Marfan syndrome and the evolving spectrum of heritable thoracic aortic disease: Do we need genetics for clinical decisions?

Marfan syndrome (MFS) is a disorder of the connective tissue that is inherited in an autosomal dominant fashion and that is classically caused by mutations in the gene coding for fibrillin-1, FBN1. The high mortality of untreated MFS results almost exclusively from aortic complications such as aortic dissection and rupture. However, more than half of patients with Marfan-like features do not have MFS, but have other diseases including inherited aortic aneurysms and dissections (TAAD). We elucidate the increasing spectrum of syndromes associated with Marfan-like features and discuss the clinical implications of these diseases. We performed a systematic review to tabulate all known inherited diseases and syndromes carrying a risk for thoracic aortic disease. We discuss evidence that different syndromes with different causative genes and mutations have different prognoses and profiles of cardiovascular manifestations. We conclude that future decisions for optimized management of patients with inherited TAAD require a comprehensive clinical and genetic work-up.

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Cardiomyopathy in Genetic Aortic Diseases

Frontiers in Pediatrics ◽

10.3389/fped.2021.682390 ◽

2021 ◽

Vol 9 ◽

Author(s):

Laura Muiño-Mosquera ◽

Julie De Backer

Keyword(s):

Marfan Syndrome ◽

Myocardial Dysfunction ◽

Genetic Defect ◽

Positive Family History ◽

Aortic Disease ◽

Aortic Aneurysms ◽

Aortic Diseases ◽

Pathogenic Variants ◽

Fibrillin 1

Genetic aortic diseases are a group of illnesses characterized by aortic aneurysms or dissection in the presence of an underlying genetic defect. They are part of the broader spectrum of heritable thoracic aortic disease, which also includes those cases of aortic aneurysm or dissection with a positive family history but in whom no genetic cause is identified. Aortic disease in these conditions is a major cause of mortality, justifying clinical and scientific emphasis on the aorta. Aortic valve disease and atrioventricular valve abnormalities are known as important additional manifestations that require careful follow-up and management. The archetype of genetic aortic disease is Marfan syndrome, caused by pathogenic variants in the Fibrillin-1 gene. Given the presence of fibrillin-1 microfibers in the myocardium, myocardial dysfunction and associated arrhythmia are conceivable and have been shown to contribute to morbidity and mortality in patients with Marfan syndrome. In this review, we will discuss data on myocardial disease from human studies as well as insights obtained from the study of mouse models of Marfan syndrome. We will elaborate on the various phenotypic presentations in childhood and in adults and on the topic of arrhythmia. We will also briefly discuss the limited data available on other genetic forms of aortic disease.

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Screening for Familial Thoracic Aortic Aneurysms with Aortic Imaging Does Not Detect All Potential Carriers of the Disease

Aorta ◽

10.12945/j.aorta.2015.14-052 ◽

2015 ◽

Vol 03 (01) ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Matias Hannuksela ◽

Eva-Lena Stattin ◽

Bengt Johansson ◽

Bo Carlberg

Keyword(s):

Thoracic Aorta ◽

Autosomal Dominant ◽

Aortic Disease ◽

Aortic Aneurysms ◽

Aortic Dilatation ◽

Expected Number ◽

Thoracic Aortic Disease ◽

First Degree Relatives ◽

Number Of Individuals ◽

Second Degree

Background: About 20% of patients with thoracic aortic aneurysm or dissection (TAAD) have a first-degree relative with a similar disease. The familial form (FTAAD) of the disease is inherited in an autosomal-dominant pattern. Current guidelines for thoracic aortic disease recommend screening of first-degree relatives of TAAD patients. In known familial disease, screening of both first- and second-degree relatives is recommended. However, the outcomes of such a screening program are unknown. Methods: We screened all first- and second-degree relatives in seven families with known FTAAD with echocardiography. No underlying gene defect had been detected in these families. Results: Of 119 persons investigated, 13 had known thoracic aortic disease. In the remaining 106 cases, we diagnosed 19 additional individuals with a dilated ascending thoracic aorta; for an autosomal-dominant disease, the expected number of individuals in this group would have been 40 (p<0.0001). Further, only one of the 20 first-degree relatives younger than 40 years had a dilated aorta, although the expected number of individuals with a disease-causing mutation would have been 10. Conclusions: In most families with TAAD, a diagnosis still relies on measuring the diameter of the thoracic aorta. We show that a substantial number of previously unknown cases of aortic dilatation can be identified by screening family members. It is, however, not possible to consider anyone free of the condition, even if the aortic diameter is normal, especially at a younger age.

