The European Rare Disease Network for HHT Frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care.

Hereditary haemorrhagic telangiectasia (HHT) is a complex, multisystemic vascular dysplasia affecting approximately 85,000 European Citizens. In 2016, eight founding centres operating within 6 countries, set up a working group dedicated to HHT within what became the European Reference Network on Rare Multisystemic Vascular Diseases. By launch, combined experience exceeded 10,000 HHT patients, and Chairs representing 7 separate specialties provided a median of 24 years' experience in HHT. Integrated were expert patients who focused discussions on the patient experience. Following a 2016-2017 survey to capture priorities, and underpinned by more than 40 monthly meetings, and new data acquisitions, VASCERN HHT generated position statements that distinguish expert HHT care from non-expert HHT practice. Leadership was by specialists in the relevant sub-discipline(s), and 100% consensus was required amongst all clinicians before statements were published or disseminated. One major set of outputs targeted all healthcare professionals and their HHT patients, and include the new Orphanet definition; Do's and Don'ts for common situations; Outcome Measures suitable for all consultations; COVID-19; and anticoagulation. The second output set span aspects of vascular pathophysiology where greater understanding will assist organ-specific specialist clinicians to provide more informed care to HHT patients. These cover cerebral vascular malformations and screening; mucocutaneous telangiectasia and differential diagnosis; anti-angiogenic therapies; circulatory interplays between anaemia and arteriovenous malformations; and microbiological strategies to counteract loss of normal pulmonary capillary function. Overall, the integrated outputs, and documented current practices, provide frameworks for approaches that augment the health and safety of HHT patients in diverse health-care settings.

Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease with an estimated prevalence of 1 in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage, and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop evidence-based consensus guidelines for the management and prevention of HHT-related symptoms and complications. The guidelines were developed using the AGREE II (Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in HHT from 15 countries, guidelines methodologists, health care workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6 priority topic areas. A systematic literature search was done in June 2019, and articles meeting a priori criteria were included to generate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved. The expert panel generated and approved 6 new recommendations for each of the following 6 priority topic areas: epistaxis, gastrointestinal bleeding, anemia and iron deficiency, liver VMs, pediatric care, and pregnancy and delivery (36 total). The recommendations highlight new evidence in existing topics from the first International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of key components of HHT care into clinical practice.

Does severe bleeding in HHT patients respond to intravenous bevacizumab? Review of the literature and case series.

BACKGROUND: Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disorder, with a wide variety of clinical manifestations due to the presence of multiple arteriovenous manifestations. Severe bleeding from the gastrointestinal (GI) tract and/or epistaxis presents a significant problem in a subgroup of patients and systemic bevacizumab, an angiogenesis inhibitor, has been suggested to benefit these patients. OBJECTIVE: To perform a review of the literature concerning the efficacy of systemic bevacizumab in treatment of bleeding from the nose or GI tract in patients with HHT, including patients from our own HHT-center. METHODS: A literature review was performed using the guideline "Preferred Reporting Items for systematic Reviews and MetaAnalysis statement" (PRISMA). RESULTS: After careful selection, we finally analysed the results of eight case series and 33 case reports. Among 195 patients 171 (88%) had reduced bleeding after bevacizumab. CONCLUSIONS: Based on the literature review and data from our own case series, systemic bevacizumab is very promising as treatment for HHT patients with severe epistaxis and/or GI-bleeding. However, care should be taken using bevacizumab, a potent angiogenesis inhibitor; long-term side effects have not been studied in this population. A randomized controlled study is warranted to support the results in HHT patients.

Pulmonary arteriovenous malformations: a radiological and clinical investigation of 136 patients with long-term follow-up.

AIM: To assess the clinical outcome of patients with and without hereditary haemorrhagic telangiectasia (HHT) after embolisation of pulmonary arteriovenous malformations (PAVM) from a single national centre. MATERIALS AND METHODS: The present register-based observational study including all patients with PAVM treated with embolisation at a reference centre for HHT and PAVM was undertaken over a 20-year period. Demographic data, HHT genotyping, clinical presentation, and outcome were registered. Patients with HHT were compared to the patients without HHT. Clinical examination, contrast-enhanced echocardiography, and computed tomography (CT) were used to assess the clinical outcome at follow-up. RESULTS: One hundred and thirty-six patients with 339 PAVM underwent embolisation during the study period: 22 did not have HHT; 62% had HHT1, 10% had HHT2, 4% had JP-HHT, 8% had clinical HHT without identified genetic mutations. Solitary PAVM were more common among patients without HHT than with HHT. Mean follow-up after the first embolisation was 58 months. Mean age at first embolisation was 46.5 years, and at last follow-up 51.8 years. The clinical success without shunt at follow-up was 87%. The 30-day mortality related to the embolisation was 0%. Twenty patients died during follow-up (mean age 69 years). Most patients could be treated during one session, but many will need a long follow-up with repeated clinical examinations and embolisation. CONCLUSION: The majority of patients referred for embolisation of PAVM had HHT. Multiple PAVM is associated with HHT. Patients with PAVM should be screened for HHT and patients with HHT for PAVM. Embolisation is a safe procedure with high clinical success.

