7 Key Symptoms of Hereditary Hemorrhagic Telangiectasia You Should Know

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare genetic disorder that affects blood vessels throughout the body. This condition causes abnormal connections between arteries and veins, leading to fragile blood vessels that can bleed easily. HHT affects approximately 1 in 5,000 to 8,000 people worldwide and is inherited in an autosomal dominant pattern, meaning only one parent needs to carry the gene for a child to potentially develop the condition.

The hallmark of HHT is the formation of telangiectases—small, abnormal blood vessels visible on the skin and mucous membranes—and arteriovenous malformations (AVMs) in internal organs. These vascular abnormalities can cause a range of symptoms from mild to severe, significantly impacting quality of life. Early recognition of symptoms is crucial for proper management and preventing serious complications.

1. Recurrent Nosebleeds (Epistaxis)

Recurrent nosebleeds are often the earliest and most common symptom of HHT, affecting more than 90% of patients. These nosebleeds typically begin during childhood or adolescence, though they can start at any age.

Characteristics of HHT-related nosebleeds:

• Spontaneous bleeding without obvious trauma or trigger
• Frequent episodes occurring weekly or even daily
• Bleeding that may last from several minutes to over an hour
• Often occurring from both nostrils at different times
• Tendency to worsen with age

The nosebleeds occur because telangiectases form on the nasal mucosa (the lining inside the nose), creating fragile blood vessels that rupture easily. Even minor irritation from dry air, nose blowing, or slight trauma can trigger bleeding. Some patients experience such severe and frequent nosebleeds that they develop iron-deficiency anemia, requiring medical intervention to manage blood loss and maintain adequate iron levels.

2. Telangiectases on Skin and Mucous Membranes

Telangiectases are small, red or purple spots that appear on the skin and mucous membranes. These are actually clusters of dilated blood vessels visible through the skin surface. They are a defining feature of HHT and typically develop during adulthood, becoming more numerous with age.

Common locations for telangiectases include:

• Face, particularly around the nose, cheeks, and chin
• Lips and tongue
• Fingertips and nail beds
• Inside the mouth and on the gums
• Conjunctiva of the eyes
• Chest and trunk

These lesions typically measure 1-3 millimeters in diameter and appear flat or slightly raised. They blanch (turn white) when pressed and quickly refill with blood when pressure is released. While telangiectases on the skin are primarily a cosmetic concern, those in the mouth or gastrointestinal tract can bleed spontaneously or with minor trauma, contributing to chronic blood loss and anemia.

3. Gastrointestinal Bleeding

Gastrointestinal (GI) bleeding is a significant symptom that typically manifests later in life, usually after age 40, though it can occur earlier. This occurs when telangiectases develop along the lining of the digestive tract, from the stomach through the intestines.

Signs of gastrointestinal bleeding may include:

• Black, tarry stools (melena) indicating upper GI bleeding
• Bright red blood in stools (hematochezia) from lower GI bleeding
• Anemia symptoms such as fatigue, weakness, and pale skin
• Positive fecal occult blood tests
• Iron deficiency despite supplementation

GI bleeding in HHT is often chronic and gradual rather than acute and severe. However, the cumulative blood loss can lead to severe anemia requiring regular blood transfusions and iron supplementation. The bleeding sites can be difficult to identify and treat because telangiectases may be scattered throughout the entire GI tract.

4. Shortness of Breath and Exercise Intolerance

Shortness of breath and reduced exercise capacity can result from pulmonary arteriovenous malformations (PAVMs), which are abnormal connections between arteries and veins in the lungs. These occur in approximately 30-50% of people with HHT.

Respiratory symptoms related to PAVMs include:

• Shortness of breath during physical activity or at rest
• Reduced ability to exercise or perform daily activities
• Cyanosis (bluish discoloration of lips and fingertips) due to low oxygen levels
• Clubbing of fingers (enlargement and rounding of fingertips)
• Platypnea (worsening shortness of breath when sitting or standing upright)

PAVMs allow blood to bypass the normal filtering mechanism of the lungs, which can lead to reduced oxygen levels in the blood (hypoxemia). Additionally, PAVMs pose serious risks including stroke, brain abscess, and rupture leading to life-threatening bleeding into the chest cavity. These complications can occur even in patients without noticeable respiratory symptoms, making screening important for all HHT patients.

