Hereditary haemorrhagic telangiectasia

ABSTRACT Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding

proteins of the BMP signalling pathway. Up to 90% of disease-causal variants are observed in _ENG_ and _ACVRL1_, with _SMAD4_ and _GDF2_ less frequently responsible for HHT. In adults, the

most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases. Arteriovenous malformations

(AVMs) in the lungs, liver and the central nervous system cause additional major complications and often complex symptoms, primarily due to vascular shunting, which is right-to-left through

pulmonary AVMs (causing ischaemic stroke or cerebral abscess) and left-to-right through systemic AVMs (causing high cardiac output). Children usually experience isolated epistaxis; in rare

cases, childhood complications occur from large AVMs in the lungs or central nervous system. Management goals encompass control of epistaxis and intestinal bleeding from telangiectases,

screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members. Novel therapeutics, such as systemic

antiangiogenic therapies, are actively being investigated. Although HHT is associated with increased morbidity, the appropriate screening and treatment of visceral AVMs, and the effective

management of bleeding and anaemia, improves quality of life and overall survival. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

institution ACCESS OPTIONS Access through your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $29.99 / 30 days

cancel any time Learn more Subscribe to this journal Receive 1 digital issues and online access to articles $119.00 per year only $119.00 per issue Learn more Buy this article * Purchase on

SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about

institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS ALTERED HYPOXIA INDUCIBLE FACTOR REGULATION IN HEREDITARY HAEMORRHAGIC

TELANGIECTASIA Article Open access 07 April 2022 VON WILLEBRAND DISEASE Article 25 July 2024 OUTCOMES OF PATIENTS WITH JUVENILE POLYPOSIS-HEREDITARY HAEMORRHAGIC TELANGIECTASIA CAUSED BY

PATHOGENIC _SMAD4_ VARIANTS IN A PAN-SCOTLAND COHORT Article Open access 16 April 2024 REFERENCES * McAllister, K. A. et al. Endoglin, a TGF-β binding protein of endothelial cells, is the

gene for hereditary haemorrhagic telangiectasia type 1. _Nat. Genet._ 8, 345–351 (1994). Article  CAS  PubMed  Google Scholar  * Johnson, D. W. et al. Mutations in the activin receptor-like

kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. _Nat. Genet._ 13, 189–195 (1996). Article  CAS  PubMed  Google Scholar  * Gallione, C. J. et al. A combined syndrome of

juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). _Lancet_ 363, 852–859 (2004). Article  CAS  PubMed  Google Scholar  * Balachandar,

S. et al. Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. _Am. J.

Med. Genet. A_ 188, 959–964 (2022). Article  CAS  PubMed  Google Scholar  * Wooderchak-Donahue, W. L. et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with

hereditary hemorrhagic telangiectasia. _Am. J. Hum. Genet._ 93, 530–537 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Goumans, M.-J., Zwijsen, A., Ten Dijke, P. &

Bailly, S. Bone morphogenetic proteins in vascular homeostasis and disease. _Cold Spring Harb. Perspect. Biol._ 10, a031989 (2018). Article  PubMed  PubMed Central  Google Scholar  *

Shovlin, C. L. et al. Updates on diagnostic criteria for hereditary haemorrhagic telangiectasia in the light of whole genome sequencing of ‘gene-negative’ individuals recruited to the 100000

Genomes Project. _J. Med. Genet._ 61, 182–185 (2024). Article  CAS  PubMed  Google Scholar  * Shovlin, C. L. et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia

(Rendu–Osler–Weber syndrome). _Am. J. Med. Genet._ 91, 66–67 (2000). Article  CAS  PubMed  Google Scholar  * Zhang, E., Virk, Z. M., Rodriguez-Lopez, J. & Al-Samkari, H. Hereditary

hemorrhagic telangiectasia may be the most morbid inherited bleeding disorder in women. _Blood Adv._ 8, 3166–3172 (2024). Article  PubMed  PubMed Central  Google Scholar  * Kelly, C.,

Buscarini, E., Manfredi, G., Gregory, S. & Heneghan, M. A. Hepatic manifestations of hereditary haemorrhagic telangiectasia. _Liver Int._ 44, 2220–2234 (2024). Article  CAS  PubMed 

Google Scholar  * Krings, T. et al. Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age. Review of 50 consecutive patients aged 1 day–60 years.

_Neuroradiology_ 47, 711–720 (2005). Article  CAS  PubMed  Google Scholar  * Kjeldsen, A. D., Vase, P. & Green, A. Hereditary haemorrhagic telangiectasia: a population-based study of

prevalence and mortality in Danish patients. _J. Intern. Med._ 245, 31–39 (1999). Article  CAS  PubMed  Google Scholar  * Plauchu, H., de Chadarévian, J. P., Bideau, A. & Robert, J. M.

Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. _Am. J. Med. Genet._ 32, 291–297 (1989). Article  CAS  PubMed  Google

Scholar  * Lesca, G. et al. Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of _ACVRL1_ mutations in French and Italian patients. _Eur. J. Hum. Genet._ 16,

742–749 (2008). Article  CAS  PubMed  Google Scholar  * Dakeishi, M. et al. Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan.

_Hum. Mutat._ 19, 140–148 (2002). Article  CAS  PubMed  Google Scholar  * Serra, M. M., Papi, M. & Serrano, C. Prevalence of hereditary hemorrhagic telangiectasia in a medical care

program organization in Buenos Aires, Argentina. _Medicina_ 84, 221–226 (2024). PubMed  Google Scholar  * Donaldson, J. W., McKeever, T. M., Hall, I. P., Hubbard, R. B. & Fogarty, A. W.

Complications and mortality in hereditary hemorrhagic telangiectasia: a population-based study. _Neurology_ 84, 1886–1893 (2015). Article  PubMed  PubMed Central  Google Scholar  * McDonald,

J. et al. Frequency of epistaxis and telangiectasia in patients with hereditary hemorrhagic telangiectasia (HHT) in comparison with the general population: Curaçao diagnostic criteria

revisited. _Genet. Med._ 25, 100865 (2023). Article  CAS  PubMed  Google Scholar  * Kilian, A. et al. Genotype–phenotype correlations in children with HHT. _J. Clin. Med._ 9, 2714 (2020).

Article  PubMed  PubMed Central  Google Scholar  * Faughnan, M. E. et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. _Ann.

Intern. Med._ 173, 989–1001 (2020). Article  PubMed  Google Scholar  * Shovlin, C. L. et al. British Thoracic Society clinical statement on pulmonary arteriovenous malformations. _Thorax_

72, 1154–1163 (2017). Article  PubMed  Google Scholar  * European Association for the Study of the Liver. EASL clinical practice guidelines: vascular diseases of the liver. _J. Hepatol._ 64,

179–202 (2016). Article  Google Scholar  * Eker, O. F. et al. European Reference Network for Rare Vascular Diseases (VASCERN) position statement on cerebral screening in adults and children

with hereditary haemorrhagic telangiectasia (HHT). _Orphanet J. Rare Dis._ 15, 165 (2020). Article  PubMed  PubMed Central  Google Scholar  * Shovlin, C. L. et al. The European Rare Disease

Network for HHT Frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care. _Eur. J. Med. Genet._ 65, 104370 (2022). Article  CAS  PubMed  Google

Scholar  * Dupuis-Girod, S. et al. European Reference Network for Rare Vascular Diseases (VASCERN): when and how to use intravenous bevacizumab in hereditary haemorrhagic telangiectasia

(HHT)? _Eur. J. Med. Genet._ 65, 104575 (2022). Article  CAS  PubMed  Google Scholar  * Thompson, K. P. et al. Predictors of mortality in patients with hereditary hemorrhagic telangiectasia.

