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• W2029046570 abstract "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; HHT1 mapping to chromosome 9q34.1 (ENG) and HHT2 mapping to chromosome 12q31 (ALK-1). Objective. To evaluate and describe the diversity of clinical manifestations in a Danish population of HHT patients with known HHT1 or HHT2 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. Hereditary haemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease is an autosomal dominantly inherited disease. HHT is characterized by a wide variety of clinical manifestations [1], in some patients symptoms are subtle and result in minor inconvenience only, whereas in other patients the disease is devastating for normal life. Between one- and two-thirds of the patients will seek medical advice on treatment [2]. The symptoms are caused by a generalized defect in the architecture of the small blood vessels which leads to formation of arteriovenous anastomoses often presenting as telangiectatic lesions in the skin and mucosa causing epistaxis and gastrointestinal (GI) bleeding. The arteriovenous anastomoses may also appear in the viscera, and development of pulmonary arteriovenous malformations (PAVMs) are seen in 15–25% of the cases [3, 4]. Embolization is the first-line treatment of PAVM [5, 6]. Neurological symptoms in HHT patients may be the result of paradoxical cerebral embolization through a PAVM. The morbidity amongst HHT patients as a result of stroke has previously been estimated with an increased odds ratio of 7.6 [4, 7]. The neurological symptoms may also be caused by cerebral arteriovenous malformations (CAVM). Haitjema et al. [3] reported that 11% of the HHT patients in his population study had CAVM, and results have shown an annual bleeding risk of 0.4–2.0% in patients with CAVM [8, 9]. During the last few years, the genetics of HHT have been studied extensively. HHT is a genetically heterogeneous disorder 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 both types the mutations impair blood vessel growth and repair. It has been established that patients with the genetic type HHT1 develop PAVM more frequently than patients with HHT2 [10]. Regarding other clinical manifestations of HHT the importance of genotype has not been fully exposed, although more severe disease in HHT1 than HHT2 has been suggested [11]. Recently mutations in MADH4 might represent a third locus for HHT as the mutation was identified in patients suffering from a combined disease with both HHT and juvenile polyposis [12]. The aim of the present study was to estimate the differences in clinical symptoms of patients having HHT1 and HHT2. The study was conducted as a comprehensive regional population survey in the County of Fyn, Denmark [13]. The point prevalence of HHT on 1 January 1995 was 15.6 per 100 000 [14] and all these patients were evaluated according to clinical symptoms and disease-causing mutation. The clinical part of the study was conducted in the period 1 January 1995 to 1 January 1997, this was prior to the development of the international consensus criteria [15]. During the study period we based the HHT diagnosis on (i) presence of multiple, at least 15, telangiectatic lesions, and (ii) either a positive family history, or recurrent episodes of bleeding. One of the authors (A.D.K.) clinically assessed all participants. Furthermore all patient files were later carefully evaluated according to the international consensus criteria, finding that all HHT patients fulfilled the Curaçao criteria. A questionnaire concerning HHT symptoms with special regard to epistaxis, GI bleeding and occurrence of neurological symptoms was completed during an interview in 1995–1997. At the time of interview a clinical examination including ENT examination and neurological evaluation was also completed. The local ethical committee had approved the project. Epistaxis was rated according to the bleeding frequency. Grade 0: no epistaxis during the last year. Grade 1 (mild epistaxis): monthly or yearly epistaxis, at least once a year. Grade 2 (moderate epistaxis): weekly epistaxis, at least once a week. Grade 3 (severe epistaxis): daily epistaxis or previous nasal dermatoplasty. Concerning GI bleeding we divided the patients into three categories: (i) no history of GI bleeding; (ii) history of GI bleeding as either hematemese or melena, and (iii) severe GI bleeding if the patient had received 6 units of blood or more within the last 6 months prior to inclusion due to GI bleeding [16]. In patients who received blood transfusions the bleeding site (GI bleeding or epistaxis) was defined as recorded in the hospital records. If the clinical examination or the history revealed previous neurological disease, the incident was included if it could be verified through review of hospital records. Finally, a search for neurological diagnoses in the Regional Inpatient Register was performed. Stroke was defined according to the World Health Organization criteria: ‘Rapidly developed clinical signs of focal disturbance of cerebral function, lasting more than 24 h or leading to death, with no apparent cause other than vascular origin’ [17]. All participants were offered screening for PAVM with pulse oxymetry and contrast echocardiography (CE) [18]. All patients with positive CE were referred for pulmonary angiography (PA). PAVM demonstrated at PA was characterized by at least one feeding