Marfan syndrome (MFS) is an autosomal dominant, age-related but highly penetrant condition with substantial intrafamilial and interfamilial variability. MFS is caused by pathogenetic variants in FBN1, which encodes fibrillin-1, a major structural component of the extracellular matrix that provides support to connective tissues, particularly in arteries, the pericondrium and structures in the eye. Up to 25% of individuals with MFS have de novo variants. The most prominent manifestations of MFS are asymptomatic aortic root aneurysms, aortic dissections, dislocation of the ocular lens (ectopia lentis) and skeletal abnormalities that are characterized by overgrowth of the long bones. MFS is diagnosed based on the Ghent II nosology; genetic testing confirming the presence of a FBN1 pathogenetic variant is not always required for diagnosis but can help distinguish MFS from other heritable thoracic aortic disease syndromes that can present with skeletal features similar to those in MFS. Untreated aortic root aneurysms can progress to life-threatening acute aortic dissections. Management of MFS requires medical therapy to slow the rate of growth of aneurysms and decrease the risk of dissection. Routine surveillance with imaging techniques such as transthoracic echocardiography, CT or MRI is necessary to monitor aneurysm growth and determine when to perform prophylactic repair surgery to prevent an acute aortic dissection.
Subscribe to Journal
Get full journal access for 1 year
only $59.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hollister, D. W., Godfrey, M., Sakai, L. Y. & Pyeritz, R. E. Immunohistologic abnormalities of the microfibrillar-fiber system in the Marfan syndrome. N. Engl. J. Med. 323, 152–159 (1990). This article describes decreases in an extracellular matrix protein, fibrillin-1, in skin samples and in the matrix of explanted dermal fibroblasts from patients with MFS.
Sakai, L. Y., Keene, D. R. & Engvall, E. Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J. Cell Biol. 103, 2499–2509 (1986).
Dietz, H. C. et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337–339 (1991). The first study identifying the mutations in the gene for fibrillin-1, FBN1, in patients with MFS, thus determining that FBN1 mutations are the cause of MFS.
Milewicz, D. M., Pyeritz, R. E., Crawford, E. S. & Byers, P. H. Marfan syndrome: defective synthesis, secretion, and extracellular matrix formation of fibrillin by cultured dermal fibroblasts. J. Clin. Invest. 89, 79–86 (1992).
Chiu, H. H., Wu, M. H., Chen, H. C., Kao, F. Y. & Huang, S. K. Epidemiological profile of Marfan syndrome in a general population: a national database study. Mayo Clin. Proc. 89, 34–42 (2014).
Arnaud, P. et al. Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome. Genet. Med. 23, 865–871 (2021).
Arnaud, P. et al. Clinical relevance of genotype-phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants. Genet. Med. 23, 1296–1304 (2021). This study, with the largest cohort of patients with MFS published to date, shows FBN1 genotype–phenotype correlations for both aortic and extra-aortic features, which can be used for optimal risk stratification and personalized medicine for patients with MFS.
McKusick, V. A. Heritable Disorders of Connective Tissue 4th edn (Mosby, 1972).
McKusick, V. A. The cardiovascular aspects of Marfan’s syndrome: a heritable disorder of connective tissue. Circulation 11, 321–342 (1955). The first study to describe the thoracic aortic aneurysms and dissections and mitral valve abnormalitites in patients with MFS.
Murdoch, J. L., Walker, B. A., Halpern, B. L., Kuzma, J. W. & McKusick, V. A. Life expectancy and causes of death in the Marfan syndrome. N. Engl. J. Med. 286, 804–808 (1972).
Pyeritz, R. E. & McKusick, V. A. The Marfan syndrome: diagnosis and management. N. Engl. J. Med. 300, 772–777 (1979).
Silverman, D. I. et al. Life expectancy in the Marfan syndrome. Am. J. Cardiol. 75, 157–160 (1995).
Finkbohner, R., Johnston, D., Crawford, E. S., Coselli, J. & Milewicz, D. M. Marfan syndrome. Long-term survival and complications after aortic aneurysm repair. Circulation 91, 728–733 (1995).
Pyeritz, R. E. Marfan syndrome: improved clinical history results in expanded natural history. Genet. Med. 21, 1683–1690 (2019).
den Hartog, A. W. et al. The risk for type B aortic dissection in Marfan syndrome. J. Am. Coll. Cardiol. 65, 246–254 (2015).
de Beaufort, H. W. L. et al. Aortic dissection in patients with Marfan syndrome based on the IRAD data. Ann. Cardiothorac. Surg. 6, 633–641 (2017).
Loeys, B. L. et al. The revised Ghent nosology for the Marfan syndrome. J. Med. Genet. 47, 476–485 (2010).
Pyeritz, R. E. The Marfan syndrome. Annu. Rev. Med. 51, 481–510 (2000).
Habashi, J. P. et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312, 117–121 (2006).
Lacro, R. V. et al. Atenolol versus losartan in children and young adults with Marfan’s syndrome. N. Engl. J. Med. 371, 2061–2071 (2014). Following studies in mice in which losartan blocked thoracic aortic aneurysm formation better than the standard of care, β-adrenergic receptor blockade, in this clinical trial both losartan and β-adrenergic receptor blockers had similar effects on aortic root growth in children and young adults with MFS.
Groth, K. A. et al. Prevalence, incidence, and age at diagnosis in Marfan syndrome. Orphanet. J. Rare. Dis. 10, 153 (2015).
Beighton, P. et al. International nosology of heritable disorders of connective tissue, Berlin, 1986. Am. J. Med. Genet. 29, 581–594 (1988).
Fuchs, J. Marfan syndrome and other systemic disorders with congenital ectopia lentis. A Danish national survey. Acta Paediatr. 86, 947–952 (1997).
De Paepe, A., Devereux, R. B., Dietz, H. C., Hennekam, R. C. & Pyeritz, R. E. Revised diagnostic criteria for the Marfan syndrome. Am. J. Med. Genet. 62, 417–426 (1996).
Faivre, L. et al. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am. J. Med. Genet. A 123A, 204–207 (2003).
Le, G. C. et al. Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am. J. Hum. Genet. 89, 7–14 (2011).
Ades, L. C., Holman, K. J., Brett, M. S., Edwards, M. J. & Bennetts, B. Ectopia lentis phenotypes and the FBN1 gene. Am. J. Med. Genet. A 126, 284–289 (2004).
Milewicz, D. M. et al. A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome. J. Clin. Invest. 95, 2373–2378 (1995).
Milewicz, D. M. et al. Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. Circulation 94, 2708–2711 (1996).
Faivre, L. et al. Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion. Am. J. Med. Genet. A 149A, 854–860 (2009).
Guo, D. C. et al. Heritable thoracic aortic disease genes in sporadic aortic dissection. J. Am. Coll. Cardiol. 70, 2728–2730 (2017).
