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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. Protocol clinical, radiological, and histological examinations were performed at regular intervals. Fourteen patients were included (13 women and one man). Median age at LT was 52.5 years (range: 33.1-66.7). In eight patients (seven female), disease recurrence was diagnosed by abnormal radiological features, suggestive of microcirculatory disturbances. Typical vascular lesions, including telangiectasia, were demonstrated by liver biopsy in five of these patients. The median interval between LT and diagnosis of recurrence was 127 months (range: 74-184). The risk of recurrence increased over time; estimated cumulative risk was 47.9% at 15 years. Liver tissue analysis found the coexistence of an angiogenic process combined with endothelial microchimerism, as shown by the presence of vascular lining cells of recipient origin. Conclusion: The present data show that disease recurrence occurs, usually after a long delay, in a significant number of patients treated by LT for liver complications of HHT. This strongly supports the necessity of a lifelong follow-up and suggests that therapeutic strategy needs discussion and evaluation, especially of the role of potential adjuvant treatments to LT, such as antiangiogenic medications, when recurrent disease appears.

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. Results: Seventy-four MFS patients and thirty-six healthy controls were examined. In the MFS group, grades 1, 2, 3, and 4 were present in 15, 24, 17, and 7 patients, respectively, whereas 11 patients in this group did not present ectopia lentis. In the control group, grades 0 and 1 were observed in 30 and 6 individuals, respectively. Sensitivity to ectopia lentis of at least grade 2 was 64.9%, with 100% specificity, whereas sensitivity to ectopia lentis of at least grade 1 was 85.1%, with 83.3% specificity. The positive predictive value of ectopia lentis that was greater than or equal to grade 2 was 100%, whereas that of ectopia lentis greater than or equal to grade 1 was 91.3%. Conclusions: High positive predictive values s were found to be associated with grades 2 and higher of the five-grade classification of ectopia lentis. This classification should help to harmonize clinical practices for this major feature of MFS.

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. 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. Results Twenty-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. Conclusion HHT 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.

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. Methods We listed all difficulties encountered in the first database. We focused on three themes: database technical characteristics, database design (the number and characteristics of variables and the overall structure) and data entry. Based on this expertise, we defined the characteristics that should lead to an optimization of the database. We then compared the performance of these databases in terms of available data. Results The first database had 1273 fields spread out on 14 forms. A total of 838 patients was entered from 2001 to 2005 and among the 1273 fields, 205 (16%) had no data at all. The new database gathered 362 fields from the first database and 173 new fields. These fields were rearranged into 443 variables. A total of 1410 patients directly seen by the clinicians were entered. For patients seen by clinicians each variable used for defining the disease was available for at least 93% of patients. Conclusion Items to be included in a specific database should be carefully selected in order to achieve good results and an epidemiological utility.

Summary 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. Methods Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 ( COL3A1 ). Celiprolol was administered twice daily and uptitrated every 6 months by steps of 100 mg to a maximum of 400 mg per day. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. Findings 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15–0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. Interpretation We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. Funding French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

La maladie de Rendu Osler, encore appelee telangiectasie hemorragique hereditaire (HHT) touche une personne sur 5 000 a 8 000. Une large etude epidemiologique realisee en France a montre une concentration geographique dans le Jura. Cette pathologie se definit par la presence d’epistaxis, de telangiectasies cutanees ou muqueuses et une transmission de type autosomique dominant. Les complications des telangiectasies cutanees ou muqueuses sont plutot hemorragiques alors que les manifestations viscerales, moins frequentes, se compliquent de fistules arterioveineuses dans le poumon, le foie ou le systeme nerveux. Les genes responsables de cette pathologie, ENG, ACVRL1, MADH4 , interviennent tous dans la voie de signalisation de la famille TGFβ dans la cellule endotheliale. La decouverte recente de BMP9 comme etant le ligand du recepteur ALK1 et de son corecepteur l’endogline montre que cette voie de signalisation controle la phase de maturation de l’angiogenese. L’invalidation de ces genes dans des modeles murins reproduit la maladie et a permis de confirmer que cette pathologie serait due a une hyperproliferation endotheliale. La prise en charge est encore actuellement symptomatique, cependant le caractere angiogenique de cette pathologie laisse entrevoir une possibilite therapeutique interessante par le biais de modulateurs de cette angiogenese.

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/m(2) before OLT to 3.0 L/minute/m(2) 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.

