Does an ENG (Endoglin) missense variant plus a large venous varix indicate a diagnosis of Hereditary Hemorrhagic Telangiectasia (HHT)?

Does an ENG Missense Variant Plus Large Venous Varix Indicate HHT?

An ENG missense variant alone with a large venous varix is insufficient to diagnose HHT—you must apply the Curaçao criteria and determine if the patient meets at least 3 of 4 clinical features (epistaxis, telangiectasias, visceral AVMs, or affected first-degree relative) for a definite diagnosis. 1

Critical Diagnostic Framework

The Curaçao Criteria Are Paramount

The diagnosis of HHT is primarily clinical, not genetic. 1, 2 You need to systematically assess:

• Spontaneous and recurrent epistaxis (present in >90% of adults with HHT) 1
• Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose) 1
• Visceral lesions: pulmonary AVMs, hepatic AVMs, cerebral AVMs, spinal AVMs, or GI telangiectasias 1
• First-degree relative with HHT diagnosed by these same criteria 1

Definite HHT requires 3 criteria; possible/suspected HHT requires 2 criteria; unlikely with fewer than 2. 1

Why Genetic Testing Alone Is Insufficient

While ENG mutations cause HHT type 1, several critical caveats apply:

• Not all ENG variants are pathogenic—missense variants require functional analysis to determine disease causation, as approximately 6% of identified variants are of unknown significance 3
• Genetic testing identifies mutations in only 87% of patients who meet all 4 Curaçao criteria, meaning 13% of clinically definite HHT patients have no identifiable mutation 3
• The highest mutation detection rate (87%) occurs only in probands meeting all 4 clinical criteria, dropping substantially in those with fewer clinical features 3

The Venous Varix Problem

A "large venous varix" is not a recognized HHT manifestation in the diagnostic criteria. HHT causes:

• Arteriovenous malformations (direct artery-to-vein connections bypassing capillaries) 4, 5
• Telangiectasias (small mucocutaneous vascular lesions) 1

Isolated venous varices without arteriovenous shunting do not fit the HHT vascular phenotype. 4 This raises concern that either:

1. The lesion is being mischaracterized and is actually an AVM
2. The patient has a different vascular disorder
3. This is an incidental finding unrelated to the ENG variant

Algorithmic Approach to This Patient

Step 1: Verify Clinical Criteria

Systematically document presence/absence of:

• Recurrent spontaneous epistaxis (mean onset age 11 years) 6
• Mucocutaneous telangiectasias on lips, tongue, fingers, face 1
• Family history of HHT in parents, siblings, or children 1

Step 2: Screen for Visceral AVMs

Since this patient has an ENG variant (HHT type 1 if pathogenic), prioritize:

• Pulmonary AVM screening with contrast echocardiography or chest CT—PAVMs are more frequent and larger in HHT1 6
• Cerebral AVM screening with brain MRI—cerebral AVMs occur more commonly in HHT1 6
• Liver screening with Doppler ultrasonography (though less common in HHT1 than HHT2) 6

Never perform liver biopsy due to hemorrhage risk. 1, 6

Step 3: Characterize the "Venous Varix"

Obtain detailed vascular imaging to determine if this represents:

• An arteriovenous malformation with venous outflow dilation (consistent with HHT)
• A true isolated venous varix (not consistent with HHT)
• Hepatic vascular shunting (arteriohepatic, arterioportal, or portohepatic) 4

Step 4: Assess Variant Pathogenicity

The ENG missense variant requires evaluation for:

• Prior reporting in HHT databases as pathogenic/likely pathogenic
• Functional consequences through in silico prediction tools 3
• Segregation with disease in family members if available 7

Important caveat: Even novel ENG variants in the promoter region can be pathogenic through transcriptional dysregulation, so location and functional analysis matter. 7

Clinical Decision Points

If the patient meets ≥3 Curaçao criteria: Diagnose definite HHT regardless of genetic testing results, as 13% of clinically definite cases have no identifiable mutation. 3

If the patient meets 2 Curaçao criteria: Diagnose possible HHT and pursue genetic confirmation, but recognize that the missense variant's pathogenicity must be established. 1

If the patient meets <2 Curaçao criteria: The diagnosis is unlikely even with an ENG variant, as the variant may be of unknown significance or the patient may be a non-penetrant carrier. 1, 3

Management Implications

If HHT is confirmed or strongly suspected:

• Refer to multidisciplinary HHT center for comprehensive management 1
• Screen asymptomatic family members given 50% inheritance risk 1
• Implement presymptomatic PAVM treatment to prevent stroke and cerebral abscess (critical in HHT1) 6
• Initiate iron replacement and monitor for anemia from bleeding 1
• Avoid invasive liver procedures including biopsy 1, 6

The presence of an ENG variant does not establish HHT diagnosis—clinical phenotype determines diagnosis, and genetic testing serves to confirm and enable family screening. 1, 2