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ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Mutations in either ENG or ACVRL1 account for around 85% of cases, and 10% are large deletions and duplications. Here we present a large novel deletion in ACVRL1 gene and its molecular characterization in a 3 generation Italian family. We employed short tandem repeats (STRs) analysis, direct sequencing, multiplex ligation-dependant probe amplification (MLPA) analysis, and 'deletion-specific' PCR methods. STRs Analysis at ENG and ACVRL1 loci suggested a positive linkage for ACVRL1. Direct sequencing of this gene did not identify any mutations, while MLPA identified a large deletion. These results were confirmed and exactly characterized with a 'deletion-specific' PCR: the deletion size is 4,594 bp and breakpoints in exon 3 and intron 8 show the presence of short direct repeats of 7 bp [GCCCCAC]. We hypothesize, as causative molecular mechanism, the replication slippage model. Understanding the fine mechanisms associated with genomic rearrangements may indicate the nonrandomness of these events, highlighting hot spots regions. The complete concordance among MLPA, STRs analysis and 'deletion-specific PCR' supports the usefulness of MLPA in HHT molecular analysis.
Molecular syndromology 03/2013; 4(3):119-24.
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Sebastiaan Velthuis, Elisabetta Buscarini,
Marco W F van Gent,
Pietro Gazzaniga,
Guido Manfredi,
Cesare Danesino,
Wouter J Schonewille,
Cornelis J J Westermann,
Repke J Snijder,
Johannes J Mager,
Martijn C Post
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ABSTRACT: BACKGROUND: A pulmonary right-to-left shunt (RLS) carries the risk of cerebral paradoxical embolization and severe neurological complications. Recognising patients at risk is important to facilitate appropriate management strategies, but a direct relation between pulmonary shunt size and risk of complications remains controversial. OBJECTIVE: This study evaluated the potential relation between pulmonary shunt size on transthoracic contrast echocardiography (TTCE) and prevalence of cerebral manifestations in persons screened for hereditary haemorrhagic telangiectasia (HHT). METHODS: We conducted a two-center, cross-sectional study of all consecutive persons screened for HHT between 2004 and 2011. Pulmonary shunt grading was performed according to contrast opacification of the left ventricle on TTCE (grade 0, no microbubbles; 1, <30 microbubbles; 2, 30-100 microbubbles; 3, >100 microbubbles). Cerebral manifestations were defined as ischemic stroke, transient ischemic attack or brain abscess, diagnosed by a neurologist and confirmed by appropriate imaging techniques. RESULTS: A pulmonary RLS was present in 530 out of 1038 patients (51.1%, mean age 44.3±15.6 years, 58.6% women). The presence of a cerebral manifestation (n=51) differed significantly between pulmonary shunt grades on TTCE; 1.4%, 0.4%, 6.5% and 20.9% for grade 0, 1, 2 and 3 respectively. Pulmonary shunt grade 1 was not associated with an increased prevalence of cerebral manifestations (OR 0.44, 95%CI 0.05-4.13, p=0.47), while pulmonary shunt grade 2 (OR 4.78, 95%CI 1.14-20.0, p=0.03) and grade 3 (OR 10.4, 95%CI 2.4-45.3, p=0.002) were both independent predictors for the prevalence of a cerebral ischemic event or brain abscess. CONCLUSION: Pulmonary RLS grade on TTCE is strongly associated with the prevalence of cerebral complications in patients screened for HHT.
