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Marfan syndrome(MFS)

MedGen UID:
44287
Concept ID:
C0024796
Disease or Syndrome
Synonyms: FBN1-Related Thoracic Aortic Aneurysms and Aortic Dissections; Marfan syndrome type 1; Marfan syndrome, classic; MARFAN SYNDROME, TYPE I; Marfan's syndrome; Marfanoid hypermobility syndrome; MFS
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Marfan syndrome (19346006); Marfan's syndrome (19346006); Marfan's disease (19346006)
 
Gene (location): FBN1 (15q21.1)
OMIM®: 154700
Orphanet: ORPHA558

Disease characteristics

Excerpted from the GeneReview: Marfan Syndrome
Marfan syndrome is a systemic disorder of connective tissue with a high degree of clinical variability. Cardinal manifestations involve the ocular, skeletal, and cardiovascular systems. FBN1 pathogenic variants associate with a broad phenotypic continuum, ranging from isolated features of Marfan syndrome to neonatal presentation of severe and rapidly progressive disease in multiple organ systems. Myopia is the most common ocular feature; displacement of the lens from the center of the pupil, seen in approximately 60% of affected individuals, is a hallmark feature. People with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and early cataract formation. The skeletal system involvement is characterized by bone overgrowth and joint laxity. The extremities are disproportionately long for the size of the trunk (dolichostenomelia). Overgrowth of the ribs can push the sternum in (pectus excavatum) or out (pectus carinatum). Scoliosis is common and can be mild or severe and progressive. The major sources of morbidity and early mortality in the Marfan syndrome relate to the cardiovascular system. Cardiovascular manifestations include dilatation of the aorta at the level of the sinuses of Valsalva, a predisposition for aortic tear and rupture, mitral valve prolapse with or without regurgitation, tricuspid valve prolapse, and enlargement of the proximal pulmonary artery. With proper management, the life expectancy of someone with Marfan syndrome approximates that of the general population. [from GeneReviews]
Authors:
Harry C Dietz   view full author information

Additional descriptions

From OMIM
A heritable disorder of fibrous connective tissue, Marfan syndrome shows striking pleiotropism and clinical variability. The cardinal features occur in 3 systems--skeletal, ocular, and cardiovascular (McKusick, 1972; Pyeritz and McKusick, 1979; Pyeritz, 1993). It shares overlapping features with congenital contractural arachnodactyly (121050), which is caused by mutation in the FBN2 gene (612570). Gray and Davies (1996) gave a general review. They published Kaplan-Meier survival curves for a cohort of British Marfan syndrome patients demonstrating greater survivorship in females than in males; a similar result had been reported by Murdoch et al. (1972) and by Silverman et al. (1995). Gray and Davies (1996) also proposed a grading scale for clinical comparison of the Marfan syndrome patients. The authors provided criteria for each grade and suggested uniform use of these scales may facilitate clinicomolecular correlations.  http://www.omim.org/entry/154700
From GHR
Marfan syndrome is a disorder that affects the connective tissue in many parts of the body. Connective tissue provides strength and flexibility to structures such as bones, ligaments, muscles, blood vessels, and heart valves. The signs and symptoms of Marfan syndrome vary widely in severity, timing of onset, and rate of progression.The two primary features of Marfan syndrome are vision problems caused by a dislocated lens (ectopia lentis) in one or both eyes and defects in the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). The aorta can weaken and stretch, which may lead to a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may cause the aortic valve to leak, which can lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can be life threatening.Many people with Marfan syndrome have additional heart problems including a leak in the valve that connects two of the four chambers of the heart (mitral valve prolapse) or the valve that regulates blood flow from the heart into the aorta (aortic valve regurgitation). Leaks in these valves can cause shortness of breath, fatigue, and an irregular heartbeat felt as skipped or extra beats (palpitations).Individuals with Marfan syndrome are usually tall and slender, have elongated fingers and toes (arachnodactyly), and have an arm span that exceeds their body height. Other common features include a long and narrow face, crowded teeth, an abnormal curvature of the spine (scoliosis or kyphosis), and either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum). Some individuals develop an abnormal accumulation of air in the chest cavity that can result in the collapse of a lung (spontaneous pneumothorax). A membrane called the dura, which surrounds the brain and spinal cord, can be abnormally enlarged (dural ectasia) in people with Marfan syndrome. Dural ectasia can cause pain in the back, abdomen, legs, or head. Most individuals with Marfan syndrome have some degree of nearsightedness (myopia). Clouding of the lens (cataract) may occur in mid-adulthood, and increased pressure within the eye (glaucoma) occurs more frequently in people with Marfan syndrome than in those without the condition.The features of Marfan syndrome can become apparent anytime between infancy and adulthood. Depending on the onset and severity of signs and symptoms, Marfan can be fatal early in life; however, the majority of affected individuals survive into mid- to late adulthood.  https://ghr.nlm.nih.gov/condition/marfan-syndrome

