Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)

Epidemiology

Demographics

Incidence: 1 in 5000 to 1 in 8000 in France, Denmark, and Japan
- Higher prevalence in isolated communities

Etiology

Autosomal Dominant
- Mutations in endoglin-1 (HHT1) and ALK-1 (HHT2) genes (play role in TGFß signaling): mutations result in decreased levels of these proteins on vascular endothelium
- HHT1 mutations may produce earlier onset of vascular complications than other mutations
- HHT2 mutations also are at risk for pulmonary HTN (similar to those with BMPR2 mutations)
- Mutations in Smad4 (HHT3) (play role in TGFß signaling): results in juvenile polyposis-HHT overlap syndrome

Physiology

Disorder of vascular development

Clinical Manifestations

Dermatologic Manifestations

Mucocutaneous Telangiectasias (see Telangiectasias, Telangiectasias)
- Epidemiology
  - Usually Diagnosed in Adulthood (Usually Absent or Subtle Earlier in Life)
- Physiology
  - Mucocutaneous Telangiectasias Develop Progressively with Aging
- Clinical: usually cosmetic (bleeding is uncommon and rarely clinically significant)
  - Buccal Mucosa: common site
  - Lips: common site
  - Tongue: common site
  - Fingertips: common site

Gastrointestinal/Hepatic Manifestations

Gastrointestinal Telangiectasias
- Epidemiology
  - Approximately 33% of Cases Experience Recurrent Gastrointestinal Hemorrhage
  - Most Cases of Gastrointestinal Hemorrhage Occur in Patients >40 y/o
- Physiology
  - Gastrointestinal Telangiectasias Develop Progressively with Aging
- Clinical
  - Telangiectasias May Occur Anywhere in the Gastrointestinal Tract
    - Gastric Telangiectasias: common site
    - Duodenal Telangiectasias: common site
    - Colonic Telangiectasias: less common site
  - Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, Gastrointestinal Hemorrhage)
Hepatic Telangiectasias
- Epidemiology: hepatic involvement occurs in approximately 66% of cases (although it is usually asymptomatic)
- Clinical
  - Left-to-Right Shunt (with or without High-Output Congestive Heart Failure) (see Intracardiac and Extracardiac Shunt, Intracardiac and Extracardiac Shunt): due to large AVM creating a communication between the hepatic artery and hepatic vein
  - Portal Hypertension (see Portal Hypertension, Portal Hypertension): due to AVM creating a communication between the hepatic artery and portal vein, as well as increased sinusoidal blood flow (causing fibrosis and pseudocirrhosis of the liver)
Pancreatic Arteriovenous Malformation (AVM)
- Diagnosis: may be diagnosed by CT

Neurologic Manifestations

Brain Arteriovenous Malformation (AVM) (see Brain Arteriovenous Malformation, Brain Arteriovenous Malformation)
- Epidemiology
  - Age of Development Depends on the Specific Type (Although Most are Believed to Develop During Childhood)
- Clinical
  - High-Flow Arteriovenous Fistula (with/without High-Output Congestive Heart Failure): usually occur only in children
  - Intracerebral Hemorrhage (see Intracerebral Hemorrhage, Intracerebral Hemorrhage)
  - Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident, Ischemic Cerebrovascular Accident): due to ischemia of surrounding tissue associated with a steal phenomenon
  - Seizures (see Seizures, Seizures)
  - Telangiectasias
Migraines (see Migraines, Migraines)
- Epidemiology: associated with presence of pulmonary arteriovenous malformation (AVM)
Spinal Arteriovenous Malformation (AVM) (see xxxx, xxxx)

Otolaryngologic Manifestations

Nasal Muscosal Telangiectasias
- Epidemiology: common early in the course (with onset during childhood)
- Clinical: epistaxis (see Epistaxis, Epistaxis)

Pulmonary Manifestations

Pulmonary Arteriovenous Malformation (AVM) (see Pulmonary Arteriovenous Malformation, Pulmonary Arteriovenous Malformation)
- Epidemiology: usually diagnosed after puberty (although some are diagnosed during childhood)
- Clinical: asymptomatic in approximately 50% of cases (Thorax, 1999) [MEDLINE]
  - Pulmonary Bruit (see Pulmonary Bruit, Pulmonary Bruit)
  - Chest Pain: present in 14% of cases
  - Cyanosis (see Cyanosis, Cyanosis): present in 30% of cases
  - Dyspnea (see Dyspnea, Dyspnea): present in 48% of cases
  - Hemoptysis (see Hemoptysis, Hemoptysis): present in 11% of cases
    - Rarely Occurs in Non-Pregnant Cases
    - Due to Rupture of AVM into the Bronchus
  - Hemothorax (see Pleural Effusion-Hemothorax, Pleural Effusion-Hemothorax)
    - Rarely Occurs in Non-Pregnant Cases
    - Due to Rupture of AVM into the Pleural Space
  - Paradoxical Embolism (see Intracardiac and Extracardiac Shunt, Intracardiac and Extracardiac Shunt)
    - Clubbing (see Clubbing, Clubbing)
    - Hypoxemia (see Hypoxemia, Hypoxemia)
    - Polycythemia (see Polycythemia, Polycythemia)
Pulmonary Hypertension (see Pulmonary Hypertension, Pulmonary Hypertension)
- Mechanisms (World J Cardiol, 2015) [MEDLINE]
  - Increased Pulmonary Blood Flow Associated with Systemic AVM and/or Anemia
  - Small Vessel Pulmonary Hypertension (Similar to Idiopathic Pulmonary Arterial Hypertension) (see Idiopathic Pulmonary Arterial Hypertension, Idiopathic Pulmonary Arterial Hypertension)
Venous Thromboembolism (see Deep Venous Thrombosis, Deep Venous Thrombosis and Acute Pulmonary Embolism, Acute Pulmonary Embolism)
- Epidemiology: increased risk
- Physiology: associated with decreased serum iron levels and increased plasma factor VIII levels (Thorax, 2012) [MEDLINE]
- Treatment: treatment of venous thromboembolism may be problematic, due to significant risk of anticoagulation in these patients (NEJM, 2013) [MEDLINE]

Treatment

Family Screening: no child of an affected parent can be excluded from having HHT without genetic testing

References

Clinical

Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax. 1999;54(8):714 [MEDLINE]
Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia. Thorax. 2012 Apr;67(4):328-33. Epub 2011 Dec 14 [MEDLINE]
Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets. PLoS One. 2014;9(2):e88812. Epub 2014 Feb 19 [MEDLINE]
Pulmonary hypertension in hereditary haemorrhagic telangiectasia. World J Cardiol. 2015 May;7(5):230-7 [MEDLINE]

Treatment

Antiplatelet and anticoagulant agents in hereditary hemorrhagic telangiectasia. N Engl J Med. 2013 Feb;368(9):876-8 [MEDLINE]