Chest 02/2013; · 5.25 Impact Factor
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ABSTRACT: BACKGROUND: Defensive medicine is becoming more frequent behaviour and has an impact on the economic 'health' of national healthcare systems. AIM: The aim of this study was to clarify the impact of defensive medicine on gastroenterological practices in Lombardy. METHODS: Gastroenterologists attending the Lombardy Annual Gastroenterological Conference received a questionnaire based on multiple choice tests and visual analogue scales. The questionnaire was divided into three parts evaluating the respondent's characteristics, the number of procedures prescribed, and the percentage of those performed with a defensive purpose. RESULTS: Sixty-four of 107 participants (60%) completed the questionnaire, 94% of whom reported practising defensive medicine. The percentage of defensively requested procedures amounted to 18% of all digestive endoscopies, 8.9% of abdominal ultrasonography scans, 4.9% of abdominal computed tomography or magnetic resonance scans, and 12.2% of all consultations. The total number of defensive procedures prescribed per month by the participants was 878, and 31.7% of the performed procedures (n=4897) were reported to defensively based. On the basis of the 2012 regional reimbursement fees, the yearly cost of defensive procedures prescribed and/or performed by all gastroenterologists in Lombardy was estimated to be € 8,637,835. CONCLUSIONS: Our findings indicate that defensive medicine profoundly affects current medical practices among gastroenterologists, and has a considerable economic impact.
Digestive and Liver Disease 02/2013; · 3.05 Impact Factor
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ABSTRACT: Acute biliary pancreatitis (ABP) is a clinical condition that can rapidly evolve into a life-threatening one. Endoscopic retrograde cholangiopancreatography (ERCP) has been considered the standard treatment of ABP for many years, though it entails the risk of morbidity and mortality. Endoscopic ultrasonography (EUS) can reliably diagnose choledocholithiasis avoiding unnecessary ERCP in patients with no stones in the biliary tract.
We undertook a systematic review of the randomized controlled trials and clinical trials comparing EUS and ERCP to evaluate procedure performance, complication rates, clinical course of pancreatitis, and hospital stay according to the treatment given.
A computerized bibliographic search was performed from 1994 to April 2010. Two reviewers assessed the methodological quality of eligible trials and independently extracted data from the included trials.
Seven studies enrolled 545 patients with acute pancreatitis of suspected biliary origin. Only one was a randomized controlled trial. EUS had a lower failure rate than ERCP in all the studies included, avoiding ERCP in 71.2% of cases. No complications were related to EUS, whereas sphincterotomy was associated with bleeding in up to 22% of patients. The procedures did not influence the clinical course of pancreatitis.
A strategy based on EUS before ERCP in patients with ABP may be an effective alternative to diagnostic ERCP.
European journal of gastroenterology & hepatology 05/2011; 23(5):367-74. · 1.66 Impact Factor
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ABSTRACT: Endoscopic ultrasonography is an established diagnostic tool for pancreatic masses and chronic pancreatitis. In recent years there has been a growing interest in the worldwide medical community in autoimmune pancreatitis (AIP), a form of chronic pancreatitis caused by an autoimmune process. This paper reviews the current available literature about the endoscopic ultrasonographic findings of AIP and the role of this imaging technique in the management of this protean disease.
World Journal of Gastroenterology 04/2011; 17(16):2080-5. · 2.47 Impact Factor
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ABSTRACT: Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) is an autosomal dominant vascular disorder characterized by severe and recurrent nosebleeds, muco-cutaneous telangiectasias, and, in some cases, life-threatening visceral arteriovenous malformations. Ocular abnormalities include conjunctival telangiectasia, arteriovenous fistula, angiectasia, phlebectasia, and angioma.
We describe the ocular abnormalities in 8 patients from a pedigree with hereditary hemorrhagic telangiectasia. This article also reviews and discusses the relevant literature.
Five patients (62.5%) had conjunctival telangiectasias and 3 (37.5%) retinal abnormalities, consisting mainly of choriocapillaris atrophy.
To the best of our knowledge, this is the first report describing the occurrence of choriocapillaris atrophy in patients affected by hereditary hemorrhagic telangiectasia and belonging to the same pedigree.