Middle ear disease in Danish toddlers attending nursery day-care - Applicability of OM-6, disease specific quality of life and predictors for middle ear symptoms.

OBJECTIVES: Otitis media (OM) is a very common childhood disease and impacts child quality of life (QoL) to different extends. The aim of this study was to investigate the difference in quality of life between three groups of children; Children with symptoms of ear disease within the last 4 weeks, children without any ear disease and children scheduled for ventilating tube treatment. Furthermore, we investigated predictors for experiencing middle ear symptoms. Lastly, we assessed psychometric properties of OM-6 used to assess QoL. METHODS: Four hundred ninety-four children attending nursery day-care aged 6-36 months were enrolled in the study. Caregivers were asked to recall the child's history of symptoms related to middle ear infection. The Danish version of otitis media-6 questionnaire was used to measure the children's quality of life. Data from children treated with ventilating tubes were included from a previously published study. Logistic regression was applied for determining possible predictors for experiencing ear related symptoms. RESULTS: The study had an 87% response rate, with a total of 342 children included. At the inclusion 32 (9%) children were included in the 4-week group and, while 307 children were allocated to the non-4 week group. The children in the 4-week group were significantly younger and were more likely to have siblings with a history of middle ear infection than the non-4week group. Furthermore, QoL was significantly worse in the 4-week group compared to the non-4week group. Only subtle differences were found between children with acute symptoms compared to children scheduled for tube treatment. CONCLUSIONS: As expected, children with acute symptoms of OM experience lowered QoL compared to children with no symptoms and young age as well as having siblings with a history of middle ear problems were found to be possible predictors for experiencing middle ear symptoms. Children with acute symptoms differed from children scheduled for ventilating tubes on domains related to long-term problems from OM. OM-6 has shown to be a valid instrument for assessing disease specific QoL in children with OM, however a more large-scale instrument might be necessary for detecting subtle differences between subgroups of children with OM.

The validity of nasal endoscopy in patients with chronic rhinosinusitis-An inter-rater agreement study.

OBJECTIVES: Nasal endoscopy is a cornerstone in diagnosing sinonasal disease, but different raters might generate different results using the technique. Our study aims to evaluate the agreement between multiple raters to assess the validity of nasal endoscopy. DESIGN/PARTICIPANTS: Three independent and blinded raters evaluated 28 patients (56 nasal cavities) diagnosed with chronic rhinosinusitis according to the European Position Paper on Rhinosinusitis and Nasal Polyps. The ratings were compared using unweighted Fleiss' kappa coefficients (Kf ) for each objective parameter. SETTING: The department of Otorhinolaryngology, Odense University Hospital, Denmark. MAIN OUTCOME MEASURES: The ratings were quantified in a modified Lund-Kennedy endoscopy score and focused on the objective parameters specified in the diagnostic criteria: polyps, oedema and discharge. RESULTS: The raters agreed on the findings concerning polyps and discharge but not regarding oedema with the inter-rater agreement for the different parameters being: polyps Kf =.66 (SE .07, P<.001), oedema Kf =.05 (SE .07, P=.21), discharge Kf =.35 (SE .08, P<.001), oedema exclusively in middle meatus Kf =-.07 (SE .04, P=.8) and discharge exclusively in middle meatus Kf =.16 (SE .07, P=.01). CONCLUSION: Using nasal endoscopy, the evaluation of polyps by multiple raters showed sufficient reliability indicating an acceptable objective evaluation. The evaluation of discharge achieved a fair level of agreement while the assessment of oedema could not achieve a sufficient reliability questioning the inclusion of oedema in the criteria for diagnosing sinonasal disease.

Prevalence of hereditary hemorrhagic telangiectasia in patients operated for cerebral abscess: a retrospective cohort analysis.

