What is the management approach for a patient with a suspected or identified eng (engrailed) mutation?

Management of ENG (Endoglin) Mutation

Patients with suspected or confirmed ENG mutations should undergo genetic counseling and screening for hereditary hemorrhagic telangiectasia (HHT), followed by systematic evaluation for vascular malformations in multiple organ systems, particularly pulmonary, cerebral, and hepatic arteriovenous malformations (AVMs), as ENG mutations are a causative gene for HHT and require surveillance to prevent life-threatening complications.

Genetic Testing and Diagnosis

When to Test for ENG Mutations:

• Genetic testing for ENG should be performed when BMPR2 mutations are not identified in patients with familial pulmonary arterial hypertension (PAH), in patients with idiopathic PAH who are ≤40 years old, or when PAH occurs with personal or familial history of hereditary hemorrhagic telangiectasia 1
• Testing should be conducted by certified diagnostic laboratories with expertise in interpreting cardiomyopathy and vascular disorder-related mutations 1
• In patients with diffuse liver AVMs who do not meet clinical diagnostic criteria for HHT, genetic testing for ENG (along with ALK-1) can assist in establishing an HHT diagnosis 1

Clinical Evaluation After ENG Mutation Identification

Screening for Vascular Malformations:

• Patients with confirmed ENG mutations require systematic screening for arteriovenous malformations, as these are the primary cause of morbidity and mortality in HHT 1
• Pulmonary AVMs: Screen with chest imaging, as these can cause stroke, brain abscess, or hemorrhage through paradoxical embolization 1
• Cerebral AVMs: Evaluate for risk of intracerebral hemorrhage, which is part of the clinical spectrum of HHT 1
• Hepatic vascular malformations: Assess using Doppler ultrasonography (looking for enlarged hepatic artery and intrahepatic hypervascularization) or multiphase CT (showing markedly dilated hepatic artery and diffuse telangiectases) 1

Important Caveat: Screening for liver vascular malformations in asymptomatic HHT patients is NOT recommended, as prevalence is high and there is no effective treatment for asymptomatic lesions; screening should only occur when liver involvement would establish "definite" HHT diagnosis or in research contexts 1

Cascade Family Screening

When ENG mutation is confirmed in a proband:

• Offer cascade genetic testing to all at-risk relatives to identify mutation carriers who require clinical surveillance 1
• First-degree relatives should be tested first; if unavailable or unwilling, extend testing to more distant relatives 1
• Relatives who test negative for the family mutation can be discharged from follow-up but should be advised to seek reassessment if symptoms develop 1
• For children, consider whether clinical evaluation may precede genetic testing based on parental consent and the child's best interests 1

Monitoring and Management Approach

For Confirmed ENG Mutation Carriers:

• Monitor for epistaxis (recurrent nosebleeds), which is a hallmark clinical feature of HHT 1
• Assess for cutaneous or mucosal telangiectases on physical examination 1
• Evaluate for high-output heart failure resulting from arteriohepatic and/or portohepatic shunting in patients with hepatic involvement 1
• Monitor for portal hypertension from arterioportal shunting or nodular regenerative hyperplasia, noting that liver synthetic function and platelet count typically remain normal as these patients do not have cirrhosis 1
• Watch for biliary complications from peribiliary plexus shunting causing biliary ischemia 1

Critical Pitfall: Do not perform liver biopsy for diagnosis of vascular malformations in HHT—it is often misinterpreted, provides less information than imaging, and may be dangerous 1

Genetic Counseling Requirements

• Trained professionals must offer genetic counseling following strict local regulations regarding molecular genetic diagnosis 1
• Counseling should address the autosomal dominant inheritance pattern, 50% transmission risk to offspring, and implications for family members 1
• Discuss the strong possibility of carrying disease-causing mutations in patients with sporadic or familial PAH or pulmonary veno-occlusive disease 1
• Ensure patients understand the process, risks, and benefits of genetic testing without external pressures to preserve autonomy 1