Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released 1.1.2

Condition: Ehlers-Danlos syndrome, classic type
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Condition Pairs(s)
Final Assertion
COL5A10007522 (ehlers-danlos syndrome, classic type)
Assertion Pending
COL5A20007522 (ehlers-danlos syndrome, classic type)
Assertion Pending
Actionability Rationale
This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Condition Pairs: COL5A1 0007522 (OMIM:130000) COL5A2 0007522 (OMIM:130010)
Musculoskeletal morbidity / Physical/occupational therapy program
Perinatal complications / High-risk pregnancy management

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Condition
The prevalence of Ehlers-Danlos Syndrome (EDS) type I is estimated at 1 in 20,000. However, it is likely that some individuals with milder manifestations of the disease, previously classified as EDS type II, may go undetected.
Clinical Features
(Signs / symptoms)
Previously EDS types I and II were classified separately for different phenotypic severity, but are now recognized as a continuum of findings and termed classic EDS. Classic EDS is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility. Affected individuals skin is smooth/velvety, hyperelastic, and fragile. Areas over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin) are easily split following relatively minor trauma. These wounds have delayed healing and often have stretching of scars after apparently successful healing. Other dermatologic features may include molluscoid pseudotumors (fleshy, heaped-up lesions associated with scars over pressure points) and subcutaneous spheroids (small, cyst-like nodules over the bony prominences of the arms and legs caused by calcified fat deposits). Manifestations of generalized tissue extensibility and fragility are observed in multiple organs including: cervical insufficiency during pregnancy, inguinal/umbilical hernia, hiatal/incisional hernia, or recurrent rectal prolapse in early childhood. Other problems related to joint hypermobility and instability may include: sprain, dislocations/subluxations (usually resolve spontaneously or are easily managed), chronic pain, foot deformities, temporomandibular joint dysfunction, joint effusions, and osteoarthritis. Other features may include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Structural cardiac malformations are less common in classic EDS than other forms of EDS. Mitral valve prolapse, and less frequently tricuspid valve prolapse, and aortic dilation may occur, but medical or surgical intervention is rarely necessary. Spontaneous rupture of large arteries, along with intracranial aneurysms and arteriovenous fistulae may occur in the rare individual with a severe form of classic EDS.
Classic EDS bears risk for newborns and mothers including: premature rupture of membranes/prematurity when mother or baby are affected, breech presentation (when the baby is affected) leading to dislocation of the hips or shoulder of the newborn, tearing of the perineal skin by forceps and, after delivery, extension of episiotomy incisions and prolapse of the uterus and/or bladder may occur when mother is affected.
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Natural History
(Important subgroups & survival / recovery)
Onset of EDS class is typically during the neonatal, infancy, or childhood periods. However, some individuals may have a mild phenotype and may go undiagnosed. Muscle hypotonia, delayed gross motor development, and hip dislocations can be early presentations of the disorder. Joint hypermobility depends on age, gender, family, and ethnic background. It is usually noted when a child starts to walk. Hyperflexibility of the skin is difficult to assess in young children due to abundant subcutaneous fat. When aortic dilation does occur, the dilations tend to be of little clinical consequence and the mitral valve prolapse is rarely severe. Medical or surgical intervention is rarely necessary for either. Overall mortality Is not significantly reduced in classic EDS, but has significant morbidity.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease in an individual diagnosed with classic EDS the following evaluations are recommended:
• Clinical examination of the skin with assessment of skin hyperextensibility, atrophic scars and bruises, and other manifestations of classic EDS
• Evaluation of joint mobility with use of Beighton score
• Evaluation of clotting factors if severe easy bruising is present
• Baseline echocardiogram
• Baseline ophthalmologic evaluation (Tier 4)
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Supportive therapy of joints and musculature by isotonic training at home after physiotherapeutic instructions. Physical or occupational therapists can instruct on proper joint use within normal range of motion as well as gentle muscle strengthening. Non-weight-bearing exercise, such as swimming is useful to promote muscular development, strength, and coordination. Low-resistance activities and hydrotherapy may also be beneficial. (Tier 4)
No evidence related to the use of exercise/physical therapy in classic EDS was identified. A systematic review of therapeutic exercise in joint hypermobility syndrome (JHS) identified four studies (two randomized trials and 2 cohort studies) including 142 patients. There was no consistent evidence that exercise was better than control or that joint-specific and generalized exercise differed in effectiveness. (Tier 1)
A study of 12 women with EDS-HT and chronic pain were offered multidisciplinary management including two and a half weeks in a rehabilitation unit (consisting of testing, physical training, group discussions, and lectures) followed by individual home exercise for three months with weekly guidance from a physiotherapist. Participants had statistically significant improvements in perceived performance of daily activities, muscle strength and endurance, and a reduction in kinesiophobia. The participants also reported increased participation in daily life. (Tier 5)
