El síndrome de Marfan es un trastorno hereditario que afecta el tejido conectivo, es decir, las fibras que sostienen y sujetan los órganos y otras estructuras del cuerpo. El síndrome de Marfan afecta más frecuentemente el corazón, los ojos, los vasos sanguíneos y el esqueleto.

1. Marfan Syndrome
Marfan syndrome is a genetic condition with autosomal dominant inheritance. Marfan
syndrome affects the elasticity of connective tissues throughout the body, most notably in
the cardiovascular, ocular, and musculoskeletal systems. The skin, lungs, and central
nervous system are also affected. Patients are usually tall with long limbs, fingers, and toes,
and hypermobile joints. Associated conditions include aortic aneurysm or dissection, mitral
valve prolapse, and lens dislocation. Diagnosis is made clinically with set criteria, and
genetic testing is done only when it may affect the management. Medical or surgical
management is based on clinical manifestations. Cardiovascular involvement is followed
closely, as it is the main cause of mortality.
Last updated: November 21, 2022
Epidemiology and Genetics
Epidemiology
CONTENTS
Epidemiology and Genetics
Clinical Presentation
Diagnosis
Management
Differential Diagnosis
References

2. Incidence: 1 in 5,000 live births
Affects men and women in all ethnic and racial groups
Genetics
Most commonly due to a mutation in the FBN1 gene on chromosome 15
Affects the connective tissue protein, fibrillin-1
Fibrillin-1 is the main component of microfibrils, which form elastic fibers in
connective tissue.
Mutation in FBN1 gene → impaired fibrillin protein → defective microfibrils
→ ↓ elasticity in tissues
Affects connective tissues throughout the body:
Organs
Blood vessels
Eyes
Skin
Skeletal components
Inheritance pattern: autosomal dominant
75% of patients have affected parents.
25% of cases are de novo mutations (idiopathic).
Penetrance: complete
Expressivity: variable

3. Family members with Marfan’s syndrome
Image (https://openi.nlm.nih.gov/detailedresult?img=PMC4100052_ijms-39-391-
g001&query=marfan&it=xg&lic=by&req=4&npos=24): “Family members with Marfan’s syndrome” by Birjand
Atherosclerosis and Coronary Artery Research Centre, Birjand University of Medical Sciences, Birjand, Iran. License: CC
BY 3.0 (http://creativecommons.org/licenses/by/3.0/)
Clinical Presentation
Musculoskeletal

4. Tall stature with disproportionately long extremities:
↓ upper segment to lower segment ratio (US/LS)
↑ arm span to height ratio
Long fingers and toes (arachnodactyly):
Positive thumb sign (Steinberg's sign): The distal phalanx of the adducted thumb
extends beyond the ulnar border of a clenched fist palm.
Positive wrist sign (Walker sign): The thumb and 5th finger of the hand overlap
with each other when wrapped around the contralateral wrist.
Joint laxity
Elbows may lack full extension mobility.
Vertebral column abnormalities:
Scoliosis
Kyphosis
Chest abnormalities:
Pectus excavatum (funnel chest)
Sternum protrudes inward.
Looks “caved in”
Pectus carinatum (pigeon chest or sternal kyphosis): Sternum protrudes outward.
Hindfoot valgus:
Heel points outward away from midline.
Associated with pes planus (flat foot)
Protrusio acetabuli (acetabular protrusion)
High-arched palate
Characteristic facial features:
Dolichocephaly (↓ head width:length ratio)
Enophthalmos (posterior displacement of the eyeball within the orbit)
Downslanting palpebral fissures (area between open eyelids)
Malar hypoplasia (malar or zygomatic bone is small or absent)
Retrognathia (lower jaw set back further than upper jaw)

8. Cardiovascular

9. Aortic disease is the main cause of morbidity and mortality in Marfan syndrome (MFS)
patients, and is due to degeneration of the media of the vessel walls.
Dilation or aneurysm of the aorta
Present in 50% of children
Dilation may involve thoracic aorta, abdominal aorta, or root of
pulmonary artery.
Dilation of the aortic root present in 60%–80% of adults with MFS
Aortic regurgitation
Often occurs with aortic dilation
Valve leaflets prevented from closing properly
Diastolic heart murmur on exam
Aortic dissection
Tear in the intima (innermost layer) of the aorta, allowing blood between the
intima and media (middle layer)
Life-threatening condition
Presents with sudden, severe, chest pain that radiates to the back
MFS patients account for 50% of those with aortic dissection under 40 years
of age.
↑ risk of dissection during pregnancy and postpartum
Mitral valve prolapse
Valve leaflets bulge (prolapse) into left atrium during heart systole
More frequently seen with ↑ age and in women
Systolic heart murmur and midsystolic click on exam
Can lead to mitral regurgitation
Dilation of carotid and cranial arteries
Much less common
Berry (saccular) aneurysms are typically at the exit of the circle of Willis.
Rupture of a cranial artery can cause subarachnoid hemorrhage.

