How to manage Hereditary Hemorrhagic Telangiectasia (HHT) without an Endoglin (ENG) mutation?

Management of HHT Without ENG Mutation

Patients with clinically definite HHT but no ENG mutation should undergo comprehensive genetic testing for ACVRL1, SMAD4, and GDF2 mutations, followed by mutation-specific screening protocols and stepwise treatment of bleeding manifestations regardless of genetic subtype. 1, 2

Genetic Testing Strategy

When ENG testing is negative in a patient meeting Curaçao criteria (3 of 4 features: epistaxis, telangiectasias, visceral AVMs, affected first-degree relative), proceed with:

• Simultaneous sequencing and deletion/duplication analysis of ACVRL1 (HHT type 2), which accounts for approximately 43% of HHT families and identifies causative mutations in the majority of ENG-negative cases 2
• SMAD4 testing to identify juvenile polyposis-HHT overlap syndrome, occurring in 1-2% of HHT cases but carrying substantially higher gastrointestinal cancer risk 2, 3
• GDF2 testing as part of the comprehensive panel, as mutations in ENG, ACVRL1, SMAD4, and GDF2 collectively identify 97% of clinically definite HHT cases 1, 2
• Consider expanded genetic testing for SMAD6, INHA, HIF1A, JAK2, DNM2, POSTN, ANGPTL4, and FOXO1 if standard four-gene panel is negative, as these represent putative drivers in the 8% of HHT patients with unknown genetic etiology 4

Mutation-Specific Screening Protocols

For ACVRL1 (HHT Type 2) Mutations:

• Prioritize liver screening with Doppler ultrasonography as hepatic vascular malformations are substantially more common and symptomatic in HHT2, with marked female predominance 2, 5
• Screen for pulmonary AVMs using contrast echocardiography or chest CT, though PAVMs are less frequent and smaller compared to HHT1 2, 5
• Perform brain MRI for cerebral AVM screening, as these occur less commonly in HHT2 than HHT1 5
• Never perform liver biopsy due to catastrophic hemorrhage risk from vascular malformations 1, 2

For SMAD4 Mutations (Juvenile Polyposis-HHT Overlap):

• Initiate upper GI tract surveillance every 1-3 years starting at age 18 years (earlier than age 25 for BMPR1A mutations) due to 73% prevalence of gastric polyposis 2, 3
• Recognize the critical cancer risk: all gastric cancers in one cohort occurred exclusively in SMAD4 carriers, making intensive surveillance mandatory 2, 3
• Screen for pulmonary AVMs immediately as up to 76% of SMAD4 carriers manifest HHT features including life-threatening AVMs 2, 3
• Perform brain MRI to detect cerebral vascular malformations, as nearly one in five HHT patients develop stroke or cerebral abscess 3
• Mandate management through a specialized HHT center with experience in both HHT and juvenile polyposis complications 2, 3

For Genetically Unresolved Cases:

• Apply full HHT screening protocols as if mutation-positive, since clinical diagnosis using Curaçao criteria is sufficient to warrant comprehensive organ screening 1, 2
• Screen all organ systems: pulmonary AVMs (contrast echo or chest CT), cerebral AVMs (brain MRI), hepatic involvement (Doppler ultrasound), and GI telangiectasias (endoscopy if anemia disproportionate to epistaxis) 2

Universal Treatment Algorithm (Regardless of Genetic Subtype)

Epistaxis Management (Stepwise Escalation):

1. Begin with nasal moisturization: air humidification and topical saline solution or gels to prevent mucosal cracking, though often inadequate as monotherapy 2, 3

2. Escalate to oral tranexamic acid when moisturization fails, which reduces epistaxis duration by 17.3% and composite epistaxis endpoints by 54% 2, 3

3. Proceed to local ablative therapies (laser photocoagulation, cauterization) for refractory bleeding, using resorbable packing materials to reduce rebleeding risk during removal 2

4. Reserve systemic bevacizumab for severe refractory cases failing all prior interventions, producing 50% reduction in epistaxis severity score 2, 3

Gastrointestinal Bleeding:

• Apply the same stepwise approach: tranexamic acid first, then bevacizumab for refractory cases 2
• Implement iron replacement therapy and monitor for anemia in all patients with recurrent bleeding 2

Pulmonary AVM Management:

• Perform percutaneous transcatheter embolization for all pulmonary AVMs regardless of feeding artery size, as they create right-to-left shunts causing paradoxical emboli leading to stroke or brain abscess 2
• Treat presymptomatically to prevent life-threatening complications including stroke and cerebral abscess 3, 5

Hepatic Involvement:

• Avoid invasive therapies including liver transplantation unless intensive medical therapy has failed, as most hepatic involvement is asymptomatic 2
• Grade liver involvement (0-4) based on hepatic artery diameter, peak flow velocity, resistivity index, and peripheral hepatic hypervascularization 2

Critical Clinical Pitfalls

• Never rely on genetic testing alone for diagnosis: clinical Curaçao criteria remain the diagnostic foundation, and negative genetic testing does not exclude HHT 1, 2
• Do not perform liver biopsy in any patient with proven or suspected HHT due to high hemorrhage risk 1, 2, 3
• Avoid focusing solely on hemoglobin levels: treatment decisions should prioritize quality of life, as epistaxis causes significant psychosocial morbidity, social isolation, and employment difficulties 2
• Do not miss SMAD4-associated gastrointestinal cancer risk: failure to screen for juvenile polyposis in SMAD4-positive patients leads to missed gastric cancers 2, 3
• Recognize pregnancy risks: hormonal and hemodynamic changes cause rapid PAVM growth with higher complication risk from lack of filtration and rupture 5

Multidisciplinary Coordination

• Refer all diagnosed HHT patients to a specialized HHT center with expertise in managing vascular malformations across multiple organ systems 2
• Provide genetic counseling given the 50% inheritance risk for each child of an affected parent, allowing early screening and preventive measures in family members 2
• Begin pediatric screening for pulmonary and cerebral AVMs in childhood, as epistaxis typically starts at mean age 11 years 2, 5