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Sample records for marfan syndrome study

  1. Marfan Syndrome

    MedlinePlus

    Marfan syndrome is a disorder that affects connective tissue. Connective tissues are proteins that support skin, bones, blood ... fibrillin. A problem with the fibrillin gene causes Marfan syndrome. Marfan syndrome can be mild to severe, and ...

  2. Marfan Syndrome

    MedlinePlus

    ... Like for Kids With Marfan Syndrome? en español Síndrome de Marfan Evan couldn't wait for school ... for Marfan syndrome runs in families, getting passed down to children from parents who have the disease. ...

  3. Marfan Syndrome

    MedlinePlus

    ... Like for Kids With Marfan Syndrome? en español Síndrome de Marfan Evan couldn't wait for school ... for Marfan syndrome runs in families, getting passed down to children from parents who have the disease. ...

  4. Marfan syndrome

    MedlinePlus

    Marfan syndrome is a disorder of connective tissue. This is the tissue that strengthens the body's structures. Disorders ... Marfan syndrome is caused by defects in a gene called fibrillin-1. Fibrillin-1 plays an important role ...

  5. Marfan Syndrome

    MedlinePlus

    ... Connective tissue helps support all parts of your body. It also helps control how your body grows and develops. Marfan syndrome most often affects ... A mutation, or change, in the gene that controls how the body makes fibrillin causes Marfan syndrome. Fibrillin is a ...

  6. Marfan syndrome

    PubMed Central

    Jain, Eesha; Pandey, Ramesh Kumar

    2013-01-01

    Marfan syndrome is a rare autosomal dominant disorder of the connective tissue, with skeletal, ligamentous, orooculofacial, pulmonary, abdominal, neurological and the most fatal, cardiovascular manifestations. It has no cure but early diagnosis, regular monitoring and preventive lifestyle regimen ensure a good prognosis. However, the diagnosis can be difficult as it is essentially a clinical one, relying on family history, meticulous physical examination and investigation of involved organ systems. Patients of Marfan syndrome portray very typical physical and orofacial characteristics, suggesting obvious recognition, but due to variable phenotypic expression, cases often go unnoticed unless a full range of attributing features is apparent. Dental practitioners are very likely to encounter patients of Marfan syndrome at an early age as they frequently present for dental treatment. The present case report illustrates the preliminary screening of Marfan syndrome in a dental office followed by timely diagnosis and appropriate referrals. PMID:24336584

  7. Marfan syndrome.

    PubMed

    Gonzales, Elizabeth A

    2009-12-01

    To provide an overview of Marfan syndrome (MFS), including diagnostic criteria, genetic factors involved, emerging theories for treatment, a case study, and an overview of genetic counseling for individuals and families of those with MFS. Selected research, review, and clinical articles. MFS is a connective tissue disorder with distinct physical characteristics. Recent advances in the field of genetics have traced this disease process to certain gene mutations. Affecting the optical, skeletal and cardiovascular systems, MFS can cause significant morbidity and mortality if left untreated. Close surveillance and early treatment are necessary to ensure a normal life span. It is important for the advanced practice nurse (APN) to be aware of the complications in those with MFS. Attentive surveillance can decrease mortality and morbidity associated with this syndrome. A multidisciplinary approach, utilizing the expertize of the APN, is necessary for comprehensive care.

  8. Marfan Syndrome

    PubMed Central

    Sivasankari, T; Mathew, Philips; Austin, Ravi David; Devi, Sakthi

    2017-01-01

    Marfan syndrome (MFS) is the autosomal dominant-inherited multisystem connective-tissue disorder, with a reported incidence of 1 in 10,000 individuals and equal distribution in both genders. The main clinical manifestation of this disorder consists of an exaggerated length of the upper and lower limbs, hyperlaxity, scoliosis, alterations in the cardiovascular and pulmonary systems, and atypical bone overgrowth. Orofacial manifestations such as high-arched palate, hypodontia, long narrow teeth, bifid uvula, mandibular prognathism, and temporomandibular disorders are also common. Early diagnosis of MFS is essential to prevent the cardiovascular complications and treatment of orofacial manifestations, thus to increase the quality of life of the patient. PMID:28584496

  9. Marfan syndrome (image)

    MedlinePlus

    Marfan syndrome is a disorder of connective tissue which causes skeletal defects typically recognized in a tall, lanky person. A person with Marfan syndrome may exhibit long limbs and spider-like fingers, ...

  10. Evolving phenotype of Marfan's syndrome

    PubMed Central

    Lipscomb, K.; Clayton-Smith, J.; Harris, R.

    1997-01-01

    Accepted 20 August 1996
 AIM—To examine evolution of the physical characteristics of Marfan's syndrome throughout childhood.
METHODS—40 children were ascertained during the development of a regional register for Marfan's syndrome. Evolution of the clinical characteristics was determined by repeat evaluation of 10 patients with sporadic Marfan's syndrome and 30 with a family history of the condition. DNA marker studies were used to facilitate diagnosis in those with the familial condition.
RESULTS—Musculoskeletal features predominated and evolved throughout childhood. Gene tracking enabled early diagnosis in children with familial Marfan's syndrome.
CONCLUSIONS—These observations may aid the clinical diagnosis of Marfan's syndrome in childhood, especially in those with the sporadic condition. Gene tracking has a role in the early diagnosis of familial Marfan's syndrome, allowing appropriate follow up and preventive care.

 PMID:9059160

  11. Heart and Blood Vessels in Marfan Syndrome

    MedlinePlus

    ... The Marfan Foundation Marfan & Related Disorders What is Marfan Syndrome? What are Related Disorders? What are the Signs? ... Contact Us Donate Marfan & Related Disorders What is Marfan Syndrome? What are Related Disorders? What are the Signs? ...

  12. Marfan Syndrome (For Parents)

    MedlinePlus

    ... Safety Doctors & Hospitals Q&A Recipes En Español Teachers - Looking for Health Lessons? Visit KidsHealth in the ... other talents and interests. Keep in touch with teachers and explain that even though Marfan syndrome doesn' ...

  13. Marfan Syndrome (For Parents)

    MedlinePlus

    ... later. People with Marfan syndrome also often have myopia (nearsightedness) and are at greater risk for developing ... be couch potatoes. They can and should play, exercise, and generally be active — they just have to ...

  14. Marfan syndrome: current perspectives.

    PubMed

    Pepe, Guglielmina; Giusti, Betti; Sticchi, Elena; Abbate, Rosanna; Gensini, Gian Franco; Nistri, Stefano

    2016-01-01

    Marfan syndrome (MFS) is a pleiotropic connective tissue disease inherited as an autosomal dominant trait, due to mutations in the FBN1 gene encoding fibrillin 1. It is an important protein of the extracellular matrix that contributes to the final structure of a microfibril. Few cases displaying an autosomal recessive transmission are reported in the world. The FBN1 gene, which is made of 66 exons, is located on chromosome 15q21.1. This review, after an introduction on the clinical manifestations that leads to the diagnosis of MFS, focuses on cardiovascular manifestations, pharmacological and surgical therapies of thoracic aortic aneurysm and/or dissection (TAAD), mechanisms underlying the progression of aneurysm or of acute dissection, and biomarkers associated with progression of TAADs. A Dutch group compared treatment with losartan, an angiotensin II receptor-1 blocker, vs no other additional treatment (COMPARE clinical trial). They observed that losartan reduces the aortic dilatation rate in patients with Marfan syndrome. Later on, they also reported that losartan exerts a beneficial effect on patients with Marfan syndrome carrying an FBN1 mutation that causes haploinsufficiency (quantitative mutation), while it has no significant effect on patients displaying dominant negative (qualitative) mutations. Moreover, a French group in a 3-year trial compared the administration of losartan vs placebo in patients with Marfan syndrome under treatment with beta-receptor blockers. They observed that losartan decreases blood pressure but has no effect on aortic diameter progression. Thus, beta-receptor blockers remain the gold standard therapy in patients with Marfan syndrome. Three potential biochemical markers are mentioned in this review: total homocysteine, serum transforming growth factor beta, and lysyl oxidase. Moreover, markers of oxidative stress measured in plasma, previously correlated with clinical features of Marfan syndrome, may be explored as potential

  15. Marfan syndrome: current perspectives

    PubMed Central

    Pepe, Guglielmina; Giusti, Betti; Sticchi, Elena; Abbate, Rosanna; Gensini, Gian Franco; Nistri, Stefano

    2016-01-01

    Marfan syndrome (MFS) is a pleiotropic connective tissue disease inherited as an autosomal dominant trait, due to mutations in the FBN1 gene encoding fibrillin 1. It is an important protein of the extracellular matrix that contributes to the final structure of a microfibril. Few cases displaying an autosomal recessive transmission are reported in the world. The FBN1 gene, which is made of 66 exons, is located on chromosome 15q21.1. This review, after an introduction on the clinical manifestations that leads to the diagnosis of MFS, focuses on cardiovascular manifestations, pharmacological and surgical therapies of thoracic aortic aneurysm and/or dissection (TAAD), mechanisms underlying the progression of aneurysm or of acute dissection, and biomarkers associated with progression of TAADs. A Dutch group compared treatment with losartan, an angiotensin II receptor-1 blocker, vs no other additional treatment (COMPARE clinical trial). They observed that losartan reduces the aortic dilatation rate in patients with Marfan syndrome. Later on, they also reported that losartan exerts a beneficial effect on patients with Marfan syndrome carrying an FBN1 mutation that causes haploinsufficiency (quantitative mutation), while it has no significant effect on patients displaying dominant negative (qualitative) mutations. Moreover, a French group in a 3-year trial compared the administration of losartan vs placebo in patients with Marfan syndrome under treatment with beta-receptor blockers. They observed that losartan decreases blood pressure but has no effect on aortic diameter progression. Thus, beta-receptor blockers remain the gold standard therapy in patients with Marfan syndrome. Three potential biochemical markers are mentioned in this review: total homocysteine, serum transforming growth factor beta, and lysyl oxidase. Moreover, markers of oxidative stress measured in plasma, previously correlated with clinical features of Marfan syndrome, may be explored as potential

  16. Living with Marfan Syndrome

    MedlinePlus

    ... suggest low- and moderate-impact activities, such as swimming, golf, brisk walking, hiking, and tennis. If you have a child who has Marfan syndrome, talk with his or her doctor about whether your child can take part in physical education at school. Work with your child's doctor and ...

  17. Seminoma in Marfan's syndrome.

    PubMed Central

    Epenetos, A. A.; Collis, C. H.

    1979-01-01

    A patient with a testicular seminoma and Marfan's syndrome is described. The association is unlikely to be by chance alone, and an explanation in terms of either an associated congenital defect, or a minor chromosomal anomaly, is discussed. Images Fig. 1 Fig. 2 PMID:537969

  18. [Multidisciplinary practice guideline 'Marfan syndrome'].

    PubMed

    Hilhorst-Hofstee, Yvonne

    2013-01-01

    Marfan syndrome is a multi-system disorder of dominant inheritance in which the cardiovasculature, in particular the aorta, the eyes and the skeleton are affected. Diagnostic assessment and treatment of patients who are suspected of or have Marfan syndrome should preferably be done by multidisciplinary teams such as those found in specialised Marfan syndrome centres. The practice guideline is intended for all care givers involved with the recognition, diagnosis, consultations and the medicinal and surgical treatment of Marfan patients; it includes referral criteria and information on the referral process. A diagnosis of Marfan syndrome is based on international criteria in which aortic root dilatation and dissection, ectopia lentis, an affected first-degree family member and a pathogenic FBN1 mutation are the cardinal features. Alternative diagnoses are also included in the practice guideline. Recommendations are given for the monitoring and treatment of Marfan patients during pregnancy and delivery. Advice on lifestyle is mainly focussed on sports activities.

  19. [Respiratory manifestations of Marfan's syndrome].

    PubMed

    Neuville, M; Jondeau, G; Crestani, B; Taillé, C

    2015-02-01

    Marfan's syndrome is a rare genetic disorder caused by a mutation of the gene FBN1, coding for the protein fibrillin-1. Cardiovascular, musculoskeletal and ophthalmic manifestations are the most commonly observed, but minor diagnostic criteria also include pulmonary manifestations. Pneumothorax, frequently relapsing, affects 5 to 11% of patients. Rib cage abnormalities (pectus excavatum or pectus carinatum) and apical blebs may contribute to their occurrence. Treatment does not require any specific procedure but there is an increased risk of recurrence. Pectus excavatum affects up to 60% of the patients, without any functional impairment in most cases. Surgery may be required (using the Nuss procedure) in case of cardiovascular or psychological symptoms. Marfan's syndrome is frequently associated with obstructive sleep apnoea, which may itself contribute to aortic dilatation. Some studies suggest a potential role of craniofacial abnormalities in the pathogenesis of sleep apnea in these patients. Pulmonologists should consider Marfan's syndrome when treating patients for recurrent spontaneous pneumothorax or rib cage abnormalities, since early detection of cardiac abnormalities improves the prognosis significantly. Copyright © 2014 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  20. Ambulatory (24 h) blood pressure and arterial stiffness measurement in Marfan syndrome patients: a case control feasibility and pilot study.

    PubMed

    Hillebrand, Matthias; Nouri, Ghazaleh; Hametner, Bernhard; Parragh, Stephanie; Köster, Jelena; Mortensen, Kai; Schwarz, Achim; von Kodolitsch, Yskert; Wassertheurer, Siegfried

    2016-05-06

    The aim of this work is the investigation of measures of ambulatory brachial and aortic blood pressure and indices of arterial stiffness and aortic wave reflection in Marfan patients. A case-control study was conducted including patients with diagnosed Marfan syndrome following Ghent2 nosology and healthy controls matched for sex, age and daytime brachial systolic blood pressure. For each subject a 24 h ambulatory blood pressure and 24 h pulse wave analysis measurement was performed. All parameters showed a circadian pattern whereby pressure dipping was more pronounced in Marfan patients. During daytime only Marfan patients with aortic root surgery showed increased pulse wave velocity. In contrast, various nighttime measurements, wave reflection determinants and circadian patterns showed a significant difference. The findings of our study provide evidence that ambulatory measurement of arterial stiffness parameters is feasible and that these determinants are significantly different in Marfan syndrome patients compared to controls in particular at nighttime. Further investigation is therefore indicated.

  1. How Is Marfan Syndrome Treated?

    MedlinePlus

    ... signs and symptoms. Heart Treatments Aortic dilation, or aortic aneurysm , is the most common and serious heart problem linked to Marfan syndrome. In this condition, the aorta—the main artery that carries oxygen-rich blood ...

  2. Marfan's Syndrome: Detection and Management.

    ERIC Educational Resources Information Center

    Cantwell, John D.

    1986-01-01

    Marfan's Syndrome, a disorder of connective tissue, has gained increased attention since the death of volleyball star Flo Hyman. This article reviews the disease and discusses methods of detection and management. (Author/MT)

  3. Marfan's Syndrome: Detection and Management.

    ERIC Educational Resources Information Center

    Cantwell, John D.

    1986-01-01

    Marfan's Syndrome, a disorder of connective tissue, has gained increased attention since the death of volleyball star Flo Hyman. This article reviews the disease and discusses methods of detection and management. (Author/MT)

  4. The economic impact of Marfan syndrome: a non-experimental, retrospective, population-based matched cohort study

    PubMed Central

    2014-01-01

    Background Marfan syndrome is a rare disease of the connective tissues, affecting multiple organ systems. Elevated morbidity and mortality in these patients raises the issue of costs for sickness funds and society. To date, there has been no study analysing the costs of Marfan syndrome from a sickness fund and societal perspective. Objective To estimate excess health resource utilisation, direct (non-)medical and indirect costs attributable to Marfan syndrome from a healthcare payer and a societal perspective in Germany in 2008. Methods A retrospective matched cohort study design is applied, using claims data. For isolating the causal effect of Marfan syndrome on excess costs, a genetic matching algorithm was used to reduce differences in observable characteristics between Marfan syndrome patients and the control group. 892 patients diagnosed with Marfan syndrome (ICD-10 Q87.4) were matched from a pool of 26,645 control individuals. After matching, we compared health resource utilisation and costs. Results From the sickness fund perspective, an average Marfan syndrome patient generates excess annual costs of €2496 compared with a control individual. From the societal perspective, excess annual costs amount to €15,728. For the sickness fund, the strongest cost drivers are inpatient treatment and care by non-physicians. From the sickness fund perspective, the third (25–41 years) and first (0–16 years) age quartiles reveal the greatest surplus in total costs. Marfan syndrome patients have 39% more physician contacts, a 153% longer average length of hospital stay, 119% more inpatient stays, 33% more prescriptions, 236% more medical imaging and 20% higher average prescription costs than control individuals. Depending on the prevalence, the economic impact from the sickness fund perspective ranges between €24.0 million and €61.4 million, whereas the societal economic impact extends from €151.3 million to €386.9 million. Conclusions Relative to its low

  5. The economic impact of Marfan syndrome: a non-experimental, retrospective, population-based matched cohort study.

    PubMed

    Achelrod, Dmitrij; Blankart, Carl Rudolf; Linder, Roland; von Kodolitsch, Yskert; Stargardt, Tom

    2014-06-23

    Marfan syndrome is a rare disease of the connective tissues, affecting multiple organ systems. Elevated morbidity and mortality in these patients raises the issue of costs for sickness funds and society. To date, there has been no study analysing the costs of Marfan syndrome from a sickness fund and societal perspective. To estimate excess health resource utilisation, direct (non-)medical and indirect costs attributable to Marfan syndrome from a healthcare payer and a societal perspective in Germany in 2008. A retrospective matched cohort study design is applied, using claims data. For isolating the causal effect of Marfan syndrome on excess costs, a genetic matching algorithm was used to reduce differences in observable characteristics between Marfan syndrome patients and the control group. 892 patients diagnosed with Marfan syndrome (ICD-10 Q87.4) were matched from a pool of 26,645 control individuals. After matching, we compared health resource utilisation and costs. From the sickness fund perspective, an average Marfan syndrome patient generates excess annual costs of €2496 compared with a control individual. From the societal perspective, excess annual costs amount to €15,728. For the sickness fund, the strongest cost drivers are inpatient treatment and care by non-physicians. From the sickness fund perspective, the third (25-41 years) and first (0-16 years) age quartiles reveal the greatest surplus in total costs. Marfan syndrome patients have 39% more physician contacts, a 153% longer average length of hospital stay, 119% more inpatient stays, 33% more prescriptions, 236% more medical imaging and 20% higher average prescription costs than control individuals. Depending on the prevalence, the economic impact from the sickness fund perspective ranges between €24.0 million and €61.4 million, whereas the societal economic impact extends from €151.3 million to €386.9 million. Relative to its low frequency, Marfan syndrome requires high healthcare

  6. Aortic Involvement in Pediatric Marfan syndrome: A Review.

    PubMed

    Ekhomu, Omonigho; Naheed, Zahra J

    2015-06-01

    Outlining specific protocols for the management of pediatric patients with Marfan syndrome has been challenging. This is mostly due to a dearth of clinical studies performed in pediatric patients. In Marfan syndrome, the major sources of morbidity and mortality relate to the cardiovascular system. In this review, we focus on aortic involvement seen in pediatric patients with Marfan syndrome, ranging from aortic dilatation to aortic rupture and heart failure. We discuss the histological, morphological, and pathogenetic basis of the cardiac manifestations seen in pediatric Marfan syndrome and use a specific case to depict our experienced range of cardiovascular manifestations. The survival for patients with Marfan syndrome may approach the expected survival for non-affected patients, with optimal management. With this potentiality in mind, we explore possible and actual management considerations for pediatric Marfan syndrome, examining both medical and surgical therapy modalities that can make the possibility of improved survival a reality.

  7. Birth characteristics of women with Marfan syndrome, obstetric and neonatal outcomes of their pregnancies-A nationwide cohort and case-control study.

    PubMed

    Kernell, Kristina; Sydsjö, Gunilla; Bladh, Marie; Josefsson, Ann

    2017-08-01

    The aim was to investigate birth characteristics, obstetric and neonatal outcomes of the first childbirth in women with Marfan syndrome by use of Swedish national registers since pregnancy-related outcomes in women with Marfan syndrome have only been sparsely investigated. In this national population-based cohort study and matched case-control study of Swedish women born 1973-1993, women with Marfan syndrome (n=273) were compared to women without the condition (n=1 017 265). The study population was followed until 2013. A total of 364 553 mother-firstborn-offspring pairs were analyzed. Sixty-one women with Marfan syndrome became mothers. Women with Marfan syndrome were also compared to 543 healthy controls. Women with Marfan syndrome were more often born preterm (p<0.001), small-for-gestational age (p<0.001), and delivered by cesarean section (p=0.001). Women with Marfan syndrome had no increased risk of giving birth by cesarean section (p=0.079). No increased neonatal risks in their children were found. Women with Marfan syndrome were less likely to give birth than those without (p<0.001). There were no maternal deaths. Women with Marfan syndrome were more likely to be born preterm, SGA and by cesarean section. These increased risks of preterm birth and SGA babies were not found in connection with their own first childbirth. Pregnancies with known fetal Marfan syndrome have to be carefully monitored. The results are important for obstetricians giving preconception counseling and treating women with Marfan syndrome. Further studies are needed to evaluate risks during pregnancy and long-term effects of pregnancy on the cardiovascular status of women with Marfan syndrome. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Neonatal Marfan syndrome: Report of two cases.

    PubMed

    Jurko, Tomas; Jurko, Alexander; Minarik, Milan; Micieta, Vladimir; Tonhajzerova, Ingrid; Kolarovszka, Hana; Zibolen, Mirko

    2017-07-01

    Marfan syndrome is rarely diagnosed in the neonatal period because of variable expression and age-dependent appearance of clinical signs. The prognosis is usually poor due to high probability of congestive heart failure, mitral and tricuspid regurgitations with suboptimal response to medical therapy and difficulties in surgical management. The authors have studied two cases of Marfan syndrome in the newborn period. Two cases of neonatal Marfan syndrome, one male and one female, were diagnosed by characteristic physical appearance. Both infants had significant cardiovascular abnormalities diagnosed by ultrasonography. Genetic DNA analysis in the second case confirmed the mutations in the fibrillin-1 gene located on chromosome 15q21 which is responsible for the development of Marfan syndrome. The boy died at six weeks of age with signs of rapidly progressive left ventricular failure associated with pneumonia. The second infant was having only mild signs of congestive heart failure and has been treated with beta blockers. At the age of 4 years her symptoms of congestive heart failure had worsened due to progression of mitral and tricuspid insufficiency and development of significant cardiomegaly. Mitral and tricuspid valvuloplasy had to be done at that time. Early diagnosis of Marfan syndrome in the newborn period can allow treatment in the early stages of cardiovascular abnormalities and may improve the prognosis. It also helps to explain to the family the serious health problem of their child.

  9. Sudden death in Marfan syndrome.

    PubMed

    Hugar, Basappa S; Praveen, Shivaramareddy; Kainoor, Sunil K; Shetty, Akshith Raj S

    2014-07-01

    Marfan syndrome is an autosomal dominant genetic disorder of the connective tissue. The most serious complications of this syndrome are defects of the heart valves and aorta. Aneurysms of thoracic aorta are known to develop in Marfan syndrome. Other causes for development of aneurysms of the thoracic aorta are trauma, infections, valve and arch anomalies, genetic disorders, and atherosclerosis. These aneurysms upon rupture may lead to sudden deaths. They are usually detected during routine screening or follow-up of such persons suffering from Marfan syndrome and upon death will be certified by the treating physician. Thus, an autopsy surgeon rarely comes across such deaths. One such case of sudden death due to cardiac tamponade consequent upon rupture of dissecting aortic aneurysm in a 33-year-old male who complained of throbbing pains in the chest, radiating to back, became breathless, cyanotic and died on the way to hospital is being presented here.

  10. Genetic testing in Marfan syndrome.

    PubMed

    Child, Anne H; Aragon-Martin, Jose A; Sage, Karen

    2016-01-01

    Genetic testing is aiding rapid diagnosis of Marfan syndrome as a basis for management of eye, heart and skeletal disease. The affected patient's mutation can be used as a basis for prenatal or postnatal diagnosis of offspring. Preimplantation genetic diagnosis, the technique of choice, can ensure an unaffected pregnancy.

  11. Cardiomyopathy in Marfan syndrome.

    PubMed

    Hetzer, Roland; Siegel, Günter; Delmo Walter, Eva Maria

    2016-02-01

    This report aims to evaluate the existence of primary and secondary cardiomyopathy in patients with Marfan syndrome (MFS) who underwent surgical management for primary cardiovascular sequelae of this genetic disorder. Likewise, we aim to determine whether the myocardium in MFS is susceptible to ischaemia independent of myocardial protection used during surgery. Between April 1986 and May 2012, 421 patients with MFS were surgically treated for cardiovascular manifestations. Among them, 47 (mean age: 39.45 ± 12.64, median: 36, range: 19-66, years) eventually were surgically treated for cardiomyopathy. They were grouped into A: patients who subsequently developed ischaemic cardiomyopathy and eventually underwent coronary revascularization for coronary artery disease (n = 11); B: patients who subsequently developed end-stage cardiomyopathy for which a mechanical circulatory support device was implanted to support the failing heart (n = 13) and C: patients who subsequently developed end-stage cardiomyopathy (n = 23), among whom 21 underwent primary heart transplantation, while 2 patients are still waiting for donor hearts. Retrospective analysis of the medical records of 47 patients revealed the following: In Group A, 3 (27.2%) patients had already existing ischaemic cardiomyopathy before the first various cardiovascular surgeries, while ischaemic cardiomyopathy in the other 8 (72.7%) developed postoperatively. The interval between previous surgery and development of cardiomyopathy was a mean of 8.0 ± 07 years. In Group B, 5 (38.4%) had existing primary cardiomyopathy prior to surgery, while 8 (61.5%) developed end-stage cardiomyopathy postoperatively. The interval between previous surgery and development of cardiomyopathy was a mean of 9.0 ± 4 months. In Group C, 5 (21.7%) had been diagnosed with cardiomyopathy prior to the cardiovascular surgery, while 18 (78.2%) developed end-stage cardiomyopathy postoperatively. The mean interval between previous surgery and

  12. Observational Cohort Study of Ventricular Arrhythmia in Adults with Marfan Syndrome Caused by FBN1 Mutations

    PubMed Central

    Sheikhzadeh, Sara; Keyser, Britta; Rybczynski, Meike; Sondermann, Claudia; Detter, Christian; Steven, Daniel; Robinson, Peter N.; Berger, Jürgen; Schmidtke, Jörg; Blankenberg, Stefan; Willems, Stephan; von Kodolitsch, Yskert; Hoffmann, Boris A.

    2013-01-01

    Background Marfan syndrome is associated with ventricular arrhythmia but risk factors including FBN1 mutation characteristics require elucidation. Methods and Results We performed an observational cohort study of 80 consecutive adults (30 men, 50 women aged 42±15 years) with Marfan syndrome caused by FBN1 mutations. We assessed ventricular arrhythmia on baseline ambulatory electrocardiography as >10 premature ventricular complexes per hour (>10 PVC/h), as ventricular couplets (Couplet), or as non-sustained ventricular tachycardia (nsVT), and during 31±18 months of follow-up as ventricular tachycardia (VT) events (VTE) such as sudden cardiac death (SCD), and sustained ventricular tachycardia (sVT). We identified >10 PVC/h in 28 (35%), Couplet/nsVT in 32 (40%), and VTE in 6 patients (8%), including 3 with SCD (4%). PVC>10/h, Couplet/nsVT, and VTE exhibited increased N-terminal pro–brain natriuretic peptide serum levels(P<.001). All arrhythmias related to increased NT-proBNP (P<.001), where PVC>10/h and Couplet/nsVT also related to increased indexed end-systolic LV diameters (P = .024 and P = .020), to moderate mitral valve regurgitation (P = .018 and P = .003), and to prolonged QTc intervals (P = .001 and P = .006), respectively. Moreover, VTE related to mutations in exons 24–32 (P = .021). Kaplan–Meier analysis corroborated an association of VTE with increased NT-proBNP (P<.001) and with mutations in exons 24–32 (P<.001). Conclusions Marfan syndrome with causative FBN1 mutations is associated with an increased risk for arrhythmia, and affected persons may require life-long monitoring. Ventricular arrhythmia on electrocardiography, signs of myocardial dysfunction and mutations in exons 24–32 may be risk factors of VTE. PMID:24349050

  13. Study of phenotype evolution during childhood in Marfan syndrome to improve clinical recognition.

    PubMed

    Stheneur, Chantal; Tubach, Florence; Jouneaux, Marlène; Roy, Carine; Benoist, Gregoire; Chevallier, Bertrand; Boileau, Catherine; Jondeau, Guillaume

    2014-03-01

    Because diagnosis of Marfan syndrome is difficult during infancy, we used a large cohort of children to describe the evolution of the Marfan syndrome phenotype with age. Two hundred and fifty-nine children carrying an FBN1 gene mutation and fulfilling Ghent criteria were compared with 474 non-Marfan syndrome children. Prevalence of skeletal features changed with aging: prevalence of pectus deformity increased from 43% at 0-6 years to 62% at 15-17 years, wrist signs increased from 28 to 67%, and scoliosis increased from 16 to 59%. Hypermobility decreased from 67 to 47% and pes planus decreased from 73 to 65%. Striae increased from 2 to 84%. Prevalence of ectopia lentis remained stable, varying from 66 to 72%, similar to aortic root dilatation (varying from 75 to 80%). Aortic root dilatation remained stable during follow-up in this population receiving β-blocker therapy. When comparing Marfan syndrome children with non-Marfan syndrome children, height appeared to be a simple and discriminant criterion when it was >3.3 SD above the mean. Ectopia lentis and aortic dilatation were both similarly discriminating. Ectopia lentis and aortic dilatation are the best-discriminating features, but height remains a simple discriminating variable for general practitioners when >3.3 SD above the mean. Mean aortic dilatation remains stable in infancy when children receive a β-blocker.

  14. Marfan's syndrome and the heart

    PubMed Central

    Stuart, Alan Graham; Williams, Andrew

    2007-01-01

    In recent years, there have been many advances in the treatment of cardiac disease in children with Marfan's syndrome. Early diagnosis, meticulous echocardiographic follow‐up and multidisciplinary assessment are essential. Medical treatment with β‐blockers is probably helpful in most children with aortic root dilatation. Research on TGFβ signalling and the potential treatment role of TGFβ antagonists may lead to exciting new treatments, but the results of clinical trials are awaited. In managing the cardiovascular complications of Marfan's syndrome, the paediatrician has to walk a difficult path. On the one hand, restrictive lifestyle advice and drugs may need to be prescribed, often in the context of a family history of major surgery or even sudden death. On the other hand, it is essential to encourage the often asymptomatic child to develop and mature as normally as possible. PMID:17376944

  15. Echocardiographic versus histologic findings in Marfan syndrome.

    PubMed

    Gu, Xiaoyan; He, Yihua; Li, Zhian; Han, Jiancheng; Chen, Jian; Nixon, J V Ian

    2015-02-01

    This retrospective study attempted to establish the prevalence of multiple-valve involvement in Marfan syndrome and to compare echocardiographic with histopathologic findings in Marfan patients undergoing valvular or aortic surgery. We reviewed echocardiograms of 73 Marfan patients who underwent cardiovascular surgery from January 2004 through October 2009. Tissue histology was available for comparison in 29 patients. Among the 73 patients, 66 underwent aortic valve replacement or the Bentall procedure. Histologic findings were available in 29 patients, all of whom had myxomatous degeneration. Of 63 patients with moderate or severe aortic regurgitation as determined by echocardiography, 4 had thickened aortic valves. The echocardiographic findings in 18 patients with mitral involvement included mitral prolapse in 15. Of 11 patients with moderate or severe mitral regurgitation as determined by echocardiography, 4 underwent mitral valve repair and 7 mitral valve replacement. Histologic findings among mitral valve replacement patients showed thickened valve tissue and myxomatous degeneration. Tricuspid involvement was seen echocardiographically in 8 patients, all of whom had tricuspid prolapse. Two patients had severe tricuspid regurgitation, and both underwent repair. Both mitral and tricuspid involvement were seen echocardiographically in 7 patients. Among the 73 patients undergoing cardiac surgery for Marfan syndrome, 66 had moderate or severe aortic regurgitation, although their valves manifested few histologic changes. Eighteen patients had mitral involvement (moderate or severe mitral regurgitation, prolapse, or both), and 8 had tricuspid involvement. Mitral valves were most frequently found to have histologic changes, but the tricuspid valve was invariably involved.

  16. Echocardiographic versus Histologic Findings in Marfan Syndrome

    PubMed Central

    Gu, Xiaoyan; Li, Zhian; Han, Jiancheng; Chen, Jian; Nixon, J.V. (Ian)

    2015-01-01

    This retrospective study attempted to establish the prevalence of multiple-valve involvement in Marfan syndrome and to compare echocardiographic with histopathologic findings in Marfan patients undergoing valvular or aortic surgery. We reviewed echocardiograms of 73 Marfan patients who underwent cardiovascular surgery from January 2004 through October 2009. Tissue histology was available for comparison in 29 patients. Among the 73 patients, 66 underwent aortic valve replacement or the Bentall procedure. Histologic findings were available in 29 patients, all of whom had myxomatous degeneration. Of 63 patients with moderate or severe aortic regurgitation as determined by echocardiography, 4 had thickened aortic valves. The echocardiographic findings in 18 patients with mitral involvement included mitral prolapse in 15. Of 11 patients with moderate or severe mitral regurgitation as determined by echocardiography, 4 underwent mitral valve repair and 7 mitral valve replacement. Histologic findings among mitral valve replacement patients showed thickened valve tissue and myxomatous degeneration. Tricuspid involvement was seen echocardiographically in 8 patients, all of whom had tricuspid prolapse. Two patients had severe tricuspid regurgitation, and both underwent repair. Both mitral and tricuspid involvement were seen echocardiographically in 7 patients. Among the 73 patients undergoing cardiac surgery for Marfan syndrome, 66 had moderate or severe aortic regurgitation, although their valves manifested few histologic changes. Eighteen patients had mitral involvement (moderate or severe mitral regurgitation, prolapse, or both), and 8 had tricuspid involvement. Mitral valves were most frequently found to have histologic changes, but the tricuspid valve was invariably involved. PMID:25873795

  17. [Modern aortic surgery in Marfan syndrome--2011].

    PubMed

    Kallenbach, K; Schwill, S; Karck, M

    2011-09-01

    Marfan syndrome is a hereditary disease with a prevalence of 2-3 in 10,000 births, leading to a fibrillin connective tissue disorder with manifestations in the skeleton, eye, skin, dura mater and in particular the cardiovascular system. Since other syndromes demonstrate similar vascular manifestations, but therapy may differ significantly, diagnosis should be established using the revised Ghent nosology in combination with genotypic analysis in specialized Marfan centres. The formation of aortic root aneurysms with the subsequent risk of acute aortic dissection type A (AADA) or aortic rupture limits life expectancy in patients with Marfan syndrome. Therefore, prophylactic replacement of the aortic root needs to be performed before the catastrophic event of AADA can occur. The goal of surgery is the complete resection of pathological aortic tissue. This can be achieved with excellent results by using a (mechanically) valved conduit that replaces both the aortic valve and the aortic root (Bentall operation). However, the need for lifelong anticoagulation with Coumadin can be avoided using the aortic valve sparing reimplantation technique according to David. The long-term durability of the reconstructed valve is favourable, and further technical improvements may improve longevity. Although results of prospective randomised long-term studies comparing surgical techniques are lacking, the David operation has become the surgical method of choice for aortic root aneurysms, not only at the Heidelberg Marfan Centre. Replacement of the aneurysmal dilated aortic arch is performed under moderate hypothermic circulatory arrest combined with antegrade cerebral perfusion using a heart-lung machine, which we also use in thoracic or thoracoabdominal aneurysms. Close post-operative follow-up in a Marfan centre is pivotal for the early detection of pathological changes on the diseased aorta.

  18. Questions & Answers about...Marfan Syndrome.

    ERIC Educational Resources Information Center

    National Inst. of Arthritis and Musculoskeletal and Skin Diseases (NIH), Bethesda, MD.

    This fact sheet answers general questions about Marfan syndrome, a heritable condition that affects the connective tissue. It describes the characteristics of the disorder, the diagnostic process, and ways to manage symptoms. Characteristics include: (1) people with Marfan syndrome are typically very tall, slender, and loose jointed; (2) more than…

  19. The Marfan Syndrome: A Booklet for Teachers.

    ERIC Educational Resources Information Center

    Bernhardt, Barbara A.

    This booklet explains characteristics of Marfan Syndrome, an inherited disorder of connective tissue which can be life-threatening if untreated. Medical problems affecting various parts of the body such as the heart, the skeleton, the eyes and the skin associated with Marfan Syndrome are discussed. Possible medical emergencies are identified.…

  20. Health supervision for children with Marfan syndrome.

    PubMed

    Tinkle, Brad T; Saal, Howard M

    2013-10-01

    Marfan syndrome is a systemic, heritable connective tissue disorder that affects many different organ systems and is best managed by using a multidisciplinary approach. The guidance in this report is designed to assist the pediatrician in recognizing the features of Marfan syndrome as well as caring for the individual with this disorder.

  1. Clinical and molecular study of 320 children with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with pathogenic FBN1 mutations.

    PubMed

    Faivre, Laurence; Masurel-Paulet, Alice; Collod-Béroud, Gwenaëlle; Callewaert, Bert L; Child, Anne H; Stheneur, Chantal; Binquet, Christine; Gautier, Elodie; Chevallier, Bertrand; Huet, Frédéric; Loeys, Bart L; Arbustini, Eloisa; Mayer, Karin; Arslan-Kirchner, Mine; Kiotsekoglou, Anatoli; Comeglio, Paolo; Grasso, Maurizia; Halliday, Dorothy J; Béroud, Christophe; Bonithon-Kopp, Claire; Claustres, Mireille; Robinson, Peter N; Adès, Lesley; De Backer, Julie; Coucke, Paul; Francke, Uta; De Paepe, Anne; Boileau, Catherine; Jondeau, Guillaume

    2009-01-01

    From a large series of 1009 probands with pathogenic FBN1 mutations, data for 320 patients <18 years of age at the last follow-up evaluation were analyzed (32%). At the time of diagnosis, the median age was 6.5 years. At the last examination, the population was classified as follows: neonatal Marfan syndrome, 14%; severe Marfan syndrome, 19%; classic Marfan syndrome, 32%; probable Marfan syndrome, 35%. Seventy-one percent had ascending aortic dilation, 55% ectopia lentis, and 28% major skeletal system involvement. Even when aortic complications existed in childhood, the rates of aortic surgery and aortic dissection remained low (5% and 1%, respectively). Some diagnostic features (major skeletal system involvement, striae, dural ectasia, and family history) were more frequent in the 10- to <18-year age group, whereas others (ascending aortic dilation and mitral abnormalities) were more frequent in the population with neonatal Marfan syndrome. Only 56% of children could be classified as having Marfan syndrome, according to international criteria, at their last follow-up evaluation when the presence of a FBN1 mutation was not considered as a major feature, with increasing frequency in the older age groups. Eighty-five percent of child probands fulfilled international criteria after molecular studies, which indicates that the discovery of a FBN1 mutation can be a valuable diagnostic aid in uncertain cases. The distributions of mutation types and locations in this pediatric series revealed large proportions of probands carrying mutations located in exons 24 to 32 (33%) and in-frame mutations (75%). Apart from lethal neonatal Marfan syndrome, we confirm that the majority of clinical manifestations of Marfan syndrome increase with age, which emphasizes the poor applicability of the international criteria to this diagnosis in childhood and the need for follow-up monitoring in cases of clinical suspicion of Marfan syndrome.

  2. [Clinical aspects of Marfan syndrome].

    PubMed

    Belsing, Tina Zimmermann; Lund, Allan Meldgaard; Søndergaard, Lars; Friis-Hansen, Lennart; Abildstrøm, Steen Zabell

    2011-01-31

    Marfan syndrome (MFS) and MFS-related diseases are inherited connective tissue disorders involving several organ systems. The diagnosis of MFS is difficult as the many symptoms overlap with those of other systemic connective tissue diseases. The phenotype is progressive. Effective surgical therapy and standardized follow-up programs have led to an improved lifespan for the affected individuals. Selective angiotensin II, type 1 (AT1) blockers may improve several manifestations of MFS, but the outcome of clinical trials is presently unknown. This review describes the importance of a coordinated strategy for diagnosis, treatment and follow-up.

  3. Intraocular lens subluxation in marfan syndrome.

    PubMed

    Rodrigo, Bolaños-Jiménez; Paulina, López-Lizárraga E; Francesc, March de R; Eduardo, Telich-Tarriba J; Alejandro, Navas

    2014-01-01

    Ectopia lentis (EL) is a major criteria for the diagnosis of Marfan syndrome, it may vary from an asymptomatic mild displacement to a significant subluxation that places the equator of the lens in the pupillary axis. The purpose of this work is to present the case of a patient with Marfan syndrome who received treatment for subluxation at our institution. A 51-year-old female diagnosed with Marfan syndrome presented to the emergency department with bilateral eye redness, foreign body sensation and crusting around the eyes on awakening. She had the following history of cardiac and ophthalmologic complications, including: 1. Lens subluxation 2. High myopia 3. Aortic root dilation, 4. Mitral valve prolapse and 5. Tricuspid insufficiency. The ophthalmological management of Marfan patients is challenging and periodical follow-up is needed. Surgical versus conservative management is controversial, each case needs to be evaluated individually to analyze the risks and benefits of the procedures.

  4. Intraocular Lens Subluxation in Marfan Syndrome

    PubMed Central

    Rodrigo, Bolaños-Jiménez; Paulina, López-Lizárraga E; Francesc, March de R; Eduardo, Telich-Tarriba J; Alejandro, Navas

    2014-01-01

    Purpose : Ectopia lentis (EL) is a major criteria for the diagnosis of Marfan syndrome, it may vary from an asymptomatic mild displacement to a significant subluxation that places the equator of the lens in the pupillary axis. The purpose of this work is to present the case of a patient with Marfan syndrome who received treatment for subluxation at our institution. Case Report : A 51-year-old female diagnosed with Marfan syndrome presented to the emergency department with bilateral eye redness, foreign body sensation and crusting around the eyes on awakening. She had the following history of cardiac and ophthalmologic complications, including: 1. Lens subluxation 2. High myopia 3. Aortic root dilation, 4. Mitral valve prolapse and 5. Tricuspid insufficiency. Conclusion : The ophthalmological management of Marfan patients is challenging and periodical follow-up is needed. Surgical versus conservative management is controversial, each case needs to be evaluated individually to analyze the risks and benefits of the procedures. PMID:25279020

  5. Characterization of pain, disability, and psychological burden in Marfan syndrome.

    PubMed

    Speed, Traci J; Mathur, Vani A; Hand, Matthew; Christensen, Bryt; Sponseller, Paul D; Williams, Kayode A; Campbell, Claudia M

    2017-02-01

    The clinical manifestations of Marfan syndrome frequently cause pain. This study aimed to characterize pain in a cohort of adults with Marfan syndrome and investigate demographic, physical, and psychological factors associated with pain and pain-related disability. Two hundred and forty-five participants (73% female, 89% non-Hispanic white, 90% North American) completed an online questionnaire assessing clinical features of Marfan syndrome, pain severity, pain-related disability, physical and mental health, depressive symptoms, pain catastrophizing, and insomnia. Eighty-nine percent of respondents reported having pain with 28% of individuals reporting pain as a presenting symptom of Marfan syndrome. Almost half of individuals reported that pain has spread from its initial site. Participants in our study reported poor physical and mental health functioning, moderate pain-related disability, and mild levels of depressive symptoms, sleep disturbances, and pain catastrophizing. Those who identified pain as an initial symptom of Marfan syndrome and those who reported that pain had spread from its initial site reported greater psychological burden compared with those without pain as an initial symptom or pain spreading. Physical health is the largest predictor of pain severity and pain-related disability. While pain catastrophizing and worse mental health functioning are significant correlates of pain severity and pain-related disability, respectively. Pain is a significant and persistent problem in Marfan syndrome and is associated with profound disability and psychological burden. Further studies are indicated to better characterize the directionality of pain, pain-related disability, and psychological burden in Marfan syndrome. © 2016 Wiley Periodicals, Inc.

  6. Marfan syndrome: An eyesight of syndrome.

    PubMed

    Kumar, Ashok; Agarwal, Sarita

    2014-12-01

    Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the glycoprotein gene fibrillin-1 (FBN1). Aortic root dilation and mitral valve prolapse are the main presentations among the cardiovascular malformations of MFS. The revised Ghent diagnostics nosology of Marfan syndrome is established in accordance with a combination of major and minor clinical manifestations in various organ systems and the family history. The pathogenesis of Marfan syndrome has not been fully elucidated. However, fibrillin-1 gene mutations are believed to exert a dominant negative effect. The treatment includes prophylactic β-blockers and angiotensin II-receptor blockers in order to slow down the dilation of the ascending aorta and prophylactic aortic surgery. Importantly, β-blocker therapy may reduce TGF-β activation, which has been recognized as a contributory factor in MFS. The identification of a mutation allows for early diagnosis, prognosis, genetic counseling, preventive management of carriers and reassurance for unaffected relatives. The importance of knowing in advance the location of the putative family mutation is highlighted by its straightforward application to prenatal and postnatal screening. The present article aims to provide an overview of this rare hereditary disorder.

  7. Corneal Deformation Response and Ocular Geometry: A Non-invasive Diagnostic Strategy in Marfan Syndrome

    PubMed Central

    Beene, Lauren C.; Traboulsi, Elias I.; Seven, Ibrahim; Ford, Matthew R.; Roy, Abhijit Sinha; Butler, Robert S.; Dupps, William J.

    2015-01-01

    Purpose To evaluate corneal air-puff deformation responses and ocular geometry as predictors of Marfan syndrome. Design Prospective observational clinical study Methods Sixteen investigator-derived, 4 standard Ocular Response Analyzer (ORA), and geometric variables from corneal tomography and optical biometry using Oculus Pentacam and IOL Master were assessed for discriminative value in Marfan syndrome, measuring right eyes of 24 control and 13 Marfan syndrome subjects. Area under the receiver operating characteristic (AUROC) curve was assessed in univariate and multivariate analyses Results Six investigator-derived ORA variables successfully discriminated Marfan syndrome. The best lone disease predictor was Concavity Min (Marfan syndrome 47.5 ± 20, control 69 ± 14, p = 0.003; AUROC = 0.80). Corneal hysteresis and corneal resistance factor were decreased (Marfan syndrome CH 9.45 ± 1.62, control CH 11.24 ± 1.21, p = 0.01; Marfan syndrome CRF 9.77 ± 1.65, control CRF 11.03 ± 1.72, p = 0.01) and corneas were flatter in Marfan syndrome (Marfan syndrome Kmean 41.25 ± 2.09 D, control Kmean 42.70 ± 1.81 D, p = 0.046). No significant differences were observed in central corneal thickness, axial eye length, or intraocular pressure. A multivariate regression model incorporating corneal curvature and hysteresis loop area (HLA) provided the best predictive value for Marfan syndrome (AUROC = 0.85). Conclusions This study describes novel biodynamic features of corneal deformation responses in Marfan syndrome, including increased deformation, decreased bending resistance, and decreased energy dissipation capacity. A predictive model incorporating HLA and corneal curvature shows greatest potential for non-invasive clinical diagnosis of Marfan syndrome. PMID:26432567

  8. Corneal Deformation Response and Ocular Geometry: A Noninvasive Diagnostic Strategy in Marfan Syndrome.

    PubMed

    Beene, Lauren C; Traboulsi, Elias I; Seven, Ibrahim; Ford, Matthew R; Sinha Roy, Abhijit; Butler, Robert S; Dupps, William J

    2016-01-01

    To evaluate corneal air-puff deformation responses and ocular geometry as predictors of Marfan syndrome. Prospective observational clinical study. Sixteen investigator-derived, 4 standard Ocular Response Analyzer (ORA), and geometric variables from corneal tomography and optical biometry using Oculus Pentacam and IOL Master were assessed for discriminative value in Marfan syndrome, measuring right eyes of 24 control and 13 Marfan syndrome subjects. Area under the receiver operating characteristic (AUROC) curve was assessed in univariate and multivariate analyses. Six investigator-derived ORA variables successfully discriminated Marfan syndrome. The best lone disease predictor was Concavity Min (Marfan syndrome 47.5 ± 20, control 69 ± 14, P = .003; AUROC = 0.80). Corneal hysteresis (CH) and corneal resistance factor (CRF) were decreased (Marfan syndrome CH 9.45 ± 1.62, control CH 11.24 ± 1.21, P = .01; Marfan syndrome CRF 9.77 ± 1.65, control CRF 11.03 ± 1.72, P = .01) and corneas were flatter in Marfan syndrome (Marfan syndrome Kmean 41.25 ± 2.09 diopter, control Kmean 42.70 ± 1.81 diopter, P = .046). No significant differences were observed in central corneal thickness, axial eye length, or intraocular pressure. A multivariate regression model incorporating corneal curvature and hysteresis loop area (HLA) provided the best predictive value for Marfan syndrome (AUROC = 0.85). This study describes novel biodynamic features of corneal deformation responses in Marfan syndrome, including increased deformation, decreased bending resistance, and decreased energy dissipation capacity. A predictive model incorporating HLA and corneal curvature shows greatest potential for noninvasive clinical diagnosis of Marfan syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Psychiatric and neuropsychological issues in Marfan syndrome: A critical review of the literature.

    PubMed

    Gritti, Antonella; Pisano, Simone; Catone, Gennaro; Iuliano, Raffaella; Salvati, Tiziana; Gritti, Paolo

    2015-01-01

    The cooccurrence of Marfan syndrome and psychiatric disorders has been reported for many years. Furthermore, neuropsychological deficits have been shown to be associated with Marfan syndrome. The aim of the present article is to summarize findings from the sparse studies and case reports available. The results hold clinical and therapeutic implications and suggest that psychological and neuropsychological domains in Marfan syndrome patients should be carefully assessed. In particular, some patients may require specific rehabilitation programs. On this basis, a multidisciplinary approach to Marfan syndrome treatment seems mandatory.

  10. Marfan Foundation

    MedlinePlus

    ... The Marfan Foundation Marfan & Related Disorders What is Marfan Syndrome? What are Related Disorders? What are the Signs? ... Click to see what's happening around the country! Marfan syndrome is a life-threatening genetic disorder, and an ...

  11. Analysis of phenotype and genotype information for the diagnosis of Marfan syndrome.

    PubMed

    Sheikhzadeh, S; Kade, C; Keyser, B; Stuhrmann, M; Arslan-Kirchner, M; Rybczynski, M; Bernhardt, A M; Habermann, C R; Hillebrand, M; Mir, T; Robinson, P N; Berger, J; Detter, C; Blankenberg, S; Schmidtke, J; von Kodolitsch, Y

    2012-09-01

    Marfan syndrome is considered a clinical diagnosis. Three diagnostic classifications comprising first, Marfan genotype with a causative FBN1 gene mutation; second, Marfan phenotype with clinical criteria of the original Ghent nosology (Ghent-1); and third, phenotype with clinical criteria of its current revision (Ghent-2) in 300 consecutive persons referred for confirmation or exclusion of Marfan syndrome (150 men, 150 women aged 35 ± 13 years) were used. Sequencing of TGBR1/2 genes was performed in 128 persons without FBN1 mutation. Marfan genotype was present in 140, Ghent-1 phenotype in 139, and Ghent-2 phenotype in 124 of 300 study patients. Marfan syndrome was confirmed in 94 and excluded in 129 persons consistently by all classifications, but classifications were discordant in 77 persons. With combined genotype and phenotype information confirmation of Marfan syndrome was finally achieved in 126 persons by Ghent-1 and in 125 persons by Ghent-2 among 140 persons with Marfan genotype, and exclusion was accomplished in 139 persons by Ghent-1 and in 141 persons by Ghent-2 among 160 persons without Marfan genotype. In total, genotype information changed final diagnoses in 22 persons with Ghent-1, and in 32 persons with Ghent-2. It is concluded that genotype information is essential for diagnosis or exclusion of Marfan syndrome.

  12. Aneurysms of medium-sized arteries in Marfan syndrome.

    PubMed

    Awais, Mazen; Williams, David M; Deeb, G Michael; Shea, Michael J

    2013-11-01

    Marfan syndrome is a relatively common connective tissue disorder that causes skin, ocular, skeletal, and cardiovascular abnormalities. High morbidity and mortality occur with aortic aneurysm and dissection. Other large-artery aneurysms, including carotid, subclavian, and iliac artery aneurysms, have also been associated with Marfan syndrome. It is not clear whether small- to medium-sized artery aneurysms are associated with Marfan syndrome. This report describes 4 patients with Marfan syndrome who have associated small- to medium-sized artery aneurysms with several complications. Additional investigations are needed to determine whether Marfan syndrome can cause small- to medium-sized artery aneurysms and how patients with these aneurysms should be treated.

  13. Marfan Syndrome and Related Heritable Thoracic Aortic Aneurysms and Dissections.

    PubMed

    De Backer, Julie; Renard, Marjolijn; Campens, Laurence; Mosquera, Laura Muino; De Paepe, Anne; Coucke, Paul; Callewaert, Bert; Kodolitsch, Yskert von

    2015-01-01

    In this overview we aim to address a number of recent insights and developments regarding clinical aspects, etiology, and treatment of Heritable Thoracic Aortic Disease (H-TAD). We will focus on monogenetic disorders related to aortic aneurysms. H-TADs are rare but they provide a unique basis for the study of underlying pathogenetic pathways in the complex disease process of aneurysm formation. The understanding of pathomechanisms may help us to identify medical treatment targets to improve prognosis. Among the monogenetic aneurysm disorders, Marfan syndrome is considered as a paradigm entity and many insights are derived from the study of clinical, genetic and animal models for Marfan syndrome. We will therefore first provide a detailed overview of the various aspects of Marfan syndrome after which we will give an overview of related H-TAD entities.

  14. Pulmonary involvement in patients with Marfan Syndrome.

    PubMed

    Corsico, A G; Grosso, A; Tripon, B; Albicini, F; Gini, E; Mazzetta, A; Di Vincenzo, E M; Agnesi, M E; Tsana Tegomo, E; Ronzoni, V; Arbustini, E; Cerveri, I

    2014-06-01

    Pulmonary involvement is not generally considered a main feature of Marfan syndrome, an autosomal connective tissue disorder caused by mutations in fibrillin 1. Thanks to the substantial progress in treatments, life expectation of these patients has been dramatically improved determining changes in different organ systems. The number of patients with pulmonary pathology may be higher than expected. Objective of the study was to evaluate the pulmonary involvement in all the patients referring to the largest Italian center for Marfan syndrome, assessing clinical examination and lung function tests. Clinical history, spirometry, lung volumes and diffusing capacity have been assessed in 64 patients of our national referral center. None of the patients reported chronic respiratory symptoms. Fourteen percent reported a previous pneumothorax and 3 blebs and 45% had moderate to severe rib cage abnormalities. Twenty-three percent had cardiothoracic surgery. Two of the 19 patients with chest TC performed at our hospital were diagnosed with emphysema and were both non smoker; 7 had subpleural apical blebs. Only 37% of patients had normal lung function; 19% showed a restrictive pattern and 44% an obstructive pattern or an isolated diffusion impairment or an isolated hyperinflation. All patients with pneumothorax showed an obstructive pattern and diffusion impairment. In the absence of early respiratory symptoms, pulmonary abnormalities should be detected and monitored before they aggravate. Particular attention should be paid to prevent pneumothorax. Our results support the importance of lung volume determination to identify patients in which pulmonary parenchyma require a careful chest CT evaluation.

  15. The Marfan Syndrome [and] Fact Sheet.

    ERIC Educational Resources Information Center

    Pyeritz, Reed E.; Conant, Julia

    This introduction to the Marfan syndrome, a heritable disorder of connective tissue primarily affecting the bones and ligaments, eyes, cardiovascular system, and lungs, is intended for a general audience. The question-and-answer format was chosen by individuals with the syndrome to reflect their major questions and concerns. It incorporates the…

  16. The Marfan Syndrome [and] Fact Sheet.

    ERIC Educational Resources Information Center

    Pyeritz, Reed E.; Conant, Julia

    This introduction to the Marfan syndrome, a heritable disorder of connective tissue primarily affecting the bones and ligaments, eyes, cardiovascular system, and lungs, is intended for a general audience. The question-and-answer format was chosen by individuals with the syndrome to reflect their major questions and concerns. It incorporates the…

  17. Prevalence, incidence, and age at diagnosis in Marfan Syndrome.

    PubMed

    Groth, Kristian A; Hove, Hanne; Kyhl, Kasper; Folkestad, Lars; Gaustadnes, Mette; Vejlstrup, Niels; Stochholm, Kirstine; Østergaard, John R; Andersen, Niels H; Gravholt, Claus H

    2015-12-02

    Marfan syndrome is a genetic disorder with considerable morbidity and mortality. Presently, clinicians use the 2010 revised Ghent nosology, which includes optional genetic sequencing of the FBN1 gene, to diagnose patients. So far, only a few studies based on older diagnostic criteria have reported a wide range of prevalence and incidence. Our aim was to study prevalence, incidence, and age at diagnosis in patients with Marfan syndrome. Using unique Danish patient-registries, we identified all possible Marfan syndrome patients recorded by the Danish healthcare system (1977-2014). Following, we confirmed or rejected the diagnosis according to the 2010 revised Ghent nosology. We identified a total of 1628 persons with possible Marfan syndrome. We confirmed the diagnosis in 412, whereof 46 were deceased, yielding a maximum prevalence of 6.5/100,000 at the end of 2014. The annual median incidence was 0.19/100,000 (range: 0.0-0.7) which increased significantly with an incidence rate ratio of 1.03 (95% CI: 1.02-1.04, p < 0.001). We found a median age at diagnose of 19.0 years (range: 0.0-74). The age at diagnosis increased during the study period, uninfluenced by the changes in diagnostic criteria. We found no gender differences. The increasing prevalence of Marfan syndrome during the study period is possibly due to build-up of a registry. Since early diagnosis is essential in preventing aortic events, diagnosing Marfan syndrome remains a task for both pediatricians and physicians caring for adults.

  18. LEOPARD syndrome is not linked to the Marfan syndrome and the Watson syndrome loci

    SciTech Connect

    Rass-Rothchild, A.: Abeliovitch, D.; Kornstein, A. |

    1994-09-01

    The acronym LEOPARD stands for a syndromic association of Lentigines, Eletrocardiographic changes, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth and sensorineural Deafness. Inheritance is autosomal dominant with high penetrance and variable expressivity. In 1990 Torok et al. reported on the association of LEOPARD and Marfan syndrome. In addition a clinical similarity (cardiac and cutaneous involvement) exists with the Watson syndrome (neurofibromatosis and pulmonic stenosis) which is linked to the marker D17S33 on chromosome 17. We studied possible linkage of LEOPARD syndrome to the Marfan syndrome locus on chromosome 15 (D15S1, MF13, and (TAAAA)n repeats) and to the NF-1 locus on chromosome 17 in a family with 9 cases of LEOPARD syndrome. Close linkage between LEOPARD syndrome and both the Marfan locus on chromosome 15 and the NF-1 locus on chromosome 17 was excluded (lod score <-2.0 through {theta} = 0.1).

  19. The risk for type B aortic dissection in Marfan syndrome.

    PubMed

    den Hartog, Alexander W; Franken, Romy; Zwinderman, Aeilko H; Timmermans, Janneke; Scholte, Arthur J; van den Berg, Maarten P; de Waard, Vivian; Pals, Gerard; Mulder, Barbara J M; Groenink, Maarten

    2015-01-27

    Aortic dissections involving the descending aorta are a major clinical problem in patients with Marfan syndrome. The purpose of this study was to identify clinical parameters associated with type B aortic dissection and to develop a risk model to predict type B aortic dissection in patients with Marfan syndrome. Patients with the diagnosis of Marfan syndrome and magnetic resonance imaging or computed tomographic imaging of the aorta were followed for a median of 6 years for the occurrence of type B dissection or the combined end point of type B aortic dissection, distal aortic surgery, and death. A model using various clinical parameters as well as genotyping was developed to predict the risk for type B dissection in patients with Marfan syndrome. Between 1998 and 2013, 54 type B aortic dissections occurred in 600 patients with Marfan syndrome (mean age 36 ± 14 years, 52% male). Independent variables associated with type B aortic dissection were prior prophylactic aortic surgery (hazard ratio: 2.1; 95% confidence interval: 1.2 to 3.8; p = 0.010) and a proximal descending aorta diameter ≥27 mm (hazard ratio: 2.2; 95% confidence interval: 1.1 to 4.3; p = 0.020). In the risk model, the 10-year occurrence of type B aortic dissection in low-, moderate-, and high-risk patients was 6%, 19%, and 34%, respectively. Angiotensin II receptor blocker therapy was associated with fewer type B aortic dissections (hazard ratio: 0.3; 95% confidence interval: 0.1 to 0.9; p = 0.030). Patients with Marfan syndrome with prior prophylactic aortic surgery are at substantial risk for type B aortic dissection, even when the descending aorta is only slightly dilated. Angiotensin II receptor blocker therapy may be protective in the prevention of type B aortic dissections. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  20. Economic and care considerations of Marfan syndrome.

    PubMed

    Blankart, Carl Rudolf; Milstein, Ricarda; Rybczynski, Meike; Schüler, Helke; von Kodolitsch, Yskert

    2016-10-01

    Marfan syndrome is a rare multisystem disease of the connective tissue, which affects multiple organ systems. advances in healthcare have doubled the life-expectancy of patients over the past three decades. to date, there is no comprehensive review that consolidates economic considerations and care for marfan patients. Areas covered: Present research suggests that there may be a link between treatment pattern, disease progression and economic costs of Marfan syndrome. It indicates that an early detection of the disease and preventive interventions achieve a dual aim. From a patient perspective, it may reduce the amount of emergency surgery or intervention, and inpatient stays. In addition, it slows disease progression, lowers lifestyle restrictions, reduces psychological stress, and improves health-related quality of life. Expert commentary: Early detection and preventive measures are likely to achieve a dual aim by simultaneously containing costs and reducing the number and length of inpatient stays.

  1. Preimplantation genetic testing for Marfan syndrome.

    PubMed

    Harton, G L; Tsipouras, P; Sisson, M E; Starr, K M; Mahoney, B S; Fugger, E F; Schulman, J D; Kilpatrick, M W; Levinson, G; Black, S H

    1996-09-01

    Marfan syndrome (MFS) is an autosomal dominant disease that affects the skeletal, ocular and cardiovascular systems. Defects in the gene that codes for fibrillin (FBN-1) are responsible for MFS. Here we report the world's first use of preimplantation genetic testing (PGT) to achieve a clinical pregnancy and live birth of a baby free of a Marfan mutation. One or two blastomeres from each embryo were tested for a CA repeat within the FBN-1 gene. The prospective mother is homozygous for the CA repeat (2/2) and has two normal copies of the FBN-1 gene, while the prospective father is heterozygous for the CA repeat (1/2), and is affected with the Marfan syndrome. In the father's family, allele 2 segregates with the mutated FBN-1 gene. For PGT, any embryo diagnosed as heterozygous for the CA repeat (1/2) would be presumed to have inherited normal FBN-1 genes from the father and the mother and be unaffected. One in-vitro fertilization (IVF) cycle yielded 12 embryos for preimplantation testing; six of the embryos were heterozygous for the CA repeat (1/2) and presumed to be free of the Marfan mutation. Five of the six embryos were subsequently transferred into the uterus. The fetus was tested by chorionic villus sampling and found to be free of the Marfan mutation by the same linkage analysis, had a normal fetal echocardiogram, and was normal at birth.

  2. Impact of aortic aneurysm on hospitalizations in patients with marfan syndrome: a multi-institutional study.

    PubMed

    Collins, R Thomas; Phomakay, Venusa; Zarate, Yuri A; Tang, Xinyu

    2015-01-01

    Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder affecting 1 in 3,000 people. Cardiovascular involvement is a prominent feature of MFS, with aortic dissection and/or rupture being the leading cause of death. Advances in the medical and surgical care of patients with MFS have improved survival. Hospital resource utilization and outcomes have not been evaluated in a large population of patients with MFS. We sought to analyze pediatric hospital resource utilization and outcomes in patients with MFS. Nationally distributed data from 43 pediatric hospitals in the 2004-2011 Pediatric Health Information System database were used to identify patients admitted to the hospital with International Classification of Diseases-9th Revision codes for a diagnosis of MFS. Aortic aneurysm (AA) with or without dissection, length of stay (LOS), and hospital charges were determined. During the study period, there were 1,978 admissions in 1,228 patients with MFS. AA was present in 217 (11%) admissions in 188 (15%) patients (63% male). Mean age of patients with AA was 13.8 ± 5.9 years. Aortic dissection or rupture was present in 15 (7% with AA) admissions in 15 (8% with AA) patients (mean age 15.7 ± 5.2 years). Other cardiac diagnoses occurred more commonly in the AA cohort (p < 0.0001), regardless of the reason for admission. Cardiothoracic surgical procedures were performed in 116 AA admissions (53%). Mean LOS, hospital charges per admission, and charges per day were significantly higher in AA cohort compared to those without AA. In-hospital mortality for AA was 2%. The presence of AA in patients with MFS increases hospital resource utilization. Cardiothoracic surgeries are commonly performed in this cohort. Other cardiovascular diagnoses are more prevalent in patients with AA suggesting a more severe phenotype.

  3. Abnormal fibrillin metabolism in bovine Marfan syndrome.

    PubMed Central

    Potter, K. A.; Hoffman, Y.; Sakai, L. Y.; Byers, P. H.; Besser, T. E.; Milewicz, D. M.

    1993-01-01

    Bovine Marfan syndrome is a disorder that closely resembles human Marfan syndrome in its clinical signs and pathological lesions. The similarities between the human and bovine diseases suggest that similar metabolic defects could be responsible. Although indirect immunofluorescent assays for fibrillin in skin biopsies did not distinguish affected cattle from control animals, cultures of skin fibroblasts of affected animals were distinguished from normal, unrelated control animals and normal half-siblings on the basis of fibrillin staining. After 72 to 96 hours in culture, stained with anti-fibrillin monoclonal antibody 201, hyperconfluent fibroblast cultures of affected cattle had less immunoreactive fibrillin than control cultures, and the staining pattern was granular rather than fibrillar. Under similar culture conditions, normal bovine aortic smooth muscle cells produced large amounts of immunoreactive fibrillin, but smooth muscle cells from a single affected cow showed markedly less fibrillin staining. In pulse-chase metabolic labeling experiments with [35S]cysteine, dermal fibroblasts from 6 affected calves, incorporated far less fibrillin into the extracellular matrix than control cells. These findings are similar to those reported in human Marfan syndrome, and they suggest that the bovine Marfan syndrome, like the human disorder, is caused by a mutation in fibrillin, leading to defective microfibrillar synthesis. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8456941

  4. Marfan syndrome. Part 1: pathophysiology and diagnosis.

    PubMed

    Cañadas, Victoria; Vilacosta, Isidre; Bruna, Isidoro; Fuster, Valentin

    2010-05-01

    Marfan syndrome is a connective-tissue disease inherited in an autosomal dominant manner and caused mainly by mutations in the gene FBN1. This gene encodes fibrillin-1, a glycoprotein that is the main constituent of the microfibrils of the extracellular matrix. Most mutations are unique and affect a single amino acid of the protein. Reduced or abnormal fibrillin-1 leads to tissue weakness, increased transforming growth factor beta signaling, loss of cell-matrix interactions, and, finally, to the different phenotypic manifestations of Marfan syndrome. Since the description of FBN1 as the gene affected in patients with this disorder, great advances have been made in the understanding of its pathogenesis. The development of several mouse models has also been crucial to our increased understanding of this disease, which is likely to change the treatment and the prognosis of patients in the coming years. Among the many different clinical manifestations of Marfan syndrome, cardiovascular involvement deserves special consideration, owing to its impact on prognosis. However, the diagnosis of patients with Marfan syndrome should be made according to Ghent criteria and requires a comprehensive clinical assessment of multiple organ systems. Genetic testing can be useful in the diagnosis of selected cases.

  5. Cardiovascular Magnetic Resonance in Marfan syndrome

    PubMed Central

    2013-01-01

    This review provides an overview of Marfan syndrome with an emphasis on cardiovascular complications and cardiovascular imaging. Both pre- and post-operative imaging is addressed with an explanation of surgical management. All relevant imaging modalities are discussed with a particular focus on cardiovascular MR. PMID:23587220

  6. Marfan Syndrome: Clinical, Surgical, and Anesthetic Considerations.

    PubMed

    Castellano, José M; Silvay, George; Castillo, Javier G

    2014-09-01

    Marfan syndrome is a multisystem 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. Clinical diagnosis of Marfan syndrome has been based on the Ghent criteria since 1996. In 2010, these criteria were updated, and the revised guidelines place more emphasis on aortic root dilation, ectopia lentis, and FBN1 mutation testing in the diagnostic assessment of Marfan syndrome. Among its many different clinical manifestations, cardiovascular involvement deserves special consideration, owing to its impact on prognosis. Recent molecular, surgical, and clinical research has yielded profound new insights into the pathological mechanisms that ultimately lead to tissue degradation and weakening of the aortic wall, which has led to exciting new treatment strategies. Furthermore, with the increasing life expectancy of patients with Marfan syndrome, there has been a subtle shift in the spectrum of medical problems. Consequently, this article focuses on recent advances to highlight their potential impact on future concepts of patient care from a clinical, surgical, and anesthetic perspective. © The Author(s) 2013.

  7. Marfan syndrome type II: there is more to Marfan syndrome than fibrillin 1.

    PubMed

    Zangwill, Steven D; Brown, Matthew D; Bryke, Christine R; Cava, Joseph R; Segura, Annette D

    2006-09-01

    Marfan syndrome is a well-described autosomal dominant syndrome with widely variable clinical manifestations. Cardiovascular complications include mitral valve prolapse with or without associated mitral valve insufficiency, aortic root dilatation, and most importantly the occasional development of aortic aneurysms or rupture. Given the inconsistent phenotype along with the potentially life-threatening implications, clinicians are increasingly turning to genetic testing for definitive diagnostic confirmation. It has been well established that mutations in the FBN1 gene encoding the structural protein Fibrillin 1 is the molecular etiology of Marfan syndrome. However, there are numerous patients who meet the Ghent clinical diagnostic criteria for Marfan syndrome who do not have identifiable FBN1 mutations. Recently, mutations in TGFBR1 and TGFBR2 (transforming growth factor beta receptors 1 and 2, respectively) have been shown to result in Loeys-Dietz syndrome, a connective tissue disorder with significant phenotypic overlap with Marfan syndrome. Individuals with this Marfanoid disorder lack the ocular findings of Marfan syndrome and often have dysmorphic features such as unusual facies, cleft palate, and contractures. In addition, Loeys-Dietz syndrome patients often present in childhood with significant cardiovascular problems. This article serves to report an illustrative case of Loeys-Dietz syndrome and reviews the phenotypic consequences of FBN1 and TGFBR1 and TGFBR2 gene mutations.

  8. Quantification of aortic and cutaneous elastin and collagen morphology in Marfan syndrome by multiphoton microscopy.

    PubMed

    Cui, Jason Z; Tehrani, Arash Y; Jett, Kimberly A; Bernatchez, Pascal; van Breemen, Cornelis; Esfandiarei, Mitra

    2014-09-01

    In a mouse model of Marfan syndrome, conventional Verhoeff-Van Gieson staining displays severe fragmentation, disorganization and loss of the aortic elastic fiber integrity. However, this method involves chemical fixatives and staining, which may alter the native morphology of elastin and collagen. Thus far, quantitative analysis of fiber damage in aorta and skin in Marfan syndrome has not yet been explored. In this study, we have used an advanced noninvasive and label-free imaging technique, multiphoton microscopy to quantify fiber fragmentation, disorganization, and total volumetric density of aortic and cutaneous elastin and collagen in a mouse model of Marfan syndrome. Aorta and skin samples were harvested from Marfan and control mice aged 3-, 6- and 9-month. Elastin and collagen were identified based on two-photon excitation fluorescence and second-harmonic-generation signals, respectively, without exogenous label. Measurement of fiber length indicated significant fragmentation in Marfan vs. control. Fast Fourier transform algorithm analysis demonstrated markedly lower fiber organization in Marfan mice. Significantly reduced volumetric density of elastin and collagen and thinner skin dermis were observed in Marfan mice. Cutaneous content of elastic fibers and thickness of dermis in 3-month Marfan resembled those in the oldest control mice. Our findings of early signs of fiber degradation and thinning of skin dermis support the potential development of a novel non-invasive approach for early diagnosis of Marfan syndrome.

  9. Fibrillin mutations in the Marfan syndrome

    SciTech Connect

    Price, C.E.; Wang, M.; Wang, J.; Godfrey, M.

    1994-09-01

    The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue manifested by variable and pleiotropic defect in the skeletal, ocular, and cardiovascular systems. We have recently begun to use intron-specific primers that have become available through the International Marfan Syndrome Consortium to screen for fibrillin mutations in MFS patients. Using the genomic PCR-based approach in addition to RT-PCR methodologies, we have identified several novel mutations. A single base insertion was identified in all affected individuals of one family. The insertion of an {open_quote}A{close_quote} at position 1891 in exon 15 causes a premature stop codon and thus a truncated polypeptide. The truncated protein of 617 amino acids has an expected molecular weight of 63 kD. Metabolic labeling and immunoprecipitation studies are in progress. A C{r_arrow}T transition at position 1634 in exon 12 causing a 5th position Cys to Phe substitution in an EGF-like motif was observed in another MFS patient. Finally, we have identified a G{r_arrow}A transition at the +1 position of the donor splice site that causes the deletion of fibrillin exon 32 in a patient with the neonatal form of MFS. Exon 32 is a precursor EGF-like calcium binding motif that is located in a single stretch of 12 similar domains. We had previously identified the skipping of this exon due to an A{r_arrow}T transversion at the -2 position of the consensus acceptor splice site in another patient with neonatal MFS. The reason that the skipping of exon 32 causes a neonatal lethal MFS phenotype is presently unclear. These studies will help elucidate the role of diverse regions of fibrillin.

