Can HHT Occur Without Identifiable Genetic Mutations?
Yes, it is possible to have clinically definite HHT without an identifiable genetic mutation—approximately 3-13% of patients meeting strict Curaçao criteria test negative for mutations in known HHT genes, but this does NOT exclude the diagnosis, which remains fundamentally clinical. 1, 2
Diagnostic Foundation: Clinical Criteria Trump Genetic Testing
The diagnosis of HHT is primarily clinical, not genetic—the Curaçao criteria remain the diagnostic gold standard regardless of genetic test results. 1, 3 A definite clinical diagnosis requires 3 of 4 features:
- Spontaneous and recurrent epistaxis 1
- Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose) 1
- Visceral arteriovenous malformations (pulmonary, hepatic, cerebral, or GI) 1
- First-degree relative with HHT 1
Critical principle: Negative genetic testing does NOT exclude HHT if clinical criteria are met. 1
Genetic Testing Limitations and Detection Rates
Current genetic testing identifies causative mutations in approximately 97% of patients with clinically definite HHT (meeting all 4 Curaçao criteria), but this leaves 3% unexplained. 1, 4 The detection rate drops substantially when fewer clinical criteria are present:
- 87% detection rate in probands meeting all 4 Curaçao criteria 2
- Lower detection rates in patients with incomplete clinical presentations 2
The primary genes tested are:
- ENG (endoglin): Accounts for ~54% of HHT families (HHT type 1) 1, 5
- ACVRL1/ALK1: Accounts for ~43% of HHT families (HHT type 2) 1
- SMAD4: Causes juvenile polyposis-HHT overlap syndrome in 1-2% of cases 4
- GDF2: Rare mutations in remaining cases 1
Why Genetic Testing May Be Negative Despite True HHT
Several mechanisms explain mutation-negative HHT:
1. Technical limitations of current testing:
- Mutations in non-coding regulatory regions (promoters, deep intronic sequences) not captured by standard exon sequencing 6, 2
- Complex rearrangements or epigenetic modifications not detected by conventional methods 2
2. Undiscovered genes:
- Additional HHT-causing genes likely exist but remain unidentified 2
- The 3-13% of mutation-negative cases suggest involvement of alternate loci 2
3. Mosaicism:
- Somatic mutations occurring post-fertilization may not be detected in blood samples used for testing 2
Clinical Management of Mutation-Negative HHT
Patients with clinically definite HHT but negative genetic testing require identical screening and management as mutation-positive patients. 1 This includes:
- Pulmonary AVM screening with contrast echocardiography or chest CT—these can be treated presymptomatically to prevent stroke and cerebral abscess 1, 5
- Cerebral AVM screening with brain MRI 1, 5
- Liver screening with Doppler ultrasonography (never biopsy due to hemorrhage risk) 1, 5
- Stepwise bleeding management: Begin with nasal moisturization, escalate to oral tranexamic acid, then local ablative therapies, reserving systemic bevacizumab for refractory cases 1, 4
Critical Pitfalls to Avoid
Never dismiss HHT diagnosis based solely on negative genetic testing—the clinical phenotype determines diagnosis and management, not genetic results. 1 A patient meeting 3 Curaçao criteria has definite HHT regardless of genetic test results and requires full screening for life-threatening AVMs. 1
For family screening purposes, negative genetic testing in mutation-negative families is uninformative—family members still require clinical surveillance based on symptoms and clinical criteria rather than genetic results. 1
The practical implication: Treat the patient based on clinical presentation, not genetic test results. Genetic testing serves to confirm diagnosis, guide family screening when a mutation is identified, and provide genotype-phenotype correlation, but negative results do not exclude disease. 1, 3, 2