What is the management approach for Hereditary Hemorrhagic Telangiectasia (HHT) symptoms in individuals with heterozygous Endoglin (ENG) and SMAD4 mutations?

Management of HHT Symptoms in Heterozygous ENG and SMAD4 Mutation Carriers

Patients with heterozygous mutations in both ENG and SMAD4 require immediate comprehensive screening for arteriovenous malformations across all organ systems and intensive gastrointestinal surveillance starting at age 18, coordinated through a specialized HHT center. 1, 2

Critical Recognition of Dual Mutation Syndrome

• This represents an exceptionally rare scenario combining HHT type 1 (ENG) with juvenile polyposis-HHT overlap syndrome (SMAD4), occurring in only 1-2% of HHT cases, with up to 76% manifesting life-threatening arteriovenous malformations 1, 2
• SMAD4 mutations cause combined HHT and juvenile polyposis features, with 73% prevalence of gastric polyposis and exclusive occurrence of all gastric cancers in SMAD4 carriers in one cohort 1, 2
• ENG mutations result in more frequent and larger pulmonary AVMs compared to other HHT types, with 70-90% of patients with pulmonary AVMs having HHT 3

Mandatory Immediate Screening Protocol

Pulmonary AVM Screening (Priority #1)

• Perform contrast echocardiography or chest CT immediately upon diagnosis to detect pulmonary arteriovenous malformations, as these are more frequent and larger in HHT1 and create right-to-left shunts causing paradoxical emboli leading to stroke or brain abscess 1, 2, 3
• Treat all identified pulmonary AVMs presymptomatically with percutaneous transcatheter embolization regardless of feeding artery size due to paradoxical embolism risk 1
• Nearly one in five HHT patients develop stroke or cerebral abscess, making this screening life-saving 1

Cerebral AVM Screening (Priority #2)

• Obtain brain MRI to detect cerebral vascular malformations, as cerebral AVMs occur more commonly in HHT1 (ENG mutations) 1, 2, 3
• Cerebral AVMs can cause life-threatening hemorrhage or stroke even when asymptomatic 1

Gastrointestinal Surveillance (Priority #3 - SMAD4-Specific)

• Initiate upper GI tract surveillance every 1-3 years starting at age 18 years (earlier than the age 25 recommended for BMPR1A mutations alone) due to SMAD4 carrier status 1, 2
• This intensive surveillance is critical because all gastric cancers in one cohort occurred exclusively in SMAD4 pathogenic variant carriers 1
• Perform upper endoscopy to evaluate for both juvenile polyps and gastrointestinal telangiectasias 1

Hepatic Screening (Lower Priority)

• Perform Doppler ultrasonography as first-line imaging for liver involvement, though hepatic vascular malformations are less common in HHT1 than HHT2 1, 2, 3
• Never perform liver biopsy under any circumstances due to catastrophic hemorrhage risk from vascular malformations 1, 2, 3

Stepwise Management of Bleeding Manifestations

Epistaxis Management Algorithm

• Step 1: Begin with nasal moisturization as first-line therapy for all patients with epistaxis 1, 2
• Step 2: Escalate to oral tranexamic acid if moisturization inadequate, which reduces epistaxis duration by 17.3% and composite epistaxis endpoints by 54% 1, 2
• Step 3: Proceed to local ablative therapies if tranexamic acid fails 1
• Step 4: Reserve systemic bevacizumab for refractory cases failing all other interventions, which produces 50% reduction in epistaxis severity score 1, 2

Gastrointestinal Bleeding Management

• Apply the same stepwise approach: tranexamic acid first, then bevacizumab for refractory cases 1
• Monitor complete blood count regularly to assess anemia severity 1
• Implement iron replacement therapy for all patients with recurrent bleeding 1

Critical Coordination Requirement

• All patients with SMAD4 pathogenic variants must be managed in conjunction with a specialist HHT center with experience in evaluating and managing both HHT and juvenile polyposis complications 1, 2
• Refer to multidisciplinary team with expertise in HHT management for coordinated care across multiple organ systems 1
• Failure to coordinate through specialized centers leads to missed gastrointestinal cancers and inadequate AVM surveillance 1

Treatment Decision Framework

• Prioritize quality of life over hemoglobin levels alone when making treatment decisions, as chronic bleeding causes significant psychosocial morbidity, social isolation, employment difficulties, and impacts routine daily activities 1
• Symptoms typically appear around age 30, with epistaxis starting at mean age 11 years, requiring lifelong surveillance 3
• Pregnancy poses particular risk as hormonal and hemodynamic changes cause rapid pulmonary AVM growth with higher complication risk 3

Common Pitfalls to Avoid

• Never delay pulmonary AVM screening - asymptomatic AVMs can cause life-threatening stroke or cerebral abscess without warning 1, 2
• Never perform liver biopsy in proven or suspected HHT due to hemorrhage risk 1, 2, 3
• Never start GI surveillance at age 25 for SMAD4 carriers - must begin at age 18 due to higher gastric cancer risk 1, 2
• Never manage these patients without specialized HHT center involvement - the complexity of dual mutation syndrome requires expert coordination 1, 2