Hypermobility Syndromes: Marfan's, Ehlers-Danlos
Does this patient have a hypermobility syndrome such as Marfan syndrome, Ehlers-Danlos syndrome, or joint hypermobility syndrome?
- Marfan syndrome
- Ehlers-Danlos syndrome
- Joint hypermobility syndrome
- Differential diagnosis of MFS
- Familial ectopia lentis syndrome (ELS)
- MASS phenotype
- Beals syndrome
- Loeys-Dietz syndrome (LDS)
- Shprintzen-Goldberg syndrome (SGS)
- Familial thoracic aortic aneurysm syndrome (FTAA)
- Stickler syndrome
- Weill-Marchesani syndrome (WMS)
- Differential diagnosis of EDS
- Cutis laxa
- Tenascin-X deficiency
- Stickler syndrome
- Ullrich congenital muscular dystrophy
- Mild osteogenesis imperfecta (OI)
- Differential diagnosis of JHS
- What tests to perform?
- How should patients with Marfan syndrome, Ehlers-Danlos syndrome, or joint hypermobility syndrome be managed?
- What happens to patients with Marfan syndrome, Ehlers-Danlos syndrome, or joint hypermobility syndrome?
- How to utilize team care?
- Are there clinical practice guidelines to inform decision making?
What is the evidence?
Does this patient have a hypermobility syndrome such as Marfan syndrome, Ehlers-Danlos syndrome, or joint hypermobility syndrome?
Marfan syndrome (MFS) and Ehlers-Danlos syndrome (EDS) are connective tissue disorders with multisystem manifestations. Joint hypermobility syndrome (JHS) is a connective tissue disorder that primarily affects the musculoskeletal system. All of these disorders may present with symptoms referable to joint hypermobility, including joint pain, swelling, instability, and dislocation, as well as back pain.
Concern regarding the presence of the more severe MFS or EDS should be raised when a patient presents with hypermobile joints in the setting of an abnormal body habitus, fragile or translucent skin with sagging and redundancy, or a family history of aortic insufficiency or aortic dilatation or rupture, suggesting a more severe phenotype. These disorders have variable modes of inheritance and associated genetic defects.
Marfan syndrome (MFS) is an autosomal dominant connective tissue disease. Patients typically present with joint hypermobility, and may have pectus carinatum or excavatum, pes planus (flat feet), and scoliosis. Given their abnormally shaped chest walls, they are at risk for pneumothorax. They may also have mitral valve prolapse and myopia.
MFS is caused by a mutation in the Fibrillin-1 (FBN1) gene with an incidence of about 1 in 3300 to 1 in 5000. Finding an FBN1 mutation is not sufficient to make a diagnosis of MFS, however, as other conditions related to MFS are also caused by FBN1 mutations, such as familial ectopia lentis syndrome (ELS) and MASS phenotype (mitral valve prolapse, mild aortic dilatation, striae atrophica, and skeletal features).