Rendu-Osler-Weber disease, also known as hereditary hemorrhagic telangiectasia (HHT), has been the focus of several interdisciplinary studies over the last thirty years. An initial epidemiological survey conducted in the 1980s revealed that the prevalence of this hereditary genetic disorder in France is much higher than previously thought, and brought to light several geographical clusters of HHT carriers. The subsequent analysis of the family genealogies of carriers in the main cluster and of the demographic history of the region did not confirm the thesis of a unique founder effect at national level, but provided clues for dating the occurrence of a local mutation. Last, thanks to the recent identification of the genes responsible for HHT, the considerable genetic heterogeneity of the disease has been confirmed and a large number of different mutations existing in France have been identified. Nonetheless, many carriers living in the main geographical cluster studied previously share a single mutation associated with a specific haplotype. At the end of this study, marked by its multi-disciplinary approach and its exceptional duration, the various converging strands confirm the existence of a local founder effect and provide consistent evidence for dating this mutation.

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.

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-β receptor family. Heterozygotes with mutations in the ALK1 gene develop hereditary hemorrhagic telangiectasia type 2 (HHT2). Recently, we reported that bone morphogenetic protein (BMP)9 and BMP10 are specific ligands for ALK1 that potently inhibit microvascular endothelial cell migration and growth. These data lead us to suggest that these factors may play a role in the control of vascular quiescence. To test this hypothesis, we checked their presence in human serum. We found that human serum induced Smad1/5 phosphorylation. To identify the active factor, we tested neutralizing antibodies against BMP members and found that only the anti-BMP9 inhibited serum-induced Smad1/5 phosphorylation. The concentration of circulating BMP9 was found to vary between 2 and 12 ng/mL in sera and plasma from healthy humans, a value well above its EC 50 (50 pg/mL). These data indicated that BMP9 is circulating at a biologically active concentration. We then tested the effects of BMP9 in 2 in vivo angiogenic assays. We found that BMP9 strongly inhibited sprouting angiogenesis in the mouse sponge angiogenesis assay and that BMP9 could inhibit blood circulation in the chicken chorioallantoic membrane assay. Taken together, our results demonstrate that BMP9, circulating under a biologically active form, is a potent antiangiogenic factor that is likely to play a physiological role in the control of adult blood vessel quiescence.

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.

International audience; Objective To assess whether pulmonary arteriovenous malformation (PAVM) is associated with hereditary hemorrhagic telangiectasia (HI-IT). Study design This study wits 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. Presentations included pulmonary, symptoms (11 8), cerebral abscess (n = 2), and transient ischemic attack (TIA) (n = 1); 1 patient was asymptomatic. Nine of the 12 children (75%) had a family history of PAVM The diagnosis of HHT was con finned in all cases. A mutation in ENG was found in 9 of the 10 children available for testing. No mutation in ACVRL1 was found. During long-term follow-up (mean, 16 years), the following complications occurred: TIA (n = 2), hemoptysis (n = 2), and cerebral abscess (n = 2). Nine children experienced recurrence of PAVM The children with no recurrence were those without a family history of PAVM. Conclusions The diagnosis of HHT should be considered in a child with an apparently isolated PAVM. Because serious complications may occur at any age, we recommend screening for PAVM and long-term follow-up in children from families with HHT, especially those with air ENG mutation.

Among 353 patients with hereditary hemorrhagic telangiectasia retrospectively analyzed during the period 1985-2005, we identified 67 cases of severe infection that affected 48 patients (13.6%). Extracerebral infections accounted for 67% of all infections, and most involved Staphylococcus aureus and were associated with prolonged epistaxis. Cerebral infections accounted for 33% of all infections, were mainly due to multiple and anaerobic bacteria, and were associated with the presence of pulmonary arteriovenous malformations and a short duration of epistaxis.

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. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome.

