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

Ehlers-Danlos syndrome (Ehlers-Danlos) (SED; Q79.6) is a genetically heterogeneous disease caused by various mutations in the collagen genes or in the 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 light forms. The prevalence of cEDS was estimated at 1:20 000 [Byers 2001]. However, it is likely that some people with milder manifestations of the disease, previously classified as Type II EDS, do not go to the doctor and, therefore, go unnoticed.

Causes of the zlers-Danlos syndrome

Ehlers-Danlos syndrome is a group of connective tissue diseases that differ in inheritance type, clinical features and biochemical defect. In most cases, it is inherited in an autosomal dominant manner, accompanied by a decrease in the amount or a change in the structure of collagen. The connection of Tenascin-X protein deficiency with the risk of developing Ehlers-Danlos syndrome is described.[1]

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

1. autosomal dominant inheritance (hypermobile, classical and vascular EDS) - a defective gene that causes EDS, is transmitted by one parent, and the risk of developing this disease in each of their children is 50%
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 transmit only one type of syndrome to children.

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

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

Pathogenesis

The study of these diseases allowed a new look at the molecular pathogenesis of EDS, involving genetic defects in the biosynthesis of other extracellular matrix molecules (ECM), such as proteoglycans and tenascin-X, or genetic defects in molecules, secretion and assembly of ECM proteins. [3] In the vascular type of EDS, mutations in type III collagen (EDS IV) were identified (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 the clinical diagnosis of classical Ehlers-Danlos syndrome have mutations in the COL5A1 and COL5A2 genes encoding the α1 and α2-chain of type V collagen, respectively. [5]

Symptoms of the zlers-Danlos syndrome

It is characterized by hyperelastic skin, subcutaneous spherules, over-bending of the joints, light tissue vulnerability and hemorrhagic syndrome. [6]

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

Other dermatological features in cEDS:

• Molluscid pseudotumors.
• Subcutaneous spheroids.
• Piezo papules: small, painful, reversible hernias of the underlying globules of adipose tissue