Mizuguchi, T. et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat. Genet. 36, 855–860 (2004). A genetic study that determined that individuals with thoracic aortic disease and systemic manifestations of MFS can have mutations in genes other than FBN1; TGFBR2 mutations were identified in such individuals in this study.
LeMaire, S. A. et al. Severe aortic and arterial aneurysms associated with a TGFBR2 mutation. Nat. Clin. Pract. Cardiovasc. Med. 4, 167–171 (2007).
Peng, Q., Deng, Y., Yang, Y. & Liu, H. A novel fibrillin-1 gene missense mutation associated with neonatal Marfan syndrome: a case report and review of the mutation spectrum. BMC Pediatr. 16, 60 (2016).
Boileau, C. et al. Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomalies not linked to the fibrillin genes [see comments]. Am. J. Hum. Genet. 53, 46–54 (1993).
Loeys, B. L. et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat. Genet 37, 275–281 (2005).
Furlong, J., Kurczynski, T. W. & Hennessy, J. R. New Marfanoid syndrome with craniosynostosis. Am. J. Med. Genet. 26, 599–604 (1987).
MacFarlane, E. G. et al. Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome. J. Clin. Invest. 129, 659–675 (2019).
van de Laar, I. M. et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat. Genet. 43, 121–126 (2011).
Rienhoff, H. Y. Jr et al. 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. Am. J. Med. Genet. A 161A, 2040–2046 (2013).
Bertoli-Avella, A. M. et al. Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J. Am. Coll. Cardiol. 65, 1324–1336 (2015).
Sakai, L. Y., Keene, D. R., Glanville, R. W. & Bachinger, H. P. Purification and partial characterization of fibrillin, a cysteine-rich structural component of connective tissue microfibrils. J. Biol. Chem. 266, 14763–14770 (1991).
Corson, G. M., Chalberg, S. C., Dietz, H. C., Charbonneau, N. L. & Sakai, L. Y. Fibrillin binds calcium and is coded by cDNAs that reveal a multidomain structure and alternatively spliced exons at the 5′ end. Genomics 17, 476–484 (1993).
Lerner-Ellis, J. P. et al. 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). Mol. Genet. Metab. 112, 171–176 (2014).
Milewicz, D. M. & Duvic, M. Severe neonatal Marfan syndrome resulting from a de novo 3-bp insertion into the fibrillin gene on chromosome 15. Am. J. Hum. Genet. 54, 447–453 (1994).
Putnam, E. A. et al. Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene. Am. J. Med. Genet. 62, 233–242 (1996).
Faivre, L. et al. Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation. Eur. J. Hum. Genet. 17, 491–501 (2009).
Faivre, L. et al. 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. Am. J. Hum. Genet. 81, 454–466 (2007).
Schrijver, I., Liu, W., Brenn, T., Furthmayr, H. & Francke, U. Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am. J. Hum. Genet. 65, 1007–1020 (1999).
Schrijver, I. et al. Premature termination mutations in FBN1: distinct effects on differential allelic expression and on protein and clinical phenotypes. Am. J. Hum. Genet. 71, 223–237 (2002).
Sengle, G. & Sakai, L. Y. The fibrillin microfibril scaffold: a niche for growth factors and mechanosensation? Matrix Biol. 47, 3–12 (2015).
Sengle, G. et al. Targeting of bone morphogenetic protein growth factor complexes to fibrillin. J. Biol. Chem. 283, 13874–13888 (2008).
Ramirez, F. & Dietz, H. C. Fibrillin-rich microfibrils: structural determinants of morphogenetic and homeostatic events. J. Cell Physiol. 213, 326–330 (2007).
Chen, Y., Dabovic, B., Annes, J. P. & Rifkin, D. B. Latent TGF-β binding protein-3 (LTBP-3) requires binding to TGF-β for secretion. FEBS Lett. 517, 277–280 (2002).
Robertson, I. B. et al. Latent TGF-β-binding proteins. Matrix Biol. 47, 44–53 (2015).
Zilberberg, L. et al. Specificity of latent TGF-β binding protein (LTBP) incorporation into matrix: role of fibrillins and fibronectin. J. Cell Physiol. 227, 3828–3836 (2012).
Isogai, Z. et al. Latent transforming growth factor β-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J. Biol. Chem. 278, 2750–2757 (2003).
Ono, R. N. et al. Latent transforming growth factor β-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites. J. Biol. Chem. 284, 16872–16881 (2009).
Wipff, P. J., Rifkin, D. B., Meister, J. J. & Hinz, B. Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).
Humphrey, J. D., Milewicz, D. M., Tellides, G. & Schwartz, M. A. Cell biology. Dysfunctional mechanosensing aneurysms. Science 344, 477–479 (2014).
Waters, K. M., Rooper, L. M., Guajardo, A. & Halushka, M. K. Histopathologic differences partially distinguish syndromic aortic diseases. Cardiovasc. Pathol. 30, 6–11 (2017).
Davis, E. C. Smooth muscle cell to elastic lamina connections in developing mouse aorta. Role in aortic medial organization. Lab. Invest. 68, 89–99 (1993).
Milewicz, D. M. et al. Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annu. Rev. Genomics Hum. Genet. 9, 283–302 (2008).
Humphrey, J. D., Schwartz, M. A., Tellides, G. & Milewicz, D. M. Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circ. Res. 116, 1448–1461 (2015).
Milewicz, D. M. et al. Altered smooth muscle cell force generation as a driver of thoracic aortic aneurysms and dissections. Arterioscler. Thromb. Vasc. Biol. 37, 26–34 (2017).
Pereira, L. et al. Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat. Genet. 17, 218–222 (1997).
Pereira, L. et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc. Natl Acad. Sci. USA 96, 3819–3823 (1999).
Judge, D. P. et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J. Clin. Invest. 114, 172–181 (2004).
Carta, L. et al. Fibrillins 1 and 2 perform partially overlapping functions during aortic development. J. Biol. Chem. 281, 8016–8023 (2006).
Bunton, T. E. et al. Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome. Circ. Res. 88, 37–43 (2001).
Neptune, E. R. et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nat. Genet. 33, 407–411 (2003).
Lavoie, P. et al. Neutralization of transforming growth factor-β attenuates hypertension and prevents renal injury in uremic rats. J. Hypertens. 23, 1895–1903 (2005).
Lim, D. S. et al. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation 103, 789–791 (2001).
Gibbons, G. H., Pratt, R. E. & Dzau, V. J. Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J. Clin. Invest. 90, 456–461 (1992).
Galatioto, J. et al. Cell type-specific contributions of the angiotensin II type 1a receptor to aorta homeostasis and aneurysmal disease-brief report. Arterioscler. Thromb. Vasc. Biol. 38, 588–591 (2018).
