Telangiectasia, hereditary hemorrhagic
In medicine, hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a genetic disorder that leads to vascular malformations. more...
Signs and symptoms
HHT is characterised by telangiectasia (small vascular malformations) on the skin and mucosal linings, epistaxis (nosebleeds), and arteriovenous malformations (AVMs) in various internal organs.
Skin and mucosa telangiectasias are most remarkable on the tongue, hands/fingers, nose, lips, mouth/throat and conjunctiva.
The internal organs that can harbor AVMs often include the brain and lungs. In both, bleeding can seriously endanger life.
There are four diagnostic criteria. If three or four are met, a patient has definite HHT, while two gives a possible diagnosis:
- Spontaneous recidivating epistaxis
- Multiple teleangiectasias on typical locations (see above)
- Proven visceral AVM
- First-degree family member with HHT
When HHT is suspected, physical examination focuses on inspecting the whole skin for teleangiectasias, auscultation of the lungs and neurological examination.
Pulmonary AVMs can be anticipated by measuring oxygen levels and performing arterial blood gas (ABG) sampling. An X-ray of the chest can show susceptible lesions; in addition, low oxygen tension (<96% or a 2% decrease upon standing) or low blood oxygen levels on ABG are required for a diagnosis.
HHT is a genetic disorder by definition. It is inherited in an autosomal dominant manner.
Four forms have been described:
- HHT1: mutation of the endoglin gene (ninth chromosome). Endoglin is a receptor of TGFβ1 (transforming growth factor beta 1) and TGFβ3. It also interacts with zyxin and ZRP-1 with its intracellular domain, to control composition of focal adhesions and regulate organization of actin filaments. This form predisposes for pulmonary AVMs and early nosebleeds.
- HHT2: mutation in the alk1 gene (12th chromosome). Alk-1 (activin receptor-like kinase 1) is a TGFβ1 receptor. Less pulmonary AVMs and later nosebleeds, but an increased risk of pulmonary hypertension (supposedly due to altered TGFβ signalling or other related pathways which may lead to vascular malformations).
- HHT3: a third form has been suspected to exist, but has not yet been linked to a defective gene.
- Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome is caused by mutations in the gene SMAD4
It is possible to test patients for the presence of mutations in endoglin, ALK-1 and SMAD4. When the mutation in an affected family member has been found it is possible to test other family members and identify those people not at risk for developing the disease.
The mechanism underlying the formation of vascular malformations is not completely understood, but signalling of transforming growth factor-β1 is most likely to be involved. Possibly, connective tissue is required to support and guide proliferating blood vessels during angiogenesis, and defects in TGF-β signalling adversely affect connective tissue and matrix production.
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