Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

Blood Reviews - Tập 24 Số 6 - Trang 203-219 - 2010
Claire L. Shovlin1
1NHLI Cardiovascular Sciences, Imperial College London, UK and HHTIC London, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.

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Guttmacher, 1995, Hereditary hemorrhagic telangiectasia, New Engl J Med, 333, 918, 10.1056/NEJM199510053331407

Shovlin, 2000, Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu–Osler–Weber syndrome), Am J Med Genet, 91, 66, 10.1002/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P

Govani, 2009, Hereditary haemorrhagic telangiectasia: a clinical and scientific review, Eur J Hum Genet, 17, 860, 10.1038/ejhg.2009.35

Kjeldsen, 1999, Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients, J Intern Med, 245, 31, 10.1046/j.1365-2796.1999.00398.x

Dakeishi, 2002, Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan, Hum Mut, 19, 140, 10.1002/humu.10026

Bideau, 1992, An abnormal concentration of cases of Rendu–Osler disease in the Valserine valley of the French Jura: a geneological and demographic study, Ann Hum Biol, 19, 233, 10.1080/03014469200002112

Westermann, 2003, The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles: a family screening, Am J Med Genet, 116, 324, 10.1002/ajmg.a.10002

Lesca, 2008, Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients, Eur J Hum Genet, 16, 742, 10.1038/ejhg.2008.3

Lacout, 2010, Pancreatic involvement in hereditary hemorrhagic telangiectasia: assessment with multidetector helical CT, Radiology, 254, 479, 10.1148/radiol.09090096

Trembath, 2001, Clinical and molecular features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia, New Engl J, 345, 325, 10.1056/NEJM200108023450503

Gallione, 2004, A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia is associated with mutations in MADH4 (SMAD4), Lancet, 363, 852, 10.1016/S0140-6736(04)15732-2

Brohée, 1984, High-output right ventricular failure secondary to hepatic arteriovenous microfistulae Selective arterial embolization treatment, Arch Intern Med, 144, 1282, 10.1001/archinte.144.6.1282

Haitjema, 1996, Unusual complications after embolization of a pulmonary arteriovenous malformation, Chest, 109, 1401, 10.1378/chest.109.5.1401

Boillot, 1999, Liver transplantation resolves the hyperdynamic circulation in hereditary hemorrhagic telangiectasia with hepatic involvement, Gastroenterology, 116, 187, 10.1016/S0016-5085(99)70243-X

Garcia-Tsao, 2000, Liver disease in patients with hereditary hemorrhagic telangiectasia, N Engl J Med, 343, 931, 10.1056/NEJM200009283431305

Shovlin, 2008, Embolisation of pulmonary arteriovenous malformations: no consistent effect on pulmonary artery pressure, Eur Resp J, 32, 162, 10.1183/09031936.00126207

Shovlin, 2007, Elevated Factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism, Thromb Haemost, 98, 1031, 10.1160/TH07-01-0064

Cirulli, 2006, Patients with Hereditary Hemorrhagic Telangectasia (HHT) exhibit a deficit of polymorphonuclear cell and monocyte oxidative burst and phagocytosis: a possible correlation with altered adaptive immune responsiveness in HHT, Curr Pharm Des, 12, 1209, 10.2174/138161206776361336

McAllister, 1994, Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1, Nat Genet, 8, 345, 10.1038/ng1294-345

Johnson, 1996, Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2, Nat Genet, 13, 189, 10.1038/ng0696-189

www.hhtmutation.org. accessed April 2008.

Kjeldsen, 2005, Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia, J Int Med, 258, 349, 10.1111/j.1365-2796.2005.01555.x

Letteboer, 2006, Genotype–phenotype relationship in hereditary haemorrhagic telangiectasia, J Med Genet, 43, 371, 10.1136/jmg.2005.035451

Bossler, 2006, Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype, Hum Mutat, 27, 667, 10.1002/humu.20342

Bayrak-Toydemir, 2006, Genotype–phenotype correlation in hereditary hemorrhagic telangiectasia, Am J Med Genet A, 140, 463, 10.1002/ajmg.a.31101

Sabbà, 2007, Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers, J Thromb Haemost, 5, 1149, 10.1111/j.1538-7836.2007.02531.x

Lesca, 2007, Genotype–phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network, Genet Med, 9, 14, 10.1097/GIM.0b013e31802d8373

Park, 2009, Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia, J Clin Invest, 119, 3487

Belik, 2009, Age-dependent endothelial nitric oxide synthase uncoupling in pulmonary arteries of endoglin heterozygous mice, Am J Physiol Lung Cell Mol Physiol, 297, L1170, 10.1152/ajplung.00168.2009

Mahmoud, 2010, Pathogenesis of arteriovenous malformations in the absence of endoglin, Circ Res, 106, 1425, 10.1161/CIRCRESAHA.109.211037