Cook, J. R. et al. Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome. Arterioscler. Thromb. Vasc. Biol. 35, 911–917 (2015). Since losartan treatment was used to block TGFβ signalling and prevent aortic root growth, this study further explored the role of TGFβ signalling in a mouse model of MFS and showed that blocking this signalling pathway early was detrimental and led to earlier deaths due to dissection.
Lindsay, M. E. et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat. Genet. 44, 922–927 (2012).
Li, W. et al. Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis. J. Clin. Invest. 124, 755–767 (2014).
Wei, H. et al. Aortopathy in a mouse model of Marfan syndrome is not mediated by altered transforming growth factor β signaling. J. Am. Heart Assoc. 6, e004968 (2017).
Boileau, C. et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat. Genet. 44, 916–921 (2012).
Inamoto, S. et al. TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections. Cardiovasc. Res. 88, 520–529 (2010).
Laar, I. M. B. H.van de et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J. Med. Genet. 49, 47–57 (2012).
Regalado, E. S. et al. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ. Res. 109, 680–686 (2011).
Sellers, S. L. et al. Inhibition of Marfan syndrome aortic root dilation by losartan: role of angiotensin II receptor type 1-independent activation of endothelial function. Am. J. Pathol. 188, 574–585 (2018).
Milewicz, D. M., Prakash, S. K. & Ramirez, F. Therapeutics targeting drivers of thoracic aortic aneurysms and acute aortic dissections: insights from predisposing genes and mouse models. Annu. Rev. Med. 68, 51–67 (2017).
Pinard, A., Jones, G. T. & Milewicz, D. M. Genetics of thoracic and abdominal aortic diseases. Circ. Res. 124, 588–606 (2019).
Pedroza, A. J. et al. Single-cell transcriptomic profiling of vascular smooth muscle cell phenotype modulation in Marfan syndrome aortic aneurysm. Arterioscler. Thromb. Vasc. Biol. 40, 2195–2211 (2020).
Cook, J. R. et al. Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome. J. Clin. Invest. 124, 1329–1339 (2014).
Rouf, R. et al. Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice. JCI Insight 2, e91588 (2017).
Wisler, J. W. et al. The role of β-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome. Am. J. Physiol. Heart Circ. Physiol. 309, H1516–H1527 (2015).
Crosas-Molist, E. et al. Vascular smooth muscle cell phenotypic changes in patients with Marfan syndrome. Arterioscler. Thromb. Vasc. Biol. 35, 960–972 (2015).
Jimenez-Altayo, F. et al. Redox stress in Marfan syndrome: dissecting the role of the NADPH oxidase NOX4 in aortic aneurysm. Free Radic. Biol. Med. 118, 44–58 (2018).
Yang, H. H., Breemen, C.van & Chung, A. W. Vasomotor dysfunction in the thoracic aorta of Marfan syndrome is associated with accumulation of oxidative stress. Vasc. Pharmacol. 52, 37–45 (2010).
Chen, J. et al. Loss of smooth muscle α-actin leads to NF-κB-dependent increased sensitivity to angiotensin II in smooth muscle cells and aortic enlargement. Circ. Res. 120, 1903–1915 (2017).
Carta, L. et al. MAPKp38 is an early determinant of promiscuous Smad2/3 signaling in the aortas of fibrillin-1 (Fbn1) null mice. J. Biol. Chem. 284, 5630–5636 (2008).
Granata, A. et al. An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death. Nat. Genet. 49, 97–109 (2017).
Chung, A. W., Yang, H. H., Radomski, M. W. & van Breemen, C. Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9. Circ. Res. 102, e73–e85 (2008).
Emrich, F. C. et al. Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome. Arterioscler. Thromb. Vasc. Biol. 35, 146–154 (2015).
Merk, D. R. et al. miR-29b Participates in early aneurysm development in Marfan syndrome. Circ. Res. 110, 312–324 (2012).
Mas-Stachurska, A. et al. Cardiovascular benefits of moderate exercise training in Marfan syndrome: insights from an animal model. J. Am. Heart Assoc. 6, e006438 (2017).
Milewicz, D. M. & Ramirez, F. Therapies for thoracic aortic aneurysms and acute aortic dissections. Arterioscler. Thromb. Vasc. Biol. 39, 126–136 (2019).
LeMaire, S. A. et al. Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nat. Genet. 43, 996–1000 (2011). This study shows that common genetic variants at 15q21.1 that most likely act via FBN1 are associated with thoracic aortic disease in the general population, suggesting a common pathogenesis of aortic disease in MFS and thoracic aortic disease in the population.
Smaldone, S. et al. Fibrillin-1 regulates skeletal stem cell differentiation by modulating TGFβ activity within the marrow niche. J. Bone Min. Res. 31, 86–97 (2016).
Smaldone, S. & Ramirez, F. Fibrillin microfibrils in bone physiology. Matrix Biol. 52-54, 191–197 (2016).
Lima, B. L. et al. A new mouse model for Marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression. PLoS ONE 5, e14136 (2010).
Beene, L. C. et al. Nonselective assembly of fibrillin 1 and fibrillin 2 in the rodent ocular zonule and in cultured cells: implications for Marfan syndrome. Invest. Ophthalmol. Vis. Sci. 54, 8337–8344 (2013).
Mir, S., Wheatley, H. M., Hussels, I. E., Whittum-Hudson, J. A. & Traboulsi, E. I. A comparative histologic study of the fibrillin microfibrillar system in the lens capsule of normal subjects and subjects with Marfan syndrome. Invest. Ophthalmol. Vis. Sci. 39, 84–93 (1998).
Wheatley, H. M. et al. Immunohistochemical localization of fibrillin in human ocular tissues. Relevance to the Marfan syndrome. Arch. Ophthalmol. 113, 103–109 (1995).
Hanlon, S. D., Behzad, A. R., Sakai, L. Y. & Burns, A. R. Corneal stroma microfibrils. Exp. Eye Res. 132, 198–207 (2015).
Jones, W., Rodriguez, J. & Bassnett, S. Targeted deletion of fibrillin-1 in the mouse eye results in ectopia lentis and other ocular phenotypes associated with Marfan syndrome. Dis. Model Mech. 12, dmm037283 (2019).
Tan, L. et al. FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection. Hum. Mol. Genet. 26, 4814–4822 (2017).
Akutsu, K. et al. Characteristics in phenotypic manifestations of genetically proved Marfan syndrome in a Japanese population. Am. J. Cardiol. 103, 1146–1148 (2009).
Villamizar, C. et al. Paucity of skeletal manifestations in Hispanic families with FBN1 mutations. Eur. J. Med. Genet. 53, 80–84 (2010).
Faivre, L. et al. The new Ghent criteria for Marfan syndrome: what do they change? Clin. Genet. 81, 433–442 (2012).