Ophthalmic Genetics 03/2011; 32(1):12-7. · 0.93 Impact Factor
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Elisabetta Buscarini,
Gioacchino Leandro,
Dario Conte,
Cesare Danesino,
Erica Daina,
Guido Manfredi,
Guido Lupinacci,
Gianfranco Brambilla,
Fernanda Menozzi,
Federico De Grazia, [......],
Pasquale Blotta,
Pierangelo Forner,
Carla Olivieri,
Annalisa Perna,
Maurizio Grosso,
Giacomo Pongiglione,
Edoardo Boccardi,
Fabio Pagella,
Giorgio Rossi,
Alessandro Zambelli
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ABSTRACT: Hereditary hemorrhagic telangiectasia is a genetic disease characterized by teleangiectasias involving virtually every organ. There are limited data in the literature regarding the natural history of liver vascular malformations in hemorrhagic telangiectasia and their associated morbidity and mortality.
This prospective cohort study sought to assess the outcome of liver involvement in hereditary hemorrhagic telangiectasia patients.
We analyzed 16 years of surveillance data from a tertiary hereditary hemorrhagic telangiectasia referral center in Italy. We considered for inclusion in this study 502 consecutive Italian patients at risk of hereditary hemorrhagic telangiectasia who presented at the hereditary hemorrhagic telangiectasia referral center and underwent a multidisciplinary screening protocol for the diagnosis of hereditary hemorrhagic telangiectasia. Of the 502 individuals assessed in the center, 154 had hepatic vascular malformations and were the subject of the study; 198 patients with hereditary hemorrhagic telangiectasia and without hepatic vascular malformations were the controls. Additionally, we report the response to treatment of patients with complicated hepatic vascular malformations.
The 154 patients were included and followed for a median period of 44 months (range 12-181); of these, eight (5.2%) died from VM-related complications and 39 (25.3%) experienced complications. The average incidence rates of death and complications were 1.1 and 3.6 per 100 person-years, respectively. The median overall survival and event-free survival after diagnosis were 175 and 90 months, respectively. The rate of complete response to therapy was 63%.
This study shows that substantial morbidity and mortality are associated with liver vascular malformations in hereditary hemorrhagic telangiectasia patients.
Digestive Diseases and Sciences 02/2011; 56(7):2166-78. · 2.12 Impact Factor
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ABSTRACT: Activin A receptor, type II-like kinase 1 (also called ALK1), is a serine-threonine kinase predominantly expressed on endothelial cells surface. Mutations in its ACVRL1 encoding gene (12q11-14) cause type 2 Hereditary Haemorrhagic Telangiectasia (HHT2), an autosomal dominant multisystem vascular dysplasia. The study of the structural effects of mutations is crucial to understand their pathogenic mechanism. However, while an X-ray structure of ALK1 intracellular domain has recently become available (PDB ID: 3MY0), structure determination of ALK1 ectodomain (ALK1(EC)) has been elusive so far. We here describe the building of a homology model for ALK1(EC), followed by an extensive bioinformatic analysis, based on a set of 38 methods, of the effect of missense mutations at the sequence and structural level. ALK1(EC) potential interaction mode with its ligand BMP9 was then predicted combining modelling and docking data. The calculated model of the ALK1(EC) allowed mapping and a preliminary characterization of HHT2 associated mutations. Major structural changes and loss of stability of the protein were predicted for several mutations, while others were found to interfere mainly with binding to BMP9 or other interactors, like Endoglin (CD105), whose encoding ENG gene (9q34) mutations are known to cause type 1 HHT. This study gives a preliminary insight into the potential structure of ALK1(EC) and into the structural effects of HHT2 associated mutations, which can be useful to predict the potential effect of each single mutation, to devise new biological experiments and to interpret the biological significance of new mutations, private mutations, or non-synonymous polymorphisms.
