What is the recommended management plan for a patient with ENG (Endoglin) and SMAD4 genetic mutations and only two of the Curaçao criteria for hereditary hemorrhagic telangiectasia (HHT)?

Management of ENG and SMAD4 Mutations with Only Two Curaçao Criteria

Definitive Diagnosis Despite Incomplete Clinical Criteria

A patient with confirmed pathogenic mutations in ENG and/or SMAD4 genes should be diagnosed with HHT and managed accordingly, even with only two Curaçao criteria present, because genetic testing identifies causative mutations in 97% of patients with definite clinical HHT and the presence of a pathogenic variant is diagnostic regardless of clinical presentation. 1

The Curaçao criteria were designed as a clinical diagnostic tool before widespread genetic testing availability. While three criteria are traditionally required for "definite" clinical diagnosis and two criteria indicate "possible/suspected" HHT, the presence of a confirmed pathogenic mutation in ENG or SMAD4 supersedes clinical criteria because these mutations are highly specific for HHT. 1, 2

Critical Distinction: ENG vs SMAD4 Mutations

The management pathway diverges significantly based on which gene is mutated:

For ENG (HHT Type 1) Mutations:

• Immediate pulmonary AVM screening is mandatory using contrast echocardiography or chest CT, as PAVMs are more frequent and larger in HHT1 and can be treated presymptomatically to prevent stroke, cerebral abscess, and paradoxical emboli. 3, 4

• Cerebral AVM screening with brain MRI is required given the higher frequency of cerebral vascular malformations in HHT1 patients. 3

• Liver screening with Doppler ultrasonography should be performed, though hepatic involvement is less common in HHT1 than HHT2. 3

• Never perform liver biopsy due to catastrophic hemorrhage risk in any HHT patient. 1, 3

For SMAD4 (Juvenile Polyposis-HHT Overlap) Mutations:

• All SMAD4 patients require comprehensive HHT screening plus juvenile polyposis surveillance, as up to 76% manifest HHT features and 81-95% develop the overlap syndrome. 5, 4, 6

• Upper GI tract surveillance must begin at age 18 years (not age 25), performed every 1-3 years, because SMAD4 carriers have significantly higher risk of severe gastric polyposis (73% vs 8%) and all gastric cancers in reported cohorts occurred exclusively in SMAD4 carriers. 5, 4

• Mandatory pulmonary AVM screening with contrast echocardiography or chest CT, as patients may lack overt HHT symptoms but remain at risk of asymptomatic AVMs causing life-threatening complications. 5, 4

• Cerebral AVM screening with brain MRI to detect asymptomatic brain AVMs that can cause stroke or hemorrhage. 1

• Referral to specialist HHT center is essential, as SMAD4 patients require coordinated management of both HHT vascular complications and gastrointestinal polyposis/cancer risk. 5, 4

Universal Management for Both Genotypes

Epistaxis Management Algorithm:

1. First-line: Nasal moisturization with saline sprays or emollients. 1, 4

2. Second-line: Oral tranexamic acid if moisturization inadequate, which reduces epistaxis duration by 17.3% and composite endpoints by 54%. 1, 4

3. Third-line: Local ablative therapies (laser, cautery) for persistent bleeding. 1

4. Fourth-line: Systemic bevacizumab reserved for refractory cases failing all other interventions, producing 50% reduction in epistaxis severity. 1, 4

Iron Deficiency and Anemia Management:

• Iron replacement therapy should be implemented for all patients with recurrent bleeding, as chronic blood loss is nearly universal. 1

• Monitor hemoglobin regularly, but treatment decisions should prioritize quality of life impacts (psychosocial morbidity, social isolation, employment difficulties) rather than hemoglobin levels alone. 1

Common Pitfalls to Avoid

• Failing to screen asymptomatic mutation carriers: Patients with confirmed genetic mutations may lack overt clinical symptoms but remain at risk of life-threatening asymptomatic AVMs, particularly pulmonary and cerebral malformations. 5, 4

• Delaying GI surveillance in SMAD4 patients: All gastric cancers in one cohort occurred exclusively in SMAD4 carriers, making early and regular upper GI surveillance critical starting at age 18. 5

• Performing liver biopsy: This is absolutely contraindicated in any patient with proven or suspected HHT due to high hemorrhage risk. 1, 3

• Missing the juvenile polyposis component in SMAD4: Nearly all SMAD4 patients (81-95%) develop the overlap syndrome, requiring both HHT and polyposis management. 6

• Inadequate family screening: As an autosomal dominant condition, each child has 50% inheritance risk, requiring genetic counseling and cascade testing of at-risk relatives. 1

Age-Related Screening Considerations

• Pediatric screening should begin in childhood for pulmonary and cerebral AVMs, as epistaxis typically starts at mean age 11 years and symptoms appear around age 30. 1, 3

• SMAD4 upper GI surveillance begins at age 18, earlier than the age 25 recommended for BMPR1A mutations in isolated juvenile polyposis. 5, 4