Marfan Syndrome
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2021 ◽  
Vol 12 ◽  
Author(s):  
Pauline Arnaud ◽  
Zakaria Mougin ◽  
Catherine Boileau ◽  
Carine Le Goff

The term “fibrillinopathies” gathers various diseases with a wide spectrum of clinical features and severity but all share mutations in the fibrillin genes. The first described fibrillinopathy, Marfan syndrome (MFS), is a multisystem disease with a unique combination of skeletal, thoracic aortic aneurysm (TAA) and ocular features. The numerous FBN1 mutations identified in MFS are located all along the gene, leading to the same pathogenic mechanism. The geleophysic/acromicric dysplasias (GD/AD), characterized by short stature, short extremities, and joint limitation are described as “the mirror image” of MFS. Previously, in GD/AD patients, we identified heterozygous FBN1 mutations all affecting TGFβ-binding protein-like domain 5 (TB5). ADAMTS10, ADAMTS17 and, ADAMTSL2 are also involved in the pathogenic mechanism of acromelic dysplasia. More recently, in TAA patients, we identified mutations in THSD4, encoding ADAMTSL6, a protein belonging to the ADAMTSL family suggesting that ADAMTSL proteins are also involved in the Marfanoid spectrum. Together with human genetic data and generated knockout mouse models targeting the involved genes, we provide herein an overview of the role of fibrillin-1 in opposite phenotypes. Finally, we will decipher the potential biological cooperation of ADAMTS-fibrillin-1 involved in these opposite phenotypes.


Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1915
Author(s):  
Nadia Farooqi ◽  
Louise A. Metherell ◽  
Isabelle Schrauwen ◽  
Anushree Acharya ◽  
Qayum Khan ◽  
...  

Introduction: Cardiomyopathies are diseases of the heart muscle and are important causes of heart failure. Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy that can be acquired, syndromic or non-syndromic. The current study was conducted to explore the genetic defects in a Pakistani family with cardiac disease and features of Marfan’s syndrome (MFS). Methods: A family with left ventricle (LV) diastolic dysfunction and MFS phenotype was assessed in Pakistan. The clinical information and blood samples from the patients were collected after physical, cardiovascular, and ophthalmologic examinations. An affected individual (proband) was subjected to whole-exome sequencing (WES). The findings were further validated through Sanger sequencing in the family. Results: Through WES and sanger validation, we identified a novel variant NM_000138.4; c.1402A>G in the Fibrillin-1 (FBN1) gene that segregates with LV diastolic dysfunction and MFS. Furthermore, bioinformatic evaluation suggested that the novel variant is deleterious and disease-causing. Conclusions: This study identified for the first time a novel FBN1 variant in a family with LV diastolic dysfunction and MFS in Pakistan.


Metabolites ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 805
Author(s):  
Lisa Bartenbach ◽  
Thomas Karall ◽  
Jakob Koch ◽  
Markus Andreas Keller ◽  
Herbert Oberacher ◽  
...  

Patients with Marfan syndrome (MFS) have an increased risk of aortic aneurysm formation, dissection and development of a subtle cardiomyopathy. We analyzed amino acid and lipid metabolic pathways in MFS patients, seeking biomarker patterns as potential monitoring tools of cardiovascular risk with deterioration of myocardial function. We assessed myocardial function in 24 adult MFS patients and compared traditional laboratory values and mass spectrometry-based amino acid, phospholipid and acylcarnitine metabolomes in patients with those in healthy controls. Analytes for which values differed between patients and controls were subjected to regression analysis. A high proportion of patients had signs of impaired diastolic function and elevated serum levels of NT-proBNP. Patients had lower serum levels of taurine, histidine and PCaeC42:3 than controls. The evidence of diastolic dysfunction, aortic root dimensions and history of aortic root surgery correlated with NT-proBNP and taurine levels. Alterations in serum levels of metabolism derived analytes link MFS pathophysiology with inflammation, oxidative stress and incipient cardiomyopathy.


Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1836
Author(s):  
Anna Clara Schnause ◽  
Katalin Komlosi ◽  
Barbara Herr ◽  
Jürgen Neesen ◽  
Paul Dremsek ◽  
...  

Marfan syndrome (MFS) is a hereditary connective tissue disease caused by heterozygous mutations in the fibrillin-1 gene (FBN1) located on chromosome 15q21.1. A complex chromosomal rearrangement leading to MFS has only been reported in one case so far. We report on a mother and daughter with marfanoid habitus and no pathogenic variant in the FBN1 gene after next generation sequencing (NGS) analysis, both showing a cytogenetically reciprocal balanced translocation between chromosomes 2 and 15. By means of fluorescence in situ hybridization of Bacterial artificial chromosome (BAC) clones from the breakpoint area on chromosome 15 the breakpoint was narrowed down to a region of approximately 110 kb in FBN1. With the help of optical genome mapping (OGM), the translocation breakpoints were further refined on chromosomes 2 and 15. Sequencing of the regions affected by the translocation identified the breakpoint of chromosome 2 as well as the breakpoint of chromosome 15 in the FBN1 gene leading to its disruption. To our knowledge, this is the first report of patients with typical clinical features of MFS showing a cytogenetically reciprocal translocation involving the FBN1 gene. Our case highlights the importance of structural genome variants as an underlying cause of monogenic diseases and the useful clinical application of OGM in the elucidation of structural variants.