Bombardieri, E. et al. Marfan syndrome and related connective tissue disorders in the current era in Switzerland in 103 patients: medical and surgical management and impact of genetic testing. Swiss Med. Wkly 150, w20189 (2020).
Roman, M. J. et al. Associations of age and sex with marfan phenotype: The National Heart, Lung, and Blood Institute GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) Registry. Circ. Cardiovasc. Genet. 10, e001647 (2017).
Ladouceur, M. et al. Effect of beta-blockade on ascending aortic dilatation in children with the Marfan syndrome. Am. J. Cardiol. 99, 406–409 (2007).
Hascoet, S. et al. Incidence of cardiovascular events and risk markers in a prospective study of children diagnosed with Marfan syndrome. Arch. Cardiovasc. Dis. 113, 40–49 (2020).
Wozniak-Mielczarek, L. et al. Differences in cardiovascular manifestation of Marfan syndrome between children and adults. Pediatr. Cardiol. 40, 393–403 (2019).
Detaint, D. et al. Aortic dilatation patterns and rates in adults with bicuspid aortic valves: a comparative study with Marfan syndrome and degenerative aortopathy. Heart 100, 126–134 (2014).
Guala, A. et al. Proximal aorta longitudinal strain predicts aortic root dilation rate and aortic events in Marfan syndrome. Eur. Heart J. 40, 2047–2055 (2019).
Groenink, M. et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur. Heart J. 34, 3491–3500 (2013).
Mullen, M. et al. Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial. Lancet 394, 2263–2270 (2020).
Teixido-Tura, G. et al. Losartan versus atenolol for prevention of aortic dilation in patients with Marfan syndrome. J. Am. Coll. Cardiol. 72, 1613–1618 (2018).
Turkbey, E. B. et al. Determinants and normal values of ascending aortic diameter by age, gender, and race/ethnicity in the Multi-Ethnic Study of Atherosclerosis (MESA). J. Magn. Reson. Imaging 39, 360–368 (2014).
Jondeau, G. et al. Aortic event rate in the Marfan population: a cohort study. Circulation 125, 226–232 (2012).
Erbel, R. et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur. Heart J. 35, 2873–2926 (2014).
Hiratzka, L. F. et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation 121, e266–e369 (2010). The first treatment guidelines for thoracic aortic disease, which set the standards for thoracic aortic disease clinical and surgical management in patients with thoracic aortic disease, including patients with MFS.
Morris, S. A. et al. Increased vertebral artery tortuosity index is associated with adverse outcomes in children and young adults with connective tissue disorders. Circulation 124, 388–396 (2011).
Franken, R. et al. Increased aortic tortuosity indicates a more severe aortic phenotype in adults with Marfan syndrome. Int. J. Cardiol. 194, 7–12 (2015).
Mortensen, K. et al. Augmentation index relates to progression of aortic disease in adults with Marfan syndrome. Am. J. Hypertens. 22, 971–979 (2009).
Selamet Tierney, E. S. et al. Influence of aortic stiffness on aortic-root growth rate and outcome in patients with the Marfan syndrome. Am. J. Cardiol. 121, 1094–1101 (2018).
Jondeau, G. et al. International registry of patients carrying TGFBR1 or TGFBR2 mutations: results of the MAC (Montalcino Aortic Consortium). Circ. Cardiovasc. Genet. 9, 548–558 (2016).
Teixido-Tura, G. et al. Aortic biomechanics by magnetic resonance: early markers of aortic disease in Marfan syndrome regardless of aortic dilatation? Int. J. Cardiol. 171, 56–61 (2014).
Franken, R. et al. Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome. Heart 103, 1795–1799 (2017).
Takeda, N. et al. Impact of pathogenic FBN1 variant types on the progression of aortic disease in patients with Marfan syndrome. Circ. Genom. Precis. Med. 11, e002058 (2018).
Roman, M. J., Rosen, S. E., Kramer-Fox, R. & Devereux, R. B. Prognostic significance of the pattern of aortic root dilation in the Marfan syndrome. J. Am. Coll. Cardiol. 22, 1470–1476 (1993).
Attias, D. et al. Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circulation 120, 2541–2549 (2009).
LeMaire, S. et al. Spectrum of aortic operations in 300 patients with confirmed or suspected Marfan syndrome. Ann. Thorac. Surg. 81, 2063–2078 (2006).
Hagerty, T., Geraghty, P. & Braverman, A. C. Abdominal aortic aneurysm in Marfan syndrome. Ann. Vasc. Surg. 40, 294.e1–294.e6 (2017).
Prakash, S. K., Haden-Pinneri, K. & Milewicz, D. M. Susceptibility to acute thoracic aortic dissections in patients dying outside the hospital: an autopsy study. Am. Heart J. 162, 474–479 (2011).
Reutersberg, B. et al. Hospital incidence and in-hospital mortality of surgically and interventionally treated aortic dissections: secondary data analysis of the nationwide German diagnosis-related group statistics from 2006 to 2014. J. Am. Heart Assoc. 8, e011402 (2019).
Brouwer, C. et al. Progressive pulmonary artery dilatation is associated with type B aortic dissection in patients with Marfan syndrome. J. Clin. Med. 8, 1848 (2019).
Mimoun, L. et al. Dissection in Marfan syndrome: the importance of the descending aorta. Eur. Heart J. 32, 443–449 (2011).
Baumgartner, H. et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. Eur. Heart J. 38, 2739–2791 (2017).
Pyeritz, R. E. Marfan syndrome: current and future clinical and genetic management of cardiovascular manifestations. Semin. Thorac. Cardiovasc. Surg. 5, 11–16 (1993).
Muhlstadt, K. et al. Case-matched comparison of cardiovascular outcome in Loeys-Dietz syndrome versus Marfan syndrome. J. Clin. Med. 8, 2079 (2019).
Mueller, G. C. et al. Impact of age and gender on cardiac pathology in children and adolescents with Marfan syndrome. Pediatr. Cardiol. 34, 991–998 (2013).
Selamet Tierney, E. S. et al. Echocardiographic methods, quality review, and measurement accuracy in a randomized multicenter clinical trial of Marfan syndrome. J. Am. Soc. Echocardiogr. 26, 657–666 (2013).
Lacro, R. V. et al. Characteristics of children and young adults with Marfan syndrome and aortic root dilation in a randomized trial comparing atenolol and losartan therapy. Am. Heart J. 165, 828–835 (2013).
Seo, Y. J. et al. Infantile Marfan syndrome in a Korean tertiary referral center. Korean J. Pediatr. 59, 59–64 (2016).
Rybczynski, M. et al. Frequency of sleep apnea in adults with the Marfan syndrome. Am. J. Cardiol. 105, 1836–1841 (2010).
