Revised Ghent Criteria Research Articles

Novel FBN1 mutations are responsible for cardiovascular manifestations of Marfan syndrome.

The fibrillin-1 (FBN1) gene mutations result in Marfan syndrome (MFS) and have a variety of phenotypic variations. This disease is involved in the skeletal, ocular and cardiovascular system. Here we analyzed genotype-phenotype correlation in two Chinese families with MFS. Two patients with thoracic aortic aneurysms and dissections were diagnosed as MFS according to the revised Ghent criteria. Peripheral blood samples were collected and genomic DNAs were isolated from available cases, namely, patient-1 and his daughter and son, and patient-2 and his parents. According to the next-generation sequencing results, the mutations in FBN1 were confirmed by direct sequencing. A heterozygous frameshift mutation in exon 12 of FBN1 was found in the proband-1 and his daughter. They showed cardiovascular phenotype thoracic aortic aneurysms and dissections, a life-threatening vascular disease, and atrial septal defect respectively. One de novo missense mutation in exon 50 of FBN1 was identified only in the patient-2, showing aortic root aneurysm and aortic root dilatation. Intriguingly, two novel mutations mainly caused the cardiovascular complications in affected family members. No meaningful mutations were found in these two patients by screening all exons of 428 genes related with cardiovascular disease. The high incidence of cardiovascular manifestations might be associated with the two novel mutations in exon 12 and 50 of FBN1.

A FBN1 mutation association with different phenotypes of Marfan syndrome in a Chinese family

BackgroundPrevious studies demonstrated that patients with different FBN1 mutations often present more considerable phenotypic variation compared to different members of the related family carrying a same mutation. The purpose of our study was to identify pathogenic mutation and provide more information about genotype–phenotypic correlations in a large Chinese family with Marfan syndrome. Methods15 related family members from a Chinese 4-generation pedigree with Marfan syndrome underwent physical, ophthalmologic, radiological and cardiovascular examinations. The propositus has De Bakey III aortic dissection and didn't fulfill the revised Ghent criteria for Marfan syndrome. Nine family members have ectopia lentis and their echocardiogram was normal. Five other family members have no evidence of Marfan syndrome. Genomic DNA was isolated from blood leukocytes. The exome sequencing was employed on the propositus, then the Sanger sequencing was conducted for mutation verification in other 14 participants of this family. ResultsThe causative mutation in FBN1 discovered in the propositus was a known heterozygous missense mutation, c.1633T>G (p.R545C), in exon 14 (NM 000138). This same mutation was also identified in all 9 ectopia lentis patients and one unaffected 8-year-old girl. However, the same mutation was not discovered in other 4 unaffected family members. ConclusionsOur data enhance the information of genotype–phenotype correlation owing to FBN1 mutations. To our current knowledge, we firstly reported that the same FBN1 mutation, c. 1633C>T (Arg545Cys), was detected simultaneously in three different cardinal phenotypes (ectopia lentis, aortic dissection and unaffected) within one family. The unaffected girl with FBN1 mutation may presumably represent a rare case of nonpenetrance.

Abstract 12688: Abdominal Aortic Aneurysm in Marfan Syndrome: Time for Screening Guidelines?

Background: Marfan syndrome (MFS) leads to aortic root aneurysm, while descending thoracic aortic aneurysm (TAA) occurs less commonly. With imaging surveillance and prophylactic surgery, lifespan in MFS has increased to near normal. Abdominal aortic aneurysm (AAA) complicating Marfan syndrome is rarely reported in the literature. There are no guidelines for routine screening for AAA in MFS. We sought to characterize AAA disease in our MFS cohort. Methods: The records of 11 adults from our MFS Clinic with MFS (by Ghent or revised Ghent Criteria) and AAA disease were reviewed. Clinical features, imaging, operative reports, and outcomes were analyzed. Results: Eleven adults (9 male) with MFS and AAA, age at AAA diagnosis 43 + 15 yrs (range 18-63 yrs), were studied. Five patients smoked cigarettes. Nine of eleven patients were being treated with beta-blockers and angiotensin receptor blockers or ACE-inhibitors at the time of AAA diagnosis. Ten underwent prior aortic root replacement at age 31 + 15 yrs (range 8-62 yrs). The AAA was diagnosed 1-21 years after aortic root repair. The AAA was suprarenal in 5 patients, juxtarenal in 2, and infrarenal in 4. The size of the AAA ranged from 3.5 to 9.7 cm at time of diagnosis. Three patients had descending TAA. One patient had a prior type B dissection, not involving the abdominal aorta. Branch vessel aneurysms present in these patients included popliteal, intercostal, hepatic, subclavian and axillary. Four patients underwent open surgical repair (AAA size from 5.5 to 9.7 cm); one underwent endovascular repair; and five are being treated medically (aortic size 4.1 + 0.6 cm). One patient died suddenly with AAA size 5.7 cm at last measurement. Conclusions: Adults with MFS are at risk for developing AAA. Our cohort is the largest to date characterizing AAA in MFS. The AAAs were often very large at the time of initial diagnosis. MFS patients with AAA have a relatively high frequency of branch vessel aneurysms. Imaging to evaluate for AAA is recommended early after the diagnosis of MFS in adults and periodically thereafter to improve outcomes in this population.

Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 7: Aortic Diseases, Including Marfan Syndrome: A Scientific Statement From the American Heart Association and American College of Cardiology.

Acute aortic dissection or rupture in Marfan syndrome or other aortopathies is an important cause of sudden death in athletes.1 Increased blood pressure and aortic stress during intense physical exertion place the patient with Marfan syndrome, Loeys-Dietz syndrome, familial thoracic aortic aneurysm (TAA) and dissection syndrome, bicuspid aortic valve (BAV) aortopathy, aortic aneurysm, or other genetically triggered aortic diseases at risk for aortic catastrophe from aortic dissection or rupture or may accelerate aneurysm formation. Therefore, for people with aortic disease or a condition associated with aortic disease, discussion about safe levels of low-intensity, noncompetitive exercise should be emphasized beginning at a young age. This is important for a healthy lifestyle and to prevent social stigmatization, which may occur when physical activity is restricted excessively in young people. Marfan syndrome, an autosomal dominant disorder of connective tissue with an estimated prevalence of 1 in 5000 to 10 000, is caused by abnormal fibrillin-1 attributable to mutations in the FBN1 gene.2 Manifestations involve multiple organ systems, including the aorta, heart and valves, skeleton, eye, lungs, and dura. FBN1 mutations can be identified in the vast majority of patients satisfying the revised Ghent criteria for Marfan syndrome.2 The diagnosis of Marfan syndrome is made by use of clinical criteria, imaging, family history, and genetic testing as outlined in the revised Ghent criteria (Tables 1 and 2).2 Cardiovascular features of Marfan syndrome include mitral valve prolapse, mitral regurgitation, aortic root dilatation (most pronounced at the sinuses of Valsalva), and aortic dissection.2 The descending aorta, although less commonly involved in young patients, is also at risk for aneurysm formation and dissection. View this table: Table 1. Revised Ghent Criteria for the Diagnosis of Marfan Syndrome Other genetically triggered aortic aneurysm syndromes and conditions associated with aortopathy may increase the risk of aortic dissection in competitive athletes. …

Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome.

Three international nosologies have been proposed for the diagnosis of Marfan syndrome (MFS): the Berlin nosology in 1988; the Ghent nosology in 1996 (Ghent-1); and the revised Ghent nosology in 2010 (Ghent-2). We reviewed the literature and discussed the challenges and concepts of diagnosing MFS in adults. Ghent-1 proposed more stringent clinical criteria, which led to the confirmation of MFS in only 32%–53% of patients formerly diagnosed with MFS according to the Berlin nosology. Conversely, both the Ghent-1 and Ghent-2 nosologies diagnosed MFS, and both yielded similar frequencies of MFS in persons with a causative FBN1 mutation (90% for Ghent-1 versus 92% for Ghent-2) and in persons not having a causative FBN1 mutation (15% versus 13%). Quality criteria for diagnostic methods include objectivity, reliability, and validity. However, the nosology-based diagnosis of MFS lacks a diagnostic reference standard and, hence, quality criteria such as sensitivity, specificity, or accuracy cannot be assessed. Medical utility of diagnosis implies congruency with the historical criteria of MFS, as well as with information about the etiology, pathogenesis, diagnostic triggers, prognostic triggers, and potential complications of MFS. In addition, social and psychological utilities of diagnostic criteria include acceptance by patients, patient organizations, clinicians and scientists, practicability, costs, and the reduction of anxiety. Since the utility of a diagnosis or exclusion of MFS is context-dependent, prioritization of utilities is a strategic decision in the process of nosology development. Screening tests for MFS should be used to identify persons with MFS. To confirm the diagnosis of MFS, Ghent-1 and Ghent-2 perform similarly, but Ghent-2 is easier to use. To maximize the utility of the diagnostic criteria of MFS, a fair and transparent process of nosology development is essential.

Ghent Criteria an Aid to Diagnose Latent Systemic Diseases in Marfan Syndrome.

