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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.

Abstract  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.

Abstract  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

Abstract  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 state, although both mouse models exhibit embryonic lethality. Despite the severe phenotype of the infant, there is no molecular evidence that the child inherited two mutant HHT genes. In addition, the genetic heterogeneity now known to exist in HHT suggests that even if the child did inherit mutant HHT genes from both parents, it is possible that the child was a double-heterozygote for ALK-1 and endoglin mutations. Thus, although this early case report is intriguing, it does not solve the question of the homozygous state.

Abstract  On the other hand, study of a large inbred family affected with HHT led to the identification of a proposed homozygous individual who lived to adulthood.13 Due to the high degree of consanguinity in the family, a descendant of two affected parents was identified. This male lived to adulthood and had 13 children (from multiple wives), all of whom were affected. Using Bayes theorem, the probability that he was homozygous for an HHT-causative mutation is 0.99975. This is in stark contrast to the embryonic lethal mouse homozygous endoglin and ALK-1 knockouts. Taking at face value the correct diagnoses of all 13 children of the proposed homozygous father, these data suggest crucial differences between the roles of endoglin and ALK-1 in mouse and human development.

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