Clinical features

Aortic regurgitation
MedGen UID:
8153
Concept ID:
C0003504
Disease or Syndrome
An insufficiency of the aortic valve, leading to regurgitation (backward flow) of blood from the aorta into the left ventricle.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Premature calcification of mitral annulus
MedGen UID:
331909
Concept ID:
C1835130
Finding
Mitral annular calcification (MAC) results from progressive calcium deposition along and beneath the mitral valve annulus . MAC is a common degenerative process involving the fibrous annulus of the mitral valve, and is generally an incidental finding associated with aging. This term applies if MAC occurs at a substantially younger age than usual.
Enophthalmos
MedGen UID:
8638
Concept ID:
C0014306
Disease or Syndrome
An eye that is more deeply recessed into the plane of the face than is typical.
Glaucoma
MedGen UID:
42224
Concept ID:
C0017601
Disease or Syndrome
Glaucoma is a group of eye disorders in which the optic nerves connecting the eyes and the brain are progressively damaged. This damage can lead to reduction in side (peripheral) vision and eventual blindness. Other signs and symptoms may include bulging eyes, excessive tearing, and abnormal sensitivity to light (photophobia). The term "early-onset glaucoma" may be used when the disorder appears before the age of 40.In most people with glaucoma, the damage to the optic nerves is caused by increased pressure within the eyes (intraocular pressure). Intraocular pressure depends on a balance between fluid entering and leaving the eyes.Usually glaucoma develops in older adults, in whom the risk of developing the disorder may be affected by a variety of medical conditions including high blood pressure (hypertension) and diabetes mellitus, as well as family history. The risk of early-onset glaucoma depends mainly on heredity.Structural abnormalities that impede fluid drainage in the eye may be present at birth and usually become apparent during the first year of life. Such abnormalities may be part of a genetic disorder that affects many body systems, called a syndrome. If glaucoma appears before the age of 5 without other associated abnormalities, it is called primary congenital glaucoma.Other individuals experience early onset of primary open-angle glaucoma, the most common adult form of glaucoma. If primary open-angle glaucoma develops during childhood or early adulthood, it is called juvenile open-angle glaucoma.
Increased axial globe length
MedGen UID:
320525
Concept ID:
C1835117
Finding
Abnormal largeness of the eye with an axial length > 2.5 standard deviations from population mean.
Arachnodactyly
MedGen UID:
2047
Concept ID:
C0003706
Congenital Abnormality
An abnormal bone development that is characterized by extra long and slender hands and fingers, such that the clenched thumb extends beyond the ulnar side of the hand. Arachnodactyly can include feet and toes. Arachnodactyly has been associated with several gene mutations and syndromes.
Hammer toe
MedGen UID:
209712
Concept ID:
C1136179
Anatomical Abnormality
Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint.
Dural ectasia
MedGen UID:
377094
Concept ID:
C1851712
Finding
A widening or ballooning of the dural sac surrounding the spinal cord usually at the lumbosacral level.
Contracture
MedGen UID:
3227
Concept ID:
C0009917
Acquired Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Decreased muscle mass
MedGen UID:
373256
Concept ID:
C1837108
Finding
Arachnodactyly
MedGen UID:
2047
Concept ID:
C0003706
Congenital Abnormality
An abnormal bone development that is characterized by extra long and slender hands and fingers, such that the clenched thumb extends beyond the ulnar side of the hand. Arachnodactyly can include feet and toes. Arachnodactyly has been associated with several gene mutations and syndromes.
Contracture
MedGen UID:
3227
Concept ID:
C0009917
Acquired Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Pectus carinatum
MedGen UID:
57643
Concept ID:
C0158731
Finding
A deformity of the chest caused by overgrowth of the ribs and characterized by protrusion of the sternum.
Long narrow head
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Protrusio acetabuli
MedGen UID:
98369
Concept ID:
C0409495
Anatomical Abnormality
Intrapelvic bulging of the medial acetabular wall.
Hammer toe
MedGen UID:
209712
Concept ID:
C1136179
Anatomical Abnormality
Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint.
Premature calcification of mitral annulus
MedGen UID:
331909
Concept ID:
C1835130
Finding
Mitral annular calcification (MAC) results from progressive calcium deposition along and beneath the mitral valve annulus . MAC is a common degenerative process involving the fibrous annulus of the mitral valve, and is generally an incidental finding associated with aging. This term applies if MAC occurs at a substantially younger age than usual.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest (\
Long narrow head
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Contracture
MedGen UID:
3227
Concept ID:
C0009917
Acquired Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Incisional hernia
MedGen UID:
488830
Concept ID:
C0267716
Finding
An abdominal hernia that occurs at a site of weakness in the abdominal wall resulting from an incompletely-healed surgical wound.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Marfan syndrome in Orphanet.

