Hereditary Hemorrhagic Telangiectasia: Symptoms, Types, Causes and Treatment

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare but impactful genetic disorder characterized by abnormal blood vessel formation. Affecting approximately 1 in 5,000 people, HHT can lead to significant bleeding, anemia, and complications in multiple organ systems. This article explores the symptoms, types, causes, and modern treatments for HHT, using up-to-date research to provide a thorough and approachable guide for patients, families, and healthcare professionals.

Symptoms of Hereditary Hemorrhagic Telangiectasia

HHT can present with a range of symptoms, from subtle skin changes to life-threatening internal bleeding. Early recognition is crucial for timely intervention and improved quality of life. Understanding the most common symptoms and their progression helps patients and clinicians remain vigilant.

Symptom	Prevalence	Impact/Complication	Source(s)
Nosebleeds	>90%	Anemia, reduced quality of life	1 3 4 7 14
Telangiectases	Very common	Visible lesions, bleeding	1 2 3 7 10
GI bleeding	13-30%	Chronic anemia, transfusions	2 4 8 10
AVMs in organs	Variable	Stroke, heart failure, abscess	1 2 5 8 10

Table 1: Key Symptoms

Overview of HHT Symptoms

HHT symptoms typically become apparent in adolescence or early adulthood, though onset can vary widely. Recurrent nosebleeds (epistaxis) are often the first and most frequent sign, sometimes beginning in childhood. Small, red or purple spots called telangiectases commonly appear on the lips, tongue, face, and hands years after the initial nosebleeds. These fragile vessels can bleed easily, especially from mucosal surfaces like the nose and gastrointestinal tract 1 3 7.

Nosebleeds (Epistaxis)

• Occur in over 90% of patients, often as the earliest and most prominent symptom 1 3 14.
• Nosebleeds can be mild or severe and tend to worsen with age.
• Chronic bleeding may result in significant iron deficiency anemia, requiring iron supplements or blood transfusions 2 10.

Mucocutaneous Telangiectases

• Appear as small, blanching red or purple spots on the skin and mucous membranes (lips, tongue, face, hands).
• Usually develop 5–20 years after the first nosebleeds 1 3.
• Can cause cosmetic concerns and bleed with minor trauma 1 7.

Gastrointestinal Bleeding

• GI telangiectases may develop later in life, leading to chronic or intermittent blood loss 2 4.
• Many patients are unaware of GI bleeding until anemia becomes evident.
• Endoscopic evaluation may reveal the source of bleeding 4.

Visceral Arteriovenous Malformations (AVMs)

• AVMs can form in the lungs, liver, brain, or spine, often without symptoms until complications arise 1 2 8.
• Pulmonary AVMs may cause shortness of breath, low oxygen levels, or allow blood clots/bacteria to bypass the lungs, resulting in stroke or brain abscess 2 4 8.
• Hepatic AVMs can lead to high-output heart failure or encephalopathy 2 7.
• Cerebral AVMs can result in headaches, seizures, or hemorrhagic stroke 1 2.

Other Symptoms

• Fatigue is common, especially due to chronic anemia.
• Some patients experience neurological symptoms from brain AVMs or complications of pulmonary AVMs 2 4 5.

Types of Hereditary Hemorrhagic Telangiectasia

HHT is not a single disease but a group of related disorders, classified by genetic mutations, clinical features, and organ involvement. Identifying the specific type aids in predicting complications and tailoring family screening.

Type	Gene(s) Involved	Distinctive Features	Source(s)
HHT1	ENG (Endoglin)	More lung/brain AVMs	1 5 6 8
HHT2	ACVRL1 (ALK1)	More liver involvement	1 5 6 8
HHT3+	SMAD4, GDF2, etc.	Overlap, polyposis (SMAD4)	6 8 10
Overlap	Multiple genes	Variable, depends on mutation	5 6 10

Table 2: HHT Types

Genetic Types of HHT

HHT1 (ENG Mutation)

• Caused by mutations in the ENG gene, which encodes the protein endoglin.
• Patients with HHT1 are more likely to develop pulmonary and cerebral AVMs, with a higher risk of related complications such as stroke or brain abscess 1 5 6 8.
• Telangiectases and nosebleeds are common, but the pattern of visceral involvement helps distinguish this type.