5. Neurological Symptoms

Neurological symptoms in HHT can arise from two main sources: cerebral arteriovenous malformations (brain AVMs) or complications from pulmonary AVMs that allow blood clots or bacteria to reach the brain without being filtered by the lungs.

Neurological manifestations may include:

• Severe headaches or migraines
• Seizures
• Transient ischemic attacks (TIAs) or strokes
• Brain abscesses with symptoms like fever, confusion, and focal neurological deficits
• Hemorrhagic stroke from rupture of brain AVMs
• Vision problems or visual disturbances

Brain AVMs occur in approximately 10-20% of HHT patients and can hemorrhage, causing sudden severe headache, neurological deficits, or even death. Even without bleeding, brain AVMs can cause seizures or headaches due to their effects on surrounding brain tissue. Meanwhile, paradoxical emboli (blood clots traveling through PAVMs to the brain) and septic emboli (bacteria-laden clots leading to brain abscess) represent serious complications that require preventive measures.

6. Liver Involvement and Related Symptoms

Hepatic (liver) vascular malformations occur in approximately 30-80% of HHT patients, though most remain asymptomatic. When symptomatic, liver involvement can cause various complications due to abnormal blood flow through the organ.

Symptoms of liver involvement include:

• Right upper abdominal pain or discomfort
• Hepatomegaly (enlarged liver)
• High-output cardiac failure symptoms (shortness of breath, leg swelling, fatigue)
• Portal hypertension leading to abdominal swelling (ascites)
• Biliary disease symptoms including jaundice and cholangitis
• Encephalopathy (confusion due to liver dysfunction)

The liver malformations can create shunts that force the heart to work harder to pump blood through abnormal pathways, potentially leading to high-output heart failure. This occurs because large volumes of blood bypass normal liver circulation, returning too quickly to the heart. Additionally, the abnormal vessels can compress bile ducts, leading to biliary complications. While many patients with liver involvement remain symptom-free, those who develop symptoms often face significant challenges in management.

7. Anemia and Fatigue

Chronic anemia is one of the most debilitating symptoms of HHT, resulting from cumulative blood loss from multiple sites. This symptom affects quality of life significantly and is often underestimated in its impact on daily functioning.

Features of HHT-related anemia include:

• Persistent fatigue and lack of energy
• Weakness and reduced stamina
• Pale skin, nail beds, and mucous membranes
• Dizziness or lightheadedness, especially when standing
• Rapid or irregular heartbeat
• Difficulty concentrating and brain fog
• Cold hands and feet
• Restless legs syndrome

The anemia in HHT is typically iron-deficiency anemia caused by chronic blood loss from nosebleeds, GI bleeding, or both. Some patients lose significant amounts of blood daily, making it difficult to maintain normal iron stores even with supplementation. The fatigue can be profound, affecting work performance, social activities, and overall quality of life. Many patients require regular iron infusions or blood transfusions to maintain adequate hemoglobin levels and manage symptoms.

Main Causes of Hereditary Hemorrhagic Telangiectasia

Hereditary Hemorrhagic Telangiectasia is caused by genetic mutations that are passed down through families. Understanding the genetic basis helps explain why the condition runs in families and how it develops.

Genetic mutations: HHT is caused by mutations in several genes that play crucial roles in blood vessel development and maintenance. The most commonly affected genes are:

• ENG gene (HHT type 1): Accounts for approximately 40% of cases and encodes endoglin, a protein involved in blood vessel formation
• ACVRL1 gene (HHT type 2): Responsible for about 40% of cases and produces ALK1 protein, which also regulates blood vessel development
• SMAD4 gene: Causes a combined syndrome of HHT and juvenile polyposis, accounting for about 2% of cases
• Other genes: Additional genes like GDF2 have been identified in rare cases

Autosomal dominant inheritance: HHT follows an autosomal dominant inheritance pattern, meaning:

• Only one copy of the mutated gene from either parent is sufficient to cause the disorder
• Each child of an affected parent has a 50% chance of inheriting the mutation
• Both males and females are equally affected
• The condition typically appears in multiple generations of a family

Mechanism of disease: The genetic mutations disrupt normal signaling pathways involved in blood vessel formation and maintenance, specifically the TGF-beta (transforming growth factor-beta) pathway. This disruption leads to:

• Abnormal connections between arteries and veins without normal capillary beds in between
• Weakened blood vessel walls that are prone to bleeding
• Formation of telangiectases on skin and mucous membranes
• Development of larger AVMs in organs like the lungs, brain, and liver

Spontaneous mutations: In rare cases (estimated at 10-20% of HHT cases), the genetic mutation occurs spontaneously without being inherited from a parent. These de novo mutations can then be passed on to future generations.

