Henri Plauchu

Hereditary hemorrhagic telangiectasia: from molecular biology to patient care

Summary.u2002 Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by severe and recurrent nosebleeds, mucocutaneous telangiectases, and, in some cases, life‐threatening visceral arteriovenous malformations of various types, including pulmonary, hepatic, cerebral, and spinal. Gastrointestinal telangiectases are frequent and may cause severe bleeding. HHT type 1 results from mutations in ENG on chromosome 9 (coding for endoglin), and HHT type 2 results from mutations in ACVRL1 on chromosome 12 (coding for activin receptor‐like kinase 1). Mutations of either of these two genes account for most clinical cases. In addition, mutations in MADH4 (encoding SMAD4), which cause a juvenile polyposis/HHT overlap syndrome, have been described, and recently, an HHT3 locus on chromosome 5 (5q31.3–5q32) has been reported. The mutated genes in HHT encode proteins that modulate transforming growth factor‐β superfamily signaling in vascular endothelial cells. Management of patients has changed considerably in the last 20 years, in terms of both treatment and the prevention of complications. The goal of this review was to describe the underlying molecular and cellular physiopathology, explore clinical and genetic diagnostic strategies for HHT, and present clinical management recommendations in order to treat symptomatic disease and to screen for vascular malformations.

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). Orthotopic liver transplantation (OLT) has been proposed as the only definitive curative treatment. The aim of this study was to evaluate the long‐term outcome of patients with hepatic involvement due to HHT after OLT with respect to mortality, cardiac and hepatic status, epistaxis, and quality of life. Patients with HHT and severe hepatic vascular malformations who underwent OLT in the Lyon Liver Transplant Unit (LLTU) from 1993 to 2007 were followed at the LLTU and the French Reference Center for HHT. Quality of life was evaluated with the Short Form 36 questionnaire. There were 13 patients who fulfilled the entry criteria of the study (12 women and 1 man). The mean age at the time of OLT was 51.8 years (range = 33‐65 years). Indications for OLT were cardiac failure (n = 9), biliary necrosis (n = 2), both cardiac failure and biliary necrosis (n = 1), and hemobilia (n = 1). The mean duration of follow‐up was 109 months (range = 1‐200 months). Twelve patients (92.3%) are still alive. For the 9 patients with HOCF, the mean cardiac index decreased from 5.4 L/minute/m2 before OLT to 3.0 L/minute/m2 after OLT. No severe hepatic complications were observed after OLT. Nine of the surviving patients (75%) experienced dramatic improvements in epistaxis and quality of life, including an ability to undertake more physical activity. In conclusion, OLT is an important therapeutic option for patients with HHT who have severe hepatic involvement. In the reported cohort, the mortality after OLT for this indication was low. Liver Transpl 16:340–347, 2010.

Cerebral abscesses in hereditary haemorrhagic telangiectasia: A clinical and microbiological evaluation

OBJECTIVESnHereditary 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.nnnPATIENTS AND METHODSnPatients with HHT and cerebral abscess in 5 French medical centers were included. Their clinical, radiological, biological data and prognosis were compared to the data of unselected patients with cerebral abscesses but without HHT included during the same period of time.nnnRESULTSnTwenty-six patients (13 men and 13 women; 44.7±17.2; range 12-79 years), with HHT and cerebral abscess were included. A pulmonary arteriovenous malformation (AVM) was present in all cases. Cerebral abscesses were solitary, supratentorial, and mostly lobar. In all cases, pathogens were anaerobic or facultative anaerobic germs (particularly streptococcus). No death was observed, but various sequels were present in up to two-thirds of the patients. We observed a recurrence of the cerebral abscess in 4 patients with a mean delay of 81 months. In comparison with the control group, cerebral abscesses were generally of later recurrence and significantly more often unique and less often due to staphylococcus.nnnCONCLUSIONnHHT cerebral abscesses are particularly linked to pulmonary arteriovenous malformations and anaerobic germs. Their clinical, radiological and bacteriological characteristics are quite different than in a control group with more solitary brain localizations, no staphylococcus infection and a significantly longer interval to recurrence.

