Ehlers-Danlos syndrome



Overview

Definition

Ehlers-Danlos syndrome (EDS) is a rare genetic disorder of connective tissue involving the skin, blood vessels, internal organs and joints. It is characterized by hyperelasticity of the skin, increased joint mobility, increased soft tissue brittleness, susceptibility to abrasion, and bleeding tendency [1].

Ehlers-Danlos syndrome was proposed and thus named by Danish dermatologist Edvard Ehlers and French dermatologist Henri-Alexandre Danlos [1].

Staging

Ehlers-Danlos syndrome can be categorized into 14 subtypes based on clinical presentation, laboratory investigations, and genetic and pathological changes. The most common types are classic, vascular, hypermobile, kyphotic, kyphoscoliotic, lax joints, and fragile skin [2-3]. The following describes only the common types.

Classic type

This is one of the most common types of Ehlers-Danlos syndrome, and patients mainly present with increased skin elasticity and characteristic cigarette paper-like atrophic scarring [4].

Vascular type

This is the most severe type of Ehlers-Danlos syndrome and presents with increased fragility of the arteries, gastrointestinal tract, and uterus, predisposing to visceral rupture, gastrointestinal perforation, and perinatal uterine rupture [5].

Joint hypermobility type

This type is the most common type of Ehlers-Danlos syndrome and is usually characterized by joint instability and tendency to dislocate or subluxate.

Posterior curvature of the spine

This type is rare, and patients usually present with severe posterior kyphosis, recurrent joint dislocations, hyperextension of cutaneous joints, and decreased muscle tone.

Laxity of joints

This type is rare and usually presents with marked and extensive joint hypermobility, posterior kyphosis, decreased muscle tone, and multiple joint dislocations, most often of the hip and ankle joints.

Skin fragility

This is a rare condition characterized by skin fragility and easy bruising, blue sclera, and marked joint hypermobility.

Morbidity

Ehlers-Danlos syndrome is clinically rare, with a reported incidence of about 1/5000, i.e., about 1 in 5000, and is most commonly seen in preterm infants, infants, and children, usually with a family history of inheritance, and can occur in both sexes, with a higher incidence in males than in females [6].

Etiology

Causes

The etiology of Ehlers-Danlos syndrome is mainly related to genetic factors, such as gene mutations and chromosomal abnormalities. Such as COL5A1, COL5A2, COL3A1, etc., these genes are mostly involved in encoding collagen or modifying collagen. Gene mutations can lead to abnormalities in the structure, production, processing, and cross-linking of collagen fibers, thus failing to provide toughness to the body’s connective tissues and resulting in the disease [7].

Predisposing factors

Premature babies and infants with a family history of the disease are susceptible to the disease.

Males are more susceptible to the disease than females.

Symptoms

Ehlers-Danlos syndrome is a group of connective tissue disorders involving the skin, blood vessels, internal organs and joints. Clinical manifestations vary by subtype, but the basic features are increased skin elasticity, increased joint mobility, increased tissue brittleness, susceptibility to abrasions, and a tendency to bleed. The following is a brief description of only the common common symptoms.

Main Symptoms

Skin

The main manifestations are increased skin elasticity and fragility, easy to abrasion, easy to form cigarette paper-like atrophic scar after trauma; thin, soft, transparent skin; increased skin folds, more common in the hands and feet; easy to sagging of the facial skin, etc.

Joints

The main manifestations are increased joint mobility, instability, recurrent joint subluxation or dislocation (e.g. shoulder joint, knee joint), chronic joint pain, accompanied by posterior scoliosis of the spine, hypotonia, osteoporosis, bone fracture, etc.

Blood vessels

The main manifestation is recurrent arterial rupture, often involving the iliac arteries, splenic arteries, hepatic arteries, renal arteries, or the aorta, which can result in large hematomas or death [8].

Visceral

The main manifestation is increased tissue fragility, which predisposes to visceral rupture, gastrointestinal perforation, perinatal uterine rupture, and in some cases, umbilical and inguinal hernias.

Other symptoms

Patients with Ehlers-Danlos syndrome often develop secondary infections, resulting in the presentation of systemic symptoms such as fever and headache [9].

Medical treatment

Department of medicine

Ehlers-Danlos syndrome is a multisystem connective tissue disease involving the skin, blood vessels, internal organs, and joints, and therefore may require multidisciplinary care.

