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Ehlers-Danlos syndrome and Marfan syndrome

Last updated: September 1, 2021

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Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that affects the microfibrils and elastin in connective tissue throughout the body. MFS is associated with disorders of the cardiovascular system (e.g., mitral valve prolapse, aortic aneurysm, and dissection), the musculoskeletal system (e.g., tall stature with disproportionately long extremities, joint hypermobility), and the eyes (e.g., subluxation of the lens of the eye).

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders with variable inheritance (including hypermobility EDS and vascular EDS), characterized by defective collagen synthesis and processing. Symptoms include varying degrees of hyperextensive skin, joint hypermobility, and tissue fragility (including that of vasculature).

The diagnosis of MFS and EDS is based on clinical criteria. Genetic testing can be used additionally to confirm or rule out the diagnosis of certain subtypes. Since there is currently no causal treatment for MFS or EDS, management typically involves an approach focusing on clinical features, including regular monitoring of complications (e.g., imaging of aortic aneurysm) and preventive care (e.g., antihypertensives to prevent aneurysm progression).

Marfan syndrome [1][2]

MarFan syndrome is caused by a gene mutation in FBN1 on chromosome 15 (Fifteen), resulting in defective Fibrillin protein.

Ehlers-Danlos syndrome [1]

Types of Ehlers-Danlos syndrome (EDS)
Hypermobile EDS (most common) Classic EDS Classical-like EDS Vascular EDS
Genetic defect
  • Unknown
  • COL5A1
  • COL5A2
  • TNXB
  • COL3A1
Affected protein
  • Tenascin X
Distinguishing features Joints
  • Generalized joint hypermobility and subluxations (e.g., patella, temporomandibular, shoulder)
Skin
  • Hyperextensibility (less severe compared to classic EDS)
Cardiovascular
  • Uncommon
  • Spontaneous arterial aneurysms, dissections
Other
  • Spontaneous organ rupture (e.g., colon, gravid uterus)
  • Characteristic facial features: prominent eyes, thin face and nose, small lips, lobeless ears

Marfan syndrome [1][3][4]

Cardiovascular

Musculoskeletal

  • Tall stature and long extremities
  • Joint hypermobility
    • Positive thumb sign: Patients are asked to place their thumbs in the palms of the same hand and then clench to form a fist. A positive thumb sign is present when the thumb protrudes beyond the ulnar border of the hand.
    • Positive wrist sign: Patients are asked to clasp the wrist of the opposite hand. A positive wrist sign is present when the little finger and thumb overlap.
  • High-arched palate
  • Arachnodactyly (achromachia); : abnormally long, slender fingers and toes
  • Pectus deformity
    • Pectus carinatum: a sternal deformity where the middle and lower portion of the sternum protrude forward (also known as sternal kyphosis)
    • Pectus excavatum: a sternal deformity where the middle and lower portion of the sternum protrudes inward
  • Pes planus (flat foot) or hindfoot valgus
  • Spinal deformities (scoliosis, hyperkyphosis)
  • Vertical overdevelopment of the head (dolichocephaly)
  • Winged scapula
  • Habitual dislocations (particularly the patella and shoulder)
  • Acetabular protrusion

Skin

Eyes

Other

The classic presentation of MFS includes aortic aneurysm or dissection, long extremities, arachnodactyly, joint hypermobility, and subluxation of the lens of the eye.

Ehlers-Danlos syndrome [5]

The clinical features discussed here are seen in all types of EDS, but their severity may vary and certain symptoms predominate depending on the specific type.

Cardiovascular

Musculoskeletal

Skin

Eyes

Other

The classic presentation of EDS involves hyperextensible skin, joint hypermobility, and a tendency to bleed easily.