Helder, M. R. et al. Management of mitral regurgitation in Marfan syndrome: outcomes of valve repair versus replacement and comparison with myxomatous mitral valve disease. J. Thorac. Cardiovasc. Surg. 148, 1020–1024 (2014).
Chivulescu, M. et al. Mitral annulus disjunction is associated with adverse outcome in Marfan and Loeys-Dietz syndromes. Eur. Heart J. Cardiovasc. Imaging https://doi.org/10.1093/ehjci/jeaa324 (2020).
Stark, V. C. et al. The pulmonary artery in pediatric patients with Marfan syndrome: an underestimated aspect of the disease. Pediatr. Cardiol. 39, 1194–1199 (2018).
Nollen, G. J. et al. Pulmonary artery root dilatation in Marfan syndrome: quantitative assessment of an unknown criterion. Heart 87, 470–471 (2002).
Lundby, R., Rand-Hendriksen, S., Hald, J. K., Pripp, A. H. & Smith, H. J. The pulmonary artery in patients with Marfan syndrome: a cross-sectional study. Genet. Med. 14, 922–927 (2012).
Kinori, M. et al. Biometry characteristics in adults and children with Marfan syndrome: from the Marfan Eye Consortium of Chicago. Am. J. Ophthalmol. 177, 144–149 (2017).
Gott, V. L. et al. Replacement of the aortic root in patients with Marfan’s syndrome. N. Engl. J. Med. 340, 1307–1313 (1999). Clinical study demonstrating that prophylactic surgical repair of aortic root aneurysms to prevent type A aortic dissections can be done with low mortality in patients with MFS.
Diller, G. P. et al. Survival prospects and circumstances of death in contemporary adult congenital heart disease patients under follow-up at a large tertiary centre. Circulation 132, 2118–2125 (2015).
Alpendurada, F. et al. Evidence for Marfan cardiomyopathy. Eur. J. Heart Fail. 12, 1085–1091 (2010).
Knosalla, C. et al. Orthotopic heart transplantation in patients with Marfan syndrome. Ann. Thorac. Surg. 83, 1691–1695 (2007).
Audenaert, T., Pauw, M.De, Francois, K. & Backer, J.De Type B aortic dissection triggered by heart transplantation in a patient with Marfan syndrome. BMJ Case Rep. 2015, bcr2015211138 (2015).
Chen, S., Fagan, L. F., Nouri, S. & Donahoe, J. L. Ventricular dysrhythmias in children with Marfan’s syndrome. Am. J. Dis. Child. 139, 273–276 (1985).
Aydin, A. et al. Observational cohort study of ventricular arrhythmia in adults with Marfan syndrome caused by FBN1 mutations. PLoS ONE 8, e81281 (2013).
Hoffmann, B. A. et al. Prospective risk stratification of sudden cardiac death in Marfan’s syndrome. Int. J. Cardiol. 167, 2539–2545 (2013).
Yetman, A. T., Bornemeier, R. A. & McCrindle, B. W. Long-term outcome in patients with Marfan syndrome: is aortic dissection the only cause of sudden death? J. Am. Coll. Cardiol. 41, 329–332 (2003).
Thompson, M. E. et al. Differential regulation of chromogranin B/secretogranin I and secretogranin II by forskolin in PC12 cells. Brain Res. Mol. Brain Res. 12, 195–202 (1992).
Sharma, T. et al. Retinal detachment in Marfan syndrome: clinical characteristics and surgical outcome. Retina 22, 423–428 (2002).
Maumenee, I. H. The eye in the Marfan syndrome. Trans. Am. Ophthalmol. Soc. 79, 684–733 (1981).
Chow, K., Pyeritz, R. E. & Litt, H. I. Abdominal visceral findings in patients with Marfan syndrome. Genet. Med. 9, 208–212 (2007).
Muino-Mosquera, L. et al. Sleep apnea and the impact on cardiovascular risk in patients with Marfan syndrome. Mol. Genet. Genom. Med. 7, e805 (2019).
von, K. Y. et al. Features of Marfan syndrome not listed in the Ghent nosology–the dark side of the disease. Expert Rev. Cardiovasc. Ther. 17, 883–915 (2019).
Speed, T. J. et al. Characterization of pain, disability, and psychological burden in Marfan syndrome. Am. J. Med. Genet. A 173, 315–323 (2017).
Handisides, J. C. et al. Health-related quality of life in children and young adults with Marfan syndrome. J. Pediatr. 204, 250–255.e1 (2019).
Warnink-Kavelaars, J. et al. Marfan syndrome in adolescence: adolescents’ perspectives on (physical) functioning, disability, contextual factors and support needs. Eur. J. Pediatr. 178, 1883–1892 (2019).
Velvin, G., Bathen, T., Rand-Hendriksen, S. & Geirdal, A. O. Systematic review of the psychosocial aspects of living with Marfan syndrome. Clin. Genet. 87, 109–116 (2015).
Guo, D. C. et al. An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease. J. Hum. Genet. 53, 1007–1011 (2008).
Hilhorst-Hofstee, Y. et al. The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family. Hum. Mutat. 31, E1915–E1927 (2010).
Arnaud, P. et al. Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome. J. Med. Genet. 54, 100–103 (2017).
Goldstein, S. A. et al. Multimodality imaging of diseases of the thoracic aorta in adults: from the American Society of Echocardiography and the European Association of Cardiovascular Imaging: endorsed by the Society of Cardiovascular Computed Tomography and Society for Cardiovascular Magnetic Resonance. J. Am. Soc. Echocardiogr. 28, 119–182 (2015).
Brown, O. R. et al. Aortic root dilatation and mitral valve prolapse in Marfan’s syndrome: an ECHOCARDIOgraphic study. Circulation 52, 651–657 (1975).
Campens, L. et al. Reference values for echocardiographic assessment of the diameter of the aortic root and ascending aorta spanning all age categories. Am. J. Cardiol. 114, 914–920 (2014).
Devereux, R. B. et al. Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons ≥15 years of age. Am. J. Cardiol. 110, 1189–1194 (2012).
Saura, D. et al. Two-dimensional transthoracic echocardiographic normal reference ranges for proximal aorta dimensions: results from the EACVI NORRE study. Eur. Heart J. Cardiovasc. Imaging 18, 167–179 (2017).
Muraru, D. et al. Ascending aorta diameters measured by echocardiography using both leading edge-to-leading edge and inner edge-to-inner edge conventions in healthy volunteers. Eur. Heart J. Cardiovasc. Imaging 15, 415–422 (2014).
Bossone, E. et al. Normal values and differences in ascending aortic diameter in a healthy population of adults as measured by the pediatric versus adult American Society of Echocardiography guidelines. J. Am. Soc. Echocardiogr. 29, 166–172 (2016).
Lopez, L. et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J. Am. Soc. Echocardiogr. 23, 465–495 (2010).