A 23-year-old tall female reported with a chief complaint of intermittent vague pain in the left lower posterior teeth region for the past two years. Her past medical history revealed that the patient has cardiac problem and visual impairment since birth and had not undergone any treatment for the same. Family history revealed that her parents and siblings are apparently healthy with no similar complaints. General examination revealed height measurement of 174.5 cms (upper segment-72.5 cms and lower segment -102 cm, long and slender extremities [Table/Fig-1] with spider- like fingers and toes (arachnodactyly) [Table/Fig-2], positive Walker’s sign [Table/Fig-3], Steinberg’s sign [Table/Fig-4] and pectus carinatum [Table/Fig-5]. Facial profile examination revealed dolicocephalic face, sunken eyes, incompetent lips, malar hypoplasia [Table/Fig-6]. Review of systems revealed impaired vision (myopia) [Table/Fig-1]: Thin and slender lower limb [Table/Fig-2]: Arachnodactyly [Table/Fig-3]: Walker’s sign (the distal phalange of the first and fifth fingers of the hand overlap when wrapped around the opposite wrist) [Table/Fig-4]: Steinberg’s sign (the thumb projects beyond the ulnar border while completely opposed within the clenched hand) [Table/Fig-5]: Pectus carinatum [Table/Fig-6]: Facial profile showing dolicocephalic face, incompetent lips, malar hypoplasia On intraoral examination patient had narrow upper and lower arch with crowding of teeth, high arched palate and multiple dental caries and root stumps [Table/Fig-7]. Correlating the history such as congenital cardiac anomaly, visual impairment and characteristic features such as dolicocephalic face, high arched palate, positive Walker’s and Steinberg’s sign the case was provisionally diagnosed as Marfan syndrome with a differential diagnosis of Ectopia Lentis syndrome, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, Beals syndrome. [Table/Fig-7]: Showing crowding of teeth in upper arch and high arched palate Orthopantomogram (OPG) revealed root stumps 16,37,46 and coronal radiolucency in 36 involving pulp associated with diffuse periapical radiolucency suggestive of periapical abscess, coronal radiolucency in 26,27,47 involving pulp suggestive of dental caries, impacted 48, prominent antegonial notch bilaterally, malformed right condyle and flattening of left condyle [Table/Fig-8]. [Table/Fig-8]: OPG reveals alteration of condylar morphology in right and left TMJ, impaction, root stumps, dental caries On referral to cardiologist patient was subjected to Echocardiogram which revealed mild mitral valve prolapse with mitral regurgitation and mild tricuspid valve prolapse with tricuspid regurgitation, aortic dilatation with Z score=2. Ophthalmologist report revealed bilateral ectopia lentis and myopia (dioptre -4). Based on the revised Ghent criteria [1] in the absence of family history with aortic dilatation (Z=2), ectopia lentis and systemic score of 9 (wrist and thumb sign-3, pectus carinatum-2, scoliosis-1, facial features-1, myopia>3 diopter-1, mitral valve prolapse-1) the case was confirmed as Marfan syndrome. Patient was adviced extraction of root stumps 16,37 and 46 under antibiotic prophylaxis (Amoxicillin 2g one hour prior to extraction) and endodontic management of 26,27,36,47. On regular review visits for endodontic treatment, apprehensive and less sociable nature of the patient was evident. Many case reports of Marfan syndrome reported in the literature though was diagnosed based on Ghent criteria, the systemic score, aortic Z score, dioptre value has not been reported for all the cases [2–4]. In the present case the diagnosis of the common and other hidden systemic manifestations was arrived based on revised Ghent criteria and the aortic Z score of 2, dioptre value of -4 and systemic score of 9 were calculated. Unique features such as bilateral condylar malformation, prominent antegonial notch which were not reported in the other cases was observed in the present case.

Cardiovascular Management of Marfan Syndrome: Implications for Nurse Practitioners

Marfan syndrome (MFS) is a genetic disorder affecting 1 in 5,000 individuals. The diagnosis is made using a combination of genetic testing and the revised Ghent criteria. MFS is associated with the cardiovascular-related risks of aortic dilation and dissection. Therefore, the main goal of medical therapy is blood pressure control using beta-blockers and lifestyle modification. Prophylactic surgical intervention remains the single, definitive measure in preventing dissection or rupture. Nurse practitioners must be vigilant in caring for this population as these cardiovascular risks can be reduced by early identification and diagnosis and timely intervention.

FBN1 Mutation Does Not Influence Handling of Patients with Confirmed Marfan Syndrome

Background: Marfan syndrome (MFS) is an inherited connective-tissue disorder, caused by a mutation in the FBN1 gene. Diagnosis of MFS relies on revised Ghent criteria (RGC) with three cardinal clinical symptoms: dilatation of sinus of Valsalva (SV), ectopia lentis (EL), and systemic manifestation (Sys). We analyzed prevalence and age of manifestation of cardinal symptoms according to RGC in patients with and without FBN1. Finally, we also wanted to evaluate whether it is suggestive to distinguish patients with or without FBN1 mutation concerning regular follow-up and prophylaxis.