_Orphanet J. Rare Dis._ 16, 12 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Kjeldsen, A., Aagaard, K. S., Tørring, P. M., Möller, S. & Green, A. 20-year follow-up

study of Danish HHT patients—survival and causes of death. _Orphanet J. Rare Dis._ 11, 157 (2016). Article  PubMed  PubMed Central  Google Scholar  * de Gussem, E. M. et al. Life expectancy

of parents with hereditary haemorrhagic telangiectasia. _Orphanet J. Rare Dis._ 11, 46 (2016). Article  PubMed  PubMed Central  Google Scholar  * Droege, F. et al. Life expectancy and

comorbidities in patients with hereditary hemorrhagic telangiectasia. _Vasc. Med._ 23, 377–383 (2018). Article  PubMed  Google Scholar  * Duarte, C. W. et al. Improved survival outcomes in

cancer patients with hereditary hemorrhagic telangiectasia. _Cancer Epidemiol. Biomark. Prev._ 23, 117–125 (2014). Article  CAS  Google Scholar  * Hosman, A. E., Devlin, H. L., Silva, B. M.

& Shovlin, C. L. Specific cancer rates may differ in patients with hereditary haemorrhagic telangiectasia compared to controls. _Orphanet J. Rare Dis._ 8, 195 (2013). Article  PubMed 

PubMed Central  Google Scholar  * Jain, K. et al. Pathogenic variant frequencies in hereditary haemorrhagic telangiectasia support clinical evidence of protection from myocardial infarction.

_J. Clin. Med._ 13, 250 (2023). Article  PubMed  PubMed Central  Google Scholar  * Shovlin, C. L., Awan, I., Cahilog, Z., Abdulla, F. N. & Guttmacher, A. E. 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._ 215, 179–185

(2016). Article  CAS  PubMed  Google Scholar  * Brown, M. A. et al. Crystal structure of BMP-9 and functional interactions with pro-region and receptors. _J. Biol. Chem._ 280, 25111–25118

(2005). Article  CAS  PubMed  Google Scholar  * David, L., Mallet, C., Mazerbourg, S., Feige, J.-J. & Bailly, S. Identification of BMP9 and BMP10 as functional activators of the orphan

activin receptor-like kinase 1 (ALK1) in endothelial cells. _Blood_ 109, 1953–1961 (2007). Article  CAS  PubMed  Google Scholar  * Scharpfenecker, M. et al. BMP-9 signals via ALK1 and

inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. _J. Cell. Sci._ 120, 964–972 (2007). Article  CAS  PubMed  Google Scholar  * Oh, S. P. et al. Activin

receptor-like kinase 1 modulates transforming growth factor-β1 signaling in the regulation of angiogenesis. _Proc. Natl Acad. Sci. USA_ 97, 2626–2631 (2000). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Goumans, M. J. et al. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFβ/ALK5 signaling. _Mol. Cell_ 12, 817–828 (2003). Article  CAS

  PubMed  Google Scholar  * Desroches-Castan, A., Tillet, E., Bouvard, C. & Bailly, S. BMP9 and BMP10: two close vascular quiescence partners that stand out. _Dev. Dyn._ 251, 178–197

(2022). Article  CAS  PubMed  Google Scholar  * Saito, T. et al. Structural basis of the human endoglin–BMP9 interaction: insights into BMP signaling and HHT1. _Cell Rep._ 19, 1917–1928

(2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Al Tabosh, T. et al. Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial

cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors. _Angiogenesis_ 27, 211–227 (2024). Article  CAS  PubMed  PubMed Central  Google Scholar  * Cao,

K., Plazzer, J.-P. & Macrae, F. SMAD4 variants and its genotype-phenotype correlations to juvenile polyposis syndrome. _Hered. Cancer Clin. Pract._ 21, 27 (2023). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Orlova, V. V. et al. Vascular defects associated with hereditary hemorrhagic telangiectasia revealed in patient-derived isogenic iPSCs in 3D vessels on

chip. _Stem Cell Rep._ 17, 1536–1545 (2022). THIS SHOWS THAT HHT GENOTYPE ALONE IS NOT SUFFICIENT TO MAKE ENDOTHELIAL CELLS BEHAVE DIFFERENTLY TO ISOGENIC CONTROL ENDOTHELIAL CELLS,

EMPHASIZING THE IMPORTANCE OF SECOND OR THIRD HITS ARISING IN THREE-DIMENSIONAL CULTURE. Article  CAS  Google Scholar  * Bernabéu-Herrero, M. E. et al. Mutations causing premature

termination codons discriminate and generate cellular and clinical variability in HHT. _Blood_ 143, 2314–2331 (2024). Article  PubMed  PubMed Central  Google Scholar  * Bernabeu, C.,

Bayrak-Toydemir, P., McDonald, J. & Letarte, M. Potential second-hits in hereditary hemorrhagic telangiectasia. _J. Clin. Med._ 9, 3571 (2020). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Snellings, D. A. et al. Somatic mutations in vascular malformations of hereditary hemorrhagic telangiectasia result in bi-allelic loss of ENG or ACVRL1. _Am. J. Hum.

Genet._ 105, 894–906 (2019). THIS WAS THE FIRST DEMONSTRATION OF A BIALLELIC LOSS IN HHT TELANGIECTASES. Article  CAS  PubMed  PubMed Central  Google Scholar  * Xiao, S. et al. Functional

filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA. _Am. J. Hum. Genet._ 110, 1903–1918

(2023). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lee, S. et al. Genetic or therapeutic neutralization of ALK1 reduces LDL transcytosis and atherosclerosis in mice. _Nat.

Cardiovasc. Res._ 2, 438–448 (2023). Article  CAS  PubMed  PubMed Central  Google Scholar  * Tao, B. et al. BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in

endothelial cells. _J. Biol. Chem._ 295, 18179–18188 (2020). Article  CAS  PubMed  Google Scholar  * Rossi, E. & Bernabeu, C. Novel vascular roles of human endoglin in pathophysiology.

_J. Thromb. Haemost._ 21, 2327–2338 (2023). Article  PubMed  Google Scholar  * Rossi, E. et al. Human endoglin as a potential new partner involved in platelet–endothelium interactions. _Cell

Mol. Life Sci._ 75, 1269–1284 (2018). Article  CAS  PubMed  Google Scholar  * Rossi, E. et al. Soluble endoglin reduces thrombus formation and platelet aggregation via interaction with

αIIbβ3 integrin. _J. Thromb. Haemost._ 21, 1943–1956 (2023). THIS OPENED UP AN INTERESTING LINE OF CLINICAL AND BASIC RESEARCH ABOUT HHT BLEEDING MECHANISMS OTHER THAN THE RUPTURE OF

TELANGIECTASES. Article  PubMed  Google Scholar  * Arthur, H. M. & Roman, B. L. An update on preclinical models of hereditary haemorrhagic telangiectasia: insights into disease

mechanisms. _Front. Med._ 9, 973964 (2022). Article  Google Scholar  * Lamouille, S., Mallet, C., Feige, J.-J. & Bailly, S. Activin receptor-like kinase 1 is implicated in the maturation

phase of angiogenesis. _Blood_ 100, 4495–4501 (2002). Article  CAS  PubMed  Google Scholar  * Genet, G. et al. Induced endothelial cell cycle arrest prevents arteriovenous malformations in

hereditary hemorrhagic telangiectasia. _Circulation_ 149, 944–962 (2024). Article  CAS  PubMed  Google Scholar  * Al Tarrass, M. et al. Large-scale phosphoproteomics reveals activation of

the MAPK/GADD45β/P38 axis and cell cycle inhibition in response to BMP9 and BMP10 stimulation in endothelial cells. _Cell Commun. Signal._ 22, 158 (2024). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Baeyens, N. et al. Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. _J. Cell Biol._ 214, 807–816 (2016). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Roman, B. L. & Hinck, A. P. ALK1 signaling in development and disease: new paradigms. _Cell Mol. Life Sci._ 74, 4539–4560 (2017). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Desroches-Castan, A. et al. Bone morphogenetic protein 9 is a paracrine factor controlling liver sinusoidal endothelial cell fenestration and

protecting against hepatic fibrosis. _Hepatology_ 70, 1392–1408 (2019). Article  CAS  PubMed  Google Scholar  * Lin, Y. et al. Role of endothelial PDGFB in arterio-venous malformations

pathogenesis. _Angiogenesis_ 27, 193–209 (2024). Article  CAS  PubMed  Google Scholar  * Ola, R. et al. PI3 kinase inhibition improves vascular malformations in mouse models of hereditary

haemorrhagic telangiectasia. _Nat. Commun._ 7, 13650 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Al Tabosh, T. et al. Hereditary hemorrhagic telangiectasia: from

signaling insights to therapeutic advances. _J. Clin. Invest._ 134, e176379 (2024). Article  CAS  PubMed  PubMed Central  Google Scholar  * Snodgrass, R. O., Chico, T. J. A. & Arthur, H.