Lebrin, 2010, Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia, Nat Med, 16, 420, 10.1038/nm.2131

Faughnan, 2009, International guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia, J Med Genet

Hoag, 2010, An epistaxis severity score for hereditary hemorrhagic telangiectasia, Laryngoscope, 120, 838, 10.1002/lary.20818

Shovlin, 2008, Primary determinants of ischaemic stroke/ brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia, Thorax, 63, 259, 10.1136/thx.2007.087452

Harvey, 2008, The impact of septodermoplasty and potassium-titanyl-phosphate (KTP) laser therapy in the treatment of hereditary hemorrhagic telangiectasia-related epistaxis, Am J Rhinol, 22, 182, 10.2500/ajr.2008.22.3145

Richmon, 2007, Use of a sprayed fibrin hemostatic sealant after laser therapy for hereditary hemorrhagic telangiectasia epistaxis, Am J Rhinol, 21, 187, 10.2500/ajr.2007.21.2969

Pagella, 2009, Correlation of severity of epistaxis with nasal telangiectasias in hereditary hemorrhagic telangiectasia (HHT) patients, Am J Rhinol Allergy, 23, 52, 10.2500/ajra.2009.23.3263

Braak, 2009, Percutaneous embolization on hereditary hemorrhagic telangiectasia patients with severe epistaxis, Rhinology, 47, 166

Lesnik, 2007, Septectomy and septal dermoplasty for the treatment of severe transfusion-dependent epistaxis in patients with hereditary hemorrhagic telangiectasia and septal perforation, Am J Rhinol, 21, 312, 10.2500/ajr.2007.21.3017

de Gussem, 2009, The effect of N-acetylcysteine on epistaxis and quality of life in patients with HHT: a pilot study, Rhinology, 47, 85

Fernandez, 2007, Therapeutic action of tranexamic acid in hereditary haemorrhagic telangiectasia (HHT): regulation of ALK-1/endoglin pathway in endothelial cells, Thromb Haemost, 97, 254, 10.1160/TH06-07-0373

Morales-Angulo, 2007, Treatment of epistaxes in hereditary haemorrhagic telangiectasia (Rendu–Osler–Weber disease) with tranexamic acid, Acta Otorrinolaringol Esp, 58, 129, 10.1016/S0001-6519(07)74897-5

Simonds, 2009, The effect of bevacizumab (Avastin) treatment on epistaxis in hereditary hemorrhagic telangiectasia, Laryngoscope, 119, 988, 10.1002/lary.20159

Davidson, 2010, Hereditary hemorrhagic telangiectasia/avastin, Laryngoscope, 120, 432, 10.1002/lary.20757

Albinana, 2010, Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): effects of raloxifene, on endoglin and ALK1 expression in endothelial cells, Thromb Haemost, 103, 525, 10.1160/TH09-07-0425

Yaniv, 2009, Antiestrogen therapy for hereditary hemorrhagic telangiectasia: a double-blind placebo-controlled clinical trial, Laryngoscope, 119, 284, 10.1002/lary.20065

Gazzaniga, 2008, Contrast echocardiography for pulmonary arteriovenous malformations (PAVMs) screening: does any bubble matter?, Eur J Echocardiogr, 10, 513, 10.1093/ejechocard/jen317

Parra, 2010, Graded contrast echocardiography in pulmonary arteriovenous malformations, Eur Respir J, 35, 1279, 10.1183/09031936.00104309

Zukotynski, 2007, Contrast echocardiography grading predicts pulmonary arteriovenous malformations on CT, Chest, 132, 18, 10.1378/chest.06-2356

van Gent, 2009, Screening for pulmonary arteriovenous malformations using transthoracic contrast echocardiography: a prospective study, Eur Respir J, 33, 85, 10.1183/09031936.00049008

van Gent, 2008, Grading of pulmonary right-to-left shunt with transthoracic contrast echocardiography: does it predict the indication for embolotherapy?, Chest, 135, 1288, 10.1378/chest.08-1266

van Gent, 2010, Real prevalence of pulmonary right-to-left shunt according to genotype in patients with hereditary hemorrhagic telangiectasia: a transthoracic contrast echocardiography study, Chest, 10.1378/chest.09-1849

Thenganatt, 2006, Migraines linked to intrapulmonary right-to-left shunt, Headache, 46, 439, 10.1111/j.1526-4610.2006.00291.x

Marziniak, 2009, An association of migraine with hereditary haemorrhagic telangiectasia independently of pulmonary right-to-left shunts, Cephalalgia, 29, 76, 10.1111/j.1468-2982.2008.01703.x

Shovlin, 2008, Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia: suggested approach for obstetric services, BJOG, 115, 1108, 10.1111/j.1471-0528.2008.01786.x

