Ehlers-Danlos syndrome, classic type

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: COL5A1 (HGNC:2209) COL5A2 (HGNC:2210)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 02/17/2025
• Curation Status: Released (2.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
COL5A1	Ehlers-Danlos syndrome, classic type (0007522)	130000	Moderate Actionability
COL5A2	Ehlers-Danlos syndrome, classic type (0007522)	130010	Moderate Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric. Given the limited effectiveness data in individuals with Ehlers-Danlos syndrome, classic type, effectiveness data were extrapolated from Ehlers-Danlos syndrome, hypermobility type.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Ehlers-Danlos syndrome, classic type-related morbidity / Referral to specialists for symptom management and anticipatory guidance	2	3N	1D	3	9ND

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of Ehlers-Danlos syndrome, classic type is estimated at 1 in 20,000. However, it is likely that some individuals with milder manifestations of the disease, may go undetected.

Clinical Features (Signs / symptoms)

Classic EDS (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and generalized joint hypermobility. Skin may be soft, velvety, doughy, and fragile. Areas over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin) are easily split following relatively minor trauma. Wound healing is poor, and stretching, thinning, and pigmentation of scars is characteristic, leading to atrophic and/or hemosiderotic scars. Other dermatologic features may include molluscoid pseudotumors, subcutaneous spheroids, piezogenic papules, elastosis perforans serpinginosa, acrocyanosis and chilblains. 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 joint and limb pain, foot deformities, temporomandibular joint dysfunction, joint effusions, and osteoarthritis. Other features may include mild muscle hypotonia with delayed motor development, problems with ambulation, fatigue and muscle cramps, skeletal morphologic alterations (scoliosis, pectus deformities, genus/hallux valgus, pes planus, clubfoot), epicanthal folds, prolonged bleeding, and easy bruising. Structural cardiac malformations are uncommon in cEDS. Mitral valve prolapse, and less frequently tricuspid valve prolapse, and aortic root dilatation may occur. Arterial aneurysm and rupture, along with intracranial aneurysms and arteriovenous fistulae may occur in the rare individual with severe cEDS. Classic EDS bears risk for newborns and mothers including premature rupture of membranes/prematurity, cervical insufficiency, perineal tearing during labor, postpartum hemorrhage, pelvic prolapse, and incontinence following delivery may occur.

Natural History (Important subgroups & survival / recovery)

Clinical presentation may occur anywhere between birth to childhood. In childhood, bruising, skin fragility, and abnormal scarring are common signs. Muscle hypotonia, delayed gross motor development, and hip dislocations can be early presentations of the disorder. Rectal prolapse may be the presenting symptom for young children. Joint hypermobility depends on age, gender, family, and ethnic background. It is usually noted when a child starts to walk. When aortic dilation does occur, it appears to be more common in young individuals and rarely progresses. Mitral valve prolapse is rarely severe. Medical or surgical intervention is rarely necessary for either. Slow wound healing leads to increased frequency of infection. Life expectancy can be shortened due to the possibility of vessel rupture but is otherwise not affected.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

1-2 in 50000

Approximately 81% of individuals with cEDS have a pathogenic variant in the COL5A1 and 16% have a pathogenic variant in COL5A2.

Tier 3

1-2 in 50000

Approximately 50% of individuals with cEDS have a de novo pathogenic variant.

Tier 4

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Penetrance is presumably 100% in both males and females.

Tier 4

>= 40 %

Two reviews of manifestations in individuals with cEDS included 171 individuals with a mean age at presentation of 30.5 years (± 20.7 years). Reported frequencies of the most common features were:

Cutaneous features

• Skin hyperextensibity 94.5%

• Easy bruising 59.7%

• Skin fragility 67.4%

• Soft, doughy skin 81%

• Piezogenic papules 80.6%

• Abnormal scarring 96%Extracutaneous features

• Joint hypermobility 77%

• Pes planus 87.3%

• Scoliosis 76.3%

• Blue/gray sclera 56.5%

• Sprain 57.4%

• Subluxation/dislocation 62.8%

• Hypotonia/weakness 12.5%

• Joint pain 46%

• Cardiovascular (early onset varicose veins, valvular issues, arterial tortuosity, fistulae, murmurs and bundle-branch blocks) 63.4%

• Chronic pain 43.1%

• Gastrointestinal (constipation, diarrhea, irritable bowel syndrome, reflux and/or hepatitis) 66.7%

• Ocular (myopia, astigmatism, keratoconus, cornea perforation, lens dislocation, glaucoma, and/or scleral ectasia) 65.7%

Tier 5

5-39 %

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. One individual had a moderate-to-severe valvular anomaly.