Other diseases are also caused by mutations in the FBN1 gene, including Shprintzen-Goldberg syndrome (SGS), a syndrome characterized by Marfanoid habitus with craniosynostosis and developmental delay, and Weill-Marchesani syndrome (WMS), a syndrome characterized by short stature, brachydactyly, microspherophakia, and joint stiffness. See
Systemic score from the revised Ghent nosology* for the diagnosis of Marfan syndrome
|Wrist and thumb sign, or Wrist or thumb sign**||3, or1|
|Pectus carinatum deformity, or Pectus excavatum or chest asymmetry||2, or1|
|Hindfoot deformity, or Plain pes planus||2, or1|
|Reduced upper segment:lower segment ratio (US/LS)†and increased arm span:height ratio¶and no severe scoliosis||1|
|Scoliosis or thoracolumbar kyphosis||1|
|Reduced elbow extension (≤ 170 degrees on full extension)||1|
|Facial features (≥ 3 out of 5): dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia||1|
|Myopia > 3 diopters||1|
|Mitral valve prolapse (all types)||1|
Revised Ghent nosology for the diagnosis of Marfan syndrome
|In the absence of family history of Marfan syndrome, any one of the following criteria is diagnostic of MFS:|
|Aortic diameter at the sinuses of Valsalva of Z ≥ 2 or aortic root dissection and ectopia lentis*|
|Aortic diameter at the sinuses of Valsalva of Z ≥ 2 or aortic root dissection and causal FBN1 mutation.|
|Aortic diameter at the sinuses of Valsalva of Z ≥ 2 or aortic root dissection and systemic score ≥ 7*|
|Ectopia lentis and causal FBN1 mutation that has been identified in a person with aortic aneurysm.|
|In the presence of family history of Marfan syndrome, any one of the following criteria is diagnostic of MFS:|
|Systemic score ≥ 7*|
|Aortic diameter at the sinuses of Valsalva of Z ≥ 2 in patients aged ≥ 20 (Z ≥ 3 in patients aged < 20) or aortic root dissection*|
Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue diseases characterized by skin hyperextensibility and fragility and articular hypermobility. There are multiple genotypic and phenotypic variants, ranging from primary articular and dermal manifestations with hypermobility and subluxation as well as fragile cigarette paper skin that scars poorly, to rare severe forms with risk of spontaneous arterial and organ rupture.
The primary defects in EDS are found in genes that encode for collagen types I, III, and V, although other genetic defects, such as mutations in PLOD1 (responsible for the kyphoscoliosis type), ADAMTS2 (responsible for the dermatosparaxis type), and tenascin-XB (responsible for an autosomal recessive form of EDS), have also been implicated.
Many types of EDS have been identified, and are described in
Ehlers-Danlos syndrome classification
|EDS Type||Name||Mode of Inheritance||Genetic Defect||Clinical Manifestations|
|I||Classic, Gravis||AD*||COL5A1COL5A2||Skin hyperextensibility.Joint hypermobility.Wide, atrophic, papyraceous scarring.Fragile skin that heals with "cigarette paper" scars.|
|II||Classic, Mitis||AD||COL5A1COL5A2||Similar to type I, but less severe.|
|IV||Vascular||AD||COL3A1||Thin, translucent skin.Easy bruisability.Spontaneous rupture of large or medium arteries, bowel, and uterus.Some patients have characteristic facies with decreased adipose tissue in the face, thin nose and lips, and large eyes.|
|VI||Kyphoscoliosis/Ocular-scoliotic||AR**||PLOD1||Congenital scoliosis.Ocular fragility with potential for rupture.Neonatal hypotonia.|
|VII||Arthrochalasia||Congenital hip dislocation.Recurrent articular subluxations.|
|VIIC||Dermatosparaxis||AR||ADAMTS2||Severe skin fragility with sagging.Redundant skin.|
Joint hypermobility syndrome
Joint hypermobility syndrome (JHS) is a connective tissue disorder characterized by joint laxity and hypermobility. Although JHS primarily affects the musculoskeletal system with symptoms of persistent joint pain, low back pain, tendonitis, bursitis, epicondylitis, and dislocation, other organs and systems, such as skin, nervous system, and gastrointestinal tract, can also be involved. Patients may have skin striae and hyperextensibility, as well as varicose veins, hernias, and uterine or rectal prolapse.