M. Hereditary haemorrhagic telangiectasia, an inherited vascular disorder in need of improved evidence-based pharmaceutical interventions. _Genes_ 12, 174 (2021). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Robert, F., Desroches-Castan, A., Bailly, S., Dupuis-Girod, S. & Feige, J.-J. Future treatments for hereditary hemorrhagic telangiectasia. _Orphanet J.

Rare Dis._ 15, 4 (2020). Article  PubMed  PubMed Central  Google Scholar  * Srinivasan, S. et al. A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. _Hum. Mol. Genet._ 12,

473–482 (2003). Article  CAS  PubMed  Google Scholar  * Bourdeau, A., Dumont, D. J. & Letarte, M. A murine model of hereditary hemorrhagic telangiectasia. _J. Clin. Invest._ 104,

1343–1351 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Tual-Chalot, S., Oh, S. P. & Arthur, H. M. Mouse models of hereditary hemorrhagic telangiectasia: recent

advances and future challenges. _Front. Genet._ 6, 25 (2015). Article  PubMed  PubMed Central  Google Scholar  * Shovlin, C. L. Supermodels and disease: insights from the HHT mice. _J. Clin.

Invest._ 104, 1335–1336 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Desroches-Castan, A. et al. Differential consequences of Bmp9 deletion on sinusoidal endothelial cell

differentiation and liver fibrosis in 129/Ola and C57BL/6 mice. _Cells_ 8, E1079 (2019). Article  Google Scholar  * Park, H. et al. Defective flow-migration coupling causes arteriovenous

malformations in hereditary hemorrhagic telangiectasia. _Circulation_ 144, 805–822 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Singh, E., Redgrave, R. E., Phillips, H. M.

& Arthur, H. M. Arterial endoglin does not protect against arteriovenous malformations. _Angiogenesis_ 23, 559–566 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Benn,

A. et al. BMP–SMAD1/5 signaling regulates retinal vascular development. _Biomolecules_ 10, 488 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Chen, H. et al.

Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development. _Proc. Natl Acad. Sci. USA_ 110, 11887–11892 (2013). Article  CAS  PubMed  PubMed Central

  Google Scholar  * Ruiz, S. et al. A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10. _Sci. Rep._ 5, 37366 (2016).

Article  PubMed  PubMed Central  Google Scholar  * Desroches-Castan, A. et al. BMP9 is a key player in endothelial identity and its loss is sufficient to induce arteriovenous malformations.

_Cardiovasc. Res._ 120, 782–795 (2024). Article  CAS  PubMed  Google Scholar  * Shaligram, S. S. et al. Bone marrow-derived Alk1 mutant endothelial cells and clonally expanded somatic Alk1

mutant endothelial cells contribute to the development of brain arteriovenous malformations in mice. _Transl. Stroke Res._ 13, 494–504 (2022). Article  CAS  PubMed  Google Scholar  * Hwan

Kim, Y. et al. Overexpression of activin receptor-like kinase 1 in endothelial cells suppresses development of arteriovenous malformations in mouse models of hereditary hemorrhagic

telangiectasia. _Circ. Res._ 127, 1122–1137 (2020). Article  CAS  PubMed  Google Scholar  * Snodgrass, R. O. et al. Therapeutic targeting of vascular malformation in a zebrafish model of

hereditary haemorrhagic telangiectasia. _Dis. Model. Mech._ 16, dmm049567 (2023). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hyldahl, S. J., El-Jaji, M. Q., Schuster, A. &

Kjeldsen, A. D. Skin and mucosal telangiectatic lesions in hereditary hemorrhagic telangiectasia patients. _Int. J. Dermatol._ 61, 1497–1505 (2022). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Geisthoff, U. et al. Trauma can induce telangiectases in hereditary hemorrhagic telangiectasia. _J. Clin. Med._ 9, 1507 (2020). Article  PubMed  PubMed Central  Google

Scholar  * Sindhar, S., O’Bryhim, B. E., Licata, J., Piccirillo, J. F. & Apte, R. S. Identification of retinal vascular lesions using ultra-widefield angiography in hereditary

hemorrhagic telangiectasia patients. _Ophthalmol. Retin._ 3, 510–515 (2019). Article  Google Scholar  * Gaillard, S. et al. Tranexamic acid for epistaxis in hereditary hemorrhagic

telangiectasia patients: a European cross-over controlled trial in a rare disease. _J. Thromb. Haemost._ 12, 1494–1502 (2014). Article  CAS  PubMed  Google Scholar  * Ingrand, I. et al.

Altered quality of life in Rendu–Osler–Weber disease related to recurrent epistaxis. _Rhinology_ 49, 155–162 (2011). Article  CAS  PubMed  Google Scholar  * Haubner, F. et al. Classification

of endonasal HHT lesions using digital microscopy. _Orphanet J. Rare Dis._ 16, 182 (2021). Article  CAS  PubMed  PubMed Central  Google Scholar  * Folz, B. J., Wollstein, A. C., Lippert, B.

M. & Werner, J. A. Morphology and distribution of nasal telangiectasia in HHT patients with epistaxis. _Am. J. Rhinol._ 19, 65–70 (2005). Article  PubMed  Google Scholar  * Mlynski, G.,

Grützenmacher, S., Plontke, S., Mlynski, B. & Lang, C. Correlation of nasal morphology and respiratory function. _Rhinology_ 39, 197–201 (2001). CAS  PubMed  Google Scholar  *

Canzonieri, C. et al. Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. _Genet. Med._ 16, 3–10

(2014). Article  CAS  PubMed  Google Scholar  * Grève, E. et al. High diagnostic and clinical impact of small-bowel capsule endoscopy in patients with hereditary hemorrhagic telangiectasia

with overt digestive bleeding and/or severe anemia. _Gastrointest. Endosc._ 71, 760–767 (2010). Article  PubMed  Google Scholar  * Chamberlain, S. M., Patel, J., Carter Balart, J., Gossage,

J. R. & Sridhar, S. Evaluation of patients with hereditary hemorrhagic telangiectasia with video capsule endoscopy: a single-center prospective study. _Endoscopy_ 39, 516–520 (2007).