  10. Fragile lung in the Marfan syndrome.

    PubMed Central

    Turner, J A; Stanley, N N

    1976-01-01

    Two cases of the Marfan syndrome presented with spontaneous pneumothorax. Both had chest radiographs showing bilateral bullae in the upper lung zones and pulmonary function tests consistent with mild emphysema. There were dereases in forced expiratory flow rates at low lung volumes, carbon monoxide transfer factor, and lung elastic recoil. It is suggested that pneumothorax and bullous emphysema in this syndrome are caused by a weakness in the pulmonary connective tissue framework. PMID:1013948

  11. Total Endovascular Aortic Repair in a Patient with Marfan Syndrome.

    PubMed

    Amako, Mau; Spear, Rafaëlle; Clough, Rachel E; Hertault, Adrien; Azzaoui, Richard; Martin-Gonzalez, Teresa; Sobocinski, Jonathan; Haulon, Stéphan

    2017-02-01

    The aim of this study is to describe a total endovascular aortic repair with branched and fenestrated endografts in a young patient with Marfan syndrome and a chronic aortic dissection. Open surgery is the gold standard to treat aortic dissections in patients with aortic disease and Marfan syndrome. In 2000, a 38-year-old man with Marfan syndrome underwent open ascending aorta repair for an acute type A aortic dissection. One year later, a redo sternotomy was performed for aortic valve replacement. In 2013, the patient presented with endocarditis and pulmonary infection, which necessitated tracheostomy and temporary dialysis. In 2014, the first stage of the endovascular repair was performed using an inner branched endograft to exclude a 77-mm distal arch and descending thoracic aortic aneurysm. In 2015, a 63-mm thoracoabdominal aortic aneurysm was excluded by implantation of a 4-fenestrated endograft. Follow-up after both endovascular repairs was uneventful. Total aortic endovascular repair was successfully performed to treat a patient with arch and thoraco-abdominal aortic aneurysm associated with chronic aortic dissection and Marfan syndrome. The postoperative images confirmed patency of the endograft and its branches, and complete exclusion of the aortic false lumen. Endovascular repair is a treatment option in patients with connective tissue disease who are not candidates for open surgery. Long-term follow-up is required to confirm these favorable early outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Aortic events in a nationwide Marfan syndrome cohort.

    PubMed

    Groth, Kristian A; Stochholm, Kirstine; Hove, Hanne; Kyhl, Kasper; Gregersen, Pernille A; Vejlstrup, Niels; Østergaard, John R; Gravholt, Claus H; Andersen, Niels H

    2017-02-01

    Marfan syndrome is associated with morbidity and mortality due to aortic dilatation and dissection. Preventive aortic root replacement has been the standard treatment in Marfan syndrome patients with aortic dilatation. In this study, we present aortic event data from a nationwide Marfan syndrome cohort. The nationwide cohort of Danish Marfan syndrome patients was established from the Danish National Patient Registry and the Cause of Death Register, where we retrieved information about aortic surgery and dissections. We associated aortic events with age, sex, and Marfan syndrome diagnosis prior or after the first aortic event. From the total cohort of 412 patients, 150 (36.4 %) had an aortic event. Fifty percent were event free at age 49.6. Eighty patients (53.3 %) had prophylactic surgery and seventy patients (46.7 %) a dissection. The yearly event rate was 0.02 events/year/patient in the period 1994-2014. Male patients had a significant higher risk of an aortic event at a younger age with a hazard ratio of 1.75 (CI 1.26-2.42, p = 0.001) compared with women. Fifty-three patients (12.9 %) were diagnosed with MFS after their first aortic event which primarily was aortic dissection [n = 44 (83.0 %)]. More than a third of MFS patients experienced an aortic event and male patients had significantly more aortic events than females. More than half of the total number of dissections was in patients undiagnosed with MFS at the time of their event. This emphasizes that diagnosing MFS is lifesaving and improves mortality risk by reducing the risk of aorta dissection.

  13. Pregnancy-related acute aortic dissection in Marfan syndrome: A review of the literature.

    PubMed

    Smith, Katherine; Gros, Bernard

    2017-04-02

    A well-established association exists between acute aortic dissection and pregnancy, particularly in women with Marfan syndrome. However, there is debate regarding appropriate management guidelines. In particular, there are differing opinions regarding when prophylactic aortic root repair should be recommended as well as the efficacy of beta blockers in this clinical scenario. The current study evaluated 10 years of published literature (2005-2015) in the PubMed/Medline database. Fifty articles, describing 72 cases of women who presented with aortic dissection in the antepartum or postpartum period were identified. Comparisons on demographic variables and clinical outcomes between cases of women with Marfan syndrome (n = 36) and without Marfan syndrome (n = 36) were conducted. There were no significant differences in demographics (age, gravidity, parity) between the Marfan and non-Marfan cases. Marfan patients presented with antepartum dissections significantly earlier in pregnancy than those without Marfan syndrome (P = .002). However, there were no significant difference between the 2 groups in maternal mortality, fetal mortality, or obstetric outcomes (mode of delivery and gestational age at delivery). Eight cases described events in Marfan women with an aortic root diameter ≤40 mm. Six events occurred in Marfan women who were managed with beta blockers. Current guidelines rely on aortic root diameter for stratification of Marfan women into risk categories, but we identified several cases that would be missed by these guidelines. Specifically, the existing literature suggest that women with Marfan syndrome should take precautions throughout pregnancy, rather than the third trimester.

  14. Increased prevalence of migraine in Marfan syndrome.

    PubMed

    Vis, Jeroen C; Timmermans, Janneke; Post, Martijn C; Budts, Werner; Schepens, Marc A A M; Thijs, Vincent; Schonewille, Wouter J; de Bie, Rob M A; Plokker, Herbert W M; Tijssen, Jan G P; Mulder, Barbara J M

    2009-08-21

    A high prevalence of migraine has been described in various forms of congenital heart disease, with and without shunt. In this study we investigated the prevalence of migraine in patients with Marfan syndrome (MFS). All 457 adult patients with MFS from the participating centres and 194 controls received a validated questionnaire about headache. Migraine was diagnosed according to the International Headache Society criteria, by three independent neurologists, blinded to patient files. Response rate was 68% and 56% in Marfan patients and controls, respectively. Forty percent of the 309 responding MFS patients (mean age 40+/-14 years; 51% females) and 28% of the 102 controls (mean age 43+/-15 years; 58% females), suffered from migraine (p=0.03). The prevalence of migraine with aura (MA) was 22% in MFS patients and 14% in controls (p=0.06). We found MFS to be an independent risk factor for having overall migraine (OR 1.7; 95%CI 1.1-2.8), also after adjustment for age and gender (OR 1.9; 95%CI 1.1-3.1; p=0.02) and for MA after adjustment for gender (OR 2.0; 95%CI 1.1-3.7; p=0.04). In patient with MFS, previous aortic root surgery appeared to be an independent risk factor for having MA (OR 2.2; 95%CI; 1.2.-4.0, p=0.01) adjusted for gender. MFS is an independent risk factor for having overall migraine and MA. Moreover, we found that a history of aortic root surgery seems to be associated with an increased risk of MA.

  15. Abdominal Aortic Aneurysm in Marfan Syndrome.

    PubMed

    Hagerty, Tracy; Geraghty, Patrick; Braverman, Alan C

    2017-04-01

    Marfan syndrome (MFS) leads to aortic root aneurysm, while descending thoracic aortic aneurysm (TAA) occurs less commonly. Abdominal aortic aneurysm (AAA) is rarely reported in MFS. Risk factors for AAA are poorly understood and there are no guidelines for AAA screening in MFS. We sought to characterize AAA among Marfan patients in our center. The records of 12 adults with MFS and AAA disease were reviewed. Clinical features, imaging, operative reports, and outcomes were analyzed. Twelve adults with MFS and AAA were studied; age at AAA diagnosis was 44 ± 15 years (range 18-63). Nine patients smoked cigarettes. Eleven patients underwent prior aortic root replacement at age 31 ± 15 years. The size of AAA was 5.0 ± 1.3 cm (range 3.5-7.5) at the time of diagnosis. The AAA was suprarenal in 5, juxtarenal in 2, and infrarenal in 5 patients. Two patients had a descending TAA. Branch vessel aneurysms were present in 7 patients. Five patients underwent open surgical repair, 5 underwent endovascular repair, and 5 are being treated medically. One patient died suddenly with AAA size 5.7 cm, 2 months before death. Three patients subsequently developed type B aortic dissection, from 3 months to 9 years after AAA diagnosis. Adults with MFS are at risk for developing AAA. Evaluation for AAA is recommended in adults with MFS and prior root replacement, especially if descending aortic or branch vessel aneurysm is present or the patient smokes cigarettes. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Neonatal Marfan syndrome: a case report.

    PubMed

    Ng, D K; Chau, K W; Black, C; Thomas, T M; Mak, K L; Boxer, M

    1999-06-01

    A case of neonatal Marfan syndrome is presented. The patient was noted to have cardiomegaly and tricuspid regurgitation on antenatal ultrasound scan. She was born with long, slender fingers and toes, an aged appearance and non-paralytic hypotonia. Echocardiogram revealed a dilated right atrium, right ventricle, dysplastic tricuspid valve and severe tricuspid regurgitation. She subsequently died of severe heart failure. Post-mortem examination showed the pathological features of lobar emphysema and cystic medial necrosis of the aorta. These features supported the diagnosis of neonatal Marfan syndrome. Nucleotide sequencing showed substitution of G by A at codon 1032 in exon 25 located in the long arm of chromosome 15. This resulted in the substitution of a cysteine by a tyrosine. A de novo mutation is suggested by the absence of affected family members.

  17. Marfan syndrome: An eyesight of syndrome☆

    PubMed Central

    Kumar, Ashok; Agarwal, Sarita

    2014-01-01

    Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the glycoprotein gene fibrillin-1 (FBN1). Aortic root dilation and mitral valve prolapse are the main presentations among the cardiovascular malformations of MFS. The revised Ghent diagnostics nosology of Marfan syndrome is established in accordance with a combination of major and minor clinical manifestations in various organ systems and the family history. The pathogenesis of Marfan syndrome has not been fully elucidated. However, fibrillin-1 gene mutations are believed to exert a dominant negative effect. The treatment includes prophylactic β-blockers and angiotensin II-receptor blockers in order to slow down the dilation of the ascending aorta and prophylactic aortic surgery. Importantly, β-blocker therapy may reduce TGF-β activation, which has been recognized as a contributory factor in MFS. The identification of a mutation allows for early diagnosis, prognosis, genetic counseling, preventive management of carriers and reassurance for unaffected relatives. The importance of knowing in advance the location of the putative family mutation is highlighted by its straightforward application to prenatal and postnatal screening. The present article aims to provide an overview of this rare hereditary disorder. PMID:25606393

  18. Diagnosis and management of Marfan syndrome.

    PubMed

    Iams, Helen D

    2010-01-01

    Marfan syndrome (MFS) is a relatively common inherited connective tissue disorder with significant morbidity and mortality. Diagnosis of this syndrome can be difficult, as many of the findings of MFS are present in other syndromes, as well as in the general population. MFS is diagnosed using the Ghent criteria, a group of clinical findings that are specific for MFS. Children and adolescents can pose diagnostic dilemmas as the stigmata of MFS are not present at birth but can evolve through adulthood. Current treatment for MFS is limited to strict blood pressure control and careful selection of physical activity. Aggressive screening and early management could significantly improve the quality of life for these patients.

  19. Marfan's syndrome. A personal perspective.

    PubMed

    Goodman, T

    1986-02-01

    Marfan's patients share the same problems as anyone with a lifelong, progressive, hereditary condition. The more knowledgeable an individual is about his disease and the more willing he is to accept the responsibility for his own well-being, the more control he has over his life. Medical and life insurance is not a luxury, but an absolute must. The need for stable insurance coverage impacts career decisions. Medication is a lifelong necessity; the patient must know what medications he takes, for what purpose, and the side effects. For patients with a cardiac prosthesis, most physicians recommend a regimen of prophylactic antibiotics before dental work or any invasive procedure. It is the responsibility of the patient to do this. Craig has cancelled dental appointments because he has forgotten to take antibiotics. Craig also takes an anticoagulant because of his prosthetic valve and fears being in a major accident and bleeding to death. Because of human body contains large amounts of connective tissue, a Marfan's patient will continue to develop problems; hernias, eye problems, joint problems, and further cardiovascular complications are all possibilities. Being realistic and maintaining a positive attitude are important in effective planning and dealing with continued adversity.

  20. Marfan syndrome is closely linked to a marker on chromosome 15q1. 5 r arrow q2. 1

    SciTech Connect

    Tsipouras, P.; Sarfarazi, M.; Devi, A. ); Weiffenbach, B. ); Boxer, M. )

    1991-05-15

    Marfan syndrome is a systemic disorder of the connective tissue inherited as an autosomal dominant trait. The disorder imparts significant morbidity and martality. The etiology of the disorder remains elusive. A recent study localized the gene for Marfan syndrome on chromosome 15. The authors present data showing that marker D15S48 is genetically linked to Marfan syndrome. Pairwise linkage analysis gave a maximum lod (logarithm of odds) score of Z = 11.78 at {theta} = 0.02. Furthermore our data suggest that the Marfan syndrome locus is possibly flanked on either side by D15S48 and D15S49.

  1. Femur Neck Fracture in a Young Marfan Syndrome Patient.

    PubMed

    Kwon, Yong-Uk; Kong, Gyu-Min; Park, Jun-Ho

    2016-12-01

    Marfan syndrome is an autosomal dominant and could decrease bone mineral density. So patients with Marfan syndrome could vulnerable to trauma in old ages. We present the first report, to the best of our knowledge, of a rare fracture of the femoral neck with a minor traumatic history in a juvenile Marfan syndrome patient whose physis is still open. Although the patient is young, her bone mineral density was low and the geometry of femur is changed like old ages. The femur neck fracture in children is very rare and only caused by high energy trauma, we concluded that the Marfan syndrome makes the bone weaker in young age and preventative medications to avoid fractures in younger Marfan syndrome patients are necessary in early ages.

  2. Femur Neck Fracture in a Young Marfan Syndrome Patient

    PubMed Central

    Kwon, Yong-Uk; Park, Jun-Ho

    2016-01-01

    Marfan syndrome is an autosomal dominant and could decrease bone mineral density. So patients with Marfan syndrome could vulnerable to trauma in old ages. We present the first report, to the best of our knowledge, of a rare fracture of the femoral neck with a minor traumatic history in a juvenile Marfan syndrome patient whose physis is still open. Although the patient is young, her bone mineral density was low and the geometry of femur is changed like old ages. The femur neck fracture in children is very rare and only caused by high energy trauma, we concluded that the Marfan syndrome makes the bone weaker in young age and preventative medications to avoid fractures in younger Marfan syndrome patients are necessary in early ages. PMID:28097118

  3. Exome sequencing identified new mutations in a Marfan syndrome family.

    PubMed

    Li, Guangxin; Yu, Jian; Wang, Kun; Wang, Bin; Wang, Minghai; Zhang, Shuguang; Qin, Shiyong; Yu, Zhenhai

    2014-01-31

    Marfan syndrome is a common autosomal dominant hereditary connective tissue disorder. There is no cure for Marfan syndrome currently. Next-generation sequencing (NGS) technology is efficient to identify genetic lesions at the exome level. Here we carried out exome sequencing of two Marfan syndrome patients. Further Sanger sequencing validation in other five members from the same family was also implemented to confirm new variants which may contribute to the pathogenesis of the disease. Two new variants, including one nonsense SNP in the Marfan syndrome gene FBN1 and one missense mutation in exon 15 of LRP1, which may be related to the phenotype of the patients were identified. The exome sequencing analysis provides us a new insight into the molecular events governing pathogenesis of Marfan syndrome. http://www.diagnosticpathology.diagnomx.eu/vs/1229110069114125.

  4. Exome sequencing identified new mutations in a Marfan syndrome family

    PubMed Central

    2014-01-01

    Marfan syndrome is a common autosomal dominant hereditary connective tissue disorder. There is no cure for Marfan syndrome currently. Next-generation sequencing (NGS) technology is efficient to identify genetic lesions at the exome level. Here we carried out exome sequencing of two Marfan syndrome patients. Further Sanger sequencing validation in other five members from the same family was also implemented to confirm new variants which may contribute to the pathogenesis of the disease. Two new variants, including one nonsense SNP in the Marfan syndrome gene FBN1 and one missense mutation in exon 15 of LRP1, which may be related to the phenotype of the patients were identified. The exome sequencing analysis provides us a new insight into the molecular events governing pathogenesis of Marfan syndrome. Virtual slide http://www.diagnosticpathology.diagnomx.eu/vs/1229110069114125. PMID:24484584

  5. Quantifying Health Status and Function in Marfan Syndrome.

    PubMed

    Rao, Sandesh S; Venuti, Kristen D; Dietz, Harry C; Sponseller, Paul D

    2016-01-01

    Two hundred thirty patients were prospectively enrolled in this study and completed various portions of the Short Form 36 and a study-specific questionnaire (visual analog scale 1 to 10, comprising three separate questionnaires) to evaluate quality of life and function in patients with Marfan syndrome. The greatest health concern was cardiac problems (high in 70% of patients), followed by spine issues and generalized fatigue (both high, in 53%). The most severe reported pain involved the back: 105 patients (46%) rated pain as 6 to 10 on the visual analog scale. Among the 72 patients who responded to work life questions, work hours were reduced because of treatment in 59 (82%) or directly because of Marfan syndrome in 29 (40%). Across all Short Form 36 domains, patients scored significantly lower than United States population norms (p<.05); physical health scores were considerably lower than mental health scores.

  6. The Prevalence of Marfan Syndrome in Korea

    PubMed Central

    2017-01-01

    The aim of this study was to assess the prevalence of Marfan syndrome (MFS) in Korean adults. Data were collected from the National Health Insurance Service in Korea from 2006 through 2013. The data consisted of primary diagnoses related to MFS (Q87.4) diagnosed according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems. The age-standardized prevalence of MFS in adults was calculated using the estimated Korean population in 2010 as a reference. Overall, the prevalence of MFS was 0.90 per 100,000 persons in 2006 and 2.27 in 2013. For males in 2013, the prevalence per 100,000 persons was 2.61 in overall and 4.32 in 15–19 years-old. For females in 2013, the prevalence per 100,000 persons was 1.92 in overall and 3.02 in 10–14 years-old. In conclusion, currently, the age-standardized overall prevalence of MFS was 2.27 persons per 100,000 persons. And the overall age-standardized prevalence of MFS increased between 2006 and 2013 especially in 15–19 years-old males and 10–14 years-old females. PMID:28244281

  7. Marfan syndrome-an orthodontic perspective.

    PubMed

    Utreja, Achint; Evans, Carla A

    2009-03-01

    Marfan syndrome is a heritable disorder of connective tissue that can affect the heart, blood vessels, lungs, eyes, bones, and ligaments. It is characterized by tall stature, elongated extremities, scoliosis, and a protruded or caved-in breastbone. Patients typically have a long, narrow face. A high-arched palate produced by a narrow maxilla and skeletal Class II malocclusion due to mandibular retrognathia are other common features. For a patient with no family history of the disorder, at least three body systems must be affected before a diagnosis can be made. Individuals affected by the syndrome routinely seek orthodontic treatment to correct the orofacial manifestations. In this report, the authors present the records of three patients with Marfan syndrome who were treated at a dental school. Two patients had severe periodontal disease in the absence of significant contributing local factors. The presentation of systemic symptoms and typical physical characteristics varied. The syndrome thus went unnoticed in one patient for many years. We discuss here the observed intraoral findings and the progress of orthodontic treatment to provide a brief overview of the challenges involved in treating such patients.

  8. Genotype-phenotype analysis of F-helix mutations at the kinase domain of TGFBR2, including a type 2 Marfan syndrome familial study

    PubMed Central

    Zhang, Lin; Gao, Ling-Gen; Zhang, Ming

    2012-01-01

    Purpose Transforming growth factor beta receptor II (TGFBR2) gene mutations are associated with Marfan syndrome; however, the relationship between the mutations and clinical phenotypes are not clear. Methods Genomic DNA from peripheral blood leukocytes of a Chinese proband with Marfan syndrome, five of the proband’s relatives, and 100 unrelated Chinese control subjects were isolated and screened for fibrillin-1 (FBN1) and TGFBR2 gene mutations by direct sequencing, and a genotype-phenotype study was performed following a review of the literature on TGFBR2 mutations in the search area. Also, the structure of TGFBR2 protein before and after gene mutation was analyzed. Results The results identified a novel missense TGFBR2 mutation p.V453E (c.1358T>A) in the proband and two relatives that was located in the F-helix in the kinase domain of TGFBR2. No such genetic change was observed in the unrelated controls. No FBN1 mutation was detected in any of the subjects. Genotype-phenotype analyses indicated that F-helix mutations are related to type 2 Marfan syndrome and Loeys-Dietz syndrome, and these mutations can lead to severe cardiovascular (93.8%) and skeletal (81.3%) lesions and minor ocular lesions (25%). Losartan treatment can slow-down the progression of aortic lesions. Conclusions The findings extend the mutation spectrum of Marfan syndrome, and that mutations at the F-helix in the kinase domain of TGFBR2 may be associated with the development of severe cardiovascular and skeletal lesions and minor ocular lesions. These findings have implications for genetic testing, diagnosis, and treatment in individuals with transforming growth factor beta (TGF-β) signaling-related disorders. PMID:22259224

  9. Genotype-phenotype analysis of F-helix mutations at the kinase domain of TGFBR2, including a type 2 Marfan syndrome familial study.

    PubMed

    Zhang, Lin; Gao, Ling-Gen; Zhang, Ming; Zhou, Xian-Liang

    2012-01-01

    Transforming growth factor beta receptor II (TGFBR2) gene mutations are associated with Marfan syndrome; however, the relationship between the mutations and clinical phenotypes are not clear. Genomic DNA from peripheral blood leukocytes of a Chinese proband with Marfan syndrome, five of the proband's relatives, and 100 unrelated Chinese control subjects were isolated and screened for fibrillin-1 (FBN1) and TGFBR2 gene mutations by direct sequencing, and a genotype-phenotype study was performed following a review of the literature on TGFBR2 mutations in the search area. Also, the structure of TGFBR2 protein before and after gene mutation was analyzed. The results identified a novel missense TGFBR2 mutation p.V453E (c.1358T>A) in the proband and two relatives that was located in the F-helix in the kinase domain of TGFBR2. No such genetic change was observed in the unrelated controls. No FBN1 mutation was detected in any of the subjects. Genotype-phenotype analyses indicated that F-helix mutations are related to type 2 Marfan syndrome and Loeys-Dietz syndrome, and these mutations can lead to severe cardiovascular (93.8%) and skeletal (81.3%) lesions and minor ocular lesions (25%). Losartan treatment can slow-down the progression of aortic lesions. The findings extend the mutation spectrum of Marfan syndrome, and that mutations at the F-helix in the kinase domain of TGFBR2 may be associated with the development of severe cardiovascular and skeletal lesions and minor ocular lesions. These findings have implications for genetic testing, diagnosis, and treatment in individuals with transforming growth factor beta (TGF-β) signaling-related disorders.

  10. Cionni endocapsular ring implantation in Marfan's Syndrome.

    PubMed

    Bahar, Irit; Kaiserman, Igor; Rootman, David

    2007-11-01

    To evaluate the visual outcomes, intraoperative and postoperative complications of Cionni ring implantation in eyes with a subluxated lens associated with Marfan Syndrome. This case series included 15 eyes of 12 patients aged 19-56 years with a subluxated lens secondary to Marfan's syndrome operataed at the Departament of Ophtalmology, Toronto Western Hospital between 2003 and 2007. A 2-eyelet Cionni ring and an AcrySof (Alcon) foldable intraocular lens (IOL) were implanted in 13 eyes. Two eyes had trans-scleral IOL fixation in the ciliary sulcus. Best-corrected visual acuity, wavefront evaluation of eye aberration and complication rates were analysed. In all eyes, capsular bag centration was excellent. Preoperative visual acuity ranged from 20/50 to counting fingers, and improved to better than 20/40 in all eyes. The mean follow-up duration was 14+/-9.49 months. The most frequent postoperative complication was posterior capsule opacification, which occurred in 3 eyes (18.7%), 2 of which required a neodymium:YAG posterior capsulotomy. No eye developed retinal detachment. Total eye aberration, tilt and high-order aberrations with a 6-mm pupil diameter decreased significantly after surgery (n = 5): Total eye aberration decreased from a mean of 14.8+/-5.5 preoperatively to 2.1+/-4.3 microns after the operation. Tilt was decreased from 4.1+/-2.5 to 0.12+/-2.1 microns, and high-order aberrations decreased from 4.37+/-3.8 microns, before the operation, to 1.47+/-3.5 after the operation. Cionni ring implantation is an effective procedure to correct partial lens subluxation and has few complications (during 14 months of follow-up) in patients with Marfan's Syndrome.

  11. Estrogen-mediated Height Control in Girls with Marfan Syndrome.

    PubMed

    Lee, Dong-Yun; Hyun, Hye Sun; Huh, Rimm; Jin, Dong-Kyu; Kim, Duk-Kyung; Yoon, Byung-Koo; Choi, DooSeok

    2016-02-01

    This study evaluated the efficacy of a stepwise regimen of estradiol valerate for height control in girls with Marfan syndrome. Eight girls with Marfan syndrome who had completed estrogen treatment for height control were included. Estradiol valerate was started at a dose of 2 mg/day, and then was increased. The projected final height was estimated using the initial height percentile (on a disease-specific growth curve for Korean Marfan syndrome [gcPFHt]), and the initial bone age (baPFHt). After the estrogen treatment, the projected final height was compared to the actual final height (FHt). The median baseline chronological and bone age were 10.0 and 10.5 years, respectively. After a median of 36.5 months of treatment, the median FHt (172.6 cm) was shorter than the median gcPFHt (181.0 cm) and baPFHt (175.9 cm). In the six patients who started treatment before the age of 11 years, the median FHt (171.8 cm) was shorter than the median gcPFHt (181.5 cm) and baPFHt (177.4 cm) after treatment. The median differences between the FHt and gcPFHt and baPFHt were 9.2 and 8.3 cm, respectively. In two patients started treatment after the age of 11, the differences between FHt and gcPFHt, and baPFHt after treatment were -4 and 1.4 cm, and -1.2 and 0 cm for each case, respectively. A stepwise increasing regimen of estradiol valerate may be an effective treatment for height control in girls with Marfan syndrome, especially when started under 11 years old.

  12. Estrogen-mediated Height Control in Girls with Marfan Syndrome

    PubMed Central

    Huh, Rimm; Jin, Dong-Kyu; Kim, Duk-Kyung; Yoon, Byung-Koo

    2016-01-01

    This study evaluated the efficacy of a stepwise regimen of estradiol valerate for height control in girls with Marfan syndrome. Eight girls with Marfan syndrome who had completed estrogen treatment for height control were included. Estradiol valerate was started at a dose of 2 mg/day, and then was increased. The projected final height was estimated using the initial height percentile (on a disease-specific growth curve for Korean Marfan syndrome [gcPFHt]), and the initial bone age (baPFHt). After the estrogen treatment, the projected final height was compared to the actual final height (FHt). The median baseline chronological and bone age were 10.0 and 10.5 years, respectively. After a median of 36.5 months of treatment, the median FHt (172.6 cm) was shorter than the median gcPFHt (181.0 cm) and baPFHt (175.9 cm). In the six patients who started treatment before the age of 11 years, the median FHt (171.8 cm) was shorter than the median gcPFHt (181.5 cm) and baPFHt (177.4 cm) after treatment. The median differences between the FHt and gcPFHt and baPFHt were 9.2 and 8.3 cm, respectively. In two patients started treatment after the age of 11, the differences between FHt and gcPFHt, and baPFHt after treatment were -4 and 1.4 cm, and -1.2 and 0 cm for each case, respectively. A stepwise increasing regimen of estradiol valerate may be an effective treatment for height control in girls with Marfan syndrome, especially when started under 11 years old. PMID:26839483

  13. Challenges in the diagnosis of Marfan syndrome.

    PubMed

    Summers, Kim M; West, Jennifer A; Peterson, Madelyn M; Stark, Denis; McGill, James J; West, Malcolm J

    2006-06-19

    Marfan syndrome (MFS) is a multisystem disorder of connective tissue that is inherited in an autosomal dominant fashion, and results from mutations in the FBN1 gene on chromosome 15. Diagnosis is challenging as it requires definition of diverse clinical features and input from a variety of specialists. Genetic testing of FBN1 is time consuming, expensive and complex, and may not solve the diagnostic dilemma. Failure to make a diagnosis or making an inappropriate diagnosis of MFS has social, lifestyle and medical consequences for the individual as well as the family.

  14. Musculo-skeletal abnormalities in patients with Marfan syndrome.

    PubMed

    Al Kaissi, Ali; Zwettler, Elisabeth; Ganger, Rudolf; Schreiner, Simone; Klaushofer, Klaus; Grill, Franz

    2013-01-01

    A leptosomic body type is tall and thin with long hands. Marfanoid features may be familial in nature or pathological, as occurs in congenital contractual arachnodactyly (Beal's syndrome) and Shprintzen-Goldberg syndrome mimicking some of the changes of Marfan syndrome, although not accompanied by luxation of lens and dissecting aneurysm of aorta. In this article we collected eight patients who were consistent with the diagnosis of Marfan syndrome via phenotypic and genotypic characterization. Our patients manifested a constellation of variable presentations of musculo-skeletal abnormalities ranging from developmental dysplasia of the hip, protrusio acetabuli, leg length inequality, patellar instability, scoliosis, to early onset osteoarthritis. Each abnormality has been treated accordingly. This is the first paper which includes the diagnosis and the management of the associated musculo-skeletal abnormalities in patients with Marfan syndrome, stressing that patients with Marfan syndrome are exhibiting great variability in the natural history and the severity of musculo-skeletal abnormalities.

  15. Living with Marfan syndrome III. Quality of life and reproductive planning.

    PubMed

    Peters, K F; Kong, F; Hanslo, M; Biesecker, B B

    2002-08-01

    As individuals with Marfan syndrome are increasingly diagnosed earlier in life and prior to life-threatening cardiovascular events, there is opportunity to study factors that influence their reproductive planning and quality of life. In this study of 174 affected adults, the overall quality of life was reported to be adequate, although it was significantly decreased within the spiritual/psychological domain. Approximately 62% agreed that having Marfan syndrome significantly affected their reproductive decision-making. This view was correlated with age of diagnosis, mitral valve prolapse, and the view that Marfan syndrome has adverse consequences on life. Sixty-nine percent reported personal interest in prenatal testing for Marfan syndrome. Respondents most commonly cited increased worries about personal health and the recurrence risk as ways that Marfan syndrome affects their reproductive decisions. Age, striae, back pain, and low quality of life were each independently correlated with lack of sex drive. These results affirm the importance of both clinical and psychosocial issues on affected adults' reproductive decision-making and sexual well-being. Genetic professionals are ideally positioned to discuss concerns about quality of life and reproduction with patients with Marfan syndrome and refer those with significant concerns for further evaluation and management.

  16. Muscle fibrillin deficiency in Marfan's syndrome myopathy

    PubMed Central

    Behan, W; Longman, C; Petty, R; Comeglio, P; Child, A; Boxer, M; Foskett, P; Harriman, D

    2003-01-01

    Objective: To report a family with Marfan's syndrome in whom a myopathy was associated with respiratory failure; muscle biopsies from affected individuals were examined to determine whether there were abnormalities in fibrillin. Methods: 21 family members underwent detailed clinical examination, including neurological and pulmonary assessment. Muscle biopsies in the most severely affected cases were immunostained using monoclonal antibodies to specific fibrillin components. Genomic DNA from all 21 members was analysed for mutations in the fibrillin gene, FBN1, on 15q21. Results: 13 individuals had a C4621T base change in exon 37 of the FBN1 gene, which in four cases segregated with muscle weakness or evidence of respiratory muscle dysfunction or both. Their muscle biopsies revealed an abnormality in fibrillin immunoreactivity. Conclusions: Abnormalities in fibrillin can be detected in muscle biopsies from patients with Marfan's syndrome who have myopathy. This pedigree, with a point mutation in FBN1, also draws attention to the potential for respiratory failure associated with myopathy. PMID:12700307

  17. Severe neonatal Marfan syndrome resulting from a de novo 3-bp insertion into the fibrillin gene on chromosome 15.

    PubMed Central

    Milewicz, D. M.; Duvic, M.

    1994-01-01

    Severe neonatal Marfan syndrome has features of the Marfan syndrome and congenital contractural arachnodactyly present at birth, along with unique features such as loose, redundant skin and pulmonary emphysema. Since the Marfan syndrome and congenital contractural arachnodactyly are due to mutations in different genes, it has been uncertain whether neonatal Marfan syndrome is due to mutations in the fibrillin gene on chromosome 15 or in another gene. We studied an infant with severe neonatal Marfan syndrome. Dermal fibroblasts were metabolically labeled and found to secret fibrillin inefficiently when compared with control cells. Reverse transcription and amplification of the proband's fibroblast RNA was used to identify a 3-bp insertion between nucleotides 480-481 or 481-482 of the fibrillin cDNA. The insertion maintains the reading frame of the protein and inserts a cysteine between amino acids 160 and 161 in an epidermal growth-factor-like motif of fibrillin. This 3-bp insertion was not found in the fibrillin gene in 70 unrelated, unaffected individuals and 11 unrelated individuals with the Marfan syndrome. We conclude that neonatal Marfan syndrome is the result of mutations in the fibrillin gene on chromosome 15 and is part of the Marfan syndrome spectrum. Images Figure 1 Figure 2 Figure 3 PMID:8116614

  18. Prenatal diagnosis and a donor splice site mutation in fibrillin in a family with Marfan syndrome

    SciTech Connect

    Godfrey, M.; Vandemark, N.; Wang, M.; Han, J.; Rao, V.H. ); Velinov, M.; Tsipouras, P. ); Wargowski, D.; Becker, J.; Robertson, W.; Droste, S. )

    1993-08-01

    The Marfan syndrome, an autosomal dominant connective tissue disorder, is manifested by abnormalities in the cardiovascular, skeletal, and ocular systems. Recently, fibrillin, an elastic-associated microfibrillar glycoprotein, has been linked to the Marfan syndrome, and fibrillin mutations in affected individuals have been documented. In this study, genetic linkage analysis with fibrillin-specific markers was used to establish the prenatal diagnosis in an 11-wk-gestation fetus in a four-generation Marfan kindred. At birth, skeletal changes suggestive of the Marfan syndrome were observed. Reverse transcription-PCR amplification of the fibrillin gene mRNA detected a deletion of 123 bp in one allele in affected relatives. This deletion corresponds to an exon encoding an epidermal growth factor-like motif. Examination of genomic DNA showed a G[yields]C transversion at the +1 consensus donor splice site. 45 refs., 7 figs.

  19. Outcomes of Aortic Valve-Sparing Operations in Marfan Syndrome.

    PubMed

    David, Tirone E; David, Carolyn M; Manlhiot, Cedric; Colman, Jack; Crean, Andrew M; Bradley, Timothy

    2015-09-29

    In many cardiac units, aortic valve-sparing operations have become the preferred surgical procedure to treat aortic root aneurysm in patients with Marfan syndrome, based on relatively short-term outcomes. This study examined the long-term outcomes of aortic valve-sparing operations in patients with Marfan syndrome. All patients with Marfan syndrome operated on for aortic root aneurysm from 1988 through 2012 were followed prospectively for a median of 10 years. Follow-up was 100% complete. Time-to-event analyses were calculated using the Kaplan-Meier method with log-rank test for comparisons. A total of 146 patients with Marfan syndrome had aortic valve-sparing operations. Reimplantation of the aortic valve was performed in 121 and remodeling of the aortic root was performed in 25 patients. Mean age was 35.7 ± 11.4 years and two-thirds were men. Nine patients had acute, 2 had chronic type A, and 3 had chronic type B aortic dissections before surgery. There were 1 operative and 6 late deaths, 5 caused by complications of dissections. Mortality rate at 15 years was 6.8 ± 2.9%, higher than the general population matched for age and sex. Five patients required reoperation on the aortic valve: 2 for endocarditis and 3 for aortic insufficiency. Three patients developed severe, 4 moderate, and 3 mild-to-moderate aortic insufficiency. Rate of aortic insufficiency at 15 years was 7.9 ± 3.3%, lower after reimplantation than remodeling. Nine patients developed new distal aortic dissections during follow-up. Rate of dissection at 15 years was 16.5 ± 3.4%. Aortic valve-sparing operations in patients with Marfan syndrome were associated with low rates of valve-related complications in long-term follow-up. Residual and new aortic dissections were the leading cause of death. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  20. What Are the Signs and Symptoms of Marfan Syndrome?

    MedlinePlus

    ... respectively. Teeth that are too crowded. Flat feet. Stretch marks on the skin also are a common trait in people who have Marfan syndrome. Stretch marks usually appear on the lower back, buttocks, shoulders, ...

  1. Clinical Characteristics of Marfan Syndrome in Korea.

    PubMed

    Lim, A Young; Song, Ju Sun; Kim, Eun Kyoung; Jang, Shin Yi; Chung, Tae-Young; Choi, Seung-Hyuk; Sung, Kiick; Huh, June; Kang, I-Seok; Choe, Yeon Hyeon; Ki, Chang-Seok; Kim, Duk-Kyung

    2016-11-01

    Marfan syndrome (MFS) is a connective tissue disorder with autosomal dominant inheritance and a highly variable clinical spectrum. However, there are limited data available on the clinical features of Korean patients with MFS. The aim of the present study was to describe the clinical characteristics and outcomes of Korean patients with MFS. We included all patients who were diagnosed with MFS between January 1995 and May 2015 at a single tertiary medical center. Patients with an MFS-related disorder including MASS phenotype (myopia, mitral valve prolapse, borderline and non-progressive aortic root dilatation, skeletal findings, and striae), mitral valve prolapse syndrome, and ectopia lentis syndrome were excluded. A total of 343 Korean patients aged ≥15 years who satisfied the revised Ghent nosology were included. The mean patient age at diagnosis was 35.9±12.6 years and 172 (50.1%) patients were male. Median follow-up duration was 52.8 months. A total of 303 patients (88.6%) had aortic root dilatation with Z score ≥2 or aortic root dissection. Ectopia lentis was relatively less common (163 patients, 55.1%) and systemic score ≥7 was found in 217 patients (73.8%). Among 219 probands, a family history of MFS was present in 97 patients (44.5%) and sporadic cases in 121 patients (55.5%). Among the 157 probands who underwent genetic analysis, 141 (89.8%) had an FBN1 mutation associated with aortic root aneurysm/dissection. Aortic dissection (AD) or intramural hematoma (IMH) was identified in 110 patients (32.1%). Among the 221 patients without AD or IMH, descending aortic aneurysms were identified in 19 patients (8.6%). Two hundred thirteen patients (62%) underwent cardiovascular surgery of any type. Eight patients died during follow-up. We described the clinical characteristics and outcomes of Korean MFS patients. Cardiovascular manifestations were commonly detected and FBN1 mutation was present in approximately 90% of patients. In contrast, ectopia lentis was

  2. Clinical Characteristics of Marfan Syndrome in Korea

    PubMed Central

    Lim, A Young; Song, Ju Sun; Kim, Eun Kyoung; Jang, Shin Yi; Chung, Tae-Young; Choi, Seung-Hyuk; Sung, Kiick; Huh, June; Kang, I-Seok; Choe, Yeon Hyeon; Ki, Chang-Seok

    2016-01-01

    Background and Objectives Marfan syndrome (MFS) is a connective tissue disorder with autosomal dominant inheritance and a highly variable clinical spectrum. However, there are limited data available on the clinical features of Korean patients with MFS. The aim of the present study was to describe the clinical characteristics and outcomes of Korean patients with MFS. Subjects and Methods We included all patients who were diagnosed with MFS between January 1995 and May 2015 at a single tertiary medical center. Patients with an MFS-related disorder including MASS phenotype (myopia, mitral valve prolapse, borderline and non-progressive aortic root dilatation, skeletal findings, and striae), mitral valve prolapse syndrome, and ectopia lentis syndrome were excluded. A total of 343 Korean patients aged ≥15 years who satisfied the revised Ghent nosology were included. Results The mean patient age at diagnosis was 35.9±12.6 years and 172 (50.1%) patients were male. Median follow-up duration was 52.8 months. A total of 303 patients (88.6%) had aortic root dilatation with Z score ≥2 or aortic root dissection. Ectopia lentis was relatively less common (163 patients, 55.1%) and systemic score ≥7 was found in 217 patients (73.8%). Among 219 probands, a family history of MFS was present in 97 patients (44.5%) and sporadic cases in 121 patients (55.5%). Among the 157 probands who underwent genetic analysis, 141 (89.8%) had an FBN1 mutation associated with aortic root aneurysm/dissection. Aortic dissection (AD) or intramural hematoma (IMH) was identified in 110 patients (32.1%). Among the 221 patients without AD or IMH, descending aortic aneurysms were identified in 19 patients (8.6%). Two hundred thirteen patients (62%) underwent cardiovascular surgery of any type. Eight patients died during follow-up. Conclusion We described the clinical characteristics and outcomes of Korean MFS patients. Cardiovascular manifestations were commonly detected and FBN1 mutation was present

  3. Early onset marfan syndrome: Atypical clinical presentation of two cases

    PubMed Central

    Ozyurt, A; Baykan, A; Argun, M; Pamukcu, O; Halis, H; Korkut, S; Yuksel, Z; Gunes, T; Narin, N

    2015-01-01

    Early onset Marfan Syndrome (eoMFS) is a rare, severe form of Marfan Syndrome (MFS). The disease has a poor prognosis and most patients present with resistance to heart failure treatment during the newborn period. This report presents two cases of eoMFS with similar clinical features diagnosed in the newborn period and who died at an early age due to the complications related to the involvement of the cardiovascular system. PMID:26929908

  4. Engineered mutations in fibrillin-1 leading to Marfan syndrome act at the protein, cellular and organismal levels.

    PubMed

    Zeyer, Karina A; Reinhardt, Dieter P

    2015-01-01

    Fibrillins are the major components of microfibrils in the extracellular matrix of elastic and non-elastic tissues. They are multi-domain proteins, containing primarily calcium binding epidermal growth factor-like (cbEGF) domains and 8-cysteine/transforming growth factor-beta binding protein-like (TB) domains. Mutations in the fibrillin-1 gene give rise to Marfan syndrome, a connective tissue disorder with clinical complications in the cardiovascular, skeletal, ocular and other organ systems. Here, we review the consequences of engineered Marfan syndrome mutations in fibrillin-1 at the protein, cellular and organismal levels. Representative point mutations associated with Marfan syndrome in affected individuals have been introduced and analyzed in recombinant fibrillin-1 fragments. Those mutations affect fibrillin-1 on a structural and functional level. Mutations which impair folding of cbEGF domains can affect protein trafficking. Protein folding disrupted by some mutations can lead to defective secretion in mutant fibrillin-1 fragments, whereas fragments with other Marfan mutations are secreted normally. Many Marfan mutations render fibrillin-1 more susceptible to proteolysis. There is also evidence that some mutations affect heparin binding. Few mutations have been further analyzed in mouse models. An extensively studied mouse model of Marfan syndrome expresses mouse fibrillin-1 with a missense mutation (p.C1039G). The mice display similar characteristics to human patients with Marfan syndrome. Overall, the analyses of engineered mutations leading to Marfan syndrome provide important insights into the pathogenic molecular mechanisms exerted by mutated fibrillin-1.

  5. Pathophysiology and Japanese clinical characteristics in Marfan syndrome.

    PubMed

    Fujita, Daishi; Takeda, Norifumi; Imai, Yasushi; Inuzuka, Ryo; Komuro, Issei; Hirata, Yasunobu

    2014-08-01

    Marfan syndrome is an autosomal dominant heritable disorder of the connective tissue, caused by mutations of the gene FBN1, which encodes fibrillin-1, a major component of the microfibrils of the extracellular matrix. Fibrillin-1 interacts with transforming growth factor-β (TGF-β), and dysregulated TGF-β signaling plays a major role in the development of connective tissue disease and familial aortic aneurysm and dissection, including Marfan syndrome. Losartan, an angiotensin II blocker, has the potential to reduce TGF-β signaling and is expected to be an additional therapeutic option. Clinical diagnosis is made using the Ghent nosology, which requires comprehensive patient assessment and has been proven to work well, but evaluation of some of the diagnostic criteria by a single physician is difficult and time-consuming. A Marfan clinic was established at the University of Tokyo Hospital in 2005, together with cardiologists, cardiac surgeons, pediatricians, orthopedists, and ophthalmologists in one place, for the purpose of speedy and accurate evaluation and diagnosis of Marfan syndrome. In this review, we discuss the recent progress in diagnosis and treatment of Marfan syndrome, and the characteristics of Japanese patients with Marfan syndrome.

  6. [Marfan syndrome and related connective tissue disorders].

    PubMed

    Steindl, Katharina

    2013-11-27

    Marfan syndrome is an autosomal dominantly inherited connective tissue disorder with a prevalence of approximately 1:5000 people. Typical manifestations affect the cardiovascular system, eyes, skeleton, lungs, skin and dura mater. Most patients have a so-called marfanoid habitus with tall stature, long and narrow limbs, a long and narrow head shape and other skeletal abnormalities. Of particular medical importance are the possible complications such as severe scoliosis or pectus excavatum, spontaneous pneumothorax, retinal detachment, or an acute glaucoma evoked by lens luxation. However, the most dangerous complication is acute dissection of the ascending aorta, which is usually the result of a slowly progressive aortic dilatation. With the introduction of therapies the average life expectancy of previously just 32 years could be raised to above 60 years.

  7. Genetic testing of the FBN1 gene in Chinese patients with Marfan/Marfan-like syndrome.

    PubMed

    Yang, Hang; Luo, Mingyao; Chen, Qianlong; Fu, Yuanyuan; Zhang, Jing; Qian, Xiangyang; Sun, Xiaogang; Fan, Yuxin; Zhou, Zhou; Chang, Qian

    2016-08-01

    Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder typically involving the ocular, skeletal and cardiovascular systems, and aortic aneurysms/dissection mainly contributes to its mortality. Here, we performed genetic testing of the FBN1 gene in 39 Chinese probands with Marfan/Marfan-like syndrome and their related family members by Sanger sequencing. In total, 29 pathogenic/likely pathogenic FBN1 mutations, including 17 novel ones, were identified. In addition, most MFS patients with aortic disease (62%) had a truncating or splicing mutation. These results expand the FBN1 mutation spectrum and enrich our knowledge of genotype-phenotype correlations. Genetic testing for MFS and its related aortic diseases is increasingly important for early intervention and treatment.

  8. A prospective, randomized, placebo-controlled, double-blind, multicenter study of the effects of irbesartan on aortic dilatation in Marfan syndrome (AIMS trial): study protocol

    PubMed Central

    2013-01-01

    Background Cardiovascular complications are the leading cause of mortality and morbidity in Marfan syndrome (MFS), a dominantly inherited disorder caused by mutations in the gene that encodes fibrillin-1. There are approximately 18,000 patients in the UK with MFS. Current treatment includes careful follow-up, beta blockers, and prophylactic surgical intervention; however, there is no known treatment which effectively prevents the rate of aortic dilatation in MFS. Preclinical, neonatal, and pediatric studies have indicated that angiotensin receptor blockers (ARBs) may reduce the rate of aortic dilatation. This trial will investigate the effects of irbesartan on aortic dilatation in Marfan syndrome. Methods/Design The Aortic Irbesartan Marfan Study (AIMS) is an investigator-led, prospective, randomized, placebo-controlled, double-blind, phase III, multicenter trial. Currently, 26 centers in the UK will recruit 490 clinically confirmed MFS patients (aged ≥6 to ≤40 years) using the revised Ghent diagnostic criteria. Patients will be randomized to irbesartan or placebo. Aortic root dilatation will be measured by transthoracic echocardiography at baseline and annually thereafter. The primary outcome is the absolute change in aortic root diameter per year measured by echocardiography. The follow-up period will be a minimum of 36 months with an expected mean follow-up period of 48 months. Discussion This is the first clinical trial to evaluate the ARB irbesartan versus placebo in reducing the rate of aortic root dilatation in MFS. Not only will this provide useful information on the safety and efficacy of ARBs in MFS, it will also provide a rationale basis for potentially lifesaving therapy for MFS patients. Trial registration ISRCTN, 90011794 PMID:24289736

  9. Severe neonatal marfan syndrome resulting from a De Novo 3-bp insertion into the fibrillin gene on chromosome 15

    SciTech Connect

    Milewicz, D.M.; Duvic, M. )

    1994-03-01

    Severe neonatal Marfan syndrome has features of the Marfan syndrome and congenital contractural arachnodactyly present at birth, along with unique features such as loose, redundant skin and pulmonary emphysema. Since the Marfan syndrome and congenital contractural arachnodactyly are due to mutations in different genes, it has been uncertain whether neonatal Marfan syndrome is due to mutations in the fibrillin gene on chromosome 15 or in another gene. The authors studied an infant with severe neonatal Marfan syndrome. Dermal fibroblasts were metabolically labeled and found to secrete fibrillin inefficiently when compared with control cells. Reverse transcription and amplification of the proband's fibroblast RNA was used to identify a 3-bp insertion between nucleotides 480-481 or 481-482 of the fibrillin cDNA. The insertion maintains the reading frame of the protein and inserts a cysteine between amino acids 160 and 161 in an epidermal growth-factor-like motif of fibrillin. This 3-bp insertion was not found in the fibrillin gene in 70 unrelated, unaffected individuals and 11 unrelated individuals with the Maran syndrome. The authors conclude that neonatal Marfan syndrome is the result of mutations in the fibrillin gene on chromosome 15 and is part of the Marfan syndrome spectrum. 32 refs., 3 figs.

  10. Vascular smooth muscle cell phenotypic changes in patients with Marfan syndrome.

    PubMed

    Crosas-Molist, Eva; Meirelles, Thayna; López-Luque, Judit; Serra-Peinado, Carla; Selva, Javier; Caja, Laia; Gorbenko Del Blanco, Darya; Uriarte, Juan José; Bertran, Esther; Mendizábal, Yolanda; Hernández, Vanessa; García-Calero, Carolina; Busnadiego, Oscar; Condom, Enric; Toral, David; Castellà, Manel; Forteza, Alberto; Navajas, Daniel; Sarri, Elisabet; Rodríguez-Pascual, Fernando; Dietz, Harry C; Fabregat, Isabel; Egea, Gustavo

    2015-04-01

    Marfan's syndrome is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix microfibrils and chronic tissue growth factor (TGF)-β signaling. TGF-β is a potent regulator of the vascular smooth muscle cell (VSMC) phenotype. We hypothesized that as a result of the chronic TGF-β signaling, VSMC would alter their basal differentiation phenotype, which could facilitate the formation of aneurysms. This study explores whether Marfan's syndrome entails phenotypic alterations of VSMC and possible mechanisms at the subcellular level. Immunohistochemical and Western blotting analyses of dilated aortas from Marfan patients showed overexpression of contractile protein markers (α-smooth muscle actin, smoothelin, smooth muscle protein 22 alpha, and calponin-1) and collagen I in comparison with healthy aortas. VSMC explanted from Marfan aortic aneurysms showed increased in vitro expression of these phenotypic markers and also of myocardin, a transcription factor essential for VSMC-specific differentiation. These alterations were generally reduced after pharmacological inhibition of the TGF-β pathway. Marfan VSMC in culture showed more robust actin stress fibers and enhanced RhoA-GTP levels, which was accompanied by increased focal adhesion components and higher nuclear localization of myosin-related transcription factor A. Marfan VSMC and extracellular matrix measured by atomic force microscopy were both stiffer than their respective controls. In Marfan VSMC, both in tissue and in culture, there are variable TGF-β-dependent phenotypic changes affecting contractile proteins and collagen I, leading to greater cellular and extracellular matrix stiffness. Altogether, these alterations may contribute to the known aortic rigidity that precedes or accompanies Marfan's syndrome aneurysm formation. © 2015 American Heart Association, Inc.

  11. Like Father, Like Daughter-inherited cutis aplasia occurring in a family with Marfan syndrome: a case report.

    PubMed

    Islam, Yasmin Florence Khodeja; Williams, Charles A; Schoch, Jennifer Jane; Andrews, Israel David

    2017-01-01

    We present the case of a newborn with co-occurrence of Marfan syndrome and aplasia cutis congenita (ACC) and a family history significant for Marfan syndrome and ACC in the father. This case details a previously unreported mutation in Marfan syndrome and describes a novel coinheritance of Marfan syndrome and ACC.

  12. [Marfan syndrome in pregnancy: presentation of four cases and discussion].

    PubMed

    Tzialidou, I; Oehler, K; Scharf, A; Staboulidou, I; Westhoff-Bleck, M; Hillemanns, P; Günter, H H

    2007-02-01

    The coincidence of Marfan syndrome and pregnancy means a high risk for mother and child, as it is associated with cardiovascular and obstetric complications. We report our experience of four pregnancies with the Marfan syndrome. The course of pregnancy, the peripartum management and both the maternal and neonatal outcomes of four pregnant women with the Marfan syndrome, who were treated in our department between 1995 and 2005, were retrospectively analysed. The pregnancies of two women were complicated by premature rupture of membranes (36 (th) gestational week) and premature uterine contractions with cervical incompetence (30 (th) gestational week), respectively. One patient developed class 3 (NYHA) heart failure in the 3 (rd) trimenon. Two out of four women had mild cardiovascular disease and could deliver vaginally. In the other two cases a primary Caesarean section was performed at the 36 (th) week of gestation because of severe cardiovascular morbidity. No patient had a progressive aortic dilatation, dissection or rupture. The neonatal outcome was uneventful in all cases. Three newborns underwent a genetic evaluation for the Marfan syndrome, in two of them mutations in the fibrillin 1 gene were detected. Women with the Marfan syndrome should be counselled pre-conception and observed by an interdisciplinary team during pregnancy. If the aortic root diameter is < 40 mm, without progression in pregnancy, and in the absence of severe valve insufficiency, then pregnancy is in most cases well tolerated and vaginal delivery can be performed.

  13. Preventing the aortic complications of Marfan syndrome: a case-example of translational genomic medicine

    PubMed Central

    Li-Wan-Po, Alain; Loeys, Bart; Farndon, Peter; Latham, David; Bradley, Caroline

    2011-01-01

    The translational path from pharmacological insight to effective therapy can be a long one. We aim to describe the management of Marfan syndrome as a case-example of how pharmacological and genomic insights can contribute to improved therapy. We undertook a literature search for studies of Marfan syndrome, to identify milestones in description, understanding and therapy of the syndrome. From the studies retrieved we then weaved an evidence-based description of progress. Marfan syndrome shows considerable heterogeneity in clinical presentation. It relies on defined clinical criteria with confirmation based on FBN1 mutation testing. Surgical advances have prolonged life in Marfan syndrome. First-line prophylaxis of complications with β-adrenoceptor blockers became established on the basis that reduction of aortic pressure and heart rate would help. Over-activity of proteinases, first suggested in 1980, has since been confirmed by evidence of over-expression of matrix metalloproteinases (MMP), notably MMP-2 and MMP-9. The search for MMP inhibitors led to the evaluation of doxycycline, and both animal studies and small trials, provided early evidence that this widely used antimicrobial agent was useful. Identification of the importance of TGF-β led to evaluation of angiotensin II type I receptor (AT1R) blockers with highly promising results. Combination prophylactic therapy would appear rational. Pharmacological and genomic research has provided good evidence that therapy with losartan and doxycycline would prevent the aortic complications of Marfan syndrome. If on-going well designed trials confirm their efficacy, the outlook for Marfan syndrome patients would be improved considerably. PMID:21276043

  14. [Late onset lens particle glaucoma in Marfan syndrome].

    PubMed

    Arranz-Marquez, E; Fatela-Cantillo, B; Figueroa, M; Teus, M Á

    2015-01-01

    A case is presented of an acute onset lens particle glaucoma originating from a crystalline lens spontaneously dislocated into the vitreous for more than 20 years in a patient diagnosed with Marfan syndrome. Marfan syndrome is a connective tissue disorder with autosomal dominant inheritance caused by fibrillin gene mutation. Ectopia lentis is the predominant ocular abnormality and a major diagnostic criterion. An association between Marfan syndrome and glaucoma has also been demonstrated. The reported case is unusual in that a complete spontaneous lens dislocation to vitreous was present and progressed to secondary lens particle open angle glaucoma. Copyright © 2013 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  15. Losartan in combination with propranolol slows the aortic root dilatation in neonatal Marfan syndrome.

    PubMed

    Liu, Lu-Hang; Lin, Shan-Miao; Lin, Dar-Shong; Chen, Ming-Ren

    2017-07-31

    Neonatal Marfan syndrome, in contrast to classical Marfan syndrome, is characterized by rapidly progressive multi-valvular cardiac disease and death from congestive heart failure, typically within the first year of life. Due to the rarity of this condition, treatment for neonatal Marfan syndrome has not been well studied. In this report, a combination of losartan and propranolol reduced the aortic root dilatation rate after three months of losartan therapy. Genetic analysis in this patient revealed a mutation in exon 25 of the FBN1 gene, which typically results in a shorter life expectancy. However, the patient's heart failure was controlled by losartan, propranolol and other anti-congestive medications, which may have prolonged his survival. Copyright © 2017. Published by Elsevier B.V.

  16. DRUG-BASED THERAPIES FOR VASCULAR DISEASE IN MARFAN SYNDROME: FROM MOUSE MODELS TO HUMAN PATIENTS

    PubMed Central

    Cook, Jason R.; Nistala, Harikiran; Ramirez, Francesco

    2010-01-01

    Marfan syndrome is a congenital disorder of the connective tissue with a long history of clinical and basic science breakthroughs that have forged our understanding of vascular disease pathogenesis. The biomedical importance of Marfan syndrome was recently underscored by the discovery that the underlying genetic lesion impairs both tissue integrity and transforming growth factor-β regulation of cell behavior. This discovery has led to the successful implementation of the first pharmacological intervention in a connective tissue disorder otherwise incurable by either gene- or stem cell-based therapeutic strategies. More generally, information gathered from the study of Marfan syndrome pathogenesis has the potential to improve the clinical management of common acquired disorders of connective tissue degeneration. PMID:20687182

  17. Marfan syndrome-diagnosis and management.

    PubMed

    Ammash, Naser M; Sundt, Thoralf M; Connolly, Heidi M

    2008-01-01

    Marfan syndrome (MFS) is the most common inherited disorder of connective tissue that affects multiple organ systems. This autosomal-dominant condition has an incidence of 2-3 per 10,000 individuals. Although genetic testing is available, the diagnosis is still primarily made using the Ghent criteria. Early identification and appropriate management is critical for patients with MFS who are prone to the life-threatening cardiovascular complications of aortic dissection and rupture. Advances in the understanding of the cause of MFS, early recognition of the disorder, and subsequent institution of medical and surgical therapy has resulted in dramatic improvement in the prognosis of this patient population over the past few decades. Beta-blockers have been demonstrated to slow aortic growth and thus delay the time to aortic surgery. Operative intervention has markedly changed the prognosis of patients with MFS and can be safely performed on an elective basis. Identification of presymptomatic patients is critical to reduce the frequency of catastrophic aortic events.

  18. Epidural analgesia complicated by dural ectasia in the Marfan syndrome

    PubMed Central

    Gray, Chelsea; Hofkamp, Michael P.; Noonan, Patrick T.; McAllister, Russell K.; Pilkinton, Kimberly A.; Diao, Zhiying

    2016-01-01

    Patients with the Marfan syndrome are considered to be high risk during pregnancy and warrant a complete multidisciplinary evaluation. One goal is to minimize hemodynamic fluctuations during labor since hypertensive episodes may result in aortic dissection or rupture. Although they may prevent these complications, neuraxial techniques may be complicated by dural ectasia. The case of a parturient with the Marfan syndrome and mild dural ectasia is presented. During attempted labor epidural placement, unintentional dural puncture occurred. A spinal catheter was used for adequate labor analgesia, and a resultant postdural puncture headache was alleviated by an epidural blood patch under fluoroscopic guidance. PMID:27695168

  19. Mitral valve prolapse in Marfan syndrome: an old topic revisited.

    PubMed

    Taub, Cynthia C; Stoler, Joan M; Perez-Sanz, Teresa; Chu, John; Isselbacher, Eric M; Picard, Michael H; Weyman, Arthur E

    2009-04-01

    The echocardiographic features of mitral valve prolapse (MVP) in Marfan syndrome have been well described, and the incidence of MVP in Marfan syndrome is reported to be 40-80%. However, most of the original research was performed in the late 1980s and early 1990s, when the diagnostic criteria for MVP were less specific. Our goal was to investigate the characteristics of MVP associated with Marfan syndrome using currently accepted diagnostic criteria for MVP. Between January 1990 and March 2004, 90 patients with definitive diagnosis of Marfan syndrome (based on standardized criteria with or without genetic testing) were referred to Massachusetts General Hospital for transthoracic echocardiography. Patients' gender, age, weight, height, and body surface area at initial examination were recorded. Mitral valve thickness and motion, the degree of mitral regurgitation and aortic regurgitation, and aortic dimensions were quantified blinded to patients' clinical information. There were 25 patients (28%) with MVP, among whom 80% had symmetrical bileaflet MVP. Patients with MVP had thicker mitral leaflets (5.0 +/- 1.0 mm vs. 1.8 +/- 0.5 mm, P < 0.001), more mitral regurgitation (using a scale of 1-4, 2.2 +/- 1.0 vs. 0.90 +/- 0.60, P < 0.0001), larger LVEDD, and larger dimensions of sinus of Valsalva, sinotubular junction, aortic arch, and descending aorta indexed to square root body surface area, when compared with those without MVP. When echocardiographic features of patients younger than 18 years of age and those of patients older than 18 were compared, adult Marfan patients had larger LA dimension (indexed to square root body surface area), larger sinotubular junction (indexed to square root body surface area), and more mitral regurgitation and aortic regurgitation. The prevalence of MVP in Marfan syndrome is lower than previously reported. The large majority of patients with MVP have bileaflet involvement, and those with MVP have significantly larger aortic root

  20. Current and future pharmacological treatment strategies with regard to aortic disease in Marfan syndrome.

    PubMed

    Hartog, Alexander W; Franken, Romy; Zwinderman, Aeilko H; Groenink, Maarten; Mulder, Barbara J M

    2012-04-01

    Marfan syndrome is a multisystemic connective tissue disorder caused mainly by mutations in the fibrillin-1 gene. The entire cardiovascular system is affected in patients with Marfan syndrome. Aortic root dilatation, aortic valve regurgitation or - the most feared and life-threatening symptom - aortic root dissection are the most common manifestations. Therapeutic strategies, such as prophylactic aortic root surgery and pharmacological therapy, focus on the prevention of aortic dissection. Currently, the standard medicinal treatments targeting aortic dilatation and dissection consist of agents generally used to lower blood pressure and/or the inotropic state of the heart. By these means, the cyclic repetitive forces exerted on the aortic wall are diminished and thus the onset of aortic dilatation is potentially prevented. Although these pharmacological agents may offer some benefit in reduction of aortic aneurysm expansion rate, they do not target the underlying cause of the progressive aortic degradation. This review discusses the effectiveness of frequently prescribed medications used to prevent and delay aortic complications in Marfan syndrome. New insights on the biochemical pathways leading to aortic disease are also discussed to highlight new targets for pharmacological therapy. Recent insights in the transforming growth factor beta signaling pathway and inflammatory mechanisms in a well-established mouse model of Marfan syndrome, have led to studies exploring new pharmacological treatment strategies with doxycycline, statins and angiotensin II receptor blockers. Pharmacological therapy is focused more on prevention than on delay of aortic wall pathology in Marfan syndrome. Of the new pharmacological treatment strategies targeting aortic pathology in Marfan syndrome, angiotensin receptor type 1 blockers are promising candidates, with several clinical trials currently ongoing.

  1. Aortic disease in patients with Marfan syndrome: aortic volume assessment for surveillance.

    PubMed

    den Hartog, Alexander W; Franken, Romy; de Witte, Piet; Radonic, Teodora; Marquering, Henk A; van der Steen, Wessel E; Timmermans, Janneke; Scholte, Arthur J; van den Berg, Maarten P; Zwinderman, Aeilko H; Mulder, Barbara J M; Groenink, Maarten

    2013-11-01

    To assess the reproducibility of aortic volume estimates and to serially test their use in patients with Marfan syndrome. The study was approved by the medical ethics committee and all subjects gave written informed consent. In 81 patients with Marfan syndrome and seven healthy control subjects, aortic volumes and diameters at baseline were estimated by means of contrast material-enhanced magnetic resonance (MR) imaging. At 3 years of follow-up, aortic expansion rate were calculated in a subgroup of 22 patients with Marfan syndrome. Total aortic volume was defined as volume measurement from the level of the aortic annulus to the aortic bifurcation. Intra- and interobserver agreement of aortic volume were calculated by using the intraclass correlation coefficient. Differences in variables were analyzed with the Student t test and logistic regression. Effect size was calculated. Intra- and interobserver agreement of aortic volume calculation was 0.996 and 0.980, respectively. Mean aortic volume was significantly greater in patients with Marfan syndrome than in control subjects (104 mL/m(2); 95% confidence interval [CI]: 95, 114 mL/m(2) vs 74 mL/m(2); 95% CI: 62, 87 mL/m(2); P < .001). In 22 patients with Marfan syndrome, mean aortic volume was increased at 3 years of follow-up (17 mL; 95% CI: 8, 26 mL; P = .001; effect size, 0.29), while mean aortic diameter did not increase significantly (0.4 mm; 95% CI: 0.0, 0.9 mm; P = .171; effect size, 0.13). Assessment of aortic volume is highly reproducible and may be suited for use in the detection of aortic expansion in patients with Marfan syndrome. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122310/-/DC1. RSNA, 2013

  2. Influence of maxillary constriction on nasal resistance and sleep apnea severity in patients with Marfan's syndrome.

    PubMed

    Cistulli, P A; Richards, G N; Palmisano, R G; Unger, G; Berthon-Jones, M; Sullivan, C E

    1996-11-01

    Marfan's syndrome is associated with a high prevalence of obstructive sleep apnea (OSA). As this syndrome is associated with a characteristic constricted maxilla and high-arched palate, we reasoned that nasal airway constriction and resultant high nasal airway resistance (NAR) may contribute to the development of OSA. Therefore, the aim of this study was to measure NAR in patients with Marfan's syndrome. In addition, we aimed to examine the influence of maxillary morphology on both NAR and the severity of OSA. We measured NAR in 13 consecutive patients with Marfan's syndrome and 13 control subjects. NAR was measured by posterior rhinomanometry, and expressed as the inspiratory resistance at a flow of 0.5 L/s. Dental impressions were taken to evaluate maxillary arch morphology, allowing measurement of the following distances: intercuspid (ICD), interpremolar (IPD), intermolar (IMD), and maximum hard palate height (MPH). Ten of the patients and four of the control subjects had previously undergone nocturnal polysomnography. Mean NAR for the Marfan group was more than twice that in the control group (7.7 +/- 1.2 vs 2.9 +/- 0.4 cm H2O/L/s; p < 0.005). The patients also had marked constriction of the maxillary arch compared with control subjects. Two of the lateral maxillary measurements were significantly inversely correlated with NAR. There were significant correlations between various maxillary arch measurements (MPH/ICD, MPH/IPD, MPH/IMD) and the apnea/hypopnea index. These data suggest that high NAR is a common feature of Marfan's syndrome. Maxillary constriction with a relatively high hard palate appears to be a major reason for the high NAR. The significant correlations between indexes of maxillary constriction and sleep apnea severity suggest that maxillary morphology may play an important role in the pathophysiology of OSA in Marfan's syndrome.

  3. Co-occurrence of Marfan syndrome and bipolar disorder: A fifteen year follow up.

    PubMed

    Jha, Vijendra Nath; Kumar, Manoj; Tarwani, Jatin

    2016-12-01

    Marfan syndrome, a chromosomal disorder, has been commonly associated with schizophrenia but no association with Bipolar affective disorder has been reported in the scientific literature. This case depicts the occurrence of Bipolar affective disorder in a previously undiagnosed case of Marfan syndrome. In this case patient had all manic episodes without any depressive or schizophrenia-like episodes, suggesting a diagnostic stability over a long period of over fifteen years. Studies and research are needed in this regard to look for any possible potential association between the two illnesses. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Musculo-Skeletal Abnormalities in Patients with Marfan Syndrome

    PubMed Central

    Al Kaissi, Ali; Zwettler, Elisabeth; Ganger, Rudolf; Schreiner, Simone; Klaushofer, Klaus; Grill, Franz

    2013-01-01

    Background A leptosomic body type is tall and thin with long hands. Marfanoid features may be familial in nature or pathological, as occurs in congenital contractual arachnodactyly (Beal’s syndrome) and Shprintzen-Goldberg syndrome mimicking some of the changes of Marfan syndrome, although not accompanied by luxation of lens and dissecting aneurysm of aorta. Methods In this article we collected eight patients who were consistent with the diagnosis of Marfan syndrome via phenotypic and genotypic characterization. Results Our patients manifested a constellation of variable presentations of musculo-skeletal abnormalities ranging from developmental dysplasia of the hip, protrusio acetabuli, leg length inequality, patellar instability, scoliosis, to early onset osteoarthritis. Each abnormality has been treated accordingly. Conclusion This is the first paper which includes the diagnosis and the management of the associated musculo-skeletal abnormalities in patients with Marfan syndrome, stressing that patients with Marfan syndrome are exhibiting great variability in the natural history and the severity of musculo-skeletal abnormalities. PMID:23399831

  5. Ruptured cerebral fusiform aneurysm with mucopolysaccharide deposits in the tunica media in a patient with Marfan syndrome.

    PubMed

    Kubo, Yoshitaka; Ogasawara, Kuniaki; Kurose, Akira; Kakino, Shunsuke; Tomitsuka, Nobuhiko; Ogawa, Akira

    2009-03-01

    Although aortic or cardiac complications are common in patients with Marfan syndrome, the presence of an intracranial aneurysm is comparatively rare. In this study, the authors report on their experience with resection of a ruptured fusiform aneurysm of the posterior cerebral artery in a 30-year-old woman with Marfan syndrome. Microscopic examination of the resected tissue showed many Alcian blue-staining deposits, consistent with the presence of mucopolysaccharide in the tunica media and focal fragmentation of the internal elastic lamina.

  6. Sex, pregnancy and aortic disease in Marfan syndrome.

    PubMed

    Renard, Marjolijn; Muiño-Mosquera, Laura; Manalo, Elise C; Tufa, Sara; Carlson, Eric J; Keene, Douglas R; De Backer, Julie; Sakai, Lynn Y

    2017-01-01

    Sex-related differences as well as the adverse effect of pregnancy on aortic disease outcome are well-established phenomena in humans with Marfan syndrome (MFS). The underlying mechanisms of these observations are largely unknown. In an initial (pilot) step we aimed to confirm the differences between male and female MFS patients as well as between females with and without previous pregnancy. We then sought to evaluate whether these findings are recapitulated in a pre-clinical model and performed in-depth cardiovascular phenotyping of mutant male and both nulliparous and multiparous female Marfan mice. The effect of 17β-estradiol on fibrillin-1 protein synthesis was compared in vitro using human aortic smooth muscle cells and fibroblasts. Our small retrospective study of aortic dimensions in a cohort of 10 men and 20 women with MFS (10 pregnant and 10 non-pregnant) confirmed that aortic root growth was significantly increased in the pregnant group compared to the non-pregnant group (0.64mm/year vs. 0.12mm/year, p = 0.018). Male MFS patients had significantly larger aortic root diameters compared to the non-pregnant and pregnant females at baseline and follow-up (p = 0.002 and p = 0.007, respectively), but no significant increase in aortic root growth was observed compared to the females after follow-up (p = 0.559 and p = 0.352). In the GT-8/+ MFS mouse model, multiparous female Marfan mice showed increased aortic diameters when compared to nulliparous females. Aortic dilatation in multiparous females was comparable to Marfan male mice. Moreover, increased aortic diameters were associated with more severe fragmentation of the elastic lamellae. In addition, 17β-estradiol was found to promote fibrillin-1 production by human aortic smooth muscle cells. Pregnancy-related changes influence aortic disease severity in otherwise protected female MFS mice and patients. There may be a role for estrogen in the female sex protective effect.

  7. Identification of defects in the fibrillin gene and protein in individuals with the Marfan syndrome and related disorders.

    PubMed Central

    Milewicz, D M

    1994-01-01

    The Marfan syndrome is an autosomal dominant disorder with pleiotropic manifestations that involve the cardiovascular, ocular, and skeletal systems. Through a number of investigational approaches, the gene encoding for fibrillin, the FBN1 gene on chromosome 15, has been identified as the defective gene causing the Marfan syndrome. Fibrillin is the large glycoprotein with a repetitive domain structure and is a major protein component of microfibrils, a fibrillar system closely associated with elastin in connective tissue. Mutational analysis of defects in the FBN1 gene in patients with the Marfan syndrome has revealed that most mutations are private or unique in an affected individual or family. Analysis of fibrillin protein or gene defects in individuals with related phenotypes has revealed that a perinatal lethal syndrome, termed neonatal Marfan syndrome, is due to FBN1 gene mutations. In addition, fibroblast cell strains from a subset of patients with idiopathic scoliosis have fibrillin protein defects. Last, fibroblasts from calves affected with bovine Marfan syndrome display defects in the fibrillin protein. These studies have wide-ranging implications in the diagnosis, treatment, and prevention of Marfan syndrome and related disorders. Images PMID:8180508

  8. A group of patients with Marfan's syndrome, who have finger and toe contractures, displays tendons' alterations upon an ultrasound examination: are these features common among classical Marfan patients?

    PubMed

    Melchiorre, Daniela; Pratelli, Elisa; Torricelli, Elena; Sofi, Francesco; Abbate, Rosanna; Matucci-Cerinic, Marco; Gensini, GianFranco; Pepe, Guglielmina

    2016-08-01

    The involvement of the musculoskeletal system with other mild pleiotropic manifestations represents a clinical criterion, called "systemic features," to d iagnose Marfan's syndrome. We aimed to investigate the features of the hands and feet redressable contractures present in a group of Marfan patients. In 13 patients with previously diagnosed Marfan's syndrome, an accurate clinical examination was performed. In particular the characterization of the musculoskeletal system by visual analogic scale to measure muscle pain (VAS) and muscle strength (MRC system) was carried out; the Beighton scale score was used to evaluate the articular hypermobility. Ultrasound examination (US) was performed to detect deep-superficial flexor tendons and extensor tendons of both hands, and the short and long flexor and extensor tendons of the fingers and toes in static and dynamic positions. The ImageJ program was adopted to measure a profile of tendon echo-intensity. A reduction of the thickness of all tendons was detected by US in our patients; the VAS and Beighton scale scores were in normal ranges. The profile of tendon echo-intensity showed different textural details in all Marfan patients. This study provides evidence for other contractures' localization, and for altered findings of the tendons in patients with Marfan syndrome and finger/toe contractures. These changes may be associated with structural modifications in connective tissue.