Post, 2006, Embolization of pulmonary arteriovenous malformations and decrease in prevalence of migraine, Neurology, 66, 202, 10.1212/01.wnl.0000194257.75559.b0

Remy-Jardin, 2006, Pulmonary arteriovenous malformations treated with embolotherapy: helical CT evaluation of long-term effectiveness after 2–21-year follow-up, Radiology, 239, 576, 10.1148/radiol.2391050333

Pollak, 2006, Clinical and anatomic outcomes after embolotherapy of pulmonary arteriovenous malformations, J Vasc Interv Radiol, 17, 35, 10.1097/01.RVI.0000191410.13974.B6

Hart JL, Aldin Z, Braude P, Shovlin CL, Jackson J. Embolization of pulmonary arteriovenous malformations using the Amplatzer vascular plug: successful treatment of 69 consecutive patients Eur J Radiology. 2010 [June 24, Electronic publication ahead of print]. doi:10.1007/s00330-010-1851-2.

Letourneau-Guillon, 2010, Embolization of pulmonary arteriovenous malformations with amplatzer vascular plugs: safety and midterm effectiveness, J Vasc Interv Radiol, 21, 649, 10.1016/j.jvir.2010.01.026

Brillet, 2007, Pulmonary arteriovenous malformation treated with embolotherapy: systemic collateral supply at multidetector CT angiography after 2–20-year follow-up, Radiology, 242, 267, 10.1148/radiol.2421041571

Shovlin, 2008, Management of pulmonary arteriovenous malformations in pulmonary hypertensive patients. A pressure to embolise?, Eur Respir Rev, 18, 4, 10.1183/09059180.00011102

Wilson, 2008, Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group, J Am Dent Assoc, 138, 747

Wray, 2008, Guideline Development Group. Prophylaxis against infective endocarditis for dental procedures—summary of the NICE guideline, Br Dent J, 204, 555, 10.1038/sj.bdj.2008.404

Shovlin, 2008, Post-NICE 2008: Antibiotic prophylaxis prior to dental procedures for patients with pulmonary arteriovenous malformations (PAVMs) and hereditary haemorrhagic telangiectasia, Br Dent J, 205, 531, 10.1038/sj.bdj.2008.978

Shovlin CL, Jackson JE. Pulmonary arteriovenous malformations. In: Pulmonary Circulation 3rd Edition, Arnold. Eds Peacock A, Rubin LJ; in press.

Krings, 2005, Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age. Review of 50 consecutive patients aged 1day–60years, Neuroradiology, 47, 711, 10.1007/s00234-005-1390-8

Krings, 2005, Hereditary hemorrhagic telangiectasia in children: endovascular treatment of neurovascular malformations. Results in 31 patients, Neuroradiology, 47, 946, 10.1007/s00234-005-1448-7

Dauwerse, 2010, A patient's journey: the war in my head: coping with arteriovenous malformation after a brain haemorrhage, BMJ, 340, b5400, 10.1136/bmj.b5400

Gincul, 2008, Evaluation of previously nonscreened hereditary hemorrhagic telangiectasia patients shows frequent liver involvement and early cardiac consequences, Hepatology, 48, 1377, 10.1002/hep.22514

Wanless, 1986, Nodular transformation of the liver in hereditary hemorrhagic telangiectasia, Arch Pathol Lab Med, 110, 331

Van Gent MWF, Post MC, Mager JJ, et al. Diagnostic Curacao Criteria for HHT; are they still valid? Hematology Meeting Rep 2009; 3 (4) 13.

Buscarini, 2006, Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations, Liver Int, 26, 1040, 10.1111/j.1478-3231.2006.01340.x

Dupuis-Girod, 2010, Long-term outcome of patients with hereditary hemorrhagic telangiectasia and severe hepatic involvement after orthotopic liver transplantation: a single-center study, Liver Transplant, 16, 340, 10.1002/lt.21990

Lerut, 2006, Liver transplantation for hereditary hemorrhagic telangiectasia: report of the European liver transplant registry, Ann Surg, 244, 854, 10.1097/01.sla.0000247258.35406.a4

Cura, 2010, Transjugular intrahepatic portosystemic shunt for variceal hemorrhage due to recurrent of hereditary hemorrhagic telangiectasia in a liver transplant, J Vasc Interv Radiol, 21, 135, 10.1016/j.jvir.2009.09.009

Mitchell, 2008, Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia., Liver Transpl, 14, 210, 10.1002/lt.21417

Buscarini, 2008, Bevacizumab to treat complicated liver vascular malformations in hereditary hemorrhagic telangiectasia: a word of caution, Liver Transpl, 14, 1685, 10.1002/lt.21656

Poisson, 2009, Acute paraplegia due to spinal arteriovenous fistula in two patients with hereditary hemorrhagic telangiectasia, Eur J Pediatr, 168, 135, 10.1007/s00431-008-0863-2

Cullen, 2006, Spinal arteriovenous shunts presenting before 2years of age: analysis of 13 cases, Childs Nerv Syst, 22, 1103, 10.1007/s00381-006-0075-x

Espinosa, 2008, Hereditary hemorrhagic telangectasia and spinal cord infarct: case report with a review of the neurological complications of HHT, Clin Neurol Neurosurg, 110, 484, 10.1016/j.clineuro.2008.01.005

Sense about Science. Making Sense of Screening. http://wwwsenseaboutscienceorguk/PDF/MSOScreeningpdf. 2009.