PLoS ONE 01/2011; 6(10):e26431. · 4.09 Impact Factor
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Luca Frulloni,
Massimo Falconi,
Armando Gabbrielli,
Ezio Gaia,
Rossella Graziani,
Raffaele Pezzilli,
Generoso Uomo,
Angelo Andriulli,
Gianpaolo Balzano,
Luigi Benini, [......],
Stefano Milani,
Claudio Pasquali,
Paolo Pederzoli,
Michele Pietrangeli,
Rodolfo Rocca,
Domenico Russello,
Walter Siquini,
Mario Traina,
Luigi Veneroni,
Maurizio Zilli
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ABSTRACT: This paper gives practical guidelines for diagnosis and treatment of chronic pancreatitis. Statements have been elaborated by working teams of experts, by searching for and analysing the literature, and submitted to a consensus process by using a Delphi modified procedure. The statements report recommendations on clinical and nutritional approach, assessment of pancreatic function, treatment of exocrine pancreatic failure and of secondary diabetes, treatment of pain and prevention of painful relapses. Moreover, the role of endoscopy in approaching pancreatic pain, pancreatic stones, duct narrowing and dilation, and complications was considered. Recommendations for most appropriate use of various imaging techniques and of ultrasound endoscopy are reported. Finally, a group of recommendations are addressed to the surgical treatment, with definition of right indications, timing, most appropriate procedures and techniques in different clinical conditions and targets, and clinical and functional outcomes following surgery.
Digestive and Liver Disease 11/2010; 42 Suppl 6:S381-406. · 3.05 Impact Factor
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ABSTRACT: Autoimmune pancreatitis is a form of chronic pancreatitis caused by an autoimmune process. The classical appearance of autoimmune pancreatitis in abdominal imaging is diffuse pancreatic enlargement, but the focal form appears as a mass and often involves the pancreatic head; this scenario represents a challenging diagnostic problem because these features also resemble pancreatic cancer. We present the endoscopic ultrasound findings of seven patients with autoimmune pancreatitis in order to highlight the ambiguous features and the features pivotal for the diagnosis.
JOP: Journal of the pancreas 01/2010; 11(1):78-84.
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Elisa Rossi,
Laura Boeri,
Patrizia Morbini,
Fabio Pagella,
Andrea Colombo,
Elina Matti,
Carla Olivieri,
Vincenzo Villanacci,
Antonella Minelli, Elisabetta Buscarini,
Cecilia Canzonieri,
Cesare Danesino
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ABSTRACT: Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterised by epistaxis, telangiectases, and multiorgan vascular dysplasia. Mutations of the ENG and ACVRL1 genes cause at least 80% of cases. We report the first case of merkeloma found in a patient with HHT carrying an ENG mutation. We analysed the tumour with immunohistochemical methods using primary antibodies against CD105 (endoglin), TGF-β, Smad4, CD31 and CD34. Tumour cells were positive for Smad4, weakly positive for TGF-β, and negative for CD105. Vasal endothelial cells were highly positive for CD105, CD31 and CD34. No remarkable differences between cancer and normal cells in our patient or between the patient's merkeloma and two control merkelomas were observed. The presence of a merkeloma in an HHT patient could be an occasional association, but to certainly assume it further investigations are needed.
Case Reports 01/2010; 2010.
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ABSTRACT: Endoscopic ultrasonography is currently a sensitive diagnostic and therapeutic tool with established indications, but its role in the management of portal hypertension is not well defined. This article briefly reviews indications, technologic improvements, diagnostic and interventional applications of endoscopic ultrasonography in portal hypertension.