Article  CAS  PubMed  Google Scholar  * Thielemans, L., Layton, D. M. & Shovlin, C. L. Low serum haptoglobin and blood films suggest intravascular hemolysis contributes to severe anemia

in hereditary hemorrhagic telangiectasia. _Haematologica_ 104, e127–e130 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Kjeldsen, A. D. & Kjeldsen, J. Gastrointestinal

bleeding in patients with hereditary hemorrhagic telangiectasia. _Am. J. Gastroenterol._ 95, 415–418 (2000). Article  CAS  PubMed  Google Scholar  * Shovlin, C. L. et al. Mutational and

phenotypic characterization of hereditary hemorrhagic telangiectasia. _Blood_ 136, 1907–1918 (2020). Article  PubMed  PubMed Central  Google Scholar  * Shovlin, C. L. Pulmonary arteriovenous

malformations. _Am. J. Respir. Crit. Care Med._ 190, 1217–1228 (2014). Article  PubMed  PubMed Central  Google Scholar  * Hessels, J. et al. Evolution of pulmonary arteriovenous

malformations: the role of contrast echocardiography. _Chest_ 163, 669–677 (2023). Article  CAS  PubMed  Google Scholar  * Topiwala, K. K., Patel, S. D., Pervez, M., Shovlin, C. L. &

Alberts, M. J. Ischemic stroke in patients with pulmonary arteriovenous fistulas. _Stroke_ 52, e311–e315 (2021). Article  CAS  PubMed  Google Scholar  * Boother, E. J. 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._ 65, 595–603 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Topiwala, K. K., Patel, S. D., Saver, J. L., Streib, C. D. & Shovlin, C. L. Ischemic stroke and

pulmonary arteriovenous malformations: a review. _Neurology_ 98, 188–198 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Müller-Hülsbeck, S. et al. CIRSE standards of

practice on diagnosis and treatment of pulmonary arteriovenous malformations. _Cardiovasc. Interv. Radiol._ 43, 353–361 (2020). Article  Google Scholar  * Buscarini, E. et al. Natural

history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia. _Dig. Dis. Sci._ 56, 2166–2178 (2011). Article  PubMed 

PubMed Central  Google Scholar  * Buscarini, E. et al. Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia—results of extensive

screening. _Ultraschall Med._ 25, 348–355 (2004). Article  CAS  PubMed  Google Scholar  * Buscarini, E. et al. High prevalence of hepatic focal nodular hyperplasia in subjects with

hereditary hemorrhagic telangiectasia. _Ultrasound Med. Biol._ 30, 1089–1097 (2004). Article  PubMed  Google Scholar  * Serra, M. M. et al. Central nervous system manganese induced lesions

and clinical consequences in patients with hereditary hemorrhagic telangiectasia. _Orphanet J. Rare Dis._ 12, 92 (2017). Article  CAS  PubMed  PubMed Central  Google Scholar  * Brinjikji,

W., Iyer, V. N., Wood, C. P. & Lanzino, G. Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and

meta-analysis. _J. Neurosurg._ 127, 302–310 (2017). Article  PubMed  Google Scholar  * Kim, H. et al. Hemorrhage rates from brain arteriovenous malformation in patients with hereditary

hemorrhagic telangiectasia. _Stroke_ 46, 1362–1364 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Brinjikji, W. et al. Neurovascular manifestations of hereditary hemorrhagic

telangiectasia: a consecutive series of 376 patients during 15 years. _AJNR Am. J. Neuroradiol._ 37, 1479–1486 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Schimmel, K.

et al. Arteriovenous malformations—current understanding of the pathogenesis with implications for treatment. _Int. J. Mol. Sci._ 22, 9037 (2021). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Beslow, L. A. et al. De novo brain vascular malformations in hereditary hemorrhagic telangiectasia. _Pediat. Neurol._ 155, 120–125 (2024). Article  PubMed  Google Scholar 

* Anderson, E., Sharma, L., Alsafi, A. & Shovlin, C. L. Pulmonary arteriovenous malformations may be the only clinical criterion present in genetically confirmed hereditary haemorrhagic

telangiectasia. _Thorax_ 77, 628–630 (2022). Article  PubMed  Google Scholar  * Dupuis, O., Delagrange, L. & Dupuis-Girod, S. Hereditary haemorrhagic telangiectasia and pregnancy: a

review of the literature. _Orphanet J. Rare Dis._ 15, 5 (2020). Article  PubMed  PubMed Central  Google Scholar  * Mora-Luján, J. M. et al. Gastrointestinal bleeding in patients with

hereditary hemorrhagic telangiectasia: risk factors and endoscopic findings. _J. Clin. Med._ 9, 82 (2020). Article  Google Scholar  * Shovlin, C. L. et al. European Reference Network for

Rare Vascular Diseases (VASCERN) outcome measures for hereditary haemorrhagic telangiectasia (HHT). _Orphanet J. Rare Dis._ 13, 136 (2018). Article  PubMed  PubMed Central  Google Scholar  *

Velthuis, S. et al. Grade of pulmonary right-to-left shunt on contrast echocardiography and cerebral complications: a striking association. _Chest_ 144, 542–548 (2013). Article  PubMed 

Google Scholar  * Lovering, A. T., Duke, J. W. & Elliott, J. E. Intrapulmonary arteriovenous anastomoses in humans—response to exercise and the environment. _J. Physiol._ 593, 507–520

(2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Laurie, S. S., Elliott, J. E., Goodman, R. D. & Lovering, A. T. Catecholamine-induced opening of intrapulmonary

arteriovenous anastomoses in healthy humans at rest. _J. Appl. Physiol._ 113, 1213–1222 (2012). Article  CAS  PubMed  Google Scholar  * Davis, J. T., Elliott, J. E., Duke, J. W., Cristobal,

A. & Lovering, A. T. Hyperoxia-induced stepwise reduction in blood flow through intrapulmonary, but not intracardiac, shunt during exercise. _Am. J. Physiol. Regul. Integr. Comp.

Physiol._ 325, R96–R105 (2023). Article  CAS  PubMed  PubMed Central  Google Scholar  * Alyafaie, A. et al. Arterial spin-labeling MR imaging in the detection of intracranial arteriovenous

malformations in patients with hereditary hemorrhagic telangiectasia. _AJNR Am. J. Neuroradiol._ 45, 1019–1024 (2024). Article  PubMed  Google Scholar  * Beslow, L. A. et al. Current

practice: rationale for screening children with hereditary hemorrhagic telangiectasia for brain vascular malformations. _AJNR Am. J. Neuroradiol._ 45, 1177–1184 (2024). Article  PubMed 

Google Scholar  * Cenzato, M. et al. European consensus conference on unruptured brain AVMs treatment (supported by EANS, ESMINT, EGKS, and SINCH). _Acta Neurochir._ 159, 1059–1064 (2017).

Article  PubMed  Google Scholar  * Mowers, K. L., Sekarski, L., White, A. J. & Grady, R. M. Pulmonary arteriovenous malformations in children with hereditary hemorrhagic telangiectasia:

a longitudinal study. _Pulm. Circ._ 8, 2045894018786696 (2018). Article  PubMed  PubMed Central  Google Scholar  * Hosman, A. E. et al. Screening children for pulmonary arteriovenous

malformations: evaluation of 18 years of experience. _Pediatr. Pulmonol._ 52, 1206–1211 (2017). Article  PubMed  Google Scholar  * White, A. J. et al. Brain abscess and stroke in children

and adults with hereditary hemorrhagic telangiectasia: analysis of a large national claims database. _Neurology_ 100, e2324–e2330 (2023). Article  CAS  PubMed  PubMed Central  Google Scholar

  * Ratjen, A., Au, J., Carpenter, S., John, P. & Ratjen, F. Growth of pulmonary arteriovenous malformations in pediatric patients with hereditary hemorrhagic telangiectasia. _J.

Pediat._ 208, 279–281 (2019). Article  PubMed  Google Scholar  * Al-Saleh, S. et al. Utility of contrast echocardiography for pulmonary arteriovenous malformation screening in pediatric

hereditary hemorrhagic telangiectasia. _J. Pediat._ 160, 1039–1043.e1 (2012). Article  PubMed  Google Scholar  * Kilian, A. et al. Comparing characteristics and treatment of brain vascular

malformations in children and adults with HHT. _J. Clin. Med._ 12, 2704 (2023). Article  PubMed  PubMed Central  Google Scholar  * Krings, T. et al. Neurovascular manifestations in

hereditary hemorrhagic telangiectasia: imaging features and genotype-phenotype correlations. _AJNR Am. J. Neuroradiol._ 36, 863–870 (2015). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Pahl, K. S. et al. Applicability of the Curaçao criteria for the diagnosis of hereditary hemorrhagic telangiectasia in the pediatric population. _J. Pediatr._ 197, 207–213 (2018).