Raffle, 2007

Chodick, 2007, Excess lifetime cancer mortality risk attributable to radiation exposure from computed tomography examinations in children, Isr Med Assoc J, 9, 584

Rice, 2007, APSA Education Committee Review of radiation risks from computed tomography: essentials for the pediatric surgeon, J Pediatr Surg, 42, 603, 10.1016/j.jpedsurg.2006.12.009

Thierry-Chef, 2008, Radiation dose to the brain and subsequent risk of developing brain tumors in pediatric patients undergoing interventional neuroradiology procedures, Radiat Res, 170, 553, 10.1667/RR1393.1

Román, 1978, Neurological manifestations of hereditary hemorrhagic telangiectasia (Rendu–Osler–Weber Disease): report of 2 cases and review of the literature, Ann Neurol, 4, 130, 10.1002/ana.410040207

Maher, 2001, Cerebrovascular manifestations in 321 cases of hereditary haemorrhagic telangiectasia, Stroke, 32, 877, 10.1161/01.STR.32.4.877

Braverman, 1989, Ultrastructure and organization of the cutaneous microvasculature in normal and pathologic states, J Invest Dermatol, 93, 2S, 10.1111/1523-1747.ep12580893

Braverman, 1990, Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia, J Invest Dermatol, 95, 422, 10.1111/1523-1747.ep12555569

Cooley, 1954, Pulmonary telangiectasia: report of a case proven by pulmonary biopsy, J Thorac Surg, 27, 614, 10.1016/S0096-5588(20)31002-3

Hales, 1956, Multiple small arteriovenous fistulas of the lungs, Am J Path, 32, 927

Shovlin, 1999, Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms, Thorax, 54, 714, 10.1136/thx.54.8.714

Wolinsky, 1967, A lamellar unit of aortic medial structure and function in mammals, Circ Res, 20, 99, 10.1161/01.RES.20.1.99

Owens, 2010, Adaptive changes in autogenous vein grafts for arterial reconstruction: clinical implications, J Vasc Surg, 51, 736, 10.1016/j.jvs.2009.07.102

Yater, 1949, Pulmonary arteriovenous fistula (varix), JAMA, 141, 581, 10.1001/jama.1949.02910090007002

Bourdeau, 2000, Endoglin expression is reduced on normal vessels but still detectable in arteriovenous malformations of patients with hereditary haemorrhagic telangiectasia type I, Am J Pathol, 156, 911, 10.1016/S0002-9440(10)64960-7

Kwei, 2004, Early adaptive responses of the vascular wall during venous arterialization in mice, Am J Pathol, 164, 81, 10.1016/S0002-9440(10)63099-4

Begbie, 2003, Hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu syndrome): a view from the 21st century, Postgrad Med J, 79, 18, 10.1136/pmj.79.927.18

Cottin, 2004, Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia, Am J Respir Crit Care Med, 169, 994, 10.1164/rccm.200310-1441OC

Olivieri, 2006, Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia, Genet Med, 8, 183, 10.1097/01.gim.0000204463.77319.1c

Girerd, 2010, Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation, Am J Respir Crit Care Med, 181, 851, 10.1164/rccm.200908-1284OC

Plauchu, 1989, Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population, Am J Med Genet, 32, 291, 10.1002/ajmg.1320320302

Letteboer, 2008, Genotype–phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia, Am J Med Genet A, 146A, 2733, 10.1002/ajmg.a.32243

Shovlin, 2010, Pulmonary arteriovenous malformations and other pulmonary–vascular abnormalities. Chapter 54., 1261

Livneh, 1988, Functionally reversible hepatic arteriovenous fistulas during pregnancy in patients with hereditary hemorrhagic telangiectasia, South Med J, 81, 1047, 10.1097/00007611-198808000-00026

Gammon, 1990, Osler–Weber–Rendu disease and pulmonary arteriovenous fistulas. Deterioration and embolotherapy during pregnancy, Chest, 98, 1522, 10.1378/chest.98.6.1522

Swinburne, 1986, Hereditary telangiectasia and multiple pulmonary arteriovenous fistulas. Clinical deterioration during pregnancy, Chest, 89, 459, 10.1378/chest.89.3.459

