Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterised by mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs). Mutations in genes of the transforming growth factor-β (TGF-β) signalling axis—most commonly endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1, also known as ALK1)—disrupt endothelial homeostasis, leading to fragile vessel development. Clinically, HHT presents with recurrent epistaxis, gastrointestinal bleeding and anaemia, while pulmonary, hepatic and cerebral AVMs carry risks of embolic stroke, high‐output cardiac failure and intracranial haemorrhage.

Diagnosis relies on the Curaçao criteria, combining clinical signs with family history and, increasingly, genetic confirmation. Imaging modalities such as contrast echocardiography, CT angiography or MRI are used to screen for pulmonary and cerebral AVMs, respectively. Management is multidisciplinary: iron replacement and endoscopic or laser interventions address mucosal bleeding; embolisation and surgical resection treat visceral AVMs; and emerging systemic therapies aim to modulate aberrant angiogenic signalling. Regular surveillance and individualised risk assessment underpin preventative care and reduction of life-threatening complications.

Research from Nature Portfolio

Preclinical models have illuminated signalling nodes amenable to pharmacological inhibition. In endothelial-specific knockout mice lacking ALK1, excessive PI3K/AKT pathway activation drives postnatal AVM formation across multiple organs. Pharmacological blockade of PI3K not only prevented the emergence of new malformations but also induced regression of established AVMs, illustrating a novel therapeutic avenue for lesions refractory to current interventions. This work underscores the potential to translate molecular insights into targeted therapies for HHT-related vascular anomalies.

Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management publication trend

The graph below shows the total number of articles in hereditary hemorrhagic telangiectasia: diagnosis and management across all publications each year (not limited to Nature Index journals).

Technical terms

Telangiectasia: dilation of small blood vessels near the surface of the skin or mucous membranes, leading to visible microvascular lesions.

Arteriovenous malformation (AVM): direct connection between arterial and venous systems bypassing capillaries, often resulting in high-flow vascular lesions.

Endoglin (ENG): a TGF-β co-receptor expressed on endothelial cells that modulates vascular development.

Activin receptor-like kinase 1 (ALK1): a type I receptor in the TGF-β superfamily involved in endothelial signalling and angiogenesis.

Bone morphogenetic protein 9 (BMP9): a circulating ligand that binds ALK1 and endoglin to regulate blood vessel stability.

Phosphoinositide 3-kinase (PI3K): a signalling enzyme whose inhibition has been shown to attenuate vascular malformations in HHT models.

Epistaxis: spontaneous or recurrent nosebleeds, often an early clinical feature of HHT.

References

1. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Frontiers in Genetics (2015).
2. Optimal management of hereditary hemorrhagic telangiectasia. Journal of Blood Medicine (2014).
3. PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nature Communications (2016).
4. Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia. Frontiers in Genetics (2015).
5. Hereditary hemorrhagic telangiectasia: from signaling insights to therapeutic advances. Journal of Clinical Investigation (2024).
6. Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia. Orphanet Journal of Rare Diseases (2019).