Orthopaedic Surgery - Ehlers–Danlos Syndrome

Basics

Ehlers–Danlos syndrome (EDS) refers to a heterogeneous group of inherited connective-tissue disorders caused by abnormalities affecting collagen or collagen-related proteins.

These abnormalities produce varying degrees of joint hypermobility, skin hyperextensibility and fragility, abnormal wound healing, easy bruising, and involvement of the cardiovascular, ocular, skeletal, and other organ systems.

At least 13 recognized subtypes have been described, each with a characteristic combination of clinical manifestations, inheritance patterns, and molecular abnormalities.

The age at diagnosis ranges from infancy to adulthood, depending on the severity and phenotype.

Classification

EDS encompasses several clinically and genetically distinct disorders.

Important phenotypes include classical, classical-like, cardiac-valvular, vascular, hypermobile, arthrochalasia, dermatosparaxis, kyphoscoliotic, brittle cornea, spondylodysplastic, musculocontractural, myopathic, and periodontal EDS.

Classical EDS

Classical EDS is characterized primarily by skin hyperextensibility, generalized joint hypermobility, easy bruising, and abnormal scar formation.

Subcutaneous spheroids and hernias may also occur.

Classical-Like EDS

Classical-like EDS resembles the classical form, with prominent skin and joint manifestations, but differs in its underlying genetic abnormality and certain clinical features.

Cardiac-Valvular EDS

Cardiac-valvular EDS is characterized by progressive valvular heart disease, together with connective-tissue manifestations such as skin hyperextensibility and joint abnormalities.

Chest-wall deformities such as pectus excavatum may also occur.

Vascular EDS

Vascular EDS is one of the most serious forms.

Patients are predisposed to arterial aneurysm, dissection, and rupture, sometimes at a young age.

Spontaneous rupture of hollow organs, particularly the bowel or uterus, may also occur.

Unlike some other EDS variants, generalized joint hypermobility may be less prominent.

Hypermobile EDS

Hypermobile EDS is characterized predominantly by generalized joint hypermobility, recurrent instability or dislocation, and chronic musculoskeletal pain.

Skin manifestations are usually less severe than in classical EDS.

Arthrochalasia EDS

Arthrochalasia EDS is associated with severe generalized joint hypermobility, congenital bilateral hip dislocation, muscle hypotonia, and recurrent joint instability.

Dermatosparaxis EDS

Dermatosparaxis EDS is characterized by extreme skin fragility and easy bruising.

Patients may also demonstrate short stature, redundant skin, and umbilical or other hernias.

Kyphoscoliotic EDS

Kyphoscoliotic EDS commonly presents with congenital muscular hypotonia, early-onset progressive kyphoscoliosis, generalized joint hypermobility, and recurrent subluxation or dislocation.

Reduced bone mass and osteoporosis may also be present.

Brittle Cornea Syndrome

Brittle cornea syndrome is distinguished by marked corneal thinning and fragility, which may predispose to serious ocular complications.

Musculoskeletal hypermobility may also occur.

Spondylodysplastic EDS

Spondylodysplastic EDS may present with short stature, muscle hypotonia, skeletal dysplasia, and bowing of the limbs.

Musculocontractural EDS

Musculocontractural EDS is characterized by multiple congenital contractures, distinctive craniofacial features, and characteristic abnormalities of the skin and connective tissues.

Myopathic EDS

Myopathic EDS often presents with congenital muscle hypotonia, proximal joint contractures, and hypermobility of more distal joints.

Periodontal EDS

Periodontal EDS is characterized particularly by severe early-onset periodontal disease, together with variable joint and skin manifestations.

General Prevention

EDS itself cannot be prevented, but many serious complications can be reduced through anticipatory surveillance and modification of risk.

Particular attention should be directed toward prevention of vascular rupture, excessive bleeding, recurrent joint dislocation, skin injury, and progressive spinal deformity.

Joint Protection

Patients should avoid activities that repeatedly force joints beyond their physiologic range.

Education regarding safe movement patterns, proprioception, and muscle conditioning can reduce the frequency of instability episodes.

Cardiovascular Protection

Individuals with vascular or cardiac involvement require appropriate cardiovascular surveillance.

Early recognition of aneurysm, arterial dissection, or progressive valvular disease is especially important.

Epidemiology

EDS affects both males and females.

Overall prevalence has historically been estimated at approximately 1 in 5,000 individuals, although prevalence varies considerably according to subtype and may be underestimated because milder cases are often unrecognized.

No consistent racial predilection has been established.

Risk Factors

The principal risk factor is a positive family history of EDS or characteristic manifestations, such as marked hypermobility, vascular rupture, unusual skin fragility, or recurrent joint dislocation.