It is well described that patients with pulmonary arteriovenous malformations (PAVMs) and Hereditary Hemorrhagic Telangiectasia (HHT) have an increased risk of cerebral abscess (CA). However, as both CA and HHT are rare, the proportion of patients with CA who are diagnosed with HHT has not been previously described. A retrospective study was carried out of all patients treated surgically for CA between January 1995 and September 2014 at the Department of Neurosurgery, Odense University Hospital. The cases were then cross-referenced with the Danish HHT database. Eighty patients aged 5-79 years were included. The incidence of CA was 0.33/100,000/year. Two patients (2.5%) were registered as having HHT. Bacterial pathogens were identified in 70% of all cases, most frequently streptococci species (46.3%). The most common predisposing condition was odontogenic infection (20%), followed by post-operative infection (13.8%) and post-trauma (6.3%). Patients undergoing a full diagnostic program to determine predisposing conditions causing CA increased over the 20-year period from 11.8% to 65.2%. The 3-month and 1-year mortality rates were 7.5% and 11.25%, respectively. There is an overrepresentation of HHT patients in a cohort of patients with CA, and HHT should be investigated as the cause of the CA if no other apparent cause can be identified.

JP-HHT phenotype in Danish patients with SMAD4 mutations.

Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP-HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14 patients with SMAD4-mutations. The study was a retrospective, register-based study. SMAD4 mutations carriers were identified through the Danish HHT-registry, the genetic laboratories - and the genetic departments in Denmark. The medical files from relevant departments were reviewed and symptoms of HHT, JPS, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curaçao criteria. One patient had aortic root dilation. Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation. Out of eight patients screened for aortopathy, one had aortic root dilatation, highlighting the need for additional screening for aortopathy.

The Sinonasal Outcome Test 22 score in persons without chronic rhinosinusitis.

OBJECTIVES: To determine the Sinonasal Outcome Test 22 (SNOT 22) score in persons without chronic rhinosinusitis. DESIGN AND SETTING: As part of a trans-European study selected, respondents to a survey questionnaire were invited for a clinical visit. Subjective symptoms and rhinoscopy were used for the clinical diagnosis of chronic rhinosinusitis according to EPOS. PARTICIPANTS: A total of 366 persons participated at the clinical visit and of these 268 did not have chronic rhinosinusitis. All participants completed the SNOT 22. MAIN OUTCOME MEASURES: The SNOT 22. RESULTS: The SNOT 22 score ranged from 0 to 67 with a mean score of 10.5 (CI: 9.1-11.9) and the median score was 7. Persons with allergic rhinitis and blue-collar workers had a significant higher score. CONCLUSION: The median value of 7 is taken as the normal SNOT 22 score in persons without CRS and can be used as a reference in clinical settings and research. Allergic rhinitis and occupation affect SNOT 22 in persons without CRS.

Efficacy of ESS in chronic rhinosinusitis with and without nasal polyposis: a Danish cohort study.

Endoscopic sinus surgery (ESS) for patients with severe chronic rhinosinusitis (CRS) has become a well-established treatment in cases where medical therapy fails. Even though CRS patients are divided into two subgroups, CRS with nasal polyposis (CRSwNP) and CRS without nasal polyposis (CRSsNP), most studies present only results for the total cohort. This prospective cohort study evaluated the efficacy of ESS on both quality of life and olfactory function measures, in a cohort of Danish CRS patients diagnosed according to the EPOS criteria, with results analysed separately for the CRSwNP and CRSsNP subgroups. All 97 CRS patients who underwent ESS over an 18-month trial period were evaluated preoperative by SNOT-22 score, Sniffin' Sticks score, modified Lund-Kennedy endoscopic score and Lund-Mackay CT score. Patient outcomes were reevaluated at clinical follow-up 1 and 6 months postoperative. ESS efficiently and immediately improved quality of life for both CRSwNP and CRSsNP patients, with over 50 % reduction in SNOT-22 score 1 month after surgery, which sustained 6 months postoperative. Olfactory function measured by Sniffin' Sticks score showed overall improvement in both groups. ESS efficiently improved quality of life in both CRSwNP and CRSsNP patients, and surgery lead to an overall improvement in olfactory function. However, a minor proportion of patients experienced deterioration in olfactory function after ESS.

Cerebral abscesses among Danish patients with hereditary haemorrhagic telangiectasia.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by a wide variety of clinical manifestations, including pulmonary arteriovenous malformations (PAVMs), which due to paradoxical embolization may cause cerebral abscess. OBJECTIVE: To estimate the risk of cerebral abscess among patients with HHT. METHODS: All patients with HHT included in the Danish HHT data base, between January 1995 and October 2012, have been clinically evaluated for the presence of neurological symptoms and history of previous cerebral abscess. RESULTS: A total of 337 patients with HHT have been included in the Danish database. Of these, 264 were screened for the presence of PAVM. In 117 patients, a PAVM was diagnosed; among these, we identified nine patients with a history of cerebral abscess. The prevalence of cerebral abscess among patients with HHT and PAVM was therefore 7.8%. The patients with a history of cerebral abscess were genetically evaluated, and seven had ENG mutations, one had an ALK1 mutation, and in one case, a mutation could not be identified. CONCLUSION: Patients with untreated PAVM have a considerable risk of sustaining cerebral abscesses. A cerebral abscess may be the first symptom leading to an HHT diagnosis. Patients with unexplained cerebral abscess should be evaluated for HHT and PAVM.