Orofaciodigital syndromes (OFD) are a group of diseases classified according to the phenotype and the mode of inheritance. We report on a fetus presenting with some features of the OFDs but with additional global cerebral dysgenesis. Ultrasonography at 19 weeks of pregnancy disclosed hypoplasia of the cerebral hemispheres with a large intrahemispheric cyst, as well as dysmorphic facial features and brachy-syndactyly IV-V. Fetal brain MRI confirmed these features and disclosed additional morphological anomalies: Agenesis of the vermis, complete agenesis of the corpus callosum, pachygyria of the left hemisphere. Pathological examination showed a disproportionate fetus with large head and short limbs. Dysmorphic features included hypertelorism, broad nasal root, long philtrum, severe micrognathia, microstomia, cleft palate, and lobulated tongue. Radiographs showed distal malformations of the four limbs. Neuropathological examination showed a severe disturbance of the architecture of both hemispheres, more severe on the right side, with four cystic structures located between the hemispheres. Olfactory stalks, mammillary bodies, and midline structures were absent. Cerebellum and brainstem were hypoplastic. On the right hemisphere as on most part of the left one, microscopic findings displayed a complete disruption of the developing mantle with disturbance of the neuronal migration. The present fetus fulfilled the diagnosis of OFD syndrome: Dysmorphic features, cleft palate and lobulate tongue and polysyndactylies of the feet and hands. The cerebral involvement would make it closer to OFD type VI, but brain malformations were far more severe in the present case, with complex and generalized cortical dysgenesis, evoking a disturbance occurring at a very early stage of the embryogenesis.

Resume La maladie d’Ehlers-Danlos est une affection genetique rare qui touche le sujet jeune et qui comprend six types selon la nouvelle classification etablie par Beighton en 1997. Le type hypermobile se caracterise par une hyperlaxite ligamentaire douloureuse, chronique et evolutive, ce qui impose une prise en charge pluridisciplinaire precoce et la plus rigoureuse possible afin d’eviter les complications et l’impotence inevitables qu’entrainent les luxations des petites et des grosses articulations. La prise en charge de la douleur doit rester une preoccupation dans ce type de maladie car elle affecte le sujet dans toutes ses dimensions existentielles au risque d’en faire un individu replie et handicape prematurement.

This is the first report of a fetus affected with campomelic acampomelic dysplasia presenting with increased nuchal translucency. Ultrasonography at 13 weeks of amenorrhea showed a nuchal translucency 5.6 mm thick. The karyotype performed on amniotic fluid cells was normal (46,XY). Ultrasonography at 22 weeks revealed a normal femoral length and female genitalia. A second amniocentesis was performed to confirm the karyotype and for dosage of steroid hormones. Testosterone dosage was low, corresponding to a female fetus. Ultrasonography at 32 weeks showed growth retardation of the long bones (3rd centile) that were not curved. A severe malformation syndrome was suspected and the pregnancy was terminated at 33 weeks. The fetus displayed macrocephaly, facial dysmorphism and female external genitalia. X ray showed straight and thickened long bones, hypoplastic scapulae and moderate platyspondyly. In view of the association of sex reversal, hypoplasia of the scapulae, and the presence of straight long bones, campomelic acampomelic dysplasia was suspected and confirmed by the finding of a SOX9 mutation. This case shows the importance of a careful echographic survey in a fetus with a nuchal translucency4 mm, especially if there is discordance between phenotypic and genotypic sex, since growth retardation may occur later during the pregnancy.

Hereditary hemmorrhagic telangiectasia (HHT, or Osler-Rendu-Weber syndrome) is an autosomal dominant disease characterized by arteriovenous malformations, affecting 1 out of 10,000 individuals in France. The disease is caused by mutations of two genes: ENG and ALK1 (ACVRL1). We screened the coding sequence of ENG and ALK1 in 160 unrelated French index cases. A germline mutation was identified in 100 individuals (62.5%). A total of 36 mutations were found in ENG, including three nonsense mutations, 19 small insertions/deletions leading to a frameshift, two inframe deletions, seven missense mutations, and five intronic or splice-site mutations. Of the 36 mutations, 33 were novel mutations. A total of 64 mutations were found in ALK1, including six nonsense mutations, 28 small insertions/deletions leading to a frameshift, one inframe deletion, 27 missense mutations, and two intronic or splice-site mutations. Of the 64 mutations, 27 were novel mutations. Mutations were found in most parts of the coding sequence for both genes, except ALK1 exon 5 and ENG exons 12 to 14. Missense mutations in ALK1 were more frequent in exons 7, 8, and 10. ENG cDNA was sequenced for three intronic mutations: c.689+2T>C produced an abnormal transcript excluding exon 5, c.1103+3_1103+8del activated a cryptic splice site 22 bp upstream, and c.1428G>A produced two abnormal transcripts, one including intron 11 and the other excluding exon 10. Although most of the mutations were private, some recurrent mutations in ALK1 were of particular interest. Mutation c.1112_1113dupG (p.Gly371fsX391) was found in 17 unrelated individuals sharing a common haplotype, strongly suggesting a founder effect related to the concentration of patients previously reported in a specific French region (Rhone-Alpes). Three missense mutations involved the same codon: c.1231C>T (p.Arg411Trp), c.1232G>C (p.Arg411Pro), and c.1232G>A (p.Arg411Gln) were found in seven, two, and one patients, respectively. Haplotype analysis was in favor of both a founder effect and a mutation hot-spot.

