Osler-Weber-Rendu Syndrome, more commonly known as Hereditary Hemorrhagic Telangiectasia (HHT), is an inherited genetic disorder that causes abnormal blood vessels to form throughout the body. These malformed vessels are prone to bleeding and can appear in various locations, from the surface of the skin to internal organs. The disorder’s core issue stems from direct, improper connections between arteries and veins. This structural abnormality disrupts the normal pattern of blood flow, which underlies the range of health issues associated with the condition.
Genetic Causes of the Syndrome
Hereditary Hemorrhagic Telangiectasia is an inherited condition passed down through families in a pattern known as autosomal dominant inheritance. This means an individual only needs to receive one copy of the altered gene from one parent to develop the disorder. Consequently, a person with HHT has a 50% chance of passing the gene to each of their children.
The condition is caused by mutations in genes that create proteins involved in blood vessel development. The majority of cases, approximately 85%, are linked to changes in either the `ENG` or `ACVRL1` genes, with a smaller percentage resulting from mutations in the `SMAD4` gene. These genes provide instructions for proteins active in a signaling pathway that regulates the circulatory system. A mutation disrupts this process, resulting in the fragile, abnormal structures seen in HHT.
Symptoms and Potential Complications
The most common and earliest sign of the syndrome is frequent, spontaneous nosebleeds, medically termed epistaxis, which affects about 90% of individuals and often begins in childhood. Another characteristic feature is the appearance of small, red-to-purple spots on the skin and mucous membranes, known as telangiectasias. These spots are small, dilated blood vessels that typically appear on the hands, face, lips, and inside the mouth and nose. While these skin lesions may bleed, they are often a cosmetic concern and their numbers tend to increase with age.
Beyond these visible signs, the syndrome can cause more serious internal issues through the formation of larger abnormal blood vessels called arteriovenous malformations (AVMs). An AVM is a direct tangle of arteries and veins that bypasses the capillary system, creating a high-pressure shunt that can lead to complications. AVMs can form in major organs, including the lungs, brain, liver, and gastrointestinal tract.
Pulmonary AVMs in the lungs can allow blood to bypass the normal oxygenation process, leading to shortness of breath and fatigue. They also create a risk for bacteria or small blood clots to travel directly to the brain, potentially causing a brain abscess or an embolic stroke. Brain AVMs carry a risk of hemorrhage, which can result in a stroke or seizures. In the gastrointestinal tract, telangiectasias and AVMs can cause chronic bleeding that leads to iron deficiency anemia. Liver AVMs can strain the heart by forcing it to pump an increased volume of blood, which may lead to high-output heart failure.
How the Syndrome is Diagnosed
The diagnosis of HHT is primarily clinical and guided by a set of internationally recognized standards known as the Curaçao Criteria. A physician will assess a patient for the presence of four specific features to determine if they meet the diagnostic threshold for HHT.
The criteria are:
- Spontaneous and recurrent nosebleeds.
- Multiple telangiectasias at characteristic sites, such as the lips, mouth, fingers, or nose.
- Evidence of visceral involvement, meaning the presence of AVMs in internal organs.
- A first-degree relative with a confirmed diagnosis of HHT.
A definitive diagnosis of HHT is made when a person meets at least three of these four criteria. If an individual meets two criteria, the diagnosis is considered possible or suspected, warranting further observation and screening. A diagnosis is considered unlikely if a person has fewer than two of the criteria.
In cases where the clinical diagnosis is uncertain, or for screening family members who may not yet show symptoms, genetic testing can be used. Testing can identify mutations in the `ENG`, `ACVRL1`, and `SMAD4` genes to confirm a diagnosis. Imaging tests, such as CT scans and MRIs, are also used to screen for and detect internal AVMs.
Managing Symptoms and Preventing Risks
As there is no cure for HHT, management focuses on treating symptoms to improve quality of life and preventing the serious risks associated with AVMs. The approach to care is tailored to the individual’s specific manifestations and often involves a multidisciplinary team of specialists.
For common symptoms like nosebleeds, initial treatments aim to keep the nasal passages moist through humidifiers and saline sprays or ointments. If bleeding persists, procedures such as laser therapy can be used to seal the fragile vessels inside the nose.
For the more significant risks posed by internal AVMs, management shifts to prevention and targeted intervention. Regular screening is performed to monitor for the presence and size of AVMs in the lungs, brain, and liver. If a pulmonary or brain AVM is identified that poses a high risk of rupture, a procedure called embolization is often the first line of treatment. During embolization, an interventional radiologist guides a catheter to the AVM and uses tiny coils or a special glue to block blood flow into the malformation.
In some cases, surgical removal of an AVM or stereotactic radiosurgery for brain AVMs may be recommended. For gastrointestinal bleeding that leads to anemia, iron replacement therapy is a primary treatment. Given the complexity of the disorder, ongoing care is best provided at a specialized HHT Center of Excellence. These centers offer coordinated care from experts across different medical fields, ensuring comprehensive management.