  9. Mild aerobic exercise blocks elastin fiber fragmentation and aortic dilatation in a mouse model of Marfan syndrome associated aortic aneurysm.

    PubMed

    Gibson, Christine; Nielsen, Cory; Alex, Ramona; Cooper, Kimbal; Farney, Michael; Gaufin, Douglas; Cui, Jason Z; van Breemen, Cornelis; Broderick, Tom L; Vallejo-Elias, Johana; Esfandiarei, Mitra

    2017-07-01

    Regular low-impact physical activity is generally allowed in patients with Marfan syndrome, a connective tissue disorder caused by heterozygous mutations in the fibrillin-1 gene. However, being above average in height encourages young adults with this syndrome to engage in high-intensity contact sports, which unfortunately increases the risk for aortic aneurysm and rupture, the leading cause of death in Marfan syndrome. In this study, we investigated the effects of voluntary (cage-wheel) or forced (treadmill) aerobic exercise at different intensities on aortic function and structure in a mouse model of Marfan syndrome. Four-week-old Marfan and wild-type mice were subjected to voluntary and forced exercise regimens or sedentary lifestyle for 5 mo. Thoracic aortic tissue was isolated and subjected to structural and functional studies. Our data showed that exercise improved aortic wall structure and function in Marfan mice and that the beneficial effect was biphasic, with an optimum at low intensity exercise (55-65% V̇o2max) and tapering off at a higher intensity of exercise (85% V̇o2max). The mechanism underlying the reduced elastin fragmentation in Marfan mice involved reduction of the expression of matrix metalloproteinases 2 and 9 within the aortic wall. These findings present the first evidence of potential beneficial effects of mild exercise on the structural integrity of the aortic wall in Marfan syndrome associated aneurysm. Our finding that moderate, but not strenuous, exercise protects aortic structure and function in a mouse model of Marfan syndrome could have important implications for the medical care of young Marfan patients.NEW & NOTEWORTHY The present study provides conclusive scientific evidence that daily exercise can improve aortic health in a mouse model of Marfan syndrome associated aortic aneurysm, and it establishes the threshold for the exercise intensity beyond which exercise may not be as protective. These findings establish a platform for

  10. The eye in the Marfan syndrome.

    PubMed Central

    Maumenee, I H

    1981-01-01

    One hundred sixty consecutive patients with the Marfan syndrome were reviewed for ocular, cardiovascular, and skeletal abnormalities, and were graded by severity. The most striking ocular abnormality was enlargement of the globe, presumably caused by scleral stretching. Staphylomata were not a feature of any of the patients seen, nor was keratoconus. The cornea, in fact, was flattened but not thinned. Among the 160 patients, 193 eyes showed dislocation of the lens. Dislocation of the lens was positively correlated with increased ocular axial length and with decreasing KJ readings. We postulate that the ocular pathologic changes are primarily caused by stretching of the tunica scleralis, and that the zonular fibers (thus under stress may "give" or may rupture in their area of presumably least density which may be the area of developmental fusion of the optic vesicle. In a small proportion of cases the lens dislocation was progressive. There was no correlation between ocular findings, on one hand, and the skeletal and cardiovascular abnormalities on the other. However, there was a good degree of intrafamilial consistency with regard to absence or presence of ocular pathology. The absence of correlation between the ocular and systemic findings in our data on these 160 patients is best explained by the existence of more than 1 point mutation, which may give rise to different but clinically similar phenotypes. The results of our calculations of mutation rate were compatible with such an explanation. Images FIGURE 1 A FIGURE 1 B FIGURE 1 C FIGURE 2 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 9 FIGURE 10 FIGURE 12 FIGURE 13 A FIGURE 13 B FIGURE 13 C FIGURE 13 D PMID:7043871

  11. Diagnostic challenges of Marfan syndrome in an XYY young man.

    PubMed

    Lebreiro, Ana; Martins, Elisabete; Machado, José Carlos; Abreu-Lima, Cassiano

    2012-08-01

    Tall stature is a common feature of both Marfan syndrome and XYY syndrome. Differential diagnosis between these entities has important prognostic implications. We report the case of a 21-year-old young man with a previously known diagnosis of XYY syndrome, in whom the identification of a fibrilin-1 mutation was determinant to establish an appropriate diagnosis, medical follow-up, and genetic counselling.

  12. Multisegment coloboma in a case of Marfan syndrome: another possible effect of increased TGFβ signaling.

    PubMed

    LeBlanc, Shannon K; Taranath, Deepa; Morris, Scott; Barnett, Christopher P

    2014-02-01

    Colobomata are etiologically heterogeneous and may occur as an isolated defect or as a feature of a variety of single-gene disorders, chromosomal syndromes, or malformation syndromes. Although not classically associated with Marfan syndrome, colobomata have been described in several reports of Marfan syndrome, typically involving the lens and rarely involving other ocular structures. While colobomata of the lens have been described in Marfan syndrome, there are very few reports of coloboma involving other ocular structures. We report a newborn boy presenting with coloboma of the iris, lens, retina, and optic disk who was subsequently diagnosed with Marfan syndrome. Marfan syndrome is a disorder of increased TGFβ signaling, and recent work in the mouse model suggests a role for TGFβ signaling in eye development and coloboma formation, suggesting a causal association between Marfan syndrome and coloboma.

  13. Marfan syndrome, dissecting aneurysm of the aorta, and pregnancy

    PubMed Central

    Moore, H. C.

    1965-01-01

    A patient with the Marfan syndrome died suddenly from aortic rupture and dissection in the early puerperium of her second pregnancy. Although the association of the Marfan syndrome and pregnancy is extremely rare, the case reported here being only the fifth on record, the concurrence of dissecting aneurysm or aortic dissection with pregnancy is more frequent. Furthermore it is accepted that aortic dissection in young women below the age of 40 is more common in the pregnant than those not pregnant. The cause of the enhancing effect of pregnancy is unknown but is thought to be endocrine since the stability of connective tissue can be influenced by hormones, particularly the sex steroids. An unusual feature of the present case is the florid inflammatory reaction in the adventitia of the aorta, not specifically related to pregnancy or to the Marfan syndrome, and it is assumed that in this patient the congenital defect of connective tissue assumed to be the basis of the Marfan syndrome is associated with an acute collagen change or necrosis, possibly illustrating a link between the heritable disorders of connective tissue and the diffuse collagen disease. Images PMID:14304236

  14. Assessment of bone mineral status in children with Marfan syndrome

    USDA-ARS?s Scientific Manuscript database

    Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with skeletal involvement. It is caused by mutations in fibrillin1 (FBN1) gene resulting in activation of TGF-ßeta, which developmentally regulates bone mass and matrix properties. There is no consensus regarding bone minerali...

  15. Case report: Rutherfurd syndrome associated with Marfan syndrome.

    PubMed

    Raja, T A; Albadri, S; Hood, C

    2008-09-01

    Rutherfurd syndrome is a rare genetic disorder that is primarily characterised by the classical triad of gingival fibromatosis, delayed tooth eruption and corneal dystrophy. Associated features of the condition include abnormally shaped teeth, mental retardation and aggressive behaviour. His Consultant Clinical Geneticist referred a 2-year-old boy to the Dept. of Paediatric Dentistry at Manchester Dental Hospital. The child and his father had a diagnosis of Rutherfurd Syndrome; a rare autosomal-dominant condition featuring corneal dystrophy, gingival hypertrophy, abnormally shaped teeth and delayed eruption. The only erupted teeth were 52, 71 and 81. The patient also suffers from features of Marfan syndrome, a condition he has inherited from his mother. Preventive advice was provided and the patient was placed on regular review. By the age of 4 years, 52, 61, 72, 71 and 81 were the only teeth present clinically. Maxillary and mandibular dentures were provided, which he refused to wear. At age 8 years, 31 and 41 were erupted lingual to the primary incisors. No other permanent teeth had erupted. Radiographs revealed failure of eruption of multiple primary and permanent teeth. The second premolars had formed above the unerupted mandibular primary second molars. The patient continued to refuse any intervention. Treatment options discussed included overdentures and /or removal of primary teeth and exposure of permanent teeth. This case has presented a rare syndrome with two important dental features, namely gingival hyperplasia and failure of eruption. The case has a long term follow up of 6 years and has a first time association to Marfan syndrome. It also highlights the importance of family history and how it can affect the attitude of the child towards dental treatment.

  16. [Acute carpal tunnel syndrome in a patient with Marfan syndrome].

    PubMed

    Franke, J; Wenzel, W; Rehfuss, D; Keiner, H P; Manncke, K

    2008-05-01

    Acute carpal tunnel syndrome (ACTS) is rare and is mostly the result of fractures of the distal radius or the carpal bones. This paper gives the first report of an ACTS following contusion of the wrist as the result of an extensive haematoma of the flexor tendon sheath, which did not appear until 50 hours after the injury was sustained but then developed rapidly. The patient suffers from Marfan syndrome. This disease is associated with pathologic changes to the major vessels, and especially the aorta, and of the smaller peripheral vessels. It is assumed that the haematoma arose from an aneurysm of such a small vessel. The treatment of choice in ACTS is emergency incision of the carpal tunnel.

  17. Two novel mutations of FBN1 in Jordanian patients with Marfan syndrome.

    PubMed

    Jaradat, Saied A; Abujamous, Lama A; Al-Hawamdeh, Ali A; Alawneh, Khaldoon M; Rawashdeh, Tamara A; Jaradat, Zaher M

    2015-01-01

    Marfan syndrome is an autosomal dominant inheritance disorder with a 1/5000-live-birth prevalence. More than 3000 mutations have been characterized thus far in the FBN1 gene. The goal of this study is to facilitate Marfan syndrome diagnosis in Jordanian patients using a molecular genetic testing. All of the 65 coding exons and flanking intronic sequences of the FBN1 gene were amplified using polymerase chain reaction and were subjected to sequencing in five unrelated Jordanian patients suspected of having Marfan syndrome. Four different mutations were identified, including two novel mutations: the c.1553dupG frame-shift (p.Tyr519Ilefs*14) and the c.6650G>A (p.Cys2217Tyr) missense mutations. Two other missense mutations, c.2243G>A (p.Cys748Tyr) and c.2432G>A (p.Cys811Tyr), have been previously detected. Patient number five was heterozygous for the synonymous substitution variant c.1875T>C (p.Asn625Asn; rs#25458). Additionally, eight variants in the intronic sequence of the FBN1 gene were identified, of which the c.2168-46A>G mutation was a new variant. The data provide molecular-based evidence linking Marfan syndrome to pathogenic mutations in the FBN1 gene among Jordanians for the first time. Thus, our results will contribute to the better management of the disease using molecular tools and will help in genetic counseling of the patients' families.

  18. [30-year-old Patient with suspected Marfan Syndrome and Progressive Gait disturbance].

    PubMed

    Balke, Maryam; Lehmann, Helmar C; Fink, Gereon R; Wunderlich, Gilbert

    2017-07-01

    History A 30-year-old man presented with a history of progressive muscle weakness, difficulty in concentrating, and a slender habitus since early childhood. Marfan syndrome was suspected since the age of 14. Examinations 13 years later he was examined by Marfan experts and by genetic testing and Marfan syndrome could not be confirmed. Further neurological examination revealed the suspected diagnosis of myotonic dystrophy type 1, which was confirmed by genetic testing. Treatment and course Similar to Marfan syndrome, myotonic dystrophy is a multisystemic disorder with the risk of cardiac arrythmias. It is necessary to provide an interdisciplinary care by neurologists, internists, ophthalmologists, speech therapists, and physiotherapists. Conclusion It is not enough to take the habitus as the principle sign to diagnose Marfan syndrome. Furthermore, it is essential to consider symptoms that are not typical for Marfan syndrome, such as cognitive deficiencies or progressive paresis. © Georg Thieme Verlag KG Stuttgart · New York.

  19. Marfan syndrome gene search intensifies following identification of basic defect

    SciTech Connect

    Randall, T.

    1990-10-03

    Somewhere, quite possible along chromosomes 8 and/or 15, the gene(s) for Marfan syndrome will be found. The search is intensifying following a report that faulty scaffolding in the body's connective tissue appears to be the long sought after defect behind the syndrome, and inherited disorder that has caused the premature death of young, healthy-looking individuals. Finding that something in the living masonry of the human body has proven to be a 30-year inquisition of nearly two dozen molecules that has engaged investigators worldwide. Historically, researchers have searched for a structural flaw in one of the collagen molecules to explain the cause of Marfan Syndrome. Using monoclonal antibodies, researchers have implicated microfibrils, the extracellular filaments that provide a matrix for the deposit of elastin during embryonic development.

  20. Possible extracardiac predictors of aortic dissection in Marfan syndrome

    PubMed Central

    2014-01-01

    Background According to previous studies, aortic diameter alone seems to be insufficient to predict the event of aortic dissection in Marfan syndrome (MFS). Determining the optimal schedule for preventive aortic root replacement (ARR) aortic growth rate is of importance, as well as family history, however, none of them appear to be decisive. Thus, the aim of this study was to search for potential predictors of aortic dissection in MFS. Methods A Marfan Biobank consisting of 79 MFS patients was established. Thirty-nine MFS patients who underwent ARR were assigned into three groups based on the indication for surgery (dissection, annuloaortic ectasia and prophylactic surgery). The prophylactic surgery group was excluded from the study. Transforming growth factor-β (TGF-β) serum levels were measured by ELISA, relative expression of c-Fos, matrix metalloproteinase 3 and 9 (MMP-3 and −9) were assessed by RT-PCR. Clinical parameters, including anthropometric variables - based on the original Ghent criteria were also analyzed. Results Among patients with aortic dissection, TGF-β serum level was elevated (43.78 ± 6.51 vs. 31.64 ± 4.99 ng/l, p < 0.0001), MMP-3 was up-regulated (Ln2α = 1.87, p = 0.062) and striae atrophicae were more common (92% vs. 41% p = 0.027) compared to the annuloaortic ectasia group. Conclusions We found three easily measurable parameters (striae atrophicae, TGF-β serum level, MMP-3) that may help to predict the risk of aortic dissection in MFS. Based on these findings a new classification of MFS, that is benign or malignant is also proposed, which could be taken into consideration in determining the timing of prophylactic ARR. PMID:24720641

  1. The Marfan Syndrome. Fact Sheet [and] Physical Education and Activity Guidelines.

    ERIC Educational Resources Information Center

    National Marfan Foundation, Port Washington, NY.

    This document consists of two brochures, the first explaining the Marfan Syndrome and a second providing guidelines for physical education and activity for people who have this syndrome are provided. The brochure on factual information about Marfan syndrome outlines the associated medical problems involving the cardiovascular system, the skeleton,…

  2. Management of mitral regurgitation in Marfan syndrome: Outcomes of valve repair versus replacement and comparison with myxomatous mitral valve disease.

    PubMed

    Helder, Meghana R K; Schaff, Hartzell V; Dearani, Joseph A; Li, Zhuo; Stulak, John M; Suri, Rakesh M; Connolly, Heidi M

    2014-09-01

    The study objective was to evaluate patients with Marfan syndrome and mitral valve regurgitation undergoing valve repair or replacement and to compare them with patients undergoing repair for myxomatous mitral valve disease. We reviewed the medical records of consecutive patients with Marfan syndrome treated surgically between March 17, 1960, and September 12, 2011, for mitral regurgitation and performed a subanalysis of those with repairs compared with case-matched patients with myxomatous mitral valve disease who had repairs (March 14, 1995, to July 5, 2013). Of 61 consecutive patients, 40 underwent mitral repair and 21 underwent mitral replacement (mean [standard deviation] age, 40 [18] vs 31 [19] years; P = .09). Concomitant aortic surgery was performed to a similar extent (repair, 45% [18/40] vs replacement, 43% [9/21]; P = .87). Ten-year survival was significantly better in patients with Marfan syndrome with mitral repair than in those with replacement (80% vs 41%; P = .01). Mitral reintervention did not differ between mitral repair and replacement (cumulative risk of reoperation, 27% vs 15%; P = .64). In the matched cohort, 10-year survival after repair was similar for patients with Marfan syndrome and myxomatous mitral disease (84% vs 78%; P = .63), as was cumulative risk of reoperation (17% vs 12%; P = .61). Patients with Marfan syndrome and mitral regurgitation have better survival with repair than with replacement. Survival and risk of reoperation for patients with Marfan syndrome were similar to those for patients with myxomatous mitral disease. These results support the use of mitral valve repair in patients with Marfan syndrome and moderate or more mitral regurgitation, including those having composite replacement of the aortic root. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  3. [Aortic root dilatation rate in pediatric patients with Marfan syndrome treated with losartan].

    PubMed

    Mariucci, Elisabetta; Guidarini, Marta; Donti, Andrea; Lovato, Luigi; Wischmeijer, Anita; Angeli, Emanuela; Gargiulo, Gaetano D; Picchio, Fernando M; Bonvicini, Marco

    2015-12-01

    Medical therapy with angiotensin II receptor blockers/angiotensin-converting enzyme inhibitors and/or beta-blockers was reported to reduce aortic root dilatation rates in pediatric patients with Marfan syndrome. No data are available in the literature on losartan effects after 3 years of therapy. The aim of our study was to establish whether losartan reduces aortic root dilatation rates in pediatric patients with Marfan syndrome in the mid and long term. This is a retrospective analysis of 38 pediatric patients with Marfan syndrome followed at the Marfan Clinic of S. Orsola-Malpighi Hospital of the University of Bologna (Italy). Aortic diameters were measured at sinuses of Valsalva and proximal ascending aorta with transthoracic echocardiography. After a mean follow-up of 4.5 ± 2.5 years (range 2-9 years), aortic root z score at sinuses of Valsalva and proximal ascending aorta remained stable. The average annual rate of change in aortic root z score was -0.1 ± 0.4 and 0 ± 0.3 at sinuses of Valsalva and proximal ascending aorta, respectively. The mean dose of losartan was 0.7 ± 0.3 mg/kg/day. Three patients were non-responders, probably because of late beginning or low dose of therapy. Eight patients underwent cardiac surgery (aortic root surgery in 5 and mitral valve repair in 3), all of them started losartan later in life. Despite the retrospective design of the study and the small sample size, a beneficial effect of losartan therapy was observed in pediatric patients with Marfan syndrome in the mid and long term. Late beginning or low doses of losartan can turn off the effects of therapy.

  4. Bilateral ectopia lentis with isolated lens coloboma in Marfan syndrome

    PubMed Central

    Sahu, Sabin; Yadav, Reena; Gupta, Sharad; Raj Puri, Lila

    2016-01-01

    A rare case of bilateral ectopia lentis with isolated lens coloboma in Marfan syndrome is reported. A 21-year-old female presented with decreased vision in both eyes. Her unaided visual acuity was 20/200 and 20/400 in the right and left eye, respectively, improving to 20/40 with –4.5 DS/–3.0 DC x 10° correction in the right eye and 20/80 with –10.0 DS/–6.5 Dc x10° correction in the left eye. On slit lamp examination under mydriasis, both eyes revealed ectopia lentis with lens coloboma and stretched zonules. Fundus examination revealed pigmentary changes at the fovea. On systemic evaluation, she was diagnosed with Marfan syndrome. She was prescribed a refractive correction in form of a contact lens and kept under observation. PMID:28028488

  5. Bilateral ectopia lentis with isolated lens coloboma in Marfan syndrome.

    PubMed

    Sahu, Sabin; Yadav, Reena; Gupta, Sharad; Raj Puri, Lila

    2016-01-01

    A rare case of bilateral ectopia lentis with isolated lens coloboma in Marfan syndrome is reported. A 21-year-old female presented with decreased vision in both eyes. Her unaided visual acuity was 20/200 and 20/400 in the right and left eye, respectively, improving to 20/40 with -4.5 DS/-3.0 DC x 10° correction in the right eye and 20/80 with -10.0 DS/-6.5 Dc x10° correction in the left eye. On slit lamp examination under mydriasis, both eyes revealed ectopia lentis with lens coloboma and stretched zonules. Fundus examination revealed pigmentary changes at the fovea. On systemic evaluation, she was diagnosed with Marfan syndrome. She was prescribed a refractive correction in form of a contact lens and kept under observation.

  6. Abnormal heart rate recovery and deficient chronotropic response after submaximal exercise in young Marfan syndrome patients.

    PubMed

    Peres, Paulo; Carvalho, Antônio C; Perez, Ana Beatriz A; Medeiros, Wladimir M

    2016-10-01

    Marfan syndrome patients present important cardiac structural changes, ventricular dysfunction, and electrocardiographic changes. An abnormal heart rate response during or after exercise is an independent predictor of mortality and autonomic dysfunction. The aim of the present study was to compare heart rate recovery and chronotropic response obtained by cardiac reserve in patients with Marfan syndrome subjected to submaximal exercise. A total of 12 patients on β-blocker therapy and 13 off β-blocker therapy were compared with 12 healthy controls. They were subjected to submaximal exercise with lactate measurements. The heart rate recovery was obtained in the first minute of recovery and corrected for cardiac reserve and peak lactate concentration. Peak heart rate (141±16 versus 155±17 versus 174±8 bpm; p=0.001), heart rate reserve (58.7±9.4 versus 67.6±14.3 versus 82.6±4.8 bpm; p=0.001), heart rate recovery (22±6 versus 22±8 versus 34±9 bpm; p=0.001), and heart rate recovery/lactate (3±1 versus 3±1 versus 5±1 bpm/mmol/L; p=0.003) were different between Marfan groups and controls, respectively. All the patients with Marfan syndrome had heart rate recovery values below the mean observed in the control group. The absolute values of heart rate recovery were strongly correlated with the heart rate reserve (r=0.76; p=0.001). Marfan syndrome patients have reduced heart rate recovery and chronotropic deficit after submaximal exercise, and the chronotropic deficit is a strong determinant of heart rate recovery. These changes are suggestive of autonomic dysfunction.

  7. Identification of novel FBN1 and TGFBR2 mutations in 65 probands with Marfan syndrome or Marfan-like phenotypes.

    PubMed

    Chung, Brian Hon-Yin; Lam, Stephen Tak-Sum; Tong, Tony Ming-For; Li, Susanna Yuk-Han; Lun, Kin-Shing; Chan, Daniel Hon-Chuen; Fok, Susanna Fung-Shan; Or, June Siu-Fong; Smith, David Keith; Yang, Wanling; Lau, Yu-Lung

    2009-07-01

    Marfan syndrome is an autosomal dominant connective tissue disorder, and mutations in the FBN1 and TGFBR2 genes have been identified in probands with MFS and related phenotypes. Using DHPLC and sequencing, we studied the mutation spectrum in 65 probands with Marfan syndrome and related phenotypes. A total of 24 mutations in FBN1 were identified, of which 19 (nine missense, six frameshift, two nonsense and two affecting splice junctions) were novel. In the remaining 41 probands, six were identified to have novel TGFBR2 mutations (one frameshift and five missense mutations). All novel mutations found in this study were confirmed to be absent in 50 unrelated normal individuals of the same ethnic background. In probands who fulfilled the Ghent criteria (n = 16), mutations in FBN1 were found in 81% of cases. None of those with TGFBR2 mutations fulfilled the Ghent criteria. Novel missense mutations of unknown significance were classified according to the latest ACMG guidelines and their likelihood to be causative was evaluated.

  8. Marfan syndrome and symptomatic sacral cyst: Report of two cases

    PubMed Central

    Arnold, Paul M.; Teuber, Jan

    2013-01-01

    Context Meningeal abnormalities such as dural ectasia are seen in Marfan syndrome, but spinal meningeal cysts are rarely seen. These cysts usually asymptomatic and often found incidentally on magnetic resonance imaging, large cysts may cause neurological deficits and pain secondary to nerve root compression. Design Case reports. Findings Two patients with Marfan syndrome presented with urinary symptoms secondary to dural ectasia and sacral cysts. Patient 1 had a history of low back pain, erectile dysfunction, and occasional urinary incontinence and groin pain with recent symptom worsening. He underwent L5 partial laminectomy and S1-S2 laminectomy with sacral cyst decompression. Nine weeks later, he underwent drainage of a sacral pseudomeningocele. Pain and urinary symptoms resolved, and he remains neurologically normal 2 years after surgery. Patient 2 presented after a fall on his tailbone, complaining of low back pain and difficulty urinating. Physical therapy was implemented, but after 4 weeks, urinary retention had not improved. He then underwent resection of the sacral cyst and S1-S3 laminectomy. Pain and paresthesias resolved and bowel function returned to normal. Other than needing intermittent self-catheterization, all other neurologic findings were normal 30 months after surgery. Conclusion/clinical relevance Surgical goals for sacral cysts include resection as well as closure of the dura, which can be challenging due to thinning from ectasia. Neurosurgical intervention in Marfan syndrome is associated with a high risk of dural tears and osseous complications, and should be performed only when symptoms are severe. PMID:23941798

  9. [The Marfan syndrome and related connective tissue disorders].

    PubMed

    Siepe, Matthias; Löffelbein, Florian

    2009-06-01

    The Marfan syndrome is an inherited disorder of the connective tissue which is mainly caused by a mutation in the fibrillin-1 gene. The defect in the connective tissue protein can lead to several organ dysfunctions. For the life expectancy, the cardiovascular aspect is of paramount importance. Patients with Marfan syndrome may develop aortic aneurysms and valvular heart defects. The risk of aortic aneurysms consists in the development of aortic dissection or rupture with their fatal consequences. Besides the cardiovascular manifestation, the skeletal and ocular system can also be affected. The skeletal manifestation is often characterised by long limbs, arachnodactyly, and abnormal joint flexibility along with other signs. Patients may also have dislocated lenses, ectasia of the dural sac, stretch marks, spontaneous pneumothorax, recurrent hernia, or a family history suspicious for Marfan. During the past years, other related connective tissue disorders with analogous organ manifestation have been described (e.g., Loeys-Dietz syndrome). In this article we present the basic knowledge about these connective tissue disorders, and we mention new insights in the recently explored pathophysiology of the disorder which is a possible target for future medical treatment options. Furthermore, recent new concepts for the prophylactic treatment of the aortic manifestation are explained.

  10. Atypical presentation of ectopia lentis in Marfan's syndrome.

    PubMed

    Chaudhry, Mridu; Grover, Samit; Baisakhiya, Shikha; Sharma, Neha; Bajaj, Aakarsh

    2014-02-01

    The purpose of this article is to report an unusual bilateral inferior subluxation of the lens in a patient with Marfan's syndrome. A 14-year-old boy presented with gradual painless diminution of vision in both eyes. His family history showed that his maternal uncle also had similar complaints. Systemic examination of the patient revealed no neurological deficits. Cardiovascular system examination was unremarkable. Hands and fingers were long and slender with hyperflexible joints. The ratio of arm spam to height was 1.06. He was myopic with a best-corrected visual acuity of 6/24 with -11 D spherical/- 2 D cylindrical in both eyes. Anterior chambers were deep with the presence of mild iridodonesis in both eyes. Pupillary reactions were sluggish. On pupillary dilatation, the lens was found to be subluxated inferiorly which is unlike the typical superotemporal subluxation of the lens in Marfan's syndrome. The diagnosis of Marfan's syndrome is usually made on clinical examination only, as there is no specific investigation for this condition; however, it may have atypical presentations. Therefore, it is important to recognize and report such atypical cases.

  11. Sports and Marfan Syndrome: Awareness and Early Diagnosis Can Prevent Sudden Death.

    ERIC Educational Resources Information Center

    Salim, Mubadda A.; Alpert, Bruce S.

    2001-01-01

    Physicians who work with athletes play an important role in preventing sudden death related to physical activity in people who have Marfan syndrome. Flagging those who have the physical stigmata and listening for certain cardiac auscultation sounds are early diagnostic keys that can help prevent deaths. People with Marfan syndrome should be…

  12. Sports and Marfan Syndrome: Awareness and Early Diagnosis Can Prevent Sudden Death.

    ERIC Educational Resources Information Center

    Salim, Mubadda A.; Alpert, Bruce S.

    2001-01-01

    Physicians who work with athletes play an important role in preventing sudden death related to physical activity in people who have Marfan syndrome. Flagging those who have the physical stigmata and listening for certain cardiac auscultation sounds are early diagnostic keys that can help prevent deaths. People with Marfan syndrome should be…

  13. Fibrillin abnormalities and prognosis in Marfan syndrome and related disorders

    SciTech Connect

    Aoyama, T.; Furthmayr, H.; Francke, U.; Gasner, C.

    1995-08-28

    Marfan syndrome (MFS), a multisystem autosomal-dominant disorder, is characterized by mutations of the fibrillin-1 (FBN1) gene and by abnormal patterns of synthesis, secretion, and matrix deposition of the fibrillin protein. To determine the sensitivity and specificity of fibrillin protein abnormalities in the diagnosis of MFS, we studied dermal fibroblasts from 57 patients with classical MFS, 15 with equivocal MFS, 8 with single-organ manifestations, and 16 with other connective tissue disorders including homocystinuria and Ehlers-Danlos syndrome. Abnormal fibrillin metabolism was identified in 70 samples that were classified into four different groups based on quantitation of fibrillin synthesis and matrix deposition. Significant correlations were found for phenotypic features including arachnodactyly, striae distensae, cardiovascular manifestations, and fibrillin groups II and IV, which included 70% of the MFS patients. In addition, these two groups were associated with shortened {open_quotes}event-free{close_quotes} survival and more severe cardiovascular complications than groups I and III. The latter included most of the equivocal MFS/single manifestation patients with fibrillin abnormalities. Our results indicate that fibrillin defects at the protein level per se are not specific for MFS, but that the drastically reduced fibrillin deposition, caused by a dominant-negative effect of abnormal fibrillin molecules in individuals defined as groups II and IV, is of prognostic and possibly diagnostic significance. 25 refs., 3 figs., 6 tabs.

  14. Systematic review of chronic pain in persons with Marfan syndrome.

    PubMed

    Velvin, G; Bathen, T; Rand-Hendriksen, S; Geirdal, A Ø

    2016-06-01

    The purpose of this study was to explore the literature on chronic pain in adults with Marfan syndrome (MFS), critically appraising and synthesizing relevant literature. A systematic review was conducted by searching the published literature databases using available medical, physical, psychological, social databases and other sources. All studies that addressed pain in MFS, published in peer-reviewed journals were assessed. Of 351 search results, 18 articles satisfied the eligibility criteria. All studies were cross-sectional and quantitative; no randomized controlled trials or intervention studies were found. Most studies had small sample sizes, low response rates and mainly dealt with other aspects of the diagnosis than pain. Only one article dealt mainly with pain. The research on chronic pain in MFS is limited in size and quality. Despite these limitations, studies describe that the prevalence of pain in patients with MFS is high, varying from 47 to 92% and affecting several anatomic sites. In addition, chronic pain limits daily function and few studies describe treatment options for pain in patients with MFS. Research is needed to obtain more evidence-based knowledge for developing more appropriate rehabilitation programs for people with MFS. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Fatigue in adults with Marfan syndrome, occurrence and associations to pain and other factors.

    PubMed

    Bathen, Trine; Velvin, Gry; Rand-Hendriksen, Svend; Robinson, Hilde Stendal

    2014-08-01

    This study aims to investigate how fatigue affects adults with verified Marfan syndrome (MFS) in their daily lives, by examining fatigue levels and prevalence of severe fatigue compared to the general Norwegian population and individuals with other comparable chronic conditions. We investigated associations between socio-demographic characteristics, Marfan-related health problems, pain and fatigue. A cross-sectional study was conducted, using a postal questionnaire including the Fatigue Severity Scale (FSS) and questions on socio-demographic characteristics, Marfan-related health problems and pain. One hundred seventeen persons with MFS were invited to participate, 73 answered (62%). Participants reported significantly higher FSS scores and prevalence of severe fatigue compared to the general Norwegian population and patients with rheumatoid arthritis (RA), but lower than for other chronic conditions. Participants with chronic pain reported higher fatigue scores than those without chronic pain. Participants on disability benefits reported higher fatigue scores than participants who were working or enrolled in higher education. Marfan-related health problems like aortic dissection and use of blood pressure medication were not significantly associated with fatigue. In multivariable regression analyses chronic pain and employment status were significantly associated with fatigue. The final multivariable model explained 24% of the variance in fatigue scores. Our results show that fatigue is common in MFS patients and that it interferes with their daily lives. Chronic pain and employment status show significant associations to fatigue. This implies that fatigue is important to address when meeting MFS patients in clinical practice. There is need for more research on fatigue in Marfan syndrome.

  16. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations.

    PubMed

    Comeglio, Paolo; Johnson, Philip; Arno, Gavin; Brice, Glen; Evans, Alison; Aragon-Martin, José; da Silva, Filipe Pereira; Kiotsekoglou, Anatoli; Child, Anne

    2007-09-01

    Mutations in the FBN1 gene have been characterised in patients affected by Marfan syndrome and Marfan-related disorders. Starting with genomic DNA, we analysed the FBN1 gene using PCR, SSCP and/or dHPLC analysis, and automatic sequencing of abnormal bands/peaks, in a consecutive series of 508 patients, of which 22 were children less than 5 years old. Our results are comparable with those reported by other groups. In this study we observed 193 mutations, 126 of which previously unreported. A total of 331 relatives (including 51 infants) of 120 probands for whom a family mutation had been identified here or elsewhere, were tested for the presence of that particular mutation. In addition, 4 prenatal tests were carried out. The identification of a mutation allows for early diagnosis, prognosis, genetic counselling, preventive management of carriers and reassurance for unaffected relatives. The importance of knowing in advance the location of the putative family mutation is highlighted by its straightforward application to prenatal and postnatal screening. (c) 2007 Wiley-Liss, Inc.

  17. Difficulties in diagnosing Marfan syndrome using current FBN1 databases.

    PubMed

    Groth, Kristian A; Gaustadnes, Mette; Thorsen, Kasper; Østergaard, John R; Jensen, Uffe Birk; Gravholt, Claus H; Andersen, Niels H

    2016-01-01

    The diagnostic criteria of Marfan syndrome (MFS) highlight the importance of a FBN1 mutation test in diagnosing MFS. As genetic sequencing becomes better, cheaper, and more accessible, the expected increase in the number of genetic tests will become evident, resulting in numerous genetic variants that need to be evaluated for disease-causing effects based on database information. The aim of this study was to evaluate genetic variants in four databases and review the relevant literature. We assessed background data on 23 common variants registered in ESP6500 and classified as causing MFS in the Human Gene Mutation Database (HGMD). We evaluated data in four variant databases (HGMD, UMD-FBN1, ClinVar, and UniProt) according to the diagnostic criteria for MFS and compared the results with the classification of each variant in the four databases. None of the 23 variants was clearly associated with MFS, even though all classifications in the databases stated otherwise. A genetic diagnosis of MFS cannot reliably be based on current variant databases because they contain incorrectly interpreted conclusions on variants. Variants must be evaluated by time-consuming review of the background material in the databases and by combining these data with expert knowledge on MFS. This is a major problem because we expect even more genetic test results in the near future as a result of the reduced cost and process time for next-generation sequencing.Genet Med 18 1, 98-102.

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

    PubMed

    Li, Yapeng; Xu, Jianhua; Chen, Mingjie; Du, Binbin; Li, Qiaoli; Xing, Qinghe; Zhang, Yanzhou

    2016-09-01

    Previous 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. 15 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. The 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. Our 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Identification of fibrillin-1 gene mutations in Marfan syndrome by high-resolution melting analysis.

    PubMed

    Hung, Chia-Cheng; Lin, Shin-Yu; Lee, Chien-Nan; Cheng, Hui-Yu; Lin, Chiou-Ya; Chang, Chien-Hui; Chiu, Hsin-Hui; Yu, Chih-Chieh; Lin, Shuan-Pei; Cheng, Wen-Fang; Ho, Hong-Nerng; Niu, Dau-Ming; Su, Yi-Ning

    2009-06-15

    Marfan syndrome has been associated with approximately 562 mutations in the fibrillin-1 (FBN1) gene. Mutation scanning of the FBN1 gene with DNA direct sequencing is time-consuming and expensive because of its large size. This study analyzed the diagnostic value of high-resolution melting analysis as an alternative method for scanning of the FBN1 gene. A total of 75 polymerase chain reaction (PCR) amplicons (179-301bp, average 256bp) that covered the complete coding regions and splicing sites were evaluated on the 96-well LightCycler system. Melting curves were analyzed as fluorescence derivative plots (-dF/dT vs. temperature). To determine the sensitivity of this method, a total of 82 samples from patients with Marfan syndrome and 50 unaffected individuals were analyzed. All mutations reported in this study had been confirmed previously by direct sequencing analysis. Melting analysis identified 48 heterozygous variants. The variant c.3093 G>T (exon 25) was incorrectly identified by melting curve analysis. The sensitivity of the technique in this sample was 98.78% (81/82). This study demonstrated that high-resolution melting analysis is a reliable gene scanning method with greater speed than DNA sequencing. Our results support the use of this technology as an alternative method for the diagnosis of Marfan syndrome as well as its suitability for high-throughput mutation scanning of other large genes.

  20. The prevalence and clinical impact of obesity in adults with Marfan syndrome

    PubMed Central

    Yetman, Anji T; McCrindle, Brian W

    2010-01-01

    BACKGROUND: Patients with Marfan syndrome characteristically have an asthenic body habitus and are considered to be exempt from the obesity epidemic. OBJECTIVE: To examine the prevalence and clinical impact of obesity in a cohort of adults with Marfan syndrome. METHODS: Fifty outpatients (30 female) with a mean (± SD) age of 38±13 years were studied. Demographic variables including previously identified risk factors for aortic dissection were recorded. Body mass index (BMI) was determined and patients were classified as normal (BMI less than 25 kg/m2), overweight (BMI 25 kg/m2 to 29.9 kg/m2) or obese (BMI 30 kg/m2 or greater). Other cardiovascular risk factors were examined. An adverse clinical outcome was defined as either the attainment of surgical criteria for aortic root replacement or the presence of aortic dissection. RESULTS: A family history of aortic dissection was present in 13 (26%) patients. In 23 (46%) patients, there was no known family history of Marfan syndrome. Mean BMI was 25.4±7.4 kg/m2, with 18 (36%) patients having an elevated BMI. Positive smoking status was present in 15 (30%), hypertension in 13 (26%) and hyperlipidemia in 19 (38%) patients. Adverse clinical outcome was present in 27 (54%) patients. Logistic regression analysis revealed only index case (OR 44; P<0.001) and higher BMI (OR 1.2; P=0.04) to be significantly and independently associated with increased risk of adverse clinical outcome. CONCLUSIONS: Obesity is common in adults with Marfan syndrome and is associated with an increased risk of aortic complications. PMID:20386774

  1. Edgar Allan Poe: a case description of the Marfan syndrome in an obscure short story.

    PubMed

    Battle, Robert W

    2011-07-01

    In the obscure short story “A Tale of the Ragged Mountains,” Edgar Allen Poe meticulously described a character with features remarkably consistent with the Marfan syndrome. This description appeared in fiction >50 years before the celebrated index description in the published medical research by Professor Antoine Marfan in Paris in 1896.

  2. Bilateral axillary artery aneurysms after Bentall procedure in Marfan syndrome.

    PubMed

    Haruki, Takashi; Ito, Hiroshi; Sakata, Kensuke; Kobayashi, Yurio

    2015-11-01

    A man with Marfan syndrome underwent a Bentall procedure for annuloaortic ectasia and severe aortic regurgitation at 43 years of age. Twenty-eight years after the Bentall procedure, he developed bilateral axillary artery aneurysms (length × diameter: right: 80 × 39 mm; left: 103 × 45 mm). Aneurysmectomy and reconstruction of the axillary artery were performed using an artificial vascular graft. Histological examination revealed cystic medial necrosis. The postoperative course was uneventful, but long-term follow-up is necessary.

  3. Orthopaedic Aspects of Marfan Syndrome: The Experience of a Referral Center for Diagnosis of Rare Diseases

    PubMed Central

    Fichera, Alessandro; De Luna, Vincenzo; Mancini, Federico; Caterini, Roberto

    2016-01-01

    Marfan syndrome is caused by mutations in the fibrillin-1 gene (FBN1). The most important features affect the cardiovascular system, eyes, and skeleton. The aim of this study was to report the most frequent musculoskeletal alterations observed in 146 patients affected by Marfan syndrome. Fifty-four patients (37%) underwent cardiac surgery and 11 of them received emergent surgery for acute aortic dissection. Ectopia lentis was found in 68 patients (47%) whereas myopia above 3D occurred in 46 patients (32%). Musculoskeletal anomalies were observed in all patients with Marfan syndrome. In 88 patients (60.2%), the associated “wrist and thumb sign” was present; in 58 patients (39.7%), pectus carinatum deformity; in 44 patients (30.1%), pectus excavatum; in 49 patients (33.5%), severe flatfoot; in 31 patients (21.2%), hindfoot deformity; in 54 patients (36.9%), reduced US/LS ratio or increased arm span-height ratio; in 37 patients (25.3%), scoliosis or thoracolumbar kyphosis; in 22 patients (15%), reduced elbow extension (170° or less). Acetabular protrusion was ascertained on radiographs in 27 patients (18.4%). Orthopaedic aspects of the disease are very important for an early diagnosis; however, we have not observed definite correlations between the extent of orthopaedic involvement and aortic complications. PMID:28050285

  4. Long-Term Risk for Aortic Complications After Aortic Valve Replacement in Patients With Bicuspid Aortic Valve Versus Marfan Syndrome.

    PubMed

    Itagaki, Shinobu; Chikwe, Joanna P; Chiang, Yuting P; Egorova, Natalia N; Adams, David H

    2015-06-09

    Bicuspid aortic valves are associated with valve dysfunction, ascending aortic aneurysm and dissection. Management of the ascending aorta at the time of aortic valve replacement (AVR) in these patients is controversial and has been extrapolated from experience with Marfan syndrome, despite the absence of comparative long-term outcome data. This study sought to assess whether the natural history of thoracic aortopathy after AVR in patients with bicuspid aortic valve disease is substantially different from that seen in patients with Marfan syndrome. In this retrospective comparison, outcomes of 13,205 adults (2,079 with bicuspid aortic valves, 73 with Marfan syndrome, and 11,053 control patients with acquired aortic valve disease) who underwent primary AVR without replacement of the ascending aorta in New York State between 1995 and 2010 were compared. The median follow-up time was 6.6 years. The long-term incidence of thoracic aortic dissection was significantly higher in patients with Marfan syndrome (5.5 ± 2.7%) compared with those with bicuspid valves (0.55 ± 0.21%) and control group patients (0.41 ± 0.08%, p < 0.001). Thoracic aortic aneurysms were significantly more likely to be diagnosed in late follow-up in patients with Marfan syndrome (10.8 ± 4.4%) compared with those with bicuspid valves (4.8 ± 0.8%) and control group patients (1.4 ± 0.2%) (p < 0.001). Patients with Marfan syndrome were significantly more likely to undergo thoracic aortic surgery in late follow-up (10.4 ± 4.3%) compared with those with bicuspid valves (2.5 ± 0.6%) and control group patients (0.50 ± 0.09%) (p < 0.001). The much higher long-term rates of aortic complications after AVR observed in patients with Marfan syndrome compared with those with bicuspid aortic valves confirm that operative management of patients with bicuspid aortic valves should not be extrapolated from Marfan syndrome and support discrete treatment algorithms for these different clinical entities

  5. Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome.

    PubMed

    Emrich, Fabian C; Okamura, Homare; Dalal, Alex R; Penov, Kiril; Merk, Denis R; Raaz, Uwe; Hennigs, Jan K; Chin, Jocelyn T; Miller, Miquell O; Pedroza, Albert J; Craig, Juliana K; Koyano, Tiffany K; Blankenberg, Francis G; Connolly, Andrew J; Mohr, Friedrich W; Alvira, Cristina M; Rabinovitch, Marlene; Fischbein, Michael P

    2015-01-01

    Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome. Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs. Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome. © 2014 American Heart Association, Inc.

  6. Unusual presentation of adult Marfan syndrome as a complex diaphragmatic hiatus hernia.

    PubMed

    Thakur, Shruti; Jhobta, Anupam; Sharma, Brij; Chauhan, Arun; Thakur, Charu S

    2017-07-01

    Marfan syndrome is multisystem connective tissue disorder that primarily involves the skeletal, cardiovascular, and ocular systems. The gastrointestinal complications in Marfan syndrome are rare, with only a few case reports described in the literature. We present a 25-year-old woman who presented with acute abdominal pain for 1 day. The imaging features revealed complex diaphragmatic hiatus hernia with organoaxial gastric volvulus. This is a unique case report about an adult patient with Marfan syndrome who presented with symptomatic paraesophageal hernia and organoaxial gastric volvulus. Copyright © 2014. Published by Elsevier Taiwan.

  7. Splicing mutation in the fibrillin-1 gene associated with neonatal Marfan syndrome and severe pulmonary emphysema with tracheobronchomalacia.

    PubMed

    Shinawi, Marwan; Boileau, Catherine; Brik, Riva; Mandel, Hanna; Bentur, Lea

    2005-04-01

    Neonatal Marfan syndrome is an autosomal-dominant connective tissue disease with unique clinical manifestations and mutations. We describe the clinical course of an infant with neonatal Marfan syndrome that had the novel IVS31-2A > G splice site mutation in fibrillin-1. This mutation affects the second base of the acceptor consensus splice site of intron 31, and probably leads to abnormal splicing events. The patient presented with respiratory distress and heart murmur in early neonatal life. Cardiac evaluation revealed pulmonic stenosis, atrioventricular regurgitation, and a dilated aortic root that were controlled by balloon dilatation of the pulmonic stenosis and medications for congestive heart failure. At age 3 months, he presented with severe respiratory distress caused by upper and lower airway obstruction. Imaging studies showed severe pulmonary emphysema, and a bronchoscopy demonstrated megatracheobronchomalacia, an unusual finding in this syndrome. Subsequently, the patient developed recurrent hyperinflation of the right and left lungs, with emphysematous changes and mediastinal shift. After discussing with his parents the grave prognosis for neonatal Marfan syndrome, he was discharged home with oxygen treatment and died at home at age 4.5 months. This case report demonstrates and discusses pulmonary involvement in neonatal Marfan syndrome and the difficult therapeutic challenges created by the severe cardiopulmonary abnormalities in this invariably fatal condition.

  8. Recapitulating and Correcting Marfan Syndrome in a Cellular Model

    PubMed Central

    Park, Jung Woo; Yan, Li; Stoddard, Chris; Wang, Xiaofang; Yue, Zhichao; Crandall, Leann; Robinson, Tiwanna; Chang, Yuxiao; Denton, Kyle; Li, Enqin; Jiang, Bin; Zhang, Zhenwu; Martins-Taylor, Kristen; Yee, Siu-Pok; Nie, Hong; Gu, Feng; Si, Wei; Xie, Ting; Yue, Lixia; Xu, Ren-He

    2017-01-01

    Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in FBN1 gene, which encodes a key extracellular matrix protein FIBRILLIN-1. The haplosufficiency of FBN1 has been implicated in pathogenesis of MFS with manifestations primarily in cardiovascular, muscular, and ocular tissues. Due to limitations in animal models to study the late-onset diseases, human pluripotent stem cells (PSCs) offer a homogeneic tool for dissection of cellular and molecular pathogenic mechanism for MFS in vitro. Here, we first derived induced PSCs (iPSCs) from a MFS patient with a FBN1 mutation and corrected the mutation, thereby generating an isogenic “gain-of-function” control cells for the parental MFS iPSCs. Reversely, we knocked out FBN1 in both alleles in a wild-type (WT) human embryonic stem cell (ESC) line, which served as a loss-of-function model for MFS with the WT cells as an isogenic control. Mesenchymal stem cells derived from both FBN1-mutant iPSCs and -ESCs demonstrated reduced osteogenic differentiation and microfibril formation. We further demonstrated that vascular smooth muscle cells derived from FBN1-mutant iPSCs showed less sensitivity to carbachol as demonstrated by contractility and Ca2+ influx assay, compared to the isogenic controls cells. These findings were further supported by transcriptomic anaylsis of the cells. Therefore, this study based on both gain- and loss-of-function approaches confirmed the pathogenetic role of FBN1 mutations in these MFS-related phenotypic changes. PMID:28539832

  9. Recent developments in the diagnosis of Marfan syndrome and related disorders.

    PubMed

    Summers, Kim M; West, Jennifer A; Hattam, Annette; Stark, Denis; McGill, James J; West, Malcolm J

    2012-11-05

    Marfan syndrome is a multisystem disorder of connective tissue that is inherited in an autosomal dominant fashion, and results from mutation of the FBN1 gene on human chromosome 15. There are a number of conditions of the connective tissue with a similar phenotype that can be confused with Marfan syndrome. Modifications of the diagnostic criteria have recently been published, facilitating the differentiation of Marfan syndrome from these conditions. It is still difficult to use modern genetic testing for diagnosis because Marfan syndrome can be caused by many different mutations in FBN1, a large gene with 65 coding segments, while mutations in other genes can cause overlapping phenotypes. Several clinical trials of drug therapy, including the antihypertensive drug losartan, are in progress.

  10. A Novel Fibrillin-1 Gene Mutation Leading to Marfan Syndrome in a Korean Girl.

    PubMed

    Nam, Hyo-Kyoung; Nam, Myung-Hyun; Ha, Kee-Soo; Rhie, Young-Jun; Lee, Kee-Hyoung

    2017-03-01

    Marfan syndrome is an autosomal dominant genetic disorder caused by a connective tissue defect. A nine-year-old girl was referred to our pediatric endocrinology clinic for tall stature. Physical examination revealed a lens dislocation with strabismus, high palate, positive wrist and thumb signs, joint hypermobility, and pes planus. Transthoracic echocardiography revealed dilatation of the aortic root. She was diagnosed with Marfan syndrome based on the revised Ghent diagnostic criteria. Molecular investigation identified a heterozygous c.2810G >A variation in the FBN1 gene in the patient, but not in her parents. To our knowledge, this sequence variant has been reported as a polymorphism (rs113602180), but it is the first report identifying it as the genetic cause of Marfan syndrome. We hypothesize that this de novo novel missense FBN1 mutation disrupts fibrillin-1 function and is probably involved in the development of Marfan syndrome in this patient. © 2017 by the Association of Clinical Scientists, Inc.

  11. [Post-cesarean acute aortic dissection in a Marfan syndrome patient].

    PubMed

    Onofriescu, M; Gavriluţ, Maria; Tinică, G; Diaconescu, V; Holicov, Monica; Radu, E; Aldea, Marie-Jeanne

    2007-01-01

    Marfan syndrome is an uncommon condition in pregnancy. We present the case of 37 years old gravida 1, para 1 with Marfan syndrome. She delivered at term by cesarean section, a healthy male infant weighing 3500 grams with Apgar's of 9. During the postoperative period she developed aortic dissection and was referred to the Cardiovascular Surgery Department. We described such a case and the difficult decisions that we faced.

  12. The Incidence and Severity of Physical Pain Symptoms in Marfan Syndrome: A Survey of 993 Patients.

    PubMed

    Nelson, Ariana M; Walega, David R; McCarthy, Robert J

    2015-12-01

    To characterize the incidence, severity, quality, and treatment of pain in a large cohort of Marfan patients. A web-based survey was distributed to all individuals on the Marfan Foundation listserv. Respondents who endorsed a diagnosis of Marfan syndrome were queried as to the presence, frequency, severity, location, and quality of their pain and were asked to describe the specific treatments used to manage pain. The primary outcome was the presence of pain symptoms in respondents during the 7-day period preceding completion of the survey. Of the 993 patients with a verified diagnosis of Marfan syndrome, 67% (95% confidence interval, 64%-69%) reported pain in the preceding 7 days. Median (interquartile range) "average daily pain" was 4 (3 to 5) on the numeric rating scale; "worst pain" was 7 (5 to 8). "Worst pain experienced" was ≥4 in 93% of respondents. Analgesic use to control pain related to Marfan syndrome was reported in 56% of respondents with 55% reporting <50% pain relief with this modality. Few patients underwent interventional procedures for pain control, despite intractable back and joint pain being common. A majority (52%) of respondents rated "chronic pain care" from their physicians as either "poor" or "fair." Our findings suggest that pain symptoms in Marfan patients are underestimated and likely undertreated. We propose a need for improved patient and medical provider awareness of pain management options in this population, including the development of effective algorithms to treat pain in Marfan patients.

  13. Marfan syndrome caused by a novel FBN1 mutation with associated pigmentary glaucoma.

    PubMed

    Kuchtey, John; Chang, Ta Chen; Panagis, Lampros; Kuchtey, Rachel W

    2013-04-01

    Mutations in fibrillin-1 (FBN1) cause a wide spectrum of disorders, including Marfan syndrome, which have in common defects in fibrillin-1 microfibrils. Ectopia lentis and myopia are frequently observed ocular manifestations of Marfan syndrome. Glaucoma is also associated with Marfan syndrome, though the form of glaucoma has not been well-characterized. In this report, ocular examination of a patient diagnosed with Marfan syndrome based on family history and aortic dilatation was performed, including measurement of facility of aqueous humor outflow by tonography. The patient did not have ectopia lentis at the age of 42 years. Based on optic nerve appearance, reduced outflow facility, elevated IOP with open angles and clear signs of pigment dispersion, the patient was diagnosed with pigmentary glaucoma. The patient was heterozygous for a novel truncating mutation in FBN1, p.Leu72Ter. Histology of normal human eyes revealed abundant expression of elastic fibers and fibrillin-1 in aqueous humor outflow structures. This is the first report of a patient with Marfan syndrome that is caused by a confirmed FBN1 mutation with associated pigmentary glaucoma. In addition to identifying a novel mutation of FBN1 and broadening the spectrum of associated ocular phenotypes in Marfan syndrome, our findings suggest that pigmentary glaucoma may involve defects in fibrillin-1 microfibrils.

  14. Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome or Related Phenotypes and FBN1 Mutations: An International Study

    PubMed Central

    Faivre, L. ; Collod-Beroud, G. ; Loeys, B. L. ; Child, A. ; Binquet, C. ; Gautier, E. ; Callewaert, B. ; Arbustini, E. ; Mayer, K. ; Arslan-Kirchner, M. ; Kiotsekoglou, A. ; Comeglio, P. ; Marziliano, N. ; Dietz, H. C. ; Halliday, D. ; Beroud, C. ; Bonithon-Kopp, C. ; Claustres, M. ; Muti, C. ; Plauchu, H. ; Robinson, P. N. ; Adès, L. C. ; Biggin, A. ; Benetts, B. ; Brett, M. ; Holman, K. J. ; De Backer, J. ; Coucke, P. ; Francke, U. ; De Paepe, A. ; Jondeau, G. ; Boileau, C. 

    2007-01-01

    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 TGFβ signalling). Exon 24–32 mutations define a high-risk group for cardiac manifestations associated with

  15. The molecular genetics of Marfan syndrome and related disorders

    PubMed Central

    Robinson, P N; Arteaga‐Solis, E; Baldock, C; Collod‐Béroud, G; Booms, P; De Paepe, A; Dietz, H C; Guo, G; Handford, P A; Judge, D P; Kielty, C M; Loeys, B; Milewicz, D M; Ney, A; Ramirez, F; Reinhardt, D P; Tiedemann, K; Whiteman, P; Godfrey, M

    2006-01-01

    Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin‐1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signalling and in matrix‐cell interactions. The purpose of this review is to provide a comprehensive overview of recent advances in the molecular biology of fibrillin and fibrillin‐rich microfibrils. Mutations in FBN1 and other genes found in MFS and related disorders will be discussed, and novel concepts concerning the complex and multiple mechanisms of the pathogenesis of MFS will be explained. PMID:16571647

  16. Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome.

    PubMed

    Franken, Romy; den Hartog, Alexander W; Radonic, Teodora; Micha, Dimitra; Maugeri, Alessandra; van Dijk, Fleur S; Meijers-Heijboer, Hanne E; Timmermans, Janneke; Scholte, Arthur J; van den Berg, Maarten P; Groenink, Maarten; Mulder, Barbara J M; Zwinderman, Aeilko H; de Waard, Vivian; Pals, Gerard

    2015-04-01

    It has been shown that losartan reduces aortic dilatation in patients with Marfan syndrome. However, treatment response is highly variable. This study investigates losartan effectiveness in genetically classified subgroups. In this predefined substudy of COMPARE, Marfan patients were randomized to daily receive losartan 100 mg or no losartan. Aortic root dimensions were measured by MRI at baseline and after 3 years. FBN1 mutations were classified based on fibrillin-1 protein effect into (1) haploinsufficiency, decreased amount of normal fibrillin-1, or (2) dominant negative, normal fibrillin-1 abundance with mutant fibrillin-1 incorporated in the matrix. A pathogenic FBN1 mutation was found in 117 patients, of whom 79 patients were positive for a dominant negative mutation (67.5%) and 38 for a mutation causing haploinsufficiency (32.5%). Baseline characteristics between treatment groups were similar. Overall, losartan significantly reduced aortic root dilatation rate (no losartan, 1.3±1.5 mm/3 years, n=59 versus losartan, 0.8±1.4 mm/3 years, n=58; P=0.009). However, losartan reduced only aortic root dilatation rate in haploinsufficient patients (no losartan, 1.8±1.5 mm/3 years, n=21 versus losartan 0.5±0.8 mm/3 years, n=17; P=0.001) and not in dominant negative patients (no losartan, 1.2±1.7 mm/3 years, n=38 versus losartan 0.8±1.3 mm/3 years, n=41; P=0.197). Marfan patients with haploinsufficient FBN1 mutations seem to be more responsive to losartan therapy for inhibition of aortic root dilatation rate compared with dominant negative patients. Additional treatment strategies are needed in Marfan patients with dominant negative FBN1 mutations. http://www.trialregister.nl/trialreg/index.asp; Unique Identifier: NTR1423. © 2015 American Heart Association, Inc.

  17. A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

    PubMed

    Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K; Habashi, Jennifer P; Bedja, Djahida; Whitworth, Ryan E; Lindsay, Mark E; Schoenhoff, Florian; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Ehsan, Hamid; Huso, David; Thomas, Craig J; Caulfield, Mark J; Van Eyk, Jennifer E; Judge, Daniel P; Dietz, Harry C

    2015-10-27

    Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.

  18. Mechanical assessment of elastin integrity in fibrillin-1-deficient carotid arteries: implications for Marfan syndrome

    PubMed Central

    Ferruzzi, Jacopo; Collins, Melissa J.; Yeh, Alvin T.; Humphrey, Jay D.

    2011-01-01

    Aims Elastin is the primary component of elastic fibres in arteries, which contribute significantly to the structural integrity of the wall. Fibrillin-1 is a microfibrillar glycoprotein that appears to stabilize elastic fibres mechanically and thereby to delay a fatigue-induced loss of function due to long-term repetitive loading. Whereas prior studies have addressed some aspects of ageing-related changes in the overall mechanical properties of arteries in mouse models of Marfan syndrome, we sought to assess for the first time the load-carrying capability of the elastic fibres early in maturity, prior to the development of ageing-related effects, dilatation, or dissection. Methods and results We used elastase to degrade elastin in common carotid arteries excised, at 7–9 weeks of age, from a mouse model (mgR/mgR) of Marfan syndrome that expresses fibrillin-1 at 15–25% of normal levels. In vitro biaxial mechanical tests performed before and after exposure to elastase suggested that the elastic fibres exhibited a nearly normal load-bearing capability. Observations from nonlinear optical microscopy suggested further that competent elastic fibres not only contribute to load-bearing, they also increase the undulation of collagen fibres, which endows the normal arterial wall with a more compliant response to pressurization. Conclusion These findings support the hypothesis that it is an accelerated fatigue-induced damage to or protease-related degradation of initially competent elastic fibres that render arteries in Marfan syndrome increasingly susceptible to dilatation, dissection, and rupture. PMID:21730037

  19. Inflammation Aggravates Disease Severity in Marfan Syndrome Patients

    PubMed Central

    Radonic, Teodora; de Witte, Piet; Groenink, Maarten; de Waard, Vivian; Lutter, Rene; van Eijk, Marco; Jansen, Marnix; Timmermans, Janneke; Kempers, Marlies; Scholte, Arthur J.; Hilhorst-Hofstee, Yvonne; van den Berg, Maarten P.; van Tintelen, J. Peter; Pals, Gerard; Baars, Marieke J. H.; Mulder, Barbara J. M.; Zwinderman, Aeilko H.

    2012-01-01

    Background Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far. Methodology/Principal Findings Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10−6, 95% CI: 70–159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients. Conclusion/Significance In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients. PMID:22479353

  20. 5B.05: MARFAN SYNDROME: ASSESSMENT OF AORTIC DISSECTION RISK BY ANALYSIS OF AORTIC VISCOELASTIC PROPERTIES.

    PubMed

    Grillo, A; Pini, A; Marelli, S; Gan, L; Giuliano, A; Trifirò, G; Santini, F; Salvi, L; Salvi, P; Viecca, F; Carretta, R; Parati, G

    2015-06-01

    Marfan syndrome is an autosomal dominant genetic disorder characterized by an abnormal fibrillin-1 synthesis. Aortic root dilation and dissection are the main problems affecting patients prognosis in these patients. Their pharmacological prophylaxis with losartan or with a beta-blocker counteracts the aortic root dilation, but a close follow-up is required to assess therapeutic response rate and to identify non-responders. Unfortunately genotype-phenotype studies do not allow to determine the exact risk profile in these patients and there is no reliable method to accurately predict their risk of aortic dissection. Aim of this study was to evaluate non-invasive markers for identification of Marfan patients at higher risk of aortic complications. We studied 187 Marfan patients (identified according to 2010 Revised Ghent Criteria and positive genetic analysis), age 32.3 ± 16.5 yrs (mean ± SD). 52 patients (27.8%) had undergone surgical ascending aorta replacement (David or Bentall procedure). Central pressure curves were recorded by PulsePen tonometer, and the aortic viscoelastic aortic properties were studied by determination of carotid-femoral pulse wave velocity (PWV). With reference to the age related distribution of PWV values in a normal population, defined according to Arterial-Stiffness-Collaboration, PWV mean values in Marfan patients corresponded to 60th percentile in non- operated patients and to the 67th percentile in those operated. Adult Marfan patients (n = 146) generally displayed a low blood pressure, because of the pharmacological prophylaxis, and were compared with a population of 189 adult healthy subjects (81 males), matched by age (38 ± 13 vs 38 ± 16 yrs.), heart rate (64 ± 9 bpm vs 64 ± 11 bpm) and blood pressure (mean BP = 78 ± 9 mmHg vs 79 ± 4 mmHg) values. Average PWV value was higher than in healthy controls (PWV = 7.0 ± 1.7) both in not operated (PWV = 7.6 ± 1.6; p = 0

  1. NADPH oxidase 4 attenuates cerebral artery changes during the progression of Marfan syndrome.

    PubMed

    Onetti, Yara; Meirelles, Thayna; Dantas, Ana P; Schröder, Katrin; Vila, Elisabet; Egea, Gustavo; Jiménez-Altayó, Francesc

    2016-05-01

    Marfan syndrome (MFS) is a connective tissue disorder that is often associated with the fibrillin-1 (Fbn1) gene mutation and characterized by cardiovascular alterations, predominantly ascending aortic aneurysms. Although neurovascular complications are uncommon in MFS, the improvement in Marfan patients' life expectancy is revealing other secondary alterations, potentially including neurovascular disorders. However, little is known about small-vessel pathophysiology in MFS. MFS is associated with hyperactivated transforming growth factor (TGF)-β signaling, which among numerous other downstream effectors, induces the NADPH oxidase 4 (Nox4) isoform of NADPH oxidase, a strong enzymatic source of H2O2 We hypothesized that MFS induces middle cerebral artery (MCA) alterations and that Nox4 contributes to them. MCA properties from 3-, 6-, or 9-mo-old Marfan (Fbn1(C1039G/+)) mice were compared with those from age/sex-matched wild-type littermates. At 6 mo, Marfan compared with wild-type mice developed higher MCA wall/lumen (wild-type: 0.081 ± 0.004; Marfan: 0.093 ± 0.002; 60 mmHg; P < 0.05), coupled with increased reactive oxygen species production, TGF-β, and Nox4 expression. However, wall stiffness and myogenic autoregulation did not change. To investigate the influence of Nox4 on cerebrovascular properties, we generated Marfan mice with Nox4 deficiency (Nox4(-/-)). Strikingly, Nox4 deletion in Marfan mice aggravated MCA wall thickening (cross-sectional area; Marfan: 6,660 ± 363 μm(2); Marfan Nox4(-/-): 8,795 ± 824 μm(2); 60 mmHg; P < 0.05), accompanied by decreased TGF-β expression and increased collagen deposition and Nox1 expression. These findings provide the first evidence that Nox4 mitigates cerebral artery structural changes in a murine model of MFS.

  2. A Marfan syndrome gene expression phenotype in cultured skin fibroblasts

    PubMed Central

    Yao, Zizhen; Jaeger, Jochen C; Ruzzo, Walter L; Morale, Cecile Z; Emond, Mary; Francke, Uta; Milewicz, Dianna M; Schwartz, Stephen M; Mulvihill, Eileen R

    2007-01-01

    Background Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusion Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 × 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater. PMID:17850668

  3. Genetic Dissection of Marfan Syndrome and Related Connective Tissue Disorders: An Update 2012

    PubMed Central

    Hoffjan, S.

    2012-01-01

    Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue characterized by early development of thoracic aortic aneurysms/dissections together with symptoms of the ocular and skeletal systems. While most patients/families with a classic phenotypic expression of MFS harbour mutations in the gene encoding fibrillin-1 (FBN1), genetic studies of the recent years revealed that the clinical features, as well as the mutated genes, show a high degree of overlap between MFS and other connective tissue diseases (e.g. Loeys-Dietz syndrome, Ehlers-Danlos syndrome, familial thoracic aneurysms and dissections and others). We summarize herein the current knowledge about the wide spectrum of differential diagnoses and their genetic background as well as novel therapeutic approaches in order to provide appropriate counselling and clinical follow-up for the patients. PMID:23326250

  4. [Screening of FBN1 gene mutations in a family with Marfan syndrome].

    PubMed

    Hao, Peng; Tang, Xin; Song, Hui; Wang, Li-ming; Wang, Yu-chuan; Ying, Ming; Han, Rui-fang; Li, Ning-dong

    2010-11-01

    To identify FBN1 gene mutations in a Chinese family with Marfan syndrome. Four affected and two unaffected individuals in the family were recruited after informed consent. Five ml blood samples were drawn from each family member and genomic DNA was extracted. Mutations were detected by directly sequencing to the whole coding region and exon-intron boundaries of FBN1 gene. Polyphen program was used to predict the functional and structural changes of the mutant protein. We found all four affected individuals carried FBN1gene mutations, c.2261A > G (p.Y754C), in exon18 by sequence analysis, while two unaffected family members and 100 normal controls did not have this mutation. A PSIC score of 2.6 was acquired by Polyphen program analysis. Our study supports that FBN1 gene mutation, c.2261A > G (p.Y754C), is the underlying molecular pathogenesis of this family with Marfan syndrome. This mutation is identified for the first time in Chinese population.

  5. Neonatal Marfan Syndrome: Report of a Case with an Inherited Splicing Mutation outside the Neonatal Domain.

    PubMed

    Le Gloan, Laurianne; Hauet, Quentin; David, Albert; Hanna, Nadine; Arfeuille, Chloé; Arnaud, Pauline; Boileau, Catherine; Romefort, Bénédicte; Benbrik, Nadir; Gournay, Véronique; Joram, Nicolas; Baron, Olivier; Isidor, Bertrand

    2016-02-01

    We report a child and her mother affected by Marfan syndrome. The child presented with a phenotype of neonatal Marfan syndrome, revealed by acute and refractory heart failure, finally leading to death within the first 4 months of life. Her mother had a common clinical presentation. Genetic analysis revealed an inherited FBN1 mutation. This intronic mutation (c.6163+3_6163+6del), undescribed to date, leads to exon 49 skipping, corresponding to in-frame deletion of 42 amino acids (p.Ile2014_Asp2055del). FBN1 next-generation sequencing did not show any argument for mosaicism. Association in the same family of severe neonatal and classical Marfan syndrome illustrates the intrafamilial phenotype variability.

  6. Systemic management of Marfan's syndrome during dental treatment: a case report.

    PubMed

    Hirota, Y; Sugiyama, K; Niwa, H; Matsuura, H

    1993-01-01

    Marfan's syndrome is a dominantly inherited connective tissue disorder characterized by skeletal, ocular, and cardiovascular abnormalities, such as arachnodactyly, dolichostenomelia, kyphosis, scoliosis, pectus excavatum, ectopia lentis, aortic aneurysm and dissection, aortic valve incompetence, and mitral valve prolapse. This report describes the systemic management during dental treatment of a 26-year-old man with Marfan's syndrome. Blood pressure, electrocardiogram, echocardiography, systolic time intervals, and aortic pulse wave velocity were monitored. Nitrous oxide inhalational sedation was employed. In contrast to the vasopressin, felypressin (contained in prilocaine), epinephrine (contained in lidocaine) caused an acceleration of cardiac function--increased heart rate, cardiac output, 1/pre-ejection period (PEP), and aortic pulse wave velocity and decreased PEP and left ventricular ejection time. This experience suggests that the use of anesthetics containing epinephrine in dental patients with Marfan's syndrome needs to be carefully managed.

  7. Neonatal Marfan Syndrome: Report of a Case with an Inherited Splicing Mutation outside the Neonatal Domain

    PubMed Central

    Le Gloan, Laurianne; Hauet, Quentin; David, Albert; Hanna, Nadine; Arfeuille, Chloé; Arnaud, Pauline; Boileau, Catherine; Romefort, Bénédicte; Benbrik, Nadir; Gournay, Véronique; Joram, Nicolas; Baron, Olivier; Isidor, Bertrand

    2016-01-01

    We report a child and her mother affected by Marfan syndrome. The child presented with a phenotype of neonatal Marfan syndrome, revealed by acute and refractory heart failure, finally leading to death within the first 4 months of life. Her mother had a common clinical presentation. Genetic analysis revealed an inherited FBN1 mutation. This intronic mutation (c.6163+3_6163+6del), undescribed to date, leads to exon 49 skipping, corresponding to in-frame deletion of 42 amino acids (p.Ile2014_Asp2055del). FBN1 next-generation sequencing did not show any argument for mosaicism. Association in the same family of severe neonatal and classical Marfan syndrome illustrates the intrafamilial phenotype variability. PMID:27022329

  8. [AFBN1 gene in patients with Marfan syndrome].

    PubMed

    Valiev, R R; Khusainova, R I; Kutuev, I A; Khusnutdinova, E K

    2006-01-01

    30 exons have been analyzed using SSCP in patients with MFS or related phenotypes. We report 2 missense mutations occur in calcium-binding Epidermal Growth Factor-like (EGFcb) domains and 9 polymorphisms located both in coding and noncoding regions of FBN1 gene. Three intragenic microsatellite polymorphic markers MTS-1, MTS-2 and MTS-4 have been analyzed in patients with MFS and unrelated unaffected control individuals. We found significant differences in allele frequency distribution of MTS-2 and MTS-4 loci between MFS patients and unaffected individuals. Haplotype frequency distribution on normal and mutant chromosomes were significantly different. The most common haplotype was 2-11-8 which was predominant on normal chromosomes of affected individuals. Haplotype 2-2-8 was observed in 18% of cases on mutant chromosomes and in 4% of cases on normal chromosomes. These data demonstrate possibility and application of haplotype-segregation analysis with use of these intragenic markers for diagnostic purposes in affected families by Marfan's syndrome.

  9. Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome

    PubMed Central

    Cook, Jason R.; Carta, Luca; Bénard, Ludovic; Chemaly, Elie R.; Chiu, Emily; Rao, Satish K.; Hampton, Thomas G.; Yurchenco, Peter; Costa, Kevin D.; Hajjar, Roger J.; Ramirez, Francesco

    2014-01-01

    Patients with Marfan syndrome (MFS), a multisystem disorder caused by mutations in the gene encoding the extracellular matrix (ECM) protein fibrillin 1, are unusually vulnerable to stress-induced cardiac dysfunction. The prevailing view is that MFS-associated cardiac dysfunction is the result of aortic and/or valvular disease. Here, we determined that dilated cardiomyopathy (DCM) in fibrillin 1–deficient mice is a primary manifestation resulting from ECM-induced abnormal mechanosignaling by cardiomyocytes. MFS mice displayed spontaneous emergence of an enlarged and dysfunctional heart, altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including increased angiotensin II type I receptor (AT1R) signaling and abated focal adhesion kinase (FAK) activity. Partial fibrillin 1 gene inactivation in cardiomyocytes was sufficient to precipitate DCM in otherwise phenotypically normal mice. Consistent with abnormal mechanosignaling, normal cardiac size and function were restored in MFS mice treated with an AT1R antagonist and in MFS mice lacking AT1R or β-arrestin 2, but not in MFS mice treated with an angiotensin-converting enzyme inhibitor or lacking angiotensinogen. Conversely, DCM associated with abnormal AT1R and FAK signaling was the sole abnormality in mice that were haploinsufficient for both fibrillin 1 and β1 integrin. Collectively, these findings implicate fibrillin 1 in the physiological adaptation of cardiac muscle to elevated workload. PMID:24531548

  10. Recent Clinical Drug Trials Evidence in Marfan Syndrome and Clinical Implications.

    PubMed

    Singh, Michael N; Lacro, Ronald V

    2016-01-01

    Marfan syndrome is a genetic disorder of connective tissue with principal manifestations in the cardiovascular, ocular, and skeletal systems. Cardiovascular disease, mainly progressive aortic root dilation and aortic dissection, is the leading cause of morbidity and mortality. The primary aims of this report were to examine the evidence related to medical therapy for Marfan syndrome, including recently completed randomized clinical trials on the efficacy of β-blockers and angiotensin II receptor blockers for the prophylactic treatment of aortic enlargement in Marfan syndrome, and to provide recommendations for medical therapy on the basis of available evidence. Medical therapy for Marfan syndrome should be individualized according to patient tolerance and risk factors such as age, aortic size, and family history of aortic dissection. The Pediatric Heart Network trial showed that atenolol and losartan each reduced the rate of aortic dilation. All patients with known or suspected Marfan syndrome and aortic root dilation should receive medical therapy with adequate doses of either β-blocker or angiotensin receptor blocker. The Pediatric Heart Network trial also showed that atenolol and losartan are more effective at reduction of aortic root z score in younger subjects, which suggests that medical therapy should be prescribed even in the youngest children with aortic dilation. For patients with Marfan syndrome without aortic dilation, the available evidence is less clear. If aortic dilation is severe and/or progressive, therapy with a combination of β-blocker and angiotensin receptor blocker should be considered, although trial results are mixed with respect to the efficacy of combination therapy vs monotherapy.

