Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

The prognosis of MEN1 disease has improved since 1980. Thymic tumors and duodenopancreatic tumors, including nonsecreting pancreatic tumors, increased the risk of death. Rare but aggressive adrenal tumors may also cause death. Most deaths were related to MEN1. New recommendations on abdominal and thoracic imaging are required.

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In routine practice, the risk of colorectal cancer after adenoma removal remains high and depends both on initial adenoma features and on colonoscopy surveillance practices. Gastroenterologists should encourage patients to comply with long-term colonoscopic surveillance.

Abstract-The role of the increase in the common carotid artery (CCA) intima-media wall thickness (IMT) in the atherosclerotic process is questionable. This longitudinal study examined the predictive value of CCA-IMT measured at baseline examination (at sites free of plaques) on the occurrence of atherosclerotic plaques in the extracranial carotid arteries during 4 years of follow-up study in a sample of 1010 subjects aged 59 to 71 years. Ultrasound examinations were performed at baseline and 2 years and 4 years later. The occurrence of carotid plaques during follow-up was defined as the appearance of Ն1 plaque in previously normal carotid segments and/or the appearance of new plaques in the carotid segments that previously had plaques. Key Words: carotid arteries Ⅲ atherosclerosis Ⅲ plaque Ⅲ intima-media thickness Ⅲ longitudinal studies A growing number of epidemiological studies and clinical trials use common carotid artery (CCA) intima-media wall thickness (IMT), obtained by noninvasive highresolution B-mode ultrasonography, as an early marker of systemic atherosclerosis. 1-13 Good-quality images of the far wall of the straight part of the CCA are easy to obtain, and IMT can be reliably measured in nearly all subjects. 14,15 Furthermore, increased CCA-IMT has been shown to be associated with the main cardiovascular risk factors, 1-6,16 -19 the presence of other localizations of atherosclerosis, 20 -24 and an increased risk of coronary heart disease (CHD) and stroke. [25][26][27][28][29] However, the role of increasing CCA-IMT in the atherosclerotic process is questionable. 30 CCAs are less prone to atherosclerosis than are carotid bifurcations (CBs) and internal carotid arteries (ICAs). Furthermore, varying degrees of association between CCA-IMT and of the extent and severity of coronary artery disease have been observed. 30 -32 One way to investigate the significance of increased IMT with regard to atherosclerosis is to study its relationship with confirmed atherosclerotic plaques in the same arterial system. Several cross-sectional studies have reported positive associations between CCA-IMT and the presence of plaques in the carotid arteries. 19,[33][34][35][36][37][38] In a previous investigation involving the Aging Vascular Study (EVA) study based on the baseline examination data, we also reported that higher CCA-IMT (measured at sites free of any discrete plaque) was related to locally detected atherosclerotic plaques in a large population of relatively aged subjects. 6 However, cross-sectional results do not allow for the determination of the temporal sequence and the possible direction of the relationships that would permit prediction at the individual level. Longitudinal studies are thus needed. A possible association between CCA-IMT and the subsequent development of carotid atherosclerotic plaques could suggest that intimal-medial thickening might occur in an earlier phase of the atherosclerotic process and would provide an indirect validation for the use of increased CCA-IMT measurements as an e...

This study examined the relation between arterial wall thickness and local atherosclerosis in the carotid arteries (CAs) and their specific risk factors. B-mode ultrasonography of the CAs was performed in a cohort of 516 men and 756 women aged 59 to 71 years who had been recruited for the European Vascular Aging Study. Ultrasound examination included measurement of intima-media thickness of the common CA (CCA) and the sites of plaque in the internal CA and bifurcations. Significant associations between increases in CCA intima-media thickness and both the presence and severity of atherosclerotic plaque were found in men and women. Examination of specific risk factors for increases in CCA intima-media thickness in the presence of plaque showed that, after adjustment for sex, both ultrasound measurements were independently related to age, body mass index, hypertension, and ever smoking (versus never smoking). Diabetes and current smoking were associated with intima-media thickness only, whereas hypercholesterolemia was related to plaque only. However, when subjects who were taking lipid-lowering drugs were excluded, lipoproteins and apolipoproteins were more consistently related to intima-media thickness than to plaque. In subjects free from any antihypertensive treatment, both intima-media thickness and plaques were independently associated with systolic blood pressure. After adjustment for sex and other risk factors, the odds ratio for having at least one plaque associated with a 0.10-mm increase in CCA intima-media thickness was 1.18 (95% confidence interval, 1.05 to 1.32). In this relatively aged population, increases in intima-media thickness as measured in the CCAs were clearly related to locally detected atherosclerosis and known risk factors for atherosclerosis. Longitudinal studies are needed to clarify the role of arterial wall thickening in the atherosclerotic process.

In 59- to 71-year-old subjects, increased IMT and atherosclerotic plaques were accompanied by an increase in lumen diameter of the common carotid arteries, indicating an overcompensation. Luminal enlargement observed with several risk factors and with high blood pressure in particular might be partially counteracted by high lipid levels.