differential for hepatic lesions and genetic evaluation should be considered with concomitant history of epistaxis, GI bleeding and/or evidence of other visceral AVMs.Figure 1.: CT abdomen and pelvis without contrast revealed several liver lesions, largest lesion 3.3cm in diameter.

Recognition and management of vascular lesions in von Willebrand disease

Recognition and management of vascular lesions in von Willebrand disease

Identification of Exosomal MicroRNA Signature by Liquid Biopsy in Hereditary Hemorrhagic Telangiectasia Patients.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular dysplasia characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM) in the visceral organs. The diagnosis of HHT is based on clinical Curaçao criteria, which show limited sensitivity in children and young patients. Here, we carried out a liquid biopsy by which we isolated total RNA from plasma exosome samples. A cohort of 15 HHT type 1 patients, 15 HHT type 2 patients, and 10 healthy relatives were analyzed. Upon gene expression data processing and normalization, a statistical analysis was performed to explore similarities in microRNA expression patterns among samples and detect differentially expressed microRNAs between HHT samples and the control group. We found a disease-associated molecular fingerprint of 35 miRNAs over-represented in HHT vs. controls, with eight being specific for HHT1 and 11 for HHT2; we also found 30 under-represented, including nine distinct for HHT1 and nine for HHT2. The analysis of the receiver operating characteristic (ROC) curves showed that eight miRNAs had good (AUC > 75%) or excellent (AUC > 90%) diagnosis value for HHT and even for type HHT1 and HHT2. In addition, we identified the cellular origin of these miRNAs among the cell types involved in the vascular malformations. Interestingly, we found that only some of them were incorporated into exosomes, which suggests a key functional role of these exosomal miRNAs in the pathophysiology of HHT.

Prevalence of and Factors Associated with Arterial Aneurysms in Patients with Hereditary Hemorrhagic Telangiectasia: 17-Year Retrospective Series of 418 Patients

PurposeTo estimate the prevalence of and identify characteristics associated with the presence of aneurysms in a cohort of patients with hereditary hemorrhagic telangiectasia (HHT). Materials and MethodsIn the study institution’s HHT database, 418 patients with a definite HHT diagnosis were identified based on the clinical Curaçao criteria and/or an HHT-associated genetic mutation. Regression modeling was used to evaluate the association between arterial aneurysms and older age, male sex, smoking, alcohol consumption, hypertension, hyperlipidemia, genetic mutations, the presence of arteriovenous malformations (AVMs) unrelated to the aneurysms, and HHT-related genetic mutations. ResultsForty-three (10.3%) patients had at least 1 aneurysm. Sixteen (3.8%) patients had multiple aneurysms. Of the variables analyzed, older age (odds ratio [OR] = 1.02; 95% confidence interval [CI]: 1.0–1.1), the presence of anatomically and flow-unrelated AVMs (OR = 3.2; 95% CI: 1.3–8.0), and the presence of activin A receptor type II-like 1 (ACVRL1) mutation (OR = 4.0; 95% CI: 1.5–10) were associated with the presence of at least 1 aneurysm. ConclusionsIn this cohort of patients with HHT, the prevalence of intracranial and visceral arterial aneurysms was estimated to be 10.3%. Older age, the presence of unrelated AVMs, and the presence of the ACVRL1 mutation were associated with the presence of arterial aneurysms. Further study is required to assess the clinical importance and risk of rupture of aneurysms in patients with HHT.

Diagnosis of hereditary hemorrhagic telangiectasia in a pediatric patient admitted with diabetes: the utility of genetic testing

Background: Hereditary hemorrhagic telangiectasia (HHT) formerly known as Osler-Weber-Rendu syndrome is a rare autosomal dominant disorder characterized by vascular dysplasia and a wide spectrum of clinical manifestations. Case presentation: We report the case of an undiagnosed pediatric patient who presented hypoxemia on clinical exam as the only suggestive feature for the presence of HHT. Conclusions: Although HHT diagnosis is based on the finding of characteristic clinical features genetic testing should also be implemented when a family history of the disease is present to help confirm or refute the diagnosis.