  11. Surgical outcomes of scoliosis surgery in Marfan syndrome.

    PubMed

    Zenner, Juliane; Hitzl, Wolfgang; Meier, Oliver; Auffarth, Alexander; Koller, Heiko

    2014-02-01

    Retrospective review of a case series. To present the radiologic and surgical characteristics of scoliosis treatment in patients with Marfan syndrome (MFS). The treatment of scoliosis in MFS has been reported to pose unique challenges. However, the information on surgical outcomes is sparse. In clinical practice, surgery for scoliosis in MFS is reported to confer higher perioperative risks and instrumentation-related complications compared with adolescent idiopathic scoliosis because of atypical and rigid curve patterns and the underlying desmogenic disorder. Database research identified 26 MFS patients treated surgically during 7 years at a single spine center. Three patients presented with previous failed surgeries and were excluded. The medical records, charts, and radiographs of 23 patients were analyzed focusing on curve characteristics, surgical outcomes including complications, and curve correction using modern third-generation hybrid or pedicle screw systems, and the behavior of junctional segments and compensatory curves. The sample included 18 female and 5 male patients with an average age of 18.2±9.2 years (13-52 y) at index surgery and 21.2±9.2 years (14-53 y) at follow-up, averaging 35.8±23.5 months (6-95 mo). According to the Lenke classification, 30% presented as type 1, 9% as type 2, 22% as type 3, 9% as type 4, 17% as type 5, and 13% of patients as type 6. Seventy-four percent of patients had a type C lumbar modifier. In total, 48% of patients underwent a posterior spinal fusion (PSF). Thirty percent had instrumented anterior spinal fusion (AISF), whereas 22% had a combined anterior release and staged PSF. Ninety-one percent of patients achieved solid fusion; there was 1 asymptomatic nonunion and 1 recalcitrant nonunion. Add-on phenomena were identified in 13% of patients (n=3) treated with AISF, indicating staged PSF once. In total, complications were encountered in 30% of patients, indicating redo surgery in 17% of patients. The cause for

  12. Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes.

    PubMed

    Tae, Hyun-Jin; Petrashevskaya, Natalia; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

    2016-01-15

    Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.

  13. Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes

    PubMed Central

    Tae, Hyun-Jin; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

    2015-01-01

    Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/− mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2–4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6–14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS. PMID:26566724

  14. The revised Ghent nosology for the Marfan syndrome.

    PubMed

    Loeys, Bart L; Dietz, Harry C; Braverman, Alan C; Callewaert, Bert L; De Backer, Julie; Devereux, Richard B; Hilhorst-Hofstee, Yvonne; Jondeau, Guillaume; Faivre, Laurence; Milewicz, Dianna M; Pyeritz, Reed E; Sponseller, Paul D; Wordsworth, Paul; De Paepe, Anne M

    2010-07-01

    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

  15. A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome.

    PubMed Central

    Milewicz, D M; Grossfield, J; Cao, S N; Kielty, C; Covitz, W; Jewett, T

    1995-01-01

    Dermal fibroblasts from a 13-yr-old boy with isolated skeletal features of the Marfan syndrome were used to study fibrillin synthesis and processing. Only one half of the secreted profibrillin was proteolytically processed to fibrillin outside the cell and deposited into the extracellular matrix. Electron microscopic examination of rotary shadowed microfibrils made by the proband's fibroblasts were indistinguishable from control cells. Sequencing of the FBN1 gene revealed a heterozygous C to T transition at nucleotide 8176 resulting in the substitution of a tryptophan for an arginine (R2726W), at a site immediately adjacent to a consensus sequence recognized by a cellular protease. Six other individuals in the proband's family had the FBN1 mutation that segregated with tall stature. None of the affected individuals have cardiac or ocular manifestations of the Marfan syndrome. This mutation identifies a putative site for profibrillin to fibrillin processing, and is associated with isolated skeletal features of the Marfan syndrome, indicating that the FBN1 gene is one of the genes that determines height in the general population. The cellular effect of the mutation may be equivalent to a "null" FBN1 allele and may define the phenotype associated with FBN1 "null" alleles. Images PMID:7738200

  16. Abnormal Morphology of Fibrillin Microfibrils in Fibroblast Cultures from Patients with Neonatal Marfan Syndrome

    PubMed Central

    Godfrey, Maurice; Raghunath, Michael; Cisler, Jason; Bevins, Charles L.; DePaepe, Anne; Di Rocco, Maja; Gregoritch, Jane; Imaizumi, Kiyoshi; Kaplan, Paige; Kuroki, Yoshikazu; Silberbach, Michael; Superti-Furga, Andrea; Van Thienen, Marie-Noëlle; Vetter, Ulrich; Steinmann, Beat

    1995-01-01

    The Marfan syndrome (MFS) is a connective tissue disorder manifested by variable and pleiotropic features in the skeletal, ocular, and cardiovascular systems. The average life span in MFS is about 35 years. A group with much more severe cardiovascular disease and a mean life span of approximately I year also exists. We refer to this latter group as “neonatal Marfan syndrome” (nMFS). Fibrillin defects are now known to be the cause of MFS and nMFS. Immunofluorescence studies were the first to demonstrate this association. Here we describe immunofluorescence studies in a series of 10 neonates and summarize their salient clinical features. In vitro accumulation of fibrillin reactive fibers was assayed using monoclonal antibodies to fibrillin in hyperconfluent fibroblast cultures. As was previously observed in MFS, fibroblast cultures from nMFS patients showed an apparent decrease in accumulation of immunostainable fibrillin. Significantly, however, the morphology of the immunostained fibrils in the nMFS cultures were abnormal and differed not only from control cultures, but also from those seen in cultures of MFS fibroblasts. The nMFS fibrils appeared short, fragmented, and frayed, characteristics that are not seen in MFS. Both the clinical and fibrillin morphology data provide evidence to suggest a useful subclassification of nMFS in the spectrum of MFS. ImagesFigure 1Figure 2 PMID:7778680

  17. Dilation of peripheral vessels in Marfan syndrome: importance of thoracoabdominal MR angiography.

    PubMed

    Mariucci, Elisabetta M; Lovato, Luigi; Rosati, Marzia; Palena, Luis M; Bonvicini, Marco; Fattori, Rossella

    2013-09-10

    Aim of this study was to assess vascular morphology and dimension of the entire aorta and branch vessels in MFS using thoracoabdominal MR angiography (MRA). Evaluation of vascular involvement in Marfan Syndrome (MFS) is focused to the ascending aorta, which has the major risk of dissection/rupture. From March 2006 to January 2011, 64 patients (35 ± 13 years old) with MFS underwent echocardiography and MRA of thoracic and abdominal aorta. Measurements of ascending aorta, aortic arch, descending thoracic and abdominal aorta, and aortic branch vessels were assessed. In patients with aortic dissection only non dissected vessels were considered for measurements. 64 Marfan patients were divided into 2 groups: patients in natural history (group A, 55%) and patients previously submitted to aortic root and/or ascending aorta replacement because of severe aortic dilation or dissection (group B, 45%). Dilation of the descending aorta, mostly of the aortic isthmus, occurred in 18/53 patients (8/35 group A, 10/18 group B). Abdominal aorta resulted in the normal range in group A and in 16/18 patients of group B, while iliac vessels were dilated in 7/35 patients of group A and in 10/23 patients of group B. Four patients of group B presented isolated dilation of subclavian, celiac, mesenteric, or renal arteries. Vascular dilation beyond the aortic root is not uncommon in MFS. The systematic use of MRA provides a comprehensive evaluation of the entire arterial system. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Presenting signs and clinical diagnosis in individuals referred to rule out Marfan syndrome.

    PubMed

    Hamod, Anthony; Moodie, Douglas; Clark, Brian; Traboulsi, Elias I

    2003-03-01

    To evaluate presenting signs and clinical diagnosis in a cohort of patients referred to rule out Marfan syndrome. A retrospective chart review was performed on patients referred to the Cleveland Clinic Foundation between November 1993 and July 2001 to rule out Marfan syndrome. Clinical findings necessary for the diagnosis of the disorder according to current criteria (De Paepe et al., Am J Med Genet. 1996;62:417-426) were determined through complete physical examination and testing, including an echocardiogram and a slit-lamp examination. Information regarding age, sex, reason for evaluation, family history, symptoms, and ultimate clinical diagnosis were extracted from the charts. Seventy-five patients averaging 23.5 years of age completed a comprehensive evaluation to rule out Marfan syndrome. A clinical diagnosis of this condition was made in 28 (37%) patients (12 males, 16 females). Reasons for referral included one or more of the following: (1) the finding by a physician of one or more typical clinical manifestations of the disease; (2) a known family history of the syndrome; and/or (3) curiosity on the part of the patient or family as a result of publicity about Marfan syndrome in lay or medical journals or in television programs. Twenty-eight individuals (37% of the total group) were referred because of skeletal findings common to the syndrome. Of these, 10 (36%) were diagnosed with the disease. Seven (78%) of the nine patients who presented with ocular signs or symptoms were ultimately diagnosed with the disorder. Of the 22 individuals referred because of cardiovascular signs or symptoms, nine (41%) were diagnosed with Marfan syndrome. Twelve (31%) of 39 individuals with a known family history of Marfan syndrome or symptoms common to this condition had a positive diagnosis. Of six individuals evaluated in response to publicity about the disease, two (33%) were ultimately diagnosed with the disorder. The most common reasons for evaluation to rule out Marfan

  19. Dural ectasia and FBN1 mutation screening of 40 patients with Marfan syndrome and related disorders: role of dural ectasia for the diagnosis.

    PubMed

    Attanasio, Monica; Pratelli, Elisa; Porciani, Maria Cristina; Evangelisti, Lucia; Torricelli, Elena; Pellicanò, Giannantonio; Abbate, Rosanna; Gensini, Gian Franco; Pepe, Guglielmina

    2013-07-01

    Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in the gene encoding fibrillin-1 (FBN1), a matrix component of microfibrils. Dural ectasia, i.e. enlargement of the neural canal mainly located in the lower lumbar and sacral region, frequently occurs in Marfan patients. The aim of our study was to investigate the role of dural ectasia in raising the diagnosis of Marfan syndrome and its association with FBN1 mutations. We studied 40 unrelated patients suspected for MFS, who underwent magnetic resonance imaging searching for dural ectasia. In all of them FBN1 gene analysis was also performed. Thirty-seven patients resulted affected by Marfan syndrome according to the '96 Ghent criteria; in 30 of them the diagnosis was confirmed when revaluated by the recently revised criteria (2010). Thirty-six patients resulted positive for dural ectasia. The degree of dural ectasia was grade 1 in 19 patients, grade 2 in 11 patients, and grade 3 in 6 patients. In 7 (24%) patients, the presence of dural ectasia allowed to reach a positive score for systemic feature criterion. Twenty-four patients carried an FBN1 mutation, that were represented by 13 missense (54%), and 11 (46%) mutations generating a premature termination codon (PTC, frameshifts and stop codons). No mutation was detected in the remaining 16 (6 patients with MFS and 10 with related disorders according to revised Ghent criteria). The prevalence of severe (grade 2 and grade 3) involvement of dura mater was higher in patients harbouring premature termination codon (PTC) mutations than those carrying missense-mutations (8/11 vs 2/13, P = 0.0111). Our data emphasizes the importance of dural ectasia screening to reach the diagnosis of Marfan syndrome especially when it is uncertain and indicates an association between PTC mutations and severe dural ectasia in Marfan patients.

  20. Giant pseudomeningocele causing urinary obstruction in a patient with Marfan syndrome.

    PubMed

    Stone, Jeremy G; Bergmann, Liisa L; Takamori, Ryan; Donovan, Daniel J

    2015-07-01

    Defective collagen biosynthesis in Marfan syndrome predisposes to dural defects such as dural ectasia, meningocele, and pseudomeningocele; thus, an increased index of suspicion for these conditions should be present in the clinical setting of Marfan syndrome. The authors describe a young woman with Marfan syndrome who was being treated with anticoagulants for a prosthetic heart valve and who presented with a spontaneous retroperitoneal hemorrhage requiring surgical evacuation. No CSF leak was encountered at surgery, but she developed progressively more severe positional headaches over the following year. She then experienced the sudden onset of acute urinary obstruction, at which time CT revealed a 17 × 15 × 13-cm presacral pseudomeningocele communicating with the thecal sac through a sacral bone defect. An anterior surgical approach was used for drainage of the pseudomeningocele as well as for primary closure of the dural defect with a bovine pericardial patch and autologous subcutaneous fat graft. After a short period of lumbar subarachnoid drainage of the CSF, the patient was able to resume normal activity without recurrent symptoms. To the authors' knowledge, such a pseudomeningocele in a patient with Marfan syndrome has been reported only twice, and this case features the largest pseudomeningocele to date. They also review the pertinent literature regarding presentation, diagnosis, and management of these lesions.

  1. The Marfan Syndrome: Physical Activity Guidelines for Physical Educators, Coaches and Physicians.

    ERIC Educational Resources Information Center

    Romeo, Thomas J.

    Intended for physical educators, this manual provides guidelines for providing safe and effective physical activity programs for children with Marfan syndrome, a congenital condition involving the connective tissues and the probable cause of sudden death by heart failure of some young competitive athletes in recent cases. The manual includes…

  2. The Educational and Psychological Interventions for Children and Adolescents with Marfan Syndrome.

    ERIC Educational Resources Information Center

    Stebbins, Molly S.; McIntosh, David E.

    Marfan's syndrome is an autosomal dominant chromosomal disorder of connective tissue which may cause major abnormalities in the musculoskeletal, ocular (pertaining to the eye), and cardiovascular systems of the body. A description of this disorder is presented in this paper. It affects approximately .03 to .05% of the population; approximately…

  3. Identification of FBN1 gene mutations in Ukrainian Marfan syndrome patients.

    PubMed

    Zhurayev, Rustam; Proost, Dorien; Zerbino, Dmytro; Fedorenko, Viktor; Meester, Josephina A N; VAN Laer, Lut; Loeys, Bart L

    2016-10-11

    Marfan syndrome is an autosomal dominant connective tissue disorder, predominantly affecting the ocular, skeletal and cardiovascular systems. Here, we present the results of the first genetic testing in 40 Ukrainian Marfan (-like) patients and 10 relatives. We applied a targeted next generation sequencing panel comprising FBN1 and 13 thoracic aortic aneurysm genes. We identified 27 causal mutations in FBN1, obtaining a mutation yield of 67·5%. A significant difference in age at aortic surgery between mutation positive and negative patients was observed. Thus, we conclude that genetic testing is important to identify patients at higher risk for developing life-threatening cardiovascular complications.

  4. Atenolol versus losartan in children and young adults with Marfan's syndrome.

    PubMed

    Lacro, Ronald V; Dietz, Harry C; Sleeper, Lynn A; Yetman, Anji T; Bradley, Timothy J; Colan, Steven D; Pearson, Gail D; Selamet Tierney, E Seda; Levine, Jami C; Atz, Andrew M; Benson, D Woodrow; Braverman, Alan C; Chen, Shan; De Backer, Julie; Gelb, Bruce D; Grossfeld, Paul D; Klein, Gloria L; Lai, Wyman W; Liou, Aimee; Loeys, Bart L; Markham, Larry W; Olson, Aaron K; Paridon, Stephen M; Pemberton, Victoria L; Pierpont, Mary Ella; Pyeritz, Reed E; Radojewski, Elizabeth; Roman, Mary J; Sharkey, Angela M; Stylianou, Mario P; Wechsler, Stephanie Burns; Young, Luciana T; Mahony, Lynn

    2014-11-27

    Aortic-root dissection is the leading cause of death in Marfan's 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. We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's 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. 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. Among children and young adults with Marfan's 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.).

  5. Marfan syndrome patient experiences as ascertained through postings on social media sites.

    PubMed

    Kelleher, Erin; Giampietro, Philip F; Moreno, Megan A

    2015-11-01

    Marfan syndrome (MS) is a connective tissue disorder that affects thousands of adolescents [Population Reference Bureau, 2013]. Some adolescent patients with MS may use social media to express their experiences and emotions, but little is known about what patients choose to share online. To investigate social media content related to Marfan syndrome we used search terms "Marfan syndrome" and "Marfans" on six different social media sites. The top five recent and popular posts for each site were collected and coded weekly for five weeks. Posts were excluded if they were reshared content or not in English. A codebook was developed using an iterative process to categorize posts and comments. Out of 300 posts collected 147 posts (49.0%) were included for evaluation. Categories of displayed content included personal pictures, memes and pictures featuring symptoms of MS (41.5%) and personal MS experiences (27.1% of posts). One quarter of the posts specifically mentioned a positive experience or how thankful the profile owner was for their life. A unique category of posts (13.7%) referenced Austin Carlile, a celebrity singer with MS, as a role model. Physicians and healthcare providers may consider using social media to understand common MS concerns and to place future health education materials.

  6. Prevalence of dural ectasia in Loeys-Dietz syndrome: comparison with Marfan syndrome and normal controls.

    PubMed

    Kono, Atsushi K; Higashi, Masahiro; Morisaki, Hiroko; Morisaki, Takayuki; Naito, Hiroaki; Sugimura, Kazuro

    2013-01-01

    Dural ectasia is well recognized in Marfan syndrome (MFS) as one of the major diagnostic criteria, but the exact prevalence of dural ectasia is still unknown in Loeys-Dietz syndrome (LDS), which is a recently discovered connective tissue disease. In this study, we evaluated the prevalence of dural ectasia in LDS according by using qualitative and quantitative methods and compared our findings with those for with MFS and normal controls. We retrospectively studied 10 LDS (6 males, 4 females, mean age 36.3 years) and 20 MFS cases (12 males, 8 females, mean age 37.1 years) and 20 controls (12 males, 8 females, mean age 36.1 years) both qualitatively and quantitatively using axial CT images and sagittal multi-planar reconstruction images of the lumbosacral region. For quantitative examination, we adopted two methods: method-1 (anteroposterior dural diameter of S1> L4) and method-2 (ratio of anteroposterior dural diameter/vertebral body diameter>cutoff values). The prevalence of dural ectasia among groups was compared by using Fisher's exact test and the Tukey-Kramer test. In LDS patients, the qualitative method showed 40% of dural ectasia, the quantitative method-1 50%, and the method-2 70%. In MFS patients, the corresponding prevalences were 50%, 75%, and 85%, and in controls, 0%, 0%, and 5%. Both LDS and MFS had a significantly wider dura than controls. While the prevalence of dural ectasia varied depending on differences in qualitative and quantitative methods, LDS as well as MFS, showed, regardless of method, a higher prevalence of dural ectasia than controls. This finding should help the differentiation of LDS from controls.

  7. Prevalence of Dural Ectasia in Loeys-Dietz Syndrome: Comparison with Marfan Syndrome and Normal Controls

    PubMed Central

    Kono, Atsushi K.; Higashi, Masahiro; Morisaki, Hiroko; Morisaki, Takayuki; Naito, Hiroaki; Sugimura, Kazuro

    2013-01-01

    Background and Purpose Dural ectasia is well recognized in Marfan syndrome (MFS) as one of the major diagnostic criteria, but the exact prevalence of dural ectasia is still unknown in Loeys−Dietz syndrome (LDS), which is a recently discovered connective tissue disease. In this study, we evaluated the prevalence of dural ectasia in LDS according by using qualitative and quantitative methods and compared our findings with those for with MFS and normal controls. Material and Methods We retrospectively studied 10 LDS (6 males, 4 females, mean age 36.3 years) and 20 MFS cases (12 males, 8 females, mean age 37.1 years) and 20 controls (12 males, 8 females, mean age 36.1 years) both qualitatively and quantitatively using axial CT images and sagittal multi-planar reconstruction images of the lumbosacral region. For quantitative examination, we adopted two methods: method-1 (anteroposterior dural diameter of S1> L4) and method-2 (ratio of anteroposterior dural diameter/vertebral body diameter>cutoff values). The prevalence of dural ectasia among groups was compared by using Fisher’s exact test and the Tukey−Kramer test. Results In LDS patients, the qualitative method showed 40% of dural ectasia, the quantitative method-1 50%, and the method-2 70%. In MFS patients, the corresponding prevalences were 50%, 75%, and 85%, and in controls, 0%, 0%, and 5%. Both LDS and MFS had a significantly wider dura than controls. Conclusions While the prevalence of dural ectasia varied depending on differences in qualitative and quantitative methods, LDS as well as MFS, showed, regardless of method, a higher prevalence of dural ectasia than controls. This finding should help the differentiation of LDS from controls. PMID:24086486

  8. Early Impairment of Lung Mechanics in a Murine Model of Marfan Syndrome.

    PubMed

    Uriarte, Juan J; Meirelles, Thayna; Gorbenko Del Blanco, Darya; Nonaka, Paula N; Campillo, Noelia; Sarri, Elisabet; Navajas, Daniel; Egea, Gustavo; Farré, Ramon

    2016-01-01

    Early morbidity and mortality in patients with Marfan syndrome (MFS) -a connective tissue disease caused by mutations in fibrillin-1 gene- are mainly caused by aorta aneurysm and rupture. However, the increase in the life expectancy of MFS patients recently achieved by reparatory surgery promotes clinical manifestations in other organs. Although some studies have reported respiratory alterations in MFS, our knowledge of how this connective tissue disease modifies lung mechanics is scarce. Hence, we assessed whether the stiffness of the whole lung and of its extracellular matrix (ECM) is affected in a well-characterized MFS mouse model (FBN1C1039G/+). The stiffness of the whole lung and of its ECM were measured by conventional mechanical ventilation and atomic force microscopy, respectively. We studied 5-week and 9-month old mice, whose ages are representative of early and late stages of the disease. At both ages, the lungs of MFS mice were significantly more compliant than in wild type (WT) mice. By contrast, no significant differences were found in local lung ECM stiffness. Moreover, histopathological lung evaluation showed a clear emphysematous-like pattern in MFS mice since alveolar space enlargement was significantly increased compared with WT mice. These data suggest that the mechanism explaining the increased lung compliance in MFS is not a direct consequence of reduced ECM stiffness, but an emphysema-like alteration in the 3D structural organization of the lung. Since lung alterations in MFS are almost fully manifested at an early age, it is suggested that respiratory monitoring could provide early biomarkers for diagnosis and/or follow-up of patients with the Marfan syndrome.

  9. Early Impairment of Lung Mechanics in a Murine Model of Marfan Syndrome

    PubMed Central

    Uriarte, Juan J.; Meirelles, Thayna; Gorbenko del Blanco, Darya; Nonaka, Paula N.; Campillo, Noelia; Sarri, Elisabet; Navajas, Daniel; Egea, Gustavo; Farré, Ramon

    2016-01-01

    Early morbidity and mortality in patients with Marfan syndrome (MFS) -a connective tissue disease caused by mutations in fibrillin-1 gene- are mainly caused by aorta aneurysm and rupture. However, the increase in the life expectancy of MFS patients recently achieved by reparatory surgery promotes clinical manifestations in other organs. Although some studies have reported respiratory alterations in MFS, our knowledge of how this connective tissue disease modifies lung mechanics is scarce. Hence, we assessed whether the stiffness of the whole lung and of its extracellular matrix (ECM) is affected in a well-characterized MFS mouse model (FBN1C1039G/+). The stiffness of the whole lung and of its ECM were measured by conventional mechanical ventilation and atomic force microscopy, respectively. We studied 5-week and 9-month old mice, whose ages are representative of early and late stages of the disease. At both ages, the lungs of MFS mice were significantly more compliant than in wild type (WT) mice. By contrast, no significant differences were found in local lung ECM stiffness. Moreover, histopathological lung evaluation showed a clear emphysematous-like pattern in MFS mice since alveolar space enlargement was significantly increased compared with WT mice. These data suggest that the mechanism explaining the increased lung compliance in MFS is not a direct consequence of reduced ECM stiffness, but an emphysema-like alteration in the 3D structural organization of the lung. Since lung alterations in MFS are almost fully manifested at an early age, it is suggested that respiratory monitoring could provide early biomarkers for diagnosis and/or follow-up of patients with the Marfan syndrome. PMID:27003297

  10. The importance of genetic testing in the clinical management of patients with Marfan syndrome and related disorders.

    PubMed

    Arslan-Kirchner, Mine; von Kodolitsch, Yskert; Schmidtke, Jörg

    2008-07-01

    Marfan syndrome and Marfan-related syndromes are part of a broad and overlapping spectrum of diseases that were originally defined on clinical grounds alone. They have in common a dramatically increased risk of life-threatening dissecting aortic aneurysms, which must be prevented by elective aortic replacement. Selective review of the literature supplemented by own clinical experience. Marfan syndrome and Marfan-related syndromes are phenotypically highly variable. The full-blown clinical picture is not always present, and particular symptoms can be missing altogether. Accordingly, it is often very difficult to diagnose a specific syndrome in the individual patient. In many cases, only a combination of genetic tests and clinical assessment can settle the differential diagnosis, thus enabling better prognostication and better planning of preventive measures. The diagnosis and treatment of individual patients with Marfan syndrome and Marfan-related syndromes requires an interdisciplinary approach. This can only be achieved through a coordination of medical care with centralized record-keeping of all diagnostic findings.

  11. Fibrillin levels in a severely affected Marfan syndrome patient with a null allele

    SciTech Connect

    Boxer, M.; Withers, A.P.; Al-Ghaban, Z. |

    1994-09-01

    Marfan syndrome is an autosomal dominantly inherited connective tissue disorder characterized by defects in the cardiovascular, skeletal and ocular systems. A patient was first examined in 1992 having survived an acute sortic dissection with subsequent composite repair and insertion of a prosthetic aortic valve. Clinical examination revealed arachnodactyly, narrow, high arched palate with dental crowding, an arm span exceeding her height by 10.5 cm, joint laxity and bilateral lens subluxation. Analysis of the family showed affected members in three generations and the fibrillin gene, FBN1, was shown to segregate with the disease when using polymorphic markers including an RsaI polymorphism in the 3{prime}-untranslated region of the gene. Analysis of patient mRNA for this RsaI polymorphism by RT-PCR (reverse transcriptase-PCR) amplification and restriction enzyme digestion of the PCR products showed that the copy of the gene segregating with the disease was not transcribed. No low level expression of this allele was observed despite RT-PCR amplification incorporating radioactively labelled dCTP, thus revealing a null allele phenotype. Western blotting analysis of fibrillin secreted by the patient`s dermal fibroblasts using fibrillin-specific antibodies showed only normal sized fibrillin protein. However, immunohistochemical studies of the patient`s tissue and fibroblasts showed markedly lowered levels in staining of microfibrillar structures compared with age-matched controls. This low level of expression of the protein affected in Marfan syndrome in a patient with such severe clinical manifestations is surprising since current understanding would suggest that this molecular phenotype should lead to a mild clinical disorder.

  12. Variable phenotype of Marfan syndrome in two large Australian pedigrees, one of Australian aboriginal origin

    SciTech Connect

    Wong, K.K.; Summers, K.M.; West, M.J.

    1994-09-01

    Marfan syndrome may affect the cardiovascular, ocular and skeletal systems. The gene for this autosomal dominant disease maps to chromosome 15 and codes for the extracellular matrix protein fibrillin. Phenotypic expression is very variable both within and between families, possibly due to the influence of other, unlinked, genetic factors interacting with the fibrillin gene. We report two Australian families which demonstrate the extent of inter- and intra-family phenotypic variability. Eye, cardiac and skeletal assessments were made independently. In the first family, 8 of 12 siblings and 11 of 19 of their children had ectopia lentis with or without other ocular findings. There were few cardiac signs. One child had mitral valve prolapse. He and three other children had mild dilatation of the aorta. Skeletal abnormalities were also found (3 adults and 7 children). Chest wall asymmetry was the most common skeletal finding. This family has less cardiac and skeletal involvement than is usual in Marfan syndrome, although the disease maps to chromosome 15 in the region of the fibrillin gene (LOD=4.8 at {theta}=0 with respect to CYP19). The second family is partly of Australian aboriginal origin. The disease has been traced through 5 generations. To date we have examined 37 of 84 living members. Twenty-three in 3 generations are affected. Five adults and 4 children have moderate to severe aortic dilatation and there has been at least one death due to aortic dissection. However, two adolescents with subluxed lenses and marked skeletal abnormalities have normal aortic diameters, two children have aortic dilatation without other signs and two children have only subluxed lenses. This family shows the range of phenotypic variation which can arise from mutation in the fibrillin gene, which may be influenced by the admixture of Australian aboriginal genes. These two families provide an invaluable resource for studying genetic interactions in this disease.

  13. A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome

    PubMed Central

    Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K; Habashi, Jennifer P; Bedja, Djahida; Whitworth, Ryan E; Lindsay, Mark E; Schoenhoff, Florian; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Ehsan, Hamid; Huso, David; Thomas, Craig J; Caulfield, Mark J; Van Eyk, Jennifer E; Judge, Daniel P; Dietz, Harry C

    2015-01-01

    Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. DOI: http://dx.doi.org/10.7554/eLife.08648.001 PMID:26506064

  14. Aortic surgery in patients with marfan syndrome: long-term survival, morbidity and function.

    PubMed

    Lepore, V; Jeppsson, A; Rådberg, G; Mantovani, V; Bugge, M

    2001-01-01

    The natural history of patients with Marfan syndrome is depressing, but surgical intervention on the aorta can improve the prognosis. Study results were analyzed with reference to long-term survival, morbidity and function. Seventy-four Marfan patients (51 males, 23 females; mean age 41+/-14 years), underwent first-time aortic surgery between 1977 and 1998. Follow up information regarding mortality, morbidity and functional status was obtained from patient records and by questionnaire. The mean follow up was 5 years (range: 0-19 years). Forty-seven patients (64%) had a dissection, 27 (36%) an aneurysm, and 45 (61%) patients underwent emergency operations (<4 h from arrival at hospital). In 72 patients (97%) the disease affected the ascending aorta, and implantation of a composite graft was the most frequent operation. Overall 30-day mortality was 12% (3% in elective cases, 18% in emergency cases, p <0.05). Emergency operations and surgery extended to the aortic arch were risk factors for early mortality. Overall actuarial survival was 63.4+/-8% at 10 years. Age was the only risk factor for late mortality. Seventeen patients were reoperated on due to pathologies of the remaining aorta (n = 12), pseudoaneurysms (n = 4) and aortic valve endocarditis (n = 1). A total of five patients had endocarditis; one patient with a homograft required surgery, and medical treatment was successful in the other four patients. Five patients had neurological thromboembolic episodes without permanent damage, and six had minor bleeding complications. Freedom from early and late mortality, reoperation on the aorta and major cardiovascular events (endocarditis episodes, thromboembolic/hemorrhagic strokes and other major bleeding/embolic episodes) was 33.3 +/- 8.1% at 10 years. At follow up, 98% of patients were in NYHA functional class I or II, and 80% were working. Elective aortic surgery in Marfan patients can be performed with good results. Close follow up of patients undergoing surgery

  15. DPY-17 and MUA-3 Interact for Connective Tissue-Like Tissue Integrity in Caenorhabditis elegans: A Model for Marfan Syndrome.

    PubMed

    Fotopoulos, Pauline; Kim, Jeongho; Hyun, Moonjung; Qamari, Waiss; Lee, Inhwan; You, Young-Jai

    2015-04-27

    mua-3 is a Caenorhabditis elegans homolog of the mammalian fibrillin1, a monogenic cause of Marfan syndrome. We identified a new mutation of mua-3 that carries an in-frame deletion of 131 amino acids in the extracellular domain, which allows the mutants to survive in a temperature-dependent manner; at the permissive temperature, the mutants grow normally without obvious phenotypes, but at the nonpermissive temperature, more than 90% die during the L4 molt due to internal organ detachment. Using the temperature-sensitive lethality, we performed unbiased genetic screens to isolate suppressors to find genetic interactors of MUA-3. From two independent screens, we isolated mutations in dpy-17 as a suppressor. RNAi of dpy-17 in mua-3 rescued the lethality, confirming dpy-17 is a suppressor. dpy-17 encodes a collagen known to genetically interact with dpy-31, a BMP-1/Tolloid-like metalloprotease required for TGFβ activation in mammals. Human fibrillin1 mutants fail to sequester TGFβ2 leading to excess TGFβ signaling, which in turn contributes to Marfan syndrome or Marfan-related syndrome. Consistent with that, RNAi of dbl-1, a TGFβ homolog, modestly rescued the lethality of mua-3 mutants, suggesting a potentially conserved interaction between MUA-3 and a TGFβ pathway in C. elegans. Our work provides genetic evidence of the interaction between TGFβ and a fibrillin homolog, and thus provides a simple yet powerful genetic model to study TGFβ function in development of Marfan pathology.

  16. [Genetics and prevention of genetic aortic syndromes (GAS) and of the Marfan syndrome].

    PubMed

    von Kodolitsch, Y; Blankart, C R; Vogler, M; Kallenbach, K; Robinson, P N

    2015-02-01

    Genetic aortic syndromes are autosomal-dominantly heritable aneurysms of the thoracic aorta, which carry a high risk of aortic rupture or acute thoracic aortic dissection at young age. We introduce the reader to the principles of genetic diagnostics and the medical and surgical prevention of thoracic aortic dissection in patients with genetic aortic syndromes. A cardiologist, a health economist, a patient representative, a heart surgeon, and a molecular geneticist teamed up to elucidate their perspective on major aspects of genetics and prevention of genetic aortic syndromes. Genetic aortic syndromes reflect a broad spectrum of diverse disease entities comprising the Marfan syndrome, the Loeys-Dietz syndrome or the vascular Ehlers-Danlos syndrome. The diagnosis of each respective disease entity requires combined assessment of phenotype and genotype information. A medical prevention of aortic complications such as dissection is mandatory although a curative therapy currently appears unlikely in humans. The single most important measure against acute aortic dissection is the preventive replacement of the aortic root, where valve preserving techniques appear preferable. Comprehensive prophylaxis including molecular diagnostics seem reasonable also from an economic point of view. Optimal prevention requires individualization of concepts, which entail a detailed diagnostic characterization of each specific genetic aortic syndrome including characterization of the genotype.

  17. Marfan syndrome with a complex chromosomal rearrangement including deletion of the FBN1 gene

    PubMed Central

    2012-01-01

    Background The majority of Marfan syndrome (MFS) cases is caused by mutations in the fibrillin-1 gene (FBN1), mapped to chromosome 15q21.1. Only few reports on deletions including the whole FBN1 gene, detected by molecular cytogenetic techniques, were found in literature. Results We report here on a female patient with clinical symptoms of the MFS spectrum plus craniostenosis, hypothyroidism and intellectual deficiency who presents a 1.9 Mb deletion, including the FBN1 gene and a complex rearrangement with eight breakpoints involving chromosomes 6, 12 and 15. Discussion This is the first report of MFS with a complex chromosome rearrangement involving a deletion of FBN1 and contiguous genes. In addition to the typical clinical findings of the Marfan syndrome due to FBN1 gene haploinsufficiency, the patient presents features which may be due to the other gene deletions and possibly to the complex chromosome rearrangement. PMID:22260333

  18. Value of molecular diagnosis in a family with Marfan syndrome and an atypical vascular phenotype.

    PubMed

    Lebreiro, Ana; Martins, Elisabete; Almeida, Jorge; Pimenta, Sofia; Bernardes, José Miguel; Machado, José Carlos; Abreu-Lima, Cassiano

    2011-02-01

    Marfan syndrome is mainly caused by mutations in the FBN1 gene. Diagnosis is usually based on clinical criteria, but the phenotypic presentation varies widely among affected individuals. Aortic dissection or rupture is the cause of death in over 90% of untreated patients. Early identification of individuals at risk is important given the availability of medical and surgical treatment that can significantly improve life-expectancy. Molecular testing could provide an etiologic diagnosis in patients who present with milder or atypical clinical forms of the disease. Moreover, it could contribute to preventive treatment in carriers, inform genetic counseling and offer reassurance to unaffected individuals. By describing a family with Marfan syndrome in whom the disease presented in an atypical aggressive form, this article highlights the value of tests for detecting FBN1 mutations in selected cases. Copyright © 2010 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  19. Acute aortic dissection in pregnancy in a woman with undiagnosed marfan syndrome.

    PubMed

    Master, Mandana; Day, Gavin

    2012-01-01

    We report a case of acute aortic dissection in a lady of 28 weeks of gestation with undiagnosed Marfan syndrome. The patient had been seen in our antenatal clinics. Her history documented in her pregnancy record was negative for genetic/congenital abnormalities. There was no family history documented. Subsequently, at 28 weeks of gestation, the patient presented with sudden onset chest, jaw, and back pain. Further history revealed that her father had died at the age of 27 of an aortic dissection. Echocardiography showed aortic root dissection with occlusion of aortic branches. She subsequently underwent an emergency lower segment caesarean section followed by surgical repair of type A dissection. A simultaneous type B dissection was managed conservatively. On later examination, our patient fulfilled the diagnostic criteria for phenotypic expression of Marfan syndrome. Genetic testing also confirmed that she has a mutation of the fibrillin (FBN 1) gene associated with the disease.

  20. A Case of Neonatal Marfan Syndrome: A Management Conundrum and the Role of a Multidisciplinary Team

    PubMed Central

    Carande, Elliott J.; Adwani, Satish

    2017-01-01

    Neonatal Marfan syndrome (nMFS) is a rare condition with a poor prognosis. It is genotypically and phenotypically distinct from the typical Marfan syndrome and carries a poorer prognosis. This case report describes the progression of a 14-month-old girl diagnosed with nMFS at 5 months of age. Her diagnosis followed the identification of a fibrillin-1 mutation (FBN1 gene, exon 26, chromosome 15), which is a common locus of nMFS. This patient developed severe cardiac complications resulting in congestive cardiac failure in early life and required major cardiac surgery. Since surgical intervention, our patient is still reliant on a degree of ventilator support, but the patient has gained weight and echocardiography has demonstrated improved left ventricular function and improved tricuspid and mitral valve regurgitation. Therefore, we argue the importance of a cautious multidisciplinary approach to early surgical intervention in cases of nMFS. PMID:28168077

  1. A Case of Neonatal Marfan Syndrome: A Management Conundrum and the Role of a Multidisciplinary Team.

    PubMed

    Carande, Elliott J; Bilton, Samuel J; Adwani, Satish

    2017-01-01

    Neonatal Marfan syndrome (nMFS) is a rare condition with a poor prognosis. It is genotypically and phenotypically distinct from the typical Marfan syndrome and carries a poorer prognosis. This case report describes the progression of a 14-month-old girl diagnosed with nMFS at 5 months of age. Her diagnosis followed the identification of a fibrillin-1 mutation (FBN1 gene, exon 26, chromosome 15), which is a common locus of nMFS. This patient developed severe cardiac complications resulting in congestive cardiac failure in early life and required major cardiac surgery. Since surgical intervention, our patient is still reliant on a degree of ventilator support, but the patient has gained weight and echocardiography has demonstrated improved left ventricular function and improved tricuspid and mitral valve regurgitation. Therefore, we argue the importance of a cautious multidisciplinary approach to early surgical intervention in cases of nMFS.

  2. Combined cataract surgery on a Marfan-syndrome patient (case report).

    PubMed

    Biró, Zsolt; Szabó, Ilona; Pámer, Zsuzsanna

    2014-01-01

    Combined cataract surgery of an ectopic lens was performed on a 10 years old girl with Marfan-syndrome. A Cionni capsular tension ring was implanted into the capsular bag, and the bag was pulled to its place and fixed with a scleral suture. Because of the young age of the patient a primary posterior capsulorhexis was performed, through which anterior vitrectomy was carried out and the artificial lens was implanted into the capsular bag. In the literature several surgical solutions are advised for the treatment of the ectopic lens in patients with Marfan-syndrome. We have performed a successful surgery combined with posterior capsulorhexis in our case. Because of its rarity and special surgical solution, we think this case report is interesting and can be helpful in such cases to be published.

  3. Impairment of flow-mediated dilation correlates with aortic dilation in patients with Marfan syndrome.

    PubMed

    Takata, Munenori; Amiya, Eisuke; Watanabe, Masafumi; Omori, Kazuko; Imai, Yasushi; Fujita, Daishi; Nishimura, Hiroshi; Kato, Masayoshi; Morota, Tetsuro; Nawata, Kan; Ozeki, Atsuko; Watanabe, Aya; Kawarasaki, Shuichi; Hosoya, Yumiko; Nakao, Tomoko; Maemura, Koji; Nagai, Ryozo; Hirata, Yasunobu; Komuro, Issei

    2014-07-01

    Marfan syndrome is an inherited disorder characterized by genetic abnormality of microfibrillar connective tissue proteins. Endothelial dysfunction is thought to cause aortic dilation in subjects with a bicuspid aortic valve; however, the role of endothelial dysfunction and endothelial damaging factors has not been elucidated in Marfan syndrome. Flow-mediated dilation, a noninvasive measurement of endothelial function, was evaluated in 39 patients with Marfan syndrome. Aortic diameter was measured at the aortic annulus, aortic root at the sinus of Valsalva, sinotubular junction and ascending aorta by echocardiography, and adjusted for body surface area (BSA). The mean value of flow-mediated dilation was 6.5 ± 2.4 %. Flow-mediated dilation had a negative correlation with the diameter of the ascending thoracic aorta (AscAd)/BSA (R = -0.39, p = 0.020) and multivariate analysis revealed that flow-mediated dilation was an independent factor predicting AscAd/BSA, whereas other segments of the aorta had no association. Furthermore, Brinkman index had a somewhat greater influence on flow-mediated dilation (R = -0.42, p = 0.008). Although subjects who smoked tended to have a larger AscAd compared with non-smokers (AscA/BSA: 17.3 ± 1.8 versus 15.2 ± 3.0 mm/m(2), p = 0.013), there was no significant change in flow-mediated dilation, suggesting that smoking might affect aortic dilation via an independent pathway. Common atherogenic risks, such as impairment of flow-mediated dilation and smoking status, affected aortic dilation in subjects with Marfan syndrome.

  4. Type A aortic dissection in Marfan syndrome: extent of initial surgery determines long-term outcome.

    PubMed

    Rylski, Bartosz; Bavaria, Joseph E; Beyersdorf, Friedhelm; Branchetti, Emanuela; Desai, Nimesh D; Milewski, Rita K; Szeto, Wilson Y; Vallabhajosyula, Prashanth; Siepe, Matthias; Kari, Fabian A

    2014-04-01

    Data on outcomes after Stanford type A aortic dissection in patients with Marfan syndrome are limited. We investigated the primary surgery and long-term results in patients with Marfan syndrome who suffered aortic dissection. Among 1324 consecutive patients with aortic dissection type A, 74 with Marfan syndrome (58% men; median age, 37 years [first and third quartiles, 29 and 48 years]) underwent surgical repair (85% acute dissections; 68% DeBakey I; 55% composite valved graft, 30% supracoronary ascending replacement, 15% valve-sparing aortic root replacement; 12% total arch replacement; 3% in-hospital mortality) at 2 tertiary centers in the United States and Europe over the past 25 years. The rate of aortic reintervention with resternotomy was 24% (18 of 74) and of descending aorta (thoracic+abdominal) intervention was 30% (22 of 74) at a median follow-up of 8.4 years (first and third quartiles, 2.2 and 12.7 years). Freedom from need for aortic root reoperation in patients who underwent primarily a composite valved graft or valve-sparing aortic root replacement procedure was 95±3%, 88±5%, and 79±5% and in patients who underwent supracoronary ascending replacement was 83±9%, 60±13%, 20±16% at 5, 10, and 20 years. Secondary aortic arch surgery was necessary only in patients with initial hemi-arch replacement. Emergency surgery for type A dissection in patients with Marfan syndrome is associated with low in-hospital mortality. Failure to extend the primary surgery to aortic root or arch repair leads to a highly complex clinical course. Aortic root replacement or repair is highly recommended because supracoronary ascending replacement is associated with a high need (>40%) for root reintervention.

  5. Ten-year clinical and imaging follow-up of dural ectasia in adults with Marfan syndrome.

    PubMed

    Mesfin, Addisu; Ahn, Nicholas U; Carrino, John A; Sponseller, Paul D

    2013-01-01

    Dural ectasia in the lumbosacral spine is a common feature of Marfan syndrome and is associated with low back pain and surgical complications, but its natural history is unknown. To evaluate the natural history of dural ectasia in adults with Marfan syndrome by determining if, over time, symptoms associated with dural ectasia worsen, dural ectasia imaging findings worsen, or spondylolisthesis/spondylolysis develops or worsens. Prospective cohort study. For our prospective follow-up study, we enrolled 20 patients with Marfan syndrome and dural ectasia who, from 1998 through 1999, had undergone magnetic resonance imaging (MRI) and computed tomography (CT) of the lumbosacral spine and had completed the Oswestry Disability Index (ODI) questionnaire. Of the 20, five did not meet the inclusion criterion of a completed 2009 ODI questionnaire and were excluded. The remaining 15 patients (mean age, 49.6 years; mean follow-up, 10.5 years) formed our study group. The ODI, MRI-based qualitative and quantitative measurements, CT-based quantitative measurements. We performed matched-pair analyses via Student t test and Wilcoxon signed-rank test of the ODI scores (15 pairs), dural volume of L5-S2 (eight pairs), dural sac ratio (DSR) of L4-S2 (nine pairs), development/progression of spondolysthesis/spondylolysis (11 pairs), and Fattori qualitative grading of dural ectasia size (10 pairs). Significance was set at p<.05. We found no statistical differences in the 1998/1999 and 2009 ODI scores (25.8 vs. 22.2 points), dural volume (70.4 vs. 73.9 cm(3)), or DSR (0.68, 0.78, 2.04, and 58.1 vs. 0.69, 0.83, 2.30, and 70.20). There was also no development or progression of spondylolisthesis/spondylolysis and no increase in dural ectasia size. During this 10-year period, the natural history of dural ectasia in adults with Marfan syndrome was not associated with a significant increase in ODI scores, dural ectasia size, or with the development/progression of spondylolisthesis or spondylolysis

  6. Surgical management of patients with the Marfan syndrome and dilatation of the ascending aorta.

    PubMed

    McDonald, G R; Schaff, H V; Pyeritz, R E; McKusick, V A; Gott, V L

    1981-02-01

    Until recently, surgical correction of Marfan defects of the aortic root has been undertaken with some hesitancy because of the high perioperative risk. The Division of Medical Genetics at Johns Hopkins follows about 300 patients with the Marfan syndrome, and during the past 8 years 13 of these were referred to the senior author (V.L.G.) for aortic valve replacement and repair of the ascending aorta. Preoperatively, four of the 13 patients were in New York Heart Association (NYHA) Class IV (3/4 required emergency operation), three patients were in Class III, and six were in Class II. The aortic diameter at the mid-valve level ranged from 5.3 cm to 8.2 cm on M-mode echocardiography. The first two patients received a separate Björk-Shiley prosthesis and a woven Teflon graft and the last 11 patients had a composite valve-graft with direct coronary implantation. There were no hospital deaths. Follow-up ranges from 6 months to 8.1 years and is complete for all 13 patients (mean of 23 months). Two late deaths occurred 2 and 20 months postoperatively from presumed arrhythmia and two late deaths occurred at 4 and 6 months from endocarditis. The actuarial survival rate at 3 years is 61%. Some pathologists claim that the incidence of dissection of the aorta does not increase with increasing aortic dilatation in the Marfan patient. Six of our 13 patients, however, had aortic dissection at the time of surgery (two DeBakey Type I, three Type II, and one Type III). With the low hospital mortality that can now be achieved in the Marfan patient, and with the relatively high incidence of clinically unrecognized dissection, we fell that strong consideration should be given to earlier prophylactic repair in these patients. Operation may be indicated even in the asymptomatic Marfan patient with an aortic root diameter greater than 5.5 cm.

  7. Distinct effects of losartan and atenolol on vascular stiffness in Marfan syndrome.

    PubMed

    Bhatt, Ami B; Buck, J Stewart; Zuflacht, Jonah P; Milian, Jessica; Kadivar, Samoneh; Gauvreau, Kimberlee; Singh, Michael N; Creager, Mark A

    2015-08-01

    We conducted a randomized, double-blind trial of losartan (100 mg QD) versus atenolol (50 mg QD) for 6 months in adults with Marfan syndrome. Carotid-femoral pulse wave velocity (PWV), central augmentation index (AIx), aortic diameter and left ventricular (LV) function were assessed with arterial tonometry and echocardiography. Thirty-four subjects (18 female; median age 35 years, IQR 27, 45) were randomized. Central systolic and diastolic blood pressure decreased comparably with atenolol and losartan (p = 0.64 and 0.31, respectively); heart rate decreased with atenolol (p = 0.02), but not with losartan. PWV decreased in patients treated with atenolol (-1.15 ± 1.68 m/s; p = 0.01), but not in those treated with losartan (-0.22 ± 0.59 m/s; p = 0.15; between-group difference p = 0.04). In contrast, AIx decreased in the losartan group (-9.6 ± 8.6%; p < 0.001) but not in the atenolol group (0.9 ± 6.2%, p = 0.57; between-group difference p < 0.001). There was no significant change in aortic diameters or LV ejection fraction in either treatment group. In adults with Marfan syndrome, 6 months of treatment with atenolol improves PWV, whereas losartan reduces the AIx. By improving vascular stiffness via distinct mechanisms of action, there is physiologic value to considering the use of both medications in individuals with Marfan syndrome.

  8. Overview of current surgical strategies for aortic disease in patients with Marfan syndrome.

    PubMed

    Miyahara, Shunsuke; Okita, Yutaka

    2016-09-01

    Marfan syndrome is a heritable, systemic disorder of the connective tissue with a high penetrance, named after Dr. Antoine Marfan. The most clinically important manifestations of this syndrome are cardiovascular pathologies which cause life-threatening events, such as acute aortic dissections, aortic rupture and regurgitation of the aortic valve or other artrioventricular valves leading to heart failure. These events play important roles in the life expectancy of patients with this disorder, especially prior to the development of effective surgical approaches for proximal ascending aortic disease. To prevent such catastrophic aortic events, a lower threshold has been recommended for prophylactic interventions on the aortic root. After prophylactic root replacement, disease in the aorta beyond the root and distal to the arch remains a cause for concern. Multiple surgeries are required throughout a patient's lifetime that can be problematic due to distal lesions complicated by dissection. Many controversies in surgical strategies remain, such as endovascular repair, to manage such complex cases. This review examines the trends in surgical strategies for the treatment of cardiovascular disease in patients with Marfan syndrome, and current perspectives in this field.

  9. Characterisation of four novel fibrillin-1 (FBN1) mutations in Marfan syndrome.

    PubMed Central

    Adès, L C; Haan, E A; Colley, A F; Richard, R I

    1996-01-01

    Forty-four percent of the fibrillin-1 gene (FBN1) from 19 unrelated families with Marfan syndrome was screened for putative mutations by single strand conformational polymorphism (SSCP) analysis. Four novel mutations were identified and characterised in five people, three with classical Marfan syndrome (two from one family, and one from an unrelated family), one with a more severe phenotype, and one with neonatal Marfan syndrome. The base substitutions G2113A, G2132A, T3163G, and G3458A result in amino acid substitutions A705T, C711Y, C1055G, and C1152Y, respectively. C711Y, C1055G, and C1152Y lead to replacement of a cysteine by another amino acid; the latter two occur within epidermal growth factor-like motifs in exon 25 and 27, respectively. The A705T mutation occurs at exon 16 adjacent to the GT splice site. The A705T and C711Y mutations, at exon 16 and 17, respectively, are the first documented in the second transforming growth factor-beta 1 binding protein-like motif of FBN1. Images PMID:8863159

  10. Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events.

    PubMed

    Baudhuin, Linnea M; Kotzer, Katrina E; Lagerstedt, Susan A

    2015-03-01

    Marfan syndrome is a systemic disorder that typically involves FBN1 mutations and cardiovascular manifestations. We investigated FBN1 genotype-phenotype correlations with aortic events (aortic dissection and prophylactic aortic surgery) in patients with Marfan syndrome. Genotype and phenotype information from probands (n = 179) with an FBN1 pathogenic or likely pathogenic variant were assessed. A higher frequency of truncating or splicing FBN1 variants was observed in Ghent criteria-positive patients with an aortic event (n = 34) as compared with all other probands (n = 145) without a reported aortic event (79 vs. 39%; P < 0.0001), as well as Ghent criteria-positive probands (n = 54) without an aortic event (79 vs. 48%; P = 0.0039). Most probands with an early aortic event had a truncating or splicing variant (100% (n = 12) and 95% (n = 21) of patients younger than 30 and 40 years old, respectively). Aortic events occurred at a younger median age in patients with truncating/splicing variants (29 years) as compared with those with missense variants (51 years). A trend toward a higher frequency of truncating/splicing variants in patients with aortic dissection (n = 21) versus prophylactic surgery (n = 13) (85.7 vs. 69.3%; not significant) was observed. These aortic event- and age-associated findings may have important implications for the management of Marfan syndrome patients with FBN1 truncating and splicing variants.Genet Med 17 3, 177-187.

  11. Marfan syndrome in a large family: response of family members to a screening programme.

    PubMed

    Bridges, A B; Faed, M; Boxer, M; Gray, J R; Bundy, C; Murray, A

    1992-02-01

    Reaction to medical, social, and genetic implications of Marfan syndrome was evaluated by means of two questionnaires, the first after various tests before discussion of the diagnosis, the second after full discussion of the patient's diagnosis. Thirty-seven members of a family known to be at risk for Marfan syndrome attended for both questionnaires. All patients claimed to be satisfied with the way they were informed of the results of screening; 41% of patients were more worried about their health and 48% were more worried about the future after diagnosis. Apart from 50% of the smokers reducing or stopping their intake of cigarettes there were only very minor changes in lifestyle over the first month despite the increased level of expressed anxiety. If a definitive screening test was available, 96% of patients claimed they would have chosen it, 45% felt it would have an influence on their future plans, and 78% would choose to use a method of prenatal diagnosis for Marfan syndrome if it were available.

  12. Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy.

    PubMed

    Wooderchak-Donahue, Whitney; VanSant-Webb, Chad; Tvrdik, Tatiana; Plant, Parker; Lewis, Tracey; Stocks, Jennifer; Raney, Joshua A; Meyers, Lindsay; Berg, Alizabeth; Rope, Alan F; Yetman, Anji T; Bleyl, Steven B; Mesley, Rebecca; Bull, David A; Collins, R Thomas; Ojeda, Mayra Martinez; Roberts, Amy; Lacro, Ronald; Woerner, Audrey; Stoler, Joan; Bayrak-Toydemir, Pinar

    2015-08-01

    Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.

  13. Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys-Dietz Syndromes.

    PubMed

    Takeda, Norifumi; Yagi, Hiroki; Hara, Hironori; Fujiwara, Takayuki; Fujita, Daishi; Nawata, Kan; Inuzuka, Ryo; Taniguchi, Yuki; Harada, Mutsuo; Toko, Haruhiro; Akazawa, Hiroshi; Komuro, Issei

    2016-05-25

    Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue that affects the cardiovascular, skeletal, ocular, pulmonary, and nervous systems and is usually caused by mutations in the FBN1 gene, which encodes fibrillin-1. MFS is traditionally considered to result from the structural weakness of connective tissue. However, recent investigations on molecular mechanisms indicate that increased transforming growth factor-β (TGF-β) activity plays a crucial role in the pathogenesis of MFS and related disorders, such as Loeys-Dietz syndrome (LDS), which is caused by mutation in TGF-β signaling-related genes. In addition, recent studies show that angiotensin II type 1 receptor (AT1R) signaling enhances cardiovascular pathologies in MFS, and the angiotensin II receptor blocker losartan has the potential to inhibit aortic aneurysm formation. However, the relationship between TGF-β and AT1R signaling pathways remains poorly characterized. In this review, we discuss the recent studies on the molecular mechanisms underlying cardiovascular manifestations of MFS and LDS and the ensuing strategies for management.

  14. Differential allelic expression of a fibrillin gene (FBNI) in patients with Marfan syndrome

    SciTech Connect

    Hewett, D.; Lynch, J.; Sykes, B.; Firth, H.; Child, A.

    1994-09-01

    Marfan syndrome is a connective-tissue disorder affecting cardiovascular, skeletal, and ocular systems. The major Marfan locus has been identified as the FBN1 gene on chromosome 15; this codes for the extracellular-matrix protein fibrillin, a 350-kD constituent of the 8-10-nm elastin-associated microfibrils. The authors identified five MFS patients who were heterozygous for an RsaI restriction-site dimorphism in the 3{prime} UTR of the FBN1 gene. This expressed variation was used to distinguish the mRNA output from each of the two FBN1 alleles in fibroblast cultures from these five patients. Three of the patients were shown to produce <5% of the normal level of FBN1 transcripts from one of their alleles. This null-allele phenotype was not observed in 10 nonmarfanoid fibroblast cell lines. 26 refs., 4 figs.

  15. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial.

    PubMed

    Groenink, Maarten; den Hartog, Alexander W; Franken, Romy; Radonic, Teodora; de Waard, Vivian; Timmermans, Janneke; Scholte, Arthur J; van den Berg, Maarten P; Spijkerboer, Anje M; Marquering, Henk A; Zwinderman, Aeilko H; Mulder, Barbara J M

    2013-12-01

    Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. Treatment with losartan, an angiotensin-II receptor-1 blocker, may reduce aortic dilatation rate in Marfan patients. In this multicentre, open-label, randomized controlled trial with blinded assessments, we compared losartan treatment with no additional treatment in operated and unoperated adults with Marfan syndrome. The primary endpoint was aortic dilatation rate at any predefined aortic level after 3 years of follow-up, as determined by magnetic resonance imaging. A total of 233 participants (47% female) underwent randomization to either losartan (n = 116) or no additional treatment (n = 117). Aortic root dilatation rate after 3.1 ± 0.4 years of follow-up was significantly lower in the losartan group than in controls (0.77 ± 1.36 vs. 1.35 ± 1.55 mm, P = 0.014). Aortic dilatation rate in the trajectory beyond the aortic root was not significantly reduced by losartan. In patients with prior aortic root replacement, aortic arch dilatation rate was significantly lower in the losartan group when compared with the control group (0.50 ± 1.26 vs. 1.01 ± 1.31 mm, P = 0.033). No significant differences in separate clinical endpoints or the composite endpoint (aortic dissection, elective aortic surgery, cardiovascular death) between the groups could be demonstrated. In adult Marfan patients, losartan treatment reduces aortic root dilatation rate. After aortic root replacement, losartan treatment reduces dilatation rate of the aortic arch.

  16. [Marfan syndrome: clinical and pathomorphological restructurings after surgical treatment of aortic aneurysm].

    PubMed

    Zhuraev, R K; Zerbino, D D

    2014-01-01

    The authors examined the state of patients suffering from Marfan syndrome (MS) who endured operation for ascending aorta aneurysm with replacement of the ascending aorta and aortic valve (Bentall operation), studying alterations of the skeleton, face, heart and eyes, as well as pathomorphological restructurings in the aortic wall. The study was carried out 7.0 ± 4.2 years after the operation. We examined a total of 39 patients with MS - 27 (69.2%) men and 12 (30.8%) women aged from 22 to 70 years old (average age - 42.1 ± 13.4 years). All patients were operated on for dissecting aneurysm of the ascending aorta accompanied by a considerable degree of aortic valve insufficiency or aortic ostium stenosis. The mean diameter of the aorta at the level of the sinuses of Valsalva amounted to 7.0 ± 1.3 cm (minimal - 5.0 cm, maximal - 12.0 cm), the Z-score prior to operation was 12.7 ± 6.5. The time form making the diagnosis of MS to surgical intervention for aortic aneurysm amounted to 9.6 ± 5.9 years. The condition after operative treatment in all patients was satisfactory, with the haemodynamic indices stable: systolic AP - 133.5 ± 19.1 mm Hg, diastolic AP 85.1 ± 12.9 mm Hg, heart rate 74.8 ± 7.2 bpm. The average systemic score for the symptoms and tests of MS patients amounted to 8.2 ± 3.3 points. Pathohistological alterations of the aorta in patients with Marfan syndrome consisted in pronounced restructuring of the wall with deep irreversible alternative changes. The pathological process extended in the middle aortic layer all alone the length, but not only in the portions of rupture and dissection. The main pathomorphological signs in MS were as follows: focal accumulations of mucoid substances, dystrophic alterations of smooth-muscle cells, ribbon-like anuclear zones, formation of cystlike cavities, alterations of elastic fibres - fragmentation, hyperelastosis, multiplication, thinning and straightening, zones of elastolysis.

  17. Systematic review of the psychosocial aspects of living with Marfan syndrome.

    PubMed

    Velvin, G; Bathen, T; Rand-Hendriksen, S; Geirdal, A Ø

    2015-02-01

    The purpose of this study was to explore the literature on the psychosocial aspects of Marfan syndrome (MFS), to critically appraise and to synthesize relevant literature. A mixed-method systematic review was performed by searching the published literature databases using available medical, psychological, pedagogical and social databases and other sources. All studies that addressed psychosocial aspects of MFS, published in peer-reviewed journals were assessed. Of 81 search results, 15 articles (four articles based on same study population) satisfied the eligibility criteria. All studies were cross-sectional; no intervention or randomized controlled trial (RCT) studies were found. Most studies were of small sample sizes, had low response rate or participants without a verified diagnosis. Despite these limitations, all studies described, that MFS has a significant impact on the psychosocial aspects of people's lives: Decreased quality of life; challenges in education, work and family life, depression and anxiety. Some studies indicated that the subjective perception of discomfort did not necessarily match the medical severity of a disease. The research of the psychosocial aspects of MFS is limited in size and quality. More research is needed on the psychosocial aspects of MFS in samples with a verified diagnosis to develop evidence-based knowledge and appropriate guidelines.

  18. Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome.

    PubMed

    Rand-Hendriksen, Svend; Tjeldhorn, Lena; Lundby, Rigmor; Semb, Svein Ove; Offstad, Jon; Andersen, Kai; Geiran, Odd; Paus, Benedicte

    2007-09-01

    In monogenic disorders, correlation between genotype and phenotype is a premise for predicting prognosis in affected patients. Predictive genetic testing may enable prophylaxis and promote clinical follow-up. Although Marfan syndrome (MFS) is known as a monogenic disorder, according to the present diagnostic criteria a mutation in the gene FBN1 is not sufficient for the diagnosis, which also depends on the presence of a number of clinical, radiological, and other findings. The fact that MFS patient cohorts only infrequently have been examined for all relevant phenotypic manifestations may have contributed to inconsistent reports of genotype-phenotype correlations. In the Norwegian Study of Marfan syndrome, all participants were examined for all findings contained in the Ghent nosology by the same investigators. Mutation identification was carried out by robot-assisted direct sequencing of the entire FBN1 coding sequence and MLPA analysis. A total of 46 mutations were identified in 44 unrelated patients, all fulfilling Ghent criteria. Although no statistically significant correlation could be obtained, the data indicate associations between missense or splice site mutations and ocular manifestations. While mutations in TGF-domains were associated with the fulfillment of few major criteria, severe affection was indicated in two cases with C-terminal mutations. Intrafamilial phenotypic variation among carriers of the same mutation, suggesting the influence of epigenetic facors, complicates genetic counseling. The usefulness of predictive genetic testing in FBN1 mutations requires further investigation. Copyright 2007 Wiley-Liss, Inc.

  19. Acute myeloblastic leukemia-associated Marfan syndrome and Davidoff-Dyke-Masson syndrome: a case report.

    PubMed

    Demir, Cengiz; Bay, Ali; Dilek, Imdat; Öner, Ahmet Faik

    2008-12-05

    We present herein a 23-year-old man with acute myeloblastic leukemia (AML) associated with Davidoff-Dyke-Masson syndrome (DDMS) and Marfan syndrome (MS). The diagnosis of DDMS was based on findings including left facial asymmetry, left hemiparesis, mental retardation, right cerebral hemiatrophy, dilatation of the ipsilateral lateral ventricle and calvarial thickening. The diagnosis of MS was based on clinical findings including tall stature, myopia, retinitis pigmentosa, blue scleras, scoliosis, pectus excavatum, arachnodactyly and low ratio of upper/lower body segment. The patient developed hepatosplenomegaly, gingival hypertrophy and pancytopenia. Peripheral blood film and bone marrow examination showed that most of nucleated cells were blasts; immunophenotype of those cells showed CD11+, CD13+, CD14+, CD33+ and HLA-DR+. These findings confirmed the diagnosis of AML (FAB-M5). After induction chemotherapy, remission was obtained. To the best of our knowledge, our case is the third report of AML in MS syndrome, while AML associated with DDMS and MS has not been previously reported in the literature.

  20. Epidural anesthesia for cesarean section in a patient with Marfan syndrome and dural ectasia -A case report-

    PubMed Central

    Kim, Gahyun; Ko, Justin Sangwook

    2011-01-01

    Pregnancy is considered a period of high risk for cardiovascular complications in patients with Marfan syndrome. Therefore the choice of anesthetic technique for delivery should be focused on minimizing hemodynamic fluctuations, and preferably provide adequate post-operative pain control. For this purpose, neuraxial blocks, such as spinal or epidural anesthesia, may be deemed a safe option. However, dural ectasia is present in 63-92% of patients with Marfan syndrome, and the increased amount of cerebrospinal fluid volume is thought to be one of main reasons for spinal anesthesia failure. We report herein the peri-operative management of a patient with Marfan syndrome and dural ectasia for cesarean section using epidural anesthesia. PMID:21490825

  1. Noninvasive diagnosis and management of spontaneous intracranial hypotension in patients with marfan syndrome: Case Report and Review of the Literature

    PubMed Central

    Bassani, Luigi; Graffeo, Christopher S.; Behrooz, Navid; Tyagi, Vineet; Wilson, Taylor; Penaranda, Saul; Zagzag, David; Rifkin, Daniel B; Barcellos-Hoff, Mary Helen; Fatterpekar, Girish; Placantonakis, Dimitris

    2014-01-01

    Background: Spontaneous intracranial hypotension is an uncommon clinical entity. Heritable connective tissue disorders (HCTD), such as Marfan syndrome, are frequently implicated as an underlying cause, due to dural structural weaknesses that predispose patients to spontaneous cerebrospinal fluid (CSF) leak. Due to the high prevalence of multi-system disease in HCTD, diagnosis and treatment are often complicated. Case Description: We present a 58-year-old female with Marfan syndrome on anticoagulation for a mechanical aortic valve replacement who came to medical attention with severe, acute-onset headache following a straining episode. Noninvasive magnetic resonance (MR) myelography confirmed thoracic CSF extravasations and multiple lumbar diverticula. The patient was treated conservatively and her symptoms resolved. Conclusion: We discuss the common presentation, diagnostic tools, and treatment options for spontaneous CSF leaks in patients with Marfan syndrome or related HCTD with an emphasis on noninvasive modalities and a review of the major radiographic criteria used to diagnose dural abnormalities, such as dural ectasia. PMID:24575323

  2. [Patients with aneurysms and osteoarthritis: Marfan syndrome ruled out, so what is it?].

    PubMed

    van der Linde, Denise; van de Laar, Ingrid M B H; Moelker, Adriaan; Wessels, Marja W; Bertoli-Avella, Aida M; Roos-Hesselink, Jolien W

    2013-01-01

    We describe three cases where Marfan syndrome was suspected, but genetic tests were negative. Two patients, a 38-year-old male and a 45-year-old female, were asymptomatic, but were referred to a clinical geneticist because multiple family members had died of aortic dissections at a young age. The third patient, a 55-year-old female, has been monitored for the past 26 years due to mild aortic dilatation and mitral valve prolapse after three brothers had died suddenly. At screening, all these patients were diagnosed with multiple vascular abnormalities and osteoarthritis. Pathogenic SMAD3 mutations were identified as the cause of the vascular catastrophes in these families. SMAD3 mutations cause aneurysms-osteoarthritis syndrome, an autosomal dominant disorder characterized by aneurysms, dissections and tortuosity throughout the arterial tree, early-onset osteoarthritis and mild craniofacial features. These case descriptions emphasize the importance of timely recognition of aneurysms-osteoarthritis syndrome, as this syndrome causes more aggressive and widespread cardiovascular disease than Marfan syndrome.

  3. Marfan syndrome: ocular findings and novel mutations-in pursuit of genotype-phenotype associations.

    PubMed

    Latasiewicz, Marta; Fontecilla, Christian; Millá, Elena; Sánchez, Aurora

    2016-04-01

    To analyze ocular involvement in patients diagnosed with Marfan syndrome (MFS), study their clinical findings and prognosis based on the type of FBN1 mutation, and evaluate possible genotype-phenotype correlations. Observational single-centre case series. Eleven patients diagnosed with MFS were included. All subjects met the Ghent criteria of MFS, the diagnosis was confirmed by genetic testing. All subjects underwent a complete ophthalmologic examination. We evaluated clinical data, the incidence of ectopia lentis (EL), and other eye disorders. The association of ocular signs with the type of mutation was analyzed. Four of the 11 patients had EL, of which 3 developed secondary glaucoma, and 62.5% of the phakic patients had myopia. Other ocular abnormalities included strabismus, retinal tears, retinal detachment, and amblyopia. The encountered types of mutations were premature termination codon (PTC) in 7 patients, missense in 2 cases, 1 aberration of splicing, and 1 indel mutation. Two novel mutations were found. Of the patients with EL, 2 had a missense, 1 an indel, and 1 a nonsense mutation. Myopia was the most frequent ocular involvement. Patients with a PTC mutation revealed to have a smaller risk of EL; however, more studies are required to indicate the mechanism of the correlation. Copyright © 2016 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

  4. What do French patients and geneticists think about prenatal and preimplantation diagnoses in Marfan syndrome?

    PubMed

    Coron, F; Rousseau, T; Jondeau, G; Gautier, E; Binquet, C; Gouya, L; Cusin, V; Odent, S; Dulac, Y; Plauchu, H; Collignon, P; Delrue, M-A; Leheup, B; Joly, L; Huet, F; Thevenon, J; Mace, G; Cassini, C; Thauvin-Robinet, C; Wolf, J E; Hanna, N; Sagot, P; Boileau, C; Faivre, L

    2012-12-01

    Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with manifestations mainly involving the skeletal, ocular, and cardiovascular systems. The phenotypic variability observed in MFS makes genetic counselling difficult. Prenatal diagnosis (PND) and preimplantation genetic diagnosis are technically feasible when a causal mutation is identified, but both raise many ethical questions in this condition. Little is known about opinions and practices in such reproductive issues in MFS. The goal of this study was to report on patients' points of view and geneticists' standard practices. Two different questionnaires were produced. Fifty geneticists filled in the questionnaire. Twenty-two per cent thought that PND was acceptable, 72% debatable and 6% not acceptable. Preimplantation genetic diagnosis was more often reported acceptable (34% of answers). Results varied according to the physician's experience with the disease. Fifty-four answers were collected for patients' questionnaires. Most of them (74%) were favourable to the development of prenatal testing, and believed that the choice should be given to parents. However, only a minority would opt for prenatal diagnosis for themselves. This study showed that the majority of patients were in favour of PND and that opinions among practitioners varied widely, but that overall, practitioners favoured a systematic multidisciplinary evaluation of the couple's request. © 2012 John Wiley & Sons, Ltd.

  5. A marked decrease in heart rate variability in Marfan syndrome patients with confirmed FBN1 mutations.

    PubMed

    Cherkas, Andriy; Zhuraev, Rustam

    2016-01-01

    The studies on heart rate variability (HRV), a key predictor of all-cause mortality, in Marfan syndrome (MS), up to now have not been reported, especially in patients with FBN1 mutations. Among 18 MS patients with the phenotype of MS meeting inclusion criteria 15 have had a FBN1 gene mutation. Short electrocardiography records were taken in the supine position and during orthostatic tests. The control group consisted of 30 apparently healthy nonathletes matched by age and gender. Heart rates in MS patients with the FBN1 mutation were increased in both the supine position and orthostatic test (p < 0.001). Most of the time-domain (standard deviation, pNN50) and frequency-domain (total power, very low, low, and high frequency) parameters of HRV were significantly reduced in the MS patients (p < 0.001). A marked decrease in HRV, documented in the study, may be an important clinical feature in MS patients with confirmed FBN1 gene mutations.

  6. Infusion of Hibiscus sabdariffa L. Modulates Oxidative Stress in Patients with Marfan Syndrome.

    PubMed

    Soto, María Elena; Zuñiga-Muñoz, Alejandra; Guarner Lans, Verónica; Duran-Hernández, Erendira Janet; Pérez-Torres, Israel

    2016-01-01

    Marfan syndrome (MFS) is associated with progressive aortic dilatation, endothelial dysfunction, and oxidative stress that contribute to the early acute dissection of the vessel and can end up in rupture of the aorta and sudden death. Many studies have described that the organic acids from Hibiscus sabdariffa Linne (HSL) calyces increase cellular antioxidant capacity and decrease oxidative stress. Here we evaluate if the antioxidant properties of HSL infusion improve oxidative stress in MFS patients. Activities of extra cellular super oxide dismutase (ECSOD), glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GSSG-R), glutathione (GSH), lipid peroxidation (LPO) index, total antioxidant capacity (TAC), and ascorbic acid were determined in plasma from MFS patients. Values before and after 3 months of the treatment with 2% HSL infusion were compared in control and MFS subjects. After treatment, there was a significant decrease in ECSOD (p = 0.03), EGPx (p = 0.04), GST (p = 0.03), GSH (p = 0.01), and TAC and ascorbic acid (p = 0.02) but GSSG-R activity (p = 0.04) and LPO (p = 0.02) were increased in MFS patients in comparison to patients receiving the HSL treatment and C subjects. Therefore, the infusion of HSL calyces has antioxidant properties that allow an increase in antioxidant capacity of both the enzymatic and nonenzymatic systems, in the plasma of the MSF patients.

  7. Identification of Loci Modulating the Cardiovascular and Skeletal Phenotypes of Marfan Syndrome in Mice

    PubMed Central

    Fernandes, Gustavo R.; Massironi, Silvia M. G.; Pereira, Lygia V.