Purpose: A total of 69 families affected by uveal melanoma have been reported in the literature. This report describes two additional families. In addition to presenting these cases, which constitute exceptions, the paper reviews the literature. Material and Methods: Two families, each with two affected members, were analysed in this retrospective study. The pedigree of each family has been pieced together. Results: Considering the low incidence of familial uveal melanoma in the general population, it seems unlikely that inherited genetic factors are responsible for the condition; this question remains difficult to resolve. Discussion: The characteristics of each family history are described and compared with the literature data. The mode of possible inheritance is discussed. Both the histopathology and anatomical location are studied, after which we discuss the body of evidence to establish whether there is an inherited cancer predisposition syndrome in patients with familial uveal melanoma. Conclusion: The statistical likelihood of such an uncommon tumour occurring independently in two or more family members leads us to believe that some cases of familial uveal melanoma may go unrecognized, and that reports on too few families have been published worldwide to prove the existence of a single mendelien gene. However, appropriate tissue samples, such as blood and tumour samples, should be obtained and conserved for present or future cytogenetic and molecular genetic studies.

Isolated mental retardation is clinically and genetically heterogenous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. We report here a linkage analysis in a large family including 15 members, 6 of whom presenting X-linked non-syndromic mental retardation (MRX). Two-point linkage analysis using 23 polymorphic markers covering the entire X chromosome demonstrated significant linkage between the causative gene and DXS8055 with a maximum LOD score of 2.98 at θ = 0.00. Haplotype analysis indicated location for the disease gene in a 23.1 cM interval between DXS1106 and DXS8067. This MRX localization overlaps with 7 XLMR loci (MRX23, MRX27, MRX30, MRX35, MRX47, MRX53, and MRX63). This interval contains two genes associated with non-syndromic mental retardation (NSMR), namely the PAK3 gene, encoding a p21-activated kinase (MRX30 and MRX47) and the FACL4 gene encoding a fatty acyl-CoA ligase (MRX63). As skewed X-inactivation, an apparently constant feature in FACL4 carrier females was not observed in an obligate carrier belonging to the MRX family presented here, the PAK3 gene should be considered as the strongest candidate for this MRX locus. © 2003 Wiley-Liss, Inc.

We report the cases of two familial adenomatous polyposis (FAP) families who presented with the same 2 base pair deletion (AG) at codon 1465 of the adenomatous polyposis coli (APC) gene, but showed phenotypic variability. The mutation was revealed by a simple nonradioactive method using a heteroduplex analysis and identified by a sequence analysis. This observation suggests the responsibility of modifier genes in FAP patients' phenotype.

Genetically-transferred hearing impairments account for more than 50% of cases of pediatric sensorineural hearing defects. Multiple clinical aspects are involved in genetic hearing impairment, including the involvement of other organs, genetic inheritance, and the degree and age at onset of hearing loss. Diagnosis relies on family history, on the systematic investigation of the symptomatology including an associated syndrome, and audiometry testing in parents and siblings. Analysis of the connexin 26 gene is also indicated, as it is frequently involved in this disorder. Further genetic analysis in affected families will aid in detecting other as yet unidentified genes responsible for hearing impairment.

