Наследственная геморрагическая телеангиоэктазия

 Author: Claire Shovlin, PhD, FRCP

Section Editor: Lawrence LK Leung, MD

Literature review current through: Apr 2020. | This topic last updated: Sep 30, 2019.

Наследственная геморрагическая телеангиоэктазия – или синдром Ослера-Вебера-Рандю – это заболевание, наследуемое по аутосомно-доминантому типу и встречающееся с частотой 1 на 5000-8000 человек вне зависимости от этнической и половой принадлежности. Классифицирована на 3 типа в зависимости от локализации на хромосомах (1 тип – на 9 хромосоме, 2 тип – на 12 хромосоме, 3 тип – на 5 хромосоме). Только при 2 типе развивается легочная гипертензия.

В основе заболевания лежит неполноценность сосудистого эндотелия и формирование артериовенозных мальформаций, в результате чего на различных участках кожи и слизистых оболочек губ, рта и внутренних органах образуются множественные кровоточащие ангиомы и телеангиоэктазии.
В основе заболевания лежит недостаточность капиллярного русла с наличием прямых коммуникаций между артериолами и венулами. Небольшие телеангиоэктазии располагаются подкожно или в подслизистом слое, сопровождаясь повышенной кровоточивостью при легкой травме.

Основными клиническими проявлениями являются повторяющиеся носовые кровотечения, наличие телеангиоэктазий преимущественно на слизистых губ и ротовой полости, на подушечках пальцев, а также анемия.

Наследственная геморрагическая телеангиоэктазия (НГТ) может возникать впервые, но в последующем ее унаследуют 50% потомства.

Первые клинические проявления болезни развиваются вскоре после рождения и могут прогрессировать по мере увеличения возраста пациентки. Первым манифестирует носовое кровотечение, в пубертатном возрасте – артери-венозные мальформации в легких, в 20-ти летнем возрасте – подслизистые кровоизлияния, после 50 лет – желудочно-кишечные телеангиоэктазии. До 70% пациентов имеют те или иные проявления заболевания к 16 годам и 90% к 40 годам.

Анемия развивается в результате хронических клинически незначимых кровотечений из слизистых ЖКТ. Крайне редко развивается профузное кровотечение, требующее проведения эндоскопической аблации, резекции, антибактериальной, гормональной и гемостатической терапии.

Формирование крупных артерио-венозных мальформаций встречается редко, но чаще всего локализуется в печени, головном мозге и легких, являясь причиной массивных кровотечений и смерти.

Сосудистые мальформации в печени встречаются в 30%, в головном мозге – в 10%, в легких – в 48%, в ЖКТ – в 11-40%.

Критериями диагностики НГТ являются:

• носовые кровотечения: спонтанные и повторяющиеся;
• телеангиоэктазии с локализацией на губах, языке, полости рта и носа;
• висцеральные артериовенозные мальформации: легочные, церебральные, в ЖКТ, печени, селезенки, мочевом пузыре, бронхах, влагалище;
• семейный анамнез заболевания у родственников первой линии.

При наличии трех из перечисленных критериев – диагноз считается подтвержденным. Если имеются 2 критерия – диагноз предположительный, менее 2 критериев – диагноз маловероятен.

Во время беременности риски развития осложнений повышены у пациенток с наличием артериовенозных мальформаций в легких и головном мозге в связи с их элонгацией, а также с увеличением ОЦК и сердечного выброса. В идеале, на этапе планирования беременности решается вопрос о проведении аблации крупных мальфомаций, что позволяет предупредить развитие кровотечений и эмболий во время беременности.

Если до момента наступления беременности пациентки не были обследованы, рекоменовано проведение КТ органов грудной полости с экранированием живота, но только после 12 недель. Более безопасным и достаточно информативным является проведение МРТ. 

Во втором триместре беременности может быть выполнена окклюзия сосудистых мальформаий для предотвращения риска кровотечений. МРТ должно быть выполнено для исключения мальформаций спинного мозга и для решения вопроса о возможности проведения спинальной анальгезии.

С осторожностью и только по витальным показаниям назначаются НМГ и аспирин. На фоне беременности применяются препараты железа для коррекции ЖДА. В родах рекомендовано избегать приема Вальсальвы (попытка выдоха при закрытом рте и носовых ходах), в родах проводится антибиотикопрофилактика.

