What are the variants of Hereditary Hemorrhagic Telangiectasia (HHT)?

Variants of Hereditary Hemorrhagic Telangiectasia

HHT has four recognized genetic variants: HHT Type 1 (ENG mutations), HHT Type 2 (ACVRL1/ALK1 mutations), Juvenile Polyposis-HHT Overlap Syndrome (SMAD4 mutations), and a rare variant caused by GDF2 mutations. 1, 2, 3

Primary HHT Variants

HHT Type 1 (ENG Gene)

• Caused by mutations in the endoglin (ENG) gene located on chromosome 9, accounting for approximately 54% of HHT families 1, 4, 5
• Pulmonary arteriovenous malformations (PAVMs) are significantly more frequent and larger in HHT1, occurring in 75% of patients compared to 44% in HHT2 1, 4, 6
• Cerebral AVMs occur more commonly in HHT1 (20% vs 0% in HHT2), making neurological complications including stroke and cerebral abscess exclusive to this variant 1, 4, 6
• Hepatic vascular malformations are less common in HHT1 compared to HHT2 4, 6
• Symptoms typically appear around age 30, with epistaxis starting at mean age 11 years 4

HHT Type 2 (ACVRL1/ALK1 Gene)

• Caused by mutations in the ACVRL1 (also called ALK1) gene located on chromosome 12, identified in approximately 43% of HHT families 1, 5
• Hepatic vascular malformations are substantially more common and symptomatic in HHT2 (84% vs 60% in HHT1), with marked female predominance 1, 6
• Pulmonary AVMs are less frequent and smaller compared to HHT1 6
• Severe liver involvement requiring intervention occurs exclusively in HHT2 patients 6

Juvenile Polyposis-HHT Overlap Syndrome (SMAD4 Gene)

• SMAD4 mutations cause a combined syndrome of HHT and juvenile polyposis, occurring in 1-2% of HHT cases, with up to 76% manifesting life-threatening AVMs 1, 2, 5
• SMAD4 carriers have significantly higher risk of severe gastric polyposis, with all gastric cancers in one cohort occurring exclusively in SMAD4 carriers 1, 2
• Upper GI tract surveillance must begin every 1-3 years starting at age 18 years (earlier than the age 25 recommended for other polyposis syndromes) 1, 2
• Patients may lack overt clinical symptoms of HHT but remain at risk of asymptomatic AVMs requiring comprehensive screening 1

HHT Variant with GDF2 Mutations

• GDF2 mutations represent a rare fourth genetic variant of HHT, though specific prevalence data are limited 1, 3
• This variant is included in comprehensive genetic testing panels but accounts for a small minority of cases 3

Genetic Testing Approach

• Simultaneous sequencing and deletion/duplication analysis of ENG and ACVRL1 genes identifies approximately 96% of mutations when strict Curaçao criteria are applied 1, 7
• Comprehensive genetic testing targeting ENG, ACVRL1, and SMAD4 identifies causative mutations in 97% of patients with definite clinical HHT 1, 2
• ENG and ACVRL1 mutations collectively account for approximately 85-90% of all HHT cases 1, 8, 5

Critical Clinical Distinctions Between Variants

The genotype determines screening priorities and complication risks:

• For HHT1 (ENG): Prioritize pulmonary and cerebral AVM screening, as PAVMs are larger and more frequent, and cerebral AVMs occur almost exclusively in this variant 1, 4, 6
• For HHT2 (ACVRL1): Prioritize hepatic screening, as symptomatic liver involvement requiring intervention occurs only in HHT2, particularly in older females 1, 6
• For SMAD4: Mandatory gastrointestinal surveillance starting at age 18, as gastric cancer risk is substantially elevated and occurs exclusively in this variant 1, 2

Important Caveats

• Families with the same mutation exhibit considerable phenotypic variation, so screening protocols must be comprehensive regardless of initial presentation 8
• Negative genetic testing does not exclude HHT, as clinical Curaçao criteria remain the diagnostic foundation 2
• All variants require screening for pulmonary AVMs, though frequency and size differ by genotype 1, 4