Étude épidémiologique de la maladie de Rendu-Osler en France : répartition géographique et prévalence.

Bideau Alain, Plauchu Henri, Brunet Guy y Robert J.M. — Estudio epidemiologico de la enfennedad de Rendu-Osier en Francia : reparticion geografica y prevalencia. Este estudio sobre la reparticion de la enfermedad de Rendu-Osier se basa en una encuesta postal realizada en 52 provincias francesas enviada a 23 000 medicos. El punto de partida ha sido la concentracion de enfermos observada en la region Rhone-Alpes, exten- diendo progresivamente la encuesta a otras regiones. Debiera cubrirse el territorio nacional en el ano de 1989. Las 3 331 respuestas de los medicos permitieron ubicar 392 de entre ellos en una carta de Francia y sabiendo que cada medico que se proponia representaba en promedio 4 enfermos de una misma familia, pudimos estimar una « prevalencia minima » рог provincia. La media nacional es de 1/8 345, о sea 10 veces mas de lo esperado; a nivel local 3 provincias destacan claramente : Ain (1/3 375), Deux-Sevres (1/4 287), Jura (1/5 062). Estudios complementarios han sido llevados a cabo sobre 7 provincias. Las desigualdades son grandes entre provincias continguas, incluso entre los distritos de una misma provincia. En consecuencia este estudio plantea una interrogacion sobre la difusion de la enfermedad en Francia : i existen diversos focos originales, o el gene patogeno se ha diseminado a partir de un tronco unico ?

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. We performed haplotype analysis of 116 French and Italian patients carrying 13 ACVRL1 different mutations. For five of these mutations, we estimated the age of the most recent common ancestors (MRCAs) using the ESTIAGE program. Most mutations were related to both recurrent mutational events and founder effects with age estimates ranging from 100 to 550 years. The c.1112dupG mutation, which is likely to be responsible for the very high concentration of HHT patients found in the former epidemiological study, probably occurred in one inhabitant of the Haut-Jura Mountains more than three centuries ago. The p.Arg374Gln mutation occurred independently in at least two distinct geographical areas, including the area with the second highest prevalence in the epidemiological study and where the MRCA is rather recent (about 100 years ago). Partially shared haplotypes between French and Italian patients were found for three mutations. This suggests a common origin and a possible diffusion of these mutations from Italy to France.

Ex vivo study of bevacizumab transport through porcine nasal mucosa

INTRODUCTIONnHereditary 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.nnnMATERIAL AND METHODSnTransmucosal 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 2.5h. Bevacizumab concentrations were measured by enzyme-linked immunosorbent assays. Mucosal integrity was examined by histological examination of treated mucosa.nnnRESULTSnTransmucosal transport of bevacizumab followed a Fickian diffusion process (permeability coefficient: [0.63 ± 22]× 10(-6) cm s(-1); and steady-state flux: 56.4 ± 19.6 μg cm(-2)h(-1)). Total recovery of bevacizumab throughout the 2.5h experiment was 83% of the initial dose distributed (i) at the mucosal surface (263 ± 73 μg; ∼53%) and (ii) into (95 ± 14 μg; ∼19%) and through (56 ± 26 μg; ∼11%) the mucosa. There was no evidence of any noticeable histological effects, confirming the harmlessness of nasal bevacizumab delivery.nnnCONCLUSIONnIn the present study, absorption of bevacizumab into nasal mucosa was demonstrated, providing new fundamentals that are mandatory for further clinical trials in HHT patients.

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. In most of the cases reported, the clinical presentation was acute in the pediatric population and insidious during adulthood. The prognosis of spinal AVM mainly depends on the presence or not of medullar signs and symptoms and on the delay before treatment. In conclusion, any child with a family history of HHT should be considered at risk for spinal AVM in order to improve management of such complications and to decrease the risk of neurological sequellae.