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Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1507652112 ◽

2015 ◽

Vol 112 (45) ◽

pp. 14012-14017 ◽

Cited By ~ 21

Author(s):

Lior Zilberberg ◽

Colin K. L. Phoon ◽

Ian Robertson ◽

Branka Dabovic ◽

Francesco Ramirez ◽

...

Keyword(s):

Aortic Aneurysm ◽

Marfan Syndrome ◽

Autosomal Dominant ◽

Aortic Disease ◽

Elastic Fibers ◽

Thoracic Aneurysm ◽

Tgfβ Signaling ◽

Autosomal Dominant Disorder ◽

Present Evidence ◽

Fibrillin 1

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.

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Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

Biomolecules ◽

10.3390/biom12010128 ◽

2022 ◽

Vol 12 (1) ◽

pp. 128

Author(s):

Keiichi Asano ◽

Anna Cantalupo ◽

Lauriane Sedes ◽

Francesco Ramirez

Keyword(s):

Marfan Syndrome ◽

Single Gene ◽

Gene Mutations ◽

Aortic Disease ◽

Connective Tissue Disorder ◽

Tgfβ Signaling ◽

Thoracic Aortic Disease ◽

Molecular Determinants ◽

Fibrillin 1 ◽

Experimental Findings

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFβ signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder.

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Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽

10.1093/med/9780198784906.003.0160 ◽

2018 ◽

pp. 713-715

Author(s):

Dorien Schepers ◽

Bart Loeys

Keyword(s):

Extracellular Matrix ◽

Marfan Syndrome ◽

Transforming Growth Factor Beta ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Aortic Disease ◽

Extracellular Matrix Protein ◽

Genetic Defects ◽

Fibrillin 1 ◽

Growth Factor Beta

Marfan syndrome is an autosomal dominant, multisystemic disorder, presenting with skeletal, ocular, and cardiovascular symptoms. This connective tissue disease is caused by mutations in FBN1, encoding fibrillin-1, which is an important extracellular matrix protein. Marfan syndrome shows significant clinical overlap with Loeys–Dietz syndrome, which is caused by genetic defects in components of the transforming growth factor-beta pathway: TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, and SMAD3. Overlapping clinical features between Marfan syndrome and Loeys–Dietz syndrome include aortic root aneurysm, arachnodactyly, scoliosis, and pectus deformity.

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SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105583 ◽

2019 ◽

Vol 56 (4) ◽

pp. 252-260 ◽

Cited By ~ 14

Author(s):

Ellen M Hostetler ◽

Ellen S Regalado ◽

Dong-Chuan Guo ◽

Nadine Hanna ◽

Pauline Arnaud ◽

...

Keyword(s):

Age Of Onset ◽

Cumulative Risk ◽

Aortic Disease ◽

Aortic Aneurysms ◽

Thoracic Aortic Disease ◽

Thoracic Aortic Aneurysms ◽

Missense Variants ◽

Variant Type ◽

Pathogenic Variants ◽

Reduced Penetrance

BackgroundPathogenic variants in SMAD3 cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with SMAD3 variants.MethodsAortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique SMAD3 variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.ResultsAortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed.ConclusionsSMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying SMAD3 variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with SMAD3 variants support gene-specific management of this disorder.

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Marfan Syndrome: A Case Report

Case Reports in Dentistry ◽

10.1155/2012/595343 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4

Author(s):

Rajendran Ganesh ◽

Rajendran Vijayakumar ◽

Haridoss Selvakumar

Keyword(s):

Stainless Steel ◽

Case Report ◽

Connective Tissue ◽

Blood Vessel ◽

Marfan Syndrome ◽

Autosomal Dominant ◽

The Body ◽

Tissue Protein ◽

Fibrillin 1 ◽

Systemic Disorder

Marfan syndrome is an autosomal dominant systemic disorder of the connective tissue. Children affected by the Marfan syndrome carry a mutation in one of their two copies of the gene that encodes the connective tissue protein fibrillin-1. Marfan syndrome affects most organs and tissues, especially the skeleton, lungs, eyes, heart, and the large blood vessel that distributes blood from the heart to the rest of the body. A case report of Marfan syndrome has been reported with oral features. The dental problems of the child were treated under general anesthesia and a one-month review showed intact stainless steel crowns' restorations and no signs of secondary caries.

