Classifying Ectopia Lentis in Marfan Syndrome into Five Grades of Increasing Severity.

Purpose: To describe a five-grade classification of ectopia lentis in Marfan syndrome (MFS) and to evaluate the positive predictive value of the early grades of ectopia lentis.

Methods: We prospectively included MFS patients and their healthy relatives. The anterior segment examination was classified into grades 0 to 5, and we studied the sensitivity, specificity, and positive predictive value of ectopia lentis in this classification.

Recurrence of Hereditary Hemorrhagic Telangiectasia After Liver Transplantation: Clinical Implications and Physiopathological Insights.

Liver transplantation (LT) has been proposed as a curative treatment in hereditary hemorrhagic telangiectasia (HHT) with severe hepatic involvement. We provide a long-term evaluation of graft status after LT for HHT, with a focus on the risk of recurrence. The present study included all patients prospectively followed up after LT for HHT in the Lyon Liver Transplant Unit from 1993 to 2010, with a survival of more than 1 year.

POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome.

Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA.

In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome.

Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism.

Novel VCAN mutations and evidence for unbalanced alternative splicing in the pathogenesis of Wagner syndrome.

Wagner syndrome (WS) is an autosomal dominant vitreoretinopathy affecting various ocular features and is caused by mutations in the canonical splice sites of the VCAN gene, which encodes the large chondroitin sulfate proteoglycan, versican. We report the identification of novel splice acceptor and donor-site mutations (c.4004-1G>C and c.

Ultrastructural scoring of skin biopsies for diagnosis of vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (vEDS) results from a mutation in the gene encoding alpha-1, type III pro-collagen (COL3A1) and confers fragility to skin, ligament and vascular tissue. We tested the value of skin biopsy for diagnosis of vEDS through an ultrastructure scoring procedure. Study design was a multicentric, case-control, blinded trial consisting of two phases: phase 1 was to identify an ultra-structure score providing the best discriminative value for vEDS and phase 2 was to replicate this result in a different population.

Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output.

Context: The only treatment available to restore normal cardiac output in patients with hereditary hemorrhagic telangiectasia (HHT) and cardiac failure is liver transplant. Anti-vascular endothelial growth factor treatments such as bevacizumab may be an effective treatment.

Objectives: To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and quality of life.

Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) [corrected] is a vascular dysplasia syndrome caused by mutations in transforming growth factor-β/bone morphogenetic protein pathway genes, ENG and ACVRL1. HHT [corrected] shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng(+/-) and Tgfb1(-/-) mice provides further support for genetic modification of transforming growth factor-β pathway deficits.

Ex vivo study of bevacizumab transport through porcine nasal mucosa.

Introduction: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal angiogenesis and disabling epistaxis, for which bevacizumab is reported to be a new therapeutic option. In the present study, bevacizumab transport in porcine nasal mucosa was investigated to determine antibody bioavailability.

Material And Methods: Transmucosal absorption of bevacizumab was examined by using nasal mucosa specimens mounted onto static vertical diffusion cells then treated with bevacizumab solution (25 mg mL(-1), 500 μg) for 2.

Cerebral abscesses in hereditary haemorrhagic telangiectasia: a clinical and microbiological evaluation.

Objectives: Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder that can lead to neurological manifestations including strokes and cerebral abscesses. Our objectives were to describe clinical, radiological, bacteriological, and outcome characteristics of patients with cerebral abscess and HHT, and to concurrently compare this group with a control group with cerebral abscess, but without HHT.

Patients And Methods: Patients with HHT and cerebral abscess in 5 French medical centers were included.

How to improve specific databases for clinical data in rare diseases? The example of hereditary haemorrhagic telangiectasia.

Introduction: The objectives of reference centres for rare diseases are multiple and mainly concern disease management and coordination between specialties, but they also have to improve knowledge through epidemiological studies and biomedical research. A first database was created by the hereditary haemorrhagic telangiectasia network to achieve these objectives, but facing a lack of data entered in the first database, we established a new database, named CIROCO (Clinical Investigation for the Rendu-Osler Cohort). This new database was constructed after the first database assessment.

[Rendu-Osler disease: clinical and molecular update].

The Rendu-Osler disease, also called Hereditary Hemorrhagic Telangiectasia (HHT) affects 1 in -5-8000 people. A french epidemiological study pointed out that it was particularly high in the Haut-Jura mountains in France. This pathology is characterized by frequent nosebleeds, mucocutaneous and visceral telangiectasia and hereditary autosomal-dominant trait.

Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial.

Background: Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a β(1)-adrenoceptor antagonist with a β(2)-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome.

Cardiovascular manifestations in men and women carrying a FBN1 mutation.

Aims: In patients with Marfan syndrome and other type-1 fibrillinopathies, genetic testing is becoming more easily available, leading to the identification of mutations early in the course of the disease. This study evaluates the cardiovascular (CV) risk associated with the discovery of a fibrillin-1 (FBN1) mutation.

Methods And Results: A total of 1,013 probands with pathogenic FBN1 mutations were included, among whom 965 patients [median age: 22 years (11-34), male gender 53%] had data suitable for analysis.

Rationale and design of a randomized clinical trial (Marfan Sartan) of angiotensin II receptor blocker therapy versus placebo in individuals with Marfan syndrome.