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

BACKGROUNDnPatients 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.nnnOBJECTIVEnTo clarify the contribution of capsule endoscopy in selected patients with HHT.nnnDESIGNnProspective, descriptive study.nnnSETTINGnMulticenter, two university hospital tertiary-care centers, from January 2003 to June 2007.nnnPATIENTSnThis study involved 30 patients with HHT and severe anemia (hemoglobin <9 g/dL; normal: 11-15 g/dL) and minimal epistaxis or moderate anemia but overt GI bleeding.nnnINTERVENTIONnCapsule endoscopy investigation.nnnMAIN OUTCOME MEASUREMENTSnClinical characteristics and capsule endoscopy results and their clinical consequences.nnnRESULTSnCapsule endoscopy detected gastric and small-bowel telangiectases in 14 (46.7%) and 26 (86.7%) cases, respectively. Active bleeding was present in 36.7% of cases. Diffuse telangiectases were detected in 42.3% without correlation with age, sex, or type of HHT mutation. Further investigations were carried out as a consequence of the capsule endoscopy results in 67% of cases. Treatment, consisting mostly of endoscopic argon plasma coagulation, was scheduled in 46.7% of patients.nnnLIMITATIONSnOur population was essentially composed of patients with the ALK1 mutation.nnnCONCLUSIONnThis study shows that there is a high diagnostic yield for capsule endoscopy in selected patients with HHT. Capsule endoscopy makes possible precise mapping of lesions and has a considerable impact on the management of these selected patients by using a predefined algorithm: a limited number of accessible lesions is suitable for endoscopic treatment, whereas innumerable diffuse lesions require a medical approach. We suggest that capsule endoscopy could be a first-line, noninvasive, digestive tract examination in selected patients with HHT.

Maladie de Rendu-Osler - Dysfonctionnement de la signalisation TGFβ dans les cellules endothéliales

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. The mucocutaneous telangiectasia are hemorrhagic while the visceral telangiectasia, less frequent, lead to arteriovenous fistula in the lungs, the liver and the brain. HHT disease-causing genes (ENG, ACVRL1 and MADH4) encode proteins that modulate TGFβ superfamilly signaling in vascular endothelial cells. The recent discovery that BMP9 acts as the specific ligand of the receptor ALK1 and endoglin as its co-receptor shows that this signaling pathway is involved in the maturation phase of angiogenesis. Mice heterozygous for endoglin or ALK1 defects reproduce the HHT phenotype and further support the involvement of endothelial hyper proliferation in the pathogenesis of the disease. The medical management of patients remains mainly symptomatic, however the angiogenic trait of this disease should allow us to consider in the future new -therapeutic approaches using anti-angiogenic drugs.

La consanguinité, révélateur de la structure de la population. L'exemple de la vallée de la Valserine du XVIIIe siècle à nos jours

Bideau (Alain), Brunet (Guy), Heyer (Evelyne), Plauchu (Henri). - La consanguinidad, reveladora de la estructura de la poblacion. El ejemplo del valle de Valserina desde el siglo XVIII hasta nuestros dias Los demografos-historiadores calculan tasas de matrimonios consanguineos utilizan- do generalmente las declaraciones de exencion incluidas en las actas de matrimonio. La confrontacion de esta fuente con otras (registro del Obispado y corpus genealogico) muestra las imprecisiones de dicha medida. El analisis del corpus genealogico de los cinco municipios del valle de Valserina, desde finales del siglo XVII hasta nuestros dias, permite establecer el coeficiente medio de consanguinidad de la poblacion. Las genealogias posibilitan ademas la inclusion de la consanguinidad lejana (mas alla de la cuarta generacion). De este modo se percibe la existencia de sub-poblaciones con comportamientos especificos en lo referente a eleccion del conyuge y a movilidad. La consanguinidad es una caracteristica propia de un grupo restringido de fa- milias presentes en estos mismos municipios a lo largo de los tres siglos estudiados.