Handbook of Genetic Counseling/Marfan Syndrome

Marfan Syndrome

Introduction and contractingEdit

  • What is your understanding of why you were referred to genetics
  • What are your main concerns
  • Explain that they are there to determine if they might have a genetic condition called Marfan syndrome and give overview of Marfan

Outline sessionEdit

  • I will begin by taking a family history
  • Our resident _____ will take a medical history
  • She and Dr. Doktour will perform a physical examination
  • We will then discuss whether or not we believe a diagnosis can be made or if there are other tests that need to be performed
  • If a diagnosis is made we will discuss Marfan syndrome in more detail
  • We will also answer any questions you have

Overview of Marfan syndromeEdit

  • A heritable disorder of the connective tissue that affects many organ systems, including the skeleton, lungs, eyes, heart and blood vessels.
  • The condition affects both men and women of any race or ethnic group
  • occurs in 1-2 people per every 10, 000

Symptoms of Marfan syndromeEdit

  • high degree of clinical variability
  • ocular findings: myopia, displacement of the lens, retinal detachment, glaucoma, early cataract formation
  • skeletal findings: bone overgrowth, joint laxity, long extremities, pectus excavatum or carinatum, scoliosis, high arched palate, positive wrist and thumb signs, reduced upper to lower segment, arm span to height ratio >1.05, flat feet
  • cardiovascular findings: dilatation of the aorta, aortic dissection, mitral valve prolapse, triscupsid valve prolapse, enlargement of the pulmonary artery
  • other systems involved: pulmonary, skin, nervous

Diagnosis of MarfanEdit

  • Diagnosis is made clinically (see diagnostic criteria below for details)
  • based on family history and the observation of characteristic findings in multiple organ systems
  • no family history? 2 major criteria and 1 minor (3 systems)
  • with a family history? 1 major and 1 minor (2 systems)
  • sometimes we're very confident in the diagnosis (and sometimes sure of a negative diagnosis), sometimes we're just not sure and we may follow a person for a while, sometimes we think there may be another diagnosis
  • What will a diagnosis mean
  • predisposition for aortic rupture and other heart problems so must have cardiology exams for echocardiograms (monitor aortic root growth - beta-blockers may be prescribed)
  • orthopedist exams (for early detection of scoliosis and pectus)
  • yearly ophthalmology exams (due to various eye problems that can often be treated with corrective lenses, but sometimes require surgery)
  • potential for complications during pregnancy (rapid progression of aortic root enlargement) must be closely monitored
  • 50% chance that future children will inherit Marfan syndrome

Age of Onset, natural history, and life spanEdit

  • Some signs of the syndrome are present at birth
  • The serious vascular complications may develop at any time from fetal life through old age and are the chief cause of death in these individuals
  • The use of b-adrenergic blockers has been associated with a decrease in aortic dilatation and thus increased life
  • The mean age for survival for men = 43 and women = 46
  • However, with appropriate management, individuals are reportedly living until their 70's.


  • Autosomal dominant inheritance
  • 75% have an affected parent
  • 25% due to new mutations
  • The disrupted gene is FBN1 - codes for Fibrillin (a protein constituent of connective tissue).
  • Located at 15p21
  • Molecular genetics
    • >100 mutations leading to abnormal splicing of the mRNA have been reported
    • The gene is >110 kb and is composed of 65 exons
      • A common motif is the epidermal growth factor (EGF) like domain. This domain occurs 47 times
      • Each EGF domain contains 6 conserved cysteine residues that from 3 disulfide bonds
      • 43 of the EGF domains contain a consensus sequence for calcium binding which facilitates inter and intramolecular interactions
      • Mutations in any of the conserved calcium binding sequences or the conserved cysteine residues lead to classical Marfan syndrome
  • The syndrome is fully penetrant, although the manifestations can vary considerably

Recurrence RisksEdit

  • If parent affected 50% chance future children will also be affected
  • If parent of affected child is not affected then they have a much smaller chance of having another affected child (rare cases of germline and somatic mosaicism)

Genetic TestingEdit

(available, but often not used)