10. Ocular
Dislocation of the lens (ectopia lentis)
Impaired supporting ciliary zonules fail to keep the lens in place.
Upward and temporal displacement
Occurs in 50%–80% of patients
Iridodonesis can be seen on inspection (vibration of the iris with eye movement).
Seen on slit lamp examination
Myopia (nearsightedness)
Retinal tears or detachment
Often bilateral in MFS patients
Associated with proliferative retinopathy
Glaucoma
Early cataract formation

11. Other manifestations
Skin: striae atrophicae (stretch marks)
Not associated with weight changes or pregnancy
Often in uncommon areas:
Upper arms
Axillary area
Mid and lower back
Thighs
Pulmonary: emphysematous changes in the lungs
Lung bullae predominantly in the upper lobes
↑ risk for spontaneous pneumothorax
Central nervous system (CNS): lumbosacral dural ectasia
Dilation of the dural sac surrounding the spinal cord
Symptoms:
Lower back pain
Radicular pain
Paresthesias
Bowel and bladder dysfunction
Headaches

12. Diagnosis
Revised Ghent criteria
Complex scoring system based on the presence of characteristic Marfan
syndrome manifestations
Requires varying combinations of:
Aortic root dilatation
Ectopia lentis
FBN1 gene mutation
Systemic score > 7 (see table below)
The presence, or absence, of a family history of MFS is factored in.
Genetic testing for the FBN1 mutation is done on a case-by-case basis if it will affect
management.
Imaging is used to evaluate for complications of MFS.
Radiographs → pneumothorax, protrusio acetabuli, scoliosis
Echocardiography (echo) → valvular and aortic root defects
Computed tomography (CT) of chest, abdomen, and pelvis with intravenous (IV)
contrast → aortic dissection
Magnetic resonance imaging (MRI) → dural ectasia, aortic dilation

13. Table: Systemic score for the revised Ghent criteria (a score ≥ 7 indicates major
systemic involvement)

14. Wrist and thumb sign 3 points (both)
1 point (1)
Pectus carinatum deformity 2 points
Pectus excavatum or chest asymmetry 1 point
Hindfoot deformity 2 points
Plain pes planus 1 point
Pneumothorax 2 points
Dural ectasia 2 points
Protrusio acetabuli 2 points
↓ US/LS and ↑ arm span/height and no severe scoliosis 1 point
Scoliosis or kyphosis 1 point
↓ elbow extension 1 point
Facial features (at least 3 of 5)
Dolichocephaly
Enophthalmos
Downslanting palpebral fissures
Malar hypoplasia
Retrognathia
1 point
Skin striae 1 point
Myopia 1 point
Mitral valve prolapse 1 point

15. This table does not need to be memorized, but provides insight into the important clinical
findings and the complexity of the diagnosis.

17. Management
The management of MFS is based on the clinical manifestations. A multidisciplinary
team of cardiologists, ophthalmologists, orthopedists, and cardiovascular surgeons is
needed.
General
Avoid:
Caffeine
Stimulants
Strenuous exercise
Contact sports
Activities that entail the Valsalva maneuver
Scuba diving
Genetic and preconception counseling
50% risk of transmission to children
High-risk pregnancy due to ↑ risk of aortic dissection and rupture

18. Musculoskeletal
Scoliosis treatment
Bracing
Surgery if the curve > 40 degrees
Physical therapy
Surgery may be needed for other skeletal anomalies (e.g., pectus deformities), if
severe.