artery in direct communication with the draining vein, via an aneurysmal sac. A detailed description of our mutation analysis is presented in another article [19]. Genomic DNA was isolated from peripheral leukocytes. Polymerase chain reaction (PCR) primers corresponding to intronic sequences for amplification of exon sequences was constructed by modification of the previously published primers. Denaturing gradient gel electrophoresis was performed as originally described [20] with minor modifications. Samples showing abnormal migration patterns were processed for DNA sequencing. PCR products were sequenced directly using T7 sequencing system (Amersham Pharmacia A/S, Hillerød, Denmark) and the resulting products were analysed on an ALF express DNA sequencer (Amersham Pharmacia A/S). If no mutation was identified we performed long PCR in order to identify major rearrangements. In the families where a mutation was identified the mutation was confirmed in all affected individuals. In order to reveal if new mutations were population-specific polymorphisms 100 individual non-HHT chromosomes were tested. The patients were followed for 90 months after 1 January 1995 and all deaths were recorded in the national person registration system. For each of the 73 HHT patients included in the study three individual controls were selected randomly through the Danish national person registration system. The controls were inhabitants in the County of Fyn and were age and gender matched (having birthday the same year and the same day or day after as the corresponding HHT patient). The mortality for all HHT patients and for the HHT subtypes were evaluated in a Kaplan–Meier plot and compared with the control group. Comparisons between HHT genotypes were performed using the chi-square test with Yates correction. Amongst the 73 HHT patients the disease-causing mutation was identified in 56 patients. The mutation was identified in the ENG gene in 39 (53%) persons representing 10 families consequently classified as having HHT1 whilst in 16 (22%) representing four families the mutation was identified in the Alk1 gene and classified as having HHT2. Details concerning the mutations are shown in Table 1. The remaining 18 patients represented four families. Mutation analysis was not possible in one patient representing one family as the patient did not have blood test performed. In three families with seven, nine and one individuals, respectively, we did not identify any mutations although a complete mutation analysis in the ENG and Alk1 location had been performed. Age. There was no significant difference in age distribution at inclusion between the two HHT subtypes. The mean age was 52.6 years (range 14–89) amongst HHT1 patients; whilst the HHT2 patients had a mean age of 57.2 years (range 18–87). The distributions of clinical manifestations are shown in Table 2. Gender. Amongst the 39 patients with HHT1 21 where female whereas only four of 16 HHT2 patients were female, this unequal distribution was however not significant (P = 0.07 Fishers exact test). The gender-specific subgroups concerning each clinical manifestation can be provided from the corresponding author. Epistaxis. In 27 (37%) of 73 HHT patients grade 3 epistaxis was recorded. Amongst the 39 patients with HHT1, 15 (40.5%) had grade 3 epistaxis compared to four (25%) of the HHT2 patients. This difference was not significant. There was no significant difference in age at debut of symptoms as patients with HHT1 reported age of debut at 13.3 years (range 0.1–40) compared with 21.5 (range 6–51) amongst the HHT2 patients. There were reports of GI bleeding in 28 (38%) of the 73 HHT patients with severe bleeding in eight (11%). In patients with HHT1 a history of GI bleeding was recorded in 22 (56.4%), of which six (15.3%) had severe bleeding. Amongst the HHT2 patients only three (18.8%) had a history of GI bleeding, of these only one (6.3%) reported severe bleeding. Accordingly GI bleeding was significantly more common amongst HHT1 patients than amongst HHT2 patients. In 18 (46.1%) of 39 HHT1 patients the PAVM diagnosis was established, whilst this was the case in only two (12.5%) of 16 HHT2 patients. In total 22 (30%) (9 males) of 73 HHT patients had PAVM. The prevalence is minimal as the status concerning the presence of PAVM was unknown in seven patients with HHT1 and in seven patients with HHT2, as these 14 patients declined participation in the screening. The prevalence of PAVM in HHT1 patients was significantly higher than amongst HHT2 patients. Two patients, both female (3% of the HHT patients) were diagnosed with CAVM, of which one had HHT1 and the other had HHT2. The survival of the patients was calculated after 90 months. Amongst patients with HHT1, 11 (28.2%) had died, compared with 17 (14.5%) of 117 controls, whilst amongst patients with HHT2, three (18.8%) had died compared with four (8.3% of controls). The survival in both groups was compared with age- and sex-matched controls and there were no significant differences in survival neither for the total group of 73 HHT patients nor for the HHT subtypes using Kaplan–Meier survival calculation. Survival tables considering all HHT patients and the HHT1 group are shown in 1, 2. Kaplan–Meier plot showing the 90-month survival of 73 HHT patients compared with 219 age- and gender-matched controls. There was no statistically significant difference in the survival of the two