Harry C. Dietz

Revised diagnostic criteria for the Marfan syndrome

In 1986, the diagnosis of the Marfan syndrome was codified on the basis of clinical criteria in the Berlin nosology [Beighton et al., 1988]. Over time, weaknesses have emerged in these criteria, a problem accentuated by the advent of molecular testing. In this paper, we propose a revision of diagnostic criteria for Marfan syndrome and related conditions. Most notable are: more stringent requirements for diagnosis of the Marfan syndrome in relatives of an unequivocally affected individual; skeletal involvement as a major criterion if at least 4 of 8 typical skeletal manifestations are present; potential contribution of molecular analysis to the diagnosis of Marfan syndrome; and delineation of initial criteria for diagnosis of other heritable conditions with partially overlapping phenotypes.

The revised Ghent nosology for the Marfan syndrome

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.

Marfan's syndrome.

Marfans syndrome is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin 1. Cardinal manifestations include proximal aortic aneurysm, dislocation of the ocular lens, and long-bone overgrowth. Important advances have been made in the diagnosis and medical and surgical care of affected individuals, yet substantial morbidity and premature mortality remain associated with this disorder. Progress has been made with genetically defined mouse models to elucidate the pathogenetic sequence that is initiated by fibrillin-1 deficiency. The new understanding is that many aspects of the disease are caused by altered regulation of transforming growth factor beta (TGFbeta), a family of cytokines that affect cellular performance, highlighting the potential therapeutic application of TGFbeta antagonists. Insights derived from studying this mendelian disorder are anticipated to have relevance for more common and non-syndromic presentations of selected aspects of the Marfan phenotype.

Angiotensin II Blockade and Aortic-Root Dilation in Marfan's Syndrome

BACKGROUND Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfans syndrome. Recent data from mouse models of Marfans syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfans syndrome who had severe aortic-root enlargement. METHODS We identified 18 pediatric patients with Marfans 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. RESULTS 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 Marfans 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 Marfans syndrome, was not affected by ARB therapy. CONCLUSIONS In a small cohort study, the use of ARB therapy in patients with Marfans syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.

Angiotensin II Type 2 Receptor Signaling Attenuates Aortic Aneurysm in Mice Through ERK Antagonism

Transforming growth factor–β promotes aortic aneurysm formation through activation of its “noncanonical” signaling pathway. Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor–β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal–regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.

Treatment of aortic disease in patients with Marfan syndrome.

Marfan syndrome (MFS) is a heritable disorder of the connective tissue with a prevalence of ≈1 in 3000 to 5000 individuals. The condition is inherited in an autosomal dominant manner with complete penetrance but demonstrates variable expression with significant intra- and interfamilial variation. Approximately 25% of patients do not have a family history and represent sporadic, new mutations for the condition. The cardinal features of MFS involve the cardiovascular, ocular, and skeletal systems. The most life-threatening complication of MFS is thoracic aortic aneurysms leading to aortic dissection, rupture, or both. This article focuses on medical and surgical treatment of aortic disease in patients with MFS and addresses the treatment of aortic disease in children and pregnant women with the condition. The most common cardiovascular complication in patients with MFS is progressive aortic root enlargement initially occurring at the sinuses of Valsalva. Ascending aortic aneurysm can precipitate acute type A aortic dissection, aortic rupture, aortic regurgitation (AR), or all 3, and these complications were the primary cause of death before the advent of successful preventive therapies. Treatment of the aorta consists of regular imaging to detect and quantify progression of aortic dilation, β-adrenergic receptor antagonist therapy, and prophylactic aortic repair when the dilation reaches a sufficient size to threaten dissection or cause AR. Before the era of open-heart surgery, the majority of patients with MFS died prematurely of rupture of the aorta, with an average life expectancy of 45 years.1 The success of current medical and surgical treatment of aortic disease in MFS has substantially improved the average life expectancy, extending it up to 70 years.2,3 Cardiovascular manifestations in MFS also include valvular disease involving the mitral valve, aortic valve, or both. Mitral valve prolapse is the most prevalent valvular abnormality, affecting 35% to 100% of patients.4 Mitral …

Atenolol versus Losartan in Children and Young Adults With Marfan's Syndrome

BACKGROUND Aortic-root dissection is the leading cause of death in Marfans syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfans syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change in the mean (±SE) aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139±0.013 and -0.107±0.013 standard-deviation units per year, respectively; P=0.08). Both slopes were significantly less than zero, indicating a decrease in the aortic-root diameter relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS Among children and young adults with Marfans syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.).

Recent progress towards a molecular understanding of Marfan syndrome.