Shovlin, 1995, Medical complications of pregnancy in hereditary haemorrhagic telangiectasia, Quart J Med, 88, 879

Kjeldsen, 2000, Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia, Am J Gastroenterol, 95, 415, 10.1111/j.1572-0241.2000.01792.x

Pasculli, 2004, Health-related quality of life in a rare disease: hereditary hemorrhagic telangiectasia (HHT) or Rendu–Osler–Weber disease, Qual Life Res, 13, 1715, 10.1007/s11136-004-7865-y

Lennox, 2005, The SF-36 health status questionnaire in assessing patients with epistaxis secondary to hereditary hemorrhagic telangiectasia, Am J Rhinol, 19, 71, 10.1177/194589240501900112

Aassar, 1991, The natural history of epistaxis in hereditary hemorrhagic telangiectasia, Laryngoscope, 101, 977, 10.1288/00005537-199109000-00008

Lund, 1999, A treatment algorithm for the management of epistaxis in hereditary haemorrhagic telangiectasia, Am J Rhinol, 13, 319, 10.2500/105065899782102890

Sabba, 2006, Life expectancy in patients with hereditary haemorrhagic telangiectasia, QJM, 99, 327, 10.1093/qjmed/hcl037

Morgan, 2002, Intracranial haemorrhgae in infants and children with hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu syndrome), Pediatrics, 109

de Gussem, 2009, Life expectancy of parents with hereditary hemorrhagic telangiectasia, Hematol Meet Rep, 3, 11

Goodwin, 2009, Survival in hereditary hemorrhagic telangiectasia, Hematol Meet Rep, 3, 12

Snyder, 1944, Clinical and experimental studies in human inheritance—is the homozygous form of multiple telangiectasia lethal?, J Lab Clin Med, 29, 1211

Karabegovic, 2004, No live individual homozygous for a novel endoglin mutation was found in a consanguineous Arab family with hereditary haemorrhagic telangiectasia, J Med Genet, 41, e119, 10.1136/jmg.2004.022079

El-Harith el, 2006, Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the ACVRL1 gene in a large Arab family: support of homozygous lethality, Eur J Med Genet, 49, 323, 10.1016/j.ejmg.2005.09.002

Wooderchak, 2010, Hereditary hemorrhagic telangiectasia: two distinct ENG deletions in one family, Clin Genet, 10.1111/j.1399-0004.2010.01418.x

Shovlin, 1996, Inherited diseases of the vasculature, Ann Rev Physiol, 58, 483, 10.1146/annurev.ph.58.030196.002411

Shovlin, 1998, Molecular studies on adenosine deaminase deficiency and hereditary haemorrhagic telangiectasia, Clin Sci, 94, 207, 10.1042/cs0940207

Shovlin C, Haslett C, Lamb J. The molecular and cellular basis of disease. In: Haslett C, Chilvers E, Hunter J, Boon N, eds. Davidson's Principles and Practice of Medicine 18th Edn. Edinburgh: Churchill Livingstone; 1999:1–56, and 1128–1131

Letteboer, 2007, Genetic modification of the hereditary haemorrhagic telangiectasia phenotype, Hematol Meet Rep, 1, 26

Gallione, 2010, Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome, Am J Med Genet A, 152A, 333, 10.1002/ajmg.a.33206

Cole, 2005, A new locus for hereditary haemorrhagic telangiactasia (HHT3) maps to chromosome 5, J Med Genet, 42, 577, 10.1136/jmg.2004.028712

Govani F, Shovlin C. SNP mapping of the hereditary haemorrhagic telangiectasia (HHT)3 locus on chromosome 5 excludes Sprouty 4, VE-cadherin 2 and other interval genes. Journal of Angiogenesis Research 2010;2:15. doi:10.1186/2040-2384-2-15.

Bayrak-Toydemir, 2006, A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7, Am J Med Genet, 140, 2155, 10.1002/ajmg.a.31450

Shoukier, 2008, Characterization of five novel large deletions causing hereditary haemorrhagic telangiectasia, Clin Genet, 73, 320, 10.1111/j.1399-0004.2008.00968.x

Shovlin, 2010, Hereditary haemorrhagic telangiectasia, 167

Toporsian, 2010, Spontaneous adult-onset pulmonary arterial hypertension attributable to increased endothelial oxidative stress in a murine model of hereditary hemorrhagic telangiectasia, Arterioscler Thromb Vasc Biol, 30, 509, 10.1161/ATVBAHA.109.200121

Harrison, 2003, Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia, J Med Genet, 40, 865, 10.1136/jmg.40.12.865

Abdalla, 2004, Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia, Eur Respir J, 23, 373, 10.1183/09031936.04.00085504

Massagué, 2006, The logic of TGFbeta signaling, FEBS Lett, 580, 2811, 10.1016/j.febslet.2006.04.033