    2016-01-01

    Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue, affecting mostly the skeletal, ocular and cardiovascular systems, caused by mutations in the FBN1 gene. The existence of modifier genes has been postulated based on the wide clinical variability of manifestations in patients, even among those with the same FBN1 mutation. Although isogenic mouse models of the disease were fundamental in dissecting the molecular mechanism of pathogenesis, they do not address the effect of genetic background on the disease phenotype. Here, we use a new mouse model, mgΔloxPneo, which presents different phenotype severity dependent on the genetic backgrounds, to identify genes involved in modulating MFS phenotype. F2 heterozygotes showed wide phenotypic variability, with no correlations between phenotypic severities of the different affected systems, indicating that each has its specific set of modifier genes. Individual analysis of the phenotypes, with SNP microarrays, identified two suggestive QTL each to the cardiovascular and skeletal, and one significant QTL to the skeletal phenotype. Epistatic interactions between the QTL account for 47.4% and 53.5% of variation in the skeletal and cardiovascular phenotypes, respectively. This is the first study that maps modifier loci for MFS, showing the complex genetic architecture underlying the disease. PMID:26927851

  8. Large genomic fibrillin-1 (FBN1) gene deletions provide evidence for true haploinsufficiency in Marfan syndrome.

    PubMed

    Mátyás, Gábor; Alonso, Sira; Patrignani, Andrea; Marti, Myriam; Arnold, Eliane; Magyar, István; Henggeler, Caroline; Carrel, Thierry; Steinmann, Beat; Berger, Wolfgang

    2007-08-01

    Mutations in the FBN1 gene are the major cause of Marfan syndrome (MFS), an autosomal dominant connective tissue disorder, which displays variable manifestations in the cardiovascular, ocular, and skeletal systems. Current molecular genetic testing of FBN1 may miss mutations in the promoter region or in other noncoding sequences as well as partial or complete gene deletions and duplications. In this study, we tested for copy number variations by successively applying multiplex ligation-dependent probe amplification (MLPA) and the Affymetrix Human Mapping 500 K Array Set, which contains probes for approximately 500,000 single-nucleotide polymorphisms (SNPs) across the genome. By analyzing genomic DNA of 101 unrelated individuals with MFS or related phenotypes in whom standard genetic testing detected no mutation, we identified FBN1 deletions in two patients with MFS. Our high-resolution approach narrowed down the deletion breakpoints. Subsequent sequencing of the junctional fragments revealed the deletion sizes of 26,887 and 302,580 bp, respectively. Surprisingly, both deletions affect the putative regulatory and promoter region of the FBN1 gene, strongly indicating that they abolish transcription of the deleted allele. This expectation of complete loss of function of one allele, i.e. true haploinsufficiency, was confirmed by transcript analyses. Our findings not only emphasize the importance of screening for large genomic rearrangements in comprehensive genetic testing of FBN1 but, importantly, also extend the molecular etiology of MFS by providing hitherto unreported evidence that true haploinsufficiency is sufficient to cause MFS.

  9. Infusion of Hibiscus sabdariffa L. Modulates Oxidative Stress in Patients with Marfan Syndrome

    PubMed Central

    Soto, María Elena; Zuñiga-Muñoz, Alejandra; Guarner Lans, Verónica; Duran-Hernández, Erendira Janet; Pérez-Torres, Israel

    2016-01-01

    Marfan syndrome (MFS) is associated with progressive aortic dilatation, endothelial dysfunction, and oxidative stress that contribute to the early acute dissection of the vessel and can end up in rupture of the aorta and sudden death. Many studies have described that the organic acids from Hibiscus sabdariffa Linne (HSL) calyces increase cellular antioxidant capacity and decrease oxidative stress. Here we evaluate if the antioxidant properties of HSL infusion improve oxidative stress in MFS patients. Activities of extra cellular super oxide dismutase (ECSOD), glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GSSG-R), glutathione (GSH), lipid peroxidation (LPO) index, total antioxidant capacity (TAC), and ascorbic acid were determined in plasma from MFS patients. Values before and after 3 months of the treatment with 2% HSL infusion were compared in control and MFS subjects. After treatment, there was a significant decrease in ECSOD (p = 0.03), EGPx (p = 0.04), GST (p = 0.03), GSH (p = 0.01), and TAC and ascorbic acid (p = 0.02) but GSSG-R activity (p = 0.04) and LPO (p = 0.02) were increased in MFS patients in comparison to patients receiving the HSL treatment and C subjects. Therefore, the infusion of HSL calyces has antioxidant properties that allow an increase in antioxidant capacity of both the enzymatic and nonenzymatic systems, in the plasma of the MSF patients. PMID:27413258

  10. Periosteal osteosarcoma and Marfan's syndrome: A case report and literature review.

    PubMed

    Xie, Guo-Ping; Song, Hui-Juan; Jiang, Nan; Qin, Cheng-He; Wang, Lei; Xu, Shao-Yong; Yu, Bin

    2016-01-01

    Periosteal osteosarcoma (POS) is a rare primary malignant bone tumor arising from the surface of long bones. In addition, Marfan's syndrome (MFS) is an infrequent hereditary autosomal dominant connective tissue disorder with high penetrance and variable phenotypes, which primarily affects the ocular, skeletal and cardiovascular systems. The present study reported a case of POS and MFS co-occurring in a child. A 6-year-old girl with MFS presented with pain, swelling and deformity in the right thigh following a fall. The patient was diagnosed with a right femoral shaft fracture and underwent open internal fixation surgery at a local hospital. At 2 weeks following surgery, the patient's parents observed increased swelling in the right thigh and thus, revisited the clinic. X-ray examination revealed extensive osteotylus around the fracture site and the clinician decided to remove the internal fixation. Following removal of the implant, aggravated swelling and superficial venous engorgement were observed. The patient was then admitted to Nanfang Hospital, where magnetic resonance imaging was performed, which identified symptoms of an abnormal periosteal reaction with bone erosion, indicating POS. The patient underwent a wide resection of the tumor and the histopathological examination confirmed the diagnosis of POS. No recurrence was identified at 9 months postoperatively. In conclusion, the present case report may result in increased awareness of the possibility of malignant bone tumors in a hereditary patient with osteotylus overgrowth following fracture surgery; in addition, the present case indicated a possible correlation between POS and MFS.

  11. The effects of acute and elective cardiac surgery on the anxiety traits of patients with Marfan syndrome.

    PubMed

    Benke, Kálmán; Ágg, Bence; Pólos, Miklós; Sayour, Alex Ali; Radovits, Tamás; Bartha, Elektra; Nagy, Péter; Rákóczi, Balázs; Koller, Ákos; Szokolai, Viola; Hedberg, Julianna; Merkely, Béla; Nagy, Zsolt B; Szabolcs, Zoltán

    2017-07-17

    Marfan syndrome is a genetic disease, presenting with dysfunction of connective tissues leading to lesions in the cardiovascular and skeletal muscle system. Within these symptoms, the most typical is weakness of the connective tissue in the aorta, manifesting as aortic dilatation (aneurysm). This could, in turn, become annuloaortic ectasia, or life-threatening dissection. As a result, life-saving and preventative cardiac surgical interventions are frequent among Marfan syndrome patients. Aortic aneurysm could turn into annuloaortic ectasia or life-threatening dissection, thus life-saving and preventive cardiac surgical interventions are frequent among patients with Marfan syndrome. We hypothesized that patients with Marfan syndrome have different level of anxiety, depression and satisfaction with life compared to that of the non-clinical patient population. Patients diagnosed with Marfan syndrome were divided into 3 groups: those scheduled for prophylactic surgery, those needing acute surgery, and those without need for surgery (n = 9, 19, 17, respectively). To examine the psychological features of the patients, Spielberger's anxiety (STAI) test, Beck's Depression questionnaire (BDI), the Berne Questionnaire of Subjective Well-being, and the Satisfaction with Life scale were applied. A significant difference was found in trait anxiety between healthy individuals and patients with Marfan syndrome after acute life-saving surgery (p < 0.01). The mean score of Marfan syndrome patients was 48.56 (standard deviation (SD): 5.8) as compared to the STAI population mean score of 43.72 (SD: 8.53). No difference was found between groups on the BDI (p > 0.1). Finally, a significant, medium size effect was found between patient groups on the Joy in Living scale (F (2.39) = 3.51, p = 0.040, η(2) = 0.15). Involving psychiatric and mental-health care, in addition to existing surgical treatment interventions, is essential for more successful recovery of patients with

  12. FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders.

    PubMed

    Sakai, Lynn Y; Keene, Douglas R; Renard, Marjolijn; De Backer, Julie

    2016-10-10

    FBN1 encodes the gene for fibrillin-1, a structural macromolecule that polymerizes into microfibrils. Fibrillin microfibrils are morphologically distinctive fibrils, present in all connective tissues and assembled into tissue-specific architectural frameworks. FBN1 is the causative gene for Marfan syndrome, an inherited disorder of connective tissue whose major features include tall stature and arachnodactyly, ectopia lentis, and thoracic aortic aneurysm and dissection. More than one thousand individual mutations in FBN1 are associated with Marfan syndrome, making genotype-phenotype correlations difficult. Moreover, mutations in specific regions of FBN1 can result in the opposite features of short stature and brachydactyly characteristic of Weill-Marchesani syndrome and other acromelic dysplasias. How can mutations in one molecule result in disparate clinical syndromes? Current concepts of the fibrillinopathies require an appreciation of tissue-specific fibrillin microfibril microenvironments and the collaborative relationship between the structures of fibrillin microfibril networks and biological functions such as regulation of growth factor signaling. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. A Woman With Marfan Syndrome in Pregnancy: Managing High Vascular Risk With Multidisciplinary Care.

    PubMed

    Naud, Kentia; Horne, Gabrielle; Van den Hof, Michiel

    2015-08-01

    Contexte : Bien que les femmes qui présentent des troubles affectant les tissus conjonctifs soient exposées à des risques de complications cardiovasculaires pendant la grossesse, nous ne disposons d’aucune ligne directrice en ce qui concerne les femmes enceintes dont le diamètre de l’anneau aortique est supérieur à 45 mm ou qui connaissent un élargissement rapide de l’aorte. Nous décrivons les facteurs significatifs sur le plan pratique dans le cadre de la prise en charge de la grossesse et de l’accouchement chez une femme atteinte du syndrome de Marfan.  Cas : Une femme enceinte atteinte du syndrome de Marfan nous a consultés pour obtenir des soins tertiaires à 26 semaines de gestation. La dilatation rapide de l’aorte a mené à la décision de procéder à un accouchement préterme (lequel a donné lieu à une bonne issue néonatale). Le recours à une approche multidisciplinaire a contribué à l’optimisation du monitorage et de la chronologie de l’accouchement (et à la réparation subséquente de l’aorte), en plus de permettre la planification de la prise en charge d’une potentielle catastrophe vasculaire.  Conclusion : Dans le cas des femmes enceintes qui sont atteintes du syndrome de Marfan, l’obtention d’issues maternelles et néonatales optimales dépend de la mise en œuvre d’un effort d’équipe grandement attentif et coordonné (y compris celle d’une planification méticuleuse de la prise en charge d’une potentielle catastrophe vasculaire).

  14. Visual outcomes after lensectomy and iris claw artisan intraocular lens implantation in patients with Marfan syndrome.

    PubMed

    Rabie, Hossein Mohammad; Malekifar, Parviz; Javadi, Mohammad Ali; Roshandel, Danial; Esfandiari, Hamed

    2017-08-01

    To review our experience with crystalline lens extraction and iris claw Artisan IOL implantation in patients with lens subluxation secondary to Marfan syndrome. A retrospective analysis of 12 eyes of 9 patients with lens subluxation due to Marfan syndrome who underwent crystalline lens removal and Artisan IOL (Ophtec, Groningen, Netherlands) implantation. A questionnaire of pre- and post-operative data, including demographics, pre- and postoperative comorbidities and complications was completed. Patients were evaluated for visual outcome and occurrence of complications. Uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), and spherical equivalents (SE) were compared before and after lens extraction and IOL insertion. The mean age of the participants was 30.03 ± 15.02 years, and mean post-operative follow-up time was 44.5 ± 16.4 months. Mean BCVA also showed a significant improvement from 0.5 ± 0.3 at the baseline to 0.2 ± 0.2 post-operatively (P = 0.006). SE changed significantly from -11.38 ± 1.99 preoperatively to -0.45 ± 1.65 post-operatively (P = 0.003). All eyes had the IOL implanted at desired position. Post-operative complications were retinal detachment in one case and IOL dislocation in another patient. No other complication such as ocular hypertension, angle abnormalities, clinical cystoids macular edema, and corneal decompensation was observed during the follow-up period. Artisan IOL implantation after lens extraction appears to be an attractive alternative for optical correction in cases of Marfan syndrome with ectopia lentis. It confers a significant improvement in visual acuity with reasonable risk profile.

  15. Mitral valve disease in patients with Marfan syndrome undergoing aortic root replacement.

    PubMed

    Kunkala, Meghana R; Schaff, Hartzell V; Li, Zhuo; Volguina, Irina; Dietz, Harry C; LeMaire, Scott A; Coselli, Joseph S; Connolly, Heidi

    2013-09-10

    Cardiac manifestations of Marfan syndrome include aortic root dilation and mitral valve prolapse (MVP). Only scant data exist describing MVP in patients with Marfan syndrome undergoing aortic root replacement. We retrospectively analyzed data from 166 MFS patients with MVP who were enrolled in a prospective multicenter registry of patients who underwent aortic root aneurysm repair. Of these 166 patients, 9% had mitral regurgitation (MR) grade >2, and 10% had MR grade 2. The severity of MVP and MR was evaluated by echocardiography preoperatively and ≤ 3 years postoperatively. Forty-one patients (25%) underwent composite graft aortic valve replacement, and 125 patients (75%) underwent aortic valve-sparing procedures; both groups had similar prevalences of MR grade >2 (P=0.7). Thirty-three patients (20%) underwent concomitant mitral valve (MV) intervention (repair, n=29; replacement, n=4), including all 15 patients with MR grade >2. Only 1 patient required MV reintervention during follow-up (mean clinical follow-up, 31 ± 10 months). Echocardiography performed 21 ± 13 months postoperatively revealed MR >2 in only 3 patients (2%). One early death and 2 late deaths occurred. Although the majority of patients with Marfan syndrome who undergo elective aortic root replacement have MVP, only 20% have concomitant MV procedures. These concomitant procedures do not seem to increase operative risk. In patients with MR grade ≤ 2 who do not undergo a concomitant MV procedure, the short-term incidence of progressive MR is low; however, more follow-up is needed to determine whether patients with MVP and MR grade ≤ 2 would benefit from prophylactic MV intervention.

  16. Marfan and cri du chat syndromes in an 18-month-old child: evidence of phenotype interaction.

    PubMed

    McClellan, M W; Golden, W L; Wilson, W G

    1994-10-01

    We report on an 18-month-old girl who has both the cri du chat and Marfan syndromes. She was born at term to a 29-year-old woman with the clinical diagnosis of Marfan syndrome. An evaluation for developmental delay at 2 months of age showed a karyotype of 46,XX,del(5)(15.1), consistent with cri du chat syndrome. At age 18 months she was tall (90 cm, > 95th centile), with an decreased upper segment:lower segment ratio (1.0), and microcephalic (OFC 42.5 cm, < 5th centile). Facial features were typical of cri du chat syndrome. The palm, middle finger and foot lengths were at or above the 95th centile for age. She was hypotonic, and her developmental level was approximately 8-10 months. Echocardiography showed redundant mitral valve tissue, mild mitral insufficiency, dilated aortic sinuses, and a small muscular VSD. We would have anticipated that a patient with an autosomal deletion who also had Marfan syndrome would have had growth failure. However, in this patient the skeletal features of Marfan syndrome (increased body length, decreased upper segment:lower segment ratio, and increased palm, finger, and foot length) predominate.

  17. Cardiac, skeletal, and ocular abnormalities in patients with Marfan's syndrome and in their relatives. Comparison with the cardiac abnormalities in patients with kyphoscoliosis.

    PubMed Central

    Bruno, L; Tredici, S; Mangiavacchi, M; Colombo, V; Mazzotta, G F; Sirtori, C R

    1984-01-01

    Polygraphic (including apexcardiograms and carotid pulse tracings) and M mode echocardiographic examinations were carried out in 34 symptomatic patients with Marfan's syndrome; similar studies were performed in 32 relatives and in 34 young patients with kyphoscoliotic disease. The purpose of these investigations was to determine the association between cardiac and oculoskeletal abnormalities and to identify specific patterns of disease with a poor prognosis. Polygraphic tests showed significant changes in all patients with Marfan's syndrome: 74% showed the apical systolic click and murmur of mitral valve prolapse; 48% had the diastolic murmur of aortic regurgitation; isolated mitral valve prolapse was found in 52%, 26% had isolated aortic regurgitation, and 22% had a combination of the two. Echocardiographic changes were also found in all patients: 79% had aortic root dilatation; 48% fluttering of the anterior mitral leaflet; 79% mitral valve prolapse, mostly pansystolic; 34% both mitral prolapse and aortic root dilatation; and 34% left ventricular dilatation. The severities of the cardiac and oculoskeletal abnormalities were not correlated. The high prevalence of mitral valve prolapse found in these patients, which did not vary with age or sex, was also present in their relatives: mitral prolapse was present in 38% and aortic dilatation, with or without regurgitation, in 14%. Four of the relatives had clearcut Marfan's syndrome, and at least four others a forme fruste. The metacarpal index was abnormal in 41% of the relatives; ocular abnormalities were rare. In kyphoscoliotic patients only an increase in the prevalence of mitral prolapse (18.2% in women, none in men) was found. These findings underline a complex pattern of association between cardiac, ocular, and skeletal abnormalities in patients with Marfan's syndrome and confirm an appreciable inheritability of several of the markers of the disease. Images PMID:6691872

  18. Comparative data on SD-OCT for the retinal nerve fiber layer and retinal macular thickness in a large cohort with Marfan syndrome.

    PubMed

    Xu, WanWan; Kurup, Sudhi P; Fawzi, Amani A; Durbin, Mary K; Maumenee, Irene H; Mets, Marilyn B

    2017-01-01

    To report the distribution of macular and optic nerve topography in the eyes of individuals with Marfan syndrome aged 8-56 years using spectral domain optical coherence tomography (SD-OCT). Thirty-three patients with Marfan syndrome underwent a full eye examination including slit-lamp biomicroscopy, indirect ophthalmoscopy, and axial length measurement; and SD-OCT measurements of the retinal nerve fiber layer (RNFL) and macular thickness. For patients between the ages of 8 and 12 years, the average RNFL thickness is 98 ± 9 μm, the vertical cup to disc (C:D) ratio is 0.50 ± 0.10, the central subfield thickness (CST) is 274 ± 38 μm, and the macular volume is 10.3 ± 0.6 mm(3). For patients between the ages of 13 and 17 years, the average RNFL is 86 ± 16 μm, the vertical C:D ratio is 0.35 ± 0.20, the CST is 259 ± 15 μm, and the macular volume is 10.1 ± 0.5 mm(3). For patients 18 years or older, the average RNFL is 89 ± 12 μm, the vertical C:D ratio is 0.46 ± 0.18, the CST is 262 ± 20 μm, and the macular volume is 10.2 ± 0.4 mm(3). When the average RNFL data are compared to a normative, age-adjusted database, 6 of 33 (18%) were thinner than the 5% limit. This study reports the distribution of SD-OCT data for patients with Marfan syndrome. Compared to a normative database, 18% of eyes with Marfan syndrome had RNFL thickness < 5% of the population.

  19. Risk factors for postoperative complications in lensectomy-vitrectomy with or without intraocular lens placement in ectopia lentis associated with Marfan syndrome.

    PubMed

    Fan, Fan; Luo, Yi; Liu, Xin; Lu, Yi; Zheng, Tianyu

    2014-10-01

    To analyse the surgical outcomes and postoperative complications of 23-G lensectomy-vitrectomy in the management of ectopia lentis in patients with Marfan syndrome. This retrospective study evaluated all patients with Marfan syndrome who received 23-G lensectomy-vitrectomy either through pars plana or the limbus for management of ectopia lentis between 1 January 2008 and 31 December 2011 at Eye and ENT Hospital of Fudan University. A total of 64 eyes of 39 patients with Marfan syndrome (28 males and 11 females) underwent lensectomy-vitrectomy as a primary procedure for ectopia lentis. The best-corrected visual acuity improved significantly from 0.5 (0.3-0.7) LogMar preoperatively to 0.3 (0.1-0.5) LogMar (p<0.01) at the last postoperative visit. Retinal detachment (RD) occurred in 11 eyes. Comparing the characteristics between those patients with detached and non-detached retinas, a more severe grade of lens dislocation (p=0.001) and higher axial myopia (p=0.035) were observed among those with detached retinas, whereas there were no significant differences between the two groups in terms of age (p=0.624), pseudophakia or aphakia (p=0.672), and preventive photocoagulated breaks (p=0.719). There was no significant difference in the incidence of RD between the scleral-fixated intraocular lens group and anterior chamber intraocular lens group (p=0.412). Development of RD in patients with Marfan syndrome remains a risk following surgery for ectopia lentis. Caution should be taken in eyes with severe lens dislocation or high axial myopia when planning the surgery. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  20. [The cardiovascular manifestations of Marfan's syndrome. A case report and review of the management].

    PubMed

    Bértoli, F; Remón, J A; González, R E; Poppe, N

    1993-09-01

    The authors present the clinical history of a patient with Marfan's syndrome (MS) and aortic insufficiency, who expired at 22 years of age, in order to illustrate the clinical evolution and review the management of this problem. It is known that patients with MS and heart failure due to dilatation of the aortic annulus have an early mortality of almost 100%. The authors conclude that echocardiographic follow up of these patients is vital in their medical and surgical management and that the use of beta blockers is the best medical therapy, and that prophylactic surgery with composite graft (aortic valve and ascending aorta) gives the best survival rate.

  1. [A case of Marfan syndrome with recurrent bilateral pneumothorax and anuloaortic ectasia].

    PubMed

    Yoshimura, N; Asada, T; Matsuda, H; Nohara, H; Higami, T; Nishiwaki, M; Mukohara, N; Chibana, M; Ogawa, K

    1990-02-01

    A 17-year-old male patient with Marfan syndrome was admitted due to recurrent bilateral pneumothorax which had recurred totally 11 times during the past 3 years. For the treatment of obstinately continuing right pneumothorax resection of bullae in combination with pleuropexy using OK 432 was effective. Two months thereafter Bentall operation with a composite graft consisting of a woven Dacron tube and a Björk-Shiley 27 mm aortic valve prosthesis was performed for his anuloartic ectasia. Left pneumothorax recurred 2 weeks after Bentall operation. But it was treated successfully with OK 432 injection into the left pleural cavity. Now, he is doing well as a student.

  2. Florida Sleeve Procedure Is Durable and Improves Aortic Valve Function in Marfan Syndrome Patients.

    PubMed

    Aalaei-Andabili, Seyed Hossein; Martin, Tomas; Hess, Philip; Klodell, Charles; Karimi, Ashkan; Arnaoutakis, George; Lee, Teng; Beaver, Thomas

    2017-09-01

    The Florida sleeve (FS) procedure was developed as a simplified approach for repair of functional type I aortic insufficiency secondary to aortic root aneurysm. We evaluated postoperative aortic valve function, long-term survival, and freedom from reoperation in Marfan syndrome patients who underwent the FS procedure at our center. All Marfan syndrome patients undergoing FS procedure from May 2002 to December 2014 were included. Echocardiography assessment included left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), ejection fraction, and degree of aortic insufficiency (none = 0, minimal = 1, mild = 2, moderate = 3, severe = 4). Social Security Death Index and primary care physicians' report were used for long-term follow-up. Thirty-seven Marfan syndrome patients, 21 (56.8%) men and 16 (43%) women with mean age of 35.08 ± 13.45 years underwent FL repair at our center. There was no in-hospital or 30-day death or stroke. Two patients required reoperation due to bleeding. Patients' survival rate was 94% at 1 to 8 years. Freedom from reoperation was 100% at 8 years. Twenty-five patients had postoperative follow-up echocardiography at 1 week. Aortic insufficiency grade significantly decreased after the procedure (preoperative mean ± SD: 1.76 ± 1.2 versus 1-week postoperative mean ± SD: 0.48 ± 0.71, p < 0.001), and mean LVEDD decreased from 52.23 ± 5.29 mm to 47.53 ± 8.89 mm (p = 0.086). Changes in LVESD (35.33 ± 9.97 mm to 36.58 ± 9.82 mm, p = 0.58) and ejection fraction (57.65% ± 6.22% to 55% ± 10.83%, p = 0.31) were not significant. The FS procedure can be performed safely in Marfan syndrome patients with immediate improvement in aortic valve function. Long-term survival and freedom from reoperation rates are encouraging. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  3. [Molecular mechanisms for the improvement of wound healing ability of periodontal ligament in Marfan's syndrome].

    PubMed

    Saito, Masahiro; Tsuji, Takashi

    2012-01-01

    Marfan's syndrome (MFS) is a systemic disorder of the connective tissues caused by insufficient fibrillin-1 microfibril formation and can cause cardiac complications, emphysema, ocular lens dislocation and severe periodontal disease. ADAMTSL6β, a microfibril-associated extracellular matrix protein that has been implicated in fibrillin-1 microfibril assembly is able to improve microfibril insufficiency in MFS mice model. These findings suggest a new therapeutic strategy for the treatment of MFS through ADAMTSL6β-mediated fibrillin-1 microfibril assembly. We here review effect on ADAMTSL6β to the improvement of microfibril insufficiency in periodontal tissue as a model.

  4. Management of severe asymmetric pectus excavatum complicating aortic repair in a patient with Marfan's syndrome.

    PubMed

    Yeung, Jonathan C; Marcuzzi, Danny; Peterson, Mark D; Ko, Michael A

    2016-05-01

    We describe the case of a 28-year old man with Marfan's syndrome and severe pectus excavatum who required an aortic root replacement for an ascending aortic aneurysm. There was a near-vertical angulation of the sternum that presented challenges with opening and exposure of the heart during aortic surgery. Furthermore, removal of the sternal retractor after aortic repair resulted in sudden loss of cardiac output. A Ravitch procedure was then performed to successfully close the chest without further cardiovascular compromise. We propose that patients with a severe pectus excavatum and mediastinal displacement seen on preoperative CT scanning should be considered for simultaneous, elective repair.

  5. [Causes of reoperations and their outcomes in patients with the Marfan's syndrome after correction of the ascending aorta aneurysm and aortic insufficiency].

    PubMed

    Chipiene, R; Grebelis, A; Semeniene, P; Nogiene, G

    2010-01-01

    Aim of the study was to elucidate causes of repeat operations and their outcomes in patients with the Marfan's syndrome. Between December 1972 and January 2009 60 patients with Marfan's syndrome were operated for aneurysm of the ascending aorta and aortic insufficiency. All patients were subjected to ascending aorta and aortic valve replacement with valve containing conduit. Five of 60 patients (8.3%) were subjected to 7 repeat operations (2 patients were reoperated twice). Causes of repeat interventions were: conduit dysfunction (n=3), abdominal aortic aneurysm (n=3), mitral valve prolapse (n=1). Three patients died: 2 during surgery because of impaired conduit function, one - in 1 year after repeat operation of mitral valve replacement for mitral valve prolapse with pronounced mitral insufficiency. In all cases cause of death was progressive heart failure. As an example a case of a female patient who had been subjected to repetitive surgeries because of malfunctioning conduit is presented in this paper. Main reason for reoperations was the Marfan's syndrome itself. Progression of this disease might continue after operation, alteration of the aortic wall promote dissection in regions not subjected to prosthetics. Application of prostheses especially designed for replacement of the ascending aorta excludes such causes of reoperations and death as disruption of old sutured of two parts conduits.

  6. Modelling and numerical simulation of the in vivo mechanical response of the ascending aortic aneurysm in Marfan syndrome.

    PubMed

    García-Herrera, Claudio M; Celentano, Diego J; Herrera, Emilio A

    2017-03-01

    Marfan syndrome (MFS) is a genetic disorder that affects connective tissue, impairing cardiovascular structures and function, such as heart valves and aorta. Thus, patients with Marfan disease have a higher risk of developing circulatory problems associated with mitral and aortic valves prolapse, manifested as dilated aorta and aortic aneurysm. However, little is known about the biomechanical characteristics of these structures affected with MFS. This study presents the modelling and simulation of the mechanical response of human ascending aortic aneurysms in MFS under in vivo conditions with intraluminal pressures within normotensive and hypertensive ranges. We obtained ascending aortic segments from five adults with MFS subjected to a vascular prosthesis implantation replacing an aortic aneurysm. We characterised the arterial samples via ex vivo tensile test measurements that enable fitting the material parameters of a hyperelastic isotropic constitutive model. Then, these material parameters were used in a numerical simulation of an ascending aortic aneurysm subjected to in vivo normotensive and hypertensive conditions. In addition, we assessed different constraints related to the movement of the aortic root. Overall, our results provide not only a realistic description of the mechanical behaviour of the vessel, but also useful data about stress/stretch-based criteria to predict vascular rupture. This knowledge may be included in the clinical assessment to determine risk and indicate surgical intervention.

  7. MDE heteroduplex analysis of PCR products spanning each exon of the fibrillin (FBN1) gene greatly increases the efficiency of mutation detection in the Marfan syndrome

    SciTech Connect

    Nijbroek, G.; Dietz, H.C.; Pereira, L.; Ramirz, F.

    1994-09-01

    Defects in fibrillin (FNB1) cause the Marfan syndrome (MFS). Classic Marfan phenotype cosegregates with intragenic and/or flanking marker alleles in all families tested and a significant number of FBN1 mutations have been identified in affected individuals. Using a standard method of mutation detection, SSCP analysis of overlapping RT-PCR amplimers that span the entire coding sequence, the general experience has been a low yield of identifiable mutations, ranging from 10-20%. Possible explanations included low sensitivity of mutation screening procedures, under-representation of mutant transcript in patient samples either due to deletions or mutant alleles containing premature termination codons, clustering of mutations in yet uncharacterized regions of the gene, including regulatory elements, or genetic heterogeneity. In order to compensate for a potential reduced mutant transcript stability, we have devised a method to screen directly from genomic DNA. The intronic boundaries flanking each of the 65 FBN1 exons were characterized and primer pairs were fashioned such that all splice junctions would be included in the resultant amplimers. The entire gene was screened for a panel of 9 probands with classic Marfan syndrome using mutation detection enhancement (MDE) gel heteroduplex analysis. A mutation was identified in 5/9 (55%) of patient samples. All were either missense mutations involving a cysteine residue or small deletions that did not create a frame shift. In addition, 10 novel polymorphisms were found. We conclude that the majority of mutations causing Marfan syndrome reside in the FBN1 gene and that mutations creating premature termination codons are not the predominant cause of inefficient mutation detection using RT-PCR. We are currently modifying screening methods to increase sensitivity and targeting putative FBN1 gene promoter sequences for study.

  8. Design and rationale of a prospective, collaborative meta-analysis of all randomized controlled trials of angiotensin receptor antagonists in Marfan syndrome, based on individual patient data: A report from the Marfan Treatment Trialists' Collaboration

    PubMed Central

    Pitcher, Alex; Emberson, Jonathan; Lacro, Ronald V.; Sleeper, Lynn A.; Stylianou, Mario; Mahony, Lynn; Pearson, Gail D.; Groenink, Maarten; Mulder, Barbara J.; Zwinderman, Aeilko H.; De Backer, Julie; De Paepe, Anne M.; Arbustini, Eloisa; Erdem, Guliz; Jin, Xu Yu; Flather, Marcus D.; Mullen, Michael J.; Child, Anne H.; Forteza, Alberto; Evangelista, Arturo; Chiu, Hsin-Hui; Wu, Mei-Hwan; Sandor, George; Bhatt, Ami B.; Creager, Mark A.; Devereux, Richard B.; Loeys, Bart; Forfar, J. Colin; Neubauer, Stefan; Watkins, Hugh; Boileau, Catherine; Jondeau, Guillaume; Dietz, Harry C.; Baigent, Colin

    2015-01-01

    Rationale A number of randomized trials are underway, which will address the effects of angiotensin receptor blockers (ARBs) on aortic root enlargement and a range of other end points in patients with Marfan syndrome. If individual participant data from these trials were to be combined, a meta-analysis of the resulting data, totaling approximately 2,300 patients, would allow estimation across a number of trials of the treatment effects both of ARB therapy and of β-blockade. Such an analysis would also allow estimation of treatment effects in particular subgroups of patients on a range of end points of interest and would allow a more powerful estimate of the effects of these treatments on a composite end point of several clinical outcomes than would be available from any individual trial. Design A prospective, collaborative meta-analysis based on individual patient data from all randomized trials in Marfan syndrome of (i) ARBs versus placebo (or open-label control) and (ii) ARBs versus β-blockers will be performed. A prospective study design, in which the principal hypotheses, trial eligibility criteria, analyses, and methods are specified in advance of the unblinding of the component trials, will help to limit bias owing to data-dependent emphasis on the results of particular trials. The use of individual patient data will allow for analysis of the effects of ARBs in particular patient subgroups and for time-to-event analysis for clinical outcomes. The meta-analysis protocol summarized in this report was written on behalf of the Marfan Treatment Trialists' Collaboration and finalized in late 2012, without foreknowledge of the results of any component trial, and will be made available online (http://www.ctsu.ox.ac.uk/research/meta-trials). PMID:25965707

  9. C596G mutation in FBN1 causes Marfan syndrome with exotropia in a Chinese family

    PubMed Central

    Li, Bo; Lan, Lan; Li, Lin

    2015-01-01

    Purpose To screen mutations in the fibrillin-1 (FBN1) gene in a Chinese family with autosomal dominant Marfan syndrome (MFS). Methods Patients and unaffected family members were given ophthalmic, cardiovascular, and physical examinations with a 5-year follow-up. Genomic DNA was extracted from the leukocytes of venous blood from all patients and their relatives. The entire coding region of the FBN1gene was screened with an ABI 9700 GeneAmp PCR System. The mutation identified was screened in 100 healthy and ethnically unrelated Chinese individuals. Results Mutation screening in FBN1 identified a T>G transition at position c.1786 in exon 14, leading to substitution of cysteine for glycine at codon 596 (C596G) in this four-generation Chinese family. The C596G mutation was associated with the disease phenotypes in all six patients but not found in 14 unaffected family members or the 100 ethnically unrelated and healthy controls. Conclusions A C596G mutation in FBN1 was identified in a Chinese family with MFS. Our results expand the spectrum of FBN1 mutations and contribute to the understanding of the role of FBN1 in the pathogenesis of Marfan syndrome. PMID:25729264

  10. A clinical appraisal of different Z-score equations for aortic root assessment in the diagnostic evaluation of Marfan syndrome.

    PubMed

    van Kimmenade, Roland R J; Kempers, Marlies; de Boer, Menko-Jan; Loeys, Bart L; Timmermans, Janneke

    2013-07-01

    Aortic sinus diameter dilatation expressed as a Z-score >2.0 is diagnostic in Marfan syndrome. In addition to the classic equation (Z1) for calculating Z-scores, two new equations were recently introduced (Z2 and Z3). We studied the effects of obesity, age, and the absolute cut point of 40 mm on these three equations in 2,674 echocardiographic measurements of 260 patients with Marfan syndrome. Diameters ≥40 mm were associated with Z1 scores <2.0 in 109 measurements (11.0%; 35 patients), Z2 scores <2.0 in 37 measurements (3.8%; 13 patients), and Z3 scores <2.0 in 24 measurements (2.4%; 11 patients). Mean diameters increased after the 40th birthday: 42.0 (37.3-44.8 mm interquartile range) to 42.5 (39.0-45.0 mm interquartile range; P = not significant) and mean Z1 scores decreased from 3.60 to 2.17 (P < 0.01), whereas Z2 and Z3 scores tended to increase (Z2: 3.04-3.27; Z3: 3.39-3.55; P = not significant for both). Comparing Z-scores between patients with body mass index <25 kg/m² (group A) and those with body mass index ≥25 kg/m² (group B), median Z1 scores differed between groups (Z1 = 3.00 in group A, Z1 = 1.78 in group B; P = 0.012), whereas Z2 (Z2 = 2.82 in group A, Z2 = 2.47 in group B; P = 0.52) and Z3 scores (Z3 = 2.72 in group A, Z2 = 3.12 in group B; P = 0.32) did not. Z1 scores are inferior to Z2 and Z3 scores in Marfan syndrome. In particular, the Z3 score, correcting aortic sinus diameter for body height, seems excellent.

  11. The role of the multidisciplinary health care team in the management of patients with Marfan syndrome.

    PubMed

    von Kodolitsch, Yskert; Rybczynski, Meike; Vogler, Marina; Mir, Thomas S; Schüler, Helke; Kutsche, Kerstin; Rosenberger, Georg; Detter, Christian; Bernhardt, Alexander M; Larena-Avellaneda, Axel; Kölbel, Tilo; Debus, E Sebastian; Schroeder, Malte; Linke, Stephan J; Fuisting, Bettina; Napp, Barbara; Kammal, Anna Lena; Püschel, Klaus; Bannas, Peter; Hoffmann, Boris A; Gessler, Nele; Vahle-Hinz, Eva; Kahl-Nieke, Bärbel; Thomalla, Götz; Weiler-Normann, Christina; Ohm, Gunda; Neumann, Stefan; Benninghoven, Dieter; Blankenberg, Stefan; Pyeritz, Reed E

    2016-01-01

    Marfan syndrome (MFS) is a rare, severe, chronic, life-threatening disease with multiorgan involvement that requires optimal multidisciplinary care to normalize both prognosis and quality of life. In this article, each key team member of all the medical disciplines of a multidisciplinary health care team at the Hamburg Marfan center gives a personal account of his or her contribution in the management of patients with MFS. The authors show how, with the support of health care managers, key team members organize themselves in an organizational structure to create a common meaning, to maximize therapeutic success for patients with MFS. First, we show how the initiative and collaboration of patient representatives, scientists, and physicians resulted in the foundation of Marfan centers, initially in the US and later in Germany, and how and why such centers evolved over time. Then, we elucidate the three main structural elements; a team of coordinators, core disciplines, and auxiliary disciplines of health care. Moreover, we explain how a multidisciplinary health care team integrates into many other health care structures of a university medical center, including external quality assurance; quality management system; clinical risk management; center for rare diseases; aorta center; health care teams for pregnancy, for neonates, and for rehabilitation; and in structures for patient centeredness. We provide accounts of medical goals and standards for each core discipline, including pediatricians, pediatric cardiologists, cardiologists, human geneticists, heart surgeons, vascular surgeons, vascular interventionists, orthopedic surgeons, ophthalmologists, and nurses; and of auxiliary disciplines including forensic pathologists, radiologists, rhythmologists, pulmonologists, sleep specialists, orthodontists, dentists, neurologists, obstetric surgeons, psychiatrist/psychologist, and rehabilitation specialists. We conclude that a multidisciplinary health care team is a means

  12. The role of the multidisciplinary health care team in the management of patients with Marfan syndrome

    PubMed Central

    von Kodolitsch, Yskert; Rybczynski, Meike; Vogler, Marina; Mir, Thomas S; Schüler, Helke; Kutsche, Kerstin; Rosenberger, Georg; Detter, Christian; Bernhardt, Alexander M; Larena-Avellaneda, Axel; Kölbel, Tilo; Debus, E Sebastian; Schroeder, Malte; Linke, Stephan J; Fuisting, Bettina; Napp, Barbara; Kammal, Anna Lena; Püschel, Klaus; Bannas, Peter; Hoffmann, Boris A; Gessler, Nele; Vahle-Hinz, Eva; Kahl-Nieke, Bärbel; Thomalla, Götz; Weiler-Normann, Christina; Ohm, Gunda; Neumann, Stefan; Benninghoven, Dieter; Blankenberg, Stefan; Pyeritz, Reed E

    2016-01-01

    Marfan syndrome (MFS) is a rare, severe, chronic, life-threatening disease with multiorgan involvement that requires optimal multidisciplinary care to normalize both prognosis and quality of life. In this article, each key team member of all the medical disciplines of a multidisciplinary health care team at the Hamburg Marfan center gives a personal account of his or her contribution in the management of patients with MFS. The authors show how, with the support of health care managers, key team members organize themselves in an organizational structure to create a common meaning, to maximize therapeutic success for patients with MFS. First, we show how the initiative and collaboration of patient representatives, scientists, and physicians resulted in the foundation of Marfan centers, initially in the US and later in Germany, and how and why such centers evolved over time. Then, we elucidate the three main structural elements; a team of coordinators, core disciplines, and auxiliary disciplines of health care. Moreover, we explain how a multidisciplinary health care team integrates into many other health care structures of a university medical center, including external quality assurance; quality management system; clinical risk management; center for rare diseases; aorta center; health care teams for pregnancy, for neonates, and for rehabilitation; and in structures for patient centeredness. We provide accounts of medical goals and standards for each core discipline, including pediatricians, pediatric cardiologists, cardiologists, human geneticists, heart surgeons, vascular surgeons, vascular interventionists, orthopedic surgeons, ophthalmologists, and nurses; and of auxiliary disciplines including forensic pathologists, radiologists, rhythmologists, pulmonologists, sleep specialists, orthodontists, dentists, neurologists, obstetric surgeons, psychiatrist/psychologist, and rehabilitation specialists. We conclude that a multidisciplinary health care team is a means

  13. Muscle and Bone Impairment in Children With Marfan Syndrome: Correlation With Age and FBN1 Genotype.

    PubMed

    Haine, Elsa; Salles, Jean-Pierre; Khau Van Kien, Philippe; Conte-Auriol, Françoise; Gennero, Isabelle; Plancke, Aurélie; Julia, Sophie; Dulac, Yves; Tauber, Maithé; Edouard, Thomas

    2015-08-01

    Marfan syndrome (MFS) is a rare connective tissue disorder caused by mutation in the gene encoding the extracellular matrix protein fibrillin-1 (FBN1), leading to transforming growth factor-beta (TGF-β) signaling dysregulation. Although decreased axial and peripheral bone mineral density (BMD) has been reported in adults with MFS, data about the evolution of bone mass during childhood and adolescence are limited. The aim of the present study was to evaluate bone and muscle characteristics in children, adolescents, and young adults with MFS. The study population included 48 children and young adults (22 girls) with MFS with a median age of 11.9 years (range 5.3 to 25.2 years). The axial skeleton was analyzed at the lumbar spine using dual-energy X-ray absorptiometry (DXA), whereas the appendicular skeleton (hand) was evaluated using the BoneXpert system (with the calculation of the Bone Health Index). Muscle mass was measured by DXA. Compared with healthy age-matched controls, bone mass at the axial and appendicular levels and muscle mass were decreased in children with MFS and worsened from childhood to adulthood. Vitamin D deficiency (<50 nmol/L) was found in about a quarter of patients. Serum vitamin D levels were negatively correlated with age and positively correlated with lumbar spine areal and volumetric BMD. Lean body mass (LBM) Z-scores were positively associated with total body bone mineral content (TB-BMC) Z-scores, and LBM was an independent predictor of TB-BMC values, suggesting that muscle hypoplasia could explain at least in part the bone loss in MFS. Patients with a FBN1 premature termination codon mutation had a more severe musculoskeletal phenotype than patients with an inframe mutation, suggesting the involvement of TGF-β signaling dysregulation in the pathophysiologic mechanisms. In light of these results, we recommend that measurement of bone mineral status should be part of the longitudinal clinical investigation of MFS children.

  14. Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome.

    PubMed

    Loeys, B; De Backer, J; Van Acker, P; Wettinck, K; Pals, G; Nuytinck, L; Coucke, P; De Paepe, A

    2004-08-01

    In order to estimate the contribution of mutations at the fibrillin-1 locus (FBN1) to classical Marfan syndrome (MFS) and to study possible phenotypic differences between patients with an FBN1 mutation vs. without, a comprehensive molecular study of the FBN1 gene in a cohort of 93 MFS patients fulfilling the clinical diagnosis of MFS according to the Ghent nosology was performed. The initial mutation screening by CSGE/SSCP allowed identification of an FBN1-mutation in 73 patients. Next, sequencing of all FBN1-exons was performed in 11 mutation-negative patients, while in nine others, DHPLC was used. This allowed identification of seven and five additional mutations, respectively. Southern blot analysis revealed an abnormal hybridization pattern in one more patient. A total of 23 out of the 85 mutations identified here are reported for the first time. Phenotypic comparison of MFS patients with cysteine-involving mutations vs. premature termination mutations revealed significant differences in ocular and skeletal involvement. The phenotype of the eight patients without proven FBN1 mutation did not differ from the others with respect to the presence of major cardiac, ocular, and skeletal manifestations or positive familial history. Most likely, a portion of FBN1-mutations remains undetected because of technical limitations. In conclusion, the involvement of the FBN1-gene could be demonstrated in at least 91% of all MFS patients (85/93), which strongly suggests that this gene is the predominant, if not the sole, locus for MFS. Copyright 2004 Wiley-Liss, Inc.

  15. Safety and cardiovascular behavior during pulmonary function in patients with Marfan syndrome.

    PubMed

    Cipriano, G F B; Peres, P A T; Cipriano, G; Arena, R; Carvalho, A C

    2010-07-01

    Marfan syndrome (MS) is a dominant autosomal connective tissue disease that impacts multiple systems, such as the cardiovascular system, tissue viscoelastic properties, bone calcification matrix and, most specific to the present investigation, pulmonary parenchyma. The aim of the present study was to evaluate pulmonary function (PF) in patients with MS and relate it to thoracic cage abnormalities (TCA) and the occurrence of cardiac arrhythmias during the spirometric exam (SE). A sample of 75 subjects (46 with MS) underwent clinical, anthropometric, echocardiographic, radiographic and PF evaluation; 51 subjects (33 with MS) had their electrocardiogram (ECG) information evaluated during PF. These individuals were matched and compared with a healthy control group (CG). Forced vital capacity (FVC) and forced expiratory volume (FEV) in the first second (FEV(1)) in the patients with MS were significantly lower in comparison with the CG (p = 0.012 and 0.0006) and predicted values (p = 0.04 and 0.003). Subgroup analysis based on TCA revealed differences between patients with MS with two combined abnormalities (scoliosis + pectus) in comparison with both the CG (p = 0.012 and 0.002) and patients without abnormalities (p = 0.05 and 0.006). There were no differences regarding the occurrence of arrhythmia during exertion on the SE. There was a correlation between clinical history, cardiovascular behavior and PF. PF is reduced in patients with MS, and deformities in the thoracic cage appear to contribute to this reduction. Despite the apparent structural alterations in the cardiovascular system in this population, exertion during the SE appears to be safe.

  16. Cardiovascular Benefits of Moderate Exercise Training in Marfan Syndrome: Insights From an Animal Model.

    PubMed

    Mas-Stachurska, Aleksandra; Siegert, Anna-Maria; Batlle, Monsterrat; Gorbenko Del Blanco, Darya; Meirelles, Thayna; Rubies, Cira; Bonorino, Fabio; Serra-Peinado, Carla; Bijnens, Bart; Baudin, Julio; Sitges, Marta; Mont, Lluís; Guasch, Eduard; Egea, Gustavo

    2017-09-25

    Marfan syndrome (MF) leads to aortic root dilatation and a predisposition to aortic dissection, mitral valve prolapse, and primary and secondary cardiomyopathy. Overall, regular physical exercise is recommended for a healthy lifestyle, but dynamic sports are strongly discouraged in MF patients. Nonetheless, evidence supporting this recommendation is lacking. Therefore, we studied the role of long-term dynamic exercise of moderate intensity on the MF cardiovascular phenotype. In a transgenic mouse model of MF (Fbn1(C1039G/+)), 4-month-old wild-type and MF mice were subjected to training on a treadmill for 5 months; sedentary littermates served as controls for each group. Aortic and cardiac remodeling was assessed by echocardiography and histology. The 4-month-old MF mice showed aortic root dilatation, elastic lamina rupture, and tunica media fibrosis, as well as cardiac hypertrophy, left ventricular fibrosis, and intramyocardial vessel remodeling. Over the 5-month experimental period, aortic root dilation rate was significantly greater in the sedentary MF group, compared with the wild-type group (∆mm, 0.27±0.07 versus 0.13±0.02, respectively). Exercise significantly blunted the aortic root dilation rate in MF mice compared with sedentary MF littermates (∆mm, 0.10±0.04 versus 0.27±0.07, respectively). However, these 2 groups were indistinguishable by aortic root stiffness, tunica media fibrosis, and elastic lamina ruptures. In MF mice, exercise also produced cardiac hypertrophy regression without changes in left ventricular fibrosis. Our results in a transgenic mouse model of MF indicate that moderate dynamic exercise mitigates the progression of the MF cardiovascular phenotype. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  17. Management of Marfan Syndrome during pregnancy: A real world experience from a Joint Cardiac Obstetric Service.

    PubMed

    Lim, Joanna C E-S; Cauldwell, Matthew; Patel, Roshni R; Uebing, Anselm; Curry, Ruth A; Johnson, Mark R; Gatzoulis, Michael A; Swan, Lorna

    2017-09-15

    Pregnancy in Marfan Syndrome (MFS) is associated with increased maternal risk of cardiovascular events. Given the maternal and genetic risks, pre-conception counselling is essential to facilitate informed choices. Multidisciplinary antenatal care with regular imaging is mandatory and best delivered through a Joint Cardiac Obstetric Service (JCOS). The aim of this study was to compare the care delivered in a JCOS against recognised international standards (European Society of Cardiology (ESC)). Pregnancies in women with MFS from 2005 to 2015 were identified from our institutional database. Patient records were reviewed and practice assessed against pre-determined standards based on ESC guidelines. There were 23 pregnancies in 15 women with MFS. 13/23 (57%) occurred in women with aortic dilatation at baseline. There were 3 important maternal cardiac events (type A dissection; deterioration in left ventricular function; significant left ventricular and progressive aortic dilatation). Four women did not have access to expert pre-conception counselling. These women were all referred to the JCOS late in established pregnancy. Imaging was often delayed and only 7/23 cases (30%) met the standard for minimum frequency of echocardiographic surveillance. Only 12/23 (52%) had pre-conception imaging of the whole aorta with CT/MRI. Distal aortic dilatation was identified in 7/23 cases but none of these underwent further MRI evaluation during pregnancy. Despite having a dedicated JCOS, our data show that facilitating complete obstetric and cardiac care for this group remains challenging. Education of local care providers and timely referral for expert pre-conception counselling in a JCOS are key. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Aortic biomechanics by magnetic resonance: early markers of aortic disease in Marfan syndrome regardless of aortic dilatation?

    PubMed

    Teixido-Tura, Gisela; Redheuil, Alban; Rodríguez-Palomares, Jose; Gutiérrez, Laura; Sánchez, Violeta; Forteza, Alberto; Lima, Joao A C; García-Dorado, David; Evangelista, Artur

    2014-01-15

    Previous studies demonstrated the usefulness of MRI in the evaluation of aortic biomechanics in Marfan patients with aortic dilatation. However, these parameters have not been well studied in earlier stages of aortic disease. The present work aimed to study aortic biomechanics: aortic distensibility (AD) and pulse wave velocity (PWV), by MRI in Marfan patients without advanced aortic disease. Eighty consecutive Marfan patients were compared with 36 age- and sex-matched controls. MRI images at the level of ascending, descending and abdominal aorta were used to determine AD and PWV. Marfan patients (27 men; age: 32.0 ± 10.5 years; mean aortic root diameter: 37.2 ± 4.6mm) had lower AD at all levels (ascending 2.6 ± 2.1 vs. 6.2 ± 3.7 mm Hg(-1)·10(-3), p<0.001; descending 3.1 ± 2.0 vs. 8.3 ± 4.2, p<0.001; and abdominal 4.5 ± 2.2 vs. 14.0 ± 5.2, p<0.001), higher aortic arch PWV (8.1 ± 6.5 vs. 4.3 ± 1.8m/s, p<0.01) and ascending-to-abdominal PWV (6.1 ± 3.0 vs. 4.7 ± 1.5m/s, p<0.01) compared with controls. Thirty-five Marfan patients had a non-dilated aortic root (mean aortic root diameter: 34.5 ± 3.8 mm). In multivariable analyses, after adjustment for age, pulse pressure and aortic dimensions, AD remained lower and PWV higher in Marfan patients; even Marfan patients with non-dilated aortic root showed impaired aortic biomechanics compared with controls. Z-score for ascending AD<-3.5 distinguished Marfan patients from controls with 82.5% sensitivity and 86.1% specificity. Aortic biomechanics by MRI were abnormal in the entire aorta in Marfan patients. Moreover, Marfan patients without dilated aortic root showed clear impairment of aortic biomechanics, which suggests that they may be used as early markers of aortic involvement in these patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Combined mitral valve replacement associated with the Bentall procedure, diaphragmatic hernia repair and reconstruction of the pectus excavatum in a 26-year-old patient with Marfan syndrome.

    PubMed

    Stępiński, Piotr; Stankowski, Tomasz; Aboul-Hassan, Sleiman Sebastian; Szymańska, Anna; Marczak, Jakub; Cichoń, Romuald

    2016-06-01

    A 26-year-old man with Marfan syndrome was admitted as an emergency patient with ascending aorta aneurysm, severe mitral and aortic regurgitation, diaphragmatic hernia and pectus excavatum. After completion of diagnostics a combined surgical procedure was performed.

  20. Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes.

    PubMed

    Cook, J R; Carta, L; Galatioto, J; Ramirez, F

    2015-01-01

    Cardiovascular abnormalities are the major cause of morbidity and mortality in Marfan syndrome (MFS) and a few clinically related diseases that share, with MFS, the pathogenic contribution of dysregulated transforming growth factor β (TGFβ) signaling. They include Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, aneurysm-osteoarthritis syndrome and syndromic thoracic aortic aneurysms. Unlike the causal association of MFS with mutations in an extracellular matrix protein (ECM), the aforementioned conditions are due to defects in components of the TGFβ pathway. While TGFβ antagonism is being considered as a potential new therapy for these heritable syndromes, several points still need to be clarified in relevant animal models before this strategy could be safely applied to patients. Among others, unresolved issues include whether elevated TGFβ signaling is responsible for all MFS manifestations and is the common trigger of disease in MFS and related conditions. The scope of our review is to highlight the clinical and experimental findings that have forged our understanding of the natural history and molecular pathogenesis of cardiovascular manifestations in this group of syndromic conditions. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons

    SciTech Connect

    Nijbroek, G.; Sood, S.; McIntosh, I.

    1995-07-01

    Mutations in the gene encoding fibrillin-1 (FBN1), a component of the extracellular microfibril, cause the Marfan syndrome (MFS). This statement is supported by the observations that the classic Marfan phenotype cosegregates with intragenic and/or flanking marker alleles in all families tested and that a significant number of FBN1 mutations have been identified in affected individuals. We have now devised a method to screen the entire coding sequence and flanking splice junctions of FBN1. On completion for a panel of nine probands with classic MFS, six new mutations were identified that accounted for disease in seven (78%) of nine patients. Nine additional new mutations have been characterized in the early stages of a larger screening project. These 15 mutations were equally distributed throughout the gene and, with one exception, were specific to single families. One-third of mutations created premature termination codons, and 6 of 15 substituted residues with putative significance for calcium finding to epidermal growth factor (EGF)-like domains. Mutations causing severe and rapidly progressive disease that presents in the neonatal period can occur in a larger region of the gene than previously demonstrated, and the nature of the mutation is as important a determinant as its location, in predisposing to this phenotype. 56 refs., 5 figs., 3 tabs.

  2. Association between Oro-Facial Defects and Systemic Alterations in Children Affected by Marfan Syndrome

    PubMed Central

    Docimo, Raffaella; Maturo, Paolo; D’Auria, Francesca; Grego, Susanna; Costacurta, Micaela; Perugia, Cesare; Chiariello, Luigi

    2013-01-01

    Background: It is important to establish an early diagnosis of the Marfan Syndrome (MFS) for providing an adequate pharmacological or surgical therapy. Nevertheless, this diagnosis may be complex, given the multi-organic involvement of this disease. Aims: In this work, we evaluated the oral phenotype in a group of paediatric patients with a clinical diagnosis of MFS, to quantify the association of the oro-facial defects with other systemic alterations. Settings and Design: Paediatric subjects who were aged, with a clinical diagnosis of MFS, were selected from our regional Marfan monitoring unit. Methods and Material: All the patients were subjected to Paediatric Dentistry examinations and a radiological screening with Panoramic and Cephalometric X-Rays. The aortic dilation (Aortic Z-score value), the hyperlaxity of the ligaments and scoliosis were evaluated by cardio-surgical and orthopaedics specialists. Statistical Analysis: The correlations between the oral and systemic alterations were analyzed by using the chi square test for the nominal variables. Results and Conclusions: We found a significant correlation of the Aortic Z – score with multiple oral defects which included retrognathia, malar hypoplasia, cross bite, oral respiration and an ogival palate. An association of the oral defects with hyperlaxity of the ligaments and scoliosis was also found. Thus, the data suggested that dentists should be more involved in a multidisciplinary approach, to provide an early MFS diagnosis in paediatric patients. PMID:23730650

  3. The Structural Role of Elastic Fibers in the Cornea Investigated Using a Mouse Model for Marfan Syndrome.

    PubMed

    White, Tomas L; Lewis, Philip; Hayes, Sally; Fergusson, James; Bell, James; Farinha, Luis; White, Nick S; Pereira, Lygia V; Meek, Keith M

    2017-04-01

    The presence of fibrillin-rich elastic fibers in the cornea has been overlooked in recent years. The aim of the current study was to elucidate their functional role using a mouse model for Marfan syndrome, defective in fibrillin-1, the major structural component of the microfibril bundles that constitute most of the elastic fibers. Mouse corneas were obtained from animals with a heterozygous fibrillin-1 mutation (Fbn1+/-) and compared to wild type controls. Corneal thickness and radius of curvature were calculated using optical coherence tomography microscopy. Elastic microfibril bundles were quantified and visualized in three-dimensions using serial block face scanning electron microscopy. Transmission electron microscopy was used to analyze stromal ultrastructure and proteoglycan distribution. Center-to-center average interfibrillar spacing was determined using x-ray scattering. Fbn1+/- corneas were significantly thinner than wild types and displayed a higher radius of curvature. In the Fbn1+/- corneas, elastic microfibril bundles were significantly reduced in density and disorganized compared to wild-type controls, in addition to containing a higher average center-to-center collagen interfibrillar spacing in the center of the cornea. No other differences were detected in stromal ultrastructure or proteoglycan distribution between the two groups. Proteoglycan side chains appeared to colocalize with the microfibril bundles. Elastic fibers have an important, multifunctional role in the cornea as highlighted by the differences observed between Fbn1+/- and wild type animals. We contend that the presence of normal quantities of structurally organized elastic fibers are required to maintain the correct geometry of the cornea, which is disrupted in Marfan syndrome.

  4. Epidural Anesthesia for Cesarean Section in a Pregnant Woman with Marfan Syndrome and Dural Ectasia

    PubMed Central

    Pepe, Franco; De Luca, Francesco; Privitera, Agata; Sanalitro, Elisabetta; Scarpinati, Puccio

    2017-01-01

    Marfan syndrome (MFS) is a genetic disorder of connective tissue, characterized by variable clinical features and multisystem complications. The anesthetic management during delivery is debated. Regional anesthesia has been used with success during cesarean delivery, but in some MFS patients there is a probability of erratic and inadequate spread of intrathecal local anesthetics as a result of dural ectasia. In these cases, epidural anesthesia may be a particularly useful technique during cesarean delivery because it allows an adequate spread and action of local anesthetic with a controlled onset of anesthesia, analgesia, and sympathetic block and a low risk of perioperative complications. We report the perioperative management of a patient with MFS and dural ectasia who successfully underwent cesarean section using epidural technique anesthesia. The previous pregnancy of this woman ended with cesarean section with a failed spinal anesthesia that was converted to general anesthesia due to unknown dural ectasia at that time. PMID:28611929

  5. Acute abdomen due to torsion of the wandering spleen in a patient with Marfan Syndrome.

    PubMed

    Leci-Tahiri, Laura; Tahiri, Afrim; Bajrami, Rifat; Maxhuni, Mehmet

    2013-08-05

    Wandering spleen is a very rare defect characterized by the absence or weakness of one or more of the ligaments that hold the spleen in its normal position in the upper left abdomen. Patient symptomatology is variable and ranges from mere feeling of an abdominal lump to sudden abdominal pain due to infarction. Patients may have subacute to chronic abdominal or gastrointestinal complaints. Because of nonspecific symptoms, clinical diagnosis can be difficult; hence, imaging plays an important role. A major complication is splenic torsion, which is the cause of acute abdomen. We present a case of acute abdominal pain due to torsion of wandering spleen in a patient with Marfan Syndrome, valvular heart disease, and vertebral anomalies. Preoperative diagnosis was made on the basis of ultrasonography and computed tomography, which was later confirmed on surgery, and treated successfully.

  6. Epidural Anesthesia for Cesarean Section in a Pregnant Woman with Marfan Syndrome and Dural Ectasia.

    PubMed

    Pepe, Franco; Stracquadanio, Mariagrazia; De Luca, Francesco; Privitera, Agata; Sanalitro, Elisabetta; Scarpinati, Puccio

    2017-01-01

    Marfan syndrome (MFS) is a genetic disorder of connective tissue, characterized by variable clinical features and multisystem complications. The anesthetic management during delivery is debated. Regional anesthesia has been used with success during cesarean delivery, but in some MFS patients there is a probability of erratic and inadequate spread of intrathecal local anesthetics as a result of dural ectasia. In these cases, epidural anesthesia may be a particularly useful technique during cesarean delivery because it allows an adequate spread and action of local anesthetic with a controlled onset of anesthesia, analgesia, and sympathetic block and a low risk of perioperative complications. We report the perioperative management of a patient with MFS and dural ectasia who successfully underwent cesarean section using epidural technique anesthesia. The previous pregnancy of this woman ended with cesarean section with a failed spinal anesthesia that was converted to general anesthesia due to unknown dural ectasia at that time.

  7. Novel FBN1 mutation causes Marfan syndrome with bilateral ectopia lentis and refractory glaucoma.

    PubMed

    Milla, Elena; Leszczynska, Ania; Rey, Amanda; Navarro, Manuel; Larena, Concepcion

    2012-01-01

    We report the case of a 41-year-old woman with bilateral lens subluxation and medically uncontrolled glaucoma in whom Marfan syndrome (MFS) was diagnosed. The patient underwent complete clinical eye and systemic examinations and blood samples were drawn for mutational screening of fibrillin 1 gene (FBN1). The patient was diagnosed with MFS on a clinical basis and according to the Ghent criteria and the genetic testing revealed a novel heterozygous mutation in the FBN1 gene. The patient required pars plana vitrectomy with lensectomy and Ahmed valve implantation in the vitreous cavity to control her severe glaucoma. The diagnosis of a bilateral lens luxation must be followed by complete systemic examination and genetic analysis of the FBN1 gene in order to discard MFS due to its severe systemic complications. Frequently, the condition causes an aggressive secondary glaucoma that requires surgical treatment with lensectomy, vitrectomy, and drainage device implantation in order to avoid its devastating progression toward glaucomatous optic atrophy.

  8. Losartan, an AT1 Antagonist, Prevents Aortic Aneurysm in a Mouse Model of Marfan Syndrome

    PubMed Central

    Habashi, Jennifer P.; Judge, Daniel P.; Holm, Tammy M.; Cohn, Ronald D.; Loeys, Bart L.; Cooper, Timothy K.; Myers, Loretha; Klein, Erin C.; Liu, Guosheng; Calvi, Carla; Podowski, Megan; Neptune, Enid R.; Halushka, Marc K.; Bedja, Djahida; Gabrielson, Kathleen; Rifkin, Daniel B.; Carta, Luca; Ramirez, Francesco; Huso, David L.; Dietz, Harry C.

    2006-01-01

    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. PMID:16601194

  9. The roles of two novel FBN1 gene mutations in the genotype-phenotype correlations of Marfan syndrome and ectopia lentis patients with marfanoid habitus.

    PubMed

    Li, Dan; Yu, Jie; Gu, Feng; Pang, Xiuqin; Ma, Xixin; Li, Rong; Liu, Ningpu; Ma, Xu

    2008-06-01

    Mutations in the fibrillin-1 (FBN1) gene have been identified in patients with Marfan syndrome (MFS) and Marfan-like connective tissue disorders. In this study, two Chinese families were recruited. The patients in family 1 were well characterized with MFS, while those in family 2 displayed Marfan-like disorders such as ectopia lentis (EL) and marfanoid habitus, but did not develop cardiovascular diseases. We aimed to analyze the pathogenic mutations and their relationships with phenotypes in these two Chinese families. All participants underwent complete physical, ophthalmic, and cardiovascular examinations. The 65 exons and flanking intronic sequences of FBN1 were amplified by polymerase chain reaction, and screened for mutations by denaturing high-performance liquid chromatography and sequencing. One hundred and fifteen unrelated controls were analyzed using the same methods to confirm the mutations. In family 1, we identified the mutation p.C499S in the calcium-binding epidermal growth factor (cbEGF)-like domain 3 of FBN1. In family 2, the mutation p.C908Y was identified in an interdomain region of the hybrid motif 2 linked to the cbEGF-like domain 10. It can be concluded that FBN1 mutations involving cysteine substitutions are usually associated with MFS and EL with some MFS features. Moreover, pathology seemed more serious when the mutations disrupted the three disulfide bridges in the cbEGF-like domains, which was more likely to cause typical MFS than if the mutations occurred in the hybrid motifs. Our data preliminarily establish a genotype-phenotype correlation in the diagnostic process of MFS and predominant EL with Marfan-like features.

  10. Effect of personalized external aortic root support on aortic root motion and distension in Marfan syndrome patients.

    PubMed

    Izgi, Cemil; Nyktari, Evangelia; Alpendurada, Francisco; Bruengger, Annina Studer; Pepper, John; Treasure, Tom; Mohiaddin, Raad

    2015-10-15

    Personalized external aortic root support (PEARS) is a novel surgical approach with the aim of stabilizing the aortic root size and decreasing risk of dissection in Marfan syndrome patients. A bespoke polymer mesh tailored to each patient's individual aorta shape is produced by modeling and then surgically implanted. The aim of this study is to assess the mechanical effects of PEARS on the aortic root systolic downward motion (an important determinant of aortic wall stress), aortic root distension and on the left ventricle (LV). A cohort of 27 Marfan patients had a prophylactic PEARS surgery between 2004 and 2012 with 24 having preoperative and follow-up cardiovascular magnetic resonance imaging studies. Systolic downward aortic root motion, aortic root distension, LV volumes/mass and mitral annular systolic excursion before the operation and in the latest follow-up were measured randomly and blinded. After a median follow-up of 50.5 (IQR 25.5-72) months following implantation of PEARS, systolic downward motion of aortic root was significantly decreased (12.6±3.6mm pre-operation vs 7.9±2.9mm latest follow-up, p<0.00001). There was a tendency for a decrease in systolic aortic root distension but this was not significant (median 4.5% vs 2%, p=0.35). There was no significant change in LV volumes, ejection fraction, mass and mitral annular systolic excursion in follow-up. PEARS surgery decreases systolic downward aortic root motion which is an important determinant of longitudinal aortic wall stress. Aortic wall distension and Windkessel function are not significantly impaired in the follow-up after implantation of the mesh which is also supported by the lack of deterioration of LV volumes or mass. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

  11. The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele.

    PubMed

    Aubart, Mélodie; Gross, Marie-Sylvie; Hanna, Nadine; Zabot, Marie-Thérèse; Sznajder, Marc; Detaint, Delphine; Gouya, Laurent; Jondeau, Guillaume; Boileau, Catherine; Stheneur, Chantal

    2015-05-15

    Marfan syndrome is an autosomal dominant disorder mainly caused by mutations within FBN1 gene. The disease displays large variability in age of onset or severity and very poor phenotype/genotype correlations have been demonstrated. We investigated the hypothesis that phenotype severity could be related to the variable expression level of fibrillin-1 (FBN1) synthesized from the wild-type (WT) allele. Quantitative reverse-transcription and polymerase chain reaction was used to evaluate FBN1 levels in skin fibroblasts from 80 Marfan patients with premature termination codons and in skin fibroblasts from 80 controls. Results in controls showed a 3.9-fold variation in FBN1 mRNA synthesis level between subjects. A similar 4.4-fold variation was found in the Marfan population, but the mean level of FBN1 mRNA was a half of the control population. Differential allelic expression analysis in Marfan fibroblasts showed that over 90% of FBN1 mRNA was transcribed from the wild allele and the mutated allele was not detected. In the control population, independently of the expression level of FBN1, we observed steady-state equilibrium between the two allelic-mRNAs suggesting that FBN1 expression mainly depends on trans-acting regulators. Finally, we show that a low level of residual WT FBN1 mRNA accounts for a high risk of ectopia lentis and pectus abnormality and tends to increase the risk of aortic dilatation.

  12. Multi-Scale Biomechanical Remodeling in Aging and Genetic Mutant Murine Mitral Valve Leaflets: Insights into Marfan Syndrome

    PubMed Central

    Gould, Russell A.; Sinha, Ravi; Aziz, Hamza; Rouf, Rosanne; Dietz, Harry C.; Judge, Daniel P.; Butcher, Jonathan

    2012-01-01

    Mitral valve degeneration is a key component of the pathophysiology of Marfan syndrome. The biomechanical consequences of aging and genetic mutation in mitral valves are poorly understood because of limited tools to study this in mouse models. Our aim was to determine the global biomechanical and local cell-matrix deformation relationships in the aging and Marfan related Fbn1 mutated murine mitral valve. To conduct this investigation, a novel stretching apparatus and gripping method was implemented to directly quantify both global tissue biomechanics and local cellular deformation and matrix fiber realignment in murine mitral valves. Excised mitral valve leaflets from wild-type and Fbn1 mutant mice from 2 weeks to 10 months in age were tested in circumferential orientation under continuous laser optical imaging. Mouse mitral valves stiffen with age, correlating with increases in collagen fraction and matrix fiber alignment. Fbn1 mutation resulted in significantly more compliant valves (modulus 1.34±0.12 vs. 2.51±0.31 MPa, respectively, P<.01) at 4 months, corresponding with an increase in proportion of GAGs and decrease in elastin fraction. Local cellular deformation and fiber alignment change linearly with global tissue stretch, and these slopes become more extreme with aging. In comparison, Fbn1 mutated valves have decoupled cellular deformation and fiber alignment with tissue stretch. Taken together, quantitative understanding of multi-scale murine planar tissue biomechanics is essential for establishing consequences of aging and genetic mutations. Decoupling of local cell-matrix deformation kinematics with global tissue stretch may be an important mechanism of normal and pathological biomechanical remodeling in valves. PMID:22984535

  13. Bilateral Implantation of Scleral-Fixated Cionni Endocapsular Rings and Toric Intraocular Lenses in a Pediatric Patient with Marfan's Syndrome

    PubMed Central

    Gimbel, Howard V.; Camoriano, Gerardo D.; Aman-Ullah, Muhammad

    2012-01-01

    The management of ectopia lentis in Marfan's syndrome is challenging. Multiple disease-associated factors conspire to deprive these patients of adequate vision. While optical correction with glasses and contact lenses is usually advocated early on, the irregular astigmatism and even partial aphakia that accompanies advanced cases generally warrant surgical intervention. Several surgical strategies have been devised to manage these challenging cases, including the combination of endocapsular or pars plana lensectomy and iris or scleral fixation of the intraocular lens (IOL) or IOL-bag complex. All of the reported cases have been implanted with IOLs that correct for myopia only. With toric lenses, it is now possible to correct for corneal astigmatism in these patients as well, provided that the capsular bag is maintained and can be properly centered. We report the combination of scleral-fixated Cionni endocapsular rings and toric IOLs in a pediatric patient with bilateral ectopia lentis secondary to Marfan's syndrome. PMID:22615696

  14. Repair of Multiple Subclavian and Axillary Artery Aneurysms in a 58-Year-Old Man with Marfan Syndrome

    PubMed Central

    Dolapoglu, Ahmet; Preventza, Ourania; Coselli, Joseph S.

    2016-01-01

    Dilation of the ascending aorta and aortic dissections are often seen in Marfan syndrome; however, true aneurysms of the subclavian and axillary arteries rarely seem to develop in patients who have this disease. We present the case of a 58-year-old man with Marfan syndrome who had undergone a Bentall procedure and thoracoabdominal aortic repair for an aortic dissection and who later developed multiple aneurysmal dilations of his right subclavian and axillary arteries. The aneurysms were successfully repaired by means of a surgical bypass technique in which a Dacron graft was placed between the carotid and brachial arteries. We also discuss our strategy for determining the optimal surgical approach in these patients. PMID:27777529

  15. Repair of Multiple Subclavian and Axillary Artery Aneurysms in a 58-Year-Old Man with Marfan Syndrome.

    PubMed

    Dolapoglu, Ahmet; de la Cruz, Kim I; Preventza, Ourania; Coselli, Joseph S

    2016-10-01

    Dilation of the ascending aorta and aortic dissections are often seen in Marfan syndrome; however, true aneurysms of the subclavian and axillary arteries rarely seem to develop in patients who have this disease. We present the case of a 58-year-old man with Marfan syndrome who had undergone a Bentall procedure and thoracoabdominal aortic repair for an aortic dissection and who later developed multiple aneurysmal dilations of his right subclavian and axillary arteries. The aneurysms were successfully repaired by means of a surgical bypass technique in which a Dacron graft was placed between the carotid and brachial arteries. We also discuss our strategy for determining the optimal surgical approach in these patients.

  16. Marfan syndrome with antineutrophil cytoplasmic antibody-associated systemic vasculitis presenting as severe anaemia and haematuria after the Bentall procedure.

    PubMed

    Sijia, Li; Shuangxin, Liu; Wei, Shi; Yanhai, Cui

    2013-08-01

    One month previously, a 28-year old male underwent an emergency modified Bentall procedure because of Marfan syndrome with acute aortic dissection Stanford Class A. Computed tomography of the chest did not reveal severe graft stenosis of the anastomosis. To explore the cause of anaemia, renal dysfunction and macroscopic haematuria, the patient was tested for antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis (AASV). Antimyeloperoxidase antibodies (MPO)-ANCA and antiproteinase 3 antibodies (PR3)-ANCA were strongly positive. Corticosteroid therapy was applied, followed by cyclophosphamide and azathioprine. In response to treatment, the MPO-ANCA and PR3-ANCA levels gradually decreased, proteinuria was alleviated and haemoglobin levels returned to normal after 6 months. This is the first report to highlight haemolytic anaemia and AASV with Marfan syndrome after surgery for aortic dissection.