Rheumatology

The presence of hypermobility of joints, increased skin elasticity, easy abrasion, tendency to bleed, posterior scoliosis, etc., and a family history of the disease suggests prompt consultation with the Department of Rheumatology and Immunology.

Vascular Surgery

In the case of severe internal bleeding such as arterial rupture, prompt consultation with the Department of Vascular Surgery is recommended.

Orthopedics

In the event of severe joint pain, repeated joint dislocation, etc., timely consultation with the Department of Orthopedics is recommended.

Preparation for medical treatment

Consultation: Registration, Preparation of documents, Frequently Asked Questions

Tips for medical treatment

Avoid self-medication before consultation to avoid covering up your condition.

Record the changes and characteristics of your condition to give your doctor more reference.

For patients with severe hypermobility of joints, it is recommended that they are accompanied by their family members to avoid falling.

Preparation Checklist

Symptom list

Particular attention should be paid to the time of onset of symptoms, special manifestations, etc.

Are there any manifestations such as increased skin elasticity, easy abrasion, easy formation of cigarette paper-like atrophic scar after trauma? When did the symptoms appear?

Is the skin thin, soft, transparent, with increased wrinkles and sagging of the facial skin? Since when?

Are there any signs of increased joint mobility, instability, recurrent joint dislocation, chronic joint pain with posterior scoliosis? Since when?

Are there any signs of gastrointestinal bleeding, such as abdominal pain and black stools? From when did they appear?

List of medical history

Is there a history of recurrent joint dislocation or subluxation?

Is there a history of unexplained arterial, gastrointestinal, or uterine rupture?

Is there a family history of hypermobility of joints, increased skin elasticity, etc.?

Checklist

Test results from the last six months, which can be brought to the doctor’s appointment

Laboratory tests: routine blood test, urinalysis, stool routine, blood biochemistry, etc.

Imaging examination: ultrasound, X-ray, MRI examination

Pathology examination: skin histopathology examination.

Other tests: molecular gene test, bone density test, etc.

List of medications used

Medication used in the last 3 months, if available in a box or package, bring it to the doctor’s office

Non-steroidal anti-inflammatory drugs: ibuprofen, celecoxib, etc.

Opioid painkillers: pethidine, oxycodone, etc.

Vitamin drugs: vitamin C, etc.

Beta-blockers: celiprolol, etc.

Diagnosis

Diagnosis is based on

The diagnosis of Ehlers-Danlos syndrome is complex and relies mainly on clinical manifestations and family history. It usually involves multiple systems, so it should be screened for multiple systems, and for patients who meet the diagnostic criteria, pathologic examination and molecular genetic examination should be performed to clarify the typing [2].

Medical history

The following is not necessary for the diagnosis of the disease, but the presence of the following history may provide some reference significance for the diagnosis of the disease.

History of recurrent joint dislocation or subluxation.

History of unexplained arterial, gastrointestinal, or uterine rupture.

A family history of joint hypermobility and increased skin elasticity.

Clinical manifestations

Patients may present with increased skin elasticity and brittleness, easy abrasion, cigarette paper-like atrophic scarring; thin, soft, transparent skin; increased skin folds, and easily sagging facial skin.

Increased joint mobility, recurrent joint dislocation, chronic joint pain with posterior scoliosis, hypotonia, osteoporosis, and fractures can also occur.

Increased tissue fragility may also be present, predisposing to arterial rupture, gastrointestinal perforation, and perinatal uterine rupture.

Laboratory Tests

Blood tests

It is necessary to check the white blood cell count, hemoglobin and platelets.

When hemoglobin drops rapidly in a short period of time, it often indicates that there may be active bleeding, which is a guide to the diagnosis and treatment of Ehlers-Danlos syndrome.

Urine routine

It can clarify whether the patient has proteinuria, hematuria and other conditions.

When proteinuria, hematuria and other abnormalities appear in urine routine, it suggests that there may be impaired renal function, which can assist in the diagnosis and judgment of the condition.

Stool test

It can detect the presence of red blood cells and other components in the feces.

When the red blood cell count in the feces is increased and the occult blood is positive, it suggests that there may be active bleeding in the gastrointestinal tract, which can help to clarify the condition and guide the treatment.

Blood biochemistry

Mainly includes liver function and kidney function. It can be used to assess the presence of impaired liver and kidney function.

When serum aminotransferase is elevated and blood creatinine is elevated, it suggests that there may be liver or kidney damage, which helps to diagnose and assess the patient’s organ involvement, as well as guide treatment.