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Individuals should carry an emergency health card noting information about the diagnosis, possible complications, and therapeutic measures. (Tier 4)
When skin tears occur, irregularly frayed wound margins should be excised and precisely adapted to allow rapid healing without dystrophic scarring which is especially important in the case of facial wounds; numerous fine, atraumatic stitches should be used and left in place for twice as long as usual. (Tier 4)
Ascorbic acid (vitamin C) may reduce easy bruising but has no effect on the primary findings of skin hyperextensibility, atrophic scarring, and joint hypermobility. In general, a dose of two grams per day is recommended for adults. (Tier 4)
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Because of the increased risk of skin lacerations, postpartum hemorrhages, and prolapse of the uterus and/or bladder, monitoring of women throughout pregnancy and in the postpartum period is recommended. Monitoring for preterm labor is warranted during the third trimester when the risk of premature rupture of the membranes is increased. Cervical incompetence should be anticipated and sought at each prenatal visit, with consideration of imaging at 16-20 weeks gestation to determine cervical length. (Tier 4)
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Particular considerations during surgery and use of anesthesia include: particular care during placement of spinal anesthesia to avoid post-dural puncture headache; monitoring of neuromusucular blockade; interoperative patient positioning with optimal padding, reduction of shear forces, and protection of eyes; adhesive tapes should be easily removable and avoided when possible to avoid skin damage; careful preparation of airway/ventilation to avoid pressure; careful transport and mobilization; and avoidance of tourniquets, central venous catheters, and arterial lines. (Tier 4)
After surgical interventions and other dermal wounds, wounds should be closed without tension, preferably in two layers; deep stitches should be applied generously and cutaneous sutures left in place for twice as long as usual. The borders of adjacent skin should be taped carefully to prevent stretching of the scar. Superficial wounds can be closed with butterfly bandages or dermal glue. Wounds should be closely monitored for dehiscence and inadequate scar formation. (Tier 4)
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Bone mineral density scans (DEXA) should be considered in all adults with EDS. (Tier 4)
Supportive stockings can be worn in classic EDS to help protect the shins. Elbow and/or knee pads may also be of benefit to prevent significant bruising, fragility tears, and atrophic scarring. (Tier 4)
At routine physician visits, patients should be evaluated for gastrointestinal symptoms, sleep difficulties, pain and headache, and symptoms of depression and anxiety. (Tier 4)
Guidelines are mixed with regard to monitoring aortic dilation with some recommending monitoring every 6-24 months and others stating echocardiogram is warranted only if an abnormality such as aortic dilation or mitral valve prolapse is present on baseline echocardiogram.(Tier 4)
A cohort of 27 individuals with classic and hypermobile EDS underwent an average of 6 echocardiograms in early childhood (≤14 years), as well in late childhood or adulthood (>14 years). Seven individuals were found to have dilated aortic roots before age 14 (including one patients with classic EDS), and only one individual (with hypermobile EDS) continued to show dilation after age 14. The patient whose aorta remained dilated was placed on a beta blocker and remained on it throughout the study period. None of the remaining individuals were prescribed medication because their aortas were just above the normal range. No patients had symptoms of their dilated aortic roots, and serial measurements did not indicate significant progression in these six patients. No patient with a normal aortic root in childhood had development of dilation in later childhood or adulthood.(Tier 5)
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Circumstances to Avoid
Individuals should avoid sports with heavy joint strain such as competitive and contact sport activities and activities that cause joints to overextend (e.g., pitching, gymnastics). When individuals do participate in sporting events, legs, arms, and face should be protected with athletes’ pads or bandages to avoid traumatic skin injuries leading which could lead to ugly scars. (Tier 4)
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Aspirin should be avoided. (Tier 4)
Excessive sun exposure should be avoided to prevent damage to the skin. (Tier 4)
Scar revision (vanishing) products should also be avoided as the breakdown of the scar tissue can result in atrophic scarring. (Tier 4)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Variants
No information on the prevalence of classic EDS mutations was identified; however, mutations of COL5A1 and COL5A2 are estimated to make up 50% of classic EDS, which has a prevalence estimated around 1 in 20,000. However, this number may be an underestimate given no prospective studies of COL5A1 and COL5A2 have been performed in a clinically well-defined group. (Tier 3)
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(Include any high risk racial or ethnic subgroups)
Mutations for EDS are considered fully penetrant. (Tier 4)
Information on penetrance was only available from individuals clinically suspected of having classic EDS.