  17. Retropupillary iris-claw intraocular lens in ectopia lentis in Marfan syndrome

    PubMed Central

    Faria, Mun Yueh; Ferreira, Nuno; Neto, Eliana

    2016-01-01

    Objective To report visual outcomes, complication rate, and safety of retropupillary iris-claw intraocular lens (ICIOL) in ectopia lentis in Marfan syndrome (MFS). Design Retrospective study. Methods Six eyes of three MFS patients with ectopia lentis underwent surgery for subluxation lens and retropupillary ICIOL implantation from October 2014 to October 2015 at the Department of Ophthalmology, Santa Maria Hospital in Lisbon, Portugal. Demographics, preoperative and postoperative best-corrected visual acuity (BCVA), and intraocular pressure were evaluated. Endothelium cell count was assessed using specular microscopy; anterior chamber depth was measured using Pentacam postoperatively; and intraocular lens position was viewed by ultrasound biomicroscopy. All patients were female; mean age was 20±14.264 years (range: 7–38 years). Results The average follow-up period was 6.66 months (range: 4–16 months). Preoperative BCVA was 0.568±0.149 logMAR units, and postoperative BCVA was 0.066±0.121 logMAR units. The mean BCVA gain was −0.502±0.221 on the logMAR scale. Postoperative average astigmatism and intraocular pressure were 1.292±0.697 mmHg (range: 0.5–2.25 mmHg) and 16 mmHg (range: 12–18 mmHg), respectively. The average endothelial cell density decreased from 3,121±178 cells/mm2 before surgery to 2,835±533 cells/mm2 after surgery (measured at last follow-up visit) and in the last follow-up, representing an average endothelial cell loss of 9.16%. Mean anterior chamber depth was 4.01 mm (±0.77 mm), as measured by Pentacam. No complications were found intra- or postoperatively in any of the six studied eyes. Conclusion Retropupillary ICIOL implantation is a safe and effective procedure in the treatment of aphakia in MFS eyes, without capsular support after surgery for ectopia lens. The six eyes that underwent lensectomy and retropupillary ICIOL implantation have had excellent visual outcomes with no complications so far. PMID:27382335

  18. Pelvic pain from a giant presacral Tarlov cyst successfully obliterated using aneurysm clips in a patient with Marfan syndrome.

    PubMed

    Wang, Bonnie; Moon, Seong-Jin; Olivero, William C; Wang, Huan

    2014-11-01

    Patients with Marfan syndrome used to succumb early in life from cardiovascular complications. With the current rapid advance in medical and surgical care, such patients may now have near-normal longevities. Consequently, rare late-life complications are emerging in these patients and represent challenges to clinicians for their diagnoses and treatments. The authors report a rare case of pelvic pain and genital prolapse from a giant presacral Tarlov cyst in a 67-year-old patient with Marfan syndrome. This 67-year-old Caucasian female presented with progressively severe pelvic pain, intermittent explosive diarrhea, and dysuria. Physical and bimanual examination demonstrated genital prolapse and a nontender, cyst-like mass fixed in the midline. She underwent ultrasound, CT, and eventually MRI evaluations that led to the diagnosis of a giant (6.7 × 6.4 × 6.6 cm) Tarlov cyst originating from the right S-2 nerve root sleeve/sacral foramen with intrapelvic extension. She underwent S1-S2 and S2-S3 laminectomy with obliteration of the Tarlov cyst using aneurysm clips. Postoperatively, her pelvic pain and bowel symptoms resolved and the bladder symptoms improved. The 3-month follow-up CT of abdomen/pelvis demonstrated resolution of the cyst. The present case illustrates that clinicians caring for elderly patients with Marfan syndrome need to increasingly recognize such unusual late-life complications. Also, these large Tarlov cysts can be simply and effectively obliterated with aneurysm clips.

  19. Lens coloboma in one eye and ectopia lentis in the other eye of a patient with Marfan syndrome.

    PubMed

    Thapa, Bikram Bahadur; Singh, Ramandeep; Ram, Jagat; Kumar, Abiraj

    2014-12-09

    We present a case of Marfan syndrome with lens coloboma in one eye and ectopia lentis in the other. A 14-year-old girl reported decreased vision in the left eye. Her visual acuity was 6/24 and counting fingers at 1 m in the right and left eyes, respectively. Her intraocular pressure was 15 mm Hg in both eyes. Evaluation of the right eye on slit lamp biomicroscopy under mydriasis revealed an inferiorly visible flattened and concave crystalline lens equator from 4 to 8 o'clock position along with notching and absence of zonules, suggestive of lens coloboma. Left eye examination revealed a superiorly subluxated lens from 3 to 9 o'clock position and posterior subcapsular cataract. The posterior segment evaluation of both eyes was normal. Her father, aunt and grandfather were of tall stature, characteristic of Marfan syndrome. On systemic evaluation, the patient was diagnosed as Marfan syndrome. After surgical correction she achieved vision of 6/6 in both eyes.

  20. Analysis of TGFBR1*6A variant in individuals evaluated for Marfan syndrome.

    PubMed

    Somers, Allyson E; Hinton, Robert B; Pilipenko, Valentina; Miller, Erin; Ware, Stephanie M

    2016-07-01

    Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are genetic disorders that affect connective tissue as a result of dysregulated TGF-β signaling. MFS is most frequently caused by mutations in FBN1 whereas Loeys-Dietz syndrome results from mutations in TGFBR1 or TGFBR2. There is substantial inter- and intra-familial phenotypic variability among these disorders, suggesting the presence of genetic modifiers. Previously, a polymorphism in the TGFβR1 protein termed the TFGBR1*6A allele was found to be overrepresented in patients with MFS and was identified as a low penetrance allele with suggestion as a possible modifier. To further investigate the importance of this variant, a retrospective review of genetic and phenotypic findings was conducted for 335 patients evaluated for suspicion of MFS or related disorders. In patients with a diagnosis of MFS, the presence of the TFGBR1*6A allele was not associated with phenotypic differences. Similarly, careful phenotyping of patients who carried the TFGBR1*6A allele but did not have MFS did not identify an altered frequency of specific connective tissue features. In this small cohort, the results did not reach significance to identify the TFGBR1*6A allele as a major modifier for aortic dilation, ectopia lentis, or systemic features associated with MFS or other connective tissue disorders. © 2016 Wiley Periodicals, Inc.

  1. Gene polymorphisms as risk factors for predicting the cardiovascular manifestations in Marfan syndrome. Role of folic acid metabolism enzyme gene polymorphisms in Marfan syndrome.

    PubMed

    Benke, Kálmán; Ágg, Bence; Mátyás, Gábor; Szokolai, Viola; Harsányi, Gergely; Szilveszter, Bálint; Odler, Balázs; Pólos, Miklós; Maurovich-Horvat, Pál; Radovits, Tamás; Merkely, Béla; Nagy, Zsolt B; Szabolcs, Zoltán

    2015-10-01

    Folic acid metabolism enzyme polymorphisms are believed to be responsible for the elevation of homocysteine (HCY) concentration in the blood plasma, correlating with the pathogenesis of aortic aneurysms and aortic dissection. We studied 71 Marfan patients divided into groups based on the severity of cardiovascular involvement: no intervention required (n=27, Group A); mild involvement requiring intervention (n=17, Group B); severe involvement (n=27, Group C) subdivided into aortic dilatation (n=14, Group C1) and aortic dissection (n=13, Group C2), as well as 117 control subjects. We evaluated HCY, folate, vitamin B12 and the polymorphisms of methylenetetrahydrofolate reductase (MTHFR;c.665C>T and c.1286A>C), methionine synthase (MTR;c.2756A>G) and methionine synthase reductase (MTRR;c.66A>G). Multiple comparisons showed significantly higher levels of HCY in Group C2 compared to Groups A, B, C1 and control group (p<0.0001, p<0.0001, p=0.001 and p=0.003, respectively). Folate was lower in Group C2 than in Groups A, B, C1 and control subjects (p<0.0001, p=0.02, p<0.0001 and p<0.0001, respectively). Group C2 had the highest prevalence of homozygotes for all four gene polymorphisms. Multivariate logistic regression analysis revealed that HCY plasma level was an independent risk factor for severe cardiovascular involvement (Group C; odds ratio [OR] 1.85, 95% confidence interval [CI] 1.28-2.67, p=0.001) as well as for aortic dissection (Group C2; OR 2.49, 95%CI 1.30-4.78, p=0.006). In conclusion, severe cardiovascular involvement in Marfan patients, and especially aortic dissection, is associated with higher HCY plasma levels and prevalence of homozygous genotypes of folic acid metabolism enzymes than mild or no cardiovascular involvement. These results suggest that impaired folic acid metabolism has an important role in the development and remodelling of the extracellular matrix of the aorta.

  2. Decrease in pulmonary artery pressure after administration of thoracic epidural anesthesia in a patient with Marfan syndrome awaiting aortic valve replacement procedure.

    PubMed

    Chakravarthy, Murali; Jawali, Vivek; Patil, Timmannagowda; Krishnamoorthy, Jayaprakash

    2011-08-01

    Thoracic epidural anesthesia is an adjunct to general anesthesia in cardiac surgery. Decrease in heart rate and blood pressure are frequently seen beneficial effects. There are several other hemodynamic effects of thoracic epidural anesthesia such as decrease in systemic vascular resistance, cardiac index, left ventricular stroke work index among others. However, the effect of thoracic epidural anesthesia on pulmonary artery pressure (PAP) has not been studied extensively in humans. Thoracic epidural anes-thesia decreased pulmonary artery pressure in experimen-tally induced pulmonary hypertension in animals. The mechanisms involved in such reduction are ill understood. We describe in this report, a significant reduction in PAP in a patient with Marfan's syndrome scheduled to under-go aortic valve replacement. The possible mechanisms of decrease in pulmonary artery pressure in the described case are, decrease in the venous return to the heart, decrease in the systemic vascular resistance, decrease in the right ventric-ular function and finally, improvement in myocardial contraction secondary to all the above. The possibility of Marfan's syndrome contributing to the decrease in PAP appears remote. The authors present this case to generate discussion about the possible mechanisms involved in thoracic epidural anesthesia producing beneficial effects in patients with secondary pulmonary hypertension. Thoracic epidural anesthesia appears to decrease pulmonary artery pressure by a combination of several mechanisms, some unknown to us. This occurrence, if studied and understood well could be put to clinical use in pulmonary hypertensives.

  3. Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy.

    PubMed

    Lacro, Ronald V; Guey, Lin T; Dietz, Harry C; Pearson, Gail D; Yetman, Anji T; Gelb, Bruce D; Loeys, Bart L; Benson, D Woodrow; Bradley, Timothy J; De Backer, Julie; Forbus, Geoffrey A; Klein, Gloria L; Lai, Wyman W; Levine, Jami C; Lewin, Mark B; Markham, Larry W; Paridon, Stephen M; Pierpont, Mary Ella; Radojewski, Elizabeth; Selamet Tierney, Elif Seda; Sharkey, Angela M; Wechsler, Stephanie Burns; Mahony, Lynn

    2013-05-01

    The Pediatric Heart Network designed a clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in children and young adults with Marfan syndrome randomized to receive atenolol or losartan. We report here the characteristics of the screened population and enrolled subjects. Between 2007 and 2011, 21 clinical sites randomized 608 subjects, aged 6 months to 25 years who met the original Ghent criteria and had a body surface area-adjusted aortic root diameter z-score >3.0. The mean age at study entry was 11.2 years, 60% were male, and 25% were older teenagers and young adults. The median aortic root diameter z-score was 4.0. Aortic root diameter z-score did not vary with age. Mitral valve prolapse and mitral regurgitation were more common in females. Among those with a positive family history, 56% had a family member with aortic surgery, and 32% had a family member with a history of aortic dissection. Baseline demographic, clinical, and anthropometric characteristics of the randomized cohort are representative of patients in this population with moderate to severe aortic root dilation. The high percentage of young subjects with relatives who have had aortic dissection or surgery illustrates the need for more definitive therapy; we expect that the results of the study and the wealth of systematic data collected will make an important contribution to the management of individuals with Marfan syndrome. Copyright © 2013 Mosby, Inc. All rights reserved.

  4. Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy

    PubMed Central

    Lacro, Ronald V.; Guey, Lin T.; Dietz, Harry C.; Pearson, Gail D.; Yetman, Anji T.; Gelb, Bruce D.; Loeys, Bart L.; Benson, D. Woodrow; Bradley, Timothy J.; De Backer, Julie; Forbus, Geoffrey A.; Klein, Gloria L.; Lai, Wyman W.; Levine, Jami C.; Lewin, Mark B.; Markham, Larry W.; Paridon, Stephen M.; Pierpont, Mary Ella; Radojewski, Elizabeth; Selamet Tierney, Elif Seda; Sharkey, Angela M.; Wechsler, Stephanie Burns; Mahony, Lynn

    2013-01-01

    Background The Pediatric Heart Network designed a clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in children and young adults with Marfan syndrome randomized to receive atenolol or losartan. We report here the characteristics of the screened population and enrolled subjects. Methods and results Between 2007 and 2011, 21 clinical sites randomized 608 subjects, aged 6 months to 25 years who met the original Ghent criteria and had a body surface area–adjusted aortic root diameter z-score >3.0. The mean age at study entry was 11.2 years, 60% were male, and 25% were older teenagers and young adults. The median aortic root diameter z-score was 4.0. Aortic root diameter z-score did not vary with age. Mitral valve prolapse and mitral regurgitation were more common in females. Among those with a positive family history, 56% had a family member with aortic surgery, and 32% had a family member with a history of aortic dissection. Conclusions Baseline demographic, clinical, and anthropometric characteristics of the randomized cohort are representative of patients in this population with moderate to severe aortic root dilation. The high percentage of young subjects with relatives who have had aortic dissection or surgery illustrates the need for more definitive therapy; we expect that the results of the study and the wealth of systematic data collected will make an important contribution to the management of individuals with Marfan syndrome. PMID:23622922

  5. Postmortem diagnosis of Marfan syndrome in a case of sudden death due to aortic rupture: Detection of a novel FBN1 frameshift mutation.

    PubMed

    Wang, Yunyun; Chen, Shu; Wang, Rongshuai; Huang, Sizhe; Yang, Mingzhen; Liu, Liang; Liu, Qian

    2016-04-01

    To investigate the sudden death of a 36-year-old Chinese man, a medicolegal autopsy was performed, combining forensic pathological examinations and genetic sequencing analysis to diagnose the cause of death. Genomic DNA samples were extracted from blood and subjected to high-throughput sequencing. Major findings included a dilated aortic root with a ruptured and dissected aorta and consequent tamponade of the pericardial sac. Moreover, arachnodactyly and other skeletal deformities were noted. By sequencing the fibrillin-1 gene (FBN1), five genetic variations were found, including four previously known single nucleotide polymorphisms (SNPs) and a novel frameshift mutation, leading to the diagnosis of Marfan syndrome. The frameshift mutation (c.4921delG, p.glu1641llysFsX9) detected in exon 40 led to a stop codon after the next 8 amino acids. The four SNPs included a splice site mutation (c.3464-5 G>A, rs11853943), a synonymous mutation (p.Asn625Asn, rs25458), and two missense mutations (p.Pro1148Ala, rs140598; p.Cys472Tyr, rs4775765). Genetic screening was recommended for the relatives as it was reported that the father and brother of the deceased had died at the ages of 40 and 25, respectively, from sudden cardiac failure. The son of the deceased lacked the relevant mutations. This report emphasizes the important contribution of medicolegal postmortem analysis on the molecular pathogenesis study of Marfan syndrome and early diagnosis of at-risk relatives.

  6. High incidence and severity of periodontitis in patients with Marfan syndrome in Japan.

    PubMed

    Suzuki, Jun-Ichi; Imai, Yasushi; Aoki, Mieko; Fujita, Daishi; Aoyama, Norio; Tada, Yuko; Akazawa, Hiroshi; Izumi, Yuichi; Isobe, Mitsuaki; Komuro, Issei; Nagai, Ryozo; Hirata, Yasunobu

    2015-09-01

    Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the extracellular matrix protein fibrillin-1. While it is known that patients with MFS are at high risk of dental disorders and cardiovascular diseases, little information has been provided to date. To clarify the prevalence of periodontitis in patients with MFS, their oral condition and cardiovascular complications were evaluated. The subjects were patients with MFS (n = 40) who attended the University of Tokyo hospital; age- and gender-matched healthy individuals (n = 14) constituted a control group. Cardiovascular complications and full-mouth clinical measurements, including number of teeth, probing of pocket depth (PD), bleeding on probing (BOP), and community periodontal index (CPI) were recorded. MFS patients had more frequent cardiovascular complications (95 %) compared with the controls (0 %). MFS patients had periodontitis (CPI 3 and 4) more frequently (87.5 %) than the age- and gender-matched control subjects (35.7 %). Furthermore, MFS patients had significantly more severe periodontitis (CPI 2.90 ± 0.12 vs 1.64 ± 0.32) and fewer remaining teeth (26.7 ± 0.4 vs 28.4 ± 0.4) compared with the controls. However, PD and BOP were comparable between MFS patients and the control group. A high incidence of periodontitis and cardiovascular complications was observed in Japanese MFS patients.

  7. [Marfan syndrome complicated with CD5+ CD10+ diffuse large B-cell lymphoma].

    PubMed

    Yoshitake, Kumiko; Hagiwara, Yuki; Tanae, Ken; Takahashi, Naoki; Kohri, Mika; Tamaru, Jun-ichi; Bessho, Masami; Niitsu, Nozomi

    2010-03-01

    Marfan syndrome (MFS) is caused by mutations in the gene encoding fibrillin. A 35-year-old man with MFS visited a local physician because of a sore throat. His left tonsil gradually became swollen and he was referred to our department. Histopathological examination of tonsil biopsy specimens showed diffuse proliferation of lymphoma cells with large nuclei. The tumor cells showed CD5+, CD10+, CD20+, BCL-6+, and MUM-1-. Based on these findings, the patient was diagnosed with CD5+ CD10+ diffuse large B-cell lymphoma (DLBCL). Chemotherapy combined with rituximab was administered and complete response was achieved. CD5+ DLBCL comprises approximately 5 approximately 10% of DLBCLs. In addition, CD5+ CD10+ DLBCL comprises about 5% of CD5+ DLBCLs. There may be a relationship between MFS and B-cell lymphoma because mutations in the gene encoding the receptor of transforming growth factor-beta (TGF-beta) have been implicated in the pathogenesis of MFS and downregulation of TGF-beta receptor expression has been described in the pathology of B-cell lymphoma.

  8. Periodontitis May Deteriorate Sinus of Valsalva Dilatation in Marfan Syndrome Patients.

    PubMed

    Suzuki, Jun-Ichi; Imai, Yasushi; Aoki, Mieko; Fujita, Daishi; Takeda, Norifumi; Aoyama, Norio; Wakayama, Kouji; Ikeda, Yuichi; Kumagai, Hidetoshi; Akazawa, Hiroshi; Izumi, Yuichi; Isobe, Mitsuaki; Komuro, Issei; Hirata, Yasunobu

    2016-07-27

    Marfan syndrome (MFS) is a systemic connective tissue disorder that is caused by mutations of fibrillin-1. While MFS patients are at a high risk of periodontitis and aortic diseases, little causal information has been provided to date. To clarify the relationship, their oral condition and sinus of Valsalva (SoV) were evaluated.The subjects were patients with MFS (n = 33) who attended the University of Tokyo Hospital. We divided them into two groups; MFS patients with highly dilated (the diameters were equal to or more than 39 mm) SoV (high group, n = 18) and MFS patients with mildly dilated (less than 39 mm) SoV (mild group, n = 15). Blood examinations, echocardiograms, and full-mouth clinical measurements, including number of teeth, probing pocket depth (PPD), bleeding on probing (BOP), and community periodontal index (CPI) were performed.We found that the high group patients had greater rates of BOP compared to that of the mild group. Furthermore, the high group tended to have higher serum levels of C-reactive protein, matrix metalloproteinase-9, and transforming growth factor-β compared to the mild group.Periodontitis may deteriorate SoV dilatation in MFS patients.

  9. [Management of delivery in patients with Marfan's syndrome presenting aortic dilatation].

    PubMed

    Abecassis, P; Lecinq, A; Roger-Christoph, S; Mercier, F-J; Benhamou, D

    2004-09-01

    We report the anesthesic and obstetrical management of two pregnant patients with Marfan's syndrome. An important dilatation of the root of aorta was established at the beginning of the pregnancy. Based on a review of the literature and our experience, we searched for clues to identify the ideal term and the best mode of delivery, and which type of anesthesia may be the more appropriate in patients with aortic dilatation. No consensus can be found in the literature as far as anesthesia and obstetric management of these patients is concerned. Pregnancy must be continued as long as possible to ensure adequate fetal growth but fetal extraction should not be delayed if the diameter of the aorta enlarges too much. A diameter of 40 mm is probably the higher limit to accept for vaginal delivery. Beyond, cautious cesarean section would be advisable. In the absence of dural ectasia or a technical problem, neuraxial anesthesia is a good option. According to the severity of the aortic dilatation and its evolution, specific management, based on good cooperation between obstetricians and anesthesiologists, is the key of a successful and safe childbirth.

  10. Imaging, Endoscopic and Genetic Assessment of Marfan Syndrome Presenting with Sigmoid Volvulus: A Review.

    PubMed

    Inayat, Faisal; Hurairah, Abu; Shaikh, Faiq

    2016-05-21

    The Marfan syndrome (MFS) is a pleiotropic, autosomal dominant disorder of connective tissue with highly variable clinical manifestations. It primarily involves the skeletal, cardiovascular, and ocular systems; however, gastrointestinal complications are rare. Herein, we describe the case of a 31-year-old male who initially presented with acute abdominal pain for one day. His imaging features revealed a dilated sigmoid colon, consistent with sigmoid volvulus that was immediately decompressed. Surgical resection was recommended to treat the sigmoid volvulus. Preceding the treatment, the patient underwent an extensive workup, including an echocardiography that revealed aortic root dilatation. His clinical history, physical exam, and echocardiographic findings raised the suspicion for MFS. Subsequently, the diagnosis of MFS was confirmed on genetic testing. This is a case that highlights the multidisciplinary (clinical, radiological, endoscopic, molecular/genetic) approach to diagnose a patient with MFS who presented with symptomatic sigmoid volvulus. As this presentation may be a harbinger of more severe manifestations of MFS, it is important to identify it as such in order to accomodate for timely management.

  11. Identification of fibrillin 1 gene mutations in patients with bicuspid aortic valve (BAV) without Marfan syndrome.

    PubMed

    Pepe, Guglielmina; Nistri, Stefano; Giusti, Betti; Sticchi, Elena; Attanasio, Monica; Porciani, Cristina; Abbate, Rosanna; Bonow, Robert O; Yacoub, Magdi; Gensini, Gian Franco

    2014-02-24

    Bicuspid aortic valve (BAV) is the most frequent congenital heart disease with frequent involvement in thoracic aortic dilatation, aneurysm and dissection. Although BAV and Marfan syndrome (MFS) share some clinical features, and some MFS patients with BAV display mutations in FBN1, the gene encoding fibrillin-1, the genetic background of isolated BAV is poorly defined. Ten consecutive BAV patients [8 men, age range 24-42 years] without MFS were clinically characterized. BAV phenotype and function, together with evaluation of aortic morphology, were comprehensively assessed by Doppler echocardiography. Direct sequencing of each FBN1 exon with flanking intron sequences was performed on eight patients. We detected three FBN1 mutations in two patients (aged 24 and 25 years) displaying aortic root aneurysm ≥50 mm and moderate aortic regurgitation. In particular, one patient had two mutations (p.Arg2726Trp and p.Arg636Gly) one of which has been previously associated with variable Marfanoid phenotypes. The other patient showed a pArg529Gln substitution reported to be associated with an incomplete MFS phenotype. The present findings enlarge the clinical spectrum of isolated BAV to include patients with BAV without MFS who have involvement of FBN1 gene. These results underscore the importance of accurate phenotyping of BAV aortopathy and of clinical characterization of BAV patients, including investigation of systemic connective tissue manifestations and genetic testing.

  12. Ectopia lentis as the presenting and primary feature in Marfan syndrome.

    PubMed

    Zadeh, Neda; Bernstein, Jonathan A; Niemi, Anna Kaisa; Dugan, Sarah; Kwan, Andrea; Liang, David; Hyland, James C; Hoyme, H Eugene; Hudgins, Louanne; Manning, Melanie A

    2011-11-01

    Marfan syndrome (MFS) is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems. We report on eight patients, all presenting initially with bilateral ectopia lentis (EL) during early childhood. These individuals did not have systemic manifestations of MFS, and did not fulfill the revised Ghent diagnostic criteria. However, all patients had demonstratable, disease-causing missense mutations in the FBN1 gene. Based on molecular results, cardiovascular imaging was recommended and led to the identification of mild aortic root changes in seven of the eight patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta. The findings presented in this paper validate the necessity of FBN1 gene testing in all individuals presenting with isolated EL. As we observed, these individuals are at increased risk of cardiovascular complications. Furthermore, we also noted that the majority of our patient cohort's mutations occurred in the 5' portion of the FBN1 gene, and were found to affect highly conserved cysteine residues, which may indicate a possible genotype-phenotype correlation. We conclude that in patients with isolated features of EL, FBN1 mutation analysis is necessary to aid in providing prompt diagnosis, and to identify patients at risk for potentially life-threatening complications. Additionally, knowledge of the type and location of an FBN1 mutation may be useful in providing further clinical correlation regarding phenotypic progression and appropriate medical management. Copyright © 2011 Wiley Periodicals, Inc.

  13. Strategies for prenatal and preimplantation genetic diagnosis in Marfan syndrome (MFS).

    PubMed

    Loeys, B; Nuytinck, L; Van Acker, P; Walraedt, S; Bonduelle, M; Sermon, K; Hamel, B; Sanchez, A; Messiaen, L; De Paepe, A

    2002-01-01

    Marfan syndrome (MFS) is an autosomal dominant disorder with a prevalence of 2-3 per 10 000 individuals. Symptoms range from skeletal overgrowth, cutaneous striae to ectopia lentis and aortic dilatation leading to dissection. Prenatal diagnosis was until recently mainly performed in familial cases by linkage analysis. However, mutation detection has become available with thorough screening methods. The phenotypic variability observed in MFS makes reproductive options difficult, as molecular diagnosis cannot predict clinical severity of the disease. Data are presented on 15 prenatal and/or preimplantation genetic diagnoses (PGD) in nine families, originating from Belgium, the Netherlands, Spain and France. In four families data from linkage analysis were used, whereas in five other families the causative FBN1 mutation was characterised. Four PGD cycles in two couples led to one ongoing pregnancy. In addition, two amniocenteses and nine chorionic villus (CV) samplings were performed. In five pregnancies an affected fetus was diagnosed. In one of them, the couple chose to continue the pregnancy and an affected child was born, whereas the other four couples decided to terminate the pregnancy. It is expected that the greater availability of mutation testing of the FBN1 gene will increase requests for prenatal diagnosis. PGD appears to be an acceptable alternative for couples facing ethical reproductive dilemmas. Copyright 2002 John Wiley & Sons, Ltd.

  14. Disease-specific Growth Charts of Marfan Syndrome Patients in Korea.

    PubMed

    Kwun, Younghee; Kim, Su Jin; Lee, Jieun; Isojima, Tsuyoshi; Choi, Doo-Seok; Kim, Duk-Kyung; Huh, June; Kang, I-Seok; Chang, MiSun; Cho, Sung Yoon; Sohn, Young Bae; Park, Sung Won; Jin, Dong-Kyu

    2015-07-01

    Patients with Marfan syndrome (MFS) presents with primary skeletal manifestations such as tall stature, chest wall abnormality, and scoliosis. These primary skeletal manifestations affect the growth pattern in MFS. Therefore, it is not appropriate to use normal growth charts to evaluate the growth status of MFS. We aimed to develop disease-specific growth charts for Korean MFS patients and to use these growth charts for understanding the growth patterns in MFS and managing of patients with MFS. Anthropometric data were available from 187 males and 152 females with MFS through a retrospective review of medical records. Disease-specific growth charts were generated and 3, 25, 50, 75, and 97 percentiles were calculated using the LMS (refers to λ, μ, and σ, respectively) smoothing procedure for height and weight. Comparisons between MFS patients and the general population were performed using a one-sample t-test. With regard to the height, the 50th percentile of MFS is above the normative 97th percentile in both genders. With regard to the weight, the 50 percentile of MFS is above the normative 75th percentile in male and between the normative 50th percentile and the 75th percentile in female. The disease-specific growth charts for Korean patients with MFS can be useful for monitoring growth patterns, planning the timing of growth-reductive therapy, predicting adult height and recording responses to growth-reductive therapy.

  15. Marfan Syndrome: new diagnostic criteria, same anesthesia care? Case report and review.

    PubMed

    Araújo, Maria Rita; Marques, Céline; Freitas, Sara; Santa-Bárbara, Rita; Alves, Joana; Xavier, Célia

    2016-01-01

    Marfan's Syndrome (MFS) is a disorder of connective tissue, mainly involving the cardiovascular, musculoskeletal, and ocular systems. The most severe problems include aortic root dilatation and dissection. Anesthetic management is vital for the improvement on perioperative morbidity. 61-year-old male with MFS, presenting mainly with pectus carinatum, scoliosis, ectopia lens, previous spontaneous pneumothorax and aortal aneurysm and dissection submitted to thoracoabdominal aortic prosthesis placement. Underwent routine laparoscopic cholecystectomy due to lithiasis. Important findings on preoperative examination were thoracolumbar kyphoscoliosis, metallic murmur on cardiac exam. Chest radiograph revealed Cobb angle of 70°. Echocardiogram showed evidence of aortic mechanical prosthesis with no deficits. Preoperative evaluation should focus on cardiopulmonary abnormalities. The anesthesiologist should be prepared for a potentially difficult intubation. Proper positioning and limb support prior to induction is crucial in order to avoid joint injuries. Consider antibiotic prophylaxis for subacute bacterial endocarditis. The patient should be carefully positioned to avoid joint injuries. Intraoperatively cardiovascular monitoring is mandatory: avoid maneuvers that can lead to tachycardia or hypertension, control airway pressure to prevent pneumothorax and maintain an adequate volemia to decrease chances of prolapse, especially if considering laparoscopic surgery. No single intraoperative anesthetic agent or technique has demonstrated superiority. Adequate postoperative pain management is vitally important to avoid the detrimental effects of hypertension and tachycardia. Copyright © 2014 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

  16. Glutathione system participation in thoracic aneurysms from patients with Marfan syndrome.

    PubMed

    Zúñiga-Muñoz, Alejandra María; Pérez-Torres, Israel; Guarner-Lans, Verónica; Núñez-Garrido, Elías; Velázquez Espejel, Rodrigo; Huesca-Gómez, Claudia; Gamboa-Ávila, Ricardo; Soto, María Elena

    2017-05-01

    Aortic dilatation in Marfan syndrome (MFS) is progressive. It is associated with oxidative stress and endothelial dysfunction that contribute to the early acute dissection of the vessel and can result in rupture of the aorta and sudden death. We evaluated the participation of the glutathione (GSH) system, which could be involved in the mechanisms that promote the formation and progression of the aortic aneurysms in MFS patients. Aortic aneurysm tissue was obtained during chest surgery from eight control subjects and 14 MFS patients. Spectrophotometrical determination of activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), lipid peroxidation (LPO) index, carbonylation, total antioxidant capacity (TAC), and concentration of reduced and oxidized glutathione (GSH and GSSG respectively), was performed in the homogenate from aortic aneurysm tissue. LPO index, carbonylation, TGF-β1, and GR activity were increased in MFS patients (p < 0.04), while TAC, GSH/GSSG ratio, GPx, and GST activity were significantly decreased (p < 0.04). The depletion of GSH, in spite of the elevated activity of GR, not only diminished the activity of GSH-depend GST and GPx, but increased LPO, carbonylation and decreased TAC. These changes could promote the structural and functional alterations in the thoracic aorta of MFS patients.

  17. Participation of oleic acid in the formation of the aortic aneurysm in Marfan syndrome patients.

    PubMed

    Soto, María Elena; Iturriaga Hernández, Alejandra Valeria; Guarner Lans, Verónica; Zuñiga-Muñoz, Alejandra; Aranda Fraustro, Alberto; Velázquez Espejel, Rodrigo; Pérez-Torres, Israel

    2016-03-01

    Marfan syndrome (MFS) is associated with progressive aortic dilatation and endothelial dysfunction that lead to early acute dissection and rupture of the aorta and sudden death. Alteration in fatty acid (FA) metabolism can stimulate nitric oxide (NO) overproduction which increases the activity of the inducible form of NO synthase (iNOS) that is involved in endothelial dysfunction. We evaluated the participation of FA in the formation of thoracic aneurysms in MFS and its relation to the iNOS. Oleic acid (OA), iNOS, citrulline, nitrates and nitrites, TGF-β1, TNF-α, monounsaturated FA and NO synthase activity were significantly increased (p<0.05) in tissue from the aortas of MFS. Saturated FA, eNOS and HDL were significantly decreased (p<0.05). Arachidonic acid, delta-9 desaturase tended to increase and histological examination showed an increase in cystic necrosis, elastic fibers and collagen in MFS. The increase in OA contributes to the altered pathway of iNOS, which favors endothelial dysfunction and formation of the aortic aneurysms in MFS. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Identification of fibrillin 1 gene mutations in patients with bicuspid aortic valve (BAV) without Marfan syndrome

    PubMed Central

    2014-01-01

    Background Bicuspid aortic valve (BAV) is the most frequent congenital heart disease with frequent involvement in thoracic aortic dilatation, aneurysm and dissection. Although BAV and Marfan syndrome (MFS) share some clinical features, and some MFS patients with BAV display mutations in FBN1, the gene encoding fibrillin-1, the genetic background of isolated BAV is poorly defined. Methods Ten consecutive BAV patients [8 men, age range 24–42 years] without MFS were clinically characterized. BAV phenotype and function, together with evaluation of aortic morphology, were comprehensively assessed by Doppler echocardiography. Direct sequencing of each FBN1 exon with flanking intron sequences was performed on eight patients. Results We detected three FBN1 mutations in two patients (aged 24 and 25 years) displaying aortic root aneurysm ≥50 mm and moderate aortic regurgitation. In particular, one patient had two mutations (p.Arg2726Trp and p.Arg636Gly) one of which has been previously associated with variable Marfanoid phenotypes. The other patient showed a pArg529Gln substitution reported to be associated with an incomplete MFS phenotype. Conclusions The present findings enlarge the clinical spectrum of isolated BAV to include patients with BAV without MFS who have involvement of FBN1 gene. These results underscore the importance of accurate phenotyping of BAV aortopathy and of clinical characterization of BAV patients, including investigation of systemic connective tissue manifestations and genetic testing. PMID:24564502

  19. Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFβ signaling and cell stemness.

    PubMed

    Ramirez, Francesco; Caescu, Cristina; Wondimu, Elisabeth; Galatioto, Josephine

    2017-08-04

    Mutations in fibrillin-1 cause Marfan syndrome (MFS), the most common heritable disorder of connective tissue. Fibrillin-1 assemblies (microfibrils and elastic fibers) represent a unique dual-function component of the architectural matrix. The first role is structural for they endow tissues with tensile strength and elasticity, transmit forces across them and demarcate functionally discrete areas within them. The second role is instructive in that these macroaggregates modulate a large variety of sub-cellular processes by interacting with mechanosensors, and integrin and syndecan receptors, and by modulating the bioavailability of local TGFβ signals. The multifunctional, tissue-specific nature of fibrillin-1 assemblies is reflected in the variety of clinical manifestations and disease mechanisms associated with the MFS phenotype. Characterization of mice with ubiquitous or cell type-restricted fibrillin-1 deficiency has unraveled some pathophysiological mechanisms associated with the MFS phenotype, such as altered mechanotransduction in the heart, dysregulated TGFβ signaling in the ascending aorta and perturbed stem cell fate in the bone marrow. In each case, potential druggable targets have also been identified. However, the finding that distinct disease mechanisms underlie different organ abnormalities strongly argues for developing multi-drug strategies to mitigate or even prevent both life-threatening and morbid manifestations in pediatric and adult MFS patients. Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

  20. [Marfan Syndrome: new diagnostic criteria, same anesthesia care? Case report and review].

    PubMed

    Araújo, Maria Rita; Marques, Céline; Freitas, Sara; Santa-Bárbara, Rita; Alves, Joana; Xavier, Célia

    2016-01-01

    Marfan's Syndrome (MFS) is a disorder of connective tissue, mainly involving the cardiovascular, musculoskeletal, and ocular systems. The most severe problems include aortic root dilatation and dissection. Anesthetic management is vital for the improvement on perioperative morbidity. 61-year-old male with MFS, presenting mainly with pectus carinatum, scoliosis, ectopia lens, previous spontaneous pneumothorax and aortal aneurysm and dissection submitted to thoracoabdominal aortic prosthesis placement. Underwent routine laparoscopic cholecystectomy due to lithiasis. Important findings on preoperative examination were thoracolumbar kyphoscoliosis, metallic murmur on cardiac exam. Chest radiograph revealed Cobb angle of 70°. Echocardiogram showed evidence of aortic mechanical prosthesis with no deficits. Preoperative evaluation should focus on cardiopulmonary abnormalities. The anesthesiologist should be prepared for a potentially difficult intubation. Proper positioning and limb support prior to induction is crucial in order to avoid joint injuries. Consider antibiotic prophylaxis for subacute bacterial endocarditis. The patient should be carefully positioned to avoid joint injuries. Intraoperatively cardiovascular monitoring is mandatory: avoid maneuvers that can lead to tachycardia or hypertension, control airway pressure to prevent pneumothorax and maintain an adequate volemia to decrease chances of prolapse, especially if considering laparoscopic surgery. No single intraoperative anesthetic agent or technique has demonstrated superiority. Adequate postoperative pain management is vitally important to avoid the detrimental effects of hypertension and tachycardia. Copyright © 2014 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  1. Imaging, Endoscopic and Genetic Assessment of Marfan Syndrome Presenting with Sigmoid Volvulus: A Review

    PubMed Central

    Hurairah, Abu; Shaikh, Faiq

    2016-01-01

    The Marfan syndrome (MFS) is a pleiotropic, autosomal dominant disorder of connective tissue with highly variable clinical manifestations. It primarily involves the skeletal, cardiovascular, and ocular systems; however, gastrointestinal complications are rare. Herein, we describe the case of a 31-year-old male who initially presented with acute abdominal pain for one day. His imaging features revealed a dilated sigmoid colon, consistent with sigmoid volvulus that was immediately decompressed. Surgical resection was recommended to treat the sigmoid volvulus. Preceding the treatment, the patient underwent an extensive workup, including an echocardiography that revealed aortic root dilatation. His clinical history, physical exam, and echocardiographic findings raised the suspicion for MFS. Subsequently, the diagnosis of MFS was confirmed on genetic testing. This is a case that highlights the multidisciplinary (clinical, radiological, endoscopic, molecular/genetic) approach to diagnose a patient with MFS who presented with symptomatic sigmoid volvulus. As this presentation may be a harbinger of more severe manifestations of MFS, it is important to identify it as such in order to accomodate for timely management. PMID:27382527

  2. Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome

    PubMed Central

    Zilberberg, Lior; Phoon, Colin K. L.; Robertson, Ian; Dabovic, Branka; Ramirez, Francesco; Rifkin, Daniel B.

    2015-01-01

    Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling. TGFβ is secreted from cells as a latent complex consisting of TGFβ, the TGFβ propeptide, and a molecule of latent TGFβ binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFβ levels, and has been hypothesized as an explanation for enhanced TGFβ signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFβ signaling in MFS might be due to defective interaction of latent TGFβ complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFβ complexes composed of LTBP-3 and TGFβ contributes to aortic disease progression. PMID:26494287

  3. Work participation in adults with Marfan syndrome: Demographic characteristics, MFS related health symptoms, chronic pain, and fatigue.

    PubMed

    Velvin, Gry; Bathen, Trine; Rand-Hendriksen, Svend; Geirdal, Amy Østertun

    2015-12-01

    Marfan syndrome (MFS) is a severe autosomal dominant connective tissue disorder that might influence peoples work ability. This cross sectional study aims to investigate work participation in adults with verified MFS diagnosis and to explore how the health related consequences of MFS and other factors might influence work participation. The prevalence of health problems in young adults compared to older adults with MFS was examined in association to work participation. A postal questionnaire including questions about work participation, demographic characteristics, MFS related health problems, chronic pain, and fatigue was sent to 117 adults with verified MFS (Ghent 1), and 62% answered. Fifty-nine percent were employed or students, significantly lower work participation than the General Norwegian Population (GNP), but higher than the Norwegian population of people with disability. Most young adults worked full-time despite extensive health problems, but the average age for leaving work was low. Few had received any work adaptations prior to retiring from work. In multiple logistic regression analysis, only age, lower educational level and severe fatigue were significantly associated with low work participation; not MFS related health problems or chronic pain. Fatigue appears to be the most challenging health problem to deal with in work, but the covariance is complex. Focus on vocational guidance early in life, more appropriate work adaptations, and psychosocial support might improve the possibility for sustaining in work for adults with MFS. More research about work challenges in adults with MFS is needed. © 2015 Wiley Periodicals, Inc.

  4. Evaluating Japanese patients with the Marfan syndrome using high-throughput microarray-based mutational analysis of fibrillin-1 gene.

    PubMed

    Ogawa, Naomi; Imai, Yasushi; Takahashi, Yuji; Nawata, Kan; Hara, Kazuo; Nishimura, Hiroshi; Kato, Masayoshi; Takeda, Norifumi; Kohro, Takahide; Morita, Hiroyuki; Taketani, Tsuyoshi; Morota, Tetsuro; Yamazaki, Tsutomu; Goto, Jun; Tsuji, Shoji; Takamoto, Shinichi; Nagai, Ryozo; Hirata, Yasunobu

    2011-12-15

    Marfan syndrome (MS) is an inherited connective tissue disorder, and detailed evaluations of multiple organ systems are required for its diagnosis. Genetic testing of the disease-causing fibrillin-1 gene (FBN1) is also important in this diagnostic scheme. The aim of this study was to define the clinical characteristics of Japanese patients with MS and enable the efficient and accurate diagnosis of MS with mutational analysis using a high-throughput microarray-based resequencing system. Fifty-three Japanese probands were recruited, and their clinical characteristics were evaluated using the Ghent criteria. For mutational analysis, an oligonucleotide microarray was designed to interrogate FBN1, and the entire exon and exon-intron boundaries of FBN1 were sequenced. Clinical evaluation revealed more pulmonary phenotypes and fewer skeletal phenotypes in Japanese patients with MS compared to Caucasians. The microarray-based resequencing system detected 35 kinds of mutations, including 23 new mutations. The mutation detection rate for patients who fulfilled the Ghent criteria reached 71%. Of note, splicing mutations accounted for 19% of all mutations, which is more than previously reported. In conclusion, this comprehensive approach successfully detected clinical phenotypes of Japanese patients with MS and demonstrated the usefulness and feasibility of this microarray-based high-throughput resequencing system for mutational analysis of MS. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Losartan Attenuates Degradation of Aorta and Lung Tissue Micromechanics in a Mouse Model of Severe Marfan Syndrome.

    PubMed

    Lee, Jia-Jye; Galatioto, Josephine; Rao, Satish; Ramirez, Francesco; Costa, Kevin D

    2016-10-01

    Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue due to mutations in the fibrillin-1 gene (FBN1). This study aimed at characterizing microelastic properties of the ascending aortic wall and lung parenchyma tissues from wild type (WT) and age-matched Fbn1 hypomorphic mice (Fbn1(mgR/mgR) mice) to identify tissue-specific biomechanical effects of aging and disease in MFS. Atomic force microscopy was used to indent lung parenchyma and aortic wall tissues, using Hybrid Eshelby Decomposition analysis to extract layer-specific properties of the intima and media. The intima stiffened with age and was not different between WT and Fbn1(mgR/mgR) tissues, whereas the media layer of MFS aortas showed progressive structural and mechanical degradation with a modulus that was 50% softer than WT by 3.5 months of age. Similarly, MFS mice displayed progressive structural and mechanical deterioration of lung tissue, which was over 85% softer than WT by 3.5 months of age. Chronic treatment with the angiotensin type I receptor antagonist, losartan, attenuated the aorta and lung tissue degradation, resulting in structural and mechanical properties not significantly different from age-matched WT controls. By revealing micromechanical softening of elastin-rich aorta and lung tissues with disease progression in fibrillin-1 deficient mice, our findings support the use of losartan as a prophylactic treatment that may abrogate the life-threatening symptoms of MFS.

  6. Does altered aortic flow in marfan syndrome relate to aortic root dilatation?

    PubMed Central

    Wang, Hung‐Hsuan; Chiu, Hsin‐Hui; Tseng, Wen‐Yih Isaac

    2016-01-01

    Purpose To examine possible hemodynamic alterations in adolescent to adult Marfan syndrome (MFS) patients with aortic root dilatation. Materials and Methods Four‐dimensional flow MRI was performed in 20 MFS patients and 12 age‐matched normal subjects with a 3T system. The cross‐sectional areas of 10 planes along the aorta were segmented for calculating the axial and circumferential wall shear stress (WSSaxial, WSScirc), oscillatory shear index (OSIaxial, OSIcirc), and the nonroundness (NR), presenting the asymmetry of segmental WSS. Pearson's correlation analysis was performed to present the correlations between the quantified indices and the body surface area (BSA), aortic root diameter (ARD), and Z score of the ARD. P < 0.05 indicated statistical significance. Results Patients exhibited lower WSSaxial in the aortic root and the WSScirc in the arch (P < 0.05–0.001). MFS patients exhibited higher OSIaxial and OSIcirc in the sinotubular junction and arch, but lower OSIcirc in the descending aorta (all P < 0.05). The NR values were lower in patients (P < 0.05). The WSSaxial or WSScirc exhibited moderate to strong correlations with BSA, ARD, or Z score (R2 = 0.50–0.72) in MFS patients. Conclusion The significant differences in the quantified indices, which were associated with BSA, ARD, or Z score, in MFS were opposite to previous reports for younger MFS patients, indicating that altered flows in MFS patients may depend on the disease progress. The possible time dependency of hemodynamic alterations in MFS patients strongly suggests that longitudinal follow‐up of 4D Flow is needed to comprehend disease progress. J. Magn. Reson. Imaging 2016;44:500–508. PMID:26854646

  7. Histopathology of aortic complications in bicuspid aortic valve versus Marfan syndrome: relevance for therapy?

    PubMed

    Grewal, Nimrat; Franken, Romy; Mulder, Barbara J M; Goumans, Marie-José; Lindeman, Johannes H N; Jongbloed, Monique R M; DeRuiter, Marco C; Klautz, Robert J M; Bogers, Ad J J C; Poelmann, Robert E; Groot, Adriana C Gittenberger-de

    2016-05-01

    Patients with bicuspid aortic valve (BAV) and patients with Marfan syndrome (MFS) are more prone to develop aortic dilation and dissection compared to persons with a tricuspid aortic valve (TAV). To elucidate potential common and distinct pathways of clinical relevance, we compared the histopathological substrates of aortopathy. Ascending aortic wall biopsies were divided in five groups: BAV (n = 36) and TAV (n = 23) without and with dilation and non-dilated MFS (n = 8). General histologic features, apoptosis, the expression of markers for vascular smooth muscle cell (VSMC) maturation, markers predictive for ascending aortic dilation in BAV, and expression of fibrillin-1 were investigated. Both MFS and BAV showed an altered distribution and decreased fibrillin-1 expression in the aorta and a significantly lower level of differentiated VSMC markers. Interestingly, markers predictive for aortic dilation in BAV were not expressed in the MFS aorta. The aorta in MFS was similar to the aorta in dilated TAV with regard to the presence of medial degeneration and apoptosis, while other markers for degeneration and aging like inflammation and progerin expression were low in MFS, comparable to BAV. Both MFS and BAV aortas have immature VSMCs, while MFS and TAV patients have a similar increased rate of medial degeneration. However, the mechanism leading to apoptosis is expected to be different, being fibrillin-1 mutation induced increased angiotensin-receptor-pathway signaling in MFS and cardiovascular aging and increased progerin in TAV. Our findings could explain why angiotensin inhibition is successful in MFS and less effective in TAV and BAV patients.

  8. Elevated expression levels of lysyl oxidases protect against aortic aneurysm progression in Marfan syndrome.

    PubMed

    Busnadiego, O; Gorbenko Del Blanco, D; González-Santamaría, J; Habashi, J P; Calderon, J F; Sandoval, P; Bedja, D; Guinea-Viniegra, J; Lopez-Cabrera, M; Rosell-Garcia, T; Snabel, J M; Hanemaaijer, R; Forteza, A; Dietz, H C; Egea, G; Rodriguez-Pascual, F

    2015-08-01

    Patients with Marfan syndrome (MFS) are at high risk of life-threatening aortic dissections. The condition is caused by mutations in the gene encoding fibrillin-1, an essential component in the formation of elastic fibers. While experimental findings in animal models of the disease have shown the involvement of transforming growth factor-β (TGF-β)- and angiotensin II-dependent pathways, alterations in the vascular extracellular matrix (ECM) may also play a role in the onset and progression of the aortic disease. Lysyl oxidases (LOX) are extracellular enzymes, which initiates the formation of covalent cross-linking of collagens and elastin, thereby contributing to the maturation of the ECM. Here we have explored the role of LOX in the formation of aortic aneurysms in MFS. We show that aortic tissue from MFS patients and MFS mouse model (Fbn1(C1039G/+)) displayed enhanced expression of the members of the LOX family, LOX and LOX-like 1 (LOXL1), and this is associated with the formation of mature collagen fibers. Administration of a LOX inhibitor for 8weeks blocked collagen accumulation and aggravated elastic fiber impairment, and these effects correlated with the induction of a strong and rapidly progressing aortic dilatation, and with premature death in the more severe MFS mouse model, Fbn1(mgR/mgR), without any significant effect on wild type animals. This detrimental effect occurred preferentially in the ascending portion of the aorta, with little or no involvement of the aortic root, and was associated to an overactivation of both canonical and non-canonical TGF-β signaling pathways. The blockade of angiotensin II type I receptor with losartan restored TGF-β signaling activation, normalized elastic fiber impairment and prevented the aortic dilatation induced by LOX inhibition in Fbn1(C1039G/+) mice. Our data indicate that LOX enzymes and LOX-mediated collagen accumulation play a critical protective role in aneurysm formation in MFS.

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

    PubMed Central

    von Kodolitsch, Yskert; De Backer, Julie; Schüler, Helke; Bannas, Peter; Behzadi, Cyrus; Bernhardt, Alexander M; Hillebrand, Mathias; Fuisting, Bettina; Sheikhzadeh, Sara; Rybczynski, Meike; Kölbel, Tilo; Püschel, Klaus; Blankenberg, Stefan; Robinson, Peter N

    2015-01-01

    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. PMID:26124674

  10. Circulating transforming growth factor β-1 level in Japanese patients with Marfan syndrome.

    PubMed

    Ogawa, Naomi; Imai, Yasushi; Nishimura, Hiroshi; Kato, Masayoshi; Takeda, Norifumi; Nawata, Kan; Taketani, Tsuyoshi; Morota, Tetsuro; Takamoto, Shinichi; Nagai, Ryozo; Hirata, Yasunobu

    2013-01-01

    Marfan syndrome (MFS) is an inherited connective tissue disorder mainly caused by the fibrillin-1 mutation. Deficient fibrillin-1 is thought to result in the failed sequestration of transforming growth factor β (TGFβ) and subsequent activation of the TGFβ signaling pathway, suggesting that the circulating TGFβ level may be elevated in MFS, although its accurate measurement is complex due to ex vivo release from platelet stores upon platelet activation. We measured the plasma TGFβ1 levels of 32 Japanese MFS patients (22 medically untreated, 10 treated, 20 males, 30.1 ± 9.6 years old) and 30 healthy volunteers (19 males, 29.5 ± 5.8 years old) by ruthenium-based electrochemiluminescence platform (ECL). PF4 was also measured by enzyme immunoassay (EIA) as a platelet degranulation marker. There was no significant difference in the mean plasma TGFβ1 level between the MFS group (1.31 ± 0.40 ng/mL) and controls (1.17 ± 0.33 ng/mL) (P = 0.16, NS). Also, there was no significant difference between the untreated (1.24 ± 0.37 ng/mL) and treated (1.46 ± 0.45 ng/mL) MFS patients (P = 0.15, NS). We also measured PF4, which showed wide deviations but no significant difference between the two groups (P = 0.50). A difference in circulating TGFβ1 levels between MFS patients and controls was not detected in this Japanese population. Circulating TGFβ1 is not a diagnostic and therapeutic marker for Japanese MFS patients, although our findings do not eliminate the possible association of TGFβ with the pathogenesis of MFS.

  11. [Detection of pathogenic mutations in Marfan syndrome by targeted next-generation semiconductor sequencing].

    PubMed

    Lu, Chaoxia; Wu, Wei; Xiao, Jifang; Meng, Yan; Zhang, Shuyang; Zhang, Xue

    2013-06-01

    To detect pathogenic mutations in Marfan syndrome (MFS) using an Ion Torrent Personal Genome Machine (PGM) and to validate the result of targeted next-generation semiconductor sequencing for the diagnosis of genetic disorders. Peripheral blood samples were collected from three MFS patients and a normal control with informed consent. Genomic DNA was isolated by standard method and then subjected to targeted sequencing using an Ion Ampliseq(TM) Inherited Disease Panel. Three multiplex PCR reactions were carried out to amplify the coding exons of 328 genes including FBN1, TGFBR1 and TGFBR2. DNA fragments from different samples were ligated with barcoded sequencing adaptors. Template preparation and emulsion PCR, and Ion Sphere Particles enrichment were carried out using an Ion One Touch system. The ion sphere particles were sequenced on a 318 chip using the PGM platform. Data from the PGM runs were processed using an Ion Torrent Suite 3.2 software to generate sequence reads. After sequence alignment and extraction of SNPs and indels, all the variants were filtered against dbSNP137. DNA sequences were visualized with an Integrated Genomics Viewer. The most likely disease-causing variants were analyzed by Sanger sequencing. The PGM sequencing has yielded an output of 855.80 Mb, with a > 100 × median sequencing depth and a coverage of > 98% for the targeted regions in all the four samples. After data analysis and database filtering, one known missense mutation (p.E1811K) and two novel premature termination mutations (p.E2264X and p.L871FfsX23) in the FBN1 gene were identified in the three MFS patients. All mutations were verified by conventional Sanger sequencing. Pathogenic FBN1 mutations have been identified in all patients with MFS, indicating that the targeted next-generation sequencing on the PGM sequencers can be applied for accurate and high-throughput testing of genetic disorders.

  12. Combined mitral valve replacement associated with the Bentall procedure, diaphragmatic hernia repair and reconstruction of the pectus excavatum in a 26-year-old patient with Marfan syndrome

    PubMed Central

    Stępiński, Piotr; Aboul-Hassan, Sleiman Sebastian; Szymańska, Anna; Marczak, Jakub; Cichoń, Romuald

    2016-01-01

    A 26-year-old man with Marfan syndrome was admitted as an emergency patient with ascending aorta aneurysm, severe mitral and aortic regurgitation, diaphragmatic hernia and pectus excavatum. After completion of diagnostics a combined surgical procedure was performed. PMID:27516786

  13. No Beneficial Effect of General and Specific Anti-Inflammatory Therapies on Aortic Dilatation in Marfan Mice

    PubMed Central

    den Hartog, Alexander W.; Radonic, Teodora; de Vries, Carlie J. M.; Zwinderman, Aeilko H.; Groenink, Maarten; Mulder, Barbara J. M.; de Waard, Vivian

    2014-01-01

    Aims Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. In the FBN1C1039G/+ Marfan mouse model, losartan decreases aortic root dilatation. We recently confirmed this beneficial effect of losartan in adult patients with Marfan syndrome. The straightforward translation of this mouse model to man is reassuring to test novel treatment strategies. A number of studies have shown signs of inflammation in aortic tissue of Marfan patients. This study examined the efficacy of anti-inflammatory therapies in attenuating aortic root dilation in Marfan syndrome and compared effects to the main preventative agent, losartan. Methods and Results To inhibit inflammation in FBN1C1039G/+ Marfan mice, we treated the mice with losartan (angiotensin II receptor type 1 inhibitor), methylprednisolone (corticosteroid) or abatacept (T-cell-specific inhibitor). Treatment was initiated in adult Marfan mice with already existing aortic root dilatation, and applied for eight weeks. Methylprednisolone- or abatacept-treated mice did not reveal a reduction in aortic root dilatation. In this short time frame, losartan was the only treatment that significantly reduced aorta inflammation, transforming growth factor-beta (TGF-β) signaling and aortic root dilatation rate in these adult Marfan mice. Moreover, the methylprednisolone-treated mice had significantly more aortic alcian blue staining as a marker for aortic damage. Conclusion Anti-inflammatory agents do not reduce the aortic dilatation rate in Marfan mice, but possibly increase aortic damage. Currently, the most promising therapeutic drug in Marfan syndrome is losartan, by blocking the angiotensin II receptor type 1 and thereby inhibiting pSmad2 signaling. PMID:25238161

  14. FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations.

    PubMed

    Attanasio, M; Lapini, I; Evangelisti, L; Lucarini, L; Giusti, B; Porciani, Mc; Fattori, R; Anichini, C; Abbate, R; Gensini, Gf; Pepe, G

    2008-07-01

    Fibrillin-1 gene (FBN1) mutations cause Marfan syndrome (MFS), an inherited connective tissue disorder with autosomal dominant transmission. Major clinical manifestations affect cardiovascular and skeletal apparatuses and ocular and central nervous systems. We analyzed FBN1 gene in 99 patients referred to our Center for Marfan Syndrome and Related Disorders (University of Florence, Florence, Italy): 85 were affected by MFS and 14 by other fibrillinopathies type I. We identified mutations in 80 patients. Among the 77 different mutational events, 46 had not been previously reported. They are represented by 49 missense (61%), 1 silent (1%), 13 nonsense (16%), 6 donor splice site mutations (8%), 8 small deletions (10%), and 3 small duplications (4%). The majority of missense mutations were within the calcium-binding epidermal growth factor-like domains. We found preferential associations between The Cys-missense mutations and ectopia lentis and premature termination codon mutations and skeletal manifestations. In contrast to what reported in literature, the cardiovascular system is severely affected also in patients carrying mutations in exons 1-10 and 59-65. In conclusion, we were able to detect FBN1 mutations in 88% of patients with MFS and in 36% of patients with other fibrillinopathies type I, confirming that FBN1 mutations are good predictors of classic MFS.

  15. Transscleral intraocular lens fixation with preservation of the anterior vitreous face in patients with marfan syndrome and ectopia lentis.

    PubMed

    Kim, Wan-Soo

    2010-11-01

    To evaluate the safety and efficacy of transscleral intraocular lens fixation with preservation of the anterior vitreous in the treatment of ectopia lentis in patients with Marfan syndrome. Patients who had undergone surgical intervention for ectopia lentis with or without lenticular opacity were included. Best-corrected visual acuity before and after surgery was compared. Perioperative complications were evaluated. A total of 23 patients (45 eyes) whose mean age at surgery was 16.9 ± 8.9 years were recruited. The mean follow-up period was 10.1 ± 5.8 months. Mean best-corrected visual acuity change (with respect to preoperative logarithm of the minimum angle of resolution value) was 1.03 ± 0.39. All patients showed >2 lines of improvement in visual acuity. Pupillary capture was found in 6 eyes. Medically controllable intraocular pressure elevation was noted in 12 eyes. Transscleral intraocular lens fixation with preservation of the anterior vitreous face is a safe and effective technique for treatment of ectopia lentis in patients with Marfan syndrome.

  16. Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations.

    PubMed

    Söylen, B; Singh, K K; Abuzainin, A; Rommel, K; Becker, H; Arslan-Kirchner, M; Schmidtke, J

    2009-03-01

    Marfan syndrome is an autosomal dominant disorder involving different organ systems. Marfan syndrome type 1 (MFS1) is caused by mutations in the FBN1 gene. Heterozygosity for mutations in the TGFBR1 or TGFBR2 genes cause Loeys-Dietz syndrome (LDS) types 2A and 2B that overlap with MFS1 in their clinical features. The phenotype of MFS1 is defined by the Ghent nosology, which classifies the clinical manifestations in major and minor criteria. Dural ectasia is one of the major criteria for Marfan syndrome but it is rarely tested for. We here report 22 novel and 9 recurrent mutations in the FBN1 gene in 36 patients with clinical features of Marfan syndrome. Sixty patients with identified mutations in the FBN1 gene and three patients with mutations in the TGFBR1 or TGFBR2 genes were examined for dural ectasia. Forty-seven of the 60 patients (78%) with MFS1 showed the dural ectasia criterion and 13 (22%) did not. Thirty-three (55%) patients were suspected of having Marfan syndrome and 24 (73%) of them had dural ectasia. Two of the three patients with LDS had dural ectasia.

  17. New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome

    PubMed Central

    2014-01-01

    Background Marfan syndrome (MFS) is a rare autosomal dominantly inherited connective tissue disorder with an estimated prevalence of 1:5,000. More than 1000 variants have been previously reported to be associated with MFS. However, the disease-causing effect of these variants may be questionable as many of the original studies used low number of controls. To study whether there are possible false-positive variants associated with MFS, four in silico prediction tools (SIFT, Polyphen-2, Grantham score, and conservation across species) were used to predict the pathogenicity of these variant. Results Twenty-three out of 891 previously MFS-associated variants were identified in the ESP. These variants were distributed on 100 heterozygote carriers in 6494 screened individuals. This corresponds to a genotype prevalence of 1:65 for MFS. Using a more conservative approach (cutoff value of >2 carriers in the EPS), 10 variants affected a total of 82 individuals. This gives a genotype prevalence of 1:79 (82:6494) in the ESP. A significantly higher frequency of MFS-associated variants not present in the ESP were predicted to be pathogenic with the agreement of ≥3 prediction tools, compared to the variants present in the ESP (p = 3.5 × 10−15). Conclusions This study showed a higher genotype prevalence of MFS than expected from the phenotype prevalence in the general population. The high genotype prevalence suggests that these variants are not the monogenic cause of MFS. Therefore, caution should be taken with regard to disease stratification based on these previously reported MFS-associated variants. PMID:24941995

  18. Long-term implications of emergency versus elective proximal aortic surgery in Marfan syndrome patients in the GenTAC Registry

    PubMed Central

    Song, Howard K.; Kindem, Mark; Bavaria, Joseph E.; Dietz, Harry C.; Milewicz, Dianna M.; Devereux, Richard B.; Eagle, Kim A.; Maslen, Cheryl L.; Kroner, Barbara L.; Pyeritz, Reed E.; Holmes, Kathryn W.; Weinsaft, Jonathan W.; Menashe, Victor; Ravekes, William; LeMaire, Scott A.

    2011-01-01

    Objective Marfan syndrome patients with aortic root aneurysms undergo elective aortic root replacement to avoid the life-threatening outcomes of aortic dissection and emergency repair. The long-term implications of failed aortic surveillance leading to acute dissection and emergency repair are poorly defined. We compared the long-term clinical courses of Marfan syndrome patients who survive emergency versus elective proximal aortic surgery. Methods The GenTAC Registry is an NIH-funded, multicenter database and biorepository that enrolls patients with genetically triggered thoracic aortic aneurysms. Of the 635 patients with Marfan syndrome enrolled as of March 2011, 194 had undergone proximal aortic replacement. Patients were grouped according to emergent (n=47) or elective (n=147) status at the time of surgery. Results Patients in the emergent group were more likely to have incomplete proximal aortic resection; 83% of emergency procedures included aortic root replacement, compared with 95% of elective procedures. At long-term follow-up (mean, >6 years), emergent patients had a higher incidence of chronic dissection of the distal aorta and had significantly larger diameters in distal aortic segments than elective patients. Additionally, emergent patients had undergone more operations (1.31 vs 1.11 procedures/patient; P=0.01) and had lower activity scores on a health-related quality-of-life survey. Conclusions For Marfan syndrome patients, failed aortic surveillance and consequent emergency dissection repair have important long-term implications with regard to status of the distal aorta, the need for multiple procedures, and quality of life. These findings emphasize the importance of aortic surveillance and timely elective aortic root aneurysm repair for Marfan syndrome patients. PMID:22104675

  19. Comparison of Cine-MRI and Transthoracic Echocardiography for the Assessment of Aortic Root Diameters in Patients with Suspected Marfan Syndrome.

    PubMed

    Bannas, P; Rybczynski, M; Sheikhzadeh, S; von Kodolitsch, Y; Derlin, T; Yamamura, J; Lund, G; Adam, G; Groth, M

    2015-11-01

    Patients with Marfan syndrome require repeated imaging for monitoring of aortic root aneurysms. Therefore, we evaluated the agreement and reproducibility of cine-MRI and echocardiography measurements of the sinuses of Valsalva in patients with suspected Marfan syndrome. 51 consecutive patients with suspected Marfan syndrome were prospectively examined using cine-MRI and echocardiography. Two readers independently measured aortic root diameters at the level of the sinuses of Valsalva in both cine-MRI and echocardiography. Statistics included intraclass correlation coefficient, Pearson correlation coefficient, Bland-Altman analysis, and two-sided t-test. In 38 of the 51 individuals (74.5 %), the diagnosis of Marfan syndrome was established according to the criteria of the Ghent-2 nosology. Cine-MRI measurements of the sinuses of Valsalva revealed a strong correlation with echocardiography (r = 0.929), but a statistically significant bias of -1.0  mm (p < 0.001). The mean absolute diameter for sinuses of Valsalva obtained by cine-MRI was 32.3  ±  5.8 mm as compared to 33.4  ±  5.4 mm obtained by echocardiography. Interobserver agreement of measurements of the sinuses of Valsalva was higher for cine-MRI than for echocardiography (p = 0.029). Despite small, but statistically significant differences in terms of agreement and reproducibility, cine-MRI and echocardiographic measurements of aortic root diameters provide comparable results without a significant clinical difference. Therefore both techniques may be used for monitoring of the aortic root in patients with Marfan syndrome. © Georg Thieme Verlag KG Stuttgart · New York.

  20. Dimorphic effects of TGFβ signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome

    PubMed Central

    Cook, Jason R.; Clayton, Nicholas P.; Carta, Luca; Galatioto, Josephine; Chiu, Emily; Smaldone, Silvia; Nelson, Carol A.; Cheng, Seng H.; Wentworth, Bruce M.; Ramirez, Francesco

    2015-01-01

    Objective Studies of mice with mild Marfan syndrome (MFS) have correlated the development of thoracic aortic aneurysm (TAA) with improper stimulation of non-canonical (Erk-mediated) TGFβ signaling by the angiotensin type I receptor (AT1r). This correlation was largely based on comparable TAA modifications by either systemic TGFβ neutralization or AT1r antagonism. However, subsequent investigations have called into question some key aspects of this mechanism of arterial disease in MFS. To resolve these controversial points, here we made a head-to-head comparison of the therapeutic benefits of TGFβ neutralization and AT1r antagonism in mice with progressively severe MFS (Fbn1mgR/mgR mice). Approach and Results Aneurysm growth, media degeneration, aortic levels of phosphorylated Erk and Smad proteins and the average survival of Fbn1mgR/mgR mice were compared after a ∼3 month long treatment with placebo and either the AT1r antagonist losartan or the TGFβ neutralizing antibody 1D11. In contrast to the beneficial effect of losartan, TGFβ neutralization either exacerbated or mitigated TAA formation depending on whether treatment was initiated before (post-natal day 16; P16) or after (P45) aneurysm formation, respectively. Biochemical evidence related aneurysm growth with Erk-mediated AT1r signaling, and medial degeneration with TGFβ hyperactivity that was in part AT1r-dependent. Importantly, P16-initiated treatment with losartan combined with P45-initiated administration of 1D11 prevented death of Fbn1mgR/mgR mice from ruptured TAA. Conclusions By demonstrating that promiscuous AT1r and TGFβ drive partially overlapping processes of arterial disease in MFS mice, our study argues for a therapeutic strategy against TAA that targets both signaling pathways while sparing the early protective role of TGFβ. PMID:25614286

  1. A novel fibrillin-1 mutation in an egyptian marfan family: A proband showing nephrotic syndrome due to focal segmental glomerulosclerosis.

    PubMed

    Al-Haggar, Mohammad; Bakr, Ashraf; Wahba, Yahya; Coucke, Paul J; El-Hussini, Fatma; Hafez, Mona; Eid, Riham; Eid, Abdel-Rahman; Sarhan, Amr; Shaltout, Ali; Hammad, Ayman; Yahia, Sohier; El-Rifaie, Ahmad; Abdel-Hadi, Dina

    2017-01-01

    Marfan syndrome (MFS), the founding member of connective tissue disorder, is an autosomal dominant disease; it is caused by a deficiency of the microfibrillar protein fibrillin-1 (FBN1) and characterized by involvement of three main systems; skeletal, ocular, and cardiovascular. More than one thousand mutations in FBN1 gene on chromosome 15 were found to cause MFS. Nephrotic syndrome (NS) had been described in very few patients with MFS being attributed to membranoproliferative glomerulonephritis secondary to infective endocarditis. Focal segmental glomerulosclerosis (FSGS) had been reported in NS in conjunction with MFS without confirming the diagnosis by mutational analysis of FBN1. We hereby present an Egyptian family with MFS documented at the molecular level; it showed a male proband with NS secondary to FSGS, unfortunately, we failed to make any causal link between FBN dysfunction and FSGS. In this context, we review the spectrum of renal involvements occurring in MFS patients.

  2. Revised Ghent Criteria is Comparable to Original Diagnostic Criteria for Marfan Syndrome with Increased Ability to Clinically Diagnose Related Disorders.

    PubMed

    Penpattharakul, Worawan; Pithukpakorn, Manop

    2016-01-01

    Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with major features in cardiovascular ocular and skeletal systems. Due to its genetic heterogeneity and variable expressivity, Ghent nosology was established for clinical diagnosis of MFS. In 2010, Ghent diagnostic criteria were revised to better diagnose MS and categorize its related disorders. There is no previous clinical comparison between the original and revised Ghent criteria for diagnosis of MFS in Thai patients. To compare application and efficacy of Ghent and revised Ghent criteria in adult Thai patients with clinical suspicion of MFS. This study was a retrospective analysis of patients with clinical suspicion of MFS who attended the Medical Genetics Clinic, Siriraj Hospital between January 2003 and December 2013. Patients were clinically examined for diagnosis of MFS using both the Ghent and revised Ghent criteria. Multidisciplinary data, including physical examination, echocardiography, slit-lamp examination, and genetic testing, were analyzed. Clinical and genetic data of 138 (77 males and 61 females) individuals with clinical suspicion of MFS were reviewed The most common presentation was cardiovascular manifestation. Of 92 patients diagnosed as MFS by original Ghent nosology 70 of those patients (76.1%) were also diagnosed as MFS by revised Ghent criteria. Forty-eight of 138 patients (34.8%) had undergone genetic testing, with FBN1 mutations detected in 23 patients. Twenty-two patients with detectable FBN1 mutations fulfilled both the Ghent and revised Ghent criteria. Of 22 patients whose diagnoses were not fulfilled by revised Ghent nosology, most were due to inadequate systemic score (SS). The use of revised Ghent nosology also facilitated improved diagnosis of MFS-related disorders. Revised Ghent nosology has further differentiated MFS from other MFS-related disorders and has further expanded the classification of MFS-related disorders. Genetic testing of FBN1 helps

  3. Increased aortic tortuosity indicates a more severe aortic phenotype in adults with Marfan syndrome.

    PubMed

    Franken, Romy; El Morabit, Abdelali; de Waard, Vivian; Timmermans, Janneke; Scholte, Arthur J; van den Berg, Maarten P; Marquering, Henk; Planken, Nils R N; Zwinderman, Aeilko H; Mulder, Barbara J M; Groenink, Maarten

    2015-09-01

    Patients with Marfan syndrome (MFS) have a highly variable occurrence of aortic complications. Aortic tortuosity is often present in MFS and may help to identify patients at risk for aortic complications. 3D-visualization of the total aorta by MR imaging was performed in 211 adult MFS patients (28% with prior aortic root replacement) and 20 controls. A method to assess aortic tortuosity (aortic tortuosity index: ATI) was developed and reproducibility was tested. The relation between ATI and age, and body size and aortic dimensions at baseline was investigated. Relations between ATI at baseline and the occurrence of a clinical endpoint (aortic dissection, and/or aortic surgery) and aortic dilatation rate during 3 years of follow-up were investigated. ATI intra- and interobserver agreements were excellent (ICC: 0.968 and 0.955, respectively). Mean ATI was higher in 28 age-matched MFS patients than in the controls (1.92 ± 0.2 vs. 1.82 ± 0.1, p=0.048). In the total MFS cohort, mean ATI was 1.87 ± 0.20, and correlated with age (r=0.281, p<0.001), aortic root diameter (r=0.223, p=0.006), and aortic volume expansion rate (r=0.177, p=0.026). After 49.3 ± 8.8 months follow-up, 33 patients met the combined clinical endpoint (7 dissections) with a significantly higher ATI at baseline than patients without endpoint (1.98 ± 0.2 vs. 1.86 ± 0.2, p=0.002). Patients with an ATI>1.95 had a 12.8 times higher probability of meeting the combined endpoint (log rank-test, p<0.001) and a 12.1 times higher probability of developing an aortic dissection (log rank-test, p=0.003) compared to patients with an ATI<1.95. Increased ATI is associated with a more severe aortic phenotype in MFS patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  4. Missense Mutations in FBN1 Exons 41 and 42 Cause Weill-Marchesani Syndrome with Thoracic Aortic Disease and Marfan Syndrome

    PubMed Central

    Cecchi, Alana; Ogawa, Naomi; Martinez, Hugo R.; Carlson, Alicia; Fan, Yuxin; Penny, Daniel J.; Guo, Dong-chuan; Eisenberg, Steven; Safi, Hazim; Estrera, Anthony; Lewis, Richard A.; Meyers, Deborah; Milewicz, Dianna M.

    2013-01-01

    Mutations in FBN1 cause a range of overlapping but distinct conditions including Marfan syndrome (MFS), Weill-Marchesani syndrome (WMS), familial thoracic aortic aneurysms/dissections (FTAAD), acromicric dysplasia (AD), and geleophysic dysplasia (GD). Two forms of acromelic dysplasia, AD and GD, characterized by short stature, brachydactyly, reduced joint mobility, and characteristic facies, result from heterozygous missense mutations occurring in exons 41 and 42 of FBN1; missense mutations in these exons have not been reported to cause MFS or other syndromes. Here we report on probands with MFS and WMS who have heterozygous FBN1 missense mutations in exons 41 and 42, respectively. The proband with WMS has ectopia lentis, short stature, thickened pinnae, tight skin, striae atrophicae, reduced extension of the elbows, contractures of the fingers and toes, and brachydactyly and has a missense mutation in exon 42 of FBN1 (c.5242T>C ;p.C1748R). He also experienced a previously unreported complication of WMS, an acute thoracic aortic dissection. The second proband displays classic characteristics of MFS, including ectopia lentis, skeletal features and aortic root dilatation, and has a missense mutation in exon 41 of FBN1 (c.5084G>A; p.C1695Y). These phenotypes provide evidence that missense mutations in exons 41 and 42 of FBN1 lead to MFS and WMS in addition to AD and GD and also suggest that all individuals with pathogenic FBN1 mutations in these exons should be assessed for thoracic aortic disease and ectopia lentis. Further studies are necessary to elucidate the factors responsible for the different phenotypes associated with missense mutations in these exons of FBN1. PMID:23897642

  5. Missense mutations in FBN1 exons 41 and 42 cause Weill-Marchesani syndrome with thoracic aortic disease and Marfan syndrome.