Article  PubMed  Google Scholar  * Letteboer, T. G. W. et al. Genotype–phenotype relationship in hereditary haemorrhagic telangiectasia. _J. Med. Genet._ 43, 371–377 (2006). Article  CAS 

PubMed  Google Scholar  * Giordano, P. et al. Screening for children from families with Rendu–Osler–Weber disease: from geneticist to clinician. _J. Thromb. Haemost._ 4, 1237–1245 (2006).

Article  CAS  PubMed  Google Scholar  * Kasthuri, R. S. et al. Prevalence and predictors of anemia in hereditary hemorrhagic telangiectasia. _Am. J. Hematol_.

https://doi.org/10.1002/ajh.24832 (2017). * Camaschella, C. Iron-deficiency anemia. _N. Engl. J. Med._ 372, 1832–1843 (2015). Article  PubMed  Google Scholar  * Livesey, J. A. 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_ 67, 328–333 (2012). Article  PubMed  Google Scholar  * Jørgensen, O. J. et al. Elevated FVIII levels in hereditary hemorrhagic telangiectasia:

implications for clinical management. _Laryngoscope Investig. Otolaryngol._ 9, e1196 (2024). Article  PubMed  Google Scholar  * Shovlin, C. L. et al. Ischaemic strokes in patients with

pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets. _PLoS ONE_ 9, e88812 (2014). Article  PubMed  PubMed Central

  Google Scholar  * Santhirapala, V., Williams, L. C., Tighe, H. C., Jackson, J. E. & Shovlin, C. L. Arterial oxygen content is precisely maintained by graded erythrocytotic responses in

settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations. _PLoS ONE_ 9, e90777

(2014). Article  PubMed  PubMed Central  Google Scholar  * Gawecki, F. et al. Exercise capacity reflects airflow limitation rather than hypoxaemia in patients with pulmonary arteriovenous

malformations. _QJM_ 112, 335–342 (2019). Article  CAS  PubMed  Google Scholar  * Finnamore, H. et al. Hemorrhage-adjusted iron requirements, hematinics and hepcidin define hereditary

hemorrhagic telangiectasia as a model of hemorrhagic iron deficiency. _PLoS ONE_ 8, e76516 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Joyce, K. E. et al. Whole genome

sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variation. _Blood Adv._ 6, 3956–3969 (2022). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Sharma, L. et al. Iron deficiency responses and integrated compensations in patients according to hereditary hemorrhagic telangiectasia ACVRL1, ENG and SMAD4 genotypes.

_Haematologica_ 109, 958–962 (2024). Article  CAS  PubMed  Google Scholar  * Rizvi, A. et al. Hemoglobin is a vital determinant of arterial oxygen content in hypoxemic patients with

pulmonary arteriovenous malformations. _Ann. Am. Thorac. Soc._ 14, 903–911 (2017). Article  PubMed  Google Scholar  * Geisthoff, U. W. et al. Treatment of epistaxis in hereditary hemorrhagic

telangiectasia with tranexamic acid—a double-blind placebo-controlled cross-over phase IIIB study. _Thromb. Res._ 134, 565–571 (2014). Article  CAS  PubMed  Google Scholar  * Yaniv, E.,

Preis, M., Hadar, T., Shvero, J. & Haddad, M. Antiestrogen therapy for hereditary hemorrhagic telangiectasia: a double-blind placebo-controlled clinical trial. _Laryngoscope_ 119,

284–288 (2009). Article  CAS  PubMed  Google Scholar  * Yaniv, E., Preis, M., Shevro, J., Nageris, B. & Hadar, T. Anti-estrogen therapy for hereditary hemorrhagic telangiectasia—a

long-term clinical trial. _Rhinology_ 49, 214–216 (2011). Article  CAS  PubMed  Google Scholar  * de Gussem, E. M. et al. The effect of _N_-acetylcysteine on epistaxis and quality of life in

patients with HHT: a pilot study. _Rhinology_ 47, 85–88 (2009). PubMed  Google Scholar  * Guilhem, A. et al. Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT): a

retrospective study of 46 patients. _PLoS ONE_ 12, e0188943 (2017). Article  PubMed  PubMed Central  Google Scholar  * Thompson, A. B. et al. Very low dose bevacizumab for the treatment of

epistaxis in patients with hereditary hemorrhagic telangiectasia. _Allergy Rhinol._ 5, 91–95 (2014). Article  Google Scholar  * Al-Samkari, H. et al. An international, multicenter study of

intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study. _Haematologica_ 106, 2161–2169 (2021). Article  CAS  PubMed  Google Scholar  * Chavan,

A. et al. Systemic therapy with bevacizumab in patients with hereditary hemorrhagic telangiectasia (HHT). _Vasa_ 42, 106–110 (2013). Article  PubMed  Google Scholar  * Dupuis-Girod, S. et

al. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. _JAMA_ 307, 948–955 (2012). THIS WAS THE FIRST

PROSPECTIVE STUDY TO OFFER A TARGETED ANTIANGIOGENIC THERAPEUTIC OPTION FOR MANAGING HHT. Article  CAS  PubMed  Google Scholar  * Dupuis-Girod, S. et al. Efficacy and safety of intravenous

bevacizumab on severe bleeding associated with hemorrhagic hereditary telangiectasia: a national, randomized multicenter trial. _J. Intern. Med._ 294, 761–774 (2023). Article  CAS  PubMed 

Google Scholar  * Faughnan, M. E. et al. Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. _Angiogenesis_ 22, 145–155 (2019). THIS SUMMARIZES AN INTERNATIONAL EFFORT TO

STANDARDIZE PRACTICES AND CONSIDER THE MANAGEMENT OF PATIENTS WITH HHT. Article  CAS  PubMed  Google Scholar  * Hermann, R. et al. Effect of oral nintedanib vs placebo on epistaxis in

hereditary hemorrhagic telangiectasia: the EPICURE multicenter randomized double-blind trial. _Angiogenesis_ 28, 9 (2025). Article  CAS  Google Scholar  * Lebrin, F. et al. Thalidomide

stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. _Nat. Med._ 16, 420–428 (2010). Article  CAS  PubMed  Google Scholar  *

Invernizzi, R. et al. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-randomised,

single-centre, phase 2 study. _Lancet Haematol._ 2, e465–e473 (2015). Article  PubMed  PubMed Central  Google Scholar  * H, A. S. et al. Pomalidomide for epistaxis in hereditary hemorrhagic

telangiectasia. _N. Engl. J. Med._ 391, 1015–1027 (2024). Article  Google Scholar  * Abiri, A. et al. Laser-assisted control of epistaxis in hereditary hemorrhagic telangiectasia: a

systematic review. _Lasers Surg. Med._ 52, 293–300 (2020). Article  PubMed  Google Scholar  * Thiele, B., Abdel-Aty, Y., Marks, L., Lal, D. & Marino, M. Sclerotherapy for hereditary

hemorrhagic telangiectasia-related epistaxis: a systematic review. _Ann. Otol. Rhinol. Laryngol._ 132, 82–90 (2023). Article  PubMed  Google Scholar  * Luk, L., Mace, J. C., Bhandarkar, N.

D. & Sautter, N. B. Comparison of electrosurgical plasma coagulation and potassium-titanyl-phosphate laser photocoagulation for treatment of hereditary hemorrhagic telangiectasia-related

epistaxis. _Int. Forum Allergy Rhinol._ 4, 640–645 (2014). Article  PubMed  Google Scholar  * Lund, V. J., Darby, Y., Rimmer, J., Amin, M. & Husain, S. Nasal closure for severe

hereditary haemorrhagic telangiectasia in 100 patients. The Lund modification of the Young’s procedure: a 22-year experience. _Rhinology_ 55, 135–141 (2017). Article  CAS  PubMed  Google

Scholar  * Lee, J. M. et al. Prospective pilot study of Floseal® for the treatment of anterior epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT). _J. Otolaryngol. Head.