Frequently Asked Questions

What is the difference between HHT type 1 and type 2?

HHT type 1 (caused by ENG gene mutations) and type 2 (caused by ACVRL1 gene mutations) have similar symptoms but differ in some aspects. Type 1 is more commonly associated with pulmonary AVMs and tends to have more severe lung involvement, while type 2 has a higher incidence of liver involvement. Both types can cause nosebleeds, telangiectases, and GI bleeding. Genetic testing can identify which type a person has, though management approaches are similar.

At what age do symptoms of HHT typically appear?

Symptoms can appear at any age, but they typically emerge in a predictable pattern. Nosebleeds often begin in childhood or adolescence, with about 50% of patients experiencing them by age 10 and 80% by age 20. Telangiectases on the skin usually develop in adulthood, becoming more visible after age 30. Gastrointestinal bleeding typically occurs later, often after age 40. However, there is significant variability between individuals, even within the same family.

Can HHT skip generations?

HHT does not truly skip generations, but it may appear to do so. Since HHT is an autosomal dominant disorder, each affected person has the gene mutation. However, the severity and timing of symptoms vary greatly. Some people may have very mild symptoms that go unnoticed or undiagnosed, making it seem like the condition skipped them. This variability in expression is called variable penetrance and expressivity.

How is HHT diagnosed?

HHT is diagnosed using the Curaçao Criteria, which include four features: recurrent nosebleeds, multiple telangiectases, visceral AVMs (in lungs, liver, brain, or GI tract), and a family history of HHT. A diagnosis is “definite” with three or more criteria, “possible” with two criteria, and “unlikely” with fewer than two. Genetic testing can confirm the diagnosis by identifying mutations in HHT-related genes. Imaging studies such as CT scans, MRI, or echocardiography may be used to detect internal AVMs.

Is there a cure for HHT?

Currently, there is no cure for HHT since it is a genetic disorder. However, symptoms can be managed effectively with various interventions. Management focuses on controlling bleeding, treating AVMs when necessary, and preventing complications. Regular screening for AVMs in the lungs, brain, and liver is important for early detection and treatment. Patients should work with healthcare providers experienced in HHT management to develop a personalized care plan.

Can lifestyle changes help manage HHT symptoms?

Yes, certain lifestyle modifications can help reduce symptoms, particularly nosebleeds. These include using humidifiers to keep nasal passages moist, applying lubricating ointments or gels to the nose, avoiding blood-thinning medications unless medically necessary, staying well-hydrated, and avoiding nose picking or forceful nose blowing. For anemia management, eating iron-rich foods and taking supplements as recommended by a doctor can be helpful. Patients should consult their healthcare provider before making significant lifestyle changes or starting any new supplements.

Should family members of HHT patients be tested?

Yes, first-degree relatives (parents, siblings, and children) of someone with HHT should be evaluated for the condition. Since HHT is inherited in an autosomal dominant pattern, each child of an affected parent has a 50% chance of inheriting the mutation. Early diagnosis allows for appropriate screening for AVMs and preventive measures to reduce the risk of serious complications like stroke or brain abscess. Testing can include clinical evaluation based on the Curaçao Criteria and genetic testing if the family mutation is known.

What are the most serious complications of HHT?

The most serious complications arise from AVMs in vital organs. Pulmonary AVMs can lead to stroke, brain abscess, or rupture causing life-threatening bleeding. Brain AVMs can hemorrhage, causing devastating neurological damage or death. Liver AVMs can lead to high-output heart failure. Chronic bleeding from any source can cause severe anemia requiring transfusions. However, with proper screening and management, many of these complications can be prevented or detected early when they are more treatable.

References:

• Mayo Clinic – Hereditary Hemorrhagic Telangiectasia
• National Organization for Rare Disorders (NORD) – Hereditary Hemorrhagic Telangiectasia
• GeneReviews – Hereditary Hemorrhagic Telangiectasia
• National Heart, Lung, and Blood Institute – HHT
• Orphanet – Hereditary Hemorrhagic Telangiectasia