Схема: Алгоритм ведения пациенток с наследственной геморрагической телеангиоэктазией

Литература:
1. Bideau A, Plauchu H, Brunet G, Robert J. Epidemiological investigation of Rendu-Osler disease in France: its geographical distribution and prevalence. Popul 1989; 44:3.
2. Dakeishi M, Shioya T, Wada Y, et al. Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan. Hum Mutat 2002; 19:140.
3. Kjeldsen AD, Vase P, Green A. Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. J Intern Med 1999; 245:31.
4. Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med 1995; 333:918.
5. Westermann CJ, Rosina AF, De Vries V, de Coteau PA. The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles: a family screening. Am J Med Genet A 2003; 116A:324.
6. Shovlin CL, Buscarini E, Kjeldsen AD, et al. European Reference Network For Rare Vascular Diseases (VASCERN) Outcome Measures For Hereditary Haemorrhagic Telangiectasia (HHT). Orphanet J Rare Dis 2018; 13:136.
7. Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax 2008; 63:259.
8. Donaldson JW, McKeever TM, Hall IP, et al. The UK prevalence of hereditary haemorrhagic telangiectasia and its association with sex, socioeconomic status and region of residence: a population-based study. Thorax 2014; 69:161.
9. Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review. Eur J Hum Genet 2009; 17:860.
10. Berg JN, Gallione CJ, Stenzel TT, et al. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet 1997; 61:60.
11. McAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994; 8:345.
12. Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996; 13:189.
13. Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet 2006; 43:97.
14. Wooderchak-Donahue WL, McDonald J, O'Fallon B, et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet 2013; 93:530.
15. Hernandez F, Huether R, Carter L, et al. Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia. Hum Genome Var 2015; 2:15040.
16. Bayrak-Toydemir P, McDonald J, Akarsu N, et al. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet A 2006; 140:2155.
17. http://arup.utah.edu/database/HHT/ (Accessed on August 29, 2012).
18. Kjeldsen AD, Møller TR, Brusgaard K, et al. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia. J Intern Med 2005; 258:349.
19. Letteboer TG, Mager JJ, Snijder RJ, et al. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet 2006; 43:371.
20. Sabbà C, Pasculli G, Lenato GM, et al. Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost 2007; 5:1149.
21. Lesca G, Olivieri C, Burnichon N, et al. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genet Med 2007; 9:14.
22. Bossler AD, Richards J, George C, et al. 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 2006; 27:667.
23. Govani FS, Giess A, Mollet IG, et al. Directional next-generation RNA sequencing and examination of premature termination codon mutations in endoglin/hereditary haemorrhagic telangiectasia. Mol Syndromol 2013; 4:184.
24. Bourdeau A, Cymerman U, Paquet ME, et al. Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1. Am J Pathol 2000; 156:911.
25. Arthur H, Geisthoff U, Gossage JR, et al. Executive summary of the 11th HHT international scientific conference. Angiogenesis 2015; 18:511.
26. Gkatzis K, Thalgott J, Dos-Santos-Luis D, et al. Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations. Arterioscler Thromb Vasc Biol 2016; 36:707.
27. Bertolino P, Deckers M, Lebrin F, ten Dijke P. Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders. Chest 2005; 128:585S.
28. Bailly S. HHT is not a TGF-beta disease. Blood 2008; 111:478.
29. Benzinou M, Clermont FF, Letteboer TG, et al. Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia. Nat Commun 2012; 3:616.
30. Letteboer TG, Benzinou M, Merrick CB, et al. Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14. Front Genet 2015; 6:67.
31. Pawlikowska L, Nelson J, Guo DE, et al. The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations. Am J Med Genet A 2015; 167:1262.
32. Bourdeau A, Dumont DJ, Letarte M. A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest 1999; 104:1343.
33. Gu Y, Jin P, Zhang L, et al. Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia. Blood 2006; 107:1951.
34. Urness LD, Sorensen LK, Li DY. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet 2000; 26:328.
35. Park SO, Lee YJ, Seki T, et al. ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2. Blood 2008; 111:633.
36. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 1997; 390:465.
37. Sadick H, Riedel F, Naim R, et al. 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 2005; 90:818.
38. Haitjema T, Disch F, Overtoom TT, et al. Screening family members of patients with hereditary hemorrhagic telangiectasia. Am J Med 1995; 99:519.