However, some patients have a new pathogenic variant and therefore lack an affected relative.

Genetics

The inheritance pattern varies according to EDS subtype.

Some forms are inherited in an autosomal dominant pattern, while others are autosomal recessive.

De novo pathogenic variants can also occur, so the absence of a family history does not exclude EDS.

Molecular Abnormalities

Different subtypes result from abnormalities in various collagen molecules or proteins involved in collagen processing and extracellular matrix organization.

For example, classical EDS is commonly related to abnormalities of type V collagen, while vascular EDS results from pathogenic variants affecting type III collagen.

Other forms may involve type I collagen or other matrix-associated proteins.

Etiology

EDS results from inherited abnormalities that interfere with the normal structure, production, processing, or organization of collagen and related connective-tissue proteins.

Because collagen is present throughout the body, manifestations can involve the skin, joints, blood vessels, eyes, gastrointestinal tract, and other organs.

Diagnosis

General Principles

The diagnosis is based on the clinical phenotype, family history, and established diagnostic criteria, with molecular testing used to confirm many EDS subtypes.

Evaluation by a medical geneticist or clinician experienced in hereditary connective-tissue disorders is often appropriate.

Signs

Common findings include hyperextensible skin, easy bruising, generalized joint hypermobility, recurrent joint instability, and spinal deformity.

Some patients can place their joints into positions far beyond the normal physiologic range.

Symptoms

Patients frequently report multiple joint pains, recurrent sprains or dislocations, and diffuse or poorly localized musculoskeletal discomfort.

Chronic pain may arise from repetitive instability and soft-tissue injury.

Physical Examination

General Inspection

Height and body proportions should be documented.

The patient should be examined for skeletal disproportions, chest-wall abnormalities, limb deformity, and other features that may suggest a particular subtype.

Joint Range of Motion

Joint motion should be measured systematically.

Particular attention should be paid to hyperextension of the fingers, elbows, and knees, as well as excessive motion at other joints.

Joint Stability

The shoulders, elbows, knees, ankles, and other symptomatic joints should be assessed for instability, recurrent subluxation, or dislocation.

Skin Examination

The examiner should assess the texture, elasticity, fragility, and extensibility of the skin.

Bruising, abnormal scars, or areas of previous wound breakdown should be noted.

Ocular Examination

Visual symptoms should prompt formal ophthalmologic evaluation.

Certain EDS-related disorders may cause corneal abnormalities or other potentially serious ocular manifestations.

Spine Examination

The patient should be examined for kyphosis, scoliosis, or other spinal deformity.

A forward-bend test can help detect rotational prominence associated with scoliosis.

Diagnostic Testing

Molecular Testing

Genetic testing is available for many, although not all, EDS subtypes.

Testing should ideally be performed through an experienced genetics service capable of interpreting variants in the context of the patient’s phenotype.

Bone Quality

Patients with EDS may have impaired bone quality even when conventional bone mineral density is relatively preserved.

Measures of trabecular bone microarchitecture may therefore provide additional information about skeletal strength in selected patients.

Imaging

Cardiovascular Imaging

Patients with subtypes associated with cardiovascular abnormalities may require periodic assessment of the heart, valves, aorta, and arterial system according to their specific phenotype and genetic diagnosis.

Spine Radiographs

Plain radiographs should be obtained when examination suggests scoliosis, kyphosis, spondylolisthesis, or another structural spinal deformity.

Vertebral Fractures

Adults with EDS may demonstrate vertebral fractures even when bone mineral density is not markedly reduced.

This supports the concept that abnormalities of bone quality, rather than density alone, may influence skeletal fragility.

Pathological Findings

Microscopic examination of connective tissue may demonstrate irregular or abnormally organized collagen fibers.

Such findings reflect the underlying structural abnormality of the extracellular matrix.

Cardiovascular Pathology

In severe vascular forms, arterial tissue may be unusually fragile and susceptible to aneurysm, dissection, or rupture.

Cardiac-valvular involvement may include myxomatous degeneration and abnormalities of the supporting chordae.

Differential Diagnosis

Marfan Syndrome

Marfan syndrome may also cause joint laxity and skeletal abnormalities.

However, it has a characteristic pattern involving long-bone overgrowth, ocular abnormalities, and cardiovascular disease, whereas EDS generally demonstrates more pronounced skin fragility and joint hypermobility.

Larsen Syndrome

Larsen syndrome may present with multiple congenital joint dislocations.

Unlike typical EDS, fixed contractures and cervical kyphosis are more characteristic.

Cutis Laxa

Cutis laxa should be considered when loose, redundant skin is the predominant manifestation.

The nature of the skin laxity and associated systemic features differ from those of EDS.

Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum can also produce characteristic skin and vascular abnormalities.