Neck Surg._ 48, 48 (2019). Article  PubMed  PubMed Central  Google Scholar  * Pyne, J. M. et al. Surgiflo® hemostatic matrix versus NasoPore® nasal packing following postassium titanyl

phosphate laser surgery for hereditary hemorrhagic telangiectasia: a randomized controlled trial. _Laryngoscope Investig. Otolaryngol._ 8, 328–334 (2023). Article  PubMed  PubMed Central 

Google Scholar  * May, A., Friesing-Sosnik, T., Manner, H., Pohl, J. & Ell, C. Long-term outcome after argon plasma coagulation of small-bowel lesions using double-balloon enteroscopy in

patients with mid-gastrointestinal bleeding. _Endoscopy_ 43, 759–765 (2011). Article  CAS  PubMed  Google Scholar  * Tortora, A., Marmo, C., Gasbarrini, A., Costamagna, G. & Riccioni,

M. E. Management of gastrointestinal bleeding in Rendu–Osler disease. _Rev. Recent Clin. Trials_ 15, 321–327 (2020). Article  CAS  PubMed  Google Scholar  * Manfredi, G. et al.

Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia: long-term results of endoscopic treatment. _Endosc. Int. Open._ 11, E1145–E1152 (2023). THIS IS THE LARGEST

STUDY OF PEOPLE WITH HHT WITH GASTROINTESTINAL BLEEDING, SHOWING THAT ENDOSCOPIC TREATMENT OF GASTROINTESTINAL TELANGIECTASES IS EFFECTIVE IN THE LONG TERM AND SAFE. Article  PubMed  PubMed

Central  Google Scholar  * Iyer, V. N. et al. Intravenous bevacizumab for refractory hereditary hemorrhagic telangiectasia-related epistaxis and gastrointestinal bleeding. _Mayo Clin. Proc._

93, 155–166 (2018). Article  CAS  PubMed  Google Scholar  * Hosman, A. et al. Follow-up of thalidomide treatment in patients with hereditary haemorrhagic telangiectasia. _Rhinology_ 53,

340–344 (2015). Article  CAS  PubMed  Google Scholar  * Torres-Iglesias, R. et al. Long-term use of somatostatin analogs for chronic gastrointestinal bleeding in hereditary hemorrhagic

telangiectasia. _Front. Med._ 10, 1146080 (2023). Article  Google Scholar  * Shovlin, C. et al. Prevention of serious infections in hereditary hemorrhagic telangiectasia: roles for

prophylactic antibiotics, the pulmonary capillaries—but not vaccination. _Haematologica_ 104, e85–e86 (2019). Article  CAS  PubMed  PubMed Central  Google Scholar  * Al-Sahaf, M., Anderson,

J., Nandi, J., Alsafi, A. & Shovlin, C. L. S32 elective cardiothoracic surgical resections for pulmonary arteriovenous malformations—a 16 year single-centre experience. _Thorax_ 79, A29

(2024). Google Scholar  * Alsafi, A. et al. Patients with in-situ metallic coils and Amplatzer vascular plugs used to treat pulmonary arteriovenous malformations since 1984 can safely

undergo magnetic resonance imaging. _Br. J. Radiol._ 92, 20180752 (2019). Article  PubMed  PubMed Central  Google Scholar  * Lerut, J. et al. Liver transplantation for hereditary hemorrhagic

telangiectasia: report of the European liver transplant registry. _Ann. Surg._ 244, 854–862 (2006). Article  PubMed  PubMed Central  Google Scholar  * Dupuis-Girod, S. et al. Long-term

outcome of patients with hereditary hemorrhagic telangiectasia and severe hepatic involvement after orthotopic liver transplantation: a single-center study. _Liver Transpl._ 16, 340–347

(2010). Article  PubMed  Google Scholar  * Dumortier, J. et al. Recurrence of hereditary hemorrhagic telangiectasia after liver transplantation: clinical implications and physiopathological

insights. _Hepatology_ 69, 2232–2240 (2019). Article  PubMed  Google Scholar  * Vlachou, P. A. et al. Improvement of ischemic cholangiopathy in three patients with hereditary hemorrhagic

telangiectasia following treatment with bevacizumab. _J. Hepatol._ 59, 186–189 (2013). Article  CAS  PubMed  Google Scholar  * Dupuis-Girod, S. & Buscarini, E. Hereditary hemorrhagic

telangiectasia: to transplant or not to transplant? _Liver Int._ 36, 1741–1744 (2016). Article  PubMed  Google Scholar  * Mohr, J. P. et al. Medical management with or without interventional

therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. _Lancet_ 383, 614–621 (2014). Article  CAS  PubMed  Google Scholar  *

Pasculli, G. et al. Health-related quality of life in a rare disease: hereditary hemorrhagic telangiectasia (HHT) or Rendu–Osler–Weber disease. _Qual. Life Res._ 13, 1715–1723 (2004).

Article  PubMed  Google Scholar  * Geisthoff, U. W. et al. Health-related quality of life in hereditary hemorrhagic telangiectasia. _Otolaryngol. Head. Neck Surg._ 136, 726–733 (2007).

Article  PubMed  Google Scholar  * Geirdal, A, Ø., Dheyauldeen, S., Bachmann-Harildstad, G. & Heimdal, K. Quality of life in patients with hereditary hemorrhagic telangiectasia in

Norway: a population based study. _Am. J. Med. Genet. A_ 158, 1269–1278 (2012). Article  Google Scholar  * Zarrabeitia, R. et al. Quality of life in patients with hereditary haemorrhagic

telangiectasia (HHT). _Health Qual. Life Outcomes_ 15, 19 (2017). Article  PubMed  PubMed Central  Google Scholar  * Merlo, C. A., Yin, L. X., Hoag, J. B., Mitchell, S. E. & Reh, D. D.

The effects of epistaxis on health-related quality of life in patients with hereditary hemorrhagic telangiectasia. _Int. Forum Allergy Rhinol._ 4, 921–925 (2014). Article  PubMed  Google

Scholar  * Martinent, G. et al. Hereditary hemorrhagic telangiectasia and health-related quality of life: a qualitative investigation. _Qual. Life Res._ 29, 1291–1299 (2020). Article  PubMed

  Google Scholar  * Le, T. T. T. et al. Development and validation of a quality of life measurement scale specific to hereditary hemorrhagic telangiectasia: the QoL-HHT. _Orphanet J. Rare

Dis._ 17, 281 (2022). Article  PubMed  PubMed Central  Google Scholar  * Kasthuri, R. S. et al. Development and performance of a hereditary hemorrhagic telangiectasia-specific

quality-of-life instrument. _Blood Adv._ 6, 4301–4309 (2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hanes, F. Multiple hereditary telangiectases causing hemorrhage

(hereditary haemorrhagic telangiectasia). _Bull. Johns Hopkins Med. Soc._ 63, 73 (1909). Google Scholar  * Park, S. O. et al. Real-time imaging of de novo arteriovenous malformation in a

mouse model of hereditary hemorrhagic telangiectasia. _J. Clin. Invest._ 119, 3487–3496 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Anzell, A. R. et al. Blood flow regulates

_acvrl1_ transcription via ligand-dependent Alk1 activity. _Angiogenesis_ 27, 501–522 (2024). Article  CAS  PubMed  Google Scholar  * Cheng, Y.-W. et al. Shear stress and sub-femtomolar

levels of ligand synergize to activate ALK1 signaling in endothelial cells. _Cells_ 13, 285 (2024). Article  CAS  PubMed  PubMed Central  Google Scholar  * Shovlin, C. L. et al. MEK 1

inhibition and bleeding in hereditary haemorrhagic telangiectasia. _Br. J. Haematol._ 204, 361–365 (2024). Article  CAS  PubMed  Google Scholar  * Gariballa, N., Badawi, S. & Ali, B. R.

