Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2.

Piantanida, M.; Buscarini, Elisabetta; Dellavecchia, Claudia; Minelli, Antonella; Rossi, Antonio; Buscarini, L; Danesino, Cesare

doi:10.1136/jmg.33.6.441

Cited by 83 publications

(63 citation statements)

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“…Alternatively, it is also possible that HHT may -at least in some cases -be caused by mutations in a third locus, other than the ALK1 or ENG genes. Evidence for existence of a third HHT locus had been mentioned previously (Piantanida et al, 1996;Wallace and Shovlin 2000). However, in one of these cases (Piantanida et al 1996) an ALK1 mutation was finally detected, after reevaluation, in a large Italian HHT family with liver involvement (Olivieri et al, 2002).…”

Section: Resultsmentioning

confidence: 86%

“…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.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…ALK1 mutations and liver involvement was reported for single patients (Johnson et. al., 1996;Berg et al, 1997;Trembath et al, 2001), for 2 patients each (Abdalla et al, 2003a;Berg et al, 2003), for 6 unrelated patients (Olivieri et al, 2002), and for multiple familial cases (Piantanida et al, 1996;McDonald et al, 2000;Lin et al, 2001; Abdalla et al 2003b). …”

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

et al. 2005

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Hereditary hemorrhagic telangiectasia (HHT), or Osler-Rendu-Weber syndrome, is a heterogeneous inherited disorder characterized by multi-systemic vascular dysplasia and wide variation in its phenotypic expression. Hepatic manifestation is seen in about 8 to 30 % of the patients. The molecular basis for liver involvement is unknown. We screened the two known HHT disease loci, the ALK1 (ACVRL1) and ENG genes, for mutations in a clinically well-characterized group of HHT patients with or without liver involvement. Mutations in the ALK1 gene were detected in eight out of 10 HHT patients with hepatic manifestation. Among nine HHT patients without liver involvement, four had mutations in the ALK1, and three in the ENG genes, respectively. In one patient with hepatic manifestation a mutation was detected in both the ALK1 and ENG genes. No mutation could be detected in two patients with liver involvement and, likewise, in two patients without hepatic manifestation. In this study, we have identified five novel ALK1 and one ENG disease-causing mutations. We conclude that hepatic manifestation in HHT patients is associated with mutations in the ALK1 gene, but rarely with ENG mutations. © 2005 Wiley-Liss, Inc.KEY WORDS: HHT; Osler-Rendu-Weber syndrome; ALK1; ACVRL1; ENG INTRODUCTIONOsler-Rendu-Weber syndrome or hereditary hemorrhagic telangiectasia (HHT, MIM# 187300 and 600376) is an autosomal dominat disease with age-dependent penetrance and variable expression of the clinical manifestation. The estimated prevalence is in the order of 1 out of 10,000 (Guttmacher et al., 1995). According to the Curaçao DOI: 10.1002/humu.9311 2 Kuehl et al.criteria , the clinical diagnosis of HHT requires that at least three out of four conditions, i.e. epistaxis, telangiectasia, visceral lesions, and a family history with HHT, should be present in order to ensure the diagnosis. While the cutaneous and mucocutaneous manifestations have mostly a relative good prognosis, the involvement of the visceral organs, if untreated, can trigger mortality (Kjeldsen et al., 1999;Shovlin and Letarte, 1999).Hepatic manifestation of HHT is estimated to affect about 8 to 30% of the patients (Reilly and Nostrant, 1984;Bauer et al., 1995;Kjeldsen et al., 1999). The hepatic vascular malformation can be diagnosed by ultrasound (Caselitz et al., 2003) and is mostly associated with fibrosis and/or atypical cirrhosis (Reilly and Nostrant, 1984). In severe cases, the reduced liver function associated with HHT may lead to progressive hepatic failure (Weik and Greiner 1999).Little is known about the genetic basis of the observed clinical heterogeneity of HHT. Even within the same family there could be great variations with respect to manifestation and severity of the disease. (Shovlin, 1997). Disease-causing mutations had been identified in both the endoglin (ENG, MIM# 131195) gene (McAllister et al., 1994) on chromosome 9 (HHT type 1) and in the activin receptor-like kinase (ALK1, also designated ACVRL1, MIM# 601284) gene (Johnson et al., 1996) on chromosome 12 (HHT ...

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Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2005

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“…Mutations in the ALK-1 gene in HHT-2 patients include nonsense and missense mutations, as well as insertions and deletions resulting in frameshifts (Johnson et al 1996;Piantanida et al 1996;Olivieri et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Three novel mutations in the activin receptor-like kinase 1 (ALK-1) gene in hereditary hemorrhagic telangiectasia type 2 in Brazilian patients

et al. 2007

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Hereditary hemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber disease is a systemic fibrovascular dysplasia with an autosomal dominant inheritance pattern. Mutations in two genes, endoglin and ALK-1, are known to cause HHT, both of which mediate signaling by transforming growth factor b ligands in vascular endothelial cells. Ten patients were analyzed. Diagnosis of HHT was carried out by means of family history, recurrent bleeding, and the presence of multiple telangiectases lesions. Conformation-sensitive gel electrophoresis analyses with consistent abnormal migration patterns were cloned and sequenced using the MegaBace 1000 DNA automated analyzer. Three novel mutations were identified in the coding sequence of the ALK-1 gene in five patients and their families, which demonstrated clinical manifestations of HHT type 2. These mutations included a G insertion and a T deletion of single base pairs in exons 3 and 7, as well as missense mutations in exons 7 and 8 of the ALK-1 gene. These data indicate that loss-of-function mutations in a single allele of the ALK1 locus are sufficient to contribute to defects in maintaining endothelial integrity. We suggest the high rate of mutation detection and the small size of the ALK-1 gene make genomic sequencing a viable diagnostic test for HHT2.Keywords Activin receptor-like kinase 1 (ALK1) Á Endoglin (ENG) Á Hereditary hemorrhagic telangiectasia (HHT)

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Value of Capillary Microscopy in the Diagnosis of Hereditary Hemorrhagic Telangiectasia

Mager¹,

Westermann²

2000

Arch Dermatol

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Hereditary haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 or HHT2.

Cited by 83 publications

References 18 publications

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

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

Three novel mutations in the activin receptor-like kinase 1 (ALK-1) gene in hereditary hemorrhagic telangiectasia type 2 in Brazilian patients

Value of Capillary Microscopy in the Diagnosis of Hereditary Hemorrhagic Telangiectasia

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