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

Recurrence 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