Ehlers–Danlos syndrome

What is Ehlers–Danlos syndrome?

Ehlers–Danlos syndrome (EDS) is the name given to a group of inherited disorders that involve a genetic defect in collagen and connective tissue synthesis and structure [1]. This results in:

• Fragile and hyperelastic skin
• Unstable and hyperextensible (hypermobile) joints
• Fragile tissue and blood vessels.

Hyperelasticity of elbow skin

Hypermobility

Bruises and scars

Who gets Ehlers–Danlos syndrome?

The global frequency of EDS is about 1 in 5000. EDS may occur in males and females of all races and usually first appears in young adults.

EDS has autosomal dominant and autosomal recessive inheritance patterns.

• The autosomal dominant disease occurs when only one copy of an abnormal gene is required to cause a condition. There is a 50% chance that an offspring will inherit the abnormal gene from an affected parent.
• The autosomal recessive disease requires two copies of an abnormal gene to cause disease; therefore, the child is at 25% and 50% risk of developing the disease and being the carrier of a disease, respectively.

Subtypes of Ehlers–Danlos syndrome

Under the 2017 International Classification for Ehlers-Danlos Syndromes, there are thirteen subtypes of EDS, classified according to the clinical features, inheritance pattern and molecular genetic defects.

Each is a distinct disorder that ‘runs true’ in a family. This means that members of a family affected by EDS will share the same features. Some cases do not fit neatly into a known type of EDS, and a patient may show features of more than one type. Clinical manifestations and their severity can vary significantly, even within the same family.

Hypermobile EDS is the most common subtype of EDS, followed by classical EDS and vascular EDS. The other types of EDS are very rare.

See Subtypes of Ehlers–Danlos syndrome [view table in a new tab][2,3]

What causes Ehlers–Danlos syndrome?

Collagen is one of the main building blocks of the body. It is a protein that is widely found in the structure of many tissues and organs of the body. Several types of collagen exist, each with differing properties. Collagen can provide strength and firm support, it can be elastic to allow movement, or it can be used to bind things together.

A genetic defect can cause reduced amounts of collagen, collagen disorganisation (collagen is usually organised into bundles), and alterations in the size and shape of collagen. The subtype of EDS depends on how collagen metabolism has been affected. For example, vascular EDS is caused by decreased or absent synthesis of type III collagen.

There are some types of EDS that are a result of other extracellular matrix disorders and its components (such as glycosaminoglycans) and of defects in intracellular processing.

What are the clinical features of Ehlers–Danlos syndrome?

Signs and symptoms differ in type and severity between the different types of EDS. Below is a summary of EDS clinical features based on systems.

Facial features

• A thin pinched nose
• Prominent eyes
• Lobeless ears

Periodontal involvement

• Severe and intractable inflammation of the gum
• Lack of attached gum

Musculoskeletal system

• Hypermobility — the joints bend more than usual. The fingers are most often affected, but all joints can be involved. Congenital or recurrent joint dislocations or subluxations may occur particularly in shoulders, hips and knees.
• Congenital talipes equinovarus (clubfoot) — this is a developmental deformity of the foot where one or both feet are rotated inwards and downwards.
• Congenital or early-onset kyphoscoliosis — this is an abnormal curvature of the spine.
• Arachnodactyly — abnormally long and slender fingers and toes
• Congenital or mild, to later-onset of hypotonia and gross motor delay

Hypermobile joints

Hypermobile joints

Hypermobile joints

Skin

• Skin hyperextensibility — it is easy to pull the skin away from the body, and once released, it retracts to its original state.
• Thin and translucent skin with visible underlying blood vessels
• Skin fragility — the skin easily splits and tears.
• Bruising and haematomas may arise after trivial injuries and can be seen at sites not prone to trauma.
• Acrogeria — thin wrinkled skin particularly on hands and feet
• Atrophic cutaneous scars — wounds heal very slowly resulting in gaping fish-mouth or cigarette-paper scars.
• Epicanthic folds make the bridge of the nose appear wide.
• Molluscoid pseudotumours — these are small spongy lumps 2–3 cm in diameter over pressure points such as the knees and elbows.
• Subcutaneous spheroids — calcified fat lobules which are a result of insufficient blood supply.
• Nodules — small, firm lumps just below the skin surface most often appearing on the arms and shins.
• Pretibial plaques

Hyperelasticity of cheek skin

Hyperelasticity of neck skin

Hyperelasticity of elbow skin

Ehler Danlos syndrome

Ehlers Danlos syndrome

Brusing

Wide scarring in patient with Ehlers-Danlos syndrome.

Atrophic scar

Hypopigmented scars

Pseudotumour on ankle

Pretibial plaques

See more images of Ehlers–Danlos syndrome.

