The diagnosis of Marfan syndrome (MFS) relies on defined clinical criteria (Ghent nosology), outlined by international expert opinion to facilitate accurate recognition of this genetic aneurysm syndrome and to improve patient management and counselling. These Ghent criteria, comprising a set of major and minor manifestations in different body systems, have proven to work well since with improving molecular techniques, confirmation of the diagnosis is possible in over 95% of patients. However, concerns with the current nosology are that some of the diagnostic criteria have not been sufficiently validated, are not applicable in children or necessitate expensive and specialised investigations. The recognition of variable clinical expression and the recently extended differential diagnosis further confound accurate diagnostic decision making. Moreover, the diagnosis of MFS—whether or not established correctly—can be stigmatising, hamper career aspirations, restrict life insurance opportunities, and cause psychosocial burden. An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. For the latter a new scoring system has been designed. In this revised nosology, FBN1 testing, although not mandatory, has greater weight in the diagnostic assessment. Special considerations are given to the diagnosis of MFS in children and alternative diagnoses in adults. We anticipate that these new guidelines may delay a definitive diagnosis of MFS but will decrease the risk of premature or misdiagnosis and facilitate worldwide discussion of risk and follow-up/management guidelines.

Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor–β (TGF-β) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-β signaling and can be prevented by TGF-β antagonists such as TGF-β–neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.

The Loeys–Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor β receptors 1 and 2 (TGFBR1 and TGFBR2, respectively). We undertook the clinical and molecular characterization of 52 affected families. Forty probands presented with typical manifestations of the Loeys–Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers–Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers–Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys–Dietz syndrome. We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys–Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers–Danlos syndrome (Loeys–Dietz syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys–Dietz syndrome type I, as compared with those with type II, underwent cardiovascular surgery earlier (mean age, 16.9 years vs. 26.9 years) and died earlier (22.6 years vs. 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys–Dietz syndrome from vascular Ehlers–Danlos syndrome. Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease. The severity of the clinical presentation is predictive of the outcome. Genotyping of patients presenting with symptoms like those of vascular Ehlers–Danlos syndrome may be used to guide therapy, including the use and timing of prophylactic vascular surgery.

Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor β (TGF-β) that can be mitigated by treatment with TGF-β antagonists, including angiotensin II–receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. The mean (±SD) rate of change in aortic-root diameter decreased significantly from 3.54±2.87 mm per year during previous medical therapy to 0.46±0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.