Imaging

Ultrasound

Ultrasound examination includes abdominal ultrasound and cardiac ultrasound, etc. The main purpose is to observe the gastrointestinal tract and heart.

If the results of abdominal ultrasound show enhanced echogenicity and fluid dark areas, it suggests possible gastrointestinal bleeding; if the results of cardiac ultrasound show excessive activity of the mitral valve toward the atrium, it suggests possible mitral valve prolapse.

X-ray

The main purpose is to clarify whether the patient has joint dislocation or fracture.

If the X-ray result of shoulder joint shows that the two bony joints are poorly or misaligned, it suggests that there may be shoulder dislocation; if the X-ray result of tibia shows fracture line, it suggests that there may be tibia fracture.

MRI examination

The main purpose of MRI is to observe spinal injuries and soft tissue injuries.

If the MRI results of thoracic spine show wedge-shaped changes, it suggests that there may be thoracic spine fracture; if the MRI results of the knee joint show swelling of the soft tissues around the knee joint, it suggests that there may be soft tissue injury of the knee joint.

Pathologic examination

The main purpose of pathology examination is to observe the collagen fibers of the tissues, mainly the pathology examination of skin tissues.

If the results of pathology examination show that the number of collagen fibers in the skin is reduced and disordered, while the number of elastic fibers is increased and fracture occurs, suggesting that there may be Ehlers-Danlos syndrome [10].

Other tests

Molecular genetic testing

The main purpose of molecular genetic testing is to determine whether the patient has a genetic mutation.

If the results of molecular genetic testing show mutations in genes associated with Ehlers-Danlos syndrome (e.g., COL5A1, COL3A1, etc.), it suggests that Ehlers-Danlos syndrome may be present.

Bone Densitometry

The main purpose of a bone density test is to check for osteoporosis.

If the results of the bone density test show that the bone density is lower than normal, it suggests that osteoporosis may be present.

Differential Diagnosis

Dermatolysis bullosa

Similarities: Both may present with loose, sagging skin and increased wrinkles.

Differences: In sarcopenia, the skin is inelastic and does not easily return to its original shape after stretching, there is no tendency to bruise or bleed, and there is no hypermobility of joints; in Ehlers-Danlos syndrome, the skin has increased elasticity but is not flaccid, and it can be restored to its original shape after stretching, and there is an increase in the mobility of joints, etc. [1].

Turner syndrome

Similarities: Both may present with increased skin elasticity and short stature.

Differences: Turner syndrome is also known as congenital ovarian hypoplasia syndrome. In addition to increased skin elasticity, gonadal dysplasia, webbed neck, peltate chest, and elbow ectropion are also present in Turner syndrome, which can be differentiated by chromosomal karyotype examination.

Osteogenesis imperfecta

Similarities: Both may present with joint laxity, increased mobility, osteoporosis, fractures, and blue sclera.

Differences: Osteogenesis imperfecta has normal skin elasticity and fragility, as well as hallux valgus and flat feet, malocclusion, cephalo-facial deformities, and progressive deafness; Ehlers-Danlos syndrome has increased skin elasticity and fragility [11].

Treatment

Aims of treatment: to improve patients’ quality of life and avoid serious complications.

Therapeutic principle: there is no effective treatment method, mainly focusing on symptomatic treatment. Treatment methods mainly include drug therapy, surgical treatment and physical therapy.

Drug treatment

As Ehlers-Danlos syndrome is a group of connective tissue diseases involving skin, blood vessels, internal organs and joints. The clinical manifestations of different subtypes are also different. Currently, symptomatic treatment is mainly provided by drugs to alleviate the clinical symptoms. The following is an introduction to common symptomatic drugs.

Non-steroidal anti-inflammatory drugs

Commonly used drugs such as ibuprofen and celecoxib.

These drugs can inhibit the body’s production of cyclooxygenase, thereby reducing the production of the inflammatory mediator prostaglandin and alleviating the symptoms of pain. They are suitable for conditions such as joint dislocation with pain or chronic joint pain caused by hypermobile joints as well as lax joints.

It is contraindicated in case of hypersensitivity to the components of the drug. Adverse reactions to NSAIDs include the appearance of allergies, gastrointestinal discomfort, kidney damage.

Opioid painkillers

Commonly used drugs such as pethidine and oxycodone [12-13].

This class of drugs binds to opioid receptors in the body to produce analgesia. It is used in conditions such as joint pain where NSAIDs are ineffective.

