Handbook of Genetic Counseling/Marfan Syndrome
Appearance
Marfan Syndrome
Introduction and contracting
[edit | edit source]- 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
[edit | edit source]- 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
[edit | edit source]- 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
[edit | edit source]- 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
[edit | edit source]- 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
[edit | edit source]- 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
[edit | edit source]- 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 Risks
[edit | edit source]- 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
[edit | edit source](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
[edit | edit source]- 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
[edit | edit source]- 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
[edit | edit source]- 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 | edit source]- 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
[edit | edit source]- 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
[edit | edit source]- 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
[edit | edit source]- 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
[edit | edit source]- 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
[edit | edit source]The information in this outline was last updated in 2002. Minor editorial changes, May 2006.