Multi-organ hereditary hemorrhagic telangiectasia: A case report

Area of Science:

• Genetics
• Molecular Biology
• Vascular Biology

Background:

• Type 2 hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disorder linked to ACVRL1 (ALK1) gene mutations.
• Patients typically present with recurrent bleeding, and current treatments are limited.

Observation:

• A 5-year-old Chinese patient diagnosed with HHT exhibited recurrent melena, epistaxis, and hepatic arteriovenous malformation.
• Genetic analysis identified a novel c.1121G>A mutation in the ALK1 gene, designated R374Q, in affected family members.
• This mutation was absent in unaffected relatives, confirming its heritability.

Findings:

• The R374Q mutation significantly reduced ALK1 kinase activity and Smad1 phosphorylation.
• This molecular dysfunction led to decreased collagen-1 protein levels, indicating abnormal vascular fiber generation.
• Biological studies confirmed the pathogenic role of the R374Q mutant in vascular malformations.

Implications:

• The R374Q ALK1 mutation is pathogenic in type 2 HHT, impacting vascular integrity.
• Identifying this mutation facilitates early diagnosis and genetic counseling for HHT families.
• Understanding the molecular mechanisms provides a basis for developing targeted therapies for HHT.