2021 ◽  
Author(s):  
Niels H.Andersen ◽  
Ellen-Margrethe Hauge ◽  
Thomas Baad-Hansen ◽  
Kristian A. Groth ◽  
Agnethe Berglund ◽  
...  

Abstract BackgroundMarfan syndrome is associated with abnormalities in the musculoskeletal system including scoliosis, pectus deformities, protrusio acetabuli, and foot deformities. Over a life span, many patients with Marfan syndrome will need treatment; however, the musculoskeletal morbidity over a life span is not well described. The aim of the present study was to assess the overall burden of musculoskeletal disease in patients with Marfan syndrome.Materials and MethodsA registry-based, nationwide epidemiological study of patients with a Ghent II verified Marfan syndrome diagnosis from 1977-2014. Each patient was matched on age, and sex with up to 100 controls from the background population.ResultsWe identified 407 patients with Marfan syndrome and 40,700 controls and compared their musculoskeletal diagnoses and surgical treatments using Cox proportional hazards regression (HR). The risk of a registration of a musculoskeletal diagnosis in patients with Marfan syndrome was significantly increased compared to controls (HR: 1.94 (1.69-2.24). One out of six with Marfan syndrome was registered with scoliosis (HR: 36.7 (27.5-48.9). Scoliosis was more common in women with Marfan syndrome compared to men (HR: 4.30 (1.73-1.08)). One out of 11 were registered with a pectus deformity HR: 40.8 (28.1-59.3), and one out of three with a deformity of the foot (HR: 1.9 (1.6-2.3)). The proportion of patients with Marfan syndrome (94/407) that underwent musculoskeletal surgery was also significantly higher (HR: 1.76 (1.43-2.16)). The major areas of surgery were the spine, pectus correction, and surgery of the foot/ancle. Ten patients with Marfan syndrome had elective orthopedic surgery without being recognized and diagnosed with Marfan syndrome until later in life. None of these had scoliosis, pectus deformity or a foot deformity.Among patients with an aortic dissection, the age at dissection was 34.3 years in those with at least one major musculoskeletal abnormality. In patients without a major abnormality the age at dissection was 45.1 years (p<0.01).ConclusionsThe extend of musculoskeletal disease is quite significant in Marfan syndrome and many will need corrective surgery during their life span. Surgeons should be aware of undiagnosed patients with Marfan syndrome when treating patients with a Marfan syndrome like-phenotype.


Author(s):  
Sheng Yan ◽  
Zhi-Yuan Wu ◽  
Li Ma ◽  
Zuo-Guan Chen ◽  
Yong-Peng Diao ◽  
...  

2021 ◽  
pp. 101440
Author(s):  
Chizuo Iwai ◽  
Kazunari Fushimi ◽  
Satoshi Nozawa ◽  
Shingo Komura ◽  
Shutaro Sawada ◽  
...  

2021 ◽  
Vol 23 (11) ◽  
Author(s):  
Lily Pollock ◽  
Ashley Ridout ◽  
James Teh ◽  
Colin Nnadi ◽  
Dionisios Stavroulias ◽  
...  

Abstract Purpose of Review Marfan syndrome (MFS) is an autosomal dominant heritable disorder of fibrillin-1 (FBN1) with predominantly ocular, cardiovascular, and musculoskeletal manifestations that has a population prevalence of approximately 1 in 5–10,000 (Chiu et al. Mayo Clin Proc. 89(1):34–42, 146, Dietz 3, Loeys et al. J Med Genet. 47(7):476–85, 4). Recent Findings The vascular complications of MFS still pose the greatest threat, but effective management options, such as regular cardiac monitoring and elective surgical intervention, have reduced the risk of life-threatening cardiovascular events, such as aortic dissection. Although cardiovascular morbidity and mortality remains high, these improvements in cardiovascular management have extended the life expectancy of those with MFS by perhaps 30–50 years from an estimated mean of 32 years in 1972 (Dietz 3, Gott et al. Eur J Cardio-thoracic Surg. 10(3):149–58, 147, Murdoch et al. N Engl J Med. 286(15):804–8, 148). The musculoskeletal manifestations of MFS, which to date have received less attention, can also have a significant impact on the quality of life and are likely to become more important as the age of the Marfan syndrome population increases (Hasan et al. Int J Clin Pract. 61(8):1308–1320, 127). In addition, musculoskeletal manifestations are often critically important in the diagnosis of MFS. Summary Here, we review the main clinically relevant and diagnostically useful musculoskeletal features of MFS, which together contribute to the “systemic features score” (referred to hereafter as systemic score), part of the revised Ghent nosology for MFS. We discuss current treatment strategies and highlight the need for a multidisciplinary approach to diagnosis and management. Finally, we review new pharmacological approaches that may be disease modifying and could help to improve the outcome for individuals with this syndrome.


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