Nasal Endoscopy in the Clinical Diagnosis of Hereditary Hemorrhagic Telangiectasia

To evaluate the role of nasal endoscopy for early clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) in children and to investigate the characteristics of epistaxis and mucocutaneous telangiectases in our pediatric population. From May 2016 to December 2019, a cross-sectional observational study was conducted, recruiting children aged 2-18years with a parent affected by HHT. To identify the Curaçao criteria, all children underwent collection of clinical history, mucocutaneous examination, and nasal endoscopy. The clinical data were then compared with the genetic data acquired subsequently. Seventy children (median age, 10.8years) were included. All underwent nasal endoscopy without complications. Forty-six children were positive by genetic testing; of these, 26% had skin and oral telangiectases and 91% had nasal telangiectases. The diagnostic sensitivity of the Curaçao criteria increased from 28% (95% CI, 16%-43%) to 85% (95% CI, 71%-94%; P<.0001) when the nasal telangiectases were included. The magnified and complete endoscopic view of the nasal cavities proved useful in increasing the diagnostic sensitivity of the Curaçao criteria. Such an examination turned out to be feasible and safe. For this reason, we believe that nasal endoscopy should be included in the diagnostic assessment of pediatric patients with suspected HHT.

Hereditary Hemorrhagic Telangiectasia: The Convergence of Genotype, Phenotype, and Imaging in Modern Diagnosis and Management of a Multisystem Disease.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease that manifests as vascular malformations in the brain, lung, liver, gastrointestinal tract, nasal mucosa, and skin. Diagnosis and management of HHT is guided in large part by imaging studies, making it a condition with which the radiology community needs familiarity. Proper screening and care lead to improved morbidity and mortality in patients with HHT. International guidelines were recently updated and form the basis for a detailed discussion of the role of imaging and image-guided therapy in HHT. © RSNA, 2021 Online supplemental material is available for this article.

A Multifaceted Disease of Problematic Diagnosis in Childhood; Hereditary Hemorrhagic Telangiectasia: A Case Report

Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited in an autosomal dominant manner and may involve skin, mucosa, and internal organs. HHT may cause arteriovenous, arterioportal, and portovenous shunts in the liver, resulting in cirrhosis and portal hypertension. An eight-year-old male patient with a diagnosis of myelodysplastic syndrome for two years was admitted with melena. Portal doppler ultrasonography showed a heterogeneous appearance of the liver parenchyma and splenomegaly (spleen size of 14 cm) with no portal hypertension. An extended etiological investigation for chronic liver disease was conducted. Afterliver biopsy, the patient’s general condition deteriorated, with abdominal distension and reduced hematocrit. The Doppler and hepatic angiography results together with a history of recurrent episodes of epistaxis led to the diagnosis of HHT. The patient was referred to the transplant center for liver transplantation due to the irreversible bleeding from the liver. Hepatic telangiectasias may be present in patients without hematologic disorders who have uncontrollable bleeding after liver biopsy.

Founder Effects in Hereditary Hemorrhagic Telangiectasia.

A founder effect can result from the establishment of a new population by individuals from a larger population or bottleneck events. Certain alleles may be found at much higher frequencies because of genetic drift immediately after the founder event. We provide a systematic literature review of the sporadically reported founder effects in hereditary hemorrhagic telangiectasia (HHT). All publications from the ACVRL1, ENG and SMAD4 Mutation Databases and publications searched for terms “hereditary hemorrhagic telangiectasia” and “founder” in PubMed and Scopus, respectively, were extracted. Following duplicate removal, 141 publications were searched for the terms “founder” and “founding” and the etymon “ancest”. Finally, 67 publications between 1992 and 2020 were reviewed. Founder effects were graded upon shared area of ancestry/residence, shared core haplotypes, genealogy and prevalence. Twenty-six ACVRL1 and 12 ENG variants with a potential founder effect were identified. The bigger the cluster of families with a founder mutation, the more remarkable is its influence to the populational ACVRL1/ENG ratio, affecting HHT phenotype. Being aware of founder effects might simplify the diagnosis of HHT by establishing local genetic algorithms. Families sharing a common core haplotype might serve as a basis to study potential second-hits in the etiology of HHT.

