Classical Ehlers-Danlos Syndrome · cEDS

Description

Classical Ehlers-Danlos syndrome is a heritable connective tissue disorder caused by defects in type V collagen. Pathogenic variants in COL5A1 or COL5A2 account for most cases. A specific arginine-to-cysteine substitution in type I collagen, COL1A1 c.934C>T (p.Arg312Cys), causes a small subset with a classical phenotype. Inheritance is autosomal dominant. Reported prevalence is approximately 1 in 20,000 to 1 in 40,000.

The 2017 international classification, published by Malfait and colleagues in the American Journal of Medical Genetics Part C, defines classical EDS by three major criteria: skin hyperextensibility, atrophic scarring, and generalized joint hypermobility measured by the Beighton score. Atrophic scars often appear at sites of minor trauma, classically over the knees, shins, elbows, forehead, and chin, and have a thin, papery, or cigarette-paper quality. Minor criteria include easy bruising, soft doughy skin, skin fragility with splitting at pressure points, molluscoid pseudotumors, subcutaneous spheroids, hernias, epicanthal folds, and a positive family history. The diagnosis requires the first major criterion plus either the second or third, with additional minor criteria supporting the assessment.

Vascular complications are uncommon in classical EDS and are far less frequent than in vascular EDS. Aortic root dilation has been reported and warrants baseline echocardiography. Pregnancy carries elevated risk for preterm rupture of membranes when the fetus inherits the variant.

Diagnosis is genetic. Targeted sequencing or a connective-tissue panel covering COL5A1, COL5A2, and the COL1A1 arginine-to-cysteine variant identifies a pathogenic variant in roughly 90 percent of people who meet clinical criteria. Negative genetic testing in a person who meets clinical criteria does not exclude the diagnosis. The differential should then be reviewed, including classical-like EDS and other heritable connective tissue disorders.

Treatments to date

There is no disease-modifying therapy for classical EDS. Care is supportive and is organized around tissue fragility, joint instability, and surveillance.

Skin protection reduces wound burden. Sun protection, padding over vulnerable sites for children at risk of frequent falls, and prompt attention to lacerations limit scar accumulation. Surgical wound closure follows specific principles. Sutures are placed without tension, deep dermal layers are approximated, and external sutures are left in place roughly twice as long as standard practice. Adhesive strips support the wound after suture removal. Surgeons familiar with the diagnosis plan accordingly.

Physical therapy oriented to joint stability, proprioception, and low-impact strengthening is the standard musculoskeletal intervention. High-impact activities are typically modified to reduce dislocation and soft-tissue injury risk. Bracing supports unstable joints when needed.

Cardiovascular surveillance with baseline echocardiography is recommended at diagnosis. Repeat imaging follows the findings. Pregnancy is managed by maternal-fetal medicine when the diagnosis is known, with attention to preterm membrane rupture and tissue handling at delivery.

Pain, fatigue, and autonomic symptoms are managed alongside the structural manifestations. Genetic counseling addresses the autosomal dominant inheritance pattern and reproductive options. No FDA-approved drug targets the underlying collagen defect; preclinical work on collagen-stabilizing approaches remains in early stages.