Although JHS appears to be strongly heritable, no single genetic mutation has been identified as the cause. Some authorities believe JHS to be synonymous with Hypermobility EDS (type III). Females are more commonly affected than males. See
Nine-Point Beighton hypermobility score
|One point for each of the following:|
|Passive dorsiflexion of the right 5th MCP to ≥ 90 degrees.|
|Passive dorsiflexion of the left 5th MCP to ≥ 90 degrees.|
|Passive opposition of the right thumb to the volar aspect of the right forearm.|
|Passive opposition of the left thumb to the volar aspect of the left forearm.|
|Passive extension of the right elbow to ≥ 10 degrees.|
|Passive extension of the left elbow to ≥ 10 degrees.|
|Hyperextension of the right knee to ≥ 10 degrees.|
|Hyperextension of the left knee to ≥ 10 degrees.|
|Placement of the hands flat on the floor without bending the knees.|
Revised (1998 Brighton) criteria for the diagnosis of benign joint hypermobility syndrome
|Beighton score of ≥ 4 out of 9.|
|Arthralgia for > 3 months in ≥ 4 joints.|
|Beighton score of 1, 2, or 3 out of 9 (or 0, 1, 2, or 3 if ≥ 50 years of age).|
|Arthralgia in 1 to 3 joints or back pain, spondylosis, or spondylolysis/spondylolisthesis.|
|Dislocation in > 1 joint or in 1 joint ≥ 2 times.|
|≥ 3 soft tissue lesions (e.g., tenosynovitis, epicondylitis, bursitis).|
|Skin striae, hyperextensibility, thin skin, or abnormal scarring.|
|Ptosis, myopia, or antimongoloid slant.|
|Varicose veins, hernia, or uterine or rectal prolapse.|
Several other conditions should be considered when contemplating the diagnosis of MFS, EDS, or JHS.
Differential diagnosis of MFS
Familial ectopia lentis syndrome (ELS)
Per the revised Ghent nosology, diagnostic criteria for ELS include ectopia lentis and an FBN1 mutation not previously known to cause aortic root dilatation or dissection, or absence of the FBN1 mutation. Autosomal recessive forms of ELS are associated with mutations in the LTBP2 and ADAMTSL4 genes.
Per the revised Ghent nosology, diagnostic criteria for the MASS phenotype include aortic diameter at the sinuses of Valsalva of Z < 2 and systemic score ≥ 5 with at least one skeletal manifestation and absence of ectopia lentis.
Also known as congenital contractural arachnodactyly (CCA): Characterized by Marfanoid habitus, joint contractures, and crumpled ears. Caused by a mutation in the FBN2 gene.
Loeys-Dietz syndrome (LDS)
Characterized by Marfanoid habitus, hypertelorism, bifid uvula or cleft palate, arterial tortuosity, and multiple arterial aneurysms, including aortic aneurysms. Patients may also have craniosynostosis, translucent and velvety skin, talipes equinovarus (clubfoot), and cervical spine instability. Ectopia lentis is absent.
Given the extremely high risk for aortic and arterial aneurysm formation and rupture, patients with LDS should undergo annual MR imaging from their cerebral circulation to their pelvis. LDS is caused by a mutation in the TGFBR1 or TGFBR2 gene.
Shprintzen-Goldberg syndrome (SGS)
Characterized by Marfanoid habitus with craniosynostosis and developmental delay. Caused by a mutation in the FBN1 gene.
Familial thoracic aortic aneurysm syndrome (FTAA)
Marfanoid habitus is absent. Characterized by thoracic aortic aneurysms, livedo reticularis, and iris flocculi. Caused by a mutation in the TGFBR1, TGFBR2, or ACTA2 gene.
Characterized by Marfanoid habitus, developmental delay, thrombosis, myopia, and ectopia lentis. However, the lens is usually displaced downward, unlike in MFS, where it is displaced upward. Caused by a mutation in the CBS gene.
Stickler syndrome is a heterogeneous group of heritable disorders; currently five types of Stickler syndrome have been identified. It is characterized by vitreous abnormalities, high myopia, and hearing loss. Patients may experience retinal detachment that leads to blindness. They may have a bifid uvula, cleft palate, and Pierre Robin sequence. Stickler syndrome is caused by mutations in any of the following genes: COL2A1, COL11A1, COL11A2, COL9A1, COL9A2.
Weill-Marchesani syndrome (WMS)
Unlike patients with MFS, patients with WMS have short stature and brachydactyly. WMS is also characterized by microspherophakia and joint stiffness. It is caused by a mutation in the FBN1 or ADAMTS10 gene.
Differential diagnosis of EDS
Also known as generalized elastolysis, cutis laxa is characterized by an absence of skin elasticity leading to loose and sagging skin. Unlike in EDS, when tension is applied to and then released from skin of patients with cutis laxa, it does not spring back into place due to the loss of elastin.
