What autosomal dominant (AD) bleeding disorder can be passed from parent to child to grandchild?

Hereditary Hemorrhagic Telangiectasia (HHT) is the Autosomal Dominant Bleeding Disorder That Can Pass Through Generations

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is the autosomal dominant bleeding disorder that can be passed from parent to child to grandchild through generations. 1

Disease Characteristics and Inheritance Pattern

• HHT is an autosomal dominant rare bleeding disorder with an estimated prevalence of approximately 1 in 5000 persons worldwide 1
• The disease is characterized by the presence of vascular malformations (VMs) that result in chronic bleeding, acute hemorrhage, and complications from shunting through these malformations 1
• As an autosomal dominant condition, each child of an affected parent has a 50% chance of inheriting the disease, allowing it to pass through multiple generations 1
• In 97% of patients with a definite clinical diagnosis of HHT, a causative mutation is identified in one of these genes: endoglin (ENG, HHT type 1), activin receptor-like kinase-1 (ACVRL1, HHT type 2), and SMAD4 (juvenile polyposis-HHT overlap) 1

Clinical Manifestations

• The most common symptom of HHT is epistaxis (nosebleeds), occurring in more than 90% of adults with the condition 1
• Telangiectasias on the skin and mucous membranes are characteristic findings that have age-related expression 1
• Vascular malformations can affect multiple organ systems including:
  • Nose and gastrointestinal tract, leading to chronic bleeding and anemia 1
  • Brain, causing risk of hemorrhagic stroke and seizures 2
  • Lungs, predisposing to ischemic stroke, brain abscess, dyspnea and cardiac failure 2
  • Liver, potentially causing hepatic failure in rare cases 2

Diagnosis

• Diagnosis is based on the Curaçao criteria, which include:
  • Recurrent spontaneous epistaxis
  • Multiple telangiectasias
  • Visceral lesions
  • Family history of HHT 1
• Genetic testing is recommended, particularly for asymptomatic persons from a family with known HHT 1
• The Second International HHT Guidelines recommend a comprehensive approach to diagnosis and management of HHT-related symptoms and complications 1

Clinical Impact and Management

• HHT can cause significant morbidity through chronic bleeding leading to iron deficiency anemia 1
• Epistaxis can significantly impact quality of life, causing psychosocial morbidity, social isolation, and difficulties with employment, travel, and routine daily activities 1
• Management approaches include:
  • Moisturization of nasal mucosa through air humidification and topical application of saline solution or gels 1
  • Systemic therapies including antiangiogenics and antifibrinolytics for bleeding control 1
  • Surgical interventions for severe or refractory bleeding 1
  • Iron replacement therapy for anemia 1

Distinguishing Features from Other Bleeding Disorders

• Unlike hemophilia, which is typically X-linked recessive, HHT follows an autosomal dominant inheritance pattern, affecting males and females equally 1
• Unlike von Willebrand disease, which involves defects in von Willebrand factor, HHT is caused by mutations affecting vascular integrity 3
• HHT is characterized by visible telangiectasias and vascular malformations, which are not typically seen in other bleeding disorders 4

Importance of Multidisciplinary Care

• Due to the multi-system involvement of HHT, coordinated care by specialists in multiple fields is recommended 2
• The Cure HHT Foundation has accredited centers with designated specialists for the evaluation and care of patients with HHT 2
• Screening protocols for various organ systems are essential for early detection and management of complications 2

Genetic Counseling

• Given the autosomal dominant inheritance pattern, genetic counseling is important for affected individuals and their families 1
• Prepregnancy counseling and consideration of genetic testing options are recommended for family planning 3
• Early diagnosis in family members can lead to appropriate screening and preventive measures 1, 2