Professional guidelines

PubMed

ACMG Board of Directors.
Genet Med 2015 Jan;17(1):68-9. Epub 2014 Nov 13 doi: 10.1038/gim.2014.151. PMID: 25356965
Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, Evangelista A, Falk V, Frank H, Gaemperli O, Grabenwöger M, Haverich A, Iung B, Manolis AJ, Meijboom F, Nienaber CA, Roffi M, Rousseau H, Sechtem U, Sirnes PA, Allmen RS, Vrints CJ; ESC Committee for Practice Guidelines.
Eur Heart J 2014 Nov 1;35(41):2873-926. Epub 2014 Aug 29 doi: 10.1093/eurheartj/ehu281. PMID: 25173340
Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J, Siu SC; Canadian Cardiovascular Society.
Can J Cardiol 2014 Jun;30(6):577-89. Epub 2014 Feb 28 doi: 10.1016/j.cjca.2014.02.018. PMID: 24882528
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics.
Genet Med 2013 Jul;15(7):565-74. Epub 2013 Jun 20 doi: 10.1038/gim.2013.73. PMID: 23788249Free PMC Article
Pyeritz RE; American College of Medical Genetics and Genomics.
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Arslan-Kirchner M, Arbustini E, Boileau C, Child A, Collod-Beroud G, De Paepe A, Epplen J, Jondeau G, Loeys B, Faivre L
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Maron BJ, Chaitman BR, Ackerman MJ, Bayés de Luna A, Corrado D, Crosson JE, Deal BJ, Driscoll DJ, Estes NA 3rd, Araújo CG, Liang DH, Mitten MJ, Myerburg RJ, Pelliccia A, Thompson PD, Towbin JA, Van Camp SP; Working Groups of the American Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention.; Councils on Clinical Cardiology and Cardiovascular Disease in the Young.
Circulation 2004 Jun 8;109(22):2807-16. doi: 10.1161/01.CIR.0000128363.85581.E1. PMID: 15184297
Pediatrics 1996 Nov;98(5):978-82. PMID: 8909500

External

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

Orphanet, Marfan Syndrome, 2007

Suggested Reading

PubMed

Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM
J Med Genet 2010 Jul;47(7):476-85. doi: 10.1136/jmg.2009.072785. PMID: 20591885