European journal of gastroenterology & hepatology 10/2009; 21(12):1327-32. · 1.66 Impact Factor
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Liver Transplantation 12/2008; 14(11):1685-6; author reply 1687-8. · 3.39 Impact Factor
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Journal of Hepatology 11/2008; 49(4):658-9; author reply 659-61. · 9.26 Impact Factor
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Gaetan Lesca,
Emmanuelle Genin,
Claire Blachier,
Carla Olivieri,
Florence Coulet,
Guy Brunet,
Sophie Dupuis-Girod, Elisabetta Buscarini,
Florent Soubrier,
Alain Calender,
Cesare Danesino,
Sophie Giraud,
Henri Plauchu
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ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by widespread arteriovenous malformations and caused by mutations in two major genes: ENG and ACVRL1. Two decades ago, a French epidemiological study pointed out that its prevalence was higher than previously thought and that its distribution varied greatly from one area to another, one of the highest concentrations of patients being found in the Haut-Jura mountains. Although germline mutations are usually family specific, some of them have been reported in unrelated patients, especially for ACVRL1. We performed haplotype analysis of 116 French and Italian patients carrying 13 ACVRL1 different mutations. For five of these mutations, we estimated the age of the most recent common ancestors (MRCAs) using the ESTIAGE program. Most mutations were related to both recurrent mutational events and founder effects with age estimates ranging from 100 to 550 years. The c.1112dupG mutation, which is likely to be responsible for the very high concentration of HHT patients found in the former epidemiological study, probably occurred in one inhabitant of the Haut-Jura Mountains more than three centuries ago. The p.Arg374Gln mutation occurred independently in at least two distinct geographical areas, including the area with the second highest prevalence in the epidemiological study and where the MRCA is rather recent (about 100 years ago). Partially shared haplotypes between French and Italian patients were found for three mutations. This suggests a common origin and a possible diffusion of these mutations from Italy to France.
European Journal of HumanGenetics 07/2008; 16(6):742-9. · 4.40 Impact Factor
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Gastrointestinal endoscopy 06/2008; 68(2):373-4; discussion 374. · 6.71 Impact Factor
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ABSTRACT: The purpose was to evaluate interobserver agreement on Doppler ultrasonographic (US) diagnosis of liver vascular malformations (VMs) in hereditary hemorrhagic teleangiectasia (HHT) and on their severity grading. During the interobserver agreement study, three observers with at least seven years of specific experience using Doppler US for the diagnosis of liver VMs, judged about the presence/absence of liver VMs and their severity on a set of images and videoclips. Interobserver agreement was estimated with kappa statistics. One-hundred ten cases were reviewed during interobserver study (80 cases with liver VMs, 30 without). Very good kappa values of the interobserver agreement were found for all pairs concerning the distinction between presence and absence of hepatic VMs. All observers demonstrated excellent sensitivity and specificity in identifying hepatic VMs, with their respective areas under the curve ranging from 0.97 to 0.99. Interobserver agreement among the three investigators in staging the hepatic VMs in HHT patients was moderate (Kendall's coefficient of concordance = 0.26). Study results indicate that Doppler US diagnosis of liver VMs in HHT has a high degree of agreement among ultrasonographers; a moderate agreement was found regarding severity staging.
Ultrasound in Medicine & Biology 06/2008; 34(5):718-25. · 2.29 Impact Factor
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Gaëtan Lesca,
Carla Olivieri,
Nelly Burnichon,
Fabio Pagella,
Marie-France Carette,
Brigitte Gilbert-Dussardier,
Cyril Goizet,
Joelle Roume,
Muriel Rabilloud,
Jean-Christophe Saurin,
Vincent Cottin,
Jerome Honnorat,
Florence Coulet,
Sophie Giraud,
Alain Calender,
Cesare Danesino, Elisabetta Buscarini,
Henri Plauchu
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ABSTRACT: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations (AVM), mostly cutaneous and mucous (telangiectases), but also involving the lungs (PAVM), liver (HAVM) and brain (CAVM). We studied the relationship between the phenotype and genotype in patients with a proven mutation in either ENG (HHT1) or ACVRL1 (HHT2).
Clinical features and their age of onset were compared between HHT1 and HHT2. The type of mutation was also analyzed. Clinical manifestations were distinguished from lesions found by screening.