Clinical features were examined in a study of 40 patients with suspected classic EDS from 28 families (26 probands were identified to have a COL5A1 or COL5A2 mutation). The following clinical features were identified: hyperextensible skin (39/40), skin fragility with defective scarring (38/40), and joint hypermobility (32/40). A history of recurrent/sporadic dislocations/subdislocations was present in 60% of patients. Cardiovascular signs were present among some patients including valvular regurgitation (7/40) and mitral valve prolapse (6/40). Other identified features included chronic fatigue syndrome (8/40), gastroesophageal reflux (6/40), hypotonia at birth (5/40), hernias (4/40), and delayed motor development (2/40). Neither severe aneurysmatic dilation nor arterial rupture was present in any patient. (Tier 5)
A retrospective review of patients with EDS undergoing screening echocardiography showed that at a median age of 16 years, 3/50 (6%) patients with classic EDS had aortic dilation at their first echocardiogram. No individual had a rupture of their aorta or any other blood vessel or aortic root replacement. (Tier 3)
Relative Risk
(Include any high risk racial or ethnic subgroups)
No information on relative risk was identified.
Inter- and intra-familial variability in the severity of the phenotype can be great. (Tier 4) In some families with a null variant, an affected family member can have a very mild classic phenotype while other family members may have a severe phenotype. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions include exercise, echocardiogram, increased perinatal surveillance, and avoidance of factors that may cause damage to skin or joints.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Some individuals may have a mild clinical phenotype that may escape clinical detection. Many of those affected wait for years and have seen multiple health care providers before some of the symptoms are ultimately recognized as features of an overall disorder.
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Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Condition Associations
Condition Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. F Malfait, R Wenstrup, A De Paepe. Ehlers-Danlos Syndrome, Classic Type. 2007 May 29 [Updated 2011 Aug 18]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from:
2. Tinkle BT, Atzinger CL. Ehlers-Danlos Syndrome. Management of Genetic Syndromes (Third Edition). Publisher: John Wiley & Sons, Inc. (2010) Accessed: 2016-11-01. Website:
3. Ritelli M, Dordoni C, Venturini M, Chiarelli N, Quinzani S, Traversa M, Zoppi N, Vascellaro A, Wischmeijer A, Manfredini E, Garavelli L, Calzavara-Pinton P, Colombi M. Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. Orphanet J Rare Dis. (2013) 8:58.
4. Wiesmann T, Malfait F, Castori M. Anesthesia recommendations for patients suffering from Ehlers-Danlos Syndrome. Orphan Anesthesia. Publisher: Orphanet. (2013) Accessed: 2016-11-01. Website:
5. Bathen T, Hangmann AB, Hoff M, Andersen LO, Rand-Hendriksen S. Multidisciplinary treatment of disability in ehlers-danlos syndrome hypermobility type/hypermobility syndrome: A pilot study using a combination of physical and cognitive-behavioral therapy on 12 women. Am J Med Genet A. (2013) 161A(12):3005-11.
6. Mayer K, Kennerknecht I, Steinmann B. Clinical utility gene card for: Ehlers-Danlos syndrome types I-VII and variants - update 2012. Eur J Hum Genet. (2013) 21(1).
7. Palmer S, Bailey S, Barker L, Barney L, Elliott A. The effectiveness of therapeutic exercise for joint hypermobility syndrome: a systematic review. Physiotherapy. (2014) 100(3):220-7.
8. Atzinger CL, Meyer RA, Khoury PR, Gao Z, Tinkle BT. Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome. J Pediatr. (2011) 158(5):826-830.
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