Its pattern of elastic-tissue mineralization distinguishes it from EDS.

Treatment

General Principles

Management is primarily supportive and preventive because the underlying connective-tissue defect cannot currently be corrected.

Treatment should be individualized according to the patient’s EDS subtype and affected organ systems.

Specialist Care

Referral to appropriate specialists is required when cardiovascular, ophthalmic, neurologic, gastrointestinal, or other systemic complications are present.

A medical geneticist often coordinates overall care.

Joint Instability

Surgery for instability should be considered cautiously because connective-tissue laxity and impaired tissue quality can increase the likelihood of recurrent instability, fixation failure, poor wound healing, and other complications.

Operative treatment is generally reserved for severe, function-limiting instability that has failed appropriate nonoperative management.

Arthrodesis

In selected severely unstable joints, fusion may occasionally be necessary when reconstruction cannot provide reliable stability.

Activity Modification

High-impact and collision activities should generally be minimized in patients with significant instability or vascular fragility.

Exercise is still encouraged, but activities should emphasize controlled, low-impact conditioning rather than extreme stretching or high-force loading.

Protective Measures

Protective padding and bandages may reduce bruising and hematoma formation during routine activities.

Skin trauma should be minimized whenever possible.

Medications Affecting Bleeding

Medications that impair platelet function or increase bleeding risk should be used cautiously, particularly in patients with substantial bruising or vascular fragility.

The risks and benefits of NSAIDs, aspirin, or anticoagulants should be considered individually rather than used indiscriminately.

Physical Therapy

Muscle Conditioning

Strengthening the muscles surrounding unstable joints can improve dynamic stability and may reduce pain and recurrent subluxation.

Exercise programs should prioritize controlled strengthening, proprioception, balance, and joint protection.

Prevention of Dislocation

Therapists can teach patients how to avoid provocative joint positions and how to modify daily activities to reduce repetitive instability.

Flexibility

Aggressive stretching is usually unnecessary in a disorder characterized by excessive joint mobility.

Therapy should focus more on control and stability than on achieving additional range of motion.

Surgery

General Considerations

EDS can produce segmental instability, scoliosis, kyphosis, and other structural deformities that occasionally require operative management.

Surgery is technically challenging because tissues may be fragile and healing may be less predictable.

Scoliosis

Spinal fusion may be considered for severe, progressive scoliosis, historically around curves exceeding approximately 45°, particularly when progression is likely and the patient’s overall medical status permits surgery.

The precise indication depends on curve type, progression, skeletal maturity, symptoms, and EDS subtype.

Surgical Risks

Operative planning should account for increased risks of bleeding, vascular injury, wound complications, implant failure, and recurrent deformity, especially in vascular and kyphoscoliotic forms.

Activity

Regular physical activity is usually beneficial when adapted to the individual’s phenotype.

Low-impact activities, controlled strengthening, and aerobic conditioning are generally preferable to contact sports, high-impact exercise, or activities requiring extreme joint motion.

Follow-Up

Referral

A medical geneticist is often the most appropriate specialist to coordinate routine long-term care, particularly when the subtype has not yet been clearly established.

Other specialists should be involved according to the affected organ systems.

Prognosis

Prognosis varies greatly among EDS subtypes.

Many individuals have a near-normal lifespan but experience chronic musculoskeletal symptoms, while certain forms—particularly vascular EDS—carry substantial risk of life-threatening complications.

Complications

Cardiovascular Events

Arterial aneurysm, dissection, or rupture can result in sudden life-threatening hemorrhage in vascular forms of EDS.

Cardiac-valvular disease may also progress in selected subtypes.

Joint Degeneration

Repeated instability and abnormal joint loading can lead to premature osteoarthritis and chronic musculoskeletal pain.

Recurrent Dislocations

Joint hypermobility may cause recurrent subluxations or dislocations involving the shoulders, patellae, hips, fingers, and other joints.

Spinal Deformity

Progressive scoliosis or kyphosis can occur, particularly in kyphoscoliotic forms.

Severe deformity may interfere with sitting balance, pulmonary function, or mobility.

Visual Complications

Certain EDS-related disorders may cause significant ocular abnormalities, including corneal fragility and visual impairment.

Skin and Wound Problems

Patients may experience easy bruising, skin splitting, delayed wound healing, widened scars, and hematoma formation.

These problems are particularly relevant when surgical treatment is planned.

Patient Monitoring

Long-term follow-up should be individualized according to the EDS subtype.

Monitoring may include joint stability, chronic pain, spinal alignment, skin and wound problems, cardiovascular status, ocular symptoms, bone health, and functional limitations.

Patients with potentially vascular forms require especially careful surveillance and counseling regarding symptoms that may indicate an acute arterial or visceral emergency.