HHT2 (ACVRL1/ALK1 Mutation)

• Results from mutations in the ACVRL1 gene (also known as ALK1), affecting another component of vascular signaling.
• HHT2 patients have a higher prevalence of liver AVMs, which can lead to high-output heart failure or liver dysfunction 1 5 6 8.
• Mucocutaneous symptoms are present, but lung and brain AVMs are less frequent than in HHT1.

Other Types (HHT3, SMAD4, GDF2)

• Rare mutations in SMAD4 or GDF2 genes can cause HHT or overlap syndromes.
• SMAD4 mutations may present with both HHT and juvenile polyposis syndrome (increased risk of gastrointestinal polyps and cancer) 6 10.
• Some families with clinical HHT do not have identifiable mutations in known genes, suggesting additional undiscovered variants 6.

Clinical Overlap and Variability

• Even within families, symptom severity and organ involvement can vary widely, despite identical mutations 5 6 10.
• Environmental factors and genetic modifiers likely contribute to this variability.
• Accurate genetic diagnosis helps with targeted screening and family counseling 1 6.

Causes of Hereditary Hemorrhagic Telangiectasia

Understanding what causes HHT on the genetic and molecular level is essential for diagnosis, family planning, and developing targeted therapies. HHT is a classic example of a monogenic, autosomal dominant vascular disorder.

Cause	Mechanism	Effect on Blood Vessels	Source(s)
ENG mutation	Loss of endoglin	Weak vessel walls, AVMs	1 6 8 9
ACVRL1/ALK1 mutation	Loss of ALK1 protein	Abnormal vessel development	1 6 8 9
SMAD4 mutation	TGF-β pathway defect	Polyposis + HHT features	6 10
Unknown/Other genes	Under investigation	Variable symptoms	6 8

Table 3: Causes of HHT

Genetic Basis

Autosomal Dominant Inheritance

• HHT is inherited in an autosomal dominant fashion, meaning only one copy of the mutated gene is needed for the disease to manifest 1 2 6 8.
• Each child of an affected parent has a 50% chance of inheriting HHT.

Key Genes and Pathways

• ENG (Endoglin) and ACVRL1 (ALK1) account for approximately 85–96% of cases 1 6 8.
• Both genes are involved in the TGF-β (transforming growth factor-beta) signaling pathway, which regulates blood vessel development and stability 6 8 9.
• Mutations disrupt the ability of blood vessel endothelial cells to respond to signals, resulting in fragile, abnormal vessels (telangiectases, AVMs) 8 9.
• SMAD4 mutations cause a combined syndrome of HHT and juvenile polyposis 6 10.
• GDF2 and other rare genes have also been implicated 6.

Pathophysiology of Vascular Lesions

• The hallmark of HHT is the formation of direct artery-to-vein connections (AVMs) that lack a normal capillary bed, making them prone to rupture or shunting of blood 1 9.
• Defective mechanotransduction (the ability of vessels to sense blood flow) and aberrant cell signaling play a central role in lesion formation 9.
• The precise location and severity of lesions depend on the specific gene mutation and possibly other genetic/environmental modifiers 5 6.

Diagnostic Implications

• Molecular genetic testing can confirm the diagnosis and determine the specific HHT subtype for appropriate family screening and management 1 6.
• In some patients, no mutation is found in known genes, highlighting the need for ongoing research and comprehensive gene panels 6 8.

Treatment of Hereditary Hemorrhagic Telangiectasia

Managing HHT requires a comprehensive, multidisciplinary approach focused on preventing complications, controlling bleeding, and addressing organ-specific AVMs. While there is no cure yet, advances in therapy have improved outcomes and quality of life for many patients.