  • Because FBN1 mutations have been detected in individuals with other fibrillinopathies, the presence of a mutation doesn't by itself confirm the diagnosis.
  • Mutations have not been detected in at least 25% of subjects with Marfan syndrome.
  • There exists the possibility that the Marfan syndrome phenotype may be produced by mutations in at least one other gene, for this reason, a definitive DNA-based test is not available
  • molecular genetic testing for mutations in the fibrillin-1 (FBN1) gene on chromosome locus 15q21.1
  • direct mutation screen cumbersome and inefficient due to large size
  • up to 70% show positive results
  • mutation is not identified in large number of individuals with Marfan syndrome
  • If a specific mutation is known within a family, that specific mutation can be tested individuals suspected to be affected
  • many mutations in FBN1 cause phenotype different from Marfan syndrome
  • mutational screening available on research basis
  • Linkage analysis
    • Markers are highly informative and are within the FBN1 gene
    • Nearly completely informative
    • Not available if only one affected individual in family
    • Although usually informative caution needed because locus heterogeneity not definitively excluded
  • Protein based methods
    • Being explored
    • Further research needed to determine specificity
    • Immunofluorescence studies of extracellular microfibrils with fibrillin antibodies are available as diagnostic aids

Prenatal TestingEdit

  • Available using linkage analysis if linkage has been established in affected family members
  • Or using mutational analysis when disease-causing mutation has been identified
  • Ultrasound exam in first two trimesters cannot detect manifestations of Marfan

Geneotype-Phenotype CorrelationsEdit

  • Few and none are definitive
  • Those with most severe and rapid termed "neonatal Marfan syndrome" have alterations in center of gene exons 24-32 (but not all with severe form have identified mutations and others with mutations in this region have classic or mild variants of Marfan)
  • In general mutations causing in-frame gain or loss of coding sequence associated with more severe disease
  • Premature termination result in rapid degradation of transcripts associated with mild conditions that fail to meet diagnostic criteria
  • Individuals with mutation preventing C-terminal propeptide processing had only skeletal manifestations
  • Amino acid substitution may have functional or not have functional importance

Diagnostic CriteriaEdit

  • Diganosis can be made clinically if: 2 organ systems are involved in the presence of an affected first degree relative
  • Or, involvement of the skeleton and two or more organ systems is required, as well as the presence of at least one major criterion
  • Note: skeletal system qualifies as a major criterion only if at least four major manifestations are present

Clinical Features (major and minor criteria)Edit

    • Skeletal (can develop in young children and progress during periods of rapid growth)
  • Major criteria for diagnosis:
    • Pectus carinatum (protruding sternum in convex shape)
    • Pectus excavatum requiring surgery (congenital condition in which the sternum is abnormally depressed caused by overgrowth of ribs pushing the sternum in)
    • Scoliosis (mild to severe and progressive may require bracing or surgery)
    • Reduced extension at the elbows (<170°)
    • Pes planus (flatfoot)
    • Protrusio acetabuli (pertaining to the hip bone socket where acetabulum abnormally deep and shows accelerated erosion)
    • Reduced upper to lower segment ratio
    • Wrist sign: thumb overlaps the distal phalanx of the fifth digit when grasping the contralateral wrist (due to bone overgrowth and joint laxity)
    • Thumb sign: entire nail of the thumb projects beyond the ulnar border of the hand when the hand is clenched without assistance.
  • Minor criteria:
    • Pectus excavatum of moderate severity
    • Joint hypermobility
    • High arched palate with crowded teeth
    • Specific facies: dolicocephaly, malar hypoplasia, retrognathia, down slanting palpebral fissures, deep set eyes, palate can be highly arched
    • Dolichostenomelia (extremities are disproportionately long for the size of the trunk)
    • Arachnodactyly (spider fingers long and thin)
  • Major criteria:
    • Ectopia lentis (displacement of the lens of the eye in 60% of affected and it is a hallmark feature)
  • Minor critieria:
    • Flat cornea
    • Increased axial length of globe
    • Hypoplastic iris or hypoplastic ciliary muscle
  • Major Criteria:
    • Dilitation of the ascending aorta w/ or w/o aortic regurgitation, involving the sinuses of Valsalva
    • Dissection of the ascending aorta
  • Minor criteria:
    • Mitral valve prolapse w/ or w/o mitral valve regurgitation
    • Dilatation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis before the age of 40
    • Calcification of the mital annulus before age 40
    • Dilatation or dissection of the descending thoracis or abdominal aorta before age 50.
  • Minor criteria:
    • Spontaneous pneumothorax (air in the pleural cavity)
    • Apical blebs
  • Minor criteria:
    • Striae atrophicae (stretch marks)
    • Recurrent or incisional hernia
  • Major criteria:
    • Lumbosacral dural ectasia by CT or MRI