We report on two new cases of syndromic lissencephaly in two consanguineous sibs, with skeletal abnormality, born to young, healthy, second cousin parents with healthy children. In Case 1, fetal ultrasound screening at 32 weeks of gestation showed microcephaly, skin infiltration and equinovarus feet. MRI disclosed cerebral agyria, hypoplastic cerebral mantle and posterior agenesis of the corpus callosum. The propositus, a boy, died soon after birth at term. In Case 2, fetal ultrasound study performed at 16 weeks of gestation disclosed skin infiltration. MRI at 22 weeks of gestation showed microcephaly with agenesis of corpus callosum and cerebellar hypoplasia. Pregnancy was terminated at 22 weeks of gestation. The fetus had normal 46, XY karyotype and similar anomalies found in the index case, with cranio-facial edema and arthrogryposis. X-ray films showed epiphyseal stippling of cervical vertebrae, feet and sacrum. Metacarpal bones were shortened with hypoplastic distal phalanges. Neuropathological findings were concordant with the pattern described in type III lissencephaly: an agyric brain with hypoplastic brain stem and cerebellum, severe neuronal loss of the cortical plate, matrix zone, basal ganglia, brainstem nuclei and spinal cord with axonal swelling and microcalcification. This entity seems to be a new syndromic lissencephaly type III, because of epiphyseal calcifications and metacarpophalangeal bone dysplasia.

Congenital microphthalmia is a common developmental ocular disorder characterized by shortened axial length. Isolated microphthalmia is clinically and genetically heterogeneous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Here, we studied a five-generation family of Sephardic Jewish origin that included 38 members, of whom 7 have either unilateral or bilateral microphthalmia of variable severity inherited as an autosomal dominant trait with incomplete penetrance. After exclusion of several candidate loci, we performed a genome-scan study and demonstrated linkage to chromosome 15q12-q15. Positive LOD scores were obtained with a maximum at the D15S1007 locus (maximum LOD score 3.77, at recombination fraction 0.00). Haplotype analyses supported the location of the disease-causing gene in a 13.8-cM interval between loci D15S1002 and D15S1040.

Summary The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by major abnormalities of eyes, nervous system, and kidneys. Mutations in the OCRL1 gene have been associated with the disease. OCRL1 encodes a phosphatidylinositol 4,5-biphosphate (PtdIns[4,5]P2) 5-phosphatase. We have examined the OCRL1 gene in eight unrelated patients with OCRL and have found seven new mutations and one recurrent in-frame deletion. Among the new mutations, two nonsense mutations (R317X and E558X) and three other frameshift mutations caused premature termination of the protein. A missense mutation, R483G, was located in the highly conserved PtdIns(4,5)P2 5-phosphatase domain. Finally, one frameshift mutation, 2799delC, modifies the C-terminal part of OCRL1, with an extension of six amino acids. Altogether, 70% of missense mutations are located in exon 15, and 52% of all mutations cluster in exons 11–15. We also identified two new microsatellite markers for the OCRL1 locus, and we detected a germline mosaicism in one family. This observation has direct implications for genetic counseling of Lowe syndrome families.

International audience; 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. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-β signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-β-signaling pathway.

Item does not contain fulltext 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.9265+2T>A) in two large WS families from France and the United Kingdom. To characterize their pathogenic mechanisms we performed qRT-PCR experiments on RNA from patient-derived tissues (venous blood and skin fibroblasts). We also analyzed RNA from the original Swiss family reported by Wagner (who has the previously reported c.9265+1G>A mutation). All three mutations resulted in a quantitative increase of transcript variants lacking exons 7 and/or 8. However, the magnitude of the increase varied between tissues and mutations. We discuss altered balance of VCAN splice variants in combination with reduction in glycosaminoglycan protein modifications as possible pathogenic mechanisms.

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. Design, Setting, and Patients Single-center, phase 2 trial with national recruitment from the French HHT Network. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT. Intervention Bevacizumab, 5 mg per kg, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed up for 6 months after the beginning of the treatment. Main Outcome Measure Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography. Results A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for reread, there was a response in 20 of 24 patients with normalization of cardiac index (complete response [CR]) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m 2 (range, 4.1-6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m 2 (range, 2.9-5.2; P 2 ; range, 3.0-5.1). Among 23 patients with available data at 6 months, we observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 minutes per month (range, 0-947) at inclusion, had significantly decreased at 3 months (134 minutes; range, 0-656) and 6 months (43 minutes; range, 0-310) (P = .008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated. Conclusion In this preliminary study of patients with HHT associated with severe hepatic vascular malformations and high cardiac output, administration of bevacizumab was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis. Trial Registration clinicaltrials.gov Identifier: NCT00843440

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. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1(-/-) mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HHT, [corrected] as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1. These findings contribute to a deeper understanding of the molecular pathology of HHT [corrected] in particular and to angiogenesis in general.