39. Cottin V, Plauchu H, Bayle JY, et al. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. Am J Respir Crit Care Med 2004; 169:994.
40. van Gent MW, Post MC, Snijder RJ, et al. Real prevalence of pulmonary right-to-left shunt according to genotype in patients with hereditary hemorrhagic telangiectasia: a transthoracic contrast echocardiography study. Chest 2010; 138:833.
41. Piantanida M, Buscarini E, Dellavecchia C, et al. Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2. J Med Genet 1996; 33:441.
42. McDonald JE, Miller FJ, Hallam SE, et al. Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred. Am J Med Genet 2000; 93:320.
43. Fulbright RK, Chaloupka JC, Putman CM, et al. MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. AJNR Am J Neuroradiol 1998; 19:477.
44. Brinjikji W, Iyer VN, Yamaki V, et al. Neurovascular Manifestations of Hereditary Hemorrhagic Telangiectasia: A Consecutive Series of 376 Patients during 15 Years. AJNR Am J Neuroradiol 2016; 37:1479.
45. Gallitelli M, Pasculli G, Fiore T, et al. Emergencies in hereditary haemorrhagic telangiectasia. QJM 2006; 99:15.
46. Dupuis-Girod S, Bailly S, Plauchu H. Hereditary hemorrhagic telangiectasia: from molecular biology to patient care. J Thromb Haemost 2010; 8:1447.
47. Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev 2010; 24:203.
48. Giordano P, Lenato GM, Suppressa P, et al. Hereditary hemorrhagic telangiectasia: arteriovenous malformations in children. J Pediatr 2013; 163:179.
49. Shovlin CL, Awan I, Cahilog Z, et al. Reported cardiac phenotypes in hereditary hemorrhagic telangiectasia emphasize burdens from arrhythmias, anemia and its treatments, but suggest reduced rates of myocardial infarction. Int J Cardiol 2016; 215:179.
50. Plauchu H, de Chadarévian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989; 32:291.
51. Latino GA, Al-Saleh S, Alharbi N, et al. Prevalence of pulmonary arteriovenous malformations in children versus adults with hereditary hemorrhagic telangiectasia. J Pediatr 2013; 163:282.
52. Krings T, Ozanne A, Chng SM, et al. Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age. Review of 50 consecutive patients aged 1 day-60 years. Neuroradiology 2005; 47:711.
53. Sabbà C, Pasculli G, Suppressa P, et al. Life expectancy in patients with hereditary haemorrhagic telangiectasia. QJM 2006; 99:327.
54. Silva BM, Hosman AE, Devlin HL, Shovlin CL. Lifestyle and dietary influences on nosebleed severity in hereditary hemorrhagic telangiectasia. Laryngoscope 2013; 123:1092.
55. Elphick A, Shovlin CL. Relationships between epistaxis, migraines, and triggers in hereditary hemorrhagic telangiectasia. Laryngoscope 2014; 124:1521.
56. Hoag JB, Terry P, Mitchell S, et al. An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope 2010; 120:838.
57. Karnezis TT, Davidson TM. Efficacy of intranasal Bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. Laryngoscope 2011; 121:636.
58. Kjeldsen AD, Kjeldsen J. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. Am J Gastroenterol 2000; 95:415.
59. Pasculli G, Quaranta D, Lenato GM, et al. Capillaroscopy of the dorsal skin of the hands in hereditary hemorrhagic telangiectasia. QJM 2005; 98:757.
60. Bharatha A, Faughnan ME, Kim H, et al. Brain arteriovenous malformation multiplicity predicts the diagnosis of hereditary hemorrhagic telangiectasia: quantitative assessment. Stroke 2012; 43:72.
61. Lacout A, Pelage JP, Lesur G, et al. Pancreatic involvement in hereditary hemorrhagic telangiectasia: assessment with multidetector helical CT. Radiology 2010; 254:479.
62. Gefen AM, White AJ. Asymptomatic pulmonary arteriovenous malformations in children with hereditary hemorrhagic telangiectasia. Pediatr Pulmonol 2017; 52:1194.
63. Shovlin CL, Letarte M. Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 1999; 54:714.
64. Gawecki F, Strangeways T, Amin A, et al. Exercise capacity reflects airflow limitation rather than hypoxaemia in patients with pulmonary arteriovenous malformations. QJM 2019; 112:335.
65. Gawecki F, Myers J, Shovlin CL. Veterans Specific Activity Questionnaire (VSAQ): a new and efficient method of assessing exercise capacity in patients with pulmonary arteriovenous malformations. BMJ Open Respir Res 2019; 6:e000351.
66. Shovlin C, Bamford K, Wray D. Post-NICE 2008: Antibiotic prophylaxis prior to dental procedures for patients with pulmonary arteriovenous malformations (PAVMs) and hereditary haemorrhagic telangiectasia. Br Dent J 2008; 205:531.
67. Boother EJ, Brownlow S, Tighe HC, et al. Cerebral Abscess Associated With Odontogenic Bacteremias, Hypoxemia, and Iron Loading in Immunocompetent Patients With Right-to-Left Shunting Through Pulmonary Arteriovenous Malformations. Clin Infect Dis 2017; 65:595.
68. Shovlin CL, Sodhi V, McCarthy A, et al. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services. BJOG 2008; 115:1108.