Marfan syndrome (MFS) is a systemic disorder of the connective tissue that is inherited as an autosomal dominant trait and which displays variable manifestations in the ocular, skeletal, and cardiovascular systems. These pleiotropic manifestations are accounted for by mutations in fibrillin‐1, the building block of extracellular microfibrils. During the past 10 years, we have witnessed significant progress in delineating the pathological events responsible for the manifestations of MFS. Much of this progress has been based on the creation and analysis of fibrillin‐1 mutant mouse lines that faithfully recapitulate the spectrum of clinical severity of MFS. These studies have established the critical contribution of fibrillin‐1 deficiency to disease progression through altered cell–matrix interactions and dysregulated TGF‐β signaling. As a result, our definition of MFS as the prototypical structural disorder of the connective tissue has changed to that of a developmental abnormality with broad and complex effects on the morphogenesis and function of multiple organ systems. Importantly, new biological targets have emerged that may yield exciting new opportunities for the development of productive treatment strategies in MFS.

Aortic Root Replacement in 372 Marfan Patients: Evolution of Operative Repair Over 30 Years

BACKGROUND We reviewed the evolution of practice and late results of aortic root replacement (ARR) in Marfan syndrome patients at our institution. METHODS A retrospective clinical review of Marfan patients undergoing ARR at our institution was performed. Follow-up data were obtained from hospital and office records and from telephone contact with patients or their physicians. RESULTS Between September 1976 and September 2006, 372 Marfan syndrome patients underwent ARR: 269 had a Bentall composite graft, 85 had valve-sparing ARR, 16 had ARR with homografts, and 2 had ARR with porcine xenografts. In the first 24 years of the study, 85% received a Bentall graft; during the last 8 years, 61% had a valve-sparing procedure. There was no operative or hospital mortality among the 327 patients who underwent elective repair; there were 2 deaths among the 45 patients (4.4%) who underwent emergent or urgent operative repair. There were 74 late deaths (70 Bentalls, 2 homograft, and 2 valve-sparing ARRs). The most frequent causes of late death were dissection or rupture of the residual aorta (10 of 74) and arrhythmia (9 of 74). Of the 85 patients who had a valve-sparing procedure, 40 had a David II remodeling operation; there was 1 late death in this group, and 5 patients required late aortic valve replacement for aortic insufficiency. A David I reimplantation procedure using the De Paulis Valsalva graft has been used exclusively since May 2002. All 44 patients in this last group have 0 to 1+ aortic insufficiency. CONCLUSIONS Prophylactic surgical replacement of the ascending aorta in patients with Marfan syndrome has low operative risk and can prevent aortic catastrophe in most patients. Valve-sparing procedures, particularly using the reimplantation technique with the Valsalva graft, show promise but have not yet proven as durable as the Bentall.

A Molecular Approach to the Stratification of Cardiovascular Risk in Families with Marfan's Syndrome

BACKGROUND The fibrillin gene encodes a protein in the extracellular matrix, and this protein is widely distributed in elastic tissues. The fibrillin gene is the site of mutations causing Marfans syndrome. This disorder shows a high degree of clinical variability both between and within families. Each family appears to have a unique mutation in the fibrillin gene, which precludes the routine use of mutation screening for presymptomatic diagnosis of the disorder. The goal of this study was to develop a widely applicable method of molecular diagnosis. METHODS We used three newly characterized intragenic sites of normal DNA repeat-sequence variation (i.e., polymorphisms) as markers to follow the inheritance pattern of specific copies (alleles) of the fibrillin gene in multiple kindreds with various clinical features of Marfans syndrome. RESULTS The polymorphic markers allowed identification of the particular copy of the fibrillin gene that cosegregated with Marfans syndrome in 13 of the 14 families tested. In 11 families a definite presymptomatic diagnosis of Marfans syndrome could be made in family members who had only equivocal manifestations of the disorder. In two other families, some family members demonstrated either classic Marfans syndrome or a milder but closely related phenotype. The copy of the fibrillin gene that cosegregated with classic Marfans syndrome was not inherited by family members with the latter, atypical, form of the disease. These milder phenotypes, previously diagnosed as Marfans syndrome, were not associated with aortic involvement. CONCLUSIONS These results document the usefulness of novel polymorphic DNA repeat sequences in the presymptomatic diagnosis of Marfans syndrome. Our findings also demonstrate that the various clinical phenotypes seen in selected families may be due not to single fibrillin mutations, but rather to different genetic alterations. These findings underscore the need for a modification of the current diagnostic criteria for Marfans syndrome in order to achieve accurate risk assessment.