# 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

## 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.