69. Post MC, Letteboer TG, Mager JJ, et al. A pulmonary right-to-left shunt in patients with hereditary hemorrhagic telangiectasia is associated with an increased prevalence of migraine. Chest 2005; 128:2485.
70. Stephan MJ, Nesbit GM, Behrens ML, et al. Endovascular treatment of spinal arteriovenous fistula in a young child with hereditary hemorrhagic telangiectasia. Case report. J Neurosurg 2005; 103:462.
71. Maher CO, Piepgras DG, Brown RD Jr, et al. Cerebrovascular manifestations in 321 cases of hereditary hemorrhagic telangiectasia. Stroke 2001; 32:877.
72. Mohr JP, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 2014; 383:614.
73. Buscarini E, Danesino C, Plauchu H, et al. High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia. Ultrasound Med Biol 2004; 30:1089.
74. Buonamico P, Suppressa P, Lenato GM, et al. Liver involvement in a large cohort of patients with hereditary hemorrhagic telangiectasia: echo-color-Doppler vs multislice computed tomography study. J Hepatol 2008; 48:811.
75. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol 2016; 64:179.
76. Garcia-Tsao G, Korzenik JR, Young L, et al. Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2000; 343:931.
77. DeLeve LD, Valla DC, Garcia-Tsao G, American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology 2009; 49:1729.
78. Buscarini E, Plauchu H, Garcia Tsao G, et al. Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations. Liver Int 2006; 26:1040.
79. Caselitz M, Wagner S, Chavan A, et al. Clinical outcome of transfemoral embolisation in patients with arteriovenous malformations of the liver in hereditary haemorrhagic telangiectasia (Weber-Rendu-Osler disease). Gut 1998; 42:123.
80. Fogerty RL, Greenwald JL, McDermott S, et al. Case 7-2017. A 73-Year-Old Man with Confusion and Recurrent Epistaxis. N Engl J Med 2017; 376:972.
81. Buscarini E, Buscarini L, Civardi G, et al. Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: imaging findings. AJR Am J Roentgenol 1994; 163:1105.
82. Buscarini E, Leandro G, Conte D, et al. Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia. Dig Dis Sci 2011; 56:2166.
83. Vorselaars VM, Velthuis S, Snijder RJ, et al. Pulmonary hypertension in hereditary haemorrhagic telangiectasia. World J Cardiol 2015; 7:230.
84. Girerd B, Montani D, Coulet F, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010; 181:851.
85. Devlin HL, Hosman AE, Shovlin CL. Antiplatelet and anticoagulant agents in hereditary hemorrhagic telangiectasia. N Engl J Med 2013; 368:876.
86. Livesey JA, Manning RA, Meek JH, et al. Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia. Thorax 2012; 67:328.
87. Shovlin CL, Chamali B, Santhirapala V, et al. Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets. PLoS One 2014; 9:e88812.
88. Woods HF, Youdim MB, Boulllin D, Callender S. Monoamine metabolism and platelet function in iron-deficiency anaemia. In: Iron metabolism. In CIBA Foundation Symposium 51 (new series), Elsevier, Amsterdam 1977. p.227.
89. HODGSON CH, BURCHELL HB, GOOD CA, CLAGETT OT. Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous fistula: survey of a large family. N Engl J Med 1959; 261:625.
90. Steele JG, Nath PU, Burn J, Porteous ME. An association between migrainous aura and hereditary haemorrhagic telangiectasia. Headache 1993; 33:145.
91. Marziniak M, Jung A, Guralnik V, et al. An association of migraine with hereditary haemorrhagic telangiectasia independently of pulmonary right-to-left shunts. Cephalalgia 2009; 29:76.
92. Thenganatt J, Schneiderman J, Hyland RH, et al. Migraines linked to intrapulmonary right-to-left shunt. Headache 2006; 46:439.
93. Post MC, van Gent MW, Plokker HW, et al. Pulmonary arteriovenous malformations associated with migraine with aura. Eur Respir J 2009; 34:882.
94. Post MC, Thijs V, Schonewille WJ, et al. Embolization of pulmonary arteriovenous malformations and decrease in prevalence of migraine. Neurology 2006; 66:202.
95. Hosman AE, Devlin HL, Silva BM, Shovlin CL. Specific cancer rates may differ in patients with hereditary haemorrhagic telangiectasia compared to controls. Orphanet J Rare Dis 2013; 8:195.
96. Hanneman K, Faughnan ME, Prabhudesai V. Cumulative radiation dose in patients with hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. Can Assoc Radiol J 2014; 65:135.
97. Shovlin CL, Sulaiman NL, Govani FS, et al. Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism. Thromb Haemost 2007; 98:1031.
98. Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000; 91:66.
99. Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet 2011; 48:73.
100. Mcdonald J, Bayrak-Toydemir P, Whitehead A. Curacao Criteria highly predictive of a mutation in ACVRL1 or ENG. Proceedings of the 11th International HHT Scientific Conference, June 11-14, 2015; p.33.