Recent clinical studies

Etiology

Groth KA, Stochholm K, Hove H, Kyhl K, Gregersen PA, Vejlstrup N, Østergaard JR, Gravholt CH, Andersen NH
Clin Res Cardiol 2017 Feb;106(2):105-112. Epub 2016 Aug 22 doi: 10.1007/s00392-016-1028-3. PMID: 27550511
Li Y, Xu J, Chen M, Du B, Li Q, Xing Q, Zhang Y
Clin Chim Acta 2016 Sep 1;460:102-6. Epub 2016 Jun 25 doi: 10.1016/j.cca.2016.06.031. PMID: 27353645
Price J, Magruder JT, Young A, Grimm JC, Patel ND, Alejo D, Dietz HC, Vricella LA, Cameron DE
J Thorac Cardiovasc Surg 2016 Feb;151(2):330-6. Epub 2015 Oct 27 doi: 10.1016/j.jtcvs.2015.10.068. PMID: 26704057
Peres P, Carvalho AC, Perez AB, Medeiros WM
Cardiol Young 2016 Oct;26(7):1274-81. Epub 2015 Nov 2 doi: 10.1017/S1047951115002322. PMID: 26521836
Bhatt AB, Buck JS, Zuflacht JP, Milian J, Kadivar S, Gauvreau K, Singh MN, Creager MA
Vasc Med 2015 Aug;20(4):317-25. Epub 2015 Mar 20 doi: 10.1177/1358863X15569868. PMID: 25795452

Diagnosis

Groth KA, Stochholm K, Hove H, Kyhl K, Gregersen PA, Vejlstrup N, Østergaard JR, Gravholt CH, Andersen NH
Clin Res Cardiol 2017 Feb;106(2):105-112. Epub 2016 Aug 22 doi: 10.1007/s00392-016-1028-3. PMID: 27550511
Li Y, Xu J, Chen M, Du B, Li Q, Xing Q, Zhang Y
Clin Chim Acta 2016 Sep 1;460:102-6. Epub 2016 Jun 25 doi: 10.1016/j.cca.2016.06.031. PMID: 27353645
Price J, Magruder JT, Young A, Grimm JC, Patel ND, Alejo D, Dietz HC, Vricella LA, Cameron DE
J Thorac Cardiovasc Surg 2016 Feb;151(2):330-6. Epub 2015 Oct 27 doi: 10.1016/j.jtcvs.2015.10.068. PMID: 26704057
Itagaki S, Chikwe JP, Chiang YP, Egorova NN, Adams DH
J Am Coll Cardiol 2015 Jun 9;65(22):2363-9. doi: 10.1016/j.jacc.2015.03.575. PMID: 26046728
Bhatt AB, Buck JS, Zuflacht JP, Milian J, Kadivar S, Gauvreau K, Singh MN, Creager MA
Vasc Med 2015 Aug;20(4):317-25. Epub 2015 Mar 20 doi: 10.1177/1358863X15569868. PMID: 25795452

Therapy

Lee DY, Hyun HS, Huh R, Jin DK, Kim DK, Yoon BK, Choi D
J Korean Med Sci 2016 Feb;31(2):275-9. Epub 2016 Jan 26 doi: 10.3346/jkms.2016.31.2.275. PMID: 26839483Free PMC Article
Price J, Magruder JT, Young A, Grimm JC, Patel ND, Alejo D, Dietz HC, Vricella LA, Cameron DE
J Thorac Cardiovasc Surg 2016 Feb;151(2):330-6. Epub 2015 Oct 27 doi: 10.1016/j.jtcvs.2015.10.068. PMID: 26704057
Peres P, Carvalho AC, Perez AB, Medeiros WM
Cardiol Young 2016 Oct;26(7):1274-81. Epub 2015 Nov 2 doi: 10.1017/S1047951115002322. PMID: 26521836
Itagaki S, Chikwe JP, Chiang YP, Egorova NN, Adams DH
J Am Coll Cardiol 2015 Jun 9;65(22):2363-9. doi: 10.1016/j.jacc.2015.03.575. PMID: 26046728
Bhatt AB, Buck JS, Zuflacht JP, Milian J, Kadivar S, Gauvreau K, Singh MN, Creager MA
Vasc Med 2015 Aug;20(4):317-25. Epub 2015 Mar 20 doi: 10.1177/1358863X15569868. PMID: 25795452

