Hereditary Hemorrhagic Telangiectasia

ABSTRACT

Identified over a century ago, hereditary hemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant condition characterized by multisystemic vascular malformations and hemorrhage from the associated vascular lesions. HHT may have first been described by Sutton¹ and in turn, Babington,² as a hereditary form of epistaxis. However, it was Rendu³ who first recognized the combination of hereditary epistaxis and telangiectases as a distinct clinical entity from hemophilia. At the turn of the nineteenth century, Osler⁴ and Weber⁵ produced case reports of inherited epistaxis and cutaneous and/or mucocutaneous telangiectases. Shortly thereafter, Hanes⁶ coined the term hereditary hemorrhagic telangiectasia using the three clinical features that at that time defined the disorder.

Although HHT occurs with a wide geographic distribution and has been described in all racial and in most ethnic groups, most of the literature describes Caucasian families. Whether this is due to an increased incidence in Caucasians or due to an ascertainment bias is uncertain. For example, careful examination of the oral and nasal mucosa, the tongue, and the conjunctiva is suggested to be important in individuals of African descent, in whom skin lesions may not be as obvious.⁷ The past few decades saw increased numbers of case reports of HHT kindreds from the Far East and the Indian subcontinent, suggesting that these are due to increased awareness of the disorder.

Earlier estimates of disease prevalence were approximately 1 to 2 per 100,000. However, recent epidemiologic surveys indicate that the disorder is much more frequent than originally thought, possibly due to increased awareness of and interest in this disorder. Minimal estimates of the prevalence are 1 in 2351 individuals in the French department of Ain,⁸ approximately 1 in 3500 on the Danish island of Fyn,⁹ at least 1 in 16,500 in Vermont,¹⁰ and at least 1 in 39,000 in northern England.¹¹ Some of these, in turn, may be low estimates as the disorder is often improperly diagnosed or missed altogether, until a life-threatening episode occurs.¹⁰ Nonetheless, with proper physical examination and recent advances in screening for internal vascular lesions, proper diagnosis can be made in most cases. Recent studies have indicated that in HHT kindreds, penetrance is 97 percent by age 40 to 45.^8,11

Two reports have suggested different outcomes for the homozygous state of HHT. Snyder and Doan¹² described an infant born to two HHT-affected parents, where the disease could be traced at least one generation further back for each side of the family. At birth the infant exhibited multiple cutaneous telangiectases, and died at 11 weeks of age due to hemorrhage from multiple internal “hemangiomas.” The authors suggested that the child represented the homozygous state, which they felt was a lethal form of the disease. This would be partly consistent with the mouse knockout mutations for both endoglin and ALK-1, which are lethal in the homozygous ...