Groppe, 2008, Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding, Mol Cell, 29, 157, 10.1016/j.molcel.2007.11.039

ten Dijke, 2007, Extracellular control of TGFbeta signalling in vascular development and disease, Nat Rev Mol Cell Biol, 8, 857, 10.1038/nrm2262

Derynck, 2003, Smad-dependent and Smad-independent pathways in TGF-beta family signalling, Nature, 425, 577, 10.1038/nature02006

Guo, 2009, Signaling cross-talk between TGF-β/BMP and other pathways, Cell Res, 19, 71, 10.1038/cr.2008.302

Upton, 2009, BMP and activin type-II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells, J Biol Chem, 284, 15794, 10.1074/jbc.M109.002881

Pardali, 2010, Signaling by members of the TGF-beta family in vascular morphogenesis and disease, Trends Cell Biol, 10.1016/j.tcb.2010.06.006

Abdalla, 2006, Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease, J Med Genet, 43, 97, 10.1136/jmg.2005.030833

Barbara, 1997, Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily, J Biol Chem, 274, 584, 10.1074/jbc.274.2.584

Lopez-Novoa, 2010, The physiological role of endoglin in the cardiovascular system, Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.01251.2009

Blanco, 2005, Interactions and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-beta receptor complex, J Cell Physiol, 204, 574, 10.1002/jcp.20311

Goumans, 2002, Balancing the activation state of the endotheliumvia two distinct TGF-beta type I receptors, EMBO J, 21, 1743, 10.1093/emboj/21.7.1743

Lebrin, 2004, Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction, EMBO J, 23, 4018, 10.1038/sj.emboj.7600386

Pece-Barbara, 2005, Endoglin null endothelial cells proliferate faster and are more responsive to transforming growth factor beta1 with higher affinity receptors and an activated Alk1 pathway, J Biol Chem, 280, 27800, 10.1074/jbc.M503471200

David, 2007, Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells, Blood, 109, 1953, 10.1182/blood-2006-07-034124

Scharpfenecker, 2007, BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis, J Cell Sci, 120, 964, 10.1242/jcs.002949

Park, 2008, ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2, Blood, 111, 633, 10.1182/blood-2007-08-107359

Bourdeau, 1999, A murine model of hereditary hemorrhagic telangiectasia, J Clin Invest, 104, 1343, 10.1172/JCI8088

Satomi, 2003, Cerebral vascular abnormalities in a murine model of hereditary hemorrhagic telangiectasia, Stroke, 34, 783, 10.1161/01.STR.0000056170.47815.37

Srinivasan, 2003, A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2, Hum Mol Genet, 12, 473, 10.1093/hmg/ddg050

Knudson, 1985, Hereditary cancer, oncogenes, and antioncogenes, Cancer Res, 45, 1437

Matsubara, 2000, Analysis of endoglin expression in normal brain tissue and in cerebral arteriovenous malformations, Stroke, 31, 2653, 10.1161/01.STR.31.11.2653

Arthur, 2000, Endoglin, an ancillary TGFbeta receptor, is required for extra-embryonic angiogenesis and plays a key role in heart development, Dev Biol, 217, 42, 10.1006/dbio.1999.9534

Urness, 2000, Arteriovenous malformations in mice lacking activin receptor-like kinase-1, Nat Genet, 26, 328, 10.1038/81634

Oh, 2000, Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis, Proc Natl Acad Sci USA, 97, 2626, 10.1073/pnas.97.6.2626

Shovlin, 1999, Supermodels and disease: insights from the HHT mice, J Clin Invest, 104

Carvalho, 2007, Compensatory signalling induced in the yolk sac vasculature by deletion of TGFbeta receptors in mice, J Cell Sci, 120, 4269, 10.1242/jcs.013169

Sorensen, 2003, Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGFbeta coreceptor, Dev Biol, 261, 235, 10.1016/S0012-1606(03)00158-1

Mancini, 2009, Endoglin plays distinct roles in vascular smooth muscle cell recruitment and regulation of arteriovenous identity during angiogenesis, Dev Dyn, 238, 2479, 10.1002/dvdy.22066

Gerhardt, 2003, VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia, J Cell Biol, 161, 1163, 10.1083/jcb.200302047

Gaengel, 2009, Endothelial–mural cell signaling in vascular development and angiogenesis, Arterioscler Thromb Vasc Biol, 29, 630, 10.1161/ATVBAHA.107.161521

Sato, 1989, Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta1-like molecule by plasmin during co-culture, J Cell Biol, 109, 309, 10.1083/jcb.109.1.309

Carvalho, 2004, Defective paracrine signalling by TGFbeta in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia, Development, 131, 6237, 10.1242/dev.01529