Lopez, L. et al. Pediatric Heart Network echocardiographic Z scores: comparison with other published models. J. Am. Soc. Echocardiogr. 34, 185–192 (2021).
Rutten, D. W. E. et al. Comparability of different Z-score equations for aortic root dimensions in children with Marfan syndrome. Cardiol. Young https://doi.org/10.1017/S1047951121001311 (2021).
Veldhoen, S. et al. Exact monitoring of aortic diameters in Marfan patients without gadolinium contrast: intraindividual comparison of 2D SSFP imaging with 3D CE-MRA and echocardiography. Eur. Radiol. 25, 872–882 (2015).
Hagan, P. G. et al. The international registry of acute aortic dissection (IRAD): new insights into an old disease. JAMA 283, 897–903 (2000).
Evangelista, A. et al. Imaging modalities for the early diagnosis of acute aortic syndrome. Nat. Rev. Cardiol. 10, 477–486 (2013).
Freeman, L. A. et al. CT and MRI assessment of the aortic root and ascending aorta. AJR Am. J. Roentgenol. 200, W581–W592 (2013).
Rodriguez-Palomares, J. F. et al. Multimodality assessment of ascending aortic diameters: comparison of different measurement methods. J. Am. Soc. Echocardiogr. 29, 819–826 (2016).
Burman, E. D., Keegan, J. & Kilner, P. J. Aortic root measurement by cardiovascular magnetic resonance: specification of planes and lines of measurement and corresponding normal values. Circ. Cardiovasc. Imaging 1, 104–113 (2008).
Amsallem, M. et al. Comparative assessment of ascending aortic aneurysms in Marfan patients using ECG-gated computerized tomographic angiography versus trans-thoracic echocardiography. Int. J. Cardiol. 184, 22–27 (2015).
Mendoza, D. D. et al. Impact of image analysis methodology on diagnostic and surgical classification of patients with thoracic aortic aneurysms. Ann. Thorac. Surg. 92, 904–912 (2011).
Maron, B. J. et al. Recommendations and considerations related to preparticipation screening for cardiovascular abnormalities in competitive athletes: 2007 update: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation 115, 1643–1655 (2007).
Harris, K. M., Sponsel, A., Hutter, A. M. Jr & Maron, B. J. Brief communication: cardiovascular screening practices of major North American professional sports teams. Ann. Intern. Med. 145, 507–511 (2006).
Scherer, L. R., Arn, P. H., Dressel, D. A., Pyeritz, R. M. & Haller, J. A. Jr. Surgical management of children and young adults with Marfan syndrome and pectus excavatum. J. Pediatr. Surg. 23, 1169–1172 (1988).
Redlinger, R. E. Jr et al. Minimally invasive repair of pectus excavatum in patients with Marfan syndrome and marfanoid features. J. Pediatr. Surg. 45, 193–199 (2010).
Erkula, G., Jones, K. B., Sponseller, P. D., Dietz, H. C. & Pyeritz, R. E. Growth and maturation in Marfan syndrome. Am. J. Med. Genet. 109, 100–115 (2002).
Sponseller, P. D., Hobbs, W., Riley, L. H. 3rd & Pyeritz, R. E. The thoracolumbar spine in Marfan syndrome. J. Bone Joint Surg. Am. 77, 867–876 (1995).
Loewenstein, A., Barequet, I. S., De Juan, E. Jr & Maumenee, I. H. Retinal detachment Marfan syndrome. Retina 20, 358–363 (2000).
Xu, W. et al. Comparative data on SD-OCT for the retinal nerve fiber layer and retinal macular thickness in a large cohort with Marfan syndrome. Ophthalmic Genet. 38, 34–38 (2017).
Rahmani, S., Lyon, A. T., Fawzi, A. A., Maumenee, I. H. & Mets, M. B. Retinal disease in Marfan syndrome: from the Marfan Eye Consortium of Chicago. Ophthalmic Surg. Lasers Imaging Retin. 46, 936–941 (2015).
Schou, S., Holmstrup, P., Hjorting-Hansen, E. & Lang, N. P. Plaque-induced marginal tissue reactions of osseointegrated oral implants: a review of the literature. Clin. Oral. Implant. Res. 3, 149–161 (1992).
Bard, L. A. Genetic counseling of families with Marfan syndrome and other disorders showing a Marfanoid body habitus. Ophthalmology 86, 1764–1793 (1979).
Braverman, A. C., Harris, K. M., Kovacs, R. J. & Maron, B. J. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: Task Force 7: Aortic Diseases, Including Marfan syndrome: a scientific statement from the American Heart Association and American College of Cardiology. J. Am. Coll. Cardiol. 66, 2398–2405 (2015).
Vanem, T. T. et al. Survival, causes of death, and cardiovascular events in patients with Marfan syndrome. Mol. Genet. Genom. Med. 6, 1114–1123 (2018).
Shores, J., Berger, K. R., Murphy, E. A. & Pyeritz, R. E. Progression of aortic dilatation and the benefit of long-term β-adrenergic blockade in Marfan’s syndrome. N. Engl. J. Med. 330, 1335–1341 (1994).
Elefteriades, J. A. & Farkas, E. A. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J. Am. Coll. Cardiol. 55, 841–857 (2010).
Beaven, D. W. & Murphy, E. A. Dissecting aneurysm during methonium therapy; a report on nine cases treated for hypertension. Br. Med. J. 1, 77–80 (1956).
Amende, I., Simon, R., Hood, W. P. Jr. & Lightlen, P. R. The effects of the beta-blocker atenolol and nitroglycerin on left ventricular function and geometry in man. Circulation 60, 836–849 (1979).
Simpson, C. F., Kling, J. M. & Palmer, R. F. The use of propranolol for the protection of turkeys from the development of β-aminopropionitrile-induced aortic ruptures. Angiology 19, 414–418 (1968).
Groenink, M., de, R. A., Mulder, B. J., Spaan, J. A. & van der Wall, E. E. Changes in aortic distensibility and pulse wave velocity assessed with magnetic resonance imaging following beta-blocker therapy in the Marfan syndrome. Am. J. Cardiol. 82, 203–208 (1998).
Chiu, H. H. et al. Losartan added to beta-blockade therapy for aortic root dilation in Marfan syndrome: a randomized, open-label pilot study. Mayo Clin. Proc. 88, 271–276 (2013).
Milleron, O. et al. Marfan Sartan: a randomized, double-blind, placebo-controlled trial. Eur. Heart J. 36, 2160–2166 (2015).
Forteza, A. et al. Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized clinical trial. Eur. Heart J. 37, 978–985 (2016).
Muino-Mosquera, L. et al. Efficacy of losartan as add-on therapy to prevent aortic growth and ventricular dysfunction in patients with Marfan syndrome: a randomized, double-blind clinical trial. Acta Cardiol. 72, 616–624 (2017).