Background: Recent studies have demonstrated that blockade of the angiotensin II type 1 receptor with losartan decreases aortic damage in an animal model of Marfan syndrome (a KI mouse model with a pathogenic mutation in the gene coding for fibrillin-1).

Aims: To demonstrate a beneficial effect of losartan on aortic dilatation when added to optimal therapy in patients with Marfan syndrome.

Methods: This is a multicentre, randomized, placebo-controlled, double-blind, clinical trial with a 2-year inclusion period and a 3-year follow-up period.

Long-term outcome of patients with hereditary hemorrhagic telangiectasia and severe hepatic involvement after orthotopic liver transplantation: a single-center study.

Hepatic involvement occurs in up to 74% of patients with hereditary hemorrhagic telangiectasia (HHT) and is characterized by a spectrum of arteriovenous malformations. Three different types of intrahepatic shunting may be present: hepatic artery to hepatic veins, hepatic artery to portal vein, and portal vein to hepatic vein. Hepatic involvement in HHT may lead to biliary ischemia, portal hypertension, or high-output cardiac failure (HOCF).

High diagnostic and clinical impact of small-bowel capsule endoscopy in patients with hereditary hemorrhagic telangiectasia with overt digestive bleeding and/or severe anemia.

Background: Patients with hereditary hemorrhagic telangiectasia (HHT) often present with recurrent anemia because of epistaxis or GI bleeding in relation to telangiectases mostly located in the stomach or small bowel. Capsule endoscopy is considered a major diagnostic tool for small-bowel diseases, but the impact of capsule endoscopy imaging on patient management in HHT is poorly understood.

Objective: To clarify the contribution of capsule endoscopy in selected patients with HHT.

Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders.

Background: TGFBR2 mutations were recognized recently among patients with a Marfan-like phenotype. The associated clinical and prognostic spectra remain unclear.

Methods And Results: Clinical features and outcomes of 71 patients with a TGFBR2 mutation (TGFBR2 group) were compared with 50 age- and sex-matched unaffected family members (control subjects) and 243 patients harboring FBN1 mutations (FBN1 group).

[Hereditary hemorrhagic telangiectasia].

Hereditary hemorrhagic telangiectasia (HTT, or Osler-Weber-Rendu disease) is a constitutional vascular dysplasia characterized by hemorrhagic manifestations, cutaneous or mucosal telangiectases and visceral shunting due to arteriovenous malformations. In France, its prevalence varies from 1/6,000 to 1/8,500. The diagnosis is clinical and based on the common triad: chronic epistaxis, responsible for anemias, cutaneous or mucosal telangiectases (on typical locations) and the hereditary nature of these signs inheredited in an autosomal dominant way.

Acute paraplegia due to spinal arteriovenous fistula in two patients with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by recurrent epistaxis, cutaneous telangiectasia, and visceral arteriovenous malformations (AVM). Of these, spinal AVM is a rare manifestation that concerns mainly children. In this report, we describe two cases of spinal AVM revealed by acute paraparesis due to subarachnoid hemorrhage in children with HHT and reviewed the literature on spinal arteriovenous malformations in HHT.

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

Unlabelled: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by cutaneous, mucosal, and sometimes visceral arteriovenous malformations. Severe hepatic manifestations have been characterized in a subgroup of patients, but few data are available in previously nonscreened patients. We prospectively evaluated liver involvement and its cardiac consequences in such patients.

Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders.

TGFBR1 and TGFBR2 gene mutations have been associated with Marfan syndrome types 1 and 2, Loeys-Dietz syndrome and isolated familial thoracic aortic aneurysms or dissection. In order to investigate the molecular and clinical spectrum of TGFBR2 mutations we screened the gene in 457 probands suspected of being affected with Marfan syndrome or related disorders that had been referred to our laboratory for molecular diagnosis. We identified and report 23 mutations and 20 polymorphisms.

Bone morphogenetic protein-9 is a circulating vascular quiescence factor.

Angiogenesis is a complex process, requiring a finely tuned balance between numerous stimulatory and inhibitory signals. ALK1 (activin receptor like-kinase 1) is an endothelial-specific type 1 receptor of the transforming growth factor-beta receptor family. Heterozygotes with mutations in the ALK1 gene develop hereditary hemorrhagic telangiectasia type 2 (HHT2).

Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by widespread arteriovenous malformations and caused by mutations in two major genes: ENG and ACVRL1. Two decades ago, a French epidemiological study pointed out that its prevalence was higher than previously thought and that its distribution varied greatly from one area to another, one of the highest concentrations of patients being found in the Haut-Jura mountains. Although germline mutations are usually family specific, some of them have been reported in unrelated patients, especially for ACVRL1.

Long-term follow-up in 12 children with pulmonary arteriovenous malformations: confirmation of hereditary hemorrhagic telangiectasia in all cases.

Objective: To assess whether pulmonary arteriovenous malformation (PAVM) is associated with hereditary hemorrhagic telangiectasia (HHT).

Study Design: This study was a review of 12 children (sex ratio = 1) including family history, mutation analysis, and long-term follow-up.

Results: Five children were under age 3 years when PAVM was diagnosed.