Letarte, 2005, Reduced endothelial secretion and plasma levels of transforming growth factor-ß1 in patients with hereditary haemorrhagic telangiectasia type 1, Cardiovasc Res, 68, 155, 10.1016/j.cardiores.2005.04.028

Mahmoud, 2009, Endoglin and activin receptor-like-kinase 1 are co-expressed in the distal vessels of the lung: implications for two familial vascular dysplasias, HHT and PAH, Lab Invest, 89, 15, 10.1038/labinvest.2008.112

Li, 2003, TNF alpha down-regulates CD105 expression in vascular endothelial cells: a comparative study with TGF beta 1, Anticancer Res, 23, 1189

Torsney, 2002, Inducible expression of human endoglin during inflammation and wound healing in vivo, Inflamm Res, 51, 464, 10.1007/PL00012413

Toporsian, 2005, A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia, Circ Res, 96, 684, 10.1161/01.RES.0000159936.38601.22

Maire, 1986, Videomikroskopische Untersuchungen von Telangiektasien bei Morbus Osler und Sclerodermie, Schweiz med Wschr, 116, 335

2003, British Thoracic Society guidelines for the management of suspected acute pulmonary embolism, Thorax, 58, 470, 10.1136/thorax.58.6.470

Greene, 2008

Riviere, 2009, Hereditary haemorrhagic telangiectasia and venous thromboembolism, Hematology Meeting Rep, 3, 54

Flieger, 2006, Dramatic improvement in hereditary hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab, Ann Hematol, 85, 631, 10.1007/s00277-006-0147-8

Massoud, 2004, Resolution of hereditary hemorrhagic telangiectasia and anemia with prolonged [alpha]-interferon therapy for chronic hepatitis C, J Clin Gastroenterol, 38, 377, 10.1097/00004836-200404000-00015

Wheatley-Price, 2005, Interferon for metastatic renal cell cancer causing regression of hereditary haemorrhagic telangiectasia, J Clin Gastroenterol, 39, 344, 10.1097/01.mcg.0000155137.73433.36

Sabbà, 2001, Efficacy of unusually high doses of tranexamic acid for the treatment of epistaxis in hereditary hemorrhagic telangiectasia, N Engl J Med, 345, 926, 10.1056/NEJM200109203451216

Saba, 1994, Treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid, New Engl J Med, 330, 1789, 10.1056/NEJM199406233302504

Van Cutsem, 1990, Treatment of bleeding gastrointestinal vascular malformations with oestrogen–progesterone, Lancet, 335, 953, 10.1016/0140-6736(90)91010-8

British National Formulary: Royal Pharmaceutical Society of Great Britain British Medical Association; 2010.

Loges, 2009, Development of targeted angiogenic medicine, J Thromb Haemost, 7, 21, 10.1111/j.1538-7836.2008.03203.x

Sadick, 2005, Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta1 as well as high ALK1 tissue expression, Haematologica, 90, 818

Sadick, 2005, Angiogenesis in hereditary hemorrhagic telangiectasia: VEGF165 plasma concentration in correlation to the VEGF expression and microvessel density, Int J Mol Med, 15, 15

Tseng, 2001, Phase II study of the antiangiogenesis agent thalidomide in recurrent or metastatic squamous cell carcinoma of the head and neck, Cancer Res, 92, 2364

Figg, 2001, A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer, Clin Cancer Res, 7, 1888

Kurstin, 2002, Using thalidomide in a patient with epithelioid leiomyosarcoma and Osler–Weber–Rendu disease, Oncology (Willeston Park), 16, 21

Pérez-Encinas, 2002, Is thalidomide effective for the treatment of gastrointestinal bleeding in hereditary hemorrhagic telangiectasia?, Haematologica, 87, ELT34

Therapontos, 2009, Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation, Proc Natl Acad Sci, 106, 8573, 10.1073/pnas.0901505106

Vargesson, 2009, Thalidomide-induced limb defects: resolving a 50-year-old puzzle, Bioessays, 31, 1327, 10.1002/bies.200900103

Akhurst, 2010, Taking thalidomide out of rehab, Nat Med, 16, 370, 10.1038/nm0410-370

Porteous, 1992, Hereditary haemorrhagic telangiectasia: a clinical analysis, J Med Genet, 29, 527, 10.1136/jmg.29.8.527

Shovlin, 1994, A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3, Nat Genet, 6, 205, 10.1038/ng0294-205

Letteboer, 2005, Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients, Hum Genet, 116, 8, 10.1007/s00439-004-1196-5

Prigoda NL, Savas S, Abdalla SA, et al. Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations. J Med Genet. 2006;43:722–8.