    PubMed

    Cecchi, Alana; Ogawa, Naomi; Martinez, Hugo R; Carlson, Alicia; Fan, Yuxin; Penny, Daniel J; Guo, Dong-chuan; Eisenberg, Steven; Safi, Hazim; Estrera, Anthony; Lewis, Richard A; Meyers, Deborah; Milewicz, Dianna M

    2013-09-01

    Mutations in FBN1 cause a range of overlapping but distinct conditions including Marfan syndrome (MFS), Weill-Marchesani syndrome (WMS), familial thoracic aortic aneurysms/dissections (FTAAD), acromicric dysplasia (AD), and geleophysic dysplasia (GD). Two forms of acromelic dysplasia, AD and GD, characterized by short stature, brachydactyly, reduced joint mobility, and characteristic facies, result from heterozygous missense mutations occurring in exons 41 and 42 of FBN1; missense mutations in these exons have not been reported to cause MFS or other syndromes. Here we report on probands with MFS and WMS who have heterozygous FBN1 missense mutations in exons 41 and 42, respectively. The proband with WMS has ectopia lentis, short stature, thickened pinnae, tight skin, striae atrophicae, reduced extension of the elbows, contractures of the fingers and toes, and brachydactyly and has a missense mutation in exon 42 of FBN1 (c.5242T>C; p.C1748R). He also experienced a previously unreported complication of WMS, an acute thoracic aortic dissection. The second proband displays classic characteristics of MFS, including ectopia lentis, skeletal features, and aortic root dilatation, and has a missense mutation in exon 41 of FBN1 (c.5084G>A; p.C1695Y). These phenotypes provide evidence that missense mutations in exons 41 and 42 of FBN1 lead to MFS and WMS in addition to AD and GD and also suggest that all individuals with pathogenic FBN1 mutations in these exons should be assessed for thoracic aortic disease and ectopia lentis. Further studies are necessary to elucidate the factors responsible for the different phenotypes associated with missense mutations in these exons of FBN1.

  6. Endovascular treatment of type B dissection in patients with Marfan syndrome: mid-term outcomes and aortic remodeling.

    PubMed

    Eid-Lidt, Guering; Gaspar, Jorge; Meléndez-Ramírez, Gabriela; Cervantes S, Jorge; González-Pacheco, Hector; Dámas de Los Santos, Félix; Meave-González, Aloha; Ramírez Marroquín, Samuel

    2013-12-01

    To evaluate the mid-term outcomes, and the aortic remodeling in Marfan syndrome (MFS) patients with type B dissection that were treated with endovascular repair. MFS is a relative contraindication to thoracic endovascular aortic repair (TEVAR). Mid-term aortic outcomes data in MFS after TEVAR are limited, and the occurrence of late events remains unclear. Of 89 patients that underwent TEVAR between September 2002 and February 2011, 10 patients with mid-term follow-up fulfilled the Ghent criteria for MFS and complicated type B dissection. High risk for open surgery was documented in 90%. The mean age was 35.1 ± 9.4 years and all patients presented with acute aortic syndrome complicating a chronic type B dissection (DeBakey type IIIb). Five patients underwent a Bentall surgical procedure previous to endovascular repair, and in four patients initial TEVAR was followed by surgery of the ascending aorta. Treatment was limited to endovascular repair in only one patient. In-hospital mortality was 10%. At a mean follow-up of 59.6 ± 38.9 months, the cumulated mortality was of 20% and late mortality 11.1%. The rate of secondary endoleak was 44.4%, and late reintervention of 33.3%. Survival freedom from cardiovascular death at 8 years was 80.0%, and positive remodeling was documented in 37.5% of patients. Our results suggest that TEVAR is feasible, safe, and associated with a high reintervention rate and reduced rate of positive aortic remodeling in patients with Marfan syndrome. Survival at 8 years was comparable to contemporary series of open repair. Copyright © 2013 Wiley Periodicals, Inc.

  7. High-Resolution Morphological Approach to Analyse Elastic Laminae Injuries of the Ascending Aorta in a Murine Model of Marfan Syndrome.

    PubMed

    López-Guimet, Júlia; Andilla, Jordi; Loza-Alvarez, Pablo; Egea, Gustavo

    2017-05-04

    In Marfan syndrome, the tunica media is disrupted, which leads to the formation of ascending aortic aneurysms. Marfan aortic samples are histologically characterized by the fragmentation of elastic laminae. However, conventional histological techniques using transverse sections provide limited information about the precise location, progression and 3D extension of the microstructural changes that occur in each lamina. We implemented a method using multiphoton excitation fluorescence microscopy and computational image processing, which provides high-resolution en-face images of segmented individual laminae from unstained whole aortic samples. We showed that internal elastic laminae and successive 2(nd) laminae are injured to a different extent in murine Marfan aortae; in particular, the density and size of fenestrae changed. Moreover, microstructural injuries were concentrated in the aortic proximal and convex anatomical regions. Other parameters such as the waviness and thickness of each lamina remained unaltered. In conclusion, the method reported here is a useful, unique tool for en-face laminae microstructure assessment that can obtain quantitative three-dimensional information about vascular tissue. The application of this method to murine Marfan aortae clearly shows that the microstructural damage in elastic laminae is not equal throughout the thickness of the tunica media and in the different anatomical regions of the ascending aorta.

  8. Outcome of aortic surgery in patients with Loeys-Dietz syndrome primarily treated as having Marfan syndrome.

    PubMed

    Schoenhoff, Florian S; Mueller, Christoph; Czerny, Martin; Matyas, Gabor; Kadner, Alexander; Schmidli, Juerg; Carrel, Thierry

    2014-09-01

    Loeys-Dietz syndrome (LDS) is characterized by acute aortic dissection (AAD) at aortic diameters below thresholds for intervention in patients with Marfan syndrome (MFS). The aim was to evaluate the outcome of LDS patients primarily treated as having MFS. We analysed 68 consecutive patients who underwent surgery between 1995 and 2007 under the assumption of having MFS before retrospectively being screened for LDS when genetic testing became available. These patients were followed up until 2013, and underwent a total of 115 aortic surgeries. Genetic testing was performed in 76% of the patients. Sixty per cent of these patients were positive for FBN1 mutations associated with MFS, 20% had no FBN1 mutation and 17% harboured TGFBR1/2 mutations associated with LDS. Mean follow-up was 12.7 ± 7 years. All-cause 30-day, 6-month and 1-year mortality rates were 2.9, 4.4 and 7.3%, respectively. Interestingly, initial presentation with AAD did not differ between LDS and MFS (33 vs 37%, P = 0.48) nor did long-term mortality compared with MFS patients (11 vs 16%, P = 1.0) or within MFS subgroups (FBN1 positive 13%, P = 1.0; FBN1 negative 10%, P = 1.0; not tested 25%, P = 0.62). There was no difference in the need for secondary total arch replacement between LDS and MFS patients (11 vs 14%, P = 1.0), nor within MFS subgroups (FBN1 positive 16%, P = 1.0; FBN1 negative 10%, P = 1.0; not tested 13%, P = 1.0). Total aortic replacement became necessary in 22% of LDS compared with 12% of MFS patients (P = 0.6) and did not differ significantly between MFS subgroups. Although early surgical intervention in LDS is warranted to avoid AAD, the current data suggest that once the diseased segment is repaired, there seems to be no additional burden in terms of mortality or reoperation rate compared with that in MFS patients, with or without confirmed FBN1 mutation. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All

  9. Co-expression of FBN1 with mesenchyme-specific genes in mouse cell lines: implications for phenotypic variability in Marfan syndrome

    PubMed Central

    Summers, Kim M; Raza, Sobia; van Nimwegen, Erik; Freeman, Thomas C; Hume, David A

    2010-01-01

    Mutations in the human FBN1 gene cause Marfan syndrome, a complex disease affecting connective tissues but with a highly variable phenotype. To identify genes that might participate in epistatic interactions with FBN1, and could therefore explain the observed phenotypic variability, we have looked for genes that are co-expressed with Fbn1 in the mouse. Microarray expression data derived from a range of primary mouse cells and cell lines were analysed using the network analysis tool BioLayout Express3D. A cluster of 205 genes, including Fbn1, were selectively expressed by mouse cell lines of different mesenchymal lineages and by mouse primary mesenchymal cells (preadipocytes, myoblasts, fibroblasts, osteoblasts). Promoter analysis of this gene set identified several candidate transcriptional regulators. Genes within this co-expressed cluster are candidate genetic modifiers for Marfan syndrome and for other connective tissue diseases. PMID:20551991

  10. A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome.

    PubMed

    Rienhoff, Hugh Young; Yeo, Chang-Yeol; Morissette, Rachel; Khrebtukova, Irina; Melnick, Jonathan; Luo, Shujun; Leng, Nan; Kim, Yeon-Jin; Schroth, Gary; Westwick, John; Vogel, Hannes; McDonnell, Nazli; Hall, Judith G; Whitman, Malcolm

    2013-08-01

    The transforming growth factor β (TGF-β) family of growth factors are key regulators of mammalian development and their dysregulation is implicated in human disease, notably, heritable vasculopathies including Marfan (MFS, OMIM #154700) and Loeys-Dietz syndromes (LDS, OMIM #609192). We described a syndrome presenting at birth with distal arthrogryposis, hypotonia, bifid uvula, a failure of normal post-natal muscle development but no evidence of vascular disease; some of these features overlap with MFS and LDS. A de novo mutation in TGFB3 was identified by exome sequencing. Several lines of evidence indicate the mutation is hypomorphic suggesting that decreased TGF-β signaling from a loss of TGFB3 activity is likely responsible for the clinical phenotype. This is the first example of a mutation in the coding portion of TGFB3 implicated in a clinical syndrome suggesting TGFB3 is essential for both human palatogenesis and normal muscle growth. Copyright © 2013 Wiley Periodicals, Inc.

  11. Analysis of FBN1 allele expression by dermal fibroblasts from Marfan syndrome patients

    SciTech Connect

    Putman, E.A.; Cao, S.N.; Milewicz, D.M.

    1994-09-01

    Screening for mutations in the FBN1 cDNA from Marfan patient cell strains has detected mutations in only 10-15% of patients. In an attempt to explain this poor detection rate, we examined FBN1 allele expression and fibrillin synthesis by 26 cell strains from Marfan patients. DNA from the patients and 10 controls was assessed for the presence of a polymorphic Rsa I restriction site in the 3{prime} untranslated region of the FBN1 gene. Twelve of 26 patient and 5 of 10 control DNAs were heterozygous. Fibroblast RNA from the heterozygous cell strains was reverse-transcribed and subsequently PCR amplified using a [{sup 32}P]-labelled primer, digested with Rsa I and analyzed. Although 3 samples showed no transcript from one allele by ethidium bromide staining, a Betagen scanner detected low levels (10-15%) of that allele. In addition, there was unequal expression of the two alleles in three other patients; for example, only 30% expression from one allele. The remaining patients and the controls had equal expression of each allele. Fibrillin protein synthesis by fibroblasts from these heterozygous patients was also examined. After a 30 minute pulse with [{sup 35}S]-cysteine, cell lysates were collected and proteins analyzed by SDS-PAGE. The amount of fibrillin produced relative to a reference protein was determined using a Betagen scanner. Fibrillin protein synthesis was reduced in 2 of the 3 patients with very low RNA production from one of the FBN1 alleles. All other Marfan and control cell strains showed normal amounts of fibrillin synthesized. The low expression levels from one allele may contribute to, but not fully account for, the low detection rate of FBN1 mutations. Interestingly, protein synthesis levels were not affected in 4 of 6 cell strains demonstrating low levels of RNA expression.

  12. Treatment of a Chronic Aneurysmal Aortic Dissection in a Patient with Marfan Syndrome Using a Staged Hybrid Procedure and a Fenestrated Endograft

    SciTech Connect

    Walkden, R. Miles Morgan, Rob A.; Loftus, Ian; Thompson, Matt

    2008-07-15

    Patients with aneurysmal dissections involving both the thoracic and the abdominal aorta are particularly challenging to treat with endovascular techniques because of the natural communications at the level of the visceral arteries. We present the case of a patient with Marfan syndrome with an aneurysmal aortic dissection involving the thoracic and abdominal aorta who was treated by a combination of endografts, surgical bypass, and a fenestrated tube graft.

  13. Long-term outcomes of aortic root operations for Marfan syndrome: A comparison of Bentall versus aortic valve-sparing procedures.

    PubMed

    Price, Joel; Magruder, J Trent; Young, Allen; Grimm, Joshua C; Patel, Nishant D; Alejo, Diane; Dietz, Harry C; Vricella, Luca A; Cameron, Duke E

    2016-02-01

    Prophylactic aortic root replacement improves survival in patients with Marfan syndrome with aortic root aneurysms, but the optimal procedure remains undefined. Adult patients with Marfan syndrome who had Bentall or aortic valve-sparing root replacement (VSRR) procedures between 1997 and 2013 were identified. Comprehensive follow-up information was obtained from hospital charts and telephone contact. One hundred sixty-five adult patients with Marfan syndrome (aged > 20 years) had either VSRR (n = 98; 69 reimplantation, 29 remodeling) or Bentall (n = 67) procedures. Patients undergoing Bentall procedure were older (median, 37 vs 36 years; P = .03), had larger median preoperative sinus diameter (5.5 cm vs 5.0 cm; P = .003), more aortic dissections (25.4% vs 4.1%; P < .001), higher incidence of moderate or severe aortic insufficiency (49.3% vs 14.4%; P < .001) and more urgent or emergent operations (24.6% vs 3.3%; P < .001). There were no hospital deaths and 9 late deaths in more than 17 years of follow-up (median, 7.8 deaths). Ten-year survival was 90.5% in patients undergoing Bentall procedure and 96.3% in patients undergoing VSRR (P = .10). Multivariable analysis revealed that VSRR was associated with fewer thromboembolic or hemorrhagic events (hazard ratio, 0.16; 95% confidence interval, 0.03-0.85; P = .03). There was no independent difference in long-term survival, freedom from reoperation, or freedom from endocarditis between the 2 procedures. After prophylactic root replacement in patients with Marfan syndrome, patients undergoing Bentall and valve-sparing procedures have similar late survival, freedom from root reoperation, and freedom from endocarditis. However, valve-sparing procedures result in significantly fewer thromboembolic and hemorrhagic events. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  14. Lack of segregation of a Marfan-like phenotype associating marfanoie habitus and mitral valve disease with fibrillin gene on chromosome 15

    SciTech Connect

    VanMaldergen, L.; Hilbert, P.; Gillerot, Y.

    1994-09-01

    Apart from typical Marfan syndrome (MS), several Marfan-like conditions are known. One of those is the MASS syndrome (Mitral involvement, Aortic dilatation, Skin and Skeletal abnormalities) defined by Pyeritz et al. Among these, a dominantly inherited mitral valve prolapse with marfanoid habitus have also been reported. Until now, except for a Marfan-like condition described by Boileau et al., all Marfan families are linked to fib 15. A large Belgian pedigree with 25 affected patients among 62 at risk subjects spanning four generations is described. A syndrome including marfanoid skeletal dysplasia (tall stature, dolichostenomelia, arachnodactyly, pectus carinatum joint dislocation), prolapse and/or myxomatous degeneration of the mitral valve, but without aortic dilatation of eye involvement was observed. Although the phenotype fulfills Berlin diagnostic criteria for MS, it closely resembles MASS syndrome. Preliminary linkage results show discordance aggregation insertion in the fib 15 gene, as evaluated by intragenic microsatellite fib 15. Since Dietz et al. described a similar patient with fib 15 gene, we suggest that this variant of Marfan syndrome is genetically heterogeneous and caused by mutations, some of which are allelic to classical Marfan syndrome plus a subtype, some of which are not. Linkage studies are under way to further characterize the gene involved in the present family.

  15. Atypical Neonatal Marfan Syndrome with p.Glu1073Lys Mutation of FBN1: the First Case in Korea

    PubMed Central

    2017-01-01

    Neonatal Marfan syndrome (nMFS) is considered to be on the most severe end of the spectrum of type I fibrillinopathies. The common features of nMFS include ascending aortic dilatation, severe mitral and/or tricuspid valve insufficiency, ectopia lentis, arachnodactyly, joint contractures, crumpled ear, loose skin, and pulmonary emphysema.We describe a newborn male diagnosed with nMFS. He presented several atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Molecular analysis revealed a missense mutation at nucleotide 3217 (c.3217G>A) in exon 26 of the fibrillin-1 (FBN1) gene, resulting in the substitution of a glutamate for a lysine at codon 1073 (E1073K) in the 12th calcium binding epidermal growth factor-like domain of the FBN1 protein. Here we report a rare case of Nmfs with several combined atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Our report is the first atypical nMFS case with p.Glu1073Lys mutation of FBN1 in Korea and may help clinicians with the diagnosis and follow-up of atypical nMFS. PMID:27914124

  16. Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders.

    PubMed

    Liu, W O; Oefner, P J; Qian, C; Odom, R S; Francke, U

    Marfan syndrome (MFS), a common connective tissue disorder, is caused by fibrillin-1 (FBN1) mutations that are scattered throughout the gene and are largely unique to individual families. Mutation detection in this large gene of 65 exons is a considerable technical challenge. To develop an efficient method capable of identifying all possible mutations in this gene, we have explored the use of a novel denaturing high-performance liquid chromatography (DHPLC) system. This technique compares two or more chromosomes as a mixture of denatured and reannealed PCR amplicons. Under partially denaturing conditions, heteroduplexes can be separated from homoduplexes. A panel of 94 DNA samples from individuals with MFS or related connective tissue disorders was screened exon-by-exon by this method. A total of 66 unique heteroduplex profiles was identified. Sequencing of the amplicons detected 37 novel and two previously reported mutations, as well as 15 novel and 10 known polymorphisms or unique sequence variants that are probably of no clinical significance. Of the 34 mutations found in definitive MFS cases, 16 were identified in the 21 samples that had not been screened before (76% detection rate) and 17/40 (43%) were in samples previously screened by other mutation detection methods. In 32 individuals with MFS-related phenotypes, five FBN1 mutations were identified (16%). Our results demonstrate the power of the DHPLC method to detect FBN1 mutations. It should be applicable for mutation screening in any gene in a large population.

  17. Identification of 8 new mutations in Brazilian families with Marfan syndrome. Mutations in brief no. 211. Online.

    PubMed

    Perez, A B; Pereira, L V; Brunoni, D; Zatz, M; Passos-Bueno, M R

    1999-01-01

    Marfan Syndrome (MFS) is a connective tissue disease caused by mutations in the fibrillin-1 FBN1) gene. Screening for mutations in all the 65 exons of the FBN1 gene in 34 unrelated patients were performed to compare the efficiency of SSCP versus Heteroduplex analysis and to verify if the spectrum of mutations in Brazilian patients is similar to the one previously reported. Fourteen different band shifts were detected by SSCP analysis; among these only 6 were also were also detected through Heteroduplex analysis, suggesting that SSCP analysis was a more efficient method. Except for one, the molecular alteration was confirmed in the remaining 13 cases by sequencing; five of them were neutral polymorphisms and the eight others are new pathogenic mutations, as follows: 5 missense, one nonsense and two deletions leading to a premature termination codon (PTC). All of them are located in EGF-like-calcium binding motifs (EGF-like-cb). Our findings reinforce that cysteine substitutions and PTC mutations in the region between exons 24-32 are more likely not to be associated with the neonatal phenotypes.

  18. Marfan syndrome: clinical consequences resulting from a medicolegal autopsy of a case of sudden death due to aortic rupture.

    PubMed

    Klintschar, M; Bilkenroth, U; Arslan-Kirchner, M; Schmidtke, J; Stiller, D

    2009-01-01

    To investigate the sudden death of a 31-year-old man, a medicolegal autopsy was performed. Major findings were a dilated aortic root with a longitudinal rupture of the intima and dissection of aorta and right coronary artery and consequent tamponade of the pericardial sac. Moreover, arachnodactyly and other skeletal deformities in combination with the histological finding of a pseudocystic medionecrosis of the aortic wall were noted. By sequencing of the FBN1 gene, a mutation (1622G>A) leading to the diagnosis of Marfan syndrome was found. Genetic counseling was recommended to the relatives who reported that the father of the deceased had died at the same age from aortic rupture. While fortunately the child of the deceased lacked this mutation, it was found in his younger sister. The results of the autopsy thus enabled early diagnosis and beginning of treatment in the sister and thus a considerable statistical increase in lifespan. With this report, we want to show that medicolegal autopsies can also have medical consequences for relatives. We argue that in all sudden and unexpected deaths in young persons up to 35 years an autopsy should be performed, not only to detect unnatural causes of death but also to identify heritable diseases and thus aid the relatives.

  19. Atypical Neonatal Marfan Syndrome with p.Glu1073Lys Mutation of FBN1: the First Case in Korea.

    PubMed

    Heo, Ju Sun; Song, Joo Young; Choi, Eun Young; Kim, Eun Hee; Kim, Ji Hee; Park, So Eun; Jeon, Ji Hyun

    2017-01-01

    Neonatal Marfan syndrome (nMFS) is considered to be on the most severe end of the spectrum of type I fibrillinopathies. The common features of nMFS include ascending aortic dilatation, severe mitral and/or tricuspid valve insufficiency, ectopia lentis, arachnodactyly, joint contractures, crumpled ear, loose skin, and pulmonary emphysema.We describe a newborn male diagnosed with nMFS. He presented several atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Molecular analysis revealed a missense mutation at nucleotide 3217 (c.3217G>A) in exon 26 of the fibrillin-1 (FBN1) gene, resulting in the substitution of a glutamate for a lysine at codon 1073 (E1073K) in the 12th calcium binding epidermal growth factor-like domain of the FBN1 protein. Here we report a rare case of Nmfs with several combined atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Our report is the first atypical nMFS case with p.Glu1073Lys mutation of FBN1 in Korea and may help clinicians with the diagnosis and follow-up of atypical nMFS.

  20. Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome

    PubMed Central

    Nistala, Harikiran; Lee-Arteaga, Sui; Carta, Luca; Cook, Jason R.; Smaldone, Silvia; Siciliano, Gabriella; Rifkin, Aaron N.; Dietz, Harry C.; Rifkin, Daniel B.; Ramirez, Francesco

    2010-01-01

    Reduced bone mineral density (osteopenia) is a poorly characterized manifestation of pediatric and adult patients afflicted with Marfan syndrome (MFS), a multisystem disorder caused by structural or quantitative defects in fibrillin-1 that perturb tissue integrity and TGFβ bioavailability. Here we report that mice with progressively severe MFS (Fbn1mgR/mgR mice) develop osteopenia associated with normal osteoblast differentiation and bone formation. In vivo and ex vivo experiments, respectively, revealed that adult Fbn1mgR/mgR mice respond more strongly to locally induced osteolysis and that Fbn1mgR/mgR osteoblasts stimulate pre-osteoclast differentiation more than wild-type cells. Greater osteoclastogenic potential of mutant osteoblasts was largely attributed to Rankl up-regulation secondary to improper TGFβ activation and signaling. Losartan treatment, which lowers TGFβ signaling and restores aortic wall integrity in mice with mild MFS, did not mitigate bone loss in Fbn1mgR/mgR mice even though it ameliorated vascular disease. Conversely, alendronate treatment, which restricts osteoclast activity, improved bone quality but not aneurysm progression in Fbn1mgR/mgR mice. Taken together, our findings shed new light on the pathogenesis of osteopenia in MFS, in addition to arguing for a multifaceted treatment strategy in this congenital disorder of the connective tissue. PMID:20871099

  1. Rationale and Design of a Randomized Clinical Trial of Beta Blocker Therapy (Atenolol) vs. Angiotensin II Receptor Blocker Therapy (Losartan) in Individuals with Marfan Syndrome

    PubMed Central

    Lacro, Ronald V.; Dietz, Harry C.; Wruck, Lisa M.; Bradley, Timothy J.; Colan, Steven D.; Devereux, Richard B.; Klein, Gloria L.; Li, Jennifer S.; Minich, L. LuAnn; Paridon, Stephen M.; Pearson, Gail D.; Printz, Beth F.; Pyeritz, Reed E.; Radojewski, Elizabeth; Roman, Mary J.; Saul, J. Philip; Stylianou, Mario P.; Mahony, Lynn

    2009-01-01

    Background Cardiovascular pathology, including aortic root dilation, dissection, and rupture, is the leading cause of mortality in patients with Marfan syndrome (MFS). The maximal aortic root diameter at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome. Although advances in therapy have improved life expectancy, affected individuals continue to suffer cardiovascular morbidity and mortality. Recent studies in a FBN1-targeted mouse model of MFS with aortic pathology similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture. Methods The Pediatric Heart Network designed a randomized clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in MFS subjects receiving atenolol or losartan. Individuals 6 months to 25 years of age with a body surface area-adjusted aortic root Z-score > 3.0 will be eligible for inclusion. The primary aim is to compare the effect of atenolol therapy to that of losartan therapy on the rate of aortic root growth over 3 years. Secondary endpoints include progression of aortic regurgitation; incidence of aortic dissection, aortic root surgery, and death; progression of mitral regurgitation; left ventricular size and function; echocardiographically-derived measures of central aortic stiffness; skeletal and somatic growth; and incidence of adverse drug reactions. Conclusion This randomized trial should make a substantial contribution to the management of individuals with MFS and expand our understanding of the mechanisms responsible for the aortic manifestations of this disorder. PMID:17892982

  2. Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders.

    PubMed

    Mátyás, Gábor; Arnold, Eliane; Carrel, Thierry; Baumgartner, Daniela; Boileau, Catherine; Berger, Wolfgang; Steinmann, Beat

    2006-08-01

    Very recently, heterozygous mutations in the genes encoding transforming growth factor beta receptors I (TGFBR1) and II (TGFBR2) have been reported in Loeys-Dietz aortic aneurysm syndrome (LDS). In addition, dominant TGFBR2 mutations have been identified in Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). In the past, mutations of these genes were associated with atherosclerosis and several human cancers. Here, we report a total of nine novel and one known heterozygous sequence variants in the TGFBR1 and TGFBR2 genes in nine of 70 unrelated individuals with MFS-like phenotypes who previously tested negative for mutations in the gene encoding the extracellular matrix protein fibrillin-1 (FBN1). To assess the pathogenic impact of these sequence variants, in silico analyses were performed by the PolyPhen, SIFT, and Fold-X algorithms and by means of a 3D homology model of the TGFBR2 kinase domain. Our results showed that in all but one of the patients the pathogenic effect of at least one sequence variant is highly probable (c.722C > T, c.799A > C, and c.1460G > A in TGFBR1 and c.773T > G, c.1106G > T, c.1159G > A, c.1181G > A, and c.1561T > C in TGFBR2). These deleterious alleles occurred de novo or segregated with the disease in the families, indicating a causative association between the sequence variants and clinical phenotypes. Since TGFBR2 mutations found in patients with MFS-related disorders cannot be distinguished from heterozygous TGFBR2 mutations reported in tumor samples, we emphasize the importance of segregation analysis in affected families. In order to be able to find the mutation that is indeed responsible for a MFS-related phenotype, we also propose that genetic testing for sequence alterations in TGFBR1 and TGFBR2 should be complemented by mutation screening of the FBN1 gene.

  3. Aortic and Cardiac Structure and Function Using High-Resolution Echocardiography and Optical Coherence Tomography in a Mouse Model of Marfan Syndrome

    PubMed Central

    Lee, Ling; Cui, Jason Z.; Cua, Michelle; Esfandiarei, Mitra; Sheng, Xiaoye; Chui, Winsey Audrey; Xu, Michael Haoying; Sarunic, Marinko V.; Beg, Mirza Faisal; van Breemen, Cornelius; Sandor, George G. S.

    2016-01-01

    Marfan syndrome (MFS) is an autosomal-dominant disorder of connective tissue caused by mutations in the fibrillin-1 (FBN1) gene. Mortality is often due to aortic dissection and rupture. We investigated the structural and functional properties of the heart and aorta in a [Fbn1C1039G/+] MFS mouse using high-resolution ultrasound (echo) and optical coherence tomography (OCT). Echo was performed on 6- and 12-month old wild type (WT) and MFS mice (n = 8). In vivo pulse wave velocity (PWV), aortic root diameter, ejection fraction, stroke volume, left ventricular (LV) wall thickness, LV mass and mitral valve early and atrial velocities (E/A) ratio were measured by high resolution echocardiography. OCT was performed on 12-month old WT and MFS fixed mouse hearts to measure ventricular volume and mass. The PWV was significantly increased in 6-mo MFS vs. WT (366.6 ± 19.9 vs. 205.2 ± 18.1 cm/s; p = 0.003) and 12-mo MFS vs. WT (459.5 ± 42.3 vs. 205.3 ± 30.3 cm/s; p< 0.0001). PWV increased with age in MFS mice only. We also found a significantly enlarged aortic root and decreased E/A ratio in MFS mice compared with WT for both age groups. The [Fbn1C1039G/+] mouse model of MFS replicates many of the anomalies of Marfan patients including significant aortic dilation, central aortic stiffness, LV systolic and diastolic dysfunction. This is the first demonstration of the direct measurement in vivo of pulse wave velocity non-invasively in the aortic arch of MFS mice, a robust measure of aortic stiffness and a critical clinical parameter for the assessment of pathology in the Marfan syndrome. PMID:27824871

  4. Whole exome sequencing is an efficient, sensitive and specific method of mutation detection in osteogenesis imperfecta and Marfan syndrome.

    PubMed

    McInerney-Leo, Aideen M; Marshall, Mhairi S; Gardiner, Brooke; Coucke, Paul J; Van Laer, Lut; Loeys, Bart L; Summers, Kim M; Symoens, Sofie; West, Jennifer A; West, Malcolm J; Paul Wordsworth, B; Zankl, Andreas; Leo, Paul J; Brown, Matthew A; Duncan, Emma L

    2013-01-01

    Osteogenesis imperfecta (OI) and Marfan syndrome (MFS) are common Mendelian disorders. Both conditions are usually diagnosed clinically, as genetic testing is expensive due to the size and number of potentially causative genes and mutations. However, genetic testing may benefit patients, at-risk family members and individuals with borderline phenotypes, as well as improving genetic counseling and allowing critical differential diagnoses. We assessed whether whole exome sequencing (WES) is a sensitive method for mutation detection in OI and MFS. WES was performed on genomic DNA from 13 participants with OI and 10 participants with MFS who had known mutations, with exome capture followed by massive parallel sequencing of multiplexed samples. Single nucleotide polymorphisms (SNPs) and small indels were called using Genome Analysis Toolkit (GATK) and annotated with ANNOVAR. CREST, exomeCopy and exomeDepth were used for large deletion detection. Results were compared with the previous data. Specificity was calculated by screening WES data from a control population of 487 individuals for mutations in COL1A1, COL1A2 and FBN1. The target capture of five exome capture platforms was compared. All 13 mutations in the OI cohort and 9/10 in the MFS cohort were detected (sensitivity=95.6%) including non-synonymous SNPs, small indels (<10 bp), and a large UTR5/exon 1 deletion. One mutation was not detected by GATK due to strand bias. Specificity was 99.5%. Capture platforms and analysis programs differed considerably in their ability to detect mutations. Consumable costs for WES were low. WES is an efficient, sensitive, specific and cost-effective method for mutation detection in patients with OI and MFS. Careful selection of platform and analysis programs is necessary to maximize success.

  5. Four novel FBN1 mutations: Significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome

    SciTech Connect

    Dietz, H.C.; McIntosh, I.; Pyeritz, R.E.; Francomano, C.A. ); Sakai, L.Y.; Corson, G.M.; Chalberg, S.C. )

    1993-08-01

    Defects of fibrillin (FBN1), a glycoprotein component of the extracellular microfibril, cause Marfan syndrome. This disorder is characterized by marked inter- and intrafamilial variation in phenotypic severity. To understand the molecular basis for this clinical observation, the authors have screened the fibrillin gene (FBN1) on chromosome 15, including the newly cloned 5[prime] coding sequence, for disease-producing alterations in a panel of patients with a wide range of manifestations and clinical severity. All the missense mutations identified to date, including two novel mutations discussed here, are associated with classic and moderate to severe disease and occur at residues with putative significance for calcium binding to epidermal growth factor (EGF)-like domains. In contrast, two new mutations that create premature signals for termination of translation of mRNA and are associated with reduction in the amount of mutant allele transcript produce a range of phenotypic severity. The patient with the lowest amount of mutant transcript has the mildest disease. These data support a role for altered calcium binding to EGF-like domains in the pathogenesis of Marfan syndrome and suggest a dominant negative mechanism for the pathogenesis of this disorder. 26 refs., 6 figs., 1 tab.

  6. The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD).

    PubMed

    Lerner-Ellis, Jordan P; Aldubayan, Saud H; Hernandez, Amy Lovelette; Kelly, Melissa Allard; Stuenkel, Aaron J; Walsh, Jennifer; Joshi, Victoria A

    2014-06-01

    In this study, patients suspected of having a clinical diagnosis of Marfan Syndrome (MFS), Loeys-Dietz Syndrome (LDS) and Thoracic Aortic Aneurysms and Dissections (TAAD) were referred for genetic testing and examined for mutations in the FBN1, TGFβR1, TGFβR2 and ACTA2 genes. We examined 594 samples from unrelated individuals and different combinations of genes were sequenced, including one or more of the following: FBN1, TGFβR1, TGFβR2, ACTA2, and, in some cases, FBN1 was analyzed by MLPA to detect large deletions. A total of 112 patients had a positive result. Of those, 61 had a clinical diagnosis of MFS, eight had LDS, three had TAAD and 40 patients had clinical features with no specific diagnosis provided. A total of 44 patients had an inconclusive result; of these, 12 patients were referred with a clinical diagnosis of MFS, 4 with LDS and 9 with TAAD and 19 had no clinical diagnosis. A total of 89 mutations were novel. This study reveals the rate of detection of variants in several genes associated with MFS, LDS and TAAD. The evaluation of patients by individuals with expertise in the field may decrease the likelihood of ordering unnecessary molecular testing. Nevertheless, genetic testing supports the diagnosis of MFS, LDS and TAAD. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Satisfaction with life in adults with Marfan syndrome (MFS): associations with health-related consequences of MFS, pain, fatigue, and demographic factors.

    PubMed

    Velvin, Gry; Bathen, Trine; Rand-Hendriksen, Svend; Geirdal, Amy Østertun

    2016-07-01

    The objective with this study was to explore satisfaction with life (SWL) among adults with Marfan syndrome (MFS) compared to the general Norwegian population and other patient groups and further to examine the associations between SWL and demographic factors, contact with social and health services, MFS-related health problems, chronic pain, and fatigue. This is a cross-sectional study with postal questionnaire, including the Satisfaction with Life Scale (SWLS), questions on demographic factors, health-related aspects of MFS, and validated instruments measuring chronic pain (Standardized Nordic Questionnaire) and fatigue (Fatigue Severity Scale). One hundred and seventeen adults with MFS were invited to participate, and 73 (62 %) participated. The SWLS mean score in adults with MFS was significantly lower than that reported for the general Norwegian population, but similar to or higher than that reported for other patient groups. Only fatigue, aortic dissection, and having regular contact with psychologist showed significant unique contribution to the SWLS score in the hierarchical multiple linear analyses. The total variance explained by the model was 45.2 % p ≤ 0.000, confirming that the combination of independent variables significantly predicted SWLS. The results reflect that MFS influences people's SWL and that particularly severe fatigue, aortic dissection, and psychological aspects are associated with lower SWL. This is important to take into account in the clinical work with people with MFS. Further investigation is needed, especially on larger sample groups. Studies with combination of qualitative and quantitative approaches are recommended to obtain more comprehensive and accurate knowledge about the consequences of MFS on satisfaction with life.

  8. Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms and sporadic aneurysms

    PubMed Central

    He, Rumin; Guo, Dong-Chuan; Sun, Wei; Papke, Christina L.; Duraisamy, Senthil; Estrera, Anthony L.; Safi, Hazim J.; Ahn, Chul; Buja, L. Maximilian; Arnett, Frank C.; Zhang, Jingwu; Geng, Yong-Jian; Milewicz, Dianna M.

    2008-01-01

    Objectives This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm (TAAs) in patients with Marfan syndrome (MFS), familial TAA (FTAA), and non-familial TAA cases. Background TAAs are associated with a pathologic lesion termed medial degeneration, which was described as a noninflammtory lesion. TAAs are a complication of MFS and also can be inherited in an autosomal dominant manner of FTAA. Methods Full aortic segments were collected from patients undergoing elective repair with MFS (n=5), FTAA (n=6) and TAAs (n=9), along with control aortas (n=5). Immunohistochemistry staining was performed using antibodies directed against markers of lymphocytes and macrophages. Real-time PCR analysis was performed to quantify the expression level of T cell receptor β chain variable region gene. Results Immunohistochemisty of TAA aortas demonstrated that the media and adventitia from MFS, FTAA and sporadic cases had increased numbers of T lymphocytes and macrophages when compared with control aortas. The number of T cells and macrophages in the aortic media of the aneurysm correlated inversely with the patient’s age at the time of prophylactic surgical repair of the aorta. Surprisingly, T cell receptor profiling indicated a similar clonal nature of the T cells in the aortic wall in a majority of aneurysms, whether the patient had MFS, FTAA or sporadic disease. Conclusion These results indicate that infiltration of inflammatory cells contributes to the pathogenesis of TAAs. Superantigen-driven stimulation of T lymphocytes in the aortic tissues of the TAA patients may contribute to the initial immune response. Ultramini-Abstract This study sought to investigate the infiltration of T-lymphocytes and macrophage in the aortas of patients with MFS, FTAA and sporadic TAAs. The results indicate that infiltration of inflammatory cells contributes to the pathogenesis of TAAs and superantigen-driven stimulation of T-lymphocytes may contribute to

  9. Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome.

    PubMed

    Rommel, Kathrin; Karck, Matthias; Haverich, Axel; von Kodolitsch, Yskert; Rybczynski, Meike; Müller, Götz; Singh, Krishna K; Schmidtke, Jörg; Arslan-Kirchner, Mine

    2005-12-01

    Marfan syndrome (MFS) is an autosomal-dominant disorder of the fibrous connective tissue that is typically caused by mutations in the gene coding for fibrillin-1 (FBN1), a major component of extracellular microfibrils. The clinical spectrum of MFS is highly variable and includes involvement of the cardiovascular, skeletal, ocular, and other organ systems; however, the genotype-phenotype correlations have not been well developed. Various screening methods have led to the identification of about 600 different mutations (FBN1-UMD database; www.umd.be). In this study we performed SSCP and/or direct sequencing to analyze all 65 exons of the FBN1 gene in 116 patients presenting with classic MFS or related phenotypes. Twenty-nine novel and nine recurrent mutations were identified in 38 of the analyzed patients. The mutations comprised 18 missense (47%), eight nonsense (21%), and five splice site (13%) mutations. Seven further mutations (18%) resulted from deletion, insertion, or duplication events, six of which led to a frameshift and subsequent premature termination. Additionally, we describe new polymorphisms and sequence variants. On the basis of the data presented here and in a previous study, we were able to establish highly significant correlations between the FBN1 mutation type and the MFS phenotype in a group of 76 mutation-positive patients for whom comprehensive clinical data were available. Most strikingly, there was a significantly lower incidence of ectopia lentis in patients who carried a mutation that led to a premature termination codon (PTC) or a missense mutation without cysteine involvement in FBN1, as compared to patients whose mutations involved a cysteine substitution or splice site alteration. Copyright 2005 Wiley-Liss, Inc.

  10. Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome.

    PubMed

    Cook, Jason R; Clayton, Nicholas P; Carta, Luca; Galatioto, Josephine; Chiu, Emily; Smaldone, Silvia; Nelson, Carol A; Cheng, Seng H; Wentworth, Bruce M; Ramirez, Francesco

    2015-04-01

    Studies of mice with mild Marfan syndrome (MFS) have correlated the development of thoracic aortic aneurysm (TAA) with improper stimulation of noncanonical (Erk-mediated) TGFβ signaling by the angiotensin type I receptor (AT1r). This correlation was largely based on comparable TAA modifications by either systemic TGFβ neutralization or AT1r antagonism. However, subsequent investigations have called into question some key aspects of this mechanism of arterial disease in MFS. To resolve these controversial points, here we made a head-to-head comparison of the therapeutic benefits of TGFβ neutralization and AT1r antagonism in mice with progressively severe MFS (Fbn1(mgR/mgR) mice). Aneurysm growth, media degeneration, aortic levels of phosphorylated Erk and Smad proteins and the average survival of Fbn1(mgR/mgR) mice were compared after a ≈3-month-long treatment with placebo and either the AT1r antagonist losartan or the TGFβ-neutralizing antibody 1D11. In contrast to the beneficial effect of losartan, TGFβ neutralization either exacerbated or mitigated TAA formation depending on whether treatment was initiated before (postnatal day 16; P16) or after (P45) aneurysm formation, respectively. Biochemical evidence-related aneurysm growth with Erk-mediated AT1r signaling, and medial degeneration with TGFβ hyperactivity that was in part AT1r dependent. Importantly, P16-initiated treatment with losartan combined with P45-initiated administration of 1D11 prevented death of Fbn1(mgR/mgR) mice from ruptured TAA. By demonstrating that promiscuous AT1r and TGFβ drive partially overlapping processes of arterial disease in MFS mice, our study argues for a therapeutic strategy against TAA that targets both signaling pathways although sparing the early protective role of TGFβ. © 2015 American Heart Association, Inc.

  11. Detection of 15 novel mutations in 52 children from 40 families with the Marfan or Loeys-Dietz syndrome and phenotype-genotype correlations.

    PubMed

    Pees, C; Michel-Behnke, I; Hagl, M; Laccone, F

    2014-12-01

    We report about 52 pediatric patients of 40 different families with confirmed Marfan syndrome (MFS) in 49 patients and Loeys-Dietz syndrome (LDS) in 3 patients. We found 39 different mutations, 15 of them being novel. Phenotype-genotype correlation in the 49 MFS patients showed that the majority of patients carrying mutations in exons 1-21 had ectopic lens (80%). Patients having mutations in exons 23-32 had a higher probability of aortic root dilation, in 50% even above a z score of 3. We found three children with neonatal MFS form, two of them with novel mutations. Of the three LDS patients, only one presented with the typical phenotype of LDS type 1. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Analysis of disease progression-associated gene expression profile in fibrillin-1 mutant mice: new insight into molecular pathogenesis of marfan syndrome.

    PubMed

    Kim, Koung Li; Choi, Chanmi; Suh, Wonhee

    2014-02-01

    Marfan syndrome (MFS) is a dominantly inherited connective tissue disorder caused by mutations in the gene encoding fibrillin-1 (FBN1) and is characterized by aortic dilatation and dissection, which is the primary cause of death in untreated MFS patients. However, disease progression-associated changes in gene expression in the aortic lesions of MFS patients remained unknown. Using a mouse model of MFS, FBN1 hypomorphic mouse (mgR/mgR), we characterized the aortic gene expression profiles during the progression of the MFS. Homozygous mgR mice exhibited MFS-like phenotypic features, such as fragmentation of elastic fibers throughout the vessel wall and were graded into mgR1-4 based on the pathological severity in aortic walls. Comparative gene expression profiling of WT and four mgR mice using microarrays revealed that the changes in the transcriptome were a direct reflection of the severity of aortic pathological features. Gene ontology analysis showed that genes related to oxidation/reduction, myofibril assembly, cytoskeleton organization, and cell adhesion were differentially expressed in the mgR mice. Further analysis of differentially expressed genes identified several candidate genes whose known roles were suggestive of their involvement in the progressive destruction of aorta during MFS. This study is the first genome-wide analysis of the aortic gene expression profiles associated with the progression of MFS. Our findings provide valuable information regarding the molecular pathogenesis during MFS progression and contribute to the development of new biomarkers as well as improved therapeutic strategies.

  13. Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies.

    PubMed

    Arbustini, Eloisa; Grasso, Maurizia; Ansaldi, Silvia; Malattia, Clara; Pilotto, Andrea; Porcu, Emanuele; Disabella, Eliana; Marziliano, Nicola; Pisani, Angela; Lanzarini, Luca; Mannarino, Savina; Larizza, Daniela; Mosconi, Mario; Antoniazzi, Elena; Zoia, M Cristina; Meloni, Giulia; Magrassi, Lorenzo; Brega, Agnese; Bedeschi, Maria Francesca; Torrente, Isabella; Mari, Francesca; Tavazzi, Luigi

    2005-11-01

    Marfan Syndrome (MFS) is an autosomal dominant disorder of the connective tissue due to mutations of Fibrillin-1 gene (FBN1) in more than 90% of cases and Transforming Growth Factor-Beta-Receptor2 gene (TGFB2R) in a minority of cases. Genotyping is relevant for diagnosis and genotype-phenotype correlations. We describe the FBN1 genotypes and related phenotypes of 81 patients who were referred to our attention for MFS or Marfan-like phenotypes. Patients underwent multidisciplinary pertinent evaluation in the adult or paediatric setting, according to their age. The diagnosis relied on Ghent criteria. To optimise DHPLC analysis of the FBN1 gene, all coding regions of the gene were directly sequenced in 19 cases and 10 controls: heterozygous amplicons were used as true positives. DHPLC sensitivity was 100%. Then, DHPLC was used to screen 62 other cases. We identified 74 FBN1 mutations in 81 patients: 64 were novel and 17 known. Of the 81 mutations, 41 were missense (50.6%), 27, either nonsense or frameshift mutations and predicted a premature termination codon (PTC) (33%), 11 affected splice sites (13.6%), and two predicted in-frame deletions (2.5%). Most mutations (67.9%) occurred in cbEGF-like modules. Genotype was clinically relevant for early diagnosis and conclusion of the diagnostic work-up in patients with incomplete or atypical phenotypes. Copyright 2005 Wiley-Liss, Inc.

  14. Nicolo Paganini. Musical magician and Marfan mutant?

    PubMed

    Schoenfeld, M R

    1978-01-02

    The thesis is advanced that Nicolo Paganini of Genoa (1782 to 1840), the greatest violin virtuoso of all time, owed his incomparable violin virtuosity to a fortuitous and fortunate coincidence of three factors: a soaring musical genius, a flair for the dramatic and ostentatious, and manual dexterity conferred by being born with the long fingers and hyperextensible joints of Marfan's syndrome. Ordinarily, an inborn connective tissue disorder is a calamity for the patient and a burden for society. In this particular instance, however, Marfan's syndrome bequeathed to posterity a legacy that will ennoble the human spirit for innumerable generations yet to come.

  15. Native Mitral Valve Endocarditis Caused by Neisseria elongata subsp. nitroreducens in a Patient with Marfan Syndrome: First Case in Italy and Review of the Literature

    PubMed Central

    Rossella, Parrinello; Fabio Oreste, Triolo; Renato, Trapani; Emanuele, Grassedonio; Vincenzo, Argano; Giuseppina, Novo; Silvana, Vallone; Teresa, Fasciana; Massimo, Verdecchia; Anna, Giammanco; Massimo, Midiri; Salvatore, Novo

    2016-01-01

    Neisseria elongata (NE) is an aerobic Gram-negative organism that constitutes part of the commensal human normal oropharyngeal flora. Although previously considered not to be pathogenic, it has been recognized as an occasional cause of significant infections in humans. We report here the first case in Italy of infective endocarditis of a native prolapsing mitral valve in a patient with Marfan syndrome, caused by NE subspecies nitroreducens which has been rarely isolated from clinical specimens. The culprit organism has been confirmed by mass spectrometry directly from the positive blood culture, as previously reported. The amplified gene has been deposited in GenBank under accession number KT591873. In spite of the reported aggressive nature of NE, clinical remission was promptly obtained, there being no requirement for surgery. PMID:27803825

  16. Tracheal compression in a patient with Marfan's syndrome-associated tracheomegaly treated by an XXL stent: the largest diameter airway stent ever placed in a previously undescribed airway condition.

    PubMed

    Dutau, Hervé; Cavailles, Arnaud; Fernandez-Navamuel, Iker; Breen, David P

    2009-01-01

    A 43-year-old man was referred to our institution with severe extrinsic compression of the trachea at the level of the main carina secondary to an aortic aneurysm, causing respiratory distress and requiring mechanical ventilation. The patient had a past history of Marfan's syndrome and tracheomegaly (the estimated tracheal diameter bronchoscopically was 28 mm). Palliation of the compression was successfully achieved by a custom-made, self-expandable, fully covered metallic stent with a diameter of 28 mm and a length of 60 mm. The patient was weaned off ventilation. The stent stayed in place for 2 years without major complications. This case represents the first stent ever inserted in a very rare condition combining tracheomegaly and extrinsic compression in Marfan's syndrome. It is also the first report of successful placement of the largest tracheal stent which was manufactured exclusively for the airway. (c) 2007 S. Karger AG, Basel.

  17. Left ventricular systolic dysfunction in asymptomatic Marfan syndrome patients is related to the severity of gene mutation: insights from the novel three dimensional speckle tracking echocardiography.

    PubMed

    Abd El Rahman, Mohamed; Haase, Denise; Rentzsch, Axel; Olchvary, Julia; Schäfers, Hans-Joachim; Henn, Wolfram; Wagenpfeil, Stefan; Abdul-Khaliq, Hashim

    2015-01-01

    In asymptomatic Marfan syndrome (MFS) patients we evaluated the relationship between the types of fibrillin-1 (FBN1) gene mutation and possible altered left ventricular (LV) function as assessed by three-dimensional speckle tracking echocardiography (3D-STE). Forty-five MFS patients (mean age 24 ± 15 years) and 40 age-matched healthy controls were studied. Genetic evaluation for the FBN1 gene was carried on 32 MFS patients. Gene mutation (n = 15, 47%) was classified as mild when the mutation resulted in nearly normally functioning protein, while mutations resulting in abnormally function protein were considered to be severe (n = 17, 53%). All patients and controls underwent 3D-STE for evaluation of LV function by an echocardiographer blinded to the results of the genetic testing. Compared to controls, MFS patients had significantly lower 3D-STE derived LV ejection fraction (EF, 57.43 ± 7.51 vs. 62.69 ± 4.76%, p = 0.0001), global LV longitudinal strain (LS, 14.85 ± 2.89 vs. 17.90 ± 2.01%, p = 0.0001), global LV circumferential strain (CS, 13.93 ± 2.81 vs. 16.82 ± 2.17%, p = 0.0001) and global LV area strain (AS, 25.76 ± 4.43 vs. 30.51 ± 2.61%, p = 0.0001). Apart from the global LV LS all these parameters were significantly lower in patients with severe gene mutation than in those with mild mutation (p < 0.05). In the multivariate linear regression analysis only the type of mutation had a significant influence on the 3D-STE derived LVEF (p = 0.017), global CS (p = 0.005) and global AS (p = 0.03). In asymptomatic MFS patients latent LV dysfunction can be detected using 3D STE. The LV dysfunction is mainly related to the severity of gene mutation, suggesting possible primary cardiomyopathy in MFS patients.

  18. Marfan Syndrome (For Teens)

    MedlinePlus

    ... En Español Making a Change – Your Personal Plan Hot Topics Am I in a Healthy Relationship? Who ... in extreme temperatures, such as really cold or hot weather. The key here is to check with ...

  19. What Is Marfan Syndrome?

    MedlinePlus

    ... pushes through an opening in the organ’s wall). Nervous system The brain and spinal cord are covered by ... you have any problems with breathing during sleep. Nervous system Taking medicine for pain if the membrane of ...

  20. Marfan Syndrome (For Teens)

    MedlinePlus

    ... joints are loose and flexible. They may have myopia (nearsightedness) or other vision problems (such as lens ... to be couch potatoes. They can and should exercise and be active — they just have to do ...

  1. Learning about Marfan Syndrome

    MedlinePlus

    ... Links for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers Genomic Careers National DNA Day Online Education Kit Online Genetics Education ... Subjects Research Informed Consent for Genomics Research Intellectual ...

  2. Evaluating the quality of Marfan genotype-phenotype correlations in existing FBN1 databases.

    PubMed

    Groth, Kristian A; Von Kodolitsch, Yskert; Kutsche, Kerstin; Gaustadnes, Mette; Thorsen, Kasper; Andersen, Niels H; Gravholt, Claus H

    2017-07-01

    Genetic FBN1 testing is pivotal for confirming the clinical diagnosis of Marfan syndrome. In an effort to evaluate variant causality, FBN1 databases are often used. We evaluated the current databases regarding FBN1 variants and validated associated phenotype records with a new Marfan syndrome geno-phenotyping tool called the Marfan score. We evaluated four databases (UMD-FBN1, ClinVar, the Human Gene Mutation Database (HGMD), and Uniprot) containing 2,250 FBN1 variants supported by 4,904 records presented in 307 references. The Marfan score calculated for phenotype data from the records quantified variant associations with Marfan syndrome phenotype. We calculated a Marfan score for 1,283 variants, of which we confirmed the database diagnosis of Marfan syndrome in 77.1%. This represented only 35.8% of the total registered variants; 18.5-33.3% (UMD-FBN1 versus HGMD) of variants associated with Marfan syndrome in the databases could not be confirmed by the recorded phenotype. FBN1 databases can be imprecise and incomplete. Data should be used with caution when evaluating FBN1 variants. At present, the UMD-FBN1 database seems to be the biggest and best curated; therefore, it is the most comprehensive database. However, the need for better genotype-phenotype curated databases is evident, and we hereby present such a database.Genet Med advance online publication 01 December 2016.

  3. Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome.

    PubMed

    Oller, Jorge; Méndez-Barbero, Nerea; Ruiz, E Josue; Villahoz, Silvia; Renard, Marjolijn; Canelas, Lizet I; Briones, Ana M; Alberca, Rut; Lozano-Vidal, Noelia; Hurlé, María A; Milewicz, Dianna; Evangelista, Arturo; Salaices, Mercedes; Nistal, J Francisco; Jiménez-Borreguero, Luis Jesús; De Backer, Julie; Campanero, Miguel R; Redondo, Juan Miguel

    2017-02-01

    Heritable thoracic aortic aneurysms and dissections (TAAD), including Marfan syndrome (MFS), currently lack a cure, and causative mutations have been identified for only a fraction of affected families. Here we identify the metalloproteinase ADAMTS1 and inducible nitric oxide synthase (NOS2) as therapeutic targets in individuals with TAAD. We show that Adamts1 is a major mediator of vascular homeostasis, given that genetic haploinsufficiency of Adamts1 in mice causes TAAD similar to MFS. Aortic nitric oxide and Nos2 levels were higher in Adamts1-deficient mice and in a mouse model of MFS (hereafter referred to as MFS mice), and Nos2 inactivation protected both types of mice from aortic pathology. Pharmacological inhibition of Nos2 rapidly reversed aortic dilation and medial degeneration in young Adamts1-deficient mice and in young or old MFS mice. Patients with MFS showed elevated NOS2 and decreased ADAMTS1 protein levels in the aorta. These findings uncover a possible causative role for the ADAMTS1-NOS2 axis in human TAAD and warrant evaluation of NOS2 inhibitors for therapy.

  4. Endovascular Aneurysm Repair Using a Reverse Chimney Technique in a Patient With Marfan Syndrome and Contained Ruptured Chronic Type B Dissection

    SciTech Connect

    Ketelsen, Dominik; Kalender, Guenay; Heuschmid, Martin; Syha, Roland; Mangold, Stefanie; Claussen, Claus D.; Brechtel, Klaus

    2011-10-15

    We report endovascular thoracic and abdominal aneurysm repair (EVAR) with reverse chimney technique in a patient with contained ruptured type B dissection. EVAR seems feasible as a bailout option in Marfan patients with acute life-threatening disease.

  5. AGT and ACE genes influence classic mitral valve prolapse predisposition in Marfan patients.

    PubMed

    Fatini, Cinzia; Attanasio, Monica; Porciani, Cristina; Sticchi, Elena; Padeletti, Luigi; Lapini, Ilaria; Abbate, Rosanna; Gensini, Gian Franco; Pepe, Guglielmina

    2008-01-24

    In Marfan syndrome, the mitral valve prolapse, ranging from nonclassic to classic form on the basis of the leaflet thickness, is a common condition characterized by a highly variable structural abnormality. We investigated the role of angiotensinogen (AGT) M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms in influencing the susceptibility to classic or non-classic mitral valve prolapse in Marfan patients. We studied 135 Marfan patients with mitral valve prolapse, diagnosed by echocardiography. AGT, ACE, and AT1R polymorphisms were identified by polymerase chain reaction-based restriction analysis. The frequency of the ACE D, but not AGT 235T and AT1R 1166C allele, was significantly higher in patients with classic mitral valve prolapse in comparison to that observed in the non-classic one (p=0.03). The percentage of subjects with the contemporaneous presence of ACE D and AGT 235T alleles was significantly higher in the classic mitral valve prolapse group in comparison to the non-classic one (79% vs. 55%, respectively; p=0.008). The concomitant presence of these two alleles was associated with increased susceptibility to the classic mitral valve prolapse (OR 3.02, p=0.016). Our findings show a possible role of ACE and AGT genes as predisposing factors to classic mitral valve prolapse in Marfan patients, thus suggesting a role of renin angiotensin system genes in modulating mitral valve abnormality, and the need for an interventional study with angiotensin II type 1 receptor antagonists, which considers the leaflet thickness progression in Marfan patients with MVP.

  6. A substitution at a non-glycine position in the triple-helical domain of pro alpha 2(I) collagen chains present in an individual with a variant of the Marfan syndrome.

    PubMed Central

    Phillips, C L; Shrago-Howe, A W; Pinnell, S R; Wenstrup, R J

    1990-01-01

    A substitution for a highly conserved non-glycine residue in the triple-helical domain of the pro alpha 2(I) collagen molecule was found in an individual with a variant of the Marfan syndrome. A single base change resulted in substitution of arginine618 by glutamine at the Y position of a Gly-X-Y repeat, and is responsible for the decreased migration in SDS-polyacrylamide gels of some pro alpha 2(I) chains of type I collagen synthesized by dermal fibroblasts from this individual. Family studies suggest that this substitution was inherited from the individual's father who also produces abnormally migrating pro alpha 2(I) collagen chains and shares some of the abnormal skeletal features. This single base change creates a new Bsu36 I (Sau I, Mst II) restriction site detectable in genomic DNA by Southern blot analysis when probed with a COL1A2 fragment. The analysis of 52 control individuals (103 chromosomes) was negative for the new Bsu36 I site, suggesting that the substitution is not a common polymorphism. Images PMID:1978725

  7. IL‐6 Regulates Extracellular Matrix Remodeling Associated With Aortic Dilation in a Fibrillin‐1 Hypomorphic mgR/mgR Mouse Model of Severe Marfan Syndrome

    PubMed Central

    Ju, Xiaoxi; Ijaz, Talha; Sun, Hong; LeJeune, Wanda; Vargas, Gracie; Shilagard, Tuya; Recinos, Adrian; Milewicz, Dianna M.; Brasier, Allan R.; Tilton, Ronald G.

    2014-01-01

    Background Development of thoracic aortic aneurysms is the most significant clinical phenotype in patients with Marfan syndrome. An inflammatory response has been described in advanced stages of the disease. Because the hallmark of vascular inflammation is local interleukin‐6 (IL‐6) secretion, we explored the role of this proinflammatory cytokine in the formation of aortic aneurysms and rupture in hypomorphic fibrillin‐deficient mice (mgR/mgR). Methods and Results MgR/mgR mice developed ascending aortic aneurysms with significant dilation of the ascending aorta by 12 weeks (2.7±0.1 and 1.3±0.1 for mgR/mgR versus wild‐type mice, respectively; P<0.001). IL‐6 signaling was increased in mgR/mgR aortas measured by increases in IL‐6 and SOCS3 mRNA transcripts (P<0.05) and in cytokine secretion of IL‐6, MCP‐1, and GM‐CSF (P<0.05). To investigate the role of IL‐6 signaling, we generated mgR homozygous mice with IL‐6 deficiency (DKO). The extracellular matrix of mgR/mgR mice showed significant disruption of elastin and the presence of dysregulated collagen deposition in the medial‐adventitial border by second harmonic generation multiphoton autofluorescence microscopy. DKO mice exhibited less elastin and collagen degeneration than mgR/mgR mice, which was associated with decreased activity of matrix metalloproteinase‐9 and had significantly reduced aortic dilation (1.0±0.1 versus 1.6±0.2 mm change from baseline, DKO versus mgR/mgR, P<0.05) that did not affect rupture and survival. Conclusion Activation of IL‐6‐STAT3 signaling contributes to aneurysmal dilation in mgR/mgR mice through increased MMP‐9 activity, aggravating extracellular matrix degradation. PMID:24449804

  8. Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: Identification of 20 novel mutations and two novel polymorphisms in the FBN1 gene.

    PubMed

    Mátyás, Gábor; De Paepe, Anne; Halliday, Dorothy; Boileau, Catherine; Pals, Gerard; Steinmann, Beat

    2002-04-01

    Mutations in the human fibrillin 1 gene (FBN1) cause the Marfan syndrome (MFS), an autosomal dominant connective tissue disorder. Knowledge about FBN1 mutations is important for early diagnosis, management, and genetic counseling. However, mutation detection in FBN1 is a challenge because the gene is very large in size ( approximately 200 kb) and the approximately 350 mutations detected so far are scattered over 65 exons. Conventional methods for large-scale detection of mutations are expensive, technically demanding, or time consuming. Recently, a high-capacity low-cost mutation detection method was introduced based on denaturing high-performance liquid chromatography (DHPLC). To assess the sensitivity and specificity of this method, we blindly screened 64 DNA samples of known FBN1 genotype exon-by-exon using exon-specific DHPLC conditions. Analysis of 682 PCR amplicons correctly identified 62 out of 64 known sequence variants. In three MFS patients of unknown FBN1 genotype, we detected two mutations and eight polymorphisms. Overall, 20 mutations and two polymorphisms are described here for the first time. Our results demonstrate 1) that DHPLC is a highly sensitive (89-99%, P = 0.05) method for FBN1 mutation detection; but 2) that chromatograms with moderate and weak pattern abnormalities also show false positive signals (in all 45-59%, P = 0.05); 3) that the difference in the chromatograms of heterozygous and homozygous amplicons is mostly independent of the type of sequence change; and 4) that DHPLC column conditions, additional base changes, and the amounts of injected PCR products influence significantly the shape of chromatograms. A strategy for FBN1 mutation screening is discussed. Copyright 2002 Wiley-Liss, Inc.

  9. Valve Sparing Aortic Root Replacement in Patients with Marfan Syndrome Enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions

    PubMed Central

    Song, Howard K.; Preiss, Liliana R.; Maslen, Cheryl L.; Kroner, Barbara; Devereux, Richard B.; Roman, Mary J.; Holmes, Kathryn W.; Tolunay, H. Eser; Desvigne-Nickens, Patrice; Asch, Federico M.; Milewski, Rita K.; Bavaria, Joseph; LeMaire, Scott A.

    2016-01-01

    Background The long-term outcomes of aortic valve sparing (AVS) root replacement in Marfan syndrome (MFS) patients remain uncertain. We sought to determine the utilization and outcomes of AVS root replacement in MFS patients enrolled in the Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). Methods At the time of this analysis, 788 patients with MFS were enrolled in the GenTAC Registry, of whom 288 have undergone aortic root replacement. Patients who have undergone AVS procedures were compared to those who have undergone aortic valve replacing (AVR) procedures. Results AVS root replacement was performed in 43.5% of MFS patients and the frequency of AVS increased over the past 5 years. AVS patients were younger at the time of surgery (31.0 vs. 36.3 years, p=0.006) and more likely to have had elective rather than emergency surgery compared to AVR patients. AVR patients were more likely to have had aortic valve dysfunction and aortic dissection as a primary indication for surgery. After mean follow-up of 6.2 (SD=3.6) years, none of the 87 AVS patients have required reoperation; in contrast, after mean follow up of 10.5 (SD=7.6) years, 11.5% of AVR patients have required aortic root reoperation. Aortic valve function has been durable with 95.8% of AVS patients with aortic insufficiency graded as mild or less. Conclusions AVS root replacement is performed commonly in the MFS population. The durability of the aortic repair and aortic valve function have been excellent to date. These results justify the continued use of the procedure in the elective setting. The GenTAC Registry will be a useful resource to assess the long-term durability of AVS root replacement in the future. PMID:25296451

  10. Decision-making in aortic root surgery in Marfan syndrome: bleeding, thromboembolism and risk of reintervention after valve-sparing or mechanical aortic root replacement.

    PubMed

    Schoenhoff, Florian S; Langhammer, Bettina; Wustmann, Kerstin; Reineke, David; Kadner, Alexander; Carrel, Thierry

    2015-12-01

    Valve-sparing root replacement (VSRR) is thought to reduce the rate of thromboembolic and bleeding events compared with aortic root replacement using a mechanical aortic root replacement (MRR) with a composite graft by avoiding oral anticoagulation. But as VSRR carries a certain risk for subsequent reinterventions, decision-making in the individual patient can be challenging. Of 100 Marfan syndrome (MFS) patients who underwent 169 aortic surgeries and were followed at our institution since 1995, 59 consecutive patients without a history of dissection or prior aortic surgery underwent elective VSRR or MRR and were retrospectively analysed. VSRR was performed in 29 (David n = 24, Yacoub n = 5) and MRR in 30 patients. The mean age was 33 ± 15 years. The mean follow-up after VSRR was 6.5 ± 4 years (180 patient-years) compared with 8.8 ± 9 years (274 patient-years) after MRR. Reoperation rates after root remodelling (Yacoub) were significantly higher than after the reimplantation (David) procedure (60 vs 4.2%, P = 0.01). The need for reinterventions after the reimplantation procedure (0.8% per patient-year) was not significantly higher than after MRR (P = 0.44) but follow-up after VSRR was significantly shorter (P = 0.03). There was neither significant morbidity nor mortality associated with root reoperations. There were no neurological events after VSRR compared with four stroke/intracranial bleeding events in the MRR group (log-rank, P = 0.11), translating into an event rate of 1.46% per patient-year following MRR. The calculated annual failure rate after VSRR using the reimplantation technique was lower than the annual risk for thromboembolic or bleeding events. Since the perioperative risk of reinterventions following VSRR is low, patients might benefit from VSRR even if redo surgery may become necessary during follow-up. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  11. The role of β-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome

    PubMed Central

    Wisler, James W.; Harris, Emily M.; Raisch, Michael; Mao, Lan; Kim, Jihee; Rockman, Howard A.

    2015-01-01

    Ang II type 1a receptor (AT1aR)-mediated activation of MAPKs contributes to thoracic aortic aneurysm (TAA) development in Marfan syndrome (MFS). β-Arrestin2 (βarr2) is known to mediate AT1aR-dependent MAPK activation, as well as proproliferative and profibrotic signaling in aortic vascular smooth muscle cells. Therefore, we investigated whether βarr2-dependent signaling contributes to TAA formation in MFS. We used a murine model of MFS [fibrillin (Fbn)C1039G/+] to generate an MFS murine model in combination with genetic βarr2 deletion (FbnC1039G/+/βarr2−/−). FbnC1039G/+/βarr2−/− mice displayed delayed aortic root dilation compared with FbnC1039G/+ mice. The mRNA and protein expression of several mediators of TAA formation, including matrix metalloproteinase (MMP)-2 and -9, was reduced in the aorta of FbnC1039G/+/βarr2−/− mice relative to FbnC1039G/+ mice. Activation of ERK1/2 was also decreased in the aortas of FbnC1039G/+/βarr2−/− mice compared with FbnC1039G/+ animals. Small interfering RNA targeting βarr2 inhibited angiotensin-stimulated expression of proaneurysmal signaling mediators in primary aortic root smooth muscle cells. Angiotensin-stimulated expression of the proaneurysmal signaling mediators MMP-2 and -9 was inhibited by blockade of ERK1/2 or the EGF receptor, whereas blockade of the transforming growth factor-β receptor had no effect. These results suggest that βarr2 contributes to TAA formation in MFS by regulating ERK1/2-dependent expression of proaneurysmal genes and proteins downstream of the AT1aR. Importantly, this demonstration of the unique signaling mechanism by which βarr2 contributes to aneurysm formation identifies multiple novel, potential therapeutic targets in MFS. PMID:26371162

  12. Loss of Endothelial Barrier in Marfan Mice (mgR/mgR) Results in Severe Inflammation after Adenoviral Gene Therapy

    PubMed Central

    Weymann, Alexander; Arif, Rawa; Weber, Antje; Zaradzki, Marcin; Richter, Karsten; Ensminger, Stephan; Robinson, Peter Nicholas; Wagner, Andreas H.; Karck, Matthias; Kallenbach, Klaus

    2016-01-01

    Objectives Marfan syndrome is an autosomal dominant inherited disorder of connective tissue. The vascular complications of Marfan syndrome have the biggest impact on life expectancy. The aorta of Marfan patients reveals degradation of elastin layers caused by increased proteolytic activity of matrix metalloproteinases (MMPs). In this study we performed adenoviral gene transfer of human tissue inhibitor of matrix metalloproteinases-1 (hTIMP-1) in aortic grafts of fibrillin-1 deficient Marfan mice (mgR/mgR) in order to reduce elastolysis. Methods We performed heterotopic infrarenal transplantation of the thoracic aorta in female mice (n = 7 per group). Before implantation, mgR/mgR and wild-type aortas (WT, C57BL/6) were transduced ex vivo with an adenoviral vector coding for human TIMP-1 (Ad.hTIMP-1) or β-galactosidase (Ad.β-Gal). As control mgR/mgR and wild-type aortas received no gene therapy. Thirty days after surgery, overexpression of the transgene was assessed by immunohistochemistry (IHC) and collagen in situ zymography. Histologic staining was performed to investigate inflammation, the neointimal index (NI), and elastin breaks. Endothelial barrier function of native not virus-exposed aortas was evaluated by perfusion of fluorescent albumin and examinations of virus-exposed tissue were performed by transmission electron microscopy (TEM). Results IHC and ISZ revealed sufficient expression of the transgene. Severe cellular inflammation and intima hyperplasia were seen only in adenovirus treated mgR/mgR aortas (Ad.β-Gal, Ad.hTIMP-1 NI: 0.23; 0.43), but not in native and Ad.hTIMP-1 treated WT (NI: 0.01; 0.00). Compared to native mgR/mgR and Ad.hTIMP-1 treated WT aorta, the NI is highly significant greater in Ad.hTIMP-1 transduced mgR/mgR aorta (p = 0.001; p = 0.001). As expected, untreated Marfan grafts showed significant more elastolysis compared to WT (p = 0.001). However, elastolysis in Marfan aortas was not reduced by adenoviral overexpression of hTIMP-1

  13. Genetics Home Reference: Marfan syndrome

    MedlinePlus

    ... of the body. Connective tissue provides strength and flexibility to structures such as bones, ligaments, muscles, blood ... part of the fibers that provide strength and flexibility to connective tissue . Additionally, microfibrils store molecules called ...

  14. How Is Marfan Syndrome Diagnosed?

    MedlinePlus

    ... heart's valves and aorta. Magnetic Resonance Imaging and Computed Tomography Scans Magnetic resonance imaging (MRI) is a test that uses radio waves and magnets to create detailed pictures of your organs and tissues. Computed tomography (CT) uses an x-ray machine to ...

  15. Epigenetic control of vascular smooth muscle cells in Marfan and non-Marfan thoracic aortic aneurysms

    PubMed Central

    Gomez, Delphine; Coyet, Aurélie; Ollivier, Véronique; Jeunemaitre, Xavier; Jondeau, Guillaume; Michel, Jean-Baptiste; Vranckx, Roger

    2011-01-01

    Aims Human thoracic aortic aneurysms (TAAs) are characterized by extracellular matrix breakdown associated with progressive smooth muscle cell (SMC) rarefaction. These features are present in all types of TAA: monogenic forms [mainly Marfan syndrome (MFS)], forms associated with bicuspid aortic valve (BAV), and degenerative forms. Initially described in a mouse model of MFS, the transforming growth factor-β1 (TGF-β1)/Smad2 signalling pathway is now assumed to play a role in TAA of various aetiologies. However, the relation between the aetiological diversity and the common cell phenotype with respect to TGF-β signalling remains unexplained. Methods and results This study was performed on human aortic samples, including TAA [MFS, n = 14; BAV, n = 15; and degenerative, n = 19] and normal aortas (n = 10) from which tissue extracts and human SMCs and fibroblasts were obtained. We show that all types of TAA share a complex dysregulation of Smad2 signalling, independent of TGF-β1 in TAA-derived SMCs (pharmacological study, qPCR). The Smad2 dysregulation is characterized by an SMC-specific, heritable activation and overexpression of Smad2, compared with normal aortas. The cell specificity and heritability of this overexpression strongly suggest the implication of epigenetic control of Smad2 expression. By chromatin immunoprecipitation, we demonstrate that the increases in H3K9/14 acetylation and H3K4 methylation are involved in Smad2 overexpression in TAA, in a cell-specific and transcription start site-specific manner. Conclusion Our results demonstrate the heritability, the cell specificity, and the independence with regard to TGF-β1 and genetic backgrounds of the Smad2 dysregulation in human thoracic aneurysms and the involvement of epigenetic mechanisms regulating histone marks in this process. PMID:20829218

  16. Chronobiology of Acute Aortic Dissection in the Marfan Syndrome (from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions and the International Registry of Acute Aortic Dissection).

    PubMed

    Siddiqi, Hasan K; Luminais, Steven N; Montgomery, Dan; Bossone, Eduardo; Dietz, Harry; Evangelista, Arturo; Isselbacher, Eric; LeMaire, Scott; Manfredini, Roberto; Milewicz, Dianna; Nienaber, Christoph A; Roman, Mary; Sechtem, Udo; Silberbach, Michael; Eagle, Kim A; Pyeritz, Reed E

    2017-03-01

    Marfan syndrome (MFS) is an autosomal dominant connective tissue disease associated with acute aortic dissection (AAD). We used 2 large registries that include patients with MFS to investigate possible trends in the chronobiology of AAD in MFS. We queried the International Registry of Acute Aortic Dissection (IRAD) and the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) registry to extract data on all patients with MFS who had suffered an AAD. The group included 257 patients with MFS who suffered an AAD from 1980 to 2012. The chi-square tests were used for statistical testing. Mean subject age at time of AAD was 38 years, and 61% of subjects were men. AAD was more likely in the winter/spring season (November to April) than the other half of the year (57% vs 43%, p = 0.05). Dissections were significantly more likely to occur during the daytime hours, with 65% of dissections occurring from 6 a.m. to 6 p.m. (p = 0.001). Men were more likely to dissect during the daytime hours (6 a.m. to 6 p.m.) than women (74% vs 51%, p = 0.01). These insights offer a glimpse of the times of greatest vulnerability for patients with MFS who suffer from this catastrophic event. In conclusion, the chronobiology of AAD in MFS reflects that of AAD in the general population.

