What are the management and treatment options for patients with Hereditary Hemorrhagic Telangiectasia (HHT) and potential mutations in the Endoglin (ENG) and SMAD4 genes?

Management of HHT with ENG and SMAD4 Mutations

Patients with HHT and mutations in ENG (HHT type 1) or SMAD4 (juvenile polyposis-HHT overlap) require distinct screening protocols and management strategies, with SMAD4 patients needing aggressive gastrointestinal surveillance starting at age 18 and all patients requiring comprehensive screening for life-threatening arteriovenous malformations. 1, 2

Genetic Testing and Diagnosis

• Apply 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
• Perform genetic testing targeting ENG, ACVRL1, and SMAD4 genes, which identifies causative mutations in 97% of patients with definite clinical HHT 1, 2
• Prioritize genetic testing for asymptomatic individuals from families with known HHT to enable early screening and preventive treatment 2
• Include SMAD4 testing in the initial panel, particularly when juvenile polyposis features coexist or when gastrointestinal symptoms are prominent 2

ENG (HHT Type 1) Specific Screening Requirements

Pulmonary Screening

• Screen 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
• Treat pulmonary AVMs presymptomatically to prevent life-threatening complications including stroke, cerebral abscess, and paradoxical emboli 2, 3
• Recognize that 70-90% of patients with PAVMs have HHT, making HHT1 a predominant cause 3

Cerebral Screening

• Perform MRI of the brain to detect cerebral vascular malformations, which occur more commonly in HHT1 patients compared to HHT2 2, 3

Hepatic Screening

• Use Doppler ultrasonography as first-line imaging for liver involvement, though hepatic vascular malformations are less common in HHT1 than HHT2 2, 3
• Never perform liver biopsy in any patient with proven or suspected HHT due to high hemorrhage risk 1, 2, 3

Clinical Phenotype

• Expect symptom onset around age 30, with epistaxis typically starting at mean age 11 years 3

SMAD4 (Juvenile Polyposis-HHT Overlap) Specific Management

Critical Distinction

• Recognize 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
• Understand that SMAD4 mutation carriers may lack overt clinical symptoms of HHT but remain at risk of asymptomatic AVMs requiring screening 2

Gastrointestinal Surveillance

• Initiate upper GI tract surveillance every 1-3 years starting at age 18 years (earlier than the age 25 recommended for BMPR1A mutations) 2
• Recognize that SMAD4 carriers have significantly higher risk of severe gastric polyposis, and all gastric cancers in one cohort occurred exclusively in SMAD4 carriers 2
• Perform upper endoscopy to evaluate for gastrointestinal telangiectasias, especially in patients with unexplained anemia disproportionate to epistaxis severity 2
• Failure to screen for juvenile polyposis in SMAD4-positive HHT patients leads to missed gastrointestinal cancers 2

AVM Screening for SMAD4

• Screen for pulmonary AVMs using contrast echocardiography or chest CT, as these create right-to-left shunts causing hypoxemia and risk of paradoxical emboli leading to stroke or brain abscess 2
• Screen for cerebral, hepatic, and spinal AVMs, as these develop in multiple organ systems 2
• Screen for retinal AVMs 2

Specialized Management

• Manage all SMAD4 mutation carriers in conjunction with a specialist HHT center with experience in evaluating and managing both HHT and juvenile polyposis complications 2

Universal Management Approach for Both ENG and SMAD4

Epistaxis Management Algorithm

• Begin with nasal moisturization as first-line therapy 1, 2
• Escalate to oral tranexamic acid if moisturization is inadequate, which reduces epistaxis duration by 17.3% and composite epistaxis endpoints by 54% 2
• Proceed to local ablative therapies if tranexamic acid fails 2
• Reserve systemic bevacizumab for refractory cases failing all other interventions, which produces a 50% reduction in epistaxis severity score 2

Gastrointestinal Bleeding Management

• Apply the same stepwise approach: tranexamic acid first, then bevacizumab for refractory cases 2

Anemia Management

• Implement iron replacement therapy and monitoring for all patients with recurrent bleeding 2

Procedural Precautions

• Use resorbable packing materials for epistaxis management to reduce the risk of rebleeding during packing removal 2
• Avoid invasive liver therapies including liver transplantation unless patients have failed intensive medical therapy 2

Multidisciplinary Care

• Refer all patients diagnosed with HHT to a multidisciplinary team with expertise in HHT management 2

Important Clinical Caveats

• Recognize that treatment decisions should prioritize quality of life, not just hemoglobin levels, as epistaxis causes significant psychosocial morbidity, social isolation, and employment difficulties 2
• Be aware that pregnancy poses particular risk as hormonal and hemodynamic changes cause rapid PAVM growth with higher risk of complications 3
• Understand that liver involvement is generally asymptomatic but when symptomatic can cause substantial morbidity and mortality 2
• Note that gender differences exist, with hepatic vascular malformations being more common and symptomatic in females 2