Hereditary Hemorrhagic Telangiectasia

Disease Overview

Hereditary hemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu (OWR) disease is an inherited disorder that results in the development of mucocutaneous telangiectasias and visceral organ arteriovenous malformations (AVMs).1,2 HHT is considered a rare bleeding disorder and mucosal telangiectasias causing recurrent epistaxis is the sine qua non of this disorder, with the vast majority of affected individuals developing varying degrees of epistaxis by adulthood.3 HHT can be associated with significant morbidity, decreased quality of life, and increased mortality. Unfortunately, the majority of affected individuals remain undiagnosed and at-risk for disease-related complications.

HHT is the result of gene mutations affecting various steps in transforming growth factor β signaling, which are key regulators of angiogenesis.4 The net result is a disorganized development of the vascular bed, and the formation of mucocutaneous telangiectasias. Three disease-causing genes have been identified. These are endoglin (ENG), activin A receptor ligand type I (ACVRL1 or ALK1), and SMAD family member 4 (MADH4 or SMAD4).4 Of note, mutations in SMAD4 also cause juvenile polyposis syndrome (JPS) and affected patients develop both disorders, referred to as JPS/HHT.5 ENG and ACVRL1 mutations account for the vast majority of HHT cases and appear to occur at an equal proportion overall. SMAD4 mutations account for roughly 2-3% of all HHT.

Over 750 pathogenic mutations have been identified in ENG and ACVRL1. Missense mutations are most common (, while de novo mutations and mosaicism are rare (except for SMAD4, where 25% of patients have de novo mutations). Homozygous mutations of ENG or ACVRL1 are embryonically lethal, and heterozygosity leads to haploinsufficiency and reduced levels of the functional protein.

HHT is also referred to by the eponym Osler Weber Rendu disease, in recognition of the physicians credited with the initial descriptions of this disease. In 1896, Henri Rendu described recurrent epistaxis and cutaneous ‘angiomas’ in a sailor whose mother and brother also suffered from epistaxis.6 William Osler reported on a cohort of 4 patients with familial, recurrent epistaxis and presence of mucocutaneous telangiectasias in 1901.7 Subsequently, Frederick Parkes Weber expanded on these finding in his report on eight families with recurrent epistaxis, and developmental angiomata over the skin and mucosal surfaces.8 The disease was named hereditary hemorrhagic telangiectasia in 1909.9

The exact prevalence of HHT remains unclear as the majority of affected individuals remain undiagnosed. It is estimated to affect 1in 5000-8000 individuals worldwide.10,11 HHT affects both men and women, and no racial preponderance has been observed.12