Tier 3

5-39 %

In a systematic review of vascular complications in 110 individuals with cEDS, 11% of individuals reported vascular complications including hematoma (3%), intracranial hemorrhage (1%), arterial dissection (7%), arterial aneurysm (3%) and GI bleeding (1%). Three adults died from rupture of a large or medium-sized artery (mean age: 35 years, range 28-43 years) and one 9-year-old died from multiorgan failure secondary to the rupture of an aneurysm of the superior mesenteric artery.

Tier 1

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on relative risk was identified.

Expressivity

Pathogenic variants in COL5A2 are thought to result in a phenotype at the more severe end of the cEDS spectrum.

Tier 3

The severity, specific manifestations, and progression of cEDS are variable. Intrafamilial phenotypic variability is observed.

Tier 4

Abnormal scarring can range in severity, ranging from mild to extensive scarring at multiple sites.

Tier 4

Intervention Effectiveness

Patient Management

To establish the extent of disease in an individual diagnosed with cEDS the following evaluations are recommended:

• Clinical examination of the skin with assessment of skin hyperextensibility, atrophic scars and bruises, and other manifestations of cEDS

• Evaluation of joint mobility with use of Beighton score

• Evaluation for hypotonia and motor development in infants and children

• Evaluation for easy bruising and/or prolonged bleeding

• Evaluation of clotting factors if severe easy bruising is present

• Baseline echocardiogram with aortic diameter measurement

• Genetic counseling by genetics professionals

Tier 4

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Treatment and management are symptomatic and preventative. This ideally involves multidisciplinary care by specialists in relevant fields.

Tier 4

The first principle of skin management is prevention of injury. This should focus on protective clothing; appropriate pads over bony prominences (elbows, knees, shins and knuckles) and patient education. Nonadherent dressings should be used on lacerations whenever possible to avoid further trauma to the skin. Wounds should be reapproximated and fixed in place with adhesive tape or sutures. Compression dressings should be applied, and if adhesive is required, the dressing should be thoroughly soaked before removal. For small lacerations not under tension, cyanoacrylate adhesives are more appropriate. Where sutures are required, care should be taken to maximize perfusion of skin edges, and any compressive or high-tension sutures should be avoided. Skin wounds should be closed without tension, in two layers with generous deep sutures. Sutures should be left in place for twice as long as normal. Surgeons or physicians with EDS experience should be sought when the wound is under significant tension, particularly large, in an area of low vascular supply, or in an area of high cosmetic or functional importance. However, there is a paucity of evidence regarding clinical management of skin fragility and wounds in EDS, with most studies reporting single cases, small case series or limited cohort studies.

Tier 2

The mainstay of treatment is joint protection by activity modification and joint-stabilization exercises, as surgical options are often unsuccessful. Braces are useful to improve joint stability. Referral for knee, ankle, ring, wrist, or thumb braces as needed. A soft neck collar may help with neck pain and headaches. A wheelchair or scooter can be used to decrease stress on lower-extremity joints. A waterbed, adjustable air mattress, or viscoelastic foam mattress may increase support for improved sleep quality and less pain.

Tier 4

A physiotherapeutic program is recommended for children with hypotonia and/or delayed motor development. 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.

Tier 4

A study evaluating the use of resistance training on muscle function in three individuals with genetically verified cEDS, reported that strength training 3 times a week for 4 months improved tendon and muscle properties. Mean isometric leg extension force and leg extensor power both increased by 8 and 11%, respectively. Tendon stiffness increased in response to physical training and training loads both in upper and lower body exercises increased by around 30%. When testing balance, the average sway-area of the participants decreased by 26%. Subjective fatigue also decreased.