Endoglin mutants retained in the endoplasmic reticulum exacerbate loss of function in hereditary hemorrhagic telangiectasia type 1 (HHT1) by exerting dominant negative effects on the wild

type allele. _Traffic_ 25, e12928 (2024). Article  CAS  PubMed  Google Scholar  * Soukarieh, O. et al. uAUG creating variants in the 5′UTR of ENG causing hereditary hemorrhagic

telangiectasia. _npj Genom. Med._ 8, 32 (2023). Article  CAS  PubMed  PubMed Central  Google Scholar  * Parambil, J. G. et al. Pazopanib for severe bleeding and transfusion-dependent anemia

in hereditary hemorrhagic telangiectasia. _Angiogenesis_ 25, 87–97 (2021). Article  PubMed  PubMed Central  Google Scholar  * Kovacs-Sipos, E., Holzmann, D., Scherer, T. & Soyka, M. B.

Nintedanib as a novel treatment option in hereditary haemorrhagic telangiectasia. _BMJ Case Rep._ 2017, bcr2017219393 (2017). Article  PubMed  PubMed Central  Google Scholar  * Modaressi, A.

& Shovlin, C. L. Integration of genotypic data into clinical trial design and reporting in hereditary hemorrhagic telangiectasia could help personalize treatment. _Haematologica_

https://doi.org/10.3324/haematol.2024.285809 (2024). * McCarley, S. C., Murphy, D. A., Thompson, J. & Shovlin, C. L. Pharmacogenomic considerations for anticoagulant prescription in

patients with hereditary haemorrhagic telangiectasia. _J. Clin. Med._ 12, 7710 (2023). Article  CAS  PubMed  PubMed Central  Google Scholar  * Velasco, B. et al. Vascular gene transfer

driven by endoglin and ICAM-2 endothelial-specific promoters. _Gene Ther._ 8, 897–904 (2001). Article  CAS  PubMed  Google Scholar  * Yadav, A. et al. Evaluation of Aav capsids and delivery

approaches for hereditary hemorrhagic telangiectasia gene therapy. _Transl. Stroke Res._ https://doi.org/10.1007/s12975-024-01275-4 (2024). * Zaffar, N., Ravichakaravarthy, T., Faughnan, M.

E. & Shehata, N. The use of anti-fibrinolytic agents in patients with HHT: a retrospective survey. _Ann. Hematol._ 94, 145–152 (2015). Article  CAS  PubMed  Google Scholar  * Whitehead,

K. J. et al. Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary hemorrhagic telangiectasia: a randomized clinical trial. _JAMA_ 316, 943–951 (2016).

Article  CAS  PubMed  Google Scholar  * Minami, K. & Haji, T. Intranasal topical estrogen in the management of epistaxis in hereditary hemorrhagic telangiectasia. _Acta Otolaryngol._

136, 528–531 (2016). Article  CAS  PubMed  Google Scholar  * Reh, D. D., Hur, K. & Merlo, C. A. Efficacy of a topical sesame/rose geranium oil compound in patients with hereditary

hemorrhagic telangiectasia associated epistaxis. _Laryngoscope_ 123, 820–822 (2013). Article  CAS  PubMed  Google Scholar  * Chavan, A. et al. Emerging role of bevacizumab in management of

patients with symptomatic hepatic involvement in hereditary hemorrhagic telangiectasia. _Am. J. Hematol._ 92, E641–E644 (2017). Article  CAS  PubMed  Google Scholar  * US National Library of

Medicine. _ClinicalTrials.gov_ https://clinicaltrials.gov/study/NCT04404881 (2024). * Vázquez, C., Gonzalez, M. L., Ferraris, A., Bandi, J. C. & Serra, M. M. Bevacizumab for treating

hereditary hemorrhagic telangiectasia patients with severe hepatic involvement or refractory anemia. _PLoS ONE_ 15, e0228486 (2020). Article  PubMed  PubMed Central  Google Scholar  *

Dupuis-Girod, S. et al. Effect of bevacizumab nasal spray on epistaxis duration in hereditary hemorrhagic telangectasia: a randomized clinical trial. _JAMA_ 316, 934–942 (2016). Article  CAS

  PubMed  Google Scholar  * Riss, D. et al. Intranasal submucosal bevacizumab for epistaxis in hereditary hemorrhagic telangiectasia: a double-blind, randomized, placebo-controlled trial.

_Head Neck_ 37, 783–787 (2015). Article  PubMed  Google Scholar  * Steineger, J., Osnes, T., Heimdal, K. & Dheyauldeen, S. Long-term experience with intranasal bevacizumab therapy.

_Laryngoscope_ 128, 2237–2244 (2018). Article  CAS  PubMed  Google Scholar  * Karnezis, T. T. & Davidson, T. M. Efficacy of intranasal bevacizumab (Avastin) treatment in patients with

hereditary hemorrhagic telangiectasia-associated epistaxis. _Laryngoscope_ 121, 636–638 (2011). Article  CAS  PubMed  Google Scholar  * Khoueir, N., Borsik, M., Camous, D., Herman, P. &

Verillaud, B. Injection of bevacizumab and cyanoacrylate glue for hereditary hemorrhagic telangiectasia. _Laryngoscope_ 129, 2210–2215 (2019). Article  CAS  PubMed  Google Scholar  *

Dheyauldeen, S., Østertun Geirdal, A., Osnes, T., Vartdal, L. S. & Dollner, R. Bevacizumab in hereditary hemorrhagic telangiectasia-associated epistaxis: effectiveness of an injection

protocol based on the vascular anatomy of the nose. _Laryngoscope_ 122, 1210–1214 (2012). Article  CAS  PubMed  Google Scholar  * US National Library of Medicine. _ClinicalTrials.gov_

https://clinicaltrials.gov/study/NCT03850964 (2024). * US National Library of Medicine. _ClinicalTrials.gov_ https://clinicaltrials.gov/study/NCT04976036 (2022). * US National Library of

Medicine. _ClinicalTrials.gov_ https://clinicaltrials.gov/study/NCT05406362 (2023). * US National Library of Medicine. _ClinicalTrials.gov_ https://clinicaltrials.gov/study/NCT05269849

(2024). * Hessels, J. et al. Efficacy and safety of tacrolimus as treatment for bleeding caused by hereditary hemorrhagic telangiectasia: an open-label, pilot study. _J. Clin. Med._ 11, 5280

(2022). Article  CAS  PubMed  PubMed Central  Google Scholar  * Álvarez-Hernández, P. et al. Tacrolimus as a promising drug for epistaxis and gastrointestinal bleeding in HHT. _J. Clin.

Med._ 12, 7410 (2023). Article  PubMed  PubMed Central  Google Scholar  * Dupuis-Girod, S. et al. Efficacy and safety of a 0.1% tacrolimus nasal ointment as a treatment for epistaxis in

hereditary hemorrhagic telangiectasia: a double-blind, randomized, placebo-controlled, multicenter trial. _J. Clin. Med._ 9, 1262 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar

  * Fang, J. et al. Thalidomide for epistaxis in patients with hereditary hemorrhagic telangiectasia: a preliminary study. _Otolaryngol. Head. Neck Surg._ 157, 217–221 (2017). Article 

PubMed  Google Scholar  * Baysal, M., Ümit, E. G., Kırkızlar, H. O., Özdöver, A. C. & Demir, A. M. Thalidomide for the management of bleeding episodes in patients with hereditary

hemorrhagic telangiectasia: effects on epistaxis severity score and quality of life. _Turk. J. Haematol._ 36, 43–47 (2019). Article  PubMed  PubMed Central  Google Scholar  * Contis, A. et

al. Efficacy and safety of propranolol for epistaxis in hereditary haemorrhagic telangiectasia: retrospective, then prospective study, in a total of 21 patients. _Clin. Otolaryngol._ 42,

911–917 (2017). Article  CAS  PubMed  Google Scholar  * US National Library of Medicine. _ClinicalTrials.gov_ https://clinicaltrials.gov/study/NCT04113187 (2022). * Dupuis-Girod, S. et al.

Efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. A double-blind, randomized, placebo-controlled trial. _Sci. Rep._ 9, 11986 (2019).

