*Written by Misti Blu Day McDermott for Epidemiology class
Marfan syndrome is a systemic connective tissue disorder that is strongly associated with aortic disease, causing a high prevalence of aortic dissection. Marfan Syndrome (MFS) is one of the more commonly inherited disorders affecting connective tissue. There have been rare cases reported that describe recessive fibrillin 1 gene (FBN1) mutations. Fibrillin-1 is a matrix glycoprotein that is the main component of elastin fibers within connective tissue. Fibrillin-1 allows the proteins to bind to one another, creating threadlike filaments, making up the strength and flexibility in connective tissue. This occurrence leads to excess growth factors, decreasing elasticity in tissue, and resulting in instability of tissues.
According to the National Library of Medicine, the reported rate of incidence is 1 in 5000 individuals. Marfan syndrome is a single-gene malformation, and the condition is inherited with an autosomal dominant pattern (Salik, 2020). This means the one copy of the affected gene is sufficient to cause the systemic disorder. Approximately 25% of MFS cases result from a new genetic mutation of FBN1 (NIM). Marfan syndrome occurs in individuals worldwide and does not discriminate against race or gender.
The clinical characteristics of MFS have a high degree of variability, ranging from mild to severe. Being a systemic disorder, the multiorgan disease progressively affects most of the body. This includes, but is not limited to: ocular, skeletal, and cardiovascular manifestations. Ocular features include approximately 60% of affected individuals to have ectopia lentis, as well as an increased risk of retina detachment, glaucoma, and early cataracts (Dietz, 2017). Skeletal manifestations include the overgrowth of bone, joint laxity, disproportionately long arm span, inward sternum (pectus excavatum), outward sternum (pectus carinatum), and various ranges of scoliosis. Decreased life expectancy occurs in Marfan patients due to the severity of cardiac comorbidities. The major morbidity and early mortality of Marfan syndrome is due to dilation of the aorta, which can result in dissection of the aorta. If a patient is not diagnosed, this ticking time bomb may be missed during the onset emergency prior to sudden cardiac death. Dilation of the aorta is a predisposition to a tear or rupture. Valvular heart disease may also be features of MFS.
The pathophysiology of aortic dilation is very complex. Since Fibrillin-1 is a regulator of TGF-beta bioavailability, it leads to inflammation, fibrosis, and activation of matrix metalloproteinase (Salik, 2020). The accumulation of this results in the weakening of the aortic wall. Along with aortic wall weakening, decreased collagen, and reduced structural integrity of the aorta, a perfect storm results in aortic dilation. Greater elastin fragmentation has been shown in patients with aortic root aneurism, which can be life threatening.
Mortality rate is defined as the number of deaths in a population per one hundred thousand people (Aschengrau & Seage, 2020). In a study from 2018 by the American Journal of Cardiology, the nationwide mortality rate for the Danish Marfan population unveiled data through 410,000 control patients. This register-based study shows the mortality hazard ratio among Marfan syndrome is linked to aorta disease. Groth et al. states, “The mortality hazard ratio among MFS compared with controls was significantly increased to3.6 (CI 2.8-4.7, p < 0.001); men 4.0 (CI 2.8-5.7, p < 0.001); women 3.2 (CI 2.1-4.8,p < 0.001). Aorta disease represented the main reason for the overall increased mortality with a hazard ratio of 194.6 (CI 67.4-561.7, p < 0.0001); men 208.7 (CI 53.8-809.1, p < 0.001); women 173.4 (CI 31.5-954.5, p < 0.001). “
It is vital to have early diagnosis in order to prevent a catastrophic event. Clinical management of MFS relies on the genotype-phenotype correlation of FBN1 variants. Genetic mutations in FBN1 are found 90% of MFS cases; therefore, risk stratification of suspected patients must be of importance (Becerra-Muñoz, 2018). International Classification of Functioning Disability and Health for Children and Youth (ICF-CY) compiles data using a Marfan syndrome-specific model to understand contextual factors. The model concludes that adolescents with MFS perceived limitations and restrictions in comparison to their peers: having a difficult time “keeping up” in school, sports, relationships, leisure, and work (Warnink-Kavelaars, 2019).
Despite the risks involved, an individual with Marfan syndrome can be expected to have a life expectancy similar to the general population, should they follow proper management. There is no cure for Marfan syndrome, only quality care, management, and proper treatment. Frequent evaluations and routine physician visits are important for managing the disorder. Echocardiograms, EKGs, eye exams, and other tests (CT or MRI) are important tests to spot keep features. A detailed family history, complete physical exam, and genetic testing are ways to properly diagnose this serious condition and its comorbidities.
CRISPR/Cas9 is a well-known genome editing technology, allowing researchers and scientist to genetically alter DNA. The demands for this technological tool are urgently needed for treating heritable genetic disease such as Marfan syndrome. As of 2018, Yanting Zeng et al. are taking advantage of the editing technology and are in the early stages of correcting the pathogenic Marfan mutation in FBN1. Molecular therapy showed that the BE3 (base editor) mediated perfect correction in 89% at the human embryo stage. The future holds many possibilities for the potential of correcting serious genetic conditions such as MFS.
Aschengrau, A. & Seage III, G. R. (2020). Epidemiology in public health. Burlington, MA: Jones & Bartlett Learning
Becerra-Muñoz, V. M., Gómez-Doblas, J. J., Porras-Martín, C., Such-Martínez, M., Crespo-Leiro, M. G., Barriales-Villa, R., de Teresa-Galván, E., Jiménez-Navarro, M., & Cabrera-Bueno, F. (2018). The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. Orphanet journal of rare diseases, 13(1), 16. https://doi.org/10.1186/s13023-017-0754-6
Dietz, H. (2001). Marfan Syndrome. In M. P. Adam (Eds.) et. al., GeneReviews®. University of Washington, Seattle.
Groth, Kristian A., et al. “Causes of Mortality in the Marfan Syndrome(from a Nationwide Register Study).” The American Journal of Cardiology, vol. 122, no. 7, 2018, pp. 1231–35. Crossref, doi:10.1016/j.amjcard.2018.06.034.
“Marfan Syndrome.” National Library of Medicine, 2020, ghr.nlm.nih.gov/condition/marfan-syndrome#statistics.
Salik I, Rawla P. Marfan Syndrome. [Updated 2020 Jun 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537339/
Warnink-Kavelaars, J., Beelen, A., Goedhart, T., de Koning, L. E., Nollet, F., Alsem, M. W., Menke, L. A., & Engelbert, R. (2019). Marfan syndrome in adolescence: adolescents’ perspectives on (physical) functioning, disability, contextual factors and support needs. European journal of pediatrics, 178(12), 1883–1892. https://doi.org/10.1007/s00431-019-03469-7
Zeng, Yanting, et al. “Correction of the Marfan Syndrome Pathogenic FBN1 Mutation by Base Editing in Human Cells and Heterozygous Embryos.” Molecular Therapy, vol. 26, no. 11, 2018, pp. 2631–37. Crossref, doi:10.1016/j.ymthe.2018.08.007.