In a 67-year-old man with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), which of the following statements is incorrect?

The INCORRECT Statement is E: Mutations in ≥5 genes

Statement E is incorrect because HHT is caused by mutations in 3 primary genes, not ≥5 genes. According to the Second International HHT Guidelines, in 97% of patients with a definite clinical diagnosis of HHT, a causative mutation is identified in one of three genes: endoglin (ENG, HHT type 1), activin receptor-like kinase-1 (ACVRL1/ALK1, HHT type 2), and SMAD4 (juvenile polyposis-HHT overlap) 1.

Analysis of Each Statement

Statement A: Epistaxis in childhood or adulthood - CORRECT

• Epistaxis is the most common symptom of HHT and has age-related expression 1
• This is a core diagnostic criterion in the Curaçao criteria 1

Statement B: Telangiectasias and arteriovenous malformations - CORRECT

• HHT is characterized by clinically significant vascular malformations of skin and mucous membranes as well as internal organs (brain, lung, liver) 1
• Telangiectasias show age-related appearance 1

Statement C: Gastrointestinal bleeding in adulthood - CORRECT

• GI bleeding is a recognized manifestation of HHT, particularly in adults 1
• The Second International Guidelines specifically address gastrointestinal bleeding as a priority topic area 1

Statement D: Prenatal diagnosis is not possible - REQUIRES CLARIFICATION

While the provided guidelines don't explicitly address prenatal diagnosis, genetic testing is recommended for HHT diagnosis, particularly for asymptomatic persons from families with known HHT 1. Given that the causative genes are well-characterized and genetic testing can identify mutations in 97% of definite cases, prenatal diagnosis would theoretically be possible through genetic testing if the familial mutation is known. However, this statement's accuracy depends on interpretation and available testing protocols.

Statement E: Mutations in ≥5 genes - INCORRECT

This is definitively the wrong answer. The guidelines explicitly state that mutations are identified in three genes (ENG, ACVRL1, and SMAD4), not five or more 1.

Key Clinical Pearls

The diagnosis of HHT relies on:

• Curaçao criteria for clinical diagnosis 1
• Genetic testing identifying mutations in the 3 causative genes in 97% of definite cases 1
• Recognition that HHT is autosomal dominant with prevalence of approximately 1 in 5000 1