Prognosis

Groth KA, Stochholm K, Hove H, Kyhl K, Gregersen PA, Vejlstrup N, Østergaard JR, Gravholt CH, Andersen NH
Clin Res Cardiol 2017 Feb;106(2):105-112. Epub 2016 Aug 22 doi: 10.1007/s00392-016-1028-3. PMID: 27550511
Peres P, Carvalho AC, Perez AB, Medeiros WM
Cardiol Young 2016 Oct;26(7):1274-81. Epub 2015 Nov 2 doi: 10.1017/S1047951115002322. PMID: 26521836
Beene LC, Traboulsi EI, Seven I, Ford MR, Sinha Roy A, Butler RS, Dupps WJ Jr
Am J Ophthalmol 2016 Jan;161:56-64.e1. Epub 2015 Oct 24 doi: 10.1016/j.ajo.2015.09.027. PMID: 26432567Free PMC Article
Groth KA, Hove H, Kyhl K, Folkestad L, Gaustadnes M, Vejlstrup N, Stochholm K, Østergaard JR, Andersen NH, Gravholt CH
Orphanet J Rare Dis 2015 Dec 2;10:153. doi: 10.1186/s13023-015-0369-8. PMID: 26631233Free PMC Article
Itagaki S, Chikwe JP, Chiang YP, Egorova NN, Adams DH
J Am Coll Cardiol 2015 Jun 9;65(22):2363-9. doi: 10.1016/j.jacc.2015.03.575. PMID: 26046728

Clinical prediction guides

Groth KA, Stochholm K, Hove H, Kyhl K, Gregersen PA, Vejlstrup N, Østergaard JR, Gravholt CH, Andersen NH
Clin Res Cardiol 2017 Feb;106(2):105-112. Epub 2016 Aug 22 doi: 10.1007/s00392-016-1028-3. PMID: 27550511
Peres P, Carvalho AC, Perez AB, Medeiros WM
Cardiol Young 2016 Oct;26(7):1274-81. Epub 2015 Nov 2 doi: 10.1017/S1047951115002322. PMID: 26521836
Beene LC, Traboulsi EI, Seven I, Ford MR, Sinha Roy A, Butler RS, Dupps WJ Jr
Am J Ophthalmol 2016 Jan;161:56-64.e1. Epub 2015 Oct 24 doi: 10.1016/j.ajo.2015.09.027. PMID: 26432567Free PMC Article
Itagaki S, Chikwe JP, Chiang YP, Egorova NN, Adams DH
J Am Coll Cardiol 2015 Jun 9;65(22):2363-9. doi: 10.1016/j.jacc.2015.03.575. PMID: 26046728
den Hartog AW, Franken R, Zwinderman AH, Timmermans J, Scholte AJ, van den Berg MP, de Waard V, Pals G, Mulder BJ, Groenink M
J Am Coll Cardiol 2015 Jan 27;65(3):246-54. doi: 10.1016/j.jacc.2014.10.050. PMID: 25614422

Recent systematic reviews

Gritti A, Pisano S, Catone G, Iuliano R, Salvati T, Gritti P
Int J Psychiatry Med 2015;50(4):347-60. Epub 2015 Nov 2 doi: 10.1177/0091217415612701. PMID: 26526396
Pitcher A, Emberson J, Lacro RV, Sleeper LA, Stylianou M, Mahony L, Pearson GD, Groenink M, Mulder BJ, Zwinderman AH, De Backer J, De Paepe AM, Arbustini E, Erdem G, Jin XY, Flather MD, Mullen MJ, Child AH, Forteza A, Evangelista A, Chiu HH, Wu MH, Sandor G, Bhatt AB, Creager MA, Devereux RB, Loeys B, Forfar JC, Neubauer S, Watkins H, Boileau C, Jondeau G, Dietz HC, Baigent C
Am Heart J 2015 May;169(5):605-12. Epub 2015 Feb 12 doi: 10.1016/j.ahj.2015.01.011. PMID: 25965707Free PMC Article
Velvin G, Bathen T, Rand-Hendriksen S, Geirdal AØ
Clin Genet 2015 Feb;87(2):109-16. Epub 2014 Jun 4 doi: 10.1111/cge.12422. PMID: 24813698
Hu R, Wang Z, Hu X, Wu H, Wu Z, Zhou Z
J Heart Valve Dis 2014 Jul;23(4):473-83. PMID: 25803974
Thakur V, Rankin KN, Hartling L, Mackie AS
Cardiol Young 2013 Aug;23(4):568-81. Epub 2012 Oct 19 doi: 10.1017/S1047951112001412. PMID: 23083542

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