Hereditary and Sporadic Arteriovenous Malformations (AVMs)

Introduction to AVMs

Most AVMs are sporadic, but approximately 10-30% occur in the context of known genetic syndromes, most notably hereditary hemorrhagic telangiectasia (HHT), according to the American Heart Association 1, 2, 3, 4

HHT accounts for 70-90% of patients with pulmonary AVMs and is associated with multiple AVMs throughout the body, as stated by the American College of Radiology 5
HHT is an autosomal dominant disorder caused by mutations in specific genes, including ENG, ALK1 (ACVRL1), and SMAD4, as reported by the American College of Radiology and the Journal of Neurointerventional Surgery 1, 5
ENG gene mutations are associated with HHT type 1, which is linked to cerebral and pulmonary AVMs, according to the Journal of Neurointerventional Surgery and the American College of Radiology 1, 5
ALK1 (ACVRL1) gene mutations are associated with HHT type 2, which is linked to pulmonary hypertension and hepatic AVMs, as stated by the Journal of Neurointerventional Surgery and the American College of Radiology 1, 5
SMAD4 gene mutations are associated with HHT with juvenile polyposis syndrome, occurring in 1-2% of HHT cases, according to the Journal of Neurointerventional Surgery and the American College of Radiology 1, 5
Capillary Malformation-AVM (CM-AVM) Syndrome is caused by RASA1 gene mutations and represents a distinct hereditary form separate from HHT, as reported by the Journal of Neurointerventional Surgery 1

The majority of brain AVMs (50-60%) demonstrate somatic mutations in RAS-related genes (BRAF, KRAS, MAPK), which are acquired mutations occurring during development, according to the Journal of Neurointerventional Surgery 1
AVM recurrence after complete surgical resection occurs in pediatric patients but not adults, suggesting AVMs may not be strictly congenital lesions, as stated by the American Heart Association 2, 3, 4

Multiple AVMs in the same individual, family history of AVMs or HHT-related symptoms, and presence of AVMs in multiple organ systems are indications for hereditary evaluation, as recommended by the American Stroke Association and the American College of Radiology 6, 2, 3, 4, 7, 5
The presence of a single brain AVM does not automatically indicate hereditary disease, but genetic testing should be considered when clinical features suggest HHT or when multiple AVMs are present, according to the American College of Radiology and the Journal of Neurointerventional Surgery 6, 2, 3, 4, 5