Article  PubMed  PubMed Central  Google Scholar  * Peterson, A. M. et al. Efficacy of timolol in a novel intranasal thermosensitive gel for hereditary hemorrhagic telangiectasia-associated

epistaxis: a randomized clinical trial. _JAMA Otolaryngol. Head. Neck Surg._ 146, 1006–1014 (2020). Article  PubMed  Google Scholar  * Andorfer, K. E. C. et al. TIMolol nasal spray as a

treatment for epistaxis in hereditary hemorrhagic telangiectasia (TIM-HHT)—a prospective, randomized, double-blind, controlled, cross-over trial. _Pharmaceutics_ 14, 2335 (2022). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Ichimura, K., Kikuchi, H., Imayoshi, S. & Dias, M. S. Topical application of timolol decreases the severity and frequency of epistaxis in

patients who have previously undergone nasal dermoplasty for hereditary hemorrhagic telangiectasia. _Auris Nasus Larynx_ 43, 429–432 (2016). Article  PubMed  Google Scholar  * Mei-Zahav, M.,

Blau, H., Bruckheimer, E., Zur, E. & Goldschmidt, N. Topical propranolol improves epistaxis in patients with hereditary hemorrhagic telangiectasia—a preliminary report. _J. Otolaryngol.

Head. Neck Surg._ 46, 58 (2017). Article  PubMed  PubMed Central  Google Scholar  * Mei-Zahav, M. et al. Topical propranolol improves epistaxis control in hereditary hemorrhagic

telangiectasia (HHT): a randomized double-blind placebo-controlled trial. _J. Clin. Med._ 9, 3130 (2020). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lesca, G. et al.

Genotype–phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French–Italian HHT network. _Genet. Med._ 9, 14–22 (2007). Article  PubMed  Google Scholar  * Caillot,

C. et al. Phenotypic characterisation of SMAD4 variant carriers. _J. Med. Genet._ 61, 734–740 (2024). Article  PubMed  Google Scholar  * Buonamico, P. et al. Liver involvement in a large

cohort of patients with hereditary hemorrhagic telangiectasia: echo-color-Doppler vs multislice computed tomography study. _J. Hepatol._ 48, 811–820 (2008). Article  PubMed  Google Scholar 

* Boland, C. R. Diagnosis and management of cancer risk in the gastrointestinal hamartomatous polyposis syndromes. Recommendations from the US multi-society task force on colorectal cancer.

_Am. J. Gastroenterol._ 117, 846–864 (2022). * Shovlin, C. L. et al. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu

syndrome): suggested approach for obstetric services. _BJOG_ 115, 1108–1115 (2008). Article  CAS  PubMed  Google Scholar  * de Gussem, E. M. et al. Outcomes of pregnancy in women with

hereditary hemorrhagic telangiectasia. _Obstet. Gynecol._ 123, 514–520 (2014). Article  PubMed  Google Scholar  * Delagrange, L. et al. Obstetrical and neonatal complications in hereditary

haemorrhagic telangiectasia: a retrospective study. _BJOG_ 130, 303–311 (2022). Article  PubMed  PubMed Central  Google Scholar  * Pavord, S. et al. UK guidelines on the management of iron

deficiency in pregnancy. _Br. J. Haematol._ 156, 588–600 (2012). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS The authors thank the patients for their valuable

testimonials. C.L.S. acknowledges support from the National Institute for Health Research Imperial Biomedical Research Centre, London, UK. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * ENT

department, Hôpital E Herriot, Hospices Civils de Lyon, Lyon, France Ruben Hermann * European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HHT Rare Disease Working

Group, Paris, France Ruben Hermann, Elisabetta Buscarini & Sophie Dupuis-Girod * National Heart and Lung Institute, Imperial College London, London, UK Claire L. Shovlin * Respiratory

Medicine, Imperial College Healthcare NHS Trust, London, UK Claire L. Shovlin * Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Raj S. Kasthuri *

Internal Medicine department, HHT Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina Marcelo Serra * Department of Neuroradiology, Hôpital Pierre Wertheimer, Hospices Civils de

Lyon, Bron, France Omer F. Eker * Biosanté Unit U1292, Grenoble Alpes University, INSERM, CEA, Grenoble, France Sabine Bailly & Sophie Dupuis-Girod * Gastroenterology Department, ASST

Ospedale Maggiore, Crema, Italy Elisabetta Buscarini * HHT National Reference Center and Genetic Department, Hôpital Femme-Mère-Enfants, Hospices Civils de Lyon, Bron, France Sophie

Dupuis-Girod Authors * Ruben Hermann View author publications You can also search for this author inPubMed Google Scholar * Claire L. Shovlin View author publications You can also search for

this author inPubMed Google Scholar * Raj S. Kasthuri View author publications You can also search for this author inPubMed Google Scholar * Marcelo Serra View author publications You can

also search for this author inPubMed Google Scholar * Omer F. Eker View author publications You can also search for this author inPubMed Google Scholar * Sabine Bailly View author

publications You can also search for this author inPubMed Google Scholar * Elisabetta Buscarini View author publications You can also search for this author inPubMed Google Scholar * Sophie

Dupuis-Girod View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Introduction (R.H., C.L.S. and S.D.-G.); Epidemiology (C.L.S, M.S., R.H.,

R.S.K. and S.D.-G.); Mechanisms/pathophysiology (S.B., C.L.S., R.H., E.B., M.S., R.S.K., O.F.E. and S.D.-G.); Diagnosis, screening and prevention (R.H., C.L.S., E.B., M.S., R.S.K., O.F.E.

and S.D.-G.); Management (R.H., C.L.S., E.B., M.S., R.S.K., O.F.E. and S.D.-G.); Quality of life (R.S.K. and S.D.-G.); Outlook (R.H., C.S., E.B., M.S., R.S.K, O.F.E., S.B. and S.D.-G.);

overview of the Primer (S.D.-G. and R.H.). CORRESPONDING AUTHOR Correspondence to Sophie Dupuis-Girod. ETHICS DECLARATIONS COMPETING INTERESTS C.L.S. is listed as the inventor in the patent

application filed by Imperial College London for the use of MEK1 inhibitors to treat telangiectasia in HHT (European Patent Application 23705641.1). O.F.E. is a consultant for Microvention,

CERENOVUS and Balt, and is also a member of DSMB and on the advisory board for STREAM Study. All other authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature

Reviews Disease Primers_ thanks C. Bernabeu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. ADDITIONAL INFORMATION INFORMED CONSENT The authors

affirm that patient participants provided informed consent for publication of their experiences. PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in

published maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION GLOSSARY * Cyanosis A blue appearance of the mucous membranes caused by the presence of

high quantities of deoxygenated haemoglobin in the bloodstream. * Haemoptysis Coughing up blood from the lungs. * Haemothorax Bleeding into the pleural cavity between the linings of the lung

and chest wall. * Hypoxaemia Low levels of oxygen in the blood. * Kiesselbach’s plexus Also known as Little’s area, is a physiological network of small blood vessels located in the anterior

part of the nasal septum. * Liver function tests A series of blood tests used in clinical practice to determine whether the liver is likely to be healthy, or whether it shows signs of

cytolysis (transaminase enzymes), biliary duct ischaemic injury (gamma glutamyl transferase, alkaline phosphatase, bilirubin) and impaired synthetic function (albumin). * proBNP test A

measure of circulating levels of a precursor of brain natriuretic peptide (BNP) that is released in high levels from a failing heart. RIGHTS AND PERMISSIONS Springer Nature or its licensor

(e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted

manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hermann, R.,

Shovlin, C.L., Kasthuri, R.S. _et al._ Hereditary haemorrhagic telangiectasia. _Nat Rev Dis Primers_ 11, 1 (2025). https://doi.org/10.1038/s41572-024-00585-z Download citation * Accepted:

29 November 2024 * Published: 09 January 2025 * DOI: https://doi.org/10.1038/s41572-024-00585-z SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content:

Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative