What are the recommended screenings for individuals with a positive Endoglin (ENG) mutation associated with Hereditary Hemorrhagic Telangiectasia (HHT)?

Recommended Screenings for Positive ENG Mutation HHT

Mandatory Screening Protocol

All individuals with confirmed ENG (HHT type 1) mutations require comprehensive screening for pulmonary and cerebral arteriovenous malformations, as these life-threatening complications occur more frequently in HHT1 and can be treated presymptomatically to prevent stroke, cerebral abscess, and hemorrhage. 1, 2

Pulmonary AVM Screening

• Perform contrast echocardiography or chest CT as the primary screening modality for pulmonary AVMs in all ENG mutation carriers 1, 2
• Pulmonary AVMs are significantly more frequent and larger in HHT1 (75% prevalence) compared to HHT2 (44%), making this the highest-yield screening test 3
• Screen even asymptomatic children, as 25% of pediatric HHT patients have pulmonary or cerebral AVMs on initial screening, with pulmonary AVMs found in children under age 10 4
• Rescreen for pulmonary AVMs every 5 years throughout life, as this is standard practice at 89% of North American HHT Centers of Excellence 5

Cerebral AVM Screening

• Obtain brain MRI with MRA to detect cerebral vascular malformations in all ENG mutation carriers 1, 2
• Cerebral AVMs occur exclusively or predominantly in HHT1 patients (20% prevalence in HHT1 vs 0% in HHT2), representing a genotype-specific risk 3
• Rescreen children for cerebral AVMs periodically (89% of HHT centers rescreen pediatric patients), though adult rescreening is less standardized 5

Hepatic Screening

• Use Doppler ultrasonography as first-line imaging for liver involvement 1, 2
• Hepatic vascular malformations are less common in HHT1 (60%) compared to HHT2 (84%), but screening remains important 3
• Never perform liver biopsy in any patient with proven or suspected HHT due to catastrophic hemorrhage risk 6, 1, 2

Gastrointestinal Screening

• Perform upper endoscopy to evaluate for gastrointestinal telangiectasias, particularly in patients with unexplained anemia disproportionate to epistaxis severity 1
• GI bleeding manifestations are common across both HHT subtypes 3

Critical Clinical Caveats

Avoid Dangerous Procedures

• Liver biopsy is absolutely contraindicated and can lead to "hepatic disintegration" with bile duct necrosis, liver hemorrhage, cholangitis, and sepsis 6, 1
• The risk of hemorrhage from liver biopsy far outweighs any diagnostic benefit, as imaging provides superior information 6

Genotype-Phenotype Distinctions

• ENG mutations cause predominantly congenital malformations (pulmonary and cerebral AVMs) rather than acquired lesions 3
• Neurological manifestations secondary to CAVMs/PAVMs occur only in HHT1 patients, not HHT2 3
• Target ENG gene first for mutational screening when large PAVMs are present in patients under 45 years 3

Pediatric Considerations

• Begin screening in childhood, as epistaxis typically starts at mean age 11 years and visceral AVMs can be present even earlier 1, 4
• Children with only potential HHT diagnosis (1-2 Curaçao criteria without genetic confirmation) had zero AVMs on screening, emphasizing the importance of genetic testing to identify truly at-risk children 4

Pregnancy Planning

• Counsel women with ENG mutations about pregnancy risks, as hormonal and hemodynamic changes cause rapid PAVM growth with higher risk of rupture and complications from right-to-left shunting 2

Multidisciplinary Management

• Refer all patients with confirmed ENG mutations to a specialized HHT Center of Excellence for coordinated screening and management 1
• Provide genetic counseling given the 50% inheritance risk for each child of an affected parent 1