Treatment	Indication	Effectiveness/Notes	Source(s)
Iron supplementation	Chronic bleeding/anemia	Mainstay for mild/moderate cases	2 8 10 11
Blood transfusion	Severe anemia	Acute management	2 10 11
Local therapy (nose)	Epistaxis	Pressure, packing, cautery, laser	13 14
Hormonal therapy	Nose/GI bleeding	Estrogens/antifibrinolytics	2 13 14
Bevacizumab	Severe bleeding/AVMs	Promising, reduces bleeding	10 11 14
Embolization/surgery	Pulmonary/hepatic AVMs	Prevents stroke/abscess	2 7 10
mTOR/VEGFR2 inhibitors	Experimental	Potential for AVM reversal	12
Multidisciplinary care	All patients	Improves outcomes	10 14

Table 4: HHT Treatments

Supportive Measures

• Iron supplementation is essential for nearly all patients with chronic blood loss, especially from nose or GI tract 2 8 10 11.
• Blood transfusions may be required for severe anemia or acute bleeding episodes 2 10 11.

Local Management of Bleeding

• Nasal bleeding (epistaxis): Managed with pressure, nasal packing, cauterization, or laser photocoagulation (e.g., ND-YAG laser) 13 14.
• Septal dermoplasty and topical therapies can provide longer-term relief in select cases 13.
• Hormonal therapy (e.g., estrogens) and antifibrinolytic agents (e.g., tranexamic acid) have shown benefit but may carry risks and require careful monitoring 2 13 14.

Systemic and Advanced Therapies

• Bevacizumab, an anti-VEGF antibody, has emerged as a promising systemic therapy for severe or refractory bleeding. It can be given intravenously or topically and has been shown to raise hemoglobin levels, reduce transfusion needs, and control epistaxis and GI bleeding 10 11 14.
  • Bevacizumab is generally well tolerated, with hypertension, fatigue, and proteinuria as the most common side effects 11.
• mTOR inhibitors (sirolimus) and VEGFR2 inhibitors (nintedanib) are being investigated to target the underlying molecular pathways and may help reverse or prevent AVMs in experimental models 12.

Interventional Procedures for AVMs

• Embolization is the treatment of choice for pulmonary AVMs to prevent stroke or brain abscess 2 7 10.
• Surgical resection or ligation may be necessary for inaccessible or large AVMs 2 10.
• Liver AVMs may require complex interventions or even transplantation in severe cases 2 7 10.

Multidisciplinary Care and Screening

• Given the risk of silent AVMs in the lungs, brain, or liver, screening programs (including imaging) are vital for all diagnosed patients and at-risk family members 8 10.
• Care from a team including hematologists, ENT specialists, gastroenterologists, interventional radiologists, and genetic counselors is recommended to address the full spectrum of complications 10 14.

Experimental and Future Directions

• Research into targeted molecular therapies is ongoing, with hopes for disease-modifying treatments in the future 12 14.
• Genetic counseling and early diagnosis remain key strategies for improving patient outcomes 1 6 10.

Conclusion

Hereditary Hemorrhagic Telangiectasia is a complex, lifelong condition with substantial impact on patients and families. Advances in genetics, diagnosis, and therapy have transformed care, but continued research and awareness are needed.

Key Points:

• HHT is characterized by recurrent nosebleeds, mucocutaneous telangiectases, and AVMs in multiple organs, leading to diverse symptoms 1 2 3 4.
• The condition is genetically heterogeneous, most often caused by mutations in ENG or ACVRL1, with variable clinical presentations 1 5 6 8.
• Management focuses on controlling bleeding, preventing complications from AVMs, and providing iron supplementation or transfusions as needed 2 10 11.
• New therapies such as anti-angiogenic agents (e.g., bevacizumab) and molecular pathway inhibitors offer hope for improved symptom control 10 11 12.
• Multidisciplinary care and comprehensive family screening are essential for early detection and optimal outcomes 10 14.
• Ongoing research is expanding our understanding of the disease and paving the way for targeted, personalized therapies 6 12 14.

With greater awareness and coordinated care, individuals with HHT can lead fulfilling lives, despite the challenges posed by this rare vascular disorder.