groups. Kaplan–Meier plot showing the 90-month survival of 39 HHT1 patients compared with 117 age- and gender-matched controls. There was no statistically significant difference in the survival of the two groups. Unexplained dyspnoea, cyanosis, or reduced physical capacity can be the clues to identify individuals with PAVM. The diagnosis is important in symptomatic as well as asymptomatic individuals. Treatment will improve well-being in symptomatic individuals and is expected to reduce the risk of paradoxical embolus and cerebral abscess [1, 21]. It has been established that the prevalence of PAVM in HHT families is related to the genetic type. Families with HHT1 have a higher prevalence of PAVM than families with HHT2 [10, 22]. This was confirmed in the present study where the prevalence of PAVM was 46.1% amongst HHT1 patients and 12.5% amongst HHT2 patients respectively. However the calculated prevalences were a minimum prevalence as a number of patients declined to participate in the screening programme. The patients who declined further examination included both patients in a poor general health condition with high suspicion of PAVM (previous cerebral ischaemic attack and dyspnoea), and HHT patients with no symptoms at all (the majority of patients belonged to the last group). Although the prevalence is minimal they are in accordance with previously published reports [10, 23]. It should however be considered that the gender distribution in the two HHT groups may cause bias as there were more males amongst the HHT2 patients compared with the group of HHT1 patients. This is certainly important considering the prevalence of PAVM which probably is more frequent amongst woman than men [24]. Another important issue is the fact that 36 of HHT1 patients probably due to a common ancestor shared the same disease-causing mutation, further studies with HHT1 patients may therefore show different prevalences of clinical manifestations. In the present study, we had the opportunity to study an unselected population of HHT patients as all patients in a well-defined geographical area were included. Furthermore the patients were evaluated regarding clinical symptoms both at interview and during clinical examination before the results of the mutation analysis were available. From the present results we could not confirm the results from Berg et al. [11] that HHT1 patients in all aspects of clinical symptoms are more severely affected than HHT2 patients. The study does however show a trend towards that conclusion as there was a trend towards more severe epistaxis and symptoms at a younger age in HHT1 patients, this was however not significant. Apart from showing higher prevalence of PAVM amongst HHT1 patients we also found that a history of GI bleeding was significantly more common amongst HHT1 patients than amongst patients with HHT2 and that the GI bleeding seemed to be more severe in HHT1. Concerning occurrence of CAVM, we only had two cases, one had HHT1 and the other HHT2; both were female. However, in the present study, screening for CAVM was not performed and therefore estimation of prevalence is not appropriate. During the present short follow-up period an increased mortality which we have shown previously [14] could not be confirmed for the total HHT population nor for the HHT subtypes, this is probably due to the presently relatively short observation period, as there was a tendency towards a higher mortality amongst HHT patients compared with controls. The results of the genetic testing in this population is discussed in details in an already published work [19]. In the present population seven seemingly unrelated families proved to have the same mutation, however all families are from the island of Fyn. The Funen population goes 10 000 years back and a common ancestor in the seven families seems likely [19]. In four families we did not succeed in identifying the disease-causing mutation. The recently published data from Gallione et al. [12] made us look through the family histories again however none of the patients had a history of juvenile polyposis. Further mutation analysis did not reveal the described MADH4 mutation. In an unselected population of HHT patients 53% of patients had HHT1 whilst 22% had HHT2. Screening for presence of PAVM confirmed a higher prevalence of PAVM in HHT1 patients (46.1%) than HHT2 patients (12.5%). Furthermore interviews showed that significantly more HHT1 patients (56.4%) than HHT2 patients (18.8%) had a history of GI bleeding. Increased mortality amongst HHT patients was not confirmed in the present study. The results needs confirmation in other study populations as the majority of HHT1 patients had the same mutation, and as the male/female distribution was unequal. The present results are of importance for the patients and their doctors treating them, as no matter of clinical subtype HHT may become a severe and disabling disease and screening for PAVM should be performed irrespective of the HHT subtype. Furthermore, treatment strategies for GI bleeding and epistaxis should be followed and evaluated according to the degree of clinical manifestation and not as a result of genetic subtype. No conflict of interest was declared." @default.
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• W2029046570 title "Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia" @default.
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