Ninety-three HHT1 patients and 250 HHT2 patients were included. Epistaxis occurred later in HHT2, with incomplete penetrance (P<0.0001). Symptomatic PAVMs were more frequent in HHT1 (34.4 vs. 5.2%, P<0.001), as were cerebral abscesses (7.5 vs. 0.8%, P=0.002). Gastrointestinal bleeding occurred more frequently in HHT2 (16.4 vs. 6.5%, P=0.017). Symptomatic hepatic involvement was only seen in HHT2 patients. PAVMs were more frequently detected in asymptomatic HHT1 patients (54 vs. 12.8%, P<0.0001). PAVMs and HAVMs were often family clustered in HHT1 and HHT2, respectively. Truncating mutations were associated with a higher frequency of epistaxis and telangiectasis, in HHT2.
This study shows major differences between HHT1 and HHT2 phenotypes, which should be taken into account for future clinical studies.
Genetics in Medicine 02/2007; 9(1):14-22. · 4.76 Impact Factor
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Carla Olivieri,
Fabio Pagella,
Lucia Semino,
Luca Lanzarini,
Cristina Valacca,
Andrea Pilotto,
Sabrina Corno,
Susi Scappaticci,
Guido Manfredi, Elisabetta Buscarini,
Cesare Danesino
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ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder causing vascular dysplasias. About 70-80% of HHT patients carries mutations in ENG or ACVRL1 genes, which code for a TGFbeta receptor type III and I respectively. Molecular data on a large cohort of Italian HHT patients are presented, discussing the significance of missense and splice site mutations. Mutation analysis in ENG and ACVRL1 genes was performed using single strand conformation polymorphisms (SSCP), denaturing high performance liquid chromatography (DHPLC) and subsequent direct sequencing. Overall, 101 mutations were found, with ACVRL1 involved in 71% of cases. The highest number of mutations (28/101 subjects, 14/76 different mutations referring to both genes) was in ACVRL1, exon 3. Mutation analysis was then extended to a total of 356 family members, and 162 proven to carry the mutation. New polymorphisms were identified in both genes, and evidence that ENG P131L change is not a disease-causing mutation was also provided. An in silico analysis was performed in order to characterize splice-site mutations. These results were compared to other European national studies and data from Italy, France and Spain were consistent for an higher incidence of ACVRL1 mutations.
Journal of Human Genetics 02/2007; 52(10):820-9. · 2.57 Impact Factor
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Elisabetta Buscarini,
Henry Plauchu,
Guadalupe Garcia Tsao,
Robert I White,
Carlo Sabbà,
Franklin Miller,
Jean Cristophe Saurin,
Jean Pierre Pelage,
Gaetan Lesca,
Marie Jeanne Marion,
Annalisa Perna,
Marie E Faughnan
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ABSTRACT: STUDY PURPOSE: To formulate recommendations about clinical management of liver involvement in hereditary hemorrhagic telangiectasia (HHT), using a formal consensus development process. CONSENSUS PROCESS: A nominal group technique was used. A list of main clinical, diagnostic and therapeutic issues about liver involvement in HHT was generated by the organizing committee. Panel members then scored their agreement with each statement; the median score, and standard deviation for each statement were determined for each of the three successive panel rounds. These consensus statements formed the basis for recommendations graded with the strength and quality of supporting evidence. RECOMMENDATION STATEMENTS: Doppler US is sufficiently accurate and suitable for first-line imaging of the liver in the general HHT population. Liver biopsy in any patient with proven or suspected HHT should be avoided. Liver involvement in HHT is generally asymptomatic; in the minority of patients where it is symptomatic, morbidity and mortality can be substantial. The prevalence of focal nodular hyperplasia is much higher in patients with liver involvement by HHT than in the general population. Invasive therapies for liver involvement by HHT (namely liver transplantation) should be considered only in patients who have failed to respond to intensive medical therapy.
Liver international: official journal of the International Association for the Study of the Liver 12/2006; 26(9):1040-6. · 3.82 Impact Factor