20. Cardiovascular

21. Echocardiography
Upon initial diagnosis and every 6–12 months
Evaluate and monitor aortic dilation.
Monitoring frequency is based on the rate of growth over time.
Cardiac CT or MRI
Used to confirm echo findings
Assess for additional aortic or vascular defects not seen on echo.
Medications for strict blood pressure control
Beta blockers
Angiotensin receptor blockers (ARBs)
Avoid calcium channel blockers, as these may ↑ risk of aortic complications.
Surgery
Elective aortic repair or replacement surgery is indicated if:
Diameter ≥ 50 mm
Rapid growth
Family history of dissection
Progressive aortic regurgitation
Patients considering pregnancy
Surgery or medical management for aortic dissection depends on whether the
ascending aorta is involved.
Mitral valve repair or replacement is recommended for:
Severe mitral regurgitation
Progressive left ventricular dilation or systolic dysfunction

22. Ocular
Annual ophthalmologic exams
Myopia → vision correction
Retinal tears or detachment → photocoagulation
Urgent ophthalmologic assessment for sudden vision changes
Differential Diagnosis
Homocystinuria: autosomal recessive disorder of homocysteine metabolism. Affected
individuals have marfanoid body habitus and ectopia lentis, characterized by a
downward and inward dislocation. Individuals may also have intellectual disability,
megaloblastic anemia, and thrombotic events (strokes and myocardial infarction).
Measurement of homocysteine levels aids in diagnosis. Management is via a low-
methionine diet and vitamin supplementation.
Ehlers-Danlos syndrome: an autosomal dominant connective tissue disorder affecting
collagen. The syndrome has 13 subtypes, and the inheritance pattern can be
autosomal dominant or recessive. The cardiovascular system, musculoskeletal system,
eyes, and skin are affected. Easy bruising or bleeding and dental abnormalities are also
seen. The syndrome is a clinical diagnosis, but genetic testing may be beneficial.
Management is symptomatic and based on manifestations.
Loeys-Dietz syndrome: an autosomal dominant connective tissue disorder with similar
presentation to MFS but affecting a different gene. Unlike MFS, features of
hypertelorism (widely spaced eyes), split uvula, cleft palate, easy bruising, keloid
formation, and arterial tortuosity are present. Vascular features may be more
aggressive, with aortic aneurysms seen at an early age. Genetic testing can help
differentiate between Loeys-Dietz syndrome and MFS. Management is similar to MFS.
Multiple endocrine neoplasia, type 2B (MEN 2B): an autosomal dominant syndrome
associated with medullary thyroid carcinoma, pheochromocytoma, oral
mucosal neuromas, and intestinal ganglioneuromas. Affected individuals also have a
marfanoid body habitus with skeletal abnormalities; however, the cardiovascular system
and eyes are usually not affected. Genetic testing helps in diagnosis. Surgery is
required to remove the neoplasms.
Congenital contractural arachnodactyly: also known as Beals syndrome. An
autosomal dominant condition affecting the fibrillin-2 protein. Affected individuals also
have a marfanoid body habitus and cardiovascular manifestations. Flexion contractures
in many joints restrict movement. The skin is not affected. The condition is diagnosed
with clinical criteria and genetic testing. Management is based on the clinical
manifestations.

23. References
1. Wright, M.J. & Connolly, H.M. (2016). Genetics, clinical features, and diagnosis of Marfan syndrome and
related disorders. UpToDate. Retrieved December 7, 2020, from
https://www.uptodate.com/contents/genetics-clinical-features-and-diagnosis-of-marfan-syndrome-and-
related-disorders (https://www.uptodate.com/contents/genetics-clinical-features-and-diagnosis-of-marfan-
syndrome-and-related-disorders)
2. Marfan Syndrome. MedlinePlus. https://medlineplus.gov/genetics/condition/marfan-syndrome/
(https://medlineplus.gov/genetics/condition/marfan-syndrome/)
3. Wright, M.J. & Connolly, H.M. (2020). Management of Marfan syndrome and related disorders. UpToDate.
Retrieved December 8, 2020, from https://www.uptodate.com/contents/management-of-marfan-
syndrome-and-related-disorders (https://www.uptodate.com/contents/management-of-marfan-syndrome-
and-related-disorders)
4. Inna, P. (2020). Marfan syndrome (MFS). In Thomson, J.D. (Ed.), Medscape. Retrieved December 11, 2020,
from https://emedicine.medscape.com/article/1258926-overview?src=ppc_google_rlsa-
traf_mscp_emed_t1_us (https://emedicine.medscape.com/article/1258926-overview?
src=ppc_google_rlsa-traf_mscp_emed_t1_us)
5. Pessler, F. (2020). Marfan syndrome. [online] MSD Manual Professional Version. Retrieved December 11,
2020, from https://www.msdmanuals.com/professional/pediatrics/connective-tissue-disorders-in-
children/marfan-syndrome (https://www.msdmanuals.com/professional/pediatrics/connective-tissue-
disorders-in-children/marfan-syndrome)