Silverman, D. I. et al. Family history of severe cardiovascular disease in Marfan syndrome is associated with increased aortic diameter and decreased survival. J. Am. Coll. Cardiol. 26, 1062–1067 (1995).
Brooke, B. S. et al. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N. Engl. J. Med. 358, 2787–2795 (2008).
Al-Abcha, A. et al. Meta-analysis examining the usefulness of angiotensin receptor blockers for the prevention of aortic root dilation in patients with the Marfan syndrome. Am. J. Cardiol. 128, 101–106 (2020).
Elbadawi, A. et al. Losartan for preventing aortic root dilatation in patients with Marfan syndrome: a meta-analysis of randomized trials. Cardiol. Ther. 8, 365–372 (2019).
Quint, L. E., Liu, P. S., Booher, A. M., Watcharotone, K. & Myles, J. D. Proximal thoracic aortic diameter measurements at CT: repeatability and reproducibility according to measurement method. Int. J. Cardiovasc. Imaging 29, 479–488 (2013).
Dormand, H. & Mohiaddin, R. H. Cardiovascular magnetic resonance in Marfan syndrome. J. Cardiovasc. Magn. Reson. 15, 33 (2013).
Weinrich, J. M. et al. Reliability of non-contrast magnetic resonance angiography-derived aortic diameters in Marfan patients: comparison of inner vs. outer vessel wall measurements. Int. J. Cardiovasc. Imaging 36, 1533–1542 (2020).
Mariucci, E. M. et al. Dilation of peripheral vessels in Marfan syndrome: importance of thoracoabdominal MR angiography. Int. J. Cardiol. 167, 2928–2931 (2013).
Lopez-Sainz, A. et al. Aortic branch aneurysms and vascular risk in patients with marfan syndrome. J. Am. Coll. Cardiol. 77, 3005–3012 (2021).
Nollen, G. J., Groenink, M., Tijssen, J. G., van der Wall, E. E. & Mulder, B. J. Aortic stiffness and diameter predict progressive aortic dilatation in patients with Marfan syndrome. Eur. Heart J. 25, 1146–1152 (2004).
Guala, A. et al. Decreased rotational flow and circumferential wall shear stress as early markers of descending aorta dilation in Marfan syndrome: a 4D flow CMR study. J. Cardiovasc. Magn. Reson. 21, 63 (2019).
Cavalcante, J. L., Lima, J. A., Redheuil, A. & Al-Mallah, M. H. Aortic stiffness: current understanding and future directions. J. Am. Coll. Cardiol. 57, 1511–1522 (2011).
Laurent, S. et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur. Heart J. 27, 2588–2605 (2006).
Kunkala, M. R. et al. Mitral valve disease in patients with Marfan syndrome undergoing aortic root replacement. Circulation 128, S243–S247 (2013).
JB, lP. D. W. et al. Mechanisms of recurrent aortic regurgitation after aortic valve repair: predictive value of intraoperative transesophageal echocardiography. JACC Cardiovasc. Imaging 2, 931–939 (2009).
Groner, L. K., Lau, C., Devereux, R. B. & Green, D. B. Imaging of the postsurgical aorta in Marfan syndrome. Curr. Treat. Options Cardiovasc. Med. 20, 80 (2018).
Evangelista, A. et al. Long-term outcome of aortic dissection with patent false lumen: predictive role of entry tear size and location. Circulation 125, 3133–3141 (2012).
Rylski, B. et al. Type A aortic dissection in Marfan syndrome: extent of initial surgery determines long-term outcome. Circulation 129, 1381–1386 (2014).
Martin, C. et al. Aortic complications in Marfan syndrome: should we anticipate preventive aortic root surgery? Ann. Thorac. Surg. 109, 1850–1857 (2020).
Fraser, C. D. III et al. Valve-sparing aortic root replacement in children: outcomes from 100 consecutive cases. J. Thorac. Cardiovasc. Surg. 157, 1100–1109 (2019).
David, T. E. et al. Outcomes of aortic valve-sparing operations in Marfan syndrome. J. Am. Coll. Cardiol. 66, 1445–1453 (2015).
Coselli, J. S. et al. Early and 1-year outcomes of aortic root surgery in patients with Marfan syndrome: a prospective, multicenter, comparative study. J. Thorac. Cardiovasc. Surg. 147, 1758–1767.e4 (2014).
Izgi, C. et al. External aortic root support to prevent aortic dilatation in patients with Marfan syndrome. J. Am. Coll. Cardiol. 72, 1095–1105 (2018).
Treasure, T. et al. Personalised external aortic root support (PEARS) in Marfan syndrome: analysis of 1–9 year outcomes by intention-to-treat in a cohort of the first 30 consecutive patients to receive a novel tissue and valve-conserving procedure, compared with the published results of aortic root replacement. Heart 100, 969–975 (2014).
Song, H. K. et al. Long-term implications of emergency versus elective proximal aortic surgery in patients with Marfan syndrome in the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Consortium Registry. J. Thorac. Cardiovasc. Surg. 143, 282–286 (2012).
Shalhub, S. et al. Type B aortic dissection in young individuals with confirmed and presumed heritable thoracic aortic disease. Ann. Thorac. Surg. 109, 534–540 (2020).
Pellenc, Q. et al. Optimising aortic endovascular repair in patients with Marfan syndrome. Eur. J. Vasc. Endovasc. Surg. 59, 577–585 (2020).
Peters, K. F., Kong, F., Hanslo, M. & Biesecker, B. B. Living with Marfan syndrome III. Quality of life and reproductive planning. Clin. Genet. 62, 110–120 (2002).
Goldfinger, J. Z. et al. Marfan syndrome and quality of life in the GenTAC registry. J. Am. Coll. Cardiol. 69, 2821–2830 (2017).
Nielsen, C., Ratiu, I., Esfandiarei, M., Chen, A. & Selamet Tierney, E. S. A review of psychosocial factors of Marfan syndrome: adolescents, adults, families, and providers. J. Pediatr. Genet. 8, 109–122 (2019).
The Marfan Foundation. Survey results reveal greatest obstacles to quality of life. Marfan Foundation https://www.marfan.org/about-us/news/2017/11/01/survey-results-reveal-greatest-obstacles-quality-life (2017).
Vanem, T. T., Rand-Hendriksen, S., Brunborg, C., Geiran, O. R. & Roe, C. Health-related quality of life in Marfan syndrome: a 10-year follow-up. Health Qual. Life Outcomes 18, 376 (2020).
Oller, J. et al. Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome. Nat. Med. 23, 200–212 (2017).
de la Fuente-Alonso, A. et al. Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO. Nat. Commun. 12, 2628 (2021).
Hansen, J. et al. Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms. JCI Insight 4, e127652 (2019).
