- Autosomal dominant (HHT1/HHT2). Recurrent epistaxis.
Description
Hereditary Haemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a hereditary autosomal dominant disorder characterised by arteriovenous malformations (AVMs) and telangiectasias.
Pathogenesis
HHT is a genetic disorder inherited in an autosomal dominant pattern. Mutations have been identified in at least five genes involved in the development of blood vessels:
- Most cases are due to mutations in either the ENG gene (HHT1) or the ACVRL1 gene (HHT2).
- Less commonly: SMAD4, GDF2, or RASA1 genes.
Subtypes
There are two main types (HHT1 and HHT2), which are distinguished by their genetic cause and pattern of signs and symptoms, and different propensities for developing AVMs in certain organs.
- HHT1: This subtype is caused by mutations in the ENG gene, which encodes for the protein endoglin, an essential component of the TGF-beta receptor complex. HHT1 is typically associated with a higher risk of pulmonary arteriovenous malformations (PAVMs) and cerebral arteriovenous malformations (CAVMs).
- HHT2: HHT2 results from mutations in the ACVRL1 gene that encodes for the ALK1 protein, another important component of the TGF-beta receptor complex. HHT2 patients have a higher prevalence of hepatic arteriovenous malformations (HAVMs) compared to HHT1.
Other less common subtypes:
- Juvenile Polyposis Hereditary Hemorrhagic Telangiectasia Syndrome (JP/HHT): This variant is linked to mutations in the SMAD4 gene. Affected individuals display features of both juvenile polyposis syndrome (characterised by multiple juvenile polyps in the gastrointestinal tract) and HHT. There is also an increased risk of colorectal cancer in this subtype.
- HHT3: This subtype is associated with an unidentified genetic locus on chromosome 5. It is considered a rare variant and patients exhibit typical HHT symptoms.
- HHT4: HHT4 is linked to an unidentified genetic locus on chromosome 7. As with HHT3, it is a rare variant and patients display classic HHT features.
- HHT associated with pulmonary arterial hypertension (PAH): This rare variant is due to mutations in the GDF2 gene, which encodes for the BMP9 protein, another member of the TGF-beta family. Along with typical HHT symptoms, patients also have an elevated risk of developing PAH.
- HHT-like syndrome: This rare variant is associated with mutations in the RASA1 gene. Though patients exhibit cutaneous and mucosal telangiectasias, they do not develop internal organ AVMs. This subtype is also associated with capillary malformation-arteriovenous malformation syndrome (CM-AVM).
Epidemiology, Risk Factors & Associations
- HHT affects about 1 in 5,000 people worldwide.
- No gender or ethnic predilection
- Often manifests in childhood but can present at any age with varying severity.
Clinical Features
Typical hallmarks include:
- Recurrent epistaxis: Often earliest sign, arising from nasal mucosal telangiectasias.
- Telangiectasias: Small cutaneous (especially face and hands) and mucosal vascular lesions.
- Arteriovenous malformations: Visceral AVMs may occur in multiple organs including the lungs, liver, brain, and gastrointestinal tract, posing a risk of severe complications such as stroke or brain abscess.
- Gastrointestinal haemorrhage: Chronic blood loss may culminate in iron-deficiency anaemia.
Complications
The most severe complications of HHT are caused by AVMs in the lungs and brain:
- Pulmonary AVMs can allow thrombi to bypass pulmonary capillary filtration, leading to paradoxical emboli, stroke, or brain abscesses.
- Cyanosis (due to the right to left shunt)
- Cerebral AVMs with aneurysms are prone to rupture, leading to life-threatening haemorrhagic stroke.
- Hepatic AVMs can induce high-output cardiac failure due to augmented blood flow.
- Chronic haemorrhage can lead to iron-deficiency anaemia.
- High output cardiac failure
Pathological Features
Morphology
Pathological hallmark of HHT:
- Telangiectasias are dilated venules and capillaries in the dermis, mucosa or organ systems
- AVMs are larger and involve direct connections between arteries and veins
Both telangiectasias and AVMs are typified by thin-walled dilated vessels devoid of intervening capillary beds.
Genetics
HHT arises from mutations in ENG, ACVRL1, SMAD4, GDF2, and RASA1 genes involved in the transforming growth factor-beta signalling pathway implicated in angiogenesis.
Radiological Features
General
- AVMs are commonly identified in the lung, brain, and liver. Their size can range from tiny to large.
- Pulmonary AVMs:
- Single lesion (33%), multiple lesions (50%)
- Simple (80%): 1 or more feeding arteries from the same segmental artery
- Complex (20%): Multiple feeding arteries from different segmental arteries
CXR
- A dilated pulmonary vessel or non-specific soft tissue mass with unusual orientation of adjacent vessels
CT
- Cerebral AVMs – Hyperdense nidus on non-contrast, bag of worm enhancement. Enlarged draining veins. May demonstrate intranidal aneurysm.
- Pulmonary AVMs
- Non-contrast: Homogeneous, well-circumscribed round or oval mass. Occasionally phelobiths may be seen.
- Contrast: Enhancing serpiginous mass with feeding artery, aneurysm and draining vein on early-phase sequences.
- Hepatic AVMs – May result in hepatomegaly with increased arterial flow and early venous return on contrast-enhanced scans.
MRI
- Useful for the evaluation of brain AVMs. They appear as tangles of abnormal vessels with associated signal voids on all sequences.
- T2: Fast flow generates flow voids
- MRA: Phase-contrast MRA useful for subtracting haematoma components
- Hepatic and pulmonary AVMs can be identified, with larger ones demonstrating a characteristic flow void.
Angiography
- Gold standard for diagnosing AVMs and can provide detailed information on the feeding arteries and draining veins.
Grading and Staging
There is no specific grading or staging system for HHT.
Differential Diagnosis
Clinically-based
- Juvenile polyposis syndrome: SMAD4 gene mutations can cause both HHT and juvenile polyposis syndrome, a condition characterised by the development of polyps in the gastrointestinal tract.
- Other causes of recurrent nosebleeds and/or gastrointestinal bleeding, such as coagulation disorders, must be ruled out.
Imaging-based
- Pulmonary artery aneurysm/pseudoaneurysm: Pseudoanerusym commonly caused by direct iatrogenic injury by Swans-Gans catheter. Systemic vasculitis and mycotic aneurysms are less common causes. Enhancement is identical to adjacent pulmonary arteries.
- Pulmonary hamartoma: Also a solitary pulmonary nodule. Presence of macroscopic fat is diagnostic.
- Carcinoid tumour: Avidly enhancing mass seen in a segmental location (similar to a Swan-Ganz induced false aneurysm)
Management
- Management of HHT is often multidisciplinary involving ENT specialists for nosebleeds, gastroenterologists for GI bleeding, and interventional radiologists for treatment of AVMs.
- Embolotherapy (gold standard treatment) – Placement of embolic agents (like coils or plugs) into the abnormal blood vessels to block blood flow and prevent complications. Particles, gelfoam, and liquid embolics have no role in the endovascular treatment of pulmonary arteriovenous malformations.
- Genetic counseling may be sought for affected individuals and their families.