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.