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Endovascular Repair of the Descending Thoracic Aorta: Evidence for the Change in Clinical Practice

Vascular ◽

10.1258/rsmvasc.13.3.148 ◽

2005 ◽

Vol 13 (3) ◽

pp. 148-157 ◽

Cited By ~ 20

Author(s):

Saiqa Sayed ◽

Matt M. Thompson

Keyword(s):

Thoracic Aorta ◽

Endovascular Repair ◽

Graft Infection ◽

Aortic Disease ◽

Outcome Data ◽

Aortic Aneurysms ◽

Descending Thoracic Aorta ◽

Thoracic Aortic Disease ◽

Technical Success Rate ◽

Open Conversion

The purpose was to review outcome data following endovascular repair of the descending thoracic aorta from reports published between 1994 and 2004. To accomplish this task, 1,518 patients underwent endovascular repair for thoracic aortic disease; 810 thoracic aortic aneurysms, 500 type B thoracic aortic dissections, and 106 traumatic ruptures. The 30-day mortality rate was 5.5% and 6% for late postoperative deaths. The primary technical success rate was 97%, with only 15 patients requiring open conversion. Neurologic deficits occurred in 29 patients. In total, 118 endoleaks were reported; 29 were restented, and the remainder required surgical intervention. Graft infection occurred in 6 cases, and migrations were detected in 10. The conclusion reached is that endovascular repair of descending thoracic aortic disease is feasible and can be achieved with low rates of perioperative morbidity and mortality. As few long-term data exist on the durability of thoracic stent grafts, lifelong surveillance remains necessary.

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Thoracic aortic aneurysms and other conditions

10.1093/med/9780199685288.003.1638_update_003 ◽

2016 ◽

Author(s):

Demosthenes G. Katritsis ◽

Bernard J. Gersh ◽

A. John Camm

Keyword(s):

Aortic Disease ◽

Aortic Aneurysms ◽

Thoracic Aortic Disease ◽

Thoracic Aortic Aneurysms

Thoracic aortic aneurysms, aortic atheroembolic disease, and other cardiovascular conditions associated with thoracic aortic disease are discussed.

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Microfibrils and fibrillin-1 induce integrin-mediated signaling, proliferation and migration in human endothelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00377.2009 ◽

2010 ◽

Vol 299 (5) ◽

pp. C977-C987 ◽

Cited By ~ 23

Author(s):

Boubacar Mariko ◽

Zeinab Ghandour ◽

Stéphanie Raveaud ◽

Mickaël Quentin ◽

Yves Usson ◽

...

Keyword(s):

Endothelial Cells ◽

Marfan Syndrome ◽

Intracellular Signaling ◽

Aortic Aneurysms ◽

Endothelial Cell Proliferation ◽

Elastic Fibers ◽

Calcium Stores ◽

Fibrillin 1 ◽

And Migration ◽

Proliferation And Migration

Microfibrils are macromolecular complexes associated with elastin to form elastic fibers that endow extensible tissues, such as arteries, lungs, and skin, with elasticity property. Fibrillin-1, the main component of microfibrils, is a 350-kDa glycoprotein for which genetic haploinsufficiency in humans can lead to Marfan syndrome, a severe polyfeatured pathology including aortic aneurysms and dissections. Microfibrils and fibrillin-1 fragments mediate adhesion of several cell types, including endothelial cells, while fibrillin-1 additionally triggers lung and mesangial cell migration. However, fibrillin-1-induced intracellular signaling is unknown. We have studied the signaling events induced in human umbilical venous endothelial cells (HUVECs) by aortic microfibrils as well as recombinant fibrillin-1 Arg-Gly-Asp (RGD)-containing fragments PF9 and PF14. Aortic microfibrils and PF14, not PF9, substantially and dose dependently increased HUVEC cytoplasmic and nuclear calcium levels measured using the fluorescent dye Fluo-3. This effect of PF14 was confirmed in bovine aortic endothelial cells. PF14 action in HUVECs was mediated by αvβ3 and α5β1 integrins, phospholipase-C, inosital 1,4,5-trisphosphate, and mobilization of intracellular calcium stores, whereas membrane calcium channels were not or only slightly implicated, as shown in patch-clamp experiments. Finally, PF14 enhanced endothelial cell proliferation and migration. Hence, fibrillin-1 sequences may physiologically activate endothelial cells. Genetic fibrillin-1 deficiency could alter normal endothelial signaling and, since endothelium dysfunction is an important contributor to Marfan syndrome, participate in the arterial anomalies associated with this developmental disease.

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