Holt-Oram syndrome (HOS) is an autosomal dominant condition of unknown origin characterized by congenital septal heart defects with associated malformations of the upper limbs (radial ray). Here, we report on the mapping of a gene causing HOS to the distal long arm of chromosome 12 (12q21-qter) by linkage analysis in nine informative families (Zmax = 6.81 at theta = 0 at the D12S354 locus). Also, multipoint linkage analysis places the HOS gene within the genetic interval between D12S84 and D12S79 (multipoint lod-score in log base 10 = 8.10). The mapping of a gene for HOS is, to our knowledge, the first chromosomal localization of a gene responsible for congenital septal heart defect in human. The characterization of the HOS gene will hopefully shed light on the molecular mechanisms that govern heart septation in the early stages of embryogenesis.

Hereditary multiple exostoses (EXT) is an autosomal dominant bony disorder characterized by the formation of cartilage-capped juxta-epiphyseal prominences on the long bones. Recently, a disease gene (EXT 1) has been mapped to chromosome 8q23-q24 by linkage analysis in informative families. Here, we report on the genetic mapping of a second locus (EXT 2) to the short arm of chromosome 19 by linkage to a microsatellite DNA marker at the D19S221 locus, which gives additional support to the view that EXT is a genetically heterogeneous condition.

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. We enrolled 103 patients, 66 cases defined through the revised nosology for Ehlers–Danlos syndromes and 37 control subjects selected from patients referred for other pathologies. Ultrastructure of extracellular matrix was read by three to five experienced pathologists blinded for diagnosis. We used the receiver operating curves and logistic regression analysis for ranking ultrastructure scores. We created a detailed description of lesions observed in vEDS patients with 27 items (coded 0 or 1). In the phase 1 (17 cases and 20 controls), abnormal fibroblast shape, presence of lysosomes in the fibroblast and abnormal basal lamina were found to be independent discriminative items. Addition of these three items (defining an ultrastructure score) had the best diagnosis value (area under the curve (AUC) = 0.96). In the phase 2 (49 cases, 17 controls), ultrastructure score provided odds ratio of 9.76 (95 % CI 2.91–32.78), and AUC of 0.90. The ultrastructure score of skin biopsy has predictive value for the diagnosis of vEDS. Presence of two or more signs (either abnormal fibroblast, presence of lysosomes in the fibroblast or abnormal basal lamina) is very evocative of vEDS.

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.We listed all difficulties encountered in the first database. We focused on three themes: database technical characteristics, database design (the number and characteristics of variables and the overall structure) and data entry. Based on this expertise, we defined the characteristics that should lead to an optimization of the database. We then compared the performance of these databases in terms of available data.The first database had 1273 fields spread out on 14 forms. A total of 838 patients was entered from 2001 to 2005 and among the 1273 fields, 205 (16%) had no data at all. The new database gathered 362 fields from the first database and 173 new fields. These fields were rearranged into 443 variables. A total of 1410 patients directly seen by the clinicians were entered. For patients seen by clinicians each variable used for defining the disease was available for at least 93% of patients.Items to be included in a specific database should be carefully selected in order to achieve good results and an epidemiological utility.

Background : Hepatic involvement in hereditary hemorrhagic telangiectasia (HHT) is infrequent and poorly studied. The aim of this study was to describe the clinical, radiological, and hemodynamic patterns of this involvement. Methods : Eleven consecutive patients with HHT and hepatic involvement observed within 12 years were retrospectively studied. They were 8 females and 3 males, mean age, 47. Results : The patients presented with heart failure (4 cases), hepatomegaly and murmur of the right hypochondrium (7 cases), and digestive hemorrhage (6 cases). Eight patients had anicteric cholestasis. Celiac angiography showed a dilated hepatic artery in 8 cases, disseminated intrahepatic telangiectasias in 10, and early opacification of the hepatic veins in 7. Liver dynamic computed tomography (CT) scan performed in 7 patients allowed the diagnosis of liver involvement in each case. Hemodynamic studies were performed in 5 patients. A lef-tto-right intrahepatic shunt was proven in the 5 patients. Shunt output was estimated between 25% and 58% of cardiac output. Mild pulmonary hypertension was observed in the 5 cases. Conclusions : Diagnosis of liver involvement in HHT can be made by dynamic CT scan or celiac angiography. The main feature of this involvement is high output heart failure due to left-to-right intrahepatic shunt. Thus, right-heart catheterization is necessary in these patients to confirm and evaluate the shunt.