Eye

• Thin cornea, with or without rupture
• Blue sclera
• Keratoconus — the cornea has a cone-like shape
• Keratoglobus — the globular protrusion and thinning of the cornea

Internal collagen defects

• Heart murmur (mitral valve prolapse) and weakened walls of intestines, arteries and uterus, which may rupture
• Autonomic dysfunction — transient loss of consciousness, palpitation, dizziness, chest pain and shortness of breath
• Postural orthostatic tachycardia syndrome (POTS) — fast heartbeats, which particularly occur on postural change or standing
• Repeated pneumothoraxes — these can be the initial presentation of EDS.

What are the complications of Ehlers–Danlos syndrome?

Possible complications of Ehlers-Danlos syndrome include:

• Chronic joint pain
• Poor wound healing
• Failure of surgical wound closure
• Early-onset arteritis
• Premature preterm rupture of the fetal membrane
• Hollow organ and vascular rupture
• Globe rupture, retinal detachment and glaucoma
• Epilepsy [4].

How is Ehlers–Danlos syndrome diagnosed?

Suspicion of Ehlers-Danlos syndrome should lead to a careful history and examination. The definite diagnosis of specific variant usually requires tissue biopsy and molecular genetic analysis due to the vast variety of molecular defects and clinical overlap between EDS subtypes.

Medical history

Detailed personal and family history of muscle, ocular, cutaneous, dental, cardiac, and respiratory conditions.

Clinical examination

• Full skin check — assess for hyperextensibility of the skin and abnormal scarring.
• The Beighton scale — assess for hypermobility of a joint, in which a score of 5 or more indicates generalised joint hypermobility.
• The diagnosis of subtypes of EDS is based on major and minor criteria that match with presenting signs and symptoms.

Investigations

• Skin biopsy for histology, fibroblast culture and electron microscopy
• When suspecting kyphoscoliotic EDS, a urine sample is taken to measure the ratio of lysylpridinoline to hydroxylysylpyridinoline cross-links 

Molecular genetic testing confirms the diagnosis, except in the case of hypermobile EDS, which has an unknown genetic basis.

What is the differential diagnosis for Ehlers–Danlos syndrome? 

Diseases that may be confused with EDS include:

• Osteogenesis imperfecta
• Loeys-Dietz syndrome
• Skeletal dysplasias
• Mucopolysaccharidoses
• Cutis laxa syndrome
• Pseudoxanthoma elasticum
• Ullrich congenital muscular dystrophy
• Bethlem myopathy
• Larsen syndrome
• Achondroplasia
• RIN2 syndrome
• Marfan syndrome
• Chondrodysplasia
• Congenital myopathies
• Freeman-Sheldon syndrome.

What is the treatment for Ehlers–Danlos syndrome?

Management guidelines depend on the subtype of EDS.

• Take preventative measures against serious and life-threatening complications.
• Patients should consider wearing a MedicAlert bracelet to communicate their EDS status.
• All patients with EDS should be referred for genetic counselling and appropriate specialists.

General measures

• Children may benefit from protective pads and bandages.
• Contact sports or activities that will raise intracranial pressure (like playing the trumpet) should be avoided to prevent undue trauma.
• The patient may benefit from low-resistance exercise and physiotherapy.
• Consider calcium and vitamin D supplementation to optimise bone density.
• Provide psychological support following the diagnosis.
• Patients should wear a medical warning bracelet inscribed 'type of EDS'.

Medication

• Ascorbic acid (vitamin C) has been used to reduce bruising.

Surgery and wound care

• Surgery should be carried out with caution given the risk of vascular complications.
• Wounds should be carefully closed via sutures without tension.
• Deep stitches are recommended; leave superficial stitches for extended periods of time to allow healing.

Pregnancy

• Obstetrical follow-up throughout pregnancy is recommended due to the risk of bleeding disorders and vascular, surgical and anaesthetic complications.
• Women with EDS have an increased risk of premature labour, postpartum haemorrhage, bladder and uterine prolapse, abdominal hernias and wound dehiscence.
• There are no existing obstetric management guidelines for EDS given the extensive ranges of possible implications and severity of each subtype; thus, patients are managed based on a case-by-case basis.

Screening and surveillance

• The patient should have regular blood pressure monitoring and arterial disease screening to reduce the risk of bleeding and vascular complications.
• Non-invasive screening — ultrasound, computed tomography (CT) scan, echocardiogram, and magnetic resonance imaging (MRI) may be performed to identify potential complications.
• Invasive screening procedures should be considered with care.
• Dual-energy X-ray absorptiometry (DEXA) bone density scans should be performed every few years.
• Patients with kEDS should have an eye check regularly, as they are at risk of eye complications.

What is the outcome for patients with Ehlers–Danlos syndrome?

The prognosis of patients with Ehlers-Danlos syndrome varies widely even within the same subtype. The majority of patients have a normal life expectancy and cognitive function. Individuals with vascular EDS may have a shorter life expectancy and are at higher risk of sudden death due to internal organ and major vessel rupture.