Age‐related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population

Plauchu, Henri; Chadarévian, de; Bideau, Alain; Robert, Jacques

doi:10.1002/ajmg.1320320302

Cited by 533 publications

(495 citation statements)

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“…The age and sex distributions among HHT patients in our study confirm former reports on a high proportion of females (Selmaier et al, 1993;Shovlin and Letarte, 1999) with higher age (Plauchu et al, 1989) among HHT patients with liver involvement. The same trend was seen in HHT patients with pulmonary hypertension (Harrison et al, 2003), pulmonary vessel malformations (Shovlin et al, 1995), and cerebral involvement (Shovlin and Letarte, 1999).…”

Section: Resultssupporting

confidence: 91%

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: Resultssupporting

confidence: 91%

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

et al. 2005

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“…1 HHT patients usually develop a wide range of cutaneous, mucosal, and sometimes visceral arteriovenous malformations. [2][3][4] The symptomatology is dominated by epistaxis and anemia, but potentially life-threatening visceral localizations can be present, such as pulmonary, hepatic, and cerebral vascular malformations. 5 Hepatic involvement in HHT has been described in several studies.…”

Section: H Ereditary Hemorragic Telangiectasia (Hht) Is Anmentioning

confidence: 99%

“…DS identified hepatic nodules compatible with FNH in 14 patients in this series (13.7 %), all of them women. The mean number of lesions per patient was 3.5 (range, [1][2][3][4][5][6][7][8][9][10][11][12], and the mean maximum diameter per patient was 49 mm (range, 10-90 mm). A nuclear magnetic resonance examination was performed in 11 cases and confirmed the presence of one or more nodule compatible with FNH in 10 cases.…”

Section: Prospective Screeningmentioning

confidence: 99%

Evaluation of previously nonscreened hereditary hemorrhagic telangiectasia patients shows frequent liver involvement and early cardiac consequences

Gincul¹,

Lesca²,

Gelas-Dore³

et al. 2008

Hepatology

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H ereditary hemorragic telangiectasia (HHT) is an autosomal dominant genetic disease driven by mutations in genes such as endoglin (ENG), activin receptor-like kinase type 1 (ACVRL1), and Smad-4, which control the transforming growth factor beta proliferation pathway. 1 HHT patients usually develop a wide range of cutaneous, mucosal, and sometimes visceral arteriovenous malformations. [2][3][4] The symptomatology is dominated by epistaxis and anemia, but potentially life-threatening visceral localizations can be present, such as pulmonary, hepatic, and cerebral vascular malformations. 5 Hepatic involvement in HHT has been described in several studies. 6,7 Characteristic HHT hepatic localization consists of arteriovenous shunting responsible, in severe cases, for high-output cardiac failure (fistulas between the hepatic artery and hepatic veins), ascites (fistulas between the hepatic artery and portal veins), and cholangiopathy with sepsis. Liver transplantation is the main treatment option at these advanced stages. Previous, mostly small series have shown Doppler sonography (DS) abnormalities in 30% to 70% of HHT patients. 8,9 Early and advanced DS findings include (1) enlargement, increased flow velocity, and tortuosity of hepatic artery branches; (2) increased diameter and flow velocity in he-

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“…Hereditary hemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber disease (ORW) is an autosomal dominant multisystemic vascular dysplasia (Plauchu et al 1989;Guttmacher et al 1995), characterized by severe recurrent nose bleeding, localized mucocutaneous telangiectases, gastrointestinal hemorrhage, as well as arteriovenous malformations (AVM) in the lungs, liver, gastrointestinal tract, and brain, which can cause severe ischemic injury or stroke . Gastrointestinal bleeding occurs in approximately one third of patients, especially in later life, and is well recognized (Plauchu et al 1989).…”

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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Age‐related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population

Cited by 533 publications

References 35 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

Evaluation of previously nonscreened hereditary hemorrhagic telangiectasia patients shows frequent liver involvement and early cardiac consequences

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

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