National mutation study among Danish patients with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominantly inherited vascular disease characterized by the presence of mucocutaneous telangiectasia and visceral arteriovenous malformations (AVM). The clinical diagnosis of HHT is based on the Curaçao criteria. About 85% of HHT patients carry mutations in the ENG, ACVRL1 or SMAD4 genes. Here, we report on the genetic heterogeneity in the Danish national HHT population and address the prevalence of pulmonary arteriovenous malformations (PAVM). Probands of 107 apparently unrelated families received genetic testing, including sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses of ENG, ACVRL1 and SMAD4. These 107 families included 320 patients confirmed to have HHT either clinically or genetically. In 89% of the probands (n=95), a mutation was identified. We detected 64 unique mutations of which 27 (41%) were novel. Large deletions were identified in ENG and ACVRL1. The prevalence of PAVM was 52.3% in patients with an ENG mutation and 12.9% in the ACVRL1 mutation carriers. We diagnosed 80% of the patients clinically, fulfilling the Curaçao criteria, and those remaining were diagnosed by genetic testing. It is discussed when to assign pathogenicity to missense and splice site mutations. The adding of an extra criterion to the Curaçao criteria is suggested.

Occlusion of pulmonary arteriovenous malformations by use of vascular plug.

Pulmonary arteriovenous malformations are commonly treated by embolization with coils or balloons to prevent cerebral complications and to raise the oxygenation of the blood. The Amplatzer vascular plug is a new occlusive device made of a self-expanding cylindrical nitinol mesh. It is fast and safe to position, and can be repositioned before final delivery. It is especially suited for embolization of large high-flow vessels as in pulmonary arteriovenous malformations with big feeding arteries. Two cases of successful use of the new device for treatment of large pulmonary arteriovenous malformations are described.

Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease, characterized by a wide variety of clinical manifestations, including epistaxis, gastrointestinal (GI) bleeding, pulmonary arteriovenous malformations (PAVMs) and neurological symptoms. HHT is a genetically heterogeneous disorder involving at least two loci; HHT 1 mapping to chromosome 9 q 34.1 (ENG) and HHT 2 mapping to chromosome 12 q 31 (ALK-1). OBJECTIVE: To evaluate and describe the diversity of clinical manifestations in a Danish population of HHT patients with known HHT 1 or HHT 2 subtype. DESIGN: Prospective clinical examination with genetic evaluation and follow-up. SETTING: Investigation centre was Odense University Hospital. All HHT patients in the County of Fyn were included. METHODS: HHT family members were invited to a clinical examination including registration of HHT manifestations, screening for PAVM and neurological evaluation. Blood tests were performed for analysis of disease-causing mutation, and clinical manifestations in the HHT subtypes were compared. The survival of the patients was studied in the follow-up period. RESULTS: Included in the study were 73 HHT patients representing 18 families. In 14 of the families we identified a disease-causing mutation. Thirty-nine patients (from 10 families) had HHT1 and 16 HHT patients from four families had HHT2. CONCLUSION: Amongst patients with HHT1 genotype the prevalence of PAVM was higher than amongst HHT patients with HHT2 genotype. HHT1 patients had experienced more severe GI bleeding than HHT2 patients. There was no significant difference in severity of epistaxis or age at debut. Finally the mortality over a 90-month observation period was not significantly increased.

Mutations in endoglin and in activin receptor-like kinase 1 among Danish patients with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is a rare disorder with one per 6000-10,000 affected individuals in the general Caucasian population. HHT is genetically heterogeneous, involving at least two loci HHT1 mapping to chromosome 9q34.1 and HHT2 mapping to chromosome 12q31. The loci have been identified as endoglin (ENG) and activin receptor-like kinase 1 (ALK1). In order to gain knowledge of the genotype distribution and prevalence in the Danish population and to establish a reproducible and sensitive molecular genetic test method, we developed a denaturating gradient gel electrophoresis protocol for mutation scanning of the two loci. Twenty-five Danish HHT families were tested. A total of eight new as well as seven previously reported mutations were identified. A founder mutation was characterized present in seven families and possibly introduced around 350 years ago. In one individual, a presumed spontaneous mutation was characterized. The method developed proved to be very sensitive for mutation detection in both ENG and ALK1. Genetic screening in HHT families facilitates an early treatment strategy for silent HHT manifestations in first degree relatives.