Differential diagnosis of a marfanoid body habitus
Inheritance pattern Skeletal Dermal Vascular Other
Marfan syndrome
Ehlers-Danlos syndrome
Homocystinuria
  • Fair complexion
Loeys-Dietz syndrome [9]
Multiple endocrine neoplasia 2B (MEN 2B)
  • Unaffected
Congenital contractural arachnodactyly (Beals syndrome) [10][11]
  • Unaffected

Marfan syndrome classically manifests with a superior and temporal displacement of the lens (upward and outward). Homocystinuria also results in a Marfanoid habitus, but manifests with inferior and medial displacement of the lens (downward and inward).

The differential diagnoses listed here are not exhaustive.

Applicable to MFS and EDS

  • No causal treatment
  • Interdisciplinary treatment of specific symptoms and manifestations, including:
  • Regular orthopedic, ophthalmological, and cardiological check-ups

Specific treatment [12]

Marfan syndrome [1][13]

  • Normal life expectancy: if diagnosed early and complications are managed appropriately
  • Cardiovascular complications: Disease progression should be carefully monitored and managed accordingly to prevent cardiovascular complications (e.g., aortic dissection).
  • Aortic root disease (e.g., aneurysm, dissection) is the most common cause of death.

Ehlers-Danlos syndrome [7][14][15]

  1. Wright MJ, Connolly HM. Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/genetics-clinical-features-and-diagnosis-of-marfan-syndrome-and-related-disorders.Last updated: November 2, 2016. Accessed: March 10, 2017.
  2. Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010; 47 (7): p.476-485. doi: 10.1136/jmg.2009.072785 . | Open in Read by QxMD
  3. Conway JE, Hutchins GM, Tamargo RJ. Marfan syndrome is not associated with intracranial aneurysms. Stroke. 1999; 30 (8): p.1632-1636. doi: 10.1161/01.STR.30.8.1632 . | Open in Read by QxMD
  4. Pauker SP. Clinical manifestations and diagnosis of Ehlers-Danlos syndromes. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-ehlers-danlos-syndromes.Last updated: July 8, 2016. Accessed: March 13, 2017.
  5. Wright MJ, Connolly HM. Management of Marfan syndrome and related disorders. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. http://www.uptodate.com/contents/management-of-marfan-syndrome-and-related-disorders.Last updated: September 28, 2016. Accessed: February 17, 2017.
  6. Von kodolitsch Y, Robinson PN. Marfan syndrome: an update of genetics, medical and surgical management. Heart. 2007; 93 (6): p.755-760. doi: 10.1136/hrt.2006.098798 . | Open in Read by QxMD
  7. Ehlers-Danlos Syndrome. http://www.merckmanuals.com/professional/pediatrics/connective-tissue-disorders-in-children/ehlers-danlos-syndrome. Updated: January 1, 2014. Accessed: February 17, 2017.
  8. Ehlers-Danlos Syndrome, Classic Type.
  9. Pauker SP, Stoler J. Overview of the management of Ehlers-Danlos syndromes. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/overview-of-the-management-of-ehlers-danlos-syndromes.Last updated: November 28, 2016. Accessed: March 13, 2017.
  10. Goljan EF. Rapid Review Pathology. Elsevier Saunders ; 2018
  11. Hetzer R, Gehle P, Ennker J. Cardiovascular Aspects of Marfan Syndrome. Steinkopff ; 1995
  12. Marfan Syndrome. http://www.merckmanuals.com/professional/pediatrics/connective-tissue-disorders-in-children/marfan-syndrome. Updated: January 1, 2014. Accessed: February 17, 2017.
  13. Loeys-Dietz syndrome. https://ghr.nlm.nih.gov/condition/loeys-dietz-syndrome. Updated: August 17, 2020. Accessed: September 11, 2020.
  14. Congenital contractural arachnodactyly. https://rarediseases.info.nih.gov/diseases/5899/congenital-contractural-arachnodactyly. Updated: January 31, 2017. Accessed: September 11, 2020.
  15. Rare Disease Database - Congenital Contractural Arachnodactyly. https://rarediseases.org/rare-diseases/congenital-contractural-arachnodactyly. Updated: January 1, 2018. Accessed: September 11, 2020.