  17. The borohydride-reducible compounds of human aortic elastin. Demonstration of a new cyclic amino acid in alkali hydrolysate, and changes with age and in patients with annulo-aortic ectasia including one with Marfan syndrome.

    PubMed Central

    Halme, T; Jutila, M; Vihersaari, T; Oksman, P; Light, N D; Penttinen, R

    1985-01-01

    Human aortic elastin reduced with [3H]borohydride was analysed by ion-exchange chromatography after alkali or acid hydrolysis. Alkali hydrolysates of elastins contained a radioactive peak that was eluted between proline and leucine. This peak was not present in foetal elastin, but its proportion increased steadily during aging. Aortic samples from patients with annulo-aortic ectasia (aneurysm of the ascending aorta), including one with classical Marfan syndrome, contained less elastin (CNBr-insoluble material) than did the age-matched controls. The proportion of radioactivity in the new peak of all these aortas was low when compared with age-matched controls. Gas-chromatographic/mass-spectrometric analysis suggested that it contained a cyclic derivative of a hydrated aldol-condensation product. The concentration of the cross-link precursors, lysine aldehyde and aldol-condensation product (estimated from the acid-hydrolysis product 6-chloronorleucine and the acid-degradation product of reduced aldol-condensation product) was high in very young aortas but remained quite stable after childhood. No differences were observed in cross-link profiles of acid hydrolysates between pathological and control aortas. A low proportion of radioactivity in the new peak may indicate the presence of young or immature elastin in the pathological aortas. PMID:4084226

  18. Beals Syndrome

    MedlinePlus

    ... have many of the skeletal (bone) and aortic enlargement problems as people with Marfan syndrome, and treatments ... appearance to the top of the ear Aortic enlargement and/or mitral valve regurgitation (occasionally) People with ...

  19. Histology of a Marfan aorta 4.5 years after personalized external aortic root support.

    PubMed

    Pepper, John; Goddard, Martin; Mohiaddin, Raad; Treasure, Tom

    2015-09-01

    In 2008, a 26-year old man had personalized external aortic root support (PEARS) with a macroporous mesh. He was the 16th of 46 patients to have this operation. He had a typical Marfan habitus. His mother died of this disease as did his brother, with an aortic dissection. The patient himself died suddenly 4.5 years after his PEARS operation. At autopsy, there was no blood in the pericardium. The coronary orifices and proximal arteries were normal. His bicuspid aortic valve was minimally regurgitant as it was prior to operation and remained throughout follow-up. Macroscopically the implanted mesh was embedded in the adventitia and not separable from the aortic wall. Microscopically it was fully incorporated with collagen fibres as has been seen in our animal studies. The unsupported aortic arch showed some focal fragmentation of elastic fibres and a mild increase in mucopolysaccharides consistent with Marfan syndrome. These appearances were not present in the supported aortic root, which had the histological appearance of a normal aorta. He was the first patient to die with an implant. The histological appearances suggest the possibility that the incorporated support of the aortic root allowed recovery of the microstructure of the media.

  20. Histology of a Marfan aorta 4.5 years after personalized external aortic root support

    PubMed Central

    Pepper, John; Goddard, Martin; Mohiaddin, Raad; Treasure, Tom

    2015-01-01

    In 2008, a 26-year old man had personalized external aortic root support (PEARS) with a macroporous mesh. He was the 16th of 46 patients to have this operation. He had a typical Marfan habitus. His mother died of this disease as did his brother, with an aortic dissection. The patient himself died suddenly 4.5 years after his PEARS operation. At autopsy, there was no blood in the pericardium. The coronary orifices and proximal arteries were normal. His bicuspid aortic valve was minimally regurgitant as it was prior to operation and remained throughout follow-up. Macroscopically the implanted mesh was embedded in the adventitia and not separable from the aortic wall. Microscopically it was fully incorporated with collagen fibres as has been seen in our animal studies. The unsupported aortic arch showed some focal fragmentation of elastic fibres and a mild increase in mucopolysaccharides consistent with Marfan syndrome. These appearances were not present in the supported aortic root, which had the histological appearance of a normal aorta. He was the first patient to die with an implant. The histological appearances suggest the possibility that the incorporated support of the aortic root allowed recovery of the microstructure of the media. PMID:25406424

  1. Non-marfan idiopathic medionecrosis (cystic medial necrosis) presenting with multiple visceral artery aneurysms and diffuse connective tissue fragility: Two brothers

    SciTech Connect

    Kubota, Jun; Tsunemura, Mami; Amano, Shigeko; Tokizawa, Shigemi; Oowada, Susumu; Shinkai, Hiroko; Maehara, Yasunobu; Endo, Keigo

    1997-05-15

    Two brothers with multiple visceral artery aneurysms or dilatations and diffuse connective tissue fragility who did not have clinical features of Marfan syndrome are reported. One presented with retroperitoneal hemorrhage during angiography, and idiopathic medionecrosis was proved by resection of the aneurysms. These cases belong to the heterogeneous group of Marfan syndrome. The angiographical features (multiple dilation of visceral arteries) suggests fragility of connective tissue and is predictive of hazards during and after a catheterization and operation.

  2. Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene

    SciTech Connect

    Putnam, E.A.; Cho, M.; Milewicz, D.M.

    1996-03-29

    Marfan syndrome is a dominantly inherited connective tissue disorder with a wide range of phenotypic severity. The condition is the result of mutations in FBN1, a large gene composed of 65 exons encoding the fibrillin-1 protein. While mutations causing classic manifestations of Marfan syndrome have been identified throughout the FBN1 gene, the six previously characterized mutations resulting in the severe, perinatal lethal form of Marfan syndrome have clustered in exons 24-32 of the gene. We screened 8 patients with either neonatal Marfan syndrome or severe cardiovascular complications of Marfan syndrome for mutations in this region of the gene. Using intron-based exon-specific primers, we amplified exons 23-32 from genomic DNAs, screened these fragments by single-stranded conformational polymorphism analysis, and sequenced indicated exons. This analysis documented mutations in exons 25-27 of the FBN1 mutations in 6 of these patients. These results, taken together with previously published FBN1 mutations in this region, further define the phenotype associated with mutations in exons 24-32 of the FBN1 gene, information important for the development of possible diagnostic tests and genetic counseling. 49 refs., 4 figs., 2 tabs.

  3. An aortic dissection in a young weightlifter with non-Marfan fibrillinopathy.

    PubMed

    Hogan, C J

    2005-04-01

    Aortic dissection (AD) is an uncommon condition that occurs mainly in the older patient population (>40 years). It is rare in younger people and is usually associated with trauma, Marfan's syndrome, or pregnancy. We report a case of a young weightlifter who died from an AD, and upon autopsy, was diagnosed as having non-Marfan's fibrillinopathy. We recommend that AD should be considered in symptomatic patients with any family history of early cardiac deaths, a history suggestive of a connective tissue disorder (that is, multiple joint surgeries) or who practise weightlifting.

  4. Loeys-Dietz Syndrome

    MedlinePlus

    ... syndrome is a genetic disorder of the body’s connective tissue. It has some features in common with Marfan ... a mutation, growth and development of the body’s connective tissue and other body systems is disrupted, leading to ...

  5. Questions and Answers about Marfan Syndrome

    MedlinePlus

    ... at NIAMSinfo@mail.nih.gov . Other Resources National Human Genome Research Institute Website: http://www.genome.gov ... part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), is to ...

  6. Abnormality of dermal collagen fibrils in Ehlers Danlos syndrome. Anticipation of the abnormality for the inherited hypermobile disorders.

    PubMed

    Kobayasi, Takasi

    2004-01-01

    The abnormality of dermal collagen fibrils is the ultrastructural criterion of Ehlers-Danlos syndrome (EDS). This study evaluates the clinical significance of the abnormality. Besides 348 lax patients presenting the stigmata of EDS, skin specimens from 12 normal members in the pedigree of EDS, 98 randomly selected normal individuals, 7 Marfan syndrome and 4 osteogenesis inperfecta type I, were studied by electron microscopy. The abnormality was defined by thickness, array and shape of collagen fibrils. Of 348 lax patients, 115 patients showed Beighton's score higher than 6 and constantly the abnormality (EDS). Variable numbers of the patients with scores 1 to 5 displayed the abnormality (forme fruste). The abnormality did not correspond with variation of laxity. Marfan syndrome and osteogenesis imperfecta were indistinguishable from EDS by the abnormality. Some of the normal persons in the EDS pedigree and some controls also showed the abnormality. The abnormality expressed the disposition for heritably defected collagen fibril formation.

  7. Marfan Database (second edition): software and database for the analysis of mutations in the human FBN1 gene.

    PubMed Central

    Collod-Béroud, G; Béroud, C; Adès, L; Black, C; Boxer, M; Brock, D J; Godfrey, M; Hayward, C; Karttunen, L; Milewicz, D; Peltonen, L; Richards, R I; Wang, M; Junien, C; Boileau, C

    1997-01-01

    Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were described at first in the heritable connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS. These mutations are private, essentially missense, generally non-recurrent and widely distributed throughout the gene. To date no clear genotype/phenotype relationship has been observed excepted for the localization of neonatal mutations in a cluster between exons 24 and 32. The second version of the computerized Marfan database contains 89 entries. The software has been modified to accomodate new functions and routines. PMID:9016526

  8. Dural ectasia in individuals with Marfan-like features but exclusion of mutations in the genes FBN1, TGFBR1 and TGFBR2.

    PubMed

    Sheikhzadeh, S; Rybczynski, M; Habermann, C R; Bernhardt, A M J; Arslan-Kirchner, M; Keyser, B; Kaemmerer, H; Mir, T S; Staebler, A; Oezdal, N; Robinson, P N; Berger, J; Meinertz, T; von Kodolitsch, Y

    2011-06-01

    Mutations in the genes FBN1, TGFBR1, and TGFBR2 can result in heritable connective tissue disorders comprising the Marfan syndrome and the Loeys-Dietz syndrome. Dural ectasia is a characteristic manifestation of both syndromes. However, dural ectasia has not yet been investigated in connective tissue disorders that are unrelated to mutations in the FBN1, TGFBR1 or TGFBR2 genes. Here, we assessed dural ectasia in 33 individuals both with typical manifestations of heritable connective tissue disease and in whom mutations in all three genes had been excluded. We identified 19 individuals with dural ectasia (58%), who exhibited major skeletal manifestations of the Marfan syndrome more frequently than the remaining 14 persons without dural ectasia (p = 0.06). Moreover, only persons with dural ectasia fulfilled clinical criteria of the Marfan syndrome (p = 0.01). Conversely, aortic aneurysm (12 patients; p = 0.8), aortic dissection (five patients; p = 0.1), spontaneous dissection of the carotid arteries (five patients; p = 1), and mitral valve prolapse (13 patients; p = 0.4) were similarly frequent irrespective of dural ectasia. We conclude that dural ectasia is a marker for connective tissue disease which coincides with skeletal rather than with cardiovascular manifestations, and which may involve currently uncharacterized pathogenetic mechanisms and syndromes. © 2010 John Wiley & Sons A/S.

  9. Acute aortic dissection in a young patient without Marfan fibrillinopathy: a case report.

    PubMed

    Hountis, Panagiotis; Dedeilias, Panagiotis; Bolos, Konstadinos

    2009-04-28

    Acute aortic dissection is a rare clinical entity that mainly affects patients older than 50 years. It is unusual in younger patients and its presence has been traditionally associated with trauma, Marfan syndrome, bicuspid aortic valve and pregnancy. Heavy weightlifting and other fibrillinopathies have been also implicated in the literature. We present here the case of a 26-year-old male with acute aortic dissection type A (De Bakey II), without family history of connective tissue diseases and signs of Marfan syndrome. The patient is a 26-year-old Caucasian Greek male who was presented in the emergency department with acute chest pain. Computerized tomography with contrast material showed the presence of an ascending aortic aneurysm with the question of an acute dissection type A (De Bakey II). The patient was emergently operated with replacement of the affected aortic segment and he had an uneventful clinical course. Three years follow up is essentially normal. Although extremely rare, aortic dissection is always a possibility in the differential diagnosis of chest and/or back pain in young patients and should be thoroughly investigated. The presence of an associated aneurysm makes the possibility even higher. The disease, if undiagnosed, carries the same mortality rates as in the older population. Prompt surgical intervention offers a possible cure and long term survival benefit for the patients.

  10. Acute aortic dissection in a young patient without Marfan fibrillinopathy: a case report

    PubMed Central

    2009-01-01

    Introduction Acute aortic dissection is a rare clinical entity that mainly affects patients older than 50 years. It is unusual in younger patients and its presence has been traditionally associated with trauma, Marfan syndrome, bicuspid aortic valve and pregnancy. Heavy weightlifting and other fibrillinopathies have been also implicated in the literature. We present here the case of a 26 year old male with acute aortic dissection type A (De Bakey II), without family history of connective tissue diseases and signs of Marfan syndrome. Case presentation The patient is a 26-year-old Caucasian Greek male who was presented in the emergency department with acute chest pain. Computerized tomography with contrast material showed the presence of an ascending aortic aneurysm with the question of an acute dissection type A (De Bakey II). The patient was emergently operated with replacement of the affected aortic segment and he had an uneventful clinical course. Three years follow up is essentially normal. Conclusion Although extremely rare, aortic dissection is always a possibility in the differential diagnosis of chest and/or back pain in young patients and should be thoroughly investigated. The presence of an associated aneurysm makes the possibility even higher. The disease, if undiagnosed, carries the same mortality rates as in the older population. Prompt surgical intervention offers a possible cure and long term survival benefit for the patients. PMID:20181187

  11. Klippel-Trenaunay syndrome: a case study.

    PubMed

    Meier, Susan

    2009-06-01

    Klippel-Trenaunay syndrome is a rare but well-documented congenital malformation. Klippel-Trenaunay syndrome has sometimes been used interchangeably with Klippel-Trenaunay-Weber syndrome. However, Klippel-Trenaunay syndrome is the correct term used for the triad of congenital anomalies. Klippel-Trenaunay-Weber syndrome or Parkes-Weber syndrome is accepted as a separate entity consisting of the triad of Klippel-Trenaunay syndrome accompanied by a clinically apparent arteriovenous fistula. Hemodynamically insignificant arteriovenous malformations do not preclude a diagnosis of Klippel-Trenaunay syndrome. It is important to differentiate between the 2 syndromes because treatment and prognosis are so different. Parkes-Weber syndrome has a poor prognosis for limb viability. This article describes a case study of an infant presenting with Klippel-Trenaunay including a review of the syndrome and treatment recommendations.

  12. Marfan’s syndrome

    PubMed Central

    Judge, Daniel P; Dietz, Harry C

    2006-01-01

    Marfan’s 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 β (TGFβ), a family of cytokines that affect cellular performance, highlighting the potential therapeutic application of TGF β 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. PMID:16325700

  13. Osteosarcoma in a Marfan patient with a novel premature termination codon in the FBN1 gene.

    PubMed

    Roopnariane, Adriana; Freed, Robert J; Price, Shawn; Fox, Edward J; Ritty, Timothy M

    2011-04-01

    Osteosarcoma is a malignant neoplasm of mesenchymal origin that is presumed to arise from osteoblasts. Considered a rare tumor, approximately 1000 cases of osteosarcoma are diagnosed in the United States each year, and osteosarcoma of the foot is rarer still. Marfan syndrome (MFS) is a rare genetic disorder that affects 1 in 5000 individuals and is caused by mutations in the fibrillin 1 (FBN1) gene. MFS phenotype affects several body systems, including soft connective tissue and bone. Here we report, for the first time, an individual with MFS that was treated for osteosarcoma. Surgically resected tissue was used to initiate an osteosarcoma cell line (PSU-OS-M) that exhibits attachment-independent growth and loss of contact inhibition in vitro. Genomic DNA was isolated from the tumor cells, and primers that anneal to intronic regions were used to amplify and sequence all 65 coding exons of the FBN1 gene. A two base pair insertion that results in a novel premature termination codon (PTC) was found in exon 52. Protein from the normal allele is detectable in PSU-OS-M cell-conditioned medium, but protein from the mutant allele was not detectable. Immunofluorescent microscopy demonstrates that PSU-OS-M cells can assemble fibrillin 1 microfibrils in culture, and fibronectin assembly is normal. As such, the PSU-OS-M cell line is to our knowledge the first oncogenically transformed cell line with a mutant fibrillin gene and may serve as a useful tool for studying molecular mechanisms of MFS and nonsense-mediated decay.

  14. Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomaslies not linked to the Fibrillin genes

    SciTech Connect

    Boileau, C.; Coulon, M.; Alexandre, J.-A.; Junien, C. ); Jondeau, G.; Delorme, G.; Dubourg, O.; Bourdarias, J.-P. ); Babron, M.-C.; Bonaieti-Pellie, C. ); Sakai, L. ); Melki, J. )

    1993-07-01

    The authors describe a large family with a connective-tissue disorder that exhibits some of the skeletal and cardiovascular features seen in Marfan syndrome. However, none of the 19 affected individuals displayed ocular abnormalities and therefore did not comply with recognized criteria for this disease. These patients could alternatively be diagnosed as MASS (mitral valve, aorta, skeleton, and skin) phenotype patients or represent a distinct clinical entity, i.e., a new autosomal dominant connective-tissue disorder. The fibrillin genes located on chromosomes 15 and 5 are clearly involved in the classic form of Marfan syndrome and a clinically related disorder (congenital contractural arachnodactyly), respectively. To test whether one of these genes was also implicated in this French family, the authors performed genetic analyses. Blood samples were obtained for 56 family members, and four polymorphic fibrillin gene markers, located on chromosomes 15 (Fib15) and 5 (Fib5), respectively, were tested. Linkage between the disease allele and the markers of these two genes was excluded with lod scores of [minus]11.39 (for Fib15) and [minus]13.34 (for Fib5), at 0 = .001, indicating that the mutation is at a different locus. This phenotype thus represents a new connective-tissue disorder, overlapping but different from classic Marfan syndrome. 33 refs., 1 fig. 2 tabs.

  15. XYY syndrome: a 13-year-old boy with tall stature.

    PubMed

    Jo, Won Ha; Jung, Mo Kyung; Kim, Ki Eun; Chae, Hyun Wook; Kim, Duk Hee; Kwon, Ah Reum; Kim, Ho-Seong

    2015-09-01

    When evaluating the underlying causes of tall stature, it is important to differentiate pathologic tall stature from familial tall stature. Various pathologic conditions leading to adult tall stature include excess growth hormone secretion, Marfan syndrome, androgen or estrogen deficiency, testicular feminization, and sex chromosome anomaly, such as Klinefelter syndrome and XYY syndrome. Men with 47,XYY syndrome can exhibit multiple phenotypes. A 13-year-old boy visited the hospital for evaluation of tall stature. The boy had no other physical abnormalities except tall stature. All biochemical and imaging studies were within the normal ranges. He was diagnosed with XYY syndrome in this chromosome study. When evaluating men with tall stature, XYY syndrome should be ruled out.

  16. XYY syndrome: a 13-year-old boy with tall stature

    PubMed Central

    Jo, Won Ha; Jung, Mo Kyung; Kim, Ki Eun; Chae, Hyun Wook; Kim, Duk Hee; Kwon, Ah Reum

    2015-01-01

    When evaluating the underlying causes of tall stature, it is important to differentiate pathologic tall stature from familial tall stature. Various pathologic conditions leading to adult tall stature include excess growth hormone secretion, Marfan syndrome, androgen or estrogen deficiency, testicular feminization, and sex chromosome anomaly, such as Klinefelter syndrome and XYY syndrome. Men with 47,XYY syndrome can exhibit multiple phenotypes. A 13-year-old boy visited the hospital for evaluation of tall stature. The boy had no other physical abnormalities except tall stature. All biochemical and imaging studies were within the normal ranges. He was diagnosed with XYY syndrome in this chromosome study. When evaluating men with tall stature, XYY syndrome should be ruled out. PMID:26512355

  17. Descending aortic replacement after Nuss for pectus excavatum in a Marfan patient—Case report

    PubMed Central

    Jaroszewski, Dawn; Ewais, MennatAllah; DeValeria, Patrick; Gotway, Michael; Craig Miller, D.

    2016-01-01

    Introduction The Nuss procedure for pectus excavatum (PE) repair has been successfully performed in Marfan syndrome (MFS) patients however there is concern for future risk of aortic dilation/rupture and need for emergent access with support bars in place. Case presentation We present a 45 year-old male with MFS that required descending aortic replacement shortly after modified Nuss repair. Discussion The majority of MFS patients have severe PE and repair with the Nuss procedure is not uncommon. The risk for life threatening aortic dilation, dissection, or rupture in such patients is a concern when utilizing this technique. Our work has been reported in line with the CARE criteria. Conclusion Nuss repair should be considered in MFS patients with technique modifications and careful consideration of future risk of aortic dilation and rupture. PMID:26895112

  18. A Study of Ghiselli's Hobo Syndrome

    ERIC Educational Resources Information Center

    Woo, Sang Eun

    2011-01-01

    This study attempts to clarify conceptual and operational inconsistencies in the literature around "Ghiselli's hobo syndrome." I propose that defining characteristics of hobo syndrome should include both the exhibition of frequent job movement behavior and positive attitudes about such behavior. This definition effectively differentiates…

  19. Williams 'elfin facies' Syndrome: A Case Study.

    ERIC Educational Resources Information Center

    Swartz, Stanley L.

    A review of the research literature related to Williams 'elfin facies' Syndrome (a condition including mental retardation and cardiac anomalies), a case study, and the results of an early intervention program, are reported. The medical aspects of the syndrome have been reported with sufficient consistency for a profile to emerge. Psychological…

  20. Pleuropulmonary Blastoma DICER1 Syndrome Study

    Cancer.gov

    Pleuropulmonary blastoma (PPB) is a rare tumor of the lung that affects young children. The PPB DICER1 Syndrome Study an observational clinical research study is enrolling children with PPB and their families.

  1. Pierpont syndrome: a collaborative study.

    PubMed

    Wright, Emma M M Burkitt; Suri, Mohnish; White, Susan M; de Leeuw, Nicole; Vulto-van Silfhout, Anneke T; Stewart, Fiona; McKee, Shane; Mansour, Sahar; Connell, Fiona C; Chopra, Maya; Kirk, Edwin P; Devriendt, Koen; Reardon, Willie; Brunner, Han; Donnai, Dian

    2011-09-01

    Pierpont syndrome is a multiple congenital anomaly syndrome with learning disability first described in 1998. There are only three patients with Pierpont syndrome who have previously been published in the literature. Details of a series of patients with features of this condition were therefore obtained retrospectively to better characterize its key features. These patients were noted to have distinctive shared facial characteristics, in addition to plantar fat pads and other limb abnormalities. Further individuals with equally striking hand and foot findings were identified whose facies were less characteristic, and hence we considered them unlikely to be affected with the same condition. Despite several patients with possible Pierpont syndrome having had high-resolution array CGH or SNP array, the etiology of this phenotype remains unknown. Whilst it is as yet unclear whether it is a single entity, there appears to be a group of patients in whom Pierpont syndrome may be a recognizable condition, with typical facies, particularly when smiling, and characteristic hand and foot findings.

  2. Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1

    SciTech Connect

    Edwards, M.J.; Roberts, J.; Partington, M.W.; Colley, P.W.; Hollway, G.E.; Kozman, H.M.; Mulley, J.C.

    1994-10-15

    Simple ectopia lentis (EL) was studied in a large family, by clinical examination and analysis of linkage to markers in the region of FBN1, the gene for fibrillin which causes Marfan syndrome on chromosome 15. No patient had clinical or echocardiographic evidence of Marfan syndrome, although there was a trend towards relatively longer measurements of height; lower segment; arm span; middle finger, hand, and foot length in the affected members of the family, compared with unaffected sibs of the same sex. Analysis of linkage to intragenic FBN1 markers was inconclusive because they were relatively uninformative. Construction of a multipoint background map from the CEPH reference families identified microsatellite markers linked closely to FBN1 which could demonstrate linkage of EL in this family to the FBN1 region. LINKMAP analysis detected a multipoint lod score of 5.68 at D15S119, a marker approximately 6 cM distal to FBN1, and a multipoint lod score of 5.04 at FBN1. The EL gene in this family is likely to be allelic to Marfan syndrome, and molecular characterization of the FBN1 mutation should now be possible. 25 refs., 6 figs., 2 tabs.

  3. Aortic Disease in the Young: Genetic Aneurysm Syndromes, Connective Tissue Disorders, and Familial Aortic Aneurysms and Dissections

    PubMed Central

    Cury, Marcelo; Zeidan, Fernanda; Lobato, Armando C.

    2013-01-01

    There are many genetic syndromes associated with the aortic aneurysmal disease which include Marfan syndrome (MFS), Ehlers-Danlos syndrome (EDS), Loeys-Dietz syndrome (LDS), familial thoracic aortic aneurysms and dissections (TAAD), bicuspid aortic valve disease (BAV), and autosomal dominant polycystic kidney disease (ADPKD). In the absence of familial history and other clinical findings, the proportion of thoracic and abdominal aortic aneurysms and dissections resulting from a genetic predisposition is still unknown. In this study, we propose the review of the current genetic knowledge in the aortic disease, observing, in the results that the causative genes and molecular pathways involved in the pathophysiology of aortic aneurysm disease remain undiscovered and continue to be an area of intensive research. PMID:23401778

  4. Postpolio Syndrome: Using a Single Case Study

    ERIC Educational Resources Information Center

    Obringer, S. John; Elrod, G. Franklin

    2004-01-01

    The purpose of this study was to identify the major characteristics of postpolio syndrome (PPS), investigate physical and psychological limitations, and comprehensively review current medical interventions through a single subject design. The study addresses the symptoms and characteristics, the effect on life style, and the current recommended…

  5. Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice

    PubMed Central

    MacFarlane, Elena Gallo; Takimoto, Eiki; Chaudhary, Rahul; Nagpal, Varun; Rainer, Peter P.; Bindman, Julia G.; Gerber, Elizabeth E.; Bedja, Djahida; Schiefer, Christopher; Miller, Karen L.; Zhu, Guangshuo; Myers, Loretha; Amat-Alarcon, Nuria; Lee, Dong I.; Koitabashi, Norimichi; Judge, Daniel P.; Dietz, Harry C.

    2017-01-01

    Among children with the most severe presentation of Marfan syndrome (MFS), an inherited disorder of connective tissue caused by a deficiency of extracellular fibrillin-1, heart failure is the leading cause of death. Here, we show that, while MFS mice (Fbn1C1039G/+ mice) typically have normal cardiac function, pressure overload (PO) induces an acute and severe dilated cardiomyopathy in association with fibrosis and myocyte enlargement. Failing MFS hearts show high expression of TGF-β ligands, with increased TGF-β signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-β, angiotensin II type 1 receptor (AT1R), or ERK antagonism (with neutralizing antibody, losartan, or MEK inhibitor, respectively) prevents load-induced cardiac decompensation in MFS mice, despite persistent PO. In situ analyses revealed an unanticipated axis of activation in nonmyocytes, with AT1R-dependent ERK activation driving TGF-β ligand expression that culminates in both autocrine and paracrine overdrive of TGF-β signaling. The full compensation seen in wild-type mice exposed to mild PO correlates with enhanced deposition of extracellular fibrillin-1. Taken together, these data suggest that fibrillin-1 contributes to cardiac reserve in the face of hemodynamic stress, critically implicate nonmyocytes in disease pathogenesis, and validate ERK as a therapeutic target in MFS-related cardiac decompensation. PMID:28768908

  6. Reye's Syndrome: A Review of Research Studies.

    ERIC Educational Resources Information Center

    Lopez, Thomas P.; And Others

    1982-01-01

    Clinical and pathological studies of Reye's syndrome indicate that symptoms range from influenza-related encephalitis-type disease to cranial pressure, cerebral edema, hemorrhage, and coma. Biochemical research on the blood, ammonia, and the liver is increasing in sophistication, and hopes for future insight into the etiology of Reye's syndrome…

  7. Reye's Syndrome: A Review of Research Studies.

    ERIC Educational Resources Information Center

    Lopez, Thomas P.; And Others

    1982-01-01

    Clinical and pathological studies of Reye's syndrome indicate that symptoms range from influenza-related encephalitis-type disease to cranial pressure, cerebral edema, hemorrhage, and coma. Biochemical research on the blood, ammonia, and the liver is increasing in sophistication, and hopes for future insight into the etiology of Reye's syndrome…

  8. A Family History Study of Asperger Syndrome

    ERIC Educational Resources Information Center

    Ghaziuddin, Mohammad

    2005-01-01

    Asperger syndrome (AS) is a childhood-onset disorder often described as a mild variant of autism. Although classified as a distinct disorder in the DSM-IV, its overlap with autism continues to be a matter of ongoing debate. While the family genetic origins of autism are well established, few studies have investigated this topic in AS using current…

  9. Rett syndrome and ageing: a case study.

    PubMed

    Jacobsen, K; Viken, A; von Tetzchner, S

    This case study of an elderly women with Rett syndrome is used to consider whether observed changes may be related to physiological processes involved in ageing or environmental adaptations, which is important for delivery of rehabilitation. The life story of a woman with Rett syndrome who lived to the age of 60 is presented. It is based on medical records, older and more recent videotapes, and interviews with her sister and care staff. After 21 years without walking, following intensive physiotherapy, she regained the ability to walk without support. She also showed improvement in hand use a few years before she died. During the early regression she appeared to lose social interest. The interest improved after some time, but she remained wary of people she did not know. The walking and hand use indicate that these functions may have been present to a greater extent than assumed by people in the environment and that her poor function reflects dyspraxia and lack of opportunity and training rather than lack of ability. Although more studies of elderly women with Rett syndrome is needed to answer whether the observed changes were due to physiological processes involved in ageing or environmental adaptations, the present case story demonstrates that identification of females with Rett syndrome is important at all age levels.

  10. Viewing Social Scenes: A Visual Scan-Path Study Comparing Fragile X Syndrome and Williams Syndrome

    ERIC Educational Resources Information Center

    Williams, Tracey A.; Porter, Melanie A.; Langdon, Robyn

    2013-01-01

    Fragile X syndrome (FXS) and Williams syndrome (WS) are both genetic disorders which present with similar cognitive-behavioral problems, but distinct social phenotypes. Despite these social differences both syndromes display poor social relations which may result from abnormal social processing. This study aimed to manipulate the location of…

  11. Viewing Social Scenes: A Visual Scan-Path Study Comparing Fragile X Syndrome and Williams Syndrome

    ERIC Educational Resources Information Center

    Williams, Tracey A.; Porter, Melanie A.; Langdon, Robyn

    2013-01-01

    Fragile X syndrome (FXS) and Williams syndrome (WS) are both genetic disorders which present with similar cognitive-behavioral problems, but distinct social phenotypes. Despite these social differences both syndromes display poor social relations which may result from abnormal social processing. This study aimed to manipulate the location of…

  12. [PFAPA syndrome: study of 10 cases].

    PubMed

    Antón-Martín, Pilar; Ortiz Movilla, Roberto; Álvarez García, Ana; Guillén Martín, Sara; Ruiz Jiménez, Marta; Ramos Amador, José Tomás

    2012-02-04

    «PFAPA syndrome» is an autoinflammatory entity consisting of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis. Its etiology is unknown although a dysregulation in the control of the autoinflammatory response seems to play a role. Although a genetic origin is suspected, no specific mutation has been determined yet. Corticosteroids are the mainstay of the treatment during the acute attacks. However, in long-term follow-up the role of tonsillectomy is controversial. A retrospective study of the pediatric cases diagnosed with the PFAPA syndrome was performed in our center during the last 4 years. Ten patients were diagnosed with the syndrome who received corticosteroids as the only treatment with improvement and favourable prognosis. PFAPA syndrome is the most common periodic fever disorder described in childhood whose genetic background has not been yet clarified. Our contribution with 10 patients further supports the common existence of this entity and the need to keep it in mind when having recurrent fevers. Copyright © 2011 Elsevier España, S.L. All rights reserved.

  13. Multiple lateral meningoceles, distinctive facies and skeletal anomalies: a new case of Lehman syndrome.

    PubMed

    Philip, N; Andrac, L; Moncla, A; Sigaudy, S; Zanon, N; Lena, G; Choux, M

    1995-10-01

    We describe a 19-year-old boy who presented with facial dysmorphism, multiple lateral meningoceles, skeletal abnormalities and normal intelligence. Neurofibromatosis and Marfan syndrome were excluded. Electron microscopy of the skin showed non-specific abnormalities suggesting a connective tissue disorder. The features of this boy closely resemble those in a mother and daughter with Lehman syndrome.

  14. Nonverbal Learning Disabilities: The Syndrome and a Case Study.

    ERIC Educational Resources Information Center

    Rourke, Byron P.; And Others

    1990-01-01

    Presents syndrome of nonverbal learning disabilities (NLD) and model developed to encompass its complex manifestations. Includes history of development of syndrome, types of children in whom its principal features are manifest, hypothesized neurological bases of syndrome, and test of its developmental dimensions. Provides case study and discusses…

  15. [Immunomorphometric study of megakaryocytes in patients with myelodysplastic syndrome].

    PubMed

    Marisavljević, D; Rolović, Z

    1992-01-01

    The purpose of this study was to analyse, by immunomorphometry, megakaryocytopoiesis in patients with myelodysplatsic syndrome. The results revealed that, in spite of marked megakaryocyte hyperplasia, patients with myelodysplastic syndrome suffer from severe peripheral thrombocytopenia. Megakaryocytes in myelodisplastic syndrome have, in average, small cellular and nuclear diameter and 35.3% of them (s. c. micromegakaryocyres) can be identified only by using immunohistochemical technique. In conclusion, there is severe maturation disturbancy, ineffectiveness and disregulation of megakaryocytopoiesis in myelodysplastic syndrome.

  16. Consequences of Marfan mutations to expression of fibrillin gene and to the structure of microfibrils

    SciTech Connect

    Peltonen, L.; Karttunen, L.; Rantamaeki, T.

    1994-09-01

    Marfan syndrome (MFS) is a dominantly inherited connective tissue disorder which is caused by mutations in the fibrillin-1 gene (FBN1). Over 40 family-specific FBN1 mutations have been identified. We have characterized 18 different heterozygous mutations including amino acid substitutions, premature stop, and splicing defects leading to deletions or one insertion, and one compound heterozygote with two differently mutated FBN1 alleles inherited from his affected parents. To unravel the consequences of FBN1 mutations to the transcription of FBN1 gene, we have measured the steady state levels of mRNA transcribed from the normal and mutated alleles. The missense mutations do not affect the transcription of the allele while the nonsense mutation leads to lower steady state amount of mutated allele. For the dissection of molecular pathogenesis of FBN1 mutations we have performed rotary shadowing of the microfibrils produced by the cell cultures from MFS patients. The cells from the neonatal patients with established mutations produced only disorganized fibrillin aggregates but no clearly defined microfibrils could be detected, suggesting a major role of this gene region coding for exons 24-26 in stabilization and organization of the bead structure of microfibrils. From the cells of a rare compound heterozygote case carrying two different mutations, no detectable microfibrils could be detected whereas the cells of his parents with heterozygous mutations were able to form identifiable but disorganized microfibrils. In the cells of an MFS case caused by a premature stop removing the C-terminus of fibrillin, the microfibril assembly takes place but the appropriate packing of the microfibrils is disturbed suggesting that C-terminae are actually located within the interbead domain of the microfibrils.

  17. Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G/+ Marfan Mouse Model.

    PubMed

    Hibender, Stijntje; Franken, Romy; van Roomen, Cindy; Ter Braake, Anique; van der Made, Ingeborg; Schermer, Edith E; Gunst, Quinn; van den Hoff, Maurice J; Lutgens, Esther; Pinto, Yigal M; Groenink, Maarten; Zwinderman, Aeilko H; Mulder, Barbara J M; de Vries, Carlie J M; de Waard, Vivian

    2016-08-01

    Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure-lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell-specific sirtuin-1-deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aortic dilatation in the Fbn1(C1039G/+) MFS mouse model. Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal-regulated kinases 1/2 (ERK1/2). Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate, although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal apoptotic cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor κB-dependent. Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS. © 2016 The Authors.

  18. The most common genetic syndromes and associated anomalies in Latvian patients with cleft lip with or without palate.

    PubMed

    Lace, Baiba; Barkane, Biruta; Akota, Ilze

    2006-01-01

    1 over 700 newborns every year is born with cleft lip with/or without palate, in 30% of cases there is a certain genetic mechanism underlying development of disease: chromosomal anomalies, monogenic diseases, exposure to teratogens or in utero disruptive mechanisms. The objective of our study is to describe the most common genetic syndromes and associated anomalies in patients with CL/CP in Latvia. Study material was medical records obtained from Riga Cleft Lip and Palate Centre Registry in a time period of 1980 till 2005. There was analyzed information about patients with identified genetic syndromes and associated anomalies. In a time period from 1980 till 2005, the following genetic syndromes were identified: Van der Woude, Fetal alcohol syndrome, Holzgreve syndrome, Marfan syndrome, Myotonic dystrophy, Klippel-Feil syndrome, Patau syndrome, Potter sequence and Pierre Robin sequence. 16% of CL/CP patients have recognized genetic syndromes or associated anomalies, including profound, severe and moderate mental retardation. Number is lower than expected, but still correlates with date presented in other populations. Long term follow-up of multidisciplinary specialists which includes cardiologists, clinical-geneticists and paediatricians, is needed for CL/CP patients with associated anomalies in order to identify timely side diseases and complications. Grant: Baltic-Taiwan joint research project "Identification of genes involved in craniofacial morphogenesis and susceptibility to orofacial clefting in a human genome scan 2004-2006".

  19. Prenatal and postnatal prevalence of Turner's syndrome: a registry study.

    PubMed Central

    Gravholt, C. H.; Juul, S.; Naeraa, R. W.; Hansen, J.

    1996-01-01

    OBJECTIVE--To study prevalence of Turner's syndrome in Denmark and to assess validity of prenatal diagnosis. DESIGN--Study of data on prenatal and postnatal Turner's syndrome in Danish Cytogenetic Central Register. SUBJECTS--All registered Turner's syndrome karyotypes (100 prenatal cases and 215 postnatal cases) during 1970-93. MAIN OUTCOME MEASURES--Prevalence of Turner's syndrome karyotypes among prenatally tested fetuses and Turner's syndrome among liveborn infants. RESULTS--Among infant girls, prevalence of Turner's syndrome was 32/100,000. Among female fetuses tested by amniocentesis, prevalence of Turner's syndrome karyotypes was 176/100,000 (relative risk of syndrome, 6.74 compared with prevalence among untested pregnancies). Among female fetuses tested by chorion villus sampling, prevalence of syndrome karyotypes was 392/100,000 (relative risk, 16.8). We excluded prenatal tests referred because of results of ultrasound scanning: among fetuses tested by amniocentesis revised relative risk was 5.68, while revised relative risk among fetuses tested by chorion villus sampling was 13.3. For 29 fetuses with prenatal diagnosis of possible Turner's syndrome, pregnancy was allowed to continue and 24 children were live born. Thirteen of these children were karyotyped postnatally, and diagnosis of Turner's syndrome had to be revised for eight, seven being normal girls and one boy. This gives tentative predictive value of amniocentesis in diagnosing Turner's syndrome of between 21% and 67%. There was no significant relation between mother's age and risk of Turner's syndrome. CONCLUSIONS--Discrepancy between prenatal and postnatal prevalence of Turner's syndrome challenges specificity of prenatal examination in diagnosing Turner's syndrome. PMID:8555850

  20. Pathways to Language: A Naturalistic Study of Children with Williams Syndrome and Children with Down Syndrome

    ERIC Educational Resources Information Center

    Levy, Yonata; Eilam, Ariela

    2013-01-01

    This is a naturalistic study of the development of language in Hebrew-speaking children with Williams syndrome (WS) and children with Down syndrome (DS), whose MLU extended from 1[multiplied by]0 to 4[multiplied by]4. Developmental curves over the entire span of data collection revealed minor differences between children with WS, children with DS,…

  1. Pathways to Language: A Naturalistic Study of Children with Williams Syndrome and Children with Down Syndrome

    ERIC Educational Resources Information Center

    Levy, Yonata; Eilam, Ariela

    2013-01-01

    This is a naturalistic study of the development of language in Hebrew-speaking children with Williams syndrome (WS) and children with Down syndrome (DS), whose MLU extended from 1[multiplied by]0 to 4[multiplied by]4. Developmental curves over the entire span of data collection revealed minor differences between children with WS, children with DS,…

  2. Postperfusion Syndrome in Cadaveric Liver Transplantations: A Retrospective Study

    PubMed Central

    Aydınlı, Bahar; Karadeniz, Ümit; Demir, Aslı; Güçlü, Çiğdem Yıldırım; Kazancı, Dilek; Koçulu, Rabia; Haytural, Candan; Özgök, Ayşegül; Bostancı, Erdal Birol; Zorlu, Ali

    2016-01-01

    Objective To evaluate the factors that affects the postperfusion syndrome in cadaveric liver transplantations and the effect of the postperfusion syndrome on discharge from the hospital. Methods Patients who underwent cadaveric liver transplantations between 2007 and 2013 were scanned retrospectively. Intraoperative anaesthesia records, intensive care unit follow-up forms and discharge reports were examined from patient files. Overall, 43 patients having complete data were included in the study. The postperfusion syndrome is defined as asystoli or a decrease in mean arterial pressure of more than 30%, which occurred in the first 5 min of reperfusion and continued for 1 min. Patients were divided into two groups: those who had the postperfusion syndrome and those who did not. Results The number of patients who had the postperfusion syndrome was 25 of 43 (58.1%). The MELD score of patients without the postperfusion syndrome was calculated as 16.9±3.2 and that of patients with the postperfusion syndrome was 19.7±3.6. A statistically significant relationship was detected between the postperfusion syndrome occurrence and a high MELD score (p=0.013). The diastolic blood pressure just before reperfusion was statistically lower in the group with the postperfusion syndrome than in the other group (p=0.023, 50±8 vs. 58±11). According to the logistic regression analysis, the MELD score and the decrease in diastolic blood pressure before reperfusion were defined as independent predictive factors. Conclusion According to the study, the ratio for having the postperfusion syndrome was found to be 58.1%. The independent predictor factors affecting the postperfusion syndrome were detected as the MELD score and the decrease in diastolic blood pressure before reperfusion. The postperfusion syndrome during orthotropic liver transplantation is an important issue for anaesthesiologists. The awareness of the related factors with the postperfusion syndrome may help in the development

  3. Imaging study of the painful heel syndrome

    SciTech Connect

    Williams, P.L.; Smibert, J.G.; Cox, R.; Mitchell, R.; Klenerman, L.

    1987-06-01

    A total of 45 patients with the painful heel syndrome without evidence of an associated inflammatory arthritis, seven of whom had pain in both heels, were studied using technetium-99 isotope bone scans and lateral and 45 degrees medial oblique radiographs of both feet. Of the 52 painful heels 31 (59.6%) showed increased uptake of tracer at the calcaneum. Patients with scans showing increased uptake tended to have more severe heel pain and responded more frequently to a local hydrocortisone injection. On plain x-ray, 39 of 52 painful heels (75%) and 24 of the 38 opposite nonpainful heels (63%) showed plantar spurs, compared with five of 63 (7.9%) heels in 59 age- and sex-matched controls. No evidence of stress fractures was seen.

  4. [Experimental studies of the "anticipation stress" syndrome].

    PubMed

    Vediaev, F P; Samokhvalov, V G

    1976-01-01

    Bioelectrical activity of the limbic structures (amygdala, dorsal and ventral hippocampus), the cortex and etologic responses during the formation of emotional stress of negative modality, were studied on Wistar rats under conditions of continuous many-hour neurotization. The presentation of stimuli according to a strict temporal shceme produced profound changes in the activity of the investigated cerebral structures and of the motor sphere. The established sequence in the involvement of the limbico-neocortical complex in the process of emotional stress with parallel use of the conditioned reflex to time, points to the participation of the hippocampus in the prediction of events (hippocampus leads to amygdala leads to cortex). Stages of biological reactions have been revealed, corresponding to the stages of Selye's adaptation syndrome. Stages of anxiety, adaptation and exhaustion proceeded with features characteristic of each group of animals ("inhibitory type", "steady type", "excitatory type", "overexcitatory type") and peculiar bioelectrical and etological responses.

  5. [Horner's syndrome in the dog: a retrospective study].

    PubMed

    van Hagen, M A; Kwakernaak, C M; Boevé, M H; Stades, F C

    1999-10-15

    A retrospective study was made of 43 dogs with Horner's syndrome (HS). In the group studied the golden retriever was found to be predisposed for Horner's syndrome. No predisposition in gender or age seemed to exist. Symptomatic treatment with topical 10% phenylephrine alleviates the clinical signs. Generally patients recover in 2 to 6 months.

  6. Treacher Collins syndrome: a case study.

    PubMed

    Chung, Jenny Y; Cangialosi, Thomas J; Eisig, Sidney B

    2014-11-01

    Treacher Collins syndrome is a disorder of craniofacial development with high penetrance and variable expressivity. Its incidence is approximately 1 in 50,000 live births. In this article, we describe the orthodontic treatment of an 11-year-old boy with Treacher Collins syndrome. Copyright © 2014 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.

  7. Functional Insights into Chromatin Remodelling from Studies on CHARGE Syndrome

    PubMed Central

    Basson, M. Albert; van Ravenswaaij-Arts, Conny

    2015-01-01

    CHARGE syndrome is a rare genetic syndrome characterised by a unique combination of multiple organ anomalies. Dominant loss-of-function mutations in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7), which is an ATP-dependent chromatin remodeller, have been identified as the cause of CHARGE syndrome. Here, we review recent work aimed at understanding the mechanism of CHD7 function in normal and pathological states, highlighting results from biochemical and in vivo studies. The emerging picture from this work suggests that the mechanisms by which CHD7 fine-tunes gene expression are context specific, consistent with the pleiotropic nature of CHARGE syndrome. PMID:26411921

  8. Autism Symptoms in Toddlers with Down Syndrome: A Descriptive Study

    ERIC Educational Resources Information Center

    Hepburn, Susan; Philofsky, Amy; Fidler, Deborah J.; Rogers, Sally

    2008-01-01

    Background: Research suggests that children with Down syndrome may be at increased risk of having an autism spectrum disorder; however, previous studies have not utilized comprehensive, state-of-the-art diagnostic tools to address the question of comorbid autism and Down syndrome. Method: Comprehensive evaluations for autism were conducted in 20…

  9. Incidence of Radiologically Isolated Syndrome: A Population-Based Study.

    PubMed

    Forslin, Y; Granberg, T; Jumah, A Antwan; Shams, S; Aspelin, P; Kristoffersen-Wiberg, M; Martola, J; Fredrikson, S

    2016-06-01

    Incidental MR imaging findings resembling MS in asymptomatic individuals, fulfilling the Okuda criteria, are termed "radiologically isolated syndrome." Those with radiologically isolated syndrome are at high risk of their condition converting to MS. The epidemiology of radiologically isolated syndrome remains largely unknown, and there are no population-based studies, to our knowledge. Our aim was to study the population-based incidence of radiologically isolated syndrome in a high-incidence region for MS and to evaluate the effect on radiologically isolated syndrome incidence when revising the original radiologically isolated syndrome criteria by using the latest radiologic classification for dissemination in space. All 2272 brain MR imaging scans in 1907 persons obtained during 2013 in the Swedish county of Västmanland, with a population of 259,000 inhabitants, were blindly evaluated by a senior radiologist and a senior neuroradiologist. The Okuda criteria for radiologically isolated syndrome were applied by using both the Barkhof and Swanton classifications for dissemination in space. Assessments of clinical data were performed by a radiology resident and a senior neurologist. The cumulative incidence of radiologically isolated syndrome was 2 patients (0.1%), equaling an incidence rate of 0.8 cases per 100,000 person-years, in a region with an incidence rate of MS of 10.2 cases per 100,000 person-years. There was no difference in the radiologically isolated syndrome incidence rate when applying a modified version of the Okuda criteria by using the newer Swanton classification for dissemination in space. Radiologically isolated syndrome is uncommon in a high-incidence region for MS. Adapting the Okuda criteria to use the dissemination in space-Swanton classification may be feasible. Future studies on radiologically isolated syndrome may benefit from a collaborative approach to ensure adequate numbers of participants. © 2016 by American Journal of Neuroradiology.

  10. Ultrastructural studies of the gray platelet syndrome.

    PubMed Central

    White, J. G.

    1979-01-01

    The gray platelet syndrome (GPS) is a rare inherited disorder in which peripheral blood platelets are relatively large, vacuolated, and almost devoid of cytoplasmic granulation. In the present study we have evaluated the ultrastructure and cytochemistry of platelets from 2 patients with the GPS to determine precisely which organelles are missing from their cells. The findings indicate that gray platelets contain normal numbers of mitochondria, dense bodies, peroxisomes, and lysosomes but specifically lack alpha-granules. Preliminary studies of megakaryocytes from 1 of the 2 patients suggest that the defect in granule formation may lie at the level of the Golgi zone. Images Figure 15 Figure 16 Figures 17 and 18 Figures 19 and 20 Figure 3 Figure 4 Figures 5 and 6 Figures 7 and 8 Figure 27 Figure 28 Figure 29 Figure 30 Figure 31 Figure 32 Figure 9 Figure 10 Figure 11 Figure 12 Figures 13 and 14 Figures 21 and 22 Figures 23 through 26 Figure 1 Figure 2 PMID:453324

  11. Connective tissue, Ehlers-Danlos syndrome(s), and head and cervical pain.

    PubMed

    Castori, Marco; Morlino, Silvia; Ghibellini, Giulia; Celletti, Claudia; Camerota, Filippo; Grammatico, Paola

    2015-03-01

    Ehlers-Danlos syndrome (EDS) is an umbrella term for a growing group of hereditary disorders of the connective tissue mainly manifesting with generalized joint hypermobility, skin hyperextensibility, and vascular and internal organ fragility. In contrast with other well known heritable connective tissue disorders with severe cardiovascular involvement (e.g., Marfan syndrome), most EDS patients share a nearly normal life span, but are severely limited by disabling features, such as pain, fatigue and headache. In this work, pertinent literature is reviewed with focus on prevalence, features and possible pathogenic mechanisms of headache in EDSs. Gathered data are fragmented and generally have a low level of evidence. Headache is reported in no less than 1/3 of the patients. Migraine results the most common type in the hypermobility type of EDS. Other possibly related headache disorders include tension-type headache, new daily persistent headache, headache attributed to spontaneous cerebrospinal fluid leakage, headache secondary to Chiari malformation, cervicogenic headache and neck-tongue syndrome, whose association still lacks of reliable prevalence studies. The underlying pathogenesis seems complex and variably associated with cardiovascular dysautonomia, cervical spine and temporomandibular joint instability/dysfunction, meningeal fragility, poor sleep quality, pain-killer drugs overuse and central sensitization. Particular attention is posed on a presumed subclinical cervical spine dysfunction. Standard treatment is always symptomatic and usually unsuccessful. Assessment and management procedures are discussed in order to put some basis for ameliorating the actual patients' needs and nurturing future research.

  12. A method for early evaluation of a recently introduced technology by deriving a comparative group from existing clinical data: a case study in external support of the Marfan aortic root

    PubMed Central

    Crowe, Sonya; Chan, K M John; Ranasinghe, Aaron; Attia, Rizwan; Lees, Belinda; Utley, Martin; Golesworthy, Tal; Pepper, John

    2012-01-01

    Objective During the early phase of evaluation of a new intervention, data exist for present practice. The authors propose a method of constructing a fair comparator group using these data. In this case study, the authors use the example of external aortic root support, a novel alternative to aortic root replacement. Design A matched comparison group, of similar age, aortic size and aortic valve function to those having the novel intervention, was constructed, by minimization, from among patients having conventional aortic root replacement in other hospitals during the same time frame. Setting Three cardiac surgical units in England. Patients The first 20 patients, aged 16–58 years with aortic root diameters of 40–54 mm, having external support surgery were compared with 20 patients, aged 18–63 years and aortic root diameters of 38–58 mm, who had conventional aortic root replacement, between May 2004 and December 2009. Interventions A pliant external mesh sleeve, customised by computer-aided design, encloses the whole of the ascending aorta. The comparator group had conventional aortic root replacement, 16 valve-sparing and four with composite valved grafts. Main outcome measures Duration of cardiopulmonary bypass (CPB), myocardial ischaemic time, blood loss and transfusion of blood, platelets and clotting factors. Results Comparing total root replacement and customised aortic root support surgery: CPB (median (range)) was 134 (52–316) versus 0 (0–20) min; myocardial ischaemia 114 (41–250) versus 0 (0–0) min; 4 h blood loss was 218 (85–735) versus 50 (25–400) ml; and 9/18 had blood transfusion, 9/18 platelets and 12/18 fresh frozen plasma after root replacement versus 1/20, 0/20 and 0/20, respectively, for the novel surgery. Conclusions Avoidance or large reductions in CPB, myocardial ischaemia and blood product usage were achieved with the novel surgery. These data are of use in decision analysis and health economic evaluation

  13. [Turner syndrome: Study of 42 cases].

    PubMed

    Bahíllo-Curieses, M Pilar; Prieto-Matos, Pablo; Quiroga González, Rocío; Regueras Santos, Laura; Blanco Barrio, Amaya; Rupérez Peña, Sara

    2016-10-21

    Turner syndrome (TS) is characterized by short stature, gonadal dysgenesis, and total or partial loss of X chromosome. A historical cohorts study of patients with TS≤18 years old followed up in public hospitals in Castilla y Leon was undertaken. Forty-two female patients were included (prenatal diagnosis 11.9%, neonatal diagnosis 14.3%) with current median age 11.9±4.2 years. Short stature was the reason for consultation in 87.1%. Total monosomy of X chromosome was present in 40.5%. The most frequently associated comorbidity was opthalmological (50%), with heart defects in 23.8%. Ninety-three percent were treated with growth hormone (GH), mean age at the beginning of treatment was 7.43±3.4 years and mean height standard deviation was -2.84±1.08. Final height was reached in 10 patients only (mean final height 151.47±6.09cm). Chronological age of puberty induction was 13.2±0.94 years (bone age 12.47±1.17 years). Short stature was an important clinical sign for the diagnosis of TS, accompanied in some cases by other findings, with good response to GH treatment. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  14. Candidate gene association studies in syndromic and non-syndromic cleft lip and palate

    SciTech Connect

    Daack-Hirsch, S.; Basart, A.; Frischmeyer, P.

    1994-09-01

    Using ongoing case ascertainment through a birth defects registry, we have collected 219 nuclear families with non-syndromic cleft lip and/or palate and 111 families with a collection of syndromic forms. Syndromic cases include 24 with recognized forms and 72 with unrecognized syndromes. Candidate gene studies as well as genome-wide searches for evidence of microdeletions and isodisomy are currently being carried out. Candidate gene association studies, to date, have made use of PCR-based polymorphisms for TGFA, MSX1, CLPG13 (a CA repeat associated with a human homologue of a locus that results in craniofacial dysmorphogenesis in the mouse) and an STRP found in a Van der Woude syndrome microdeletion. Control tetranucleotide repeats, which insure that population-based differences are not responsible for any observed associations, are also tested. Studies of the syndromic cases have included the same list of candidate genes searching for evidence of microdeletions and a genome-wide search using tri- and tetranucleotide polymorphic markers to search for isodisomy or structural rearrangements. Significant associations have previously been identified for TGFA, and, in this report, identified for MSX1 and nonsyndromic cleft palate only (p = 0.04, uncorrected). Preliminary results of the genome-wide scan for isodisomy has returned no true positives and there has been no evidence for microdeletion cases.

  15. Metabolic syndrome in Poland - the PONS Study.

    PubMed

    Janszky, Imre; Vatten, Lars; Romundstad, Pål; Laugsand, Lars Erik; Bjørngård, Johan Håkon; Mańczuk, Marta; Zatoński, Witold A

    2011-01-01

    In Central and Eastern European countries, cardiovascular disorders (CVD) in middle age are much more common than in Western Europe, and it is imperative to understand the causes underlying this excess disease burden. The metabolic syndrome comprises a constellation of metabolic abnormalities that increase the risk of cardiovascular disease. Data were obtained by structured interview, and by measurements of anthropometric factors and blood analyses among 3,862 individuals. Metabolic syndrome was defined according the International Diabetes Federation Task Force on Epidemiology and Prevention, as the presence of at least 3 of 5 abnormalities: 1) abdominal obesity, 2) glucose intolerance, 3) high triglycerides, 4) low HDL cholesterol, 5) high blood pressure. Overall, 1,518 participants (39.5%) had metabolic syndrome. The prevalence among females was 34.3% (877 females) vs. 49.9% (641 males) among males, and increased with age in both genders. Abdominal obesity was the most common abnormality (2,897 participants, 75.1%), followed by high blood pressure (2,741 participants, 71%), glucose intolerance (1,437 participants, 37.3%), elevated triglycerides (817 participants, 21.2%) and low HDL (615 participants, 15.9%). The prevalence of metabolic syndrome and metabolic abnormalities is high and represents strong risk factors for CVD morbidity and mortality. However, these factors are all potentially preventable by lifestyle modification and/or by pharmacological treatment. There is an urgent need for the health service to act, and to increase public awareness of metabolic syndrome.

  16. Sturge-Weber syndrome: A case study.

    PubMed

    Welty, Linda D

    2006-01-01

    Sturge-Weber syndrome (SWS) is a rare, sporadic, progressive, congenital syndrome. In its complete trisymptomatic form, SWS is physically characterized by port-wine stains over the trigeminal area, leptomeningeal angiomas usually over the parieto-occipital region, and eye abnormalities. Clinical manifestation for infants with SWS depends on the affected organs, but can include seizures, mental retardation, and glaucoma. This article begins with a case presentation of an infant with SWS and then presents the etiology, embryology, pathophysiology, clinical presentation, management, and prognosis of SWS.

  17. Study on autonomic dysfunction and metabolic syndrome in Chinese patients.

    PubMed

    Zhu, Ling; Zhao, Xiaolan; Zeng, Ping; Zhu, Jianguo; Yang, Shuwen; Liu, Annan; Song, Yuehua

    2016-11-01

    There is still a lack of simple methods and instruments for the early assessment of autonomic dysfunction in metabolic syndrome patients. Assessment of sudomotor function has been proposed to explore autonomic function, and could be used as an early biomarker for metabolic syndrome. In the present study, we use a quick and non-invasive method to measure sudomotor function, and aimed to evaluate its efficacy to identify metabolic syndrome in a Chinese population. Information on the 1,160 Chinese participants involved in the study, such as age, sex, blood pressure, waist circumference, body mass index, fasting plasma glucose and lipid profile, and SUDOSCAN, was recorded. During the sudomotor test, patients were asked to place their bare hands and feet on large electrodes. The test took 2 min to carry out, was painless and no participant preparation was required. A total of 567 participants were diagnosed with metabolic syndrome. The prevalence of metabolic syndrome correlated significantly with increasing SUDOSCAN cardiac risk score (P for trend <0.0001). Furthermore, an increase in cardiac risk score value was associated with an increase in the number of metabolic syndrome components (P for trend <0.0001). Compared with the no-risk group (cardiac risk score <20), participants in the high-risk group (cardiac risk score ≥30) had a 2.83-fold increased risk of prevalent metabolic syndrome (P < 0.0001), and 1.51-fold increased risk (P = 0.01) after adjustments. Autonomic dysfunction is correlated to components of metabolic syndrome. The role of SUDOSCAN in the screening of at-risk populations for metabolic syndrome has to be confirmed by further studies. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

  18. Math Learning Disability and Math LD Subtypes: Evidence from Studies of Turner Syndrome, Fragile X Syndrome, and Neurofibromatosis Type 1.

    ERIC Educational Resources Information Center

    Mazzocco, Michele M. M.

    2001-01-01

    This study examined whether indicators of math learning disability were observed in 35 5- and 6-year-olds with either neurofibromatosis, Turner Syndrome, or fragile X syndrome and compared to controls. Findings indicate that girls with fragile X or Turner syndrome but not neurofibromatosis are significantly more likely to have specific math…

  19. Math Learning Disability and Math LD Subtypes: Evidence from Studies of Turner Syndrome, Fragile X Syndrome, and Neurofibromatosis Type 1.

    ERIC Educational Resources Information Center

    Mazzocco, Michele M. M.

    2001-01-01

    This study examined whether indicators of math learning disability were observed in 35 5- and 6-year-olds with either neurofibromatosis, Turner Syndrome, or fragile X syndrome and compared to controls. Findings indicate that girls with fragile X or Turner syndrome but not neurofibromatosis are significantly more likely to have specific math…

  20. Stressful life events and incident metabolic syndrome: the Hoorn study.

    PubMed

    Rutters, Femke; Pilz, Stefan; Koopman, Anitra D M; Rauh, Simone P; Pouwer, Frans; Stehouwer, Coen D A; Elders, Petra J; Nijpels, Giel; Dekker, Jacqueline M

    2015-01-01

    Stressful life events are associated with the metabolic syndrome in cross-sectional studies, but prospective studies addressing this issue are rare and limited. We therefore evaluated whether the number of stressful life events is associated with incident metabolic syndrome. We assessed the association between the number of stressful life events experienced in the 5 years up until baseline and incident metabolic syndrome after 6.5 years at follow-up in the Hoorn study, a middle-aged and elderly population-based cohort. Participants with prevalent metabolic syndrome at baseline were excluded. Metabolic syndrome was defined according to the Adult Treatment Panel III, including fasting plasma glucose levels, HDL-C levels, triglyceride levels, waist circumference and hypertension. We included 1099 participants (47% male; age 60 ± 7 years). During 6.5 years of follow-up, 238 participants (22%) developed the metabolic syndrome. Logistic regression adjusted for age, sex, education level and follow-up duration showed a positive association between the number of stressful life events at baseline and incident metabolic syndrome [OR 1.13 (1.01-1.27) per event, p = 0.049]. In addition, a Poisson model showed a significant positive association between the number of stressful life events at baseline and the number of metabolic syndrome factors at follow-up [OR 1.05 (1.01-1.11) per event, p = 0.018]. Finally, we observed a significant association between the number of stressful life events at baseline and waist circumference at follow-up [adjusted for confounders β 0.86 (0.39-1.34) cm per event, p < 0.001]. Overall, we concluded that persons who reported more stressful life events at baseline had a significantly increased risk for developing metabolic syndrome during 6.5 years of follow-up, in a middle-aged and elderly population-based cohort.

  1. Growth study of cri du chat syndrome.

    PubMed

    Collins, M S; Eaton-Evans, J

    2001-10-01

    We compared the growth of children with cri du chat (5p-) syndrome with the 1990 UK growth curves. Most subjects had impaired growth, particularly of head circumference. The more emaciated the child the more pronounced the microcephaly, showing the need for growth and nutrition monitoring.

  2. Six case studies depicting the deliberate self-harm syndrome.

    PubMed

    Rosen, S; Collins, K J

    1993-04-01

    This article comprises information on self-mutilation (and specifically on the Deliberate Self-harm Syndrome) which obtained from a study of mainly American and British literature. Included is data obtained from interviews conducted with a sample of South Africans suffering from the syndrome. Etiology was explained from both a psychological and biological perspective. The former highlighted deficiencies in coping and communication skills while the latter highlighted the compulsive and pain-killer role that endorphines play. From case studies and literature it was possible to clearly distinguish the Deliberate Self-harm Syndrome as a distinct disorder-a syndrome consisting of deliberate, repetitive and private acts of self-harm in the form of cutting, burning and banging oneself. This culminates in extreme tension release.

  3. [Study on the Chinese medical syndrome distribution of ulcerative colitis].

    PubMed

    Lu, Yong-Hui; Cong, Long-Ling

    2012-04-01

    To study on the Chinese medicine (CM) syndrome distribution of ulcerative colitis (UC) and the distribution of CM syndrome types at different staging periods. From March 2007 to April 2010, 110 UC out- or inpatients at the Department of Digestive Diseases of Guangzhou Municipal Hospital of Traditional Chinese Medicine were recruited. The patients' symptoms were calculated. The systematic clustering was used. The symptom was taken as the variable in the clustering. The syndrome types were confirmed according to the clustering results. The syndrome typing was performed and its results were analyzed. There were 64 main symptoms in UC patients, including diarrhea, mushy stool, watery stool, abdominal pain, and bloody stool. Seventy cases belonged to the active period and 40 to the remission period. The UC syndrome types were sequenced from high to low as the dampness-heat of Dachang syndrome, Pi-Wei qi deficiency syndrome, Gan depression and Pi deficiency syndrome, Pi-Shen yang deficiency syndrome, blood stasis in the intestinal collaterals syndrome, yin and blood deficiency syndrome. There was statistical difference in the case number among different syndrome types (P < 0.05). In the active period, dominated were the dampness-heat of Dachang syndrome (28 cases, 25.5%), Gan depression and Pi deficiency syndrome (14 cases, 12.7%), and blood stasis in the intestinal collaterals syndrome (10 cases, 9.0%). In the remission period, dominated were Pi-Wei qi deficiency syndrome (18 cases, 16.4%) and Pi-Shen yang deficiency syndrome (10 cases, 9.0%), showing statistical difference (P<0.05). The typical symptoms of patients of the dampness-heat of Dachang syndrome were sequenced from high to low as yellow tongue fur (31 cases, 28.1%), tenesmus (26 cases, 23.6%), mucopurulent bloody stool (25 cases, 227%), diarrhea (24 cases, 21.8%), anal burning (24 cases, 21.8%), watery stool (21 cases, 19.0%), abdominal pain (19 cases, 17.2%), red tongue (19 cases, 17.2%), and greasy tongue

  4. Rett syndrome: studies of 13 affected girls.

    PubMed

    Budden, S S

    1986-01-01

    This is a presentation and discussion of clinical and laboratory data obtained on 13 girls with Rett syndrome, a progressive neurological disorder. The condition is thought to be far more prevalent than earlier reported. Family history in one patient showed presence of abnormal hand movements, increasing spasticity and psychomotor retardation in a paternal great grandaunt who died at 7 years. In the absence of chromosomal or biochemical markers, the characteristic disorder of hand movements can be used to distinguish this entity from other mental retardation, cerebral palsy and autism conditions. This report addresses the uniformity of clinical expression and highlights the differences between autism and Rett syndrome. Precocious puberty and respiratory alkalosis were not found in our patients. Feeding disorders were commonly present, and are often difficult to manage. The importance of diagnosis is emphasized as it influences long term management.

  5. The Steven Johnson syndrome. A case study.

    PubMed

    Baby, S; Doris, S

    1999-07-01

    Steven Johnson's Syndrome is a serious systemic disorder in which there are vesicobullous lesions involving the skin and mucous membranes. It can result as an immune response to an antigen or as a drug reaction. Most often it is considered as an allergic reaction. It is a self-limiting condition which responds to immediate management or may result in fluid loss, sepsis and death.

  6. [Clinical studies of pediatric malabsorption syndromes].

    PubMed

    Hosoyamada, Takashi

    2006-11-01

    Multiple cases with various types of pediatric malabsorption syndromes were evaluated. The clinical manifestations, laboratory findings, pathophysiology, and histopathological descriptions of each patient were analyzed in an effort to clear the pathogenesis of the malabsorption syndromes and the treatments were undertaken. The cases studied, included one patient with cystic fibrosis, two with lactose intolerance with lactosuria (Durand type), one with primary intestinal lymphangiectasia, two with familial hypobetalipoproteinemia, one with Hartnup disease, one with congenital chroride diarrhea, one with acrodermatitis enteropathica, one with intestinal nodular lymphoid hyperplasia (NLH), five with intractable diarrhea of early infancy and four with glycogenosis type Ia. Each case description and outcome is described below: 1. A 15-year-old Japanese boy with cystic fibrosis presented with severe symptoms, including pancreatic insufficiency, bronchiectasis, pneumothorax and hemoptysis. His prognosis was poor. Analysis of the CFTR genes of this patient revealed a homozygous large deletion from intron 16 to 17b. 2. In the sibling case of Durand type lactose intolerance, the subjects'disaccaridase activity of the small bowel, including lactase, were within normal limits. The results of per oral and per intraduodenal lactose tolerance tests confirmed lactosuria in both. These observations suggested, not only an abnormal gastric condition, but also duodenal and intestinal mucosal abnormal permeability of lactose. 3. In the case of primary intestinal lymphangiectasia, the subject had a lymphedematous right arm and hand, a grossly coarsened mucosal pattern of the upper gastrointestinal tract (identified via radiologic examination) and the presence of lymphangiectasia (confirmed via duodenal mucosal biopsy). The major laboratory findings were hypoalbuminemia, decreased immunoglobulin levels and lymphopenia resulting from loss of lymph fluid and protein into the gastro

  7. Intellectual development in Noonan syndrome: a longitudinal study.

    PubMed

    Roelofs, Renée L; Janssen, Nikki; Wingbermühle, Ellen; Kessels, Roy P C; Egger, Jos I M

    2016-07-01

    Although cognitive impairments in adults with Noonan syndrome seem to be limited to a low-average intelligence and slower processing speed, studies in children with Noonan syndrome have demonstrated more extensive cognitive problems. These include deficits in language skills, memory, attention, and executive functioning. This longitudinal study is the first to investigate intellectual development in a group of individuals with Noonan syndrome. Sixteen patients with Noonan syndrome underwent intelligence assessment both in childhood and in adulthood, using Wechsler's intelligence scales. IQ scores and Wechsler standard scores achieved in childhood and adulthood were compared. Subsequently, verbal and performance IQ in childhood were used as predictors for adult IQ and index scores. Compared with childhood scores, adult full-scale IQ and performance IQ significantly increased. Adult performance IQ was higher than verbal IQ. Childhood performance IQ and verbal IQ together predicted all adult IQ and index scores, except for the processing speed index. Childhood IQ was a significant predictor of adult intelligence in patients with Noonan syndrome. Performance IQ advanced to a normal level in adulthood, while verbal IQ did not develop proportionately, resulting in a discrepancy between adult performance IQ and verbal IQ. This finding could suggest a delay in the development of executive functioning in patients with Noonan syndrome, which seems to be outgrown in adulthood.

  8. Viewing social scenes: a visual scan-path study comparing fragile X syndrome and Williams syndrome.

    PubMed

    Williams, Tracey A; Porter, Melanie A; Langdon, Robyn

    2013-08-01

    Fragile X syndrome (FXS) and Williams syndrome (WS) are both genetic disorders which present with similar cognitive-behavioral problems, but distinct social phenotypes. Despite these social differences both syndromes display poor social relations which may result from abnormal social processing. This study aimed to manipulate the location of socially salient information within scenes to investigate the visual attentional mechanisms of: capture, disengagement, and/or general engagement. Findings revealed that individuals with FXS avoid social information presented centrally, at least initially. The WS findings, on the other hand, provided some evidence that difficulties with attentional disengagement, rather than attentional capture, may play a role in the WS social phenotype. These findings are discussed in relation to the distinct social phenotypes of these two disorders.

  9. Systemic vascular phenotypes of Loeys-Dietz syndrome in a child carrying a de novo R381P mutation in TGFBR2: a case report.

    PubMed

    Uike, Kiyoshi; Matsushita, Yuki; Sakai, Yasunari; Togao, Osamu; Nagao, Michinobu; Ishizaki, Yoshito; Nagata, Hazumu; Yamamura, Kenichiro; Torisu, Hiroyuki; Hara, Toshiro

    2013-11-12

    Loeys-Dietz syndrome, also known as Marfan syndrome type II, is a rare connective tissue disorder caused by dominant mutations in transforming growth factor-beta receptors (TGFBR1 and 2). We report a 7-year-old Japanese boy with Loeys-Dietz syndrome who carried a novel, de novo missense mutation in TGFBR2 (c.1142g > c, R381P). He showed dysmorphic faces and skeletal malformations that were typical in previous cases with Loeys-Dietz syndrome. The cardiac studies disclosed the presence of markedly dilated aortic root and patent ductus aorteriosus. The cranial magnetic resonance imaging (MRI) and angiography (MRA) detected the tortuous appearances of the bilateral middle cerebral and carotid arteries. This study depicts the systemic vascular phenotypes of a child with Loeys-Dietz syndrome that were caused by a novel heterozygous mutation of TGFR2. A large cohort with serial imaging studies for vascular phenotypes will be useful for delineating the genotype-phenotype correlations of Loeys-Dietz syndrome.

  10. A clinical study of Noonan syndrome.

    PubMed Central

    Sharland, M; Burch, M; McKenna, W M; Paton, M A

    1992-01-01

    Clinical details are presented on 151 individuals with Noonan syndrome (83 males and 68 females, mean age 12.6 years). Polyhydramnios complicated 33% of affected pregnancies. The commonest cardiac lesions were pulmonary stenosis (62%), and hypertrophic cardiomyopathy (20%), with a normal echocardiogram present in only 12.5% of all cases. Significant feeding difficulties during infancy were present in 76% of the group. Although the children were short (50% with a height less than 3rd centile), and underweight (43% with a weight less than 3rd centile), the mean head circumference of the group was on the 50th centile. Motor milestone delay was usual, the cohort having a mean age of sitting unsupported of 10 months and walking of 21 months. Abnormal vision (94%) and hearing (40%) were frequent findings, but 89% of the group were attending normal primary or secondary schools. Other associations included undescended testicles (77%), hepatosplenomegaly (50%), and evidence of abnormal bleeding (56%). The mean age at diagnosis of Noonan syndrome in this group was 9.0 years. Earlier diagnosis of this common condition would aid both clinical management and genetic counselling. Images Figure 1 Figure 2 Figure 3 PMID:1543375

  11. Retrospective Study of Obesity in Children with Down Syndrome.

    PubMed

    Basil, Janet S; Santoro, Stephanie L; Martin, Lisa J; Healy, Katherine Wusik; Chini, Barbara A; Saal, Howard M

    2016-06-01

    To assess whether children with Down syndrome in the US are at an increased risk for obesity, we determined the obesity prevalence and analyzed obesity development throughout childhood in a cohort of children with Down syndrome. In addition, we analyzed a comorbidity that is associated with Down syndrome and obesity, obstructive sleep apnea syndrome (OSAS). This study was a retrospective chart review that evaluated 303 children ages 2 through 18 years with a diagnosis of Down syndrome. All children were patients at Cincinnati Children's Hospital Medical Center with multiple height and weight measurements. To determine obesity burden, the rate of obesity was compared with a local control cohort using contingency tables. Change in obesity rate through time was determined with mixed models. Association of obesity with OSAS was determined with contingency tables. We evaluated 303 individuals, 47.8% of whom were obese (body mass index ≥95th percentile for age and sex). This was significantly higher than the general pediatric population, which had a 12.1% obesity rate (P < .0001). Body mass index z-scores did not