Genetics of Marfan Syndrome

  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Maria Descartes, MD  more...
Updated: Mar 21, 2016


Marfan syndrome (MFS) is an inherited connective tissue disorder, noteworthy for its worldwide distribution, relatively high prevalence, and clinical variability, as well as pleiotropic manifestations involving primarily the ocular, skeletal, and cardiovascular systems, some of which are life threatening. Although Marfan syndrome has historically always been considered as a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1, the study of Marfan mouse models and Marfan-related conditions has shifted our current understanding to a pathogenic model that involves dysregulation of the cytokine-transforming growth factor beta (TGF-β) signaling.[1, 2]



Marfan syndrome results from mutations in the fibrillin-1 (FBN1) gene on chromosome 15, which encodes for the glycoprotein fibrillin. Fibrillin is a major building block of microfibrils, which constitute the structural components of the suspensory ligament of the lens and serve as substrates for elastin in the aorta and other connective tissues. Abnormalities involving microfibrils weaken the aortic wall. Progressive aortic dilatation and eventual aortic dissection occur because of tension caused by left ventricular ejection impulses. Likewise, deficient fibrillin deposition leads to reduced structural integrity of the lens zonules, ligaments, lung airways, and spinal dura.

  • Production of abnormal fibrillin-1 monomers from the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formation. This pathogenetic mechanism has been termed dominant-negative because the mutant fibrillin-1 disrupts microfibril formation though the other fibrillin gene encodes normal fibrillin. This proposed mechanism is evinced by the fact that cultured skin fibroblasts from patients with Marfan syndrome produce greatly diminished and abnormal microfibrils.
  • FBN1 mutation causes several Marfanlike disorders, such as the mitral valve prolapse, aortic dilation, skin, and skeletal (MASS) phenotype or isolated ectopia lentis.
  • Recent studies have suggested that abnormalities in the transforming growth factor-beta ( TGFβ)-signaling pathway may represent a final common pathway for the development of the Marfan phenotype. [3] The gene defect ultimately leads to decreased and disordered incorporation of fibrillin into the connective tissue matrix.
  • The identification of mutations in transforming growth factor-beta receptor 2 ( TGF β R2) in patients with Marfan syndrome type II ( MFS2 mapped at 3p24.2-p25) provided direct evidence of abnormal TGFβ signaling in the pathogenesis of Marfan syndrome.
  • Abnormalities in TGF β R 2 and TGF β R1 were also reported to cause a new dominant syndrome similar to Marfan syndrome; it was associated with aortic aneurysm and congenital anomalies, including Loeys-Dietz aortic aneurysm syndrome (LDS) (Online Mendelian Inheritance in Man [OMIM] 609192). [3] These results define a new group of Marfan syndrome–related connective-tissue disorders, namely, TGFβ signalopathies, and include LDS I and LDS II ( TGFβR1 and TGFβR2) and the recently described SMAD3 and TGFβ2 disorders, which are being classified as Loeys-Dietz-like (or even types III and IV).
  • Shprintzen Goldberg syndrome (SGS) has also been found to be caused by pathogenic mutations in the SKI gene. There is quite a bit of overlap with Marfan syndrome and LDS, and it is also involved in the TGF pathway.
  • A second fibrillin gene, the FBN2 gene, is responsible for the congenital contractural arachnodactyly, known as Beals syndrome. [4]



United States

Marfan syndrome affects about 1 in 10,000 individuals[5] and perhaps as many as 1 in 3000-5000.

  • Estimates suggest that at least 200,000 people in the United States have Marfan syndrome or a related connective-tissue disorder.
  • This makes Marfan syndrome one of the most common single-gene malformation syndromes.


No geographic predilection is known.


Cardiovascular disease (aortic dilatation and dissection) is the major cause of morbidity and mortality.

Progression from mitral valve prolapse to mitral regurgitation, often in conjunction with tricuspid prolapse and regurgitation, is the most common cause of infant morbidity. If untreated, Marfan syndrome is highly lethal; the average age at death is 30-40 years.

Death after infancy usually involves ascending aortic dissection and chronic aortic regurgitation. Dissection generally occurs at the aortic root and is uncommon in childhood and adolescence.


Marfan syndrome is panethnic.


No sex predilection is known.


Marfan syndrome may be diagnosed prenatally, at birth, or well into adulthood. Neonatal presentation is associated with a more severe course than that associated with other presentations.

Most clinical features are specific to age, and some features may not manifest until relatively late in life. This feature may make diagnosis in a child difficult.

Contributor Information and Disclosures

Harold Chen, MD, MS, FAAP, FACMG Professor, Department of Pediatrics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

James Bowman, MD Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical and Translational Research, College of American Pathologists

Disclosure: Nothing to disclose.

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Adult with Marfan syndrome. Note tall and thin build, disproportionately long arms and legs, and kyphoscoliosis.
Positive wrist (Walker) sign.
Positive thumb (Steinberg) sign.
Pectus excavatum of moderate severity.
Hypermobility of finger joints.
Stretch marks (striae atrophicae) in the lower back.
Dural ectasia in the lumbosacral region.
Typical face seen in a girl with Marfan syndrome characterized by dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, and down-slanting palpebral fissures.
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