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

Abstract

HHT type 2 (HHT 2) is a multi-system vascular dysplasia caused by a mutation 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 kindred members who were evaluated systematically for associated vascular abnormalities. Pulmonary arteriovenous malformations (AVMs) were found in 6% of those screened, cerebral AVM in 7%, hepatic AVM in 17%, and spinal AVM in 3%. We discuss these and other findings in the 38 affected kindred members, as well as findings in the 13 kindred members in whom the mutation was not detected. This study shows that pulmonary, cerebral, spinal, and hepatic AVMs can all occur in HHT 2. It also adds to the evidence suggesting that pulmonary AVMs are more common in HHT 1 than in HHT 2. We identify a higher prevalence of hepatic AVMs than previously reported in either HHT 1 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 which all affected individuals have the same mutation, the clinical manifestations of HHT and their severity varied tremendously. Intrafamilial variation in expression of HHT is clearly significant, emphasizing the difficulty in establishing the diagnosis in individuals and in sub-typing families when DNA testing is not available.

Hepatic manifestation is associated withALK1 in hereditary hemorrhagic telangiectasia: Identification of five novelALK1 and one novelENG mutations

“…A significantly higher liver involvement had also been reported previously for two large HHT2 families (McDonald et al, 2000;Lin et al, 2001). The main objective of the present study is to screen systematically for mutations in the ENG and ALK1 genes of patients with HHT and liver involvement as compared to patients with HHT and no liver disease.…”

“…Our results are well in accordance with previous publications on hepatic manifestations in patients with HHT. Although liver involvement was reported for a few patients with ENG mutations, (Berg et al, 2003;Harrison et al, 2003;Cymerman et al, 2003;Shovlin et al, 1997) it was much more often reported for patients carrying mutations in the ALK1 gene (Johnson et al, 1996;Piantanida et al, 1996;Berg et al, 1997;McDonald et al, 2000;Lin et al, 2001;Trembath et al, 2001;Olivieri et al, 2002;Abdalla et al, 2003a & b ;Berg et al, 2003). Liver involvement was not routinely assessed in most of these studies, since the emphasis was mainly on the genotype and not the phenotype, or the reports were on multiple family members and not on unrelated individuals.…”

“…It is noteworthy that, even in families with high rates of liver involvement, only a subset of the mutation carriers finally develops hepatic disease (Piantanida et al, 1996;McDonald et al, 2000;Lin et al, 2001; Abdalla et al, 2003b). The phenotypic variability of HHT type 2 is also evident from our study: the same ALK1 mutation (p.Arg67Trp) was present in two unrelated HHT patients, one with (P4), and one without (P13) hepatic manifestation.…”

“…In addition, pulmonary arteriovenous malformations (PAVM) were only seen in HHT1 (Berg et al, 2003), which confirmed earlier observations . However, PAVMs can also be encountered in some patients with HHT2 (McDonald et al, 2000;Kjeldsen et al, 2001). Furthermore, ALK1 mutations were also identified in families with pulmonary hypertension and HHT (Trembath et al, 2001; Harrison et al, 2002).…”

Disease-associated mutations in conserved residues of ALK-1 kinase domain

“…17,18 Mutations are distributed throughout the ALK-1 gene. Frameshift and nonsense mutations predict nonsense mediated mRNA decay 27 and failure to produce functional protein.…”