Hereditäre hämorrhagische Teleangiektasie: Symptome und diagnostische Latenz

Zusammenfassung Hintergrund Patienten mit hereditärer hämorrhagischer Teleangiektasie (HHT) leiden unter einer systemischen Erkrankung des Gefäßbindegewebes, bei der eine Vielzahl verschiedener Symptome auftritt. Material und Methoden Die Daten aller Patienten, die sich von April 2014 bis August 2019 im Westdeutschen Morbus-Osler-Zentrum vorstellten, wurden in einer retrospektiven Studie analysiert. Ergebnisse Bei 235 Patienten konnte die Diagnose HHT als definitiv (235/282; 83 %) und bei 26 als möglich gestellt werden (26/282; 9 %). Die mittlere diagnostische Latenz zwischen Erstsymptomen und Diagnose betrug 18 Jahre. Direkte oder indirekte Blutungszeichen wurden oft als erste Symptome der Erkrankung HHT genannt (224/241; 93 %). 83 % der Patienten mit einem Grad der Behinderung gaben HHT als Hauptursache an. Insbesondere ältere, weibliche Patienten bzw. Patienten mit starker Epistaxis litten an einer chronischen Eisenmangelanämie (Eisensubstitution:148/261; 57 %; Erythrozytenkonzentrate: Mittelwert: 9 ± Standardabweichung: 41, Minimum – Maximum: 0–400, Anzahl der Patienten: 218). 10 % erhielten eine Thrombozytenaggregationshemmung oder Antikoagulation und tolerierten diese. 74 % der Patienten mit HHT pflegten ihre Nasenschleimhaut (177/238) und zeigten weniger Blutungen als Patienten ohne Nasenpflege (ESS: t-Test: 3,193; p = 0,003; Anämie: Chi-Quadrat: 5,173; p = 0,023). Schlussfolgerungen Die Diagnoselatenz der Erkrankung HHT betrug knapp 2 Jahrzehnte. Patienten mit HHT leiden insbesondere an rezidivierenden Blutungen, die dabei meistindizierte Behandlung der ersten Wahl ist eine konsequente Nasenpflege und verschiedene koagulative Therapieoptionen. Bei Begleiterkrankungen mit Indikation zur Gerinnungshemmung lohnt es sich meist, deren Einsatz zu versuchen.

Comparison of Feeding-Artery-Only versus Nidus-Plus-Feeding-Artery Embolization of Pulmonary Arteriovenous Malformations

PurposeTo compare coil embolotherapy outcomes of feeding-artery-only versus nidus-plus-feeding-artery technique for treating pulmonary arteriovenous malformations (PAVMs). Materials and MethodsA total of 219 treatment-naïve PAVMs embolized in 90 patients at a single center from 2008 to 2018 met inclusion criteria for retrospective evaluation. Of the patients, 87% had a diagnosis of hereditary hemorrhagic telangiectasia (HHT). Feeding artery (FA) diameters ≥2 mm were treated. Coil embolization techniques were classified on the basis of embolic deployment zone: (i) distal feeding artery (DFA) technique (coil-to-nidus distance ≤ 1 cm) or (ii) nidus plus feeding artery (NiFA) technique. Successful embolization predictors were assessed using a multivariate linear regression model with input from patient- and PAVM-specific variables. ResultsTreatment success was achieved in 192 of 219 PAVMs (87.7%) over a mean follow-up period of 19 months. Statistically significant predictors of success in the linear regression model included simple angioarchitecture, NiFA embolization technique, and shorter follow-up duration. Stratified by technique, success rates were 99 of 105 (94.3%) and 93 of 114 (81.6%) PAVMs for NiFA and DFA, respectively (P = .007). On average, NiFA-embolized PAVMs had a larger FA diameter (3.6 mm vs 2.7 mm, P < .001) and comprised more complex PAVMs (48% vs 22%, P < .001) than DFA. Treatment success was not significantly associated with sac size or FA diameter. ConclusionsCoil embolization of both the nidus and FA was associated with a higher persistent occlusion rate than FA embolization alone.

Pathogenesis and therapy of arteriovenous malformations: A case report and narrative review.