It is contraindicated in supraventricular tachycardia, craniocerebral injury, intracranial space-occupying lesions, chronic obstructive pulmonary disease, bronchial asthma, and severe pulmonary insufficiency. Adverse effects of opioid painkillers include mild dizziness, sweating, dry mouth, nausea, and vomiting.

Beta-blockers

Commonly used drugs such as Celiprolol.

This class of drugs can inhibit myocardial contractility and lower blood pressure by blocking β1 receptors, and may reduce the occurrence of vascular events in patients. It is suitable for patients with vascular Ehlers-Danlos syndrome.

They are contraindicated in female patients with diabetic ketoacidosis, metabolic acidosis, high levels of bradycardia, cardiogenic shock, congestive heart failure, and those who are pregnant or likely to become pregnant.Adverse effects of beta blockers include rash, palpitations, nausea, and headache.

Others

Commonly used medications such as vitamin C.

These drugs can promote wound healing and improve bleeding tendency. It is indicated for patients with Ehlers-Danlos syndrome who have experienced trauma as well as bleeding [14].

It is contraindicated for those who are allergic to the components of the drug. Adverse effects of vitamin C include causing stones, diarrhea with prolonged application of high doses, red and shiny skin, headache, frequent urination, nausea and vomiting.

Surgical treatment

Surgery is generally not recommended for Ehlers-Danlos syndrome and may cause serious complications [15].

For the posterior scoliosis type, posterior surgical treatment may be considered if the patient has significant and progressive scoliosis, combined with clinical symptoms such as low back pain.

Physical therapy

Physical therapy and the wearing of protective gear are essential to prevent joint dislocation due to increased joint mobility. It is indicated for joint dislocations caused by hypermobility as well as laxity of the joint.

For patients with increased skin fragility, avoid sports and heavy labor and wear bandages or braces, focusing on the forehead, knee and lower leg.

For patients with chronic pain, physical therapy can also provide pain relief.

Prognosis

Cure

The prognosis is not quite the same for the different subtypes of Ehlers-Danlos syndrome.

In general, the hypermobile joint type has a better prognosis; the vascular type has the worst prognosis and often results in sudden death due to rupture of an artery or rupture of an internal organ without obvious precursors; and the other types fall in between.

Prognostic factors

The prognosis of Ehlers-Danlos syndrome is influenced by a number of factors, and the following factors may contribute to a poor prognosis [1].

Combined severe trauma.

Combined gastrointestinal, uterine or arterial rupture.

Failure of the patient to take active symptomatic treatment and prevention.

Daily

Daily management

Dietary management

Pay attention to light diet and balanced nutrition. Protein intake can be increased appropriately (e.g. eggs, lean meat, milk, etc.), and fresh vegetables and fruits can be eaten in moderation to supplement vitamin intake.

Life Management

Pay attention to rest, avoid strenuous exercise and heavy physical labor.

Ensure sufficient sleep, maintain good living habits, quit smoking and limit alcohol, etc.

Wear protective gear in daily life as much as possible.

Psychological support

As the disease is rare and involves multiple systems, it is easy to miss and misdiagnose, and there is no effective treatment, patients may have anxiety, depression and other adverse emotions.

In case of emotional instability and depression, relatives and friends can enhance the escort and guidance, while psychological intervention can be given when necessary.

Disease monitoring

Observe the skin condition, whether the skin elasticity increases, whether there are subcutaneous petechiae and ecchymosis.

Observe the mobility of joints, whether there is joint dislocation, whether there is joint pain, etc.

Observe the daily stool monitoring, whether there is tarry stool.

Follow-up examination

Since the disease is relatively serious and there is no effective treatment, it is important to follow up regularly to assess the changes in the disease and to avoid serious complications.

Follow-ups are usually performed within one to two months, according to the doctor’s instructions.

Ultrasound, X-ray, MRI, bone density test and other tests may be required.

Prevention

Ehlers-Danlos syndrome, a rare class of connective tissue genetic disorders, is difficult to prevent effectively, but can help reduce the risk of morbidity and complications by, among other things, the following healthy lifestyles or behaviors [2].

Avoid strenuous exercise, heavy labor, and trauma to avoid aggravating the condition.

Wear protective gear regularly in daily life, etc.

People with family history of Ehlers-Danlos syndrome should undergo genetic counseling before marriage and pregnancy, and prenatal diagnosis during pregnancy; newborns should be screened promptly.