Are Arteriovenous Malformations (AVMs) hereditary?

Are AVMs Hereditary?

Most AVMs are sporadic (non-hereditary), but approximately 10-30% occur in the context of known genetic syndromes, most notably hereditary hemorrhagic telangiectasia (HHT). 1

Hereditary Forms of AVMs

Hereditary Hemorrhagic Telangiectasia (HHT)

• HHT accounts for 70-90% of patients with pulmonary AVMs and is associated with multiple AVMs throughout the body 1
• HHT is an autosomal dominant disorder caused by mutations in specific genes 1:
  • ENG gene mutations → HHT type 1 (associated with cerebral and pulmonary AVMs) 1
  • ALK1 (ACVRL1) gene mutations → HHT type 2 (associated with pulmonary hypertension and hepatic AVMs) 1
  • SMAD4 gene mutations → HHT with juvenile polyposis syndrome (1-2% of HHT cases) 1
• Children with genetically confirmed HHT show high prevalence of AVMs: cerebrovascular malformations in 16%, pulmonary AVMs in 45%, and liver AVMs in 52% 2
• Genetic testing can confirm diagnosis even in individuals with only a single symptom (such as nosebleeds alone), with nearly 50% of single-symptom cases having confirmed mutations 3

Capillary Malformation-AVM (CM-AVM) Syndrome

• Caused by RASA1 gene mutations 1
• Represents a distinct hereditary form separate from HHT 1

Familial AVMs Without Defined Syndrome

• Familial AVMs have been described in families without HHT or other specific genetic conditions 1
• This suggests additional, yet-to-be-identified hereditary patterns 1

Sporadic (Non-Hereditary) AVMs

Genetic Factors in Sporadic Cases

• The majority of brain AVMs (50-60%) demonstrate somatic mutations in RAS-related genes (BRAF, KRAS, MAPK) 1
• These are acquired mutations, not inherited, occurring during development 1, 4
• Current evidence suggests AVMs require both genetic predisposition and a "second hit" for formation 4

Evidence Against Purely Congenital Origin

• AVM recurrence after complete surgical resection occurs in pediatric patients but not adults, suggesting AVMs may not be strictly congenital lesions 1
• Pediatric AVMs express higher vascular endothelial growth factor than adult AVMs, potentially explaining their ability to recur and evolve 1
• The discovery of de novo AVM cases has challenged the traditional doctrine that all AVMs are congenital 4

Clinical Implications for Screening

When to Consider Hereditary Evaluation

• Multiple AVMs in the same individual (relatively common finding) 1
• Family history of AVMs or HHT-related symptoms (epistaxis, telangiectasias, visceral AVMs) 1
• Presence of AVMs in multiple organ systems (brain, lungs, liver, GI tract) 1
• Pediatric presentation, particularly with multiple lesions 2

Screening Recommendations for HHT

• Comprehensive clinical-radiological screening protocol is advisable for children with confirmed HHT, independent of symptoms 2
• Screening should include evaluation for cerebral, pulmonary, and hepatic AVMs 2
• Large AVMs are associated with symptoms and complications in childhood, while small AVMs likely carry no clinical risk 2

Important Caveats

• The presence of a single brain AVM does not automatically indicate hereditary disease 1
• Genetic testing should be considered when clinical features suggest HHT (Curacao criteria) or when multiple AVMs are present 1, 3
• Early molecular diagnosis provides opportunity for early AVM detection and prevention of complications 3
• Sporadic AVMs likely result from complex interactions between genetic susceptibility and environmental/developmental factors 4