Marfan syndrome: Progress report

Marfan syndrome is a multi-system connective tissue disorder, with primary involvement of the cardiovascular, ocular and skeletal systems. This autosomal heritable disease is mainly attributable to a defect in the FBN1 gene. Until 2010, the clinical diagnosis of Marfan syndrome was based on the Ghent criteria of 1996. Recently, the Ghent criteria have been revised. The revised guidelines of 2010 place more emphasis on aortic root dilatation, ectopia lentis and FBN1 mutation testing in the diagnostic assessment of Marfan syndrome. Although the revised Ghent criteria of 2010 are easier to apply, they do raise some issues that need to be addressed.In addition to adjustments in the diagnosis of Marfan syndrome, there is progress in the understanding of the pathophysiology in Marfan syndrome, leading to new treatment strategies. Losartan, an angiotensin II receptor type 1 blocker, has been shown to inhibit transforming growth factor beta signal transduction and thereby prevent aortic root aneurysms in a mouse model of Marfan syndrome. This article will provide a critical appraisal of the revised Ghent nosology in 2010 and will highlight future perspectives regarding the treatment of Marfan syndrome.

Characterization of large genomic deletions in the FBN1 gene using multiplex ligation-dependent probe amplification

BackgroundConnective tissue diseases characterized by aortic aneurysm, such as Marfan syndrome, Loeys-Dietz syndrome and Ehlers Danlos syndrome type IV are heterogeneous and despite overlapping phenotypes, the natural history, clinical manifestations and interventional course for each diagnosis can be quite unique. The majority of mutations involved in the etiology of these disorders are missense and nonsense mutations. However, large deletions and duplications undetected by sequencing may be implicated in their pathogenesis, and may explain the apparent lack of genotype-phenotype correlation in a subset of patients. The objective of this study was to search for large pathogenic deletions and/or duplications in the FBN1, TGFβR1, and TGFβR2 genes using multiplex-ligation dependent probe amplification (MLPA) in patients with aortopathy, in whom no mutations in the FBN1, TGFβR1, and TGFβR2 genes were identified by sequencing.MethodsThe study included 14 patients from 11 unrelated families with aortic aneurysm. Of those, six patients (including 3 first-degree relatives), fulfilled the revised Ghent criteria for Marfan syndrome, and eight had predominantly aortic aneurysm/dilatation with variable skeletal and craniofacial involvement. MLPA for FBN1, TGFβR1, and TGFβR2 was carried out in all patients. A 385 K chromosome 15 specific array was used in two patients with a deletion of the entire FBN1 in order to define its size and boundaries.ResultsWe identified two novel large deletions in the FBN1 gene in four patients of two unrelated families who met clinical diagnostic criteria for Marfan syndrome. One patient was found to have a FBN1 deletion encompassing exons 1-5. The other three patients had a 542 Kb deletion spanning the whole FBN1 gene and five additional genes (SLC24A5, MYEF2, CTXN2, SLC12A1, DUT) in the chromosome 15.ConclusionsOur findings expand the number of large FBN1 deletions, and emphasize the importance of screening for large genomic deletions in connective tissue disorders featuring aortopathies, especially for those with classic Marfan phenotype.

Critical appraisal of the revised Ghent criteria for diagnosis of Marfan syndrome

Marfan syndrome (MFS) is a connective tissue disorder with major features in cardiovascular, ocular and skeletal systems. Recently, diagnostic criteria were revised where more weight was given to the aortic root dilatation. We applied the revised Marfan nosology in an established adult Marfan population to define practical repercussions of novel criteria for clinical practice and individual patients. Out of 180 MFS patients, in 91% (n = 164) the diagnosis of MFS remained. Out of 16 patients with rejected diagnosis, four patients were diagnosed as MASS (myopia, mitral valve prolapse, borderline non-progressive aortic root dilatation, skeletal findings and striae) phenotype, three as ectopia lentis syndrome and in nine patients no alternative diagnosis was established. In 13 patients, the diagnosis was rejected because the Z-score of the aortic root was <2, although the aortic diameter was larger than 40 mm in six of them. In three other patients, the diagnosis of MFS was rejected because dural ectasia was given less weight in the revised nosology. Following the revised Marfan nosology, the diagnosis of MFS was rejected in 9% of patients, mostly because of the absence of aortic root dilatation defined as Z-score ≥2. Currently used Z-scores seem to underestimate aortic root dilatation, especially in patients with large body surface area (BSA). We recommend re-evaluation of criteria for aortic root involvement in adult patients with a suspected diagnosis of MFS.