WHAT IS IT?

• Marfan syndrome is a genetic, multi-systemic disorder that affects connective tissue. It occurs in 1 out of every 5,000-10,000 individuals and is caused by pathogenic variants in the Fibrillin 1 (FBN1) gene. Penetrance is high, and most individuals with a mutation will have some finding related to the disorder.
• Marfan syndrome is considered a classic example of variable expressivity, as some individuals may have mild symptoms and signs, such as skeletal changes, while others may have life-threatening effects if left unchecked, such as risk for aortic rupture.
• There are rigorous clinical criteria required for diagnosis of Marfan syndrome. In addition, there is clinical and genetic overlap with other related disorders.
  • Referral to a medical genetic service is required to determine if an individual is suspected of having Marfan syndrome, Loews-Dietz syndrome or Familial Thoracic Aortic Aneurysms and Dissections
  • Multiple speciality services may be involved in management; however, referral to cardiology is critical 

NOTE: Because medical interventions can prevent severe morbidity and mortality, Marfan syndrome and related disorders are on the ACMG list of secondary findings. In summary, the ACMG document on reporting such findings makes the following recommendations:

• In the course of genetic testing for research or clinical care, the laboratory may identify variants in genes unrelated to the initial indication for testing, but nevertheless may have important health implications
• Results of such secondary findings should be communicated to the individuals who may benefit from this knowledge
• An individual can ‘opt out’ of receiving secondary findings

KEY CLINICAL POINTS:

• Findings may appear in childhood or adulthood
• While height is the clinical characteristic most noted in Marfan syndrome, it is important to take in to account familial background – is the individual taller than expected for his/her family?
• Phenotype-Genotype correlation is poor
• Genetic consultation and multi-disciplinary team management is essential to maximize outcomes and prevent untoward events such that life expectancy can equal that of unaffected populations
  • Treatment and prevention of serious manifestations such as dissecting aortic aneurysm may include medication, such as beta-blockers and/or surgeries
  • Patients may be cautioned to avoid: contact sports, cardiovascular stimulants, LASIK correction and activities that cause joint injury or pain
  • Pneumothorax prevention may include avoiding breathing against resistance (such as horn instruments)
  • Consider Marfan syndrome or any related disorders a high risk pregnancy due to risk of aortic dissection – arrange for high risk referral preconception if possible

CLINICAL FINDINGS:

It is important to keep in mind, given the variable expressivity of Marfan syndrome, this list includes most possible findings, but any single affected individual will likely manifest only some of the following:

• Eye:
  • Myopia
  • Ectopia lentis (lens displacement)
  • Risk for retinal detachment, glaucoma and cataracts
• Skeletal:
  • Excessive growth with dolichostenomelia of long bones
  • Overgrowth of ribs causing pectus excavatum or pectus carinatum
  • Joint laxity and arachnodactyly (long, slender digits) which leads to classic finding of the positive ‘wrist sign’ and ‘thumb sign’
• Facial and dental features:
  • Long narrow face, with deep set eyes, flat cheekbones and receding chin
  • High arched palate with overcrowding of teeth
• Cardiovascular: connective tissue in the aorta can be affected leading to risk of aortic dilatation/dissection/rupture, aortic valve regurgitation, left heart failure
  • Children with severe Marfan syndrome may be affected with mitral valve prolapse and heart failure and managed surgically
• Other systems:
  • Dural ectasia can result in back and leg pain, causing weakness and numbness
  • Pneumothorax from lung bullae

RELATED DISORDERS:

• Loeys-Dietz syndrome: This syndrome is also characterized by skeletal characteristics commonly associated with Marfan syndrome, such as pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly and club foot (talipes equinovarus). Facial features can be prominent in severe cases, including craniosynostosis and wide spaced eyes, as well as cleft palate. However, the major distinguishing findings are related to vascular abnormalities leading to aneurysms and possible dissection beyond the aortic root – such as the cerebral, thoracic and abdominal arteries, and in some cases arterial tortuosity
  • Findings may appear in childhood or adulthood
  • Mutations that can lead to severe disease are found in TGFBR1, TGFBR2, and SMAD3 genes
  • Due to emphasis on cardiovascular manifestations, individuals are cautioned against contact sports or drugs that stimulate cardiovascular output
• Familial Thoracic Aortic Aneurysms and Dissections (TAAD): Similar to Marfan syndrome and Loews-Dietz syndrome, there is increased risk of aortic aneurysm, dissection and rupture. In the case of TAAD, it is the thoracic aorta (usually ascending) that is most prominently affected. However, the abdominal aorta and brain vasculature may demonstrate abnormal dilatation. Skeletal anomalies can overlap with Marfan syndrome, including tall stature, joint laxity, and pectus excavatum and pectus carinatum. Other findings may include livedo reticularis (purplish skin discoloration due to constriction of dermal capillaries particularly in mutations in ACTA2). There is also increased risk of coronary artery disease and stroke.
  • Findings may appear in childhood or adulthood
  • Mutations that can lead to severe disease are found in ACTA2, TGFBR1, TGFBR2, MYH11, FBN1 and SMAD3

MOLECULAR GENETICS & COUNSELING:

What gene/protein is affected and what does it do?

• FBN1: mutations in FBN1 gene cause Marfan syndrome
• Fibrillin: protein is a key component of extracellular microfibrils and can be found in both elastic and non-elastic tissues in multiple organ systems

Inheritance:

• Marfan syndrome is an autosomal dominant disorder
• 75% of individuals will inherit a mutation from one of his/her parents; in the other 25%, there is a de novo mutation

Risks to family members and future offspring:

• If a parent of an affected individual carries the pathogenic variant, the brothers and sisters of that individual have a 50% chance of having the variant
• In the case of a de novo mutation, there is still a low risk to brothers and sisters because of the possibility that a parent may have germline mosaicism
• Offspring have a 50% chance of inheriting the variant and therefore having Marfan syndrome
  • Preimplantation genetics and prenatal testing is available

Learn More – Primary Sources:

ACMG Recommendations for Reporting Incidental Findings in Clinical Exome and Genome Sequencing

Marfan Syndrome: Gene Reviews

Loeys-Dietz Syndrome: Gene Reviews

Thoracic Aortic Aneurysms and Aortic Dissections

Marfan Foundation: For Healthcare Providers

Marfan Scoring System Calulator

FBN1: OMIM

TGFBR1: OMIM

TGFBR2: OMIM

SMAD3: OMIM

ACTA2: OMIM

MYH11: OMIM

Locate a genetic counselor or genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

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