What is Hereditary Hemorrhagic Telangiectasia (HHT) type 1?

HHT Type 1 (Hereditary Hemorrhagic Telangiectasia Type 1)

HHT type 1 is an autosomal dominant vascular disorder caused by mutations in the endoglin (ENG) gene, characterized by earlier onset epistaxis and a higher frequency of pulmonary and cerebral arteriovenous malformations compared to HHT type 2. 1, 2

Genetic Basis and Pathophysiology

• HHT type 1 results from mutations in the endoglin (ENG) gene, which encodes a transmembrane protein involved in the transforming growth factor-β (TGF-β) signaling pathway expressed on vascular endothelium 1, 2
• The disease operates through haploinsufficiency, where reduced endoglin expression (approximately 47-58% of normal levels) leads to abnormal vascular development 3, 4
• Organs with naturally lower baseline endoglin expression are more susceptible to vascular malformations, explaining why only certain vascular beds develop lesions despite the mutation being present throughout the body 4
• Truncating mutations in ENG are associated with more affected organs and more severe hemorrhaging than missense mutations 5

Clinical Phenotype Distinguishing HHT1 from HHT2

Earlier and More Severe Manifestations

• Epistaxis begins at an earlier age in HHT1 patients compared to HHT2, though severity becomes similar by middle age 5
• Symptoms typically appear around age 30, with epistaxis starting at mean age 11 years 2

Organ-Specific Involvement Pattern

• Pulmonary arteriovenous malformations (PAVMs) are more frequent and larger in size in HHT1 compared to HHT2 1, 5
• Cerebral arteriovenous malformations occur more commonly in HHT1 patients 1, 5
• Hepatic vascular malformations are less common in HHT1 compared to HHT2 (which is associated with ALK1 mutations) 1, 5
• Spinal arteriovenous malformations are notably absent in HHT1, being seen only in HHT2 5

Diagnostic Approach

• Clinical diagnosis uses the Curaçao criteria requiring 3 of 4 features: spontaneous/recurrent epistaxis, multiple telangiectasias at characteristic sites, visceral lesions (PAVMs, cerebral AVMs, hepatic AVMs, GI telangiectasias), and first-degree relative with HHT 2
• Genetic testing identifies ENG mutations in 54% of HHT families and should include simultaneous sequencing and deletion/duplication analysis to detect approximately 96% of mutations 2, 6
• Genetic testing is particularly indicated for asymptomatic family members from known HHT families to enable presymptomatic screening and treatment 2

Screening Requirements for HHT1

• Pulmonary screening: All HHT1 patients require screening for PAVMs using contrast echocardiography or chest CT, as these can be treated presymptomatically to prevent life-threatening complications including stroke and cerebral abscess 1, 2
• Cerebral screening: MRI of the brain is recommended to detect cerebral vascular malformations given their higher frequency in HHT1 2
• Liver screening: Doppler ultrasonography as first-line imaging, though hepatic involvement is less common in HHT1 than HHT2 1, 2
• Critical caveat: Liver biopsy must be strictly avoided in any patient with proven or suspected HHT due to high hemorrhage risk 1, 2

Clinical Implications

• The 70-90% of patients with PAVMs have HHT, making HHT1 a predominant cause of pulmonary arteriovenous malformations 1
• Pregnancy poses particular risk as hormonal and hemodynamic changes cause rapid PAVM growth with higher risk of complications from lack of filtration and rupture 1
• Despite reduced endoglin expression, blood vessels remain structurally intact during fetal development, as demonstrated in umbilical cord and placental vessels from HHT1 newborns 3