Nistala, H., Lee-Arteaga, S., Siciliano, G., Smaldone, S. & Ramirez, F. Extracellular regulation of transforming growth factor β and bone morphogenetic protein signaling in bone. Ann. N. Y. Acad. Sci. 1192, 253–256 (2010).
Putnam, E. A., Zhang, H., Ramirez, F. & Milewicz, D. M. Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat. Genet. 11, 456–458 (1995).
Maccarrick, G. et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet. Med. 16, 576–587 (2014).
Pepin, M., Schwarze, U., Superti-Furga, A. & Byers, P. H. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N. Engl. J. Med. 342, 673–680 (2000).
Pepin, M. G. et al. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genet. Med. 16, 881–888 (2014).
Renard, M. et al. Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J. Am. Coll. Cardiol. 72, 605–615 (2018).
Van Driest, S. L. et al. Variants in ADRB1 and CYP2C9: association with response to atenolol and losartan in Marfan syndrome. J. Pediatr. 222, 213–220 e215 (2020).
Franken, R. et al. Beneficial outcome of losartan therapy depends on type of FBN1 mutation in Marfan syndrome. Circ. Cardiovasc. Genet. 8, 383–388 (2015).
Nienaber, C. A. et al. Aortic dissection. Nat. Rev. Dis. Primers 2, 16053 (2016).
Collod-Beroud, G. et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum. Mutat. 22, 199–208 (2003).
Pyeritz, R. E. in Principles and Practice of Medical Genetics 6th Ed. Ch. 153 (eds Rimoin, D. L., Pyeritz, R. E. & Korf, B. R.) (Elsevier, 2013).
Dean, J. C. S. Marfan syndrome: clinical diagnosis and management. Eur. J. Hum. Genet. 15, 724–733 (2007).
Stheneur, C. et al. Prognosis factors in probands with an FBN1 mutation diagnosed before the age of 1 year. Pediatr. Res. 69, 265–270 (2011).
Geva, T., Hegesh, J. & Frand, M. The clinical course and echocardiographic features of Marfan’s syndrome in childhood. Am. J. Dis. Child. 141, 1179–1182 (1987).
Hennekam, R. C. Severe infantile Marfan syndrome versus neonatal Marfan syndrome. Am. J. Med. Genet. A 139, 1 (2005).
Booms, P. et al. Novel exon skipping mutation in the fibrillin-1 gene: two ‘hot spots’ for the neonatal Marfan syndrome 1. Clin. Genet. 55, 110–117 (1999).
Morse, R. P. et al. Diagnosis and management of infantile Marfan syndrome. Pediatrics 86, 888–895 (1990).
Tognato, E. et al. Neonatal Marfan syndrome. Am. J. Perinatol. 36, S74–S76 (2019).
Liu, L. H., Lin, S. M., Lin, D. S. & Chen, M. R. Losartan in combination with propranolol slows the aortic root dilatation in neonatal Marfan syndrome. Pediatr. Neonatol. 59, 211–213 (2018).
Carande, E. J., Bilton, S. J. & Adwani, S. A case of neonatal Marfan syndrome: a management conundrum and the role of a multidisciplinary team. Case Rep. Pediatr. 2017, 8952428 (2017).
Krasemann, T. et al. Cardiac transplantation in neonatal Marfan syndrome–a life-saving approach. Thorac. Cardiovasc. Surg. 53 (Suppl. 2), S146–S148 (2005).
Braverman, A. C. et al. Clinical features and outcomes of pregnancy-related acute aortic dissection. JAMA Cardiol. 6, 58–66 (2021).
Roman, M. J. et al. Aortic complications associated with pregnancy in Marfan syndrome: the NHLBI National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC). J. Am. Heart Assoc. 5, e004052 (2016).
Cauldwell, M. et al. Maternal and fetal outcomes in pregnancies complicated by Marfan syndrome. Heart 105, 1725–1731 (2019).
Rossiter, J. P., Repke, J. T., Morales, A. J., Murphy, E. A. & Pyeritz, R. E. A prospective longitudinal evaluation of pregnancy in the Marfan syndrome. Am. J. Obstet. Gynecol. 173, 1599–1606 (1995).
Banerjee, A., Begaj, I. & Thorne, S. Aortic dissection in pregnancy in England: an incidence study using linked national databases. BMJ Open 5, e008318 (2015).
Meijboom, L. J. et al. Pregnancy and aortic root growth in the Marfan syndrome: a prospective study. Eur. Heart J. 26, 914–920 (2005).
Pacini, L. et al. Maternal complication of pregnancy in Marfan syndrome. Int. J. Cardiol. 136, 156–161 (2009).
Regitz-Zagrosek, V. et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur. Heart J. 39, 3165–3241 (2018).
Williams, D. et al. Pregnancy after aortic root replacement in Marfan’s syndrome: a case series and review of the literature. AJP Rep. 8, e234–e240 (2018).
Bullo, M., Tschumi, S., Bucher, B. S., Bianchetti, M. G. & Simonetti, G. D. Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review. Hypertension 60, 444–450 (2012).
Giarelli, E., Bernhardt, B. A., Mack, R. & Pyeritz, R. E. Adolescents’ transition to self-management of a chronic genetic disorder. Qual. Health Res. 18, 441–457 (2008).
Modi, A. C. et al. Pediatric self-management: a framework for research, practice, and policy. Pediatrics 129, e473–e485 (2012).
Gauci, J., Bloomfield, J., Lawn, S., Towns, S. & Steinbeck, K. Effectiveness of self-management programmes for adolescents with a chronic illness: a systematic review. J. Adv. Nurs. https://doi.org/10.1111/jan.14801 (2021).
Sattoe, J. N. T. et al. Value of an outpatient transition clinic for young people with inflammatory bowel disease: a mixed-methods evaluation. BMJ Open 10, e033535 (2020).
Giarelli, E., Bernhardt, B. A. & Pyeritz, R. E. Self-surveillance by adolescents and young adults transitioning to self-management of a chronic genetic disorder. Health Educ. Behav. 37, 133–150 (2010).
Stark, V. C. et al. The transition of pediatric Marfan patients to adult care: a challenge and its risks. Cardiovasc. Diagn. Ther. 8, 698–704 (2018).
NIH R01HL109942 and R01HL146583, American Heart Association Merit Award, Genetic Aortic Disorders Association Canada, John Ritter Foundation, Marfan Foundation to D.M.M. The authors thank the patients with Marfan syndrome who shared their story.
The authors declare no competing interests.
Peer review information
Nature Reviews Disease Primers thanks M. Groenink; D. Reinhardt, who co-reviewed with R. Zhang; P. Robinson; L. Sakai; and Y. Von Kodolitsch for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Milewicz, D.M., Braverman, A.C., De Backer, J. et al. Marfan syndrome. Nat Rev Dis Primers 7, 64 (2021). https://doi.org/10.1038/s41572-021-00298-7