Patients with cutis laxa may have craniofacial abnormalities, emphysema, aortic dilatation, and pulmonic stenosis. Mutations in multiple genes have been found to cause cutis laxa, including mutations in the elastin gene.
Mutations in the gene encoding for the copper transporting ATPase, ATP7A, have also been identified in cutis laxa. Cutis laxa resulting from this particular mutation is called occipital horn syndrome.
Leads to a phenotype that can be clinically indistinguishable from EDS.
Ullrich congenital muscular dystrophy
Also known as atonic-sclerotic dystrophy, Ullrich congenital muscular dystrophy is characterized by multiple contractures of proximal joints and hypermobility of distal joints in the setting of generalized muscle weakness. It presents in infancy or early childhood and is caused by mutations in the COL6A1, COL6A2, and COL6A3 genes.
Mild osteogenesis imperfecta (OI)
Patients with OI may manifest joint hypermobility and easy bruisability. OI is predominantly caused by mutations in the genes that encode type I collagen, COL1A1 and COL1A2.
Differential diagnosis of JHS
Non-specific joint laxity
What tests to perform?
Thorough history, including family history, and physical examination, are the most important steps in making a diagnosis of MFS. Genetic testing accompanied by genetic counseling pre- and post-testing is a key element in the diagnosis of MFS.
Echocardiography should be performed in all patients with MFS at the time of diagnosis and 6 months subsequently to determine the aortic root and ascending aortic diameters and their rates of enlargement. See below for more information on the management of MFS.
Thorough history, including family history and physical examination are the most important steps in making a diagnosis of EDS. Genetic testing accompanied by genetic counseling pre- and post-testing is a key element in the diagnosis of certain EDS types.
Skin biopsy to culture dermal fibroblasts can confirm the diagnosis of vascular EDS (type IV), arthrochalasia (types VIIA and VIIB), and dermatosparaxis (type VIIC) via biochemical testing.
Ocular-scoliotic EDS (type VI) can be diagnosed by using high performance liquid chromatography to test urinary levels of total hydroxylysyl pyridinoline and lysyl pyridinoline. An elevated ratio of lysyl pyridinoline to hydroxylysyl pyridinoline is diagnostic.
The diagnosis of JHS is a clinical one. Thorough history and physical examination are essential to making the diagnosis (see Tables IV and V above for diagnostic criteria).
How should patients with Marfan syndrome, Ehlers-Danlos syndrome, or joint hypermobility syndrome be managed?
For all patients with hypermobile joints, including those with MFS, EDS, or JHS, activities that place stress on joints should be discouraged, especially in childhood. Careful attention to optimizing mechanics is important. Patients should maintain an ideal, low body weight, and perform regular quadriceps and core strengthening exercises to protect their hypermobile joints.
Patients should undergo transesophageal echocardiography at diagnosis and again at 6 months to determine aortic root and ascending aortic diameters and their rates of dilatation. Annual echocardiography should be performed in adults with stable aortic root dilatation < 45 mm. Once aortic root diameter reaches 45 mm, echocardiographic screening should occur more frequently, such as every 6 months.
More frequent echocardiography should also be performed in the setting of rapid aortic enlargement (≥ 5 mm/year), valvular dysfunction, or cardiomyopathy. Adults with several consecutive normal echocardiograms can space out their screening to every 2-3 years.
It should be kept in mind that echocardiography measures the internal aortic diameter whereas CT and MR measure the external aortic diameter. Therefore, measurements taken by CT or MR tend to be 2 to 4 mm larger than those taken by echocardiography.
All patients with MFS and aortic involvement should receive beta blocker therapy with the goal of decreasing the rate of aortic dilatation. In patients who cannot tolerate beta blockade, angiotensin receptor blockers or angiotensin converting enzyme inhibitors should be substituted. Patients with a thoracic aortic aneurysm should be treated concurrently with beta blockers and either angiotensin receptor blockers or angiotensin converting enzyme inhibitors.