Arteriovenous malformations (AVMs) are abnormal communications between arteries and veins that lack intervening capillary beds. They have been described in almost every organ in the body, emerging sporadically or as part of well-described syndromes. Hereditary hemorrhagic telangiectasia (HHT) is a rare, progressive, and lifelong disease characterized by AVMs and recurrent hemorrhaging. In the last 2 decades, significant advances have been made in understanding the pathogenesis of this condition. The accumulation of knowledge has led to a natural evolution of therapy, from open surgery to endovascular procedures, and now to a role for medications in certain AVMs. Here, we review a case of HHT and describe the most up-to-date clinical practice, including diagnosis of HHT, subtypes of HHT, and medical therapy.

Healthcare Utilization and Costs associated with Hereditary Hemorrhagic Telangiectasia Patients in a Large US Claims Database.

ObjectiveTo assess the health care costs and utilization in patients with hereditary hemorrhagic telangiectasia (HHT) in the United States.Patients and MethodsRetrospective analysis of patients with HHT diagnosed between 2007 and 2017 was performed using deidentified administrative claims data from the OptumLabs Data Warehouse. Adult patients with new (incident) diagnosis of HHT between January 1, 2007, and December 31, 2017, were included. Comparisons were made using the Wilcoxon rank sum test.ResultsThree thousand nine hundred seventy-seven patients with a first diagnosis of HHT between 2007 and 2017 were identified, of which 3590 were matched 1:1 to non-HHT patients with similar baseline characteristics and comorbidities. These 3590 patients with HHT were 63.1% female and 83.9% white with a mean age of 51.1 ± 18.5 years, and a mean follow-up period of 3.2 ± 2.2 years (range, 1.0-11.7 years). Compared with the control group, the cumulative 5-year median total health care cost for patients with HHT was 41.4% higher ($21,118 vs $14,929; P < .001) in those with private commercial insurance and 31.7% higher ($35,462 vs $26,925; P < .001) in those with Medicare Advantage coverage. The median annual health care costs were significantly higher in patients with HHT with commercial insurance and Medicare Advantage in the first year after diagnosis ($4,333 vs $1,804; P < .001), and ($7,322 vs $5,245; P < .001), respectively, and remained higher throughout the duration of follow-up. Further analysis showed that outpatient clinic visits, hospital admission, imaging rates, invasive procedures, iron infusions, and blood transfusions were all significantly higher in the HHT group.ConclusionPatients with HHT have significantly higher health care costs compared with a matched control group. A better understanding of the reasons underlying these cost differences will provide opportunities for patients, providers, and other stakeholders to better manage this rare condition.

The clinical and genetic features of hereditary haemorrhagic telangiectasia (HHT) in central South Africa-three novel pathogenic variants.

Hereditary haemorrhagic telangiectasia (HHT) is supposedly rare in Africa, with only three pathogenic variants documented to date. We describe the clinical and genetic features of HHT patients in central South Africa, who fulfilled the Curaçao criteria. Sixteen patients (median age 38.5years, range 12-65years), from six families were included. Fifteen patients were of African descent and one was of Afrikaner descent. The mean epistaxis severity score was 3.18, and the median haemoglobin was 9.5g/dL (range 3.5-13.5g/dL). On transthoracic contrast echocardiography 69% had a shunt grade ≥ 1, but only 20% had pulmonary arteriovenous malformations (AVMs) on computed tomography of the chest. Hepatic AVMs were found in 13% of patients, while 13% had brain vascular malformations. Four patients were HIV positive, of whom two had worsening epistaxis while they had opportunistic infections and poor HIV control. We identified six pathogenic variants (four in ENG and two in ACVRL1) in the six probands, three of which had been described previously. Three variants have apparently not been reported previously: ENG c.[1336_1337dup];[ =] p.[(Asp446fs)];[( =)], ENG c.[ 690?_816+?del] p.[(?)], and ACVRL1 c.[268_274delins57];[ =] p.[(Cys90fs)];[( =)]. We confirmed the diagnosis of HHT in sixteen patients and identified pathogenic variants in ENG or ACVRL1 in all six probands in central South Africa, where HHT has been underreported. We describe three pathogenic variants: two of ENG and one of ACVRL1. We will be able to implement pre-symptomatic screening of patients in our area, and improve their management.