Hereditary hemorrhagic telangiectasia (HHT) in Akita Prefecture, Japan.

Weread with interest the article by Hisamatsu et al (1) indicating the case of Osler-Rendu-Weber disease (hereditary hemorrhagic telangiectasia, HHT) associated with hepatic arteriovenous malformation. HHTwas first described in 1864 by Sutton and later recognized and reported by Rendu, Osier, and Weber, and is thus knownas Rendu-Osler-Weber disease or Osler-Rendu-Weber disease (2, 3). This is an autosomal dominant disorder characterized by multiple telangiectatic lesions involving the skin and mucousmembranesassociated with epistaxis and other bleeding complications. HHThas been reported to occur across a wide geographic distribution throughout Europeand North America (2, 3). However, few cases have been reported in Asian countries. Also, there have been no epidemiological studies about the incidence or the prevalence of HHTin Japan. We have treated 7 families and 10 patients who had pulmonary arteriovenous malformations (PAVMs) since 1978. Ten patients (4 males, 6 females, aged 56±12 years) with HHTwere admitted for evaluation and treatment at the Second Department of Internal Medicine at Akita University School of Medicine during from 1978 to 1999. We interviewed their families to obtain precise information. The clinical criterion for the diagnosis of HHTwas the presence of any two of the following: recurrent epistaxis, telangiectases elsewhere than in the nasal mucosa, evidence of autosomal dominant inheritance, and visceral involvement (4). Pedigrees of 7 families and family membersare shown in the Fig. 1. Fifty-one persons out of 208 family members (24.8%) were diagnosed to be HHT, and 17 HHTpatients (8.2%) had PAVMs. The percentage of HHTpatients associated with PAVMswas 33.3%, which is close to the percentages (20-30%) that were reported in Europe and North America (2). HHThas an estimated prevalence of 1 in 2,351 membersof the population in the eastern France area ofAin, in 3,500 on the Danish island of Funen, in 5,155 in the Leeward Islands, 1 in 16,500 in Vermont, and 1 in 39,216 in northern England (2, 3). The population ofAkita prefecture in 1998 was reported to be 1,221,720. Therefore, if 51 HHTpatients at our university are hypothesized to be the total number, the prevalence of HHTin Akita Prefecture is roughly estimated at 1:24,000, a figure close to those reported in Vermont and northern England. Recently, the condition has been shown to be a family of disorders caused by mutations in various genes, and the genes responsible for two forms have been identified (5, 6). Genetic linkages to HHThave been established to chromosome9q33-q34 in some families and to chromosome12q in others (5). This discovery of genetic heterogeneity should bring a re-evaluation of the natural history of these disorders, because the incidence of the many clinical manifestations may vary widely amongthe various forms. A current multicenter effort is analyzing the correlations between genotype and phenotype (6). Multicenter cooperation mayalso lead to randomized prospective trials to determine the efficacy of various therapies. The development of a functional assay to provide presymptomatic diagnosis appears possible. The finding that a protein binding transforming growth factor p (TGF-p) has a key role in the disease should help elucidate the pathophysiologic features. Therapeutic advances, including gene replacement, may now be a realistic possibility given the ease of access through the bloodstream to endothelial cells, the target tissue (5, 6). Although the understanding of HHTis expanding rapidly as stated above, there have been no such studies reported so far among Japanese HHT patients. Thus, the national epidemiological survey for HHTand genetic analysis of this disease in Japan is very urgent.