Handbook of Genetic Counseling/Marfan Syndrome

Marfan Syndrome

Introduction and contracting

• 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 session

• 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 syndrome

• 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 syndrome

• 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 Marfan

• 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 span

• 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.

Genetics

• 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

Recurrance Risks

• 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 Testing

(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 Testing

• 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 Correlations

• 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 Criteria

• 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)

• • 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

Management/Treatment

• 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.

Differential

• 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 Resources

• National Marfan Foundation

22 Manhasset Avenue

Port Washington, NY 11050

phone: 1-800-8-MARFAN

http://www.marfan.org

mailto:staff@marfan.org

• Canadian Marfan Association

1-905-826-3223

http://www.marfan.ca

References

• 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

Notes

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