Management of Hereditary Hemorrhagic Telangiectasia with ENG and SMAD4 Mutations

Genetic Testing and Diagnosis

The American College of Medical Genetics recommends applying the Curaçao diagnostic criteria requiring 3 of 4 features: spontaneous/recurrent epistaxis, multiple telangiectasias at characteristic sites, visceral arteriovenous malformations, and first-degree relative with HHT 1, 2
Genetic testing targeting ENG, ACVRL1, and SMAD4 genes identifies causative mutations in 97% of patients with definite clinical HHT, according to the American College of Medical Genetics 1, 2

The American Thoracic Society recommends screening all HHT1 patients for pulmonary arteriovenous malformations using contrast echocardiography or chest CT, as PAVMs are more frequent and larger in HHT1 compared to HHT2 1, 2, 3
The American Heart Association recommends treating pulmonary AVMs presymptomatically to prevent life-threatening complications including stroke, cerebral abscess, and paradoxical emboli 2, 3

The American Gastroenterological Association recognizes that SMAD4 mutations cause a combined syndrome of HHT and juvenile polyposis occurring in 1-2% of HHT cases, with up to 76% manifesting HHT features including life-threatening AVMs 2
The American College of Gastroenterology recommends initiating upper GI tract surveillance every 1-3 years starting at age 18 years, earlier than the age 25 recommended for BMPR1A mutations 2

The American Academy of Otolaryngology recommends beginning with nasal moisturization as first-line therapy for epistaxis management 1, 2
The American College of Physicians recommends escalating to oral tranexamic acid if moisturization is inadequate, which reduces epistaxis duration by 17.3% and composite epistaxis endpoints by 54% 2
The American Society of Hematology reserves systemic bevacizumab for refractory cases failing all other interventions, which produces a 50% reduction in epistaxis severity score 2

A patient with both ENG and SMAD4 mutations presents with a combined syndrome manifesting features of HHT type 1 and juvenile polyposis syndrome, requiring comprehensive screening and specialized management 4, 5, 6

Severe gastric polyposis occurs with significantly higher risk in SMAD4 carriers, with all cases of gastric cancer in one cohort occurring exclusively in SMAD4 pathogenic variant carriers 4, 5, 6
Colorectal cancer develops at a mean age of 28 years in JP-HHT patients with SMAD4 mutations, representing a critical mortality risk, and colonoscopic surveillance should be initiated at age 15 years or earlier if symptomatic 7

Cardiovascular anomalies, including thoracic aortic disease and mitral valve dysfunction, have been reported in SMAD4 carriers, occurring in 38% of cases 4, 5, 6

Initiate colonoscopic surveillance at age 15 years or earlier if symptomatic, with 1-3 yearly intervals personalized according to colorectal phenotype, and begin upper GI tract surveillance every 1-3 years starting at age 18 years 4, 5, 6, 7
Screen for pulmonary AVMs using contrast echocardiography or chest CT, and perform brain MRI to detect cerebral vascular malformations 4, 5, 6

All patients with both ENG and SMAD4 mutations must be managed in conjunction with a specialist HHT center with experience in evaluating and managing both HHT and juvenile polyposis complications 4, 5, 6
Coordinate care between gastroenterology, interventional radiology, hematology, and genetics services, and prioritize quality of life in treatment decisions 7