  • Growth
    • All individuals should be measured periodically
    • Prepubertal girls can have height reduction by taking high-dose estrogen therapy combined with progesterone to prevent endometrial hyperplasia
  • Development
    • Physical therapy is of value in promoting motor skill development
    • Psychosocial family counseling
  • Musculoskeletal
    • Delays in gross motor development caused by joint hypermobility can be ameliorated with PT and orthopedic braces (as needed)
    • Treatment of scoliosis and kyphosis depending on the severity of the curvature
    • Pectus excavatum or carinatum may need to be repaired to prevent cardiac or pulmonary compromise
  • Cardiovascular
    • Follow with a cardiologist
    • Echocardiogram required at frequent intervals
    • b-Adrenergic blaockade has been demonstrated to slow progression of the aortic root dilatation by decreasing the stress on the aortic wall and the tunica media.
    • Graft replacement surgery if necessary
    • Most adults with Marfan syndrome will eventually need replacement of the dilated aortic root (5% operative risk) and leaking aortic valve.
    • If mitral valve prolapse is diagnosed, standard prophylaxis against bacterial endocarditis is recommended for all dental procedures.
    • Limit physical activities such as contact sports (football, basketball, hockey, volleyball, boxing, wrestling, etc.)
  • Ophthalmologic:
    • Myopia most common treated with corrective lenses
    • Adequate optical correction must be prescribed and worn
    • Assessments of refraction must be performed
    • Amblyopia must be treated aggressively
    • Lens removal for optical reasons is not recommended (the cataract of Marfan syndrome is a true indication for lens extraction)
    • When ectopia lentis is progressive and leads to complications such as iritis, glaucoma etc. the lens may need to be removed.
    • Because individuals are prone to retinal detachment, they should avoid contact sports
  • Neurologic
    • Orthostatic headache resulting from cerebrospinal fluid leakage is often transient. Treat with bed rest or corticosteroids
  • Respiratory
    • Spontaneous pneumothorax is treated by evacuation of the intrapleural air and restoration of the negative pleural pressure by insertion of a drainage test tube.


  • Many of the skeletal features common in general population
  • Other disorders caused by FBN1 mutations
    • MASS phenotype - mitral valve prolapse, borderline and nonprogressive aortic enlargement, nonspecific skin and skeletal features
    • Mitral valve prolapse syndrome - MVP with or without skeletal features
    • Predominant aortic aneurysm with other subdiagnostic features of Marfan
    • Predominant or isolated skeletal features of Marfan
    • Dominant ectopia lentis - lens dislocation with skeletal features
    • Familial ectopia lentis - associates eye and skeletal features (prolonged follow-up to differentiate it from Marfan)
    • Shprintzen-Goldberg syndrome - skeletal and heart findings with craniosynostosis and neurodevelopmental abnormalities (this is likely a genetically heterogeneous condition)
  • Other connective tissue disorders share some overlap (Ehlers-Danlos syndrome, fragile X, Stickler syndrome) Should be easily distinguished by other features though

Patient ResourcesEdit

  • National Marfan Foundation
22 Manhasset Avenue
Port Washington, NY 11050
phone: 1-800-8-MARFAN
  • Canadian Marfan Association


  • Schrijver I, Alcorn DM, Francke U. Chapter 13. (2001). Management of Genetic Syndromes. Ed. Allanson JE, Cassidy SB. New York: Wiley-Liss, Inc.
  • Jones KL (1997). Smith's Recognizable Patterns of Human Malformation. Philadelphia: W.B. Saunders Company.
  • Geneclinics: Marfan syndrome.
    • Cardiovascular
    • Pulmonary
    • Skin
    • Dura


The information in this outline was last updated in 2002. Minor editorial changes, May 2006.