Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred

DET type 2 (HHT 2) is a multi-system vascular dysplasia caused by a mutatio n in the ALK-1 gene, but the phenotype has not been well defined. We report on 51 members of an HHT 2 kindred with an ALK-1 gene mutation shown to be associated with the disorder. This ALK-1 mutation was detected in 38 kindre d members who were evaluated systematically for associated vascular abnorma lities. Pulmonary arteriovenous malformations (AVMs) were found in 6% of th ose screened, cerebral AVM in 7%, hepatic AVM in 17%, and spinal AVM in 3%. We discuss these and other findings in the 88 affected kindred members, as well as findings in the 13 kindred members in whom the mutation was not de fected. This study shows that pulmonary, cerebral, spinal, and hepatic AVMs can all occur in HHT 2, It also adds to the evidence suggesting that pulmo nary AVMs are more common in HHT 1 than in HHT 2, We identify a higher prev alence of hepatic; AVMs than previously reported in either HHT I or 2, This may be specific to the mutation in this kindred, but probably reflects the lack of routine screening for this manifestation. Even in this family in w hich all affected individuals have the same mutation, the clinical manifest ations of HHT and their severity varied tremendously. Intrafamilial variati on in expression of HHT is clearly significant, emphasizing the difficulty in establishing the diagnosis in individuals and in sub-typing families whe n DNA testing is not available. (C) 2000 Wiley-Liss,Inc.