Ehlers-Danlos syndrome: causes, symptoms, diagnosis, treatment

Ehlers-Danlos syndrome (EDS; Q79.6) is a genetically heterogeneous disease caused by various mutations in collagen genes or in genes responsible for the synthesis of enzymes involved in the maturation of collagen fibers.

Epidemiology

The true prevalence is unknown due to the difficulty of verification and the large number of mild forms. The prevalence of cEDS has been estimated at 1:20,000 [Byers 2001]. However, it is likely that some people with milder manifestations of the disease, previously classified as EDS type II, do not seek medical attention and therefore remain undetected.

Causes Ehlers-Danlos syndrome

Ehlers-Danlos syndrome is a group of connective tissue disorders that vary in their inheritance patterns, clinical features, and biochemical defects. In most cases, it is inherited in an autosomal dominant pattern and is accompanied by a decrease in the amount or a change in the structure of collagen. A link has been described between Tenascin-X protein deficiency and the risk of developing Ehlers-Danlos syndrome. [ 1 ]

There are 2 main ways of inheriting Ehlers-Danlos syndrome:

1. autosomal dominant inheritance (hypermobility, classical and vascular EDS) - the defective gene that causes EDS is passed on by one parent, and each of their children has a 50% risk of developing the condition
2. autosomal recessive inheritance (kyphoscoliotic EDS) - the defective gene is inherited from both parents, and the risk of developing this disease in each of their children is 25%

A person with Ehlers-Danlos syndrome can only pass on one type of the syndrome to their children.

For example, children of a person with hypermobility EDS cannot inherit vascular EDS.

The severity of the condition can vary within a family.[ 2 ]

Pathogenesis

The study of these diseases has provided new insights into the molecular pathogenesis of EDS, implicating genetic defects in the biosynthesis of other extracellular matrix (ECM) molecules such as proteoglycans and tenascin-X, or genetic defects in the secretion and assembly of ECM proteins. [ 3 ] Mutations in collagen type III (EDS IV) have been identified in the vascular type of EDS (Kuivaniemi et al. 1997). Structural mutations affecting N-proteinase cleavage of procollagen I have been found in rare EDS variants (EDS VII A and B) (Byers et al. 1997). [ 4 ]

It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome have mutations in the COL5A1 and COL5A2 genes, encoding the α1 and α2 chains of type V collagen, respectively.[ 5 ]

Symptoms Ehlers-Danlos syndrome

Characterized by hyperelasticity of the skin, subcutaneous spherules, hyperextension of joints, easy tissue vulnerability and hemorrhagic syndrome. [ 6 ]

The skin is fragile, which is manifested by the presence of scars and wounds after relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shin, forehead, chin). Wound healing is poor. Scars become wide, with a "cigarette" (papyrus) appearance.

Other dermatological features in cEDS:

• Molluscoid pseudotumors.
• Subcutaneous spheroids.
• Piezogenic papules: small, painful, reversible herniations of underlying fat globules through the fascia into the dermis, such as on the medial and lateral aspects of the feet when standing.
• Elastosis perforans serpiginosa: a rare skin disorder of unknown etiology characterized by red or erythematous keratotic papules, some extending outward in a serpiginous or arcuate configuration, leaving slightly atrophic lesions.
• Acrocyanosis: A painless condition caused by narrowing or constriction of small blood vessels in the skin (affecting mainly the hands), causing the affected areas to turn blue and become cold and sweaty; local swelling may occur.
• Chills: Cold injuries characterized by red, swollen skin that is tender and hot to the touch and may itch; can develop in less than two hours on skin exposed to cold.

Manifestations of generalized tissue extensibility and fragility are observed in many organs:

• Cervical insufficiency during pregnancy.
• Inguinal and umbilical hernia.
• Hiatal and postoperative hernia.
• Recurrence of rectal prolapse in early childhood.

Joints

• Complications of joint hypermobility, including dislocations of the shoulder, patella, fingers, hip, radius, and clavicle, may occur and are usually spontaneous or easily managed by the affected individual. Some individuals with cEDS may experience chronic joint and limb pain despite normal skeletal radiographs.

Other features include hypotonia with delayed motor development, fatigue and muscle spasms, and easy bruising. Mitral valve prolapse may be uncommon.