Tier 5

A prospective, randomized controlled clinical trial compared an 8-week exercise program performed into either the full hypermobile range or only to neutral knee extension. Children with joint hypermobility syndrome and knee pain (n=26) aged 7-16 years were randomly assigned to the hypermobile (n=12) or neutral (n=14) treatment group. Statistically significant pre-post improvements were made in thigh strength, child report of knee pain, and parent-reported physical and psychosocial summary scores in both treatment groups.

Tier 5

Oral vitamin C supplementation is often recommended to patients with EDS to reduce the severity of bruising and promote healing.

Tier 2

DDAVP (desmopressin) may be useful to normalize bleeding time. DDAVP may be beneficial with bruising or epistaxis, or before procedures such as dental extractions.

Tier 4

A retrospective chart review of children with clinically diagnosed EDS (unspecified type) referred for bleeding symptoms included 19 children who had a desmopressin challenge. Mean bleeding time decreased from 11.26 (+/-4.39) minutes to 5.95 (+/-2.41) minutes with treatment (P < 0.01). Only four individuals failed to have a fully correctable bleeding time; however, two of these had substantial improvement.

Tier 5

Women with cEDS should receive multidisciplinary input from obstetricians, geneticists, cardiology and rheumatology/orthopedics for pregnancy planning. 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. Physiotherapist referral should be made to address pelvic instability and pain. Echocardiography should be completed to monitor for known aortic root dilation. Monitoring for IUGR and preterm labor is warranted. Cervical insufficiency should be anticipated and sought at each prenatal visit, with consideration of imaging at 16-20 weeks gestation to determine cervical length. For vaginal delivery, prompt episiotomy should be considered to prevent excessive perineal damage and should be repaired by an experienced individual. Prophylactic desmopressin and tranexamic acid, along with postpartum oxytocin, should be considered in view of the increased risk for postpartum hemorrhage.

Tier 4

Considerations during surgery and use of anesthesia for EDS subtypes include: care during placement of spinal anesthesia to avoid post-dural puncture headache; monitoring of neuromusucular blockade; careful interoperative positioning with optimal padding, reduction of shear forces, and protection of eyes; adhesive tapes should be easily removable and avoided when possible; careful preparation of airway/ventilation; careful transport and mobilization; and avoidance of tourniquets, central venous catheters, and arterial lines.

Tier 4

Bone mineral density scans (DEXA) should be considered in all adults with EDS.

Tier 4

Surveillance

The following surveillance is recommended:

• Assessment for skin fragility at each visit

• Assessment for joint instability, occupational and physical therapy needs, mobility issues and pain at each visit

• Evaluation for hypotonia and motor development in infants and children at each visit

• Assessment for easy bruising and/or prolonged bleeding at each visit

• Evaluation of clotting factors if severe easy bruising is present

• In children with normal initial echocardiogram, frequency of follow up per pediatric cardiologist

• In adults with normal initial echocardiogram, no follow-up echocardiogram necessary

Tier 4

At routine physician visits, patients should be evaluated for gastrointestinal symptoms, sleep difficulties, pain and headache.

Tier 4

Circumstances to Avoid

To prevent skin injury, individuals should avoid contact, collision and combative sports.

Tier 2

Individuals should avoid sports with heavy joint strain such as contact sports, fighting sports, football and running. Activities that cause joints to overextend (e.g., pitching, racquet sports, gymnastics) should also be avoided. Undue trauma and excessive stretching 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

Nature of Intervention

Nature of Intervention

Interventions include exercise, echocardiogram, increased perinatal surveillance, and avoidance of factors that may cause damage to skin or joints.

Context: Adult Pediatric

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.

Context: Adult Pediatric

Classic EDS shows some clinical overlap with other EDS types as well as other inherited connective tissue disorders.

Context: Adult Pediatric

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			COL5A1			130000	0007522	0019567
COL5A2			130010	0007522	0019568

References List

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Classical Ehlers-Danlos syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=287

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