Prophylactic aortic root surgery (either composite valve graft or valve-sparing aortic root replacement) should be undertaken when aortic root diameter reaches about 50 mm. Surgery for patients with smaller aortic root diameters should be considered when:
Aortic diameter is enlarging rapidly (≥ 5 mm/year).
Aortic insufficiency is progressing.
A family member with MFS had an aortic dissection at a diameter < 50 mm.
Women who plan to become pregnant should consider elective replacement of the aortic root and ascending aorta if the diameter is > 40 mm.
Patients should have annual ophthalmologic exams, or more frequently as indicated.
Patients should undergo regular orthopedic evaluations for defects such as scoliosis and pectus abnormalities.
Strenuous exercise as well as isometric exercises that involve the Valsalva maneuver should be avoided.
Surgical correction of scoliosis or pectus deformities may be required.
Acute abdominal pain or back pain needs to be taken seriously in EDS, especially the vascular type, as it could indicate arterial rupture or dissection or intestinal perforation. Altered mental status could be a symptom of intracranial arterial rupture. Urgent CT or MR imaging should be undertaken in these emergent situations.
Uterine rupture can occur in pregnant women with EDS, especially the vascular type.
If a patient with dermatologic manifestations of EDS requires sutures, the sutures such be closely spaced and left in longer than usual.
Acute pain in patients with hypermobile joints can be managed with analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). However, chronic pain commonly develops in patients with JHS, and this type of pain is less responsive to analgesics and NSAIDs.
Patients with JHS may therefore require referral to pain management specialists for assistance with management of their chronic pain. Medications used to treat fibromyalgia, such as duloxetine, pregabalin, and milnacipran, may be useful in the treatment of chronic pain due to JHS. However, evidence is lacking.
Physical therapy is an important treatment for patients with JHS. Physical therapy can improve proprioception in damaged joints and can improve muscle strengthening. Patients can also be taught proper postures that will diminish strain on their joints. It is important to emphasize that patients with JHS need to continue to perform their physical therapy exercises once their sessions are completed. Otherwise, there is potential to lose the benefit gained from physical therapy.
Occupational therapy is also an important treatment for patients with JHS. Temporary splinting of hyperextensible small joints of the hand during certain activities may be required. Special devices, such as kitchen and writing utensils with wide grips, can help patients perform important daily activities.
Orthotics should be worn by patients with JHS who have pes planus to improve posture and decrease fatigue of lower extremity muscles.
Psychotherapy may be helpful in dealing with issues related to chronic pain, such as depression, anxiety, and poor sleep. Biofeedback and relaxation techniques may be of use.
Patient support groups can provide patient education and psychosocial support.
What happens to patients with Marfan syndrome, Ehlers-Danlos syndrome, or joint hypermobility syndrome?
In general, joint hypermobility diminishes with age.
Musculoskeletal: Scoliosis, pectus carinatum, pectus excavatum, arachnodactyly, hindfoot deformity, pes planus, protrusio acetabuli, spondylolisthesis.
Cardiovascular: Aortic root dilatation, aortic aneurysm, aortic dissection, aortic insufficiency, mitral valve prolapse, endocarditis.
Ophthalmologic: Ectopia lentis, retinal detachment, cataracts, glaucoma, myopia, amblyopia, strabismus.
Neurologic: Dural ectasia.
Pulmonary: Spontaneous pneumothorax, emphysema, restrictive lung disease, sleep apnea.
Dental: Posterior crossbite, TMJ symptoms.
Just as there is genotypic and phenotypic heterogeneity in patients with EDS, so too is there variability in the clinical course of disease. Median survival of patients with vascular EDS (type IV) is 48 years.
Musculoskeletal: Arthralgia, articular subluxation, muscle spasms, chronic pain, kyphoscoliosis.
Cardiovascular: Aortic dissection or aneurysm, arterial rupture.
Neurologic: Autonomic dysfunction (e.g., hypotension and postural orthostatic tachycardia syndrome [POTS]).
Dermatologic: Easy bruisability, scarring, skin fragility.
Hematologic: Prolonged bleeding.