[Pulmonary arteriovenous malformations. Current therapeutic principles]. / Pulmonale arteriovenøse malformationer. Moderne behandlingsprincipper.

Pulmonary arteriovenous malformations are congenital vascular malformations in the lungs, which act as shunts so that the blood is not oxygenated or filtered. These patients are typically hypoxaemic with exercise intolerance and are at high risk of paradoxical emboli to the brain. About 25% of patients with the Rendu-Osler-Weber syndrome (hereditary haemorrhagic telangiectasia) have these pulmonary malformations. A modern treatment strategy is embolisation with balloon or coils of the afferent arteries to the arteriovenous malformations. It is a minimally invasive procedure with a very high technical success and few complications. Embolisation prevents cerebral stroke and abscess and pulmonary haemorrhage and further raises the functional level. Screening for pulmonary arteriovenous malformations in patients at risk is recommended.

[Percutaneous transluminal embolization of pulmonary arteriovenous malformations]. / Perkutan transluminal embolisation af pulmonale arteriovenøse malformationer.

OBJECTIVE: The aim was to evaluate the effect of embolisation of pulmonary arteriovenous malformations (PAVM), as estimated by contrast echocardiography, arterial blood-gas analyses and functional level, and further to evaluate procedure-related and late complications. PATIENTS AND METHODS: Seventeen patients were treated on 25 occasions for a total of 48 PAVM. Fifteen patients had hereditary haemorrhagic telangiectasia (HHT). Chest X-ray, pulmonary angiography, contrast echocardiography, arterial blood-gas analyses, and functional level were analysed before and after embolisation of PAVM. The mean follow-up period was 22 months. RESULTS: Contrast intensity at contrast echocardiography decreased from median 4.0 (range 2-4) before embolisation to 1.5 after embolisation. PaO2 breathing 100% oxygen increased from mean 271 mm Hg before embolisation to 480 mm Hg after embolisation. The shunt was reduced from mean 24% before to 12% after embolisation. Most of the patients experienced an increased functional level after embolisation, and the median functional level (NYHA) increased from NYHA 2.5 to 1.2. No primary or secondary device migration, no cerebral insults, and no mortality was noted. CONCLUSION: Embolisation is a well-established method of treating PAVM, with a significant effect on oxygenation of the blood. It is a minimally invasive, lung-preserving treatment with high affectiveness and low morbidity and mortality. Patients with HHT should be screened for PAVM as a high percentage of these have PAVM.

Mutations in the ALK-1 gene and the phenotype of hereditary hemorrhagic telangiectasia in two large Danish families.

Mutations in the ENG gene on chromosome 9 (HHT 1) and in the ALK-1 gene on chromosome 12 (HHT 2) have been reported as causes of hereditary hemorrhagic telangiectasia (HHT). HHT 1 has been correlated with a higher prevalence of pulmonary arteriovenous malformations than HHT 2. Other distinct phenotype-genotype correlations have not been described. The prevalence of HHT in the county of Fyn, Denmark, was 15.6 per 100,000 on January 1, 1995. All living patients and their first-degree relatives were invited to attend a detailed clinical examination and blood was drawn for mutation analysis. In two families mutations were identified in exon 8 of the ALK-1 gene. In family 6 we found a T1193A mutation. In this family a high prevalence of PAVM and severe GI bleeding was documented, while in family 8 with a C1120T mutation no individuals with PAVM were identified and only one patient had a history of severe GI bleeding. No mutations in the endoglin locus were found in either family.

[Hereditary hemorrhagic telangiectasia. A population-based study on prevalence and mortality among Danish HHT patients]. / Hereditaer haemoragisk telangiektasi. Et populations-baseret studium af praevalens og mortalitet blandt danske HHT-patienter.

Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited disease characterized by telangiectatic lesions. The disease manifestations are variable in severity. Early death due to complications has been described. We report an investigation of the prevalence and mortality of HHT in a Danish population, based on two cross-sectional surveys in combination with a long-term follow-up study. The prevalence of HHT in the county of Funen was 13.8 per 100,000 January 1. 1974 and 15.6 per 100,000 January 1. 1995. In the HHT group as a whole we found a slightly increased mortality, however among the HHT patients younger than 60 years at inclusion the mortality of HHT patients was twice the expected. The excess mortality was fully explained by severe HHT symptoms contributing to death. Future research should aim at identification of HHT patients at particular risk of developing severe complications.