Forms

Ehlers-Danlos syndromes comprise a heterogeneous group of disorders characterized by soft connective tissue fragility and widespread manifestations in the skin, ligaments and joints, blood vessels, and internal organs. The clinical spectrum ranges from mild cutaneous and joint hyperlaxity to severe physical disability and life-threatening vascular complications.

Initially, the 11 forms of Ehlers-Danlos syndrome were named with Roman numerals to denote the types (type I, type II, etc.). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their main characteristics.[ 7 ]

The current Villefranche classification recognizes six subtypes, most of which are associated with mutations in one of the genes encoding collagen fibrillar proteins or enzymes involved in the post-translational modification of these proteins.[ 8 ]

1. Type I Classic type (OMIM 606408)
2. Type II Classic type, Ehlers-Danlos syndrome with Tenascin X deficiency
3. Type III Hypermobility Type
4. Type VIA, Type VIB Vascular type (OMIM 225320)
5. Types VIIA and VIIB Arthrochalasia type (OMIM 130060, 617821), Type VIIC Dermatosparaxis (OMIM 225410), Progeroid type
6. Type VIII Periodontitis type, Ehlers-Danlos variant with periventricular heterotopia

Establishing the correct EDS subtype has important implications for genetic counseling and management and is supported by specific biochemical and molecular studies.[ 9 ]

Diagnostics Ehlers-Danlos syndrome

The scope of examination is determined by the presence of leading clinical signs of the disease. Genealogical research and molecular genetic diagnostic methods are of significant importance.

To diagnose Ehlers-Danlos syndrome, the following requirements must be met.

• For clinical diagnosis, at least one major criterion must be present. If possible, the presence of one or more major criteria guarantees laboratory confirmation of Ehlers-Danlos syndrome.
• A minor criterion is a feature that has a lower level of diagnostic specificity. The presence of one or more minor criteria contributes to the diagnosis of one or another type of Ehlers-Danlos syndrome.
• In the absence of major criteria, minor criteria are insufficient to establish a diagnosis. The presence of minor criteria suggests a condition similar to Ehlers-Danlos syndrome, the nature of which will be clarified as its molecular basis becomes known. Since the incidence of minor criteria is significantly higher than that of major criteria, in full agreement with the Villefranche revision, the presence of only minor criteria provides grounds for diagnosing an Ehlers-like phenotype.

The diagnosis of classical syndrome is established in a patient based on minimal clinical and diagnostic criteria (skin hyperelasticity and the presence of atrophic scars) and identification by molecular genetic testing of the pathogenic gene COL5A1, COL5A2 or COL1A1.

Diagnostic criteria for Morfan syndrome and Ehlers-Danlos syndrome include joint hypermobility. If the corresponding criteria are not met, hypermobility should be considered as an independent condition.

Treatment Ehlers-Danlos syndrome

An interdisciplinary rehabilitation program combining physical and cognitive behavioral therapy showed significant changes in the perception of daily activities, significant increases in muscle strength and endurance, and a significant decrease in kinesiophobia. There were smaller changes in perceived pain. Participants also reported increased participation in daily activities.

A protein-rich diet containing bone broths, jellies, jellied dishes. Courses of massage, physiotherapy, exercise therapy. [ 10 ] Syndromic therapy depending on the severity of organ changes. Drug treatment using amino acid (carnitine, nutraminos), vitamin (vitamins D, C, E, B ₁, B ₂, B ₆ ), mineral complexes (magneB calcium-D3-Nycomed, magnerot), chondroitin sulfate orally and locally, glucosamine, ossein-hydroappatite complexes (osteokea, osteogenon), trophic drugs (ATP, inosine, lecithin, coenzyme Q10). The above drugs are taken in combined courses 2-3 times a year for 1-1.5 months.

Forecast

Ehlers-Danlos syndrome type IV (EDS) is a severe form. Patients often have a short life expectancy due to spontaneous rupture of a large-caliber artery (e.g., splenic artery, aorta) or perforation of internal organs. Arterial aneurysms, valve prolapse, and spontaneous pneumothorax are common complications. The prognosis with this type is poor.

Other types are generally not as dangerous, and people with this diagnosis can lead healthy lives. Type VI is also somewhat dangerous, although it is rare.

Children should be encouraged to choose a profession that is not associated with physical exertion or standing work.