Dental: TMJ symptoms, periodontal disease, friable oral mucosa and gingiva.
Ophthalmologic: Retinal detachment, globe rupture secondary to trauma.
Gastrointestinal: Intestinal perforation.
Gynecologic: Uterine rupture.
Musculoskeletal: Kinesiophobia (the avoidance of painful movements) can lead to muscle deconditioning, loss of function and mobility, and assumption of abnormal postures. Patients may develop chronic, widespread pain.
Neurologic: Some patients may develop autonomic dysfunction as manifested by syncope, palpitations, orthostasis, and POTS. There appears to be an association between JHS and carpal tunnel syndrome, although a causative relationship in either direction has not been elucidated at this time.
Dermatologic: Striae atrophicae usually form in adolescence, whereas striae gravidarum tend not to develop during pregnancy. Papyraceous scars may form.
Gastrointestinal: Hiatal hernias can cause GERD. Abdominal wall hernias may also occur.
Gynecologic: Parous women may develop uterine prolapse, rectal prolapse, rectocele, or cystocele.
Psychiatric: Depression and anxiety may be associated with chronic pain.
How to utilize team care?
Multidisciplinary team care is critical to the successful management of patients with MFS, EDS, and JHS.
Dentistry and orthodontics.
Obstetrics and gynecology/maternal fetal medicine.
Dentistry, orthodontics, and endodontics.
Obstetrics and gynecology/maternal fetal medicine.
Are there clinical practice guidelines to inform decision making?
MFS and EDS
Clinical practice guidelines for the diagnosis and management of patients with thoracic aortic disease help inform decision making. These guidelines were published in 2010 as a combined effort of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine.
There are no clinical practice guidelines at the time of this writing to inform decision making in JHS.
What is the evidence?
Aktas, I, Ofluoglu, D, Albay, T. "The relationship between benign joint hypermobility syndrome and carpal tunnel syndrome". Clin Rheumatol.. vol. 27. 2008. pp. 1283-7..
Beighton, P, De Paepe, A, Steinmann, B, Tsipouras, P, Wenstrup, RJ. "Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK)". Am J Med Genet.. vol. 77. 1998. pp. 31-7..
Beighton, P, Solomon, L, Soskolne, CL. "Articular mobility in an African population". Ann Rheum Dis.. vol. 32. 1973. pp. 413-8..
De Paepe, A, Devereux, RB, Dietz, HC, Hennekam, RC, Pyeritz, RE. "Revised diagnostic criteria for the Marfan syndrome". Am J Med Genet.. vol. 62. 1996. pp. 417-26..
Fernandes, NF, Schwartz, RA. "A "hyperextensive" review of Ehlers-Danlos syndrome". Cutis.. vol. 82. 2008. pp. 242-8..
Ferrell, WR, Tennant, N, Sturrock, RD, Ashton, L, Creed, G, Brydson, G. "Amelioration of symptoms by enhancement of proprioception in patients with joint hypermobility syndrome". Arthritis Rheum. vol. 50. 2004. pp. 3323-8.
Grahame, R, Bird, HA, Child, A. "The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS)". J Rheumatol.. vol. 27. 2000. pp. 1777-9..
Hakim, AJ, Grahame, R. "A simple questionnaire to detect hypermobility: an adjunct to the assessment of patients with diffuse musculoskeletal pain". Int J Clin Pract.. vol. 57. 2003. pp. 163-6..
Hakim, AJ, Grahame, R. "Non-musculoskeletal symptoms in joint hypermobility syndrome. Indirect evidence for autonomic dysfunction". Rheumatology (Oxford).. vol. 43. 2004. pp. 1194-5..
Judge, DP, Dietz, HC. "Marfan's syndrome". Lancet.. vol. 366. 2005. pp. 1965-76..
Loeys, BL. "The revised Ghent nosology for the Marfan syndrome". J Med Genet. vol. 47. 2010. pp. 476-485.
Malfait, F, Wenstrup, RJ, De Paepe, A. "Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type". Genet Med.. vol. 12. 2010. pp. 597-605..
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