Bayrak-Toydemir, 2008, Likelihood ratios to assess genetic evidence for clinical significance of uncertain variants: hereditary hemorrhagic telangiectasia as a model, Exp Mol Pathol, 85, 45, 10.1016/j.yexmp.2008.03.006

McDonald, 2009, Multiple sequence variants in hereditary hemorrhagic telangiectasia cases: illustration of complexity in molecular diagnostic interpretation, J Mol Diagn, 11, 569, 10.2353/jmoldx.2009.080148

Ng, 2003, SIFT: predicting amino acid changes that affect protein function, Nucleic Acids Res, 31, 3812, 10.1093/nar/gkg509

SIFT. http://blocks.fhcrc.org/sift/SIFT.html.

Polyphen. http://genetics.bwh.harvard.edu/pph/.

Hewes, 1985, Cerebral embolism—first manifestation of pulmonary arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia, Cardiovasc Interv Radiol, 8, 151, 10.1007/BF02552883

Haitjema, 1996, Hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu syndrome)—new insights in pathogenesis, complications, and treatment, Arch Intern Med, 156, 714, 10.1001/archinte.156.7.714

Felix, 2008, Stroke following pulmonary arteriovenous fistula embolization in a patient with HHT, Neurology, 71, 2012, 10.1212/01.wnl.0000336973.27761.45

Westermann, 2008, Stroke following pulmonary arteriovenous fistula embolization in a patient with HHT, Neurology, 73, 1427-1427

Lasjaunias, 2007, Cerebro medullary arteriovenous locations in children and adults with HHT, Haematol Meet Rep, 1, 43

Buis, 2008, Gamma knife surgery and arteriovenous malformations, J Neurosurg Pediatr, 2, 229, 10.3171/PED/2008/2/9/229

Klimo, 2007, Pediatric arteriovenous malformations: a 15-year experience with an emphasis on residual and recurrent lesions, Childs Nerv Syst, 23, 31, 10.1007/s00381-006-0245-x

da Costa, 2009, Management and clinical outcome of posterior fossa arteriovenous malformations: report on a single-centre 15-year experience, J Neurol Neurosurg Psychiatry, 80, 376, 10.1136/jnnp.2008.152710

Fulbright, 1998, MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations, Am J Neuroradiol, 19, 477

Willemse, 2000, Bleeding risk of cerebrovascular malformations in hereditary haemorrhagic telangiectasia, J Neurosurg, 92, 779, 10.3171/jns.2000.92.5.0779

Easey, 2003, Should asymptomatic patients with hereditary haemorrhagic telangiectasia (HHT) be screened for cerebral vascular malformations? Data from 22,061years of HHT patient life, J Neurol Neurosurg Psych, 74, 743, 10.1136/jnnp.74.6.743

Curie, 2007, Long-term follow-up in 12 children with pulmonary arteriovenous malformations: confirmation of hereditary hemorrhagic telangiectasia in all cases, J Pediatr Surg, 151, 299

Al-Saleh, 2009, Screening for pulmonary and cerebral arteriovenous malformations in children with hereditary haemorrhagic telangiectasia, Eur Respir J, 34, 875, 10.1183/09031936.00030009

White, 2009, Controlling haemorrhage in HHT- search for the "magic bullet": reflections from the Yale HHT Centre, Hematology Meeting Rep, 3, 19

Bown, 1985, Endoscopic laser treatment of vascular anomalies of the upper gastrointestinal tract, Gut, 26, 1338, 10.1136/gut.26.12.1338

Office of Dietary Supplements. http://odsodnihgov/factsheets/ironasp. 2010.

Vegetarian Society. Iron information sheet. http://www.vegsoc.org/info/iron.html.

Vase, 1983, Histological findings following oestrogen treatment of hereditary haemorrhagic telangiectasia. A controlled double-blind investigation, J Laryngol Otol, 97, 427, 10.1017/S0022215100094354

Kurstin, 2002, Using thalidomide in a patient with epithelioid leiomyosarcoma and Osler–Weber–Rendu disease, Oncology (Williston Park), 16, 21

Zangari, 2009, Thrombotic events in patients with cancer receiving antiangiogenesis agents, J Clin Oncol, 27, 4865, 10.1200/JCO.2009.22.3875

Cohen, 2007, FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer, Oncologist, 12, 713, 10.1634/theoncologist.12-6-713

Shovlin, 2009, Hereditary haemorrhagic telangiectasia and genetic thrombophilia, Eur J Hum Genet, 18, 405, 10.1038/ejhg.2009.205

2008

Shovlin C. Ischaemic stroke and thrombolysis- time to consider the HHT question. BMJ 2009; http://www.bmj.com/cgi/eletters/339/nov11_1/b4584.

Chan, 1992, Antibiotic prophylaxis for patients with hereditary hemorrhagic telangiectasia, J Am Acad Derm, 26, 282, 10.1016/S0190-9622(08)80330-1

Pelage, 2009, Embolization of ruptured pulmonary arteriovenous malformations in HHT patients, Hematol Meet Rep, 3, 25