Hereditary haemorrhagic telangiectasia

HHT is a multisystem vascular dysplasia defined by the presence of arteriovenous malformations (AVM), i.e. direct connections between the arterial and venous vascular bed without the interposition of capillaries. Small lesions present as mucocutaneous telangiectasias on the lips, tongue, oral cavity, nasal mucosa, fingers, and gastrointestinal tract. Larger AVM occur predominantly in the lungs, liver, and central nervous system. The cardinal feature of HHT is recurrent spontaneous epistaxis, which is experienced by more than 95% of patients. Symptoms typically begin around age 12, affecting roughly 80% of individuals by age 20 and 90% by age 30. Pulmonary AVM occur in 30-50% and create high-flow right-to-left shunts, predisposing to stroke, transient ischemic attack, and brain abscess even when asymptomatic. Hepatic AVM are detected in 40-70% (symptomatic in fewer than 10%), cerebral AVM in approximately 10%, and pulmonary arterial hypertension in 1-2%. Expressivity is highly variable between and within families, ranging from minimal epistaxis to severe iron-deficiency anemia and high-output cardiac failure.

The estimated prevalence is 1/5,000. Allele-frequency-based estimates from population genomic data suggest the true prevalence may lie between approximately 2/5,000 and 12/5,000, indicating substantial under-ascertainment of clinically mild cases.

HHT is caused by germline pathogenic variants in genes encoding components of the transforming growth factor β / BMP9-BMP10 signaling pathway in vascular endothelium. Three genes account for the molecularly resolved cases: ACVRL1 (~52%), encoding the type I receptor ALK1; ENG (~44%), encoding endoglin, a co-receptor of the TGF-β receptor complex; and SMAD4 (~1%), encoding an intracellular signaling mediator whose pathogenic variants cause a combined juvenile polyposis-HHT syndrome (JP-HHT). Disease results from haploinsufficiency, with pathogenic variants representing null alleles. Approximately 3% of individuals meeting clinical criteria remain molecularly unexplained.

HHT is inherited in an autosomal dominant pattern. Most affected individuals have an affected parent; de novo germline or postzygotic mosaic pathogenic variants are uncommon but reported. Each child of an affected individual has a 50% chance of inheriting the familial pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The clinical diagnosis is established using the :

1. recurrent spontaneous epistaxis,
2. multiple mucocutaneous telangiectasias at characteristic sites,
3. visceral AVM (pulmonary, cerebral, hepatic, spinal, or gastrointestinal), and
4. a first-degree relative with HHT.

Fulfilment of three or more criteria establishes the diagnosis; two criteria indicate possible HHT. Additional consensus frameworks include the Second International Guidelines for the Diagnosis and Treatment of HHT and proposed updates incorporating molecular confirmation as an additional diagnostic pathway. Contrast echocardiography, brain MRI, and abdominal imaging support staging and surveillance rather than initial diagnosis.

Main differential diagnoses include:

• Capillary malformation-arteriovenous malformation syndrome (CM-AVM): multiple small capillary malformations often surrounded by a white halo, with cerebral, spinal, hepatic, facial, and extremity AVMs and arteriovenous fistulas
• BMPR2-related disorder: pulmonary arterial hypertension is the typical presentation rather than mucocutaneous telangiectasias or epistaxis
• GDF2-related vascular anomaly syndrome: isolated pulmonary arterial hypertension predominates, with AVMs, epistaxis, or telangiectasias in a minority of cases. In recent years, however, GDF2 has increasingly been recognised as a causative gene for HHT itself.

• Molecular genetic testing can establish the diagnosis at the molecular level, confirming the clinical suspicion and providing the genetic basis for the condition.
• Identification of the causative pathogenic variant enables specific and individualized surveillance for pulmonary, cerebral, and hepatic AVM and is a prerequisite for targeted medical care.
• Once the familial pathogenic variant has been identified, predictive testing of at-risk relatives is technically possible and allows clarification of carrier status within the family.

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