Marfan Sartan: a randomized, double-blind, placebo-controlled trial.

AIMS: To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS). METHODS AND RESULTS: A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving ß-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (-0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (-0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)]. CONCLUSION: Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients >10 years old. ß-Blocker therapy alone should therefore remain the standard first line therapy in these patients.

A large-scale mutation search reveals genetic heterogeneity in 3M syndrome.

The 3M syndrome is a rare autosomal recessive disorder recently ascribed to mutations in the CUL7 gene and characterized by severe pre- and postnatal growth retardation. Studying a series of 33 novel cases of 3M syndrome, we have identified deleterious CUL7 mutations in 23/33 patients, including 19 novel mutations and one paternal isodisomy of chromosome 6 encompassing a CUL7 mutation. Lack of mutations in 10/33 cases and exclusion of the CUL7 locus on chromosome 6p21.1 in six consanguineous families strongly support the genetic heterogeneity of the 3M syndrome.

Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations.

STUDY PURPOSE: To formulate recommendations about clinical management of liver involvement in hereditary hemorrhagic telangiectasia (HHT), using a formal consensus development process. CONSENSUS PROCESS: A nominal group technique was used. A list of main clinical, diagnostic and therapeutic issues about liver involvement in HHT was generated by the organizing committee. Panel members then scored their agreement with each statement; the median score, and standard deviation for each statement were determined for each of the three successive panel rounds. These consensus statements formed the basis for recommendations graded with the strength and quality of supporting evidence. RECOMMENDATION STATEMENTS: Doppler US is sufficiently accurate and suitable for first-line imaging of the liver in the general HHT population. Liver biopsy in any patient with proven or suspected HHT should be avoided. Liver involvement in HHT is generally asymptomatic; in the minority of patients where it is symptomatic, morbidity and mortality can be substantial. The prevalence of focal nodular hyperplasia is much higher in patients with liver involvement by HHT than in the general population. Invasive therapies for liver involvement by HHT (namely liver transplantation) should be considered only in patients who have failed to respond to intensive medical therapy.

Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by the presence of telangiectases and arteriovenous malformations. In some families in whom a form of idiopathic pulmonary arterial hypertension cosegregated with HHT, mutations in the ACVRL1 gene were present. PURPOSE: We noninvasively measured the pulmonary artery systolic pressure (PASP) in a group of patients with HHT. METHODS: Doppler transthoracic echocardiography and mutation analysis by direct sequencing were used. RESULTS: We studied 68 patients (age 19-84 years, mean 50.75 + 15.11; 32 females) and PASP measurement was possible in 44 (64. 7%); in addition, 9 of them (20.5%) showed elevated values. Molecular analysis identified mutations in the ACVRL1 gene in 7 of these 9 subjects. Even on exclusion of relatives of the single case with known pulmonary hypertension, 5 of 37 patients (13.5%) still showed values higher than those of controls. CONCLUSION: The data indicate that elevated PASP values are a frequent and previously unrecognized complication of HHT. Because clinically significant pulmonary artery hypertension (a relevant cause of morbidity and mortality) may subsequently develop in these patients, we propose that the measurement of PASP should be included among the parameters recorded for all patients undergoing Doppler transthoracic echocardiography during routine clinical screening.

High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia.

A vascular pathogenesis of hepatic focal nodular hyperplasia (FNH) has been suggested; this study was aimed to evaluate in families with hereditary hemorrhagic telangiectasia (HHT) the prevalence of FNH, relating it to presence and stage of hepatic vascular malformations (VMs). Fifty-two HHT families underwent a screening program including abdominal Doppler sonography (US) searching for hepatic VMs; we classified them as minimal, moderate and severe, depending on the number and degree of abnormalities found by Doppler US. Presence of focal liver lesions was recorded. Diagnosis of FNH was made if at least two examinations, whether color Doppler US, liver scintigraphy, dynamic computed tomography (CT) or magnetic resonance (MR), showed suggestive findings. FNH was found in five out of 274 subjects (1.8%). All five were affected by HHT. Thus, percentage related to the group of affected patients increased to 2.9; 4/5 presented severe liver VMs. Female-to-male ratio was 4:1. FNH was single in three cases; tumor size ranged between 20 and 90 mm. During follow-up, no lesion showed a reduction in size, three showed an increase. Prevalence of FNH in patients with HHT is far greater than that reported in the general population; Doppler US role in its diagnosis and follow-up is highlighted.

Physical and transcript map of the autosomal dominant colobomatous microphthalmia locus on chromosome 15q12-q15 and refinement to a 4.4 Mb region.

Congenital microphthalmia is a developmental disorder characterized by shortened axial length of the eye. We have previously mapped the gene responsible for autosomal dominant colobomatous microphthalmia in a 5-generation family to chromosome 15q12-q15. Here, we set up a physical and transcript map of the 13.8 cM critical region, flanked by loci D15S1002 and D15S1040. Physical mapping and genetic linkage analysis using 20 novel polymorphic markers allowed the refinement of the disease locus to two intervals in close vicinity, namely a centromeric interval, bounded by microsatellite DNA markers m3-m17, and a telomeric interval, m76-m24, encompassing respectively 1.9 and 2.5 Mb. Moreover, we excluded three candidate genes, CKTSF1B1, KLF13 and CX36. Finally, although a phenomenon of anticipation was suggested by phenotypic and pedigree data, no abnormal expansion of three trinucleotide repeats mapping to the refine interval was found in affected individuals.