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.

International audience; 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 1013 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. The percentage of patients with an ascending aortic (AA) dilatation increased steadily with increasing age and reached 96% (95% CI: 94 –97%) by 60 years. The presence of aortic events (dissection or prophylactic surgery) was rare before 20 years and then increased progressively, reaching 74% (95% CI: 67–81%) by 60 years. Compared with women, men were at higher risk for AA dilatation [≤30 years: 57% (95% CI: 52– 63) vs. 50% (95% CI: 45– 55), P ¼ 0.0076] and aortic events [≤30 years: 21% (95% CI: 17–26) vs. 11% (95% CI: 8–16), P , 0.0001; adjusted HR: 1.4 (1.1 –1.8), P ¼ 0.005]. The prevalence of mitral valve (MV) prolapse [≤60 years: 77% (95% CI: 72– 82)] and MV regurgitation [≤60 years: 61% (95% CI: 53–69)] also increased steadily with age, but surgery limited to the MV remained rare [≤60 years: 13% (95% CI: 8– 21)]. No difference between genders was observed (for all P. 0.20). From 1985 to 2005 the prevalence of AA dilatation remained stable (P for trend ¼ 0.88), whereas the percentage of patients with AA dissection significantly decreased (P for trend ¼ 0.01). Conclusion The CV risk remains important in patients with an FBN1 gene mutation and is present throughout life, justifying regular aortic monitoring. Aortic dilatation or dissection should always trigger suspicion of a genetic background leading to thorough examination for extra-aortic features and comprehensive pedigree investigation.

International audience; 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. Aortic root diameter will be measured using two-dimensional echocardiography. Secondary endpoints will include incidence of aortic dissection, aortic root surgery, death, quality of life, tolerance and compliance with treatments. We aim to enroll a total of 300 patients aged > or =10 years who fulfil the Ghent criteria for Marfan syndrome. Analyses will be based on intention to treat. CONCLUSION: The results of this clinical trial could lead to profound modification of the management of aortic risk and complications in patients with Marfan syndrome and possibly in patients with thoracic aortic aneurysms of other aetiologies.

Summary. 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 receptorlike 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-b 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.

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/m(2) before OLT to 3.0 L/minute/m(2) 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.

Mutations in the GJB2 gene encoding connexin26 (CX26) account for up to 50% of cases of autosomal recessive hearing loss. In contrast, only one GJB2 mutation has been reported to date in an autosomal dominant form of isolated prelingual hearing loss. We report here a novel heterozygous 605G→T mutation in GJB2 in all affected members of a large family with late childhood onset of autosomal dominant isolated hearing loss. The resulting C202F substitution, which lies in the fourth (M4) transmembrane domain of CX26, may impair connexin oligomerisation. Finally, our study suggests that GJB2 should be screened for heterozygous mutations in patients with autosomal dominant isolated hearing impairment, whatever the severity of the disease. Keywords: C202F mutation; connexin26 gene (GJB2); autosomal dominant hearing loss

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). Aortic dilatation was present in a similar proportion of patients in both the TGFBR2 and FBN1 groups (78% versus 79%, respectively) but was highly variable. The incidence and average age for thoracic aortic surgery (31% versus 27% and 35±16 versus 39±13 years, respectively) and aortic dissection (14% versus 10% and 38±12 versus 39±9 years) were also similar in the 2 groups. Mitral valve involvement (myxomatous, prolapse, mitral regurgitation) was less frequent in the TGFBR2 than in the FBN1 group (all P TGFBR2 mutations, versus 32% with FBN1 mutations ( P =0.002). The rate of death was greater in TGFBR2 families before diagnosis but similar once the disease had been recognized. Most pregnancies were uneventful (without death or aortic dissection) in both TGFBR2 and FBN1 families (38 of 39 versus 213 of 217; P =1). Seven patients (10%) with a TGFBR2 mutation fulfilled international criteria for Marfan syndrome, 3 of whom presented with features specific for Loeys-Dietz syndrome. Conclusions— Clinical outcomes appear similar between treated patients with TGFBR2 mutations and individuals with FBN1 mutations. Prognosis depends on clinical disease expression and treatment rather than simply the presence of a TGFBR2 gene mutation.

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. Penetrance is almost complete at 50 years. Visceral complications produce highly variable manifestations: pulmonary arteriovenous malformations may be manifested by brain abscess or transient ischemic attacks, signs of chronic hypoxia or hemorrhagic rupture; neurological arteriovenous malformations can produce signs of compression or be hemorrhagic; hepatic arteriovenous malformations, which remain latent for a long time, become clinically severe in a limited proportion of patients; hemorrhagic, digestive arteriovenous malformations worsen chronic anemia. HHT is a genetic disorder; two genes (ALK1 and ENG) involved in the signaling pathway of the transforming growth factor-beta have been identified so far. Vascular homeostasis of capillaries is impaired, which leads to an accumulation in time of successive and progressive telangiectases and arteriovenous fistulas. Disease management consists in anemia management, as well as in epistaxis prevention and treatment. The management of arteriovenous malformations lies on early detection and the possibility to occlude them with interventional radiology.

International audience; Background HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. Objective The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. Methods The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. Results The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

Resume La maladie de Rendu-Osler est une genopathie hereditaire qui a fait l’objet de plusieurs etudes interdisciplinaires au fil des trois dernieres decennies. Une enquete epidemiologique menee dans les annees 1980 a d’abord permis d’en etablir la prevalence en France a un niveau nettement plus eleve que ce qui etait alors admis, et de pointer l’existence de zones de forte concentration. L’etude genealogique et l’etude de demographie historique qui ont suivi, centrees sur le principal pole de concentration, n’ont pas permis de prouver la theorie d’un effet fondateur unique a l’echelle nationale, mais d’emettre des hypotheses quant a la date d’apparition d’une mutation locale. Enfin, l’identification, au cours des dernieres annees, des genes responsables de cette maladie a permis d’en etablir la grande heterogeneite genetique et d’identifier un grand nombre de mutations differentes presentes sur le territoire francais. Toutefois, de nombreux malades residant dans le principal pole de concentration etudie precedemment partagent une mutation unique associee a un haplotype specifique. Au terme de cette etude, exceptionnelle par son aspect interdisciplinaire et sa duree, les differentes demarches convergent pour affirmer l’existence d’un effet fondateur local, et s’accordent sur une datation approximative de cette mutation.

A total of 252 chromosomes from 126 patients with phenylalanine hydroxylase (PAH) deficiencies were analyzed for both mutant genotypes and restriction fragment length polymorphism (RFLP) haplotypes at the PAH locus. The mutant genes studied originated either from Western Europe (116 alleles) or from Mediterranean countries (136 alleles). Only 27% of all mutant alleles were found to carry identified mutations, particularly mutations at codon 252 (2.3%), 261 (7.5%), 280 (6.3%), 408 (3.5%) and at the splice donor site of intron 12 (6.3%). The mutant genotypes were associated with RFLP haplotypes 7, 1, 38, 2 and 3 at the PAH locus respectively. Except for the splice mutation of intron 12, these associations were preferential, but not exclusive, since the other four mutations were found on the background of at least two RFLP haplotypes. These results, together with the observation that 85% of PAH deficient patients are heterozygotes for their mutant genotypes, emphasize the great heterogeneity of PAH deficiencies in Mediterranean countries and hamper systematic DNA testing for carrier status in this population.

International audience; 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. Subsequently, we screened the TGFBR1 gene in the first 74 patients for whom no defect had been found, and identified 6 novel mutations and 12 polymorphisms. Mutation-carrying probands displayed at referral a large clinical spectrum ranging from the Loeys-Dietz syndrome and neonatal Marfan syndrome to isolated aortic aneurysm. Furthermore, a TGFBR1 gene mutation was found in a Shprintzen-Goldberg syndrome patient. Finally, we observed that the yield of mutation detection within the two genes was very low : 4.8% for classical MFS, 4.6% for incomplete MFS and 1% for TAAD in the TGFBR2 gene; 6.2%, 6.2% and 7% respectively in the TGFBR1 gene; in contrast to LDS, where the yield was exceptionally high (87.5%).

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. Design Prospective, descriptive study. Setting Multicenter, two university hospital tertiary-care centers, from January 2003 to June 2007. Patients This study involved 30 patients with HHT and severe anemia (hemoglobin Intervention Capsule endoscopy investigation. Main Outcome Measurements Clinical characteristics and capsule endoscopy results and their clinical consequences. Results Capsule 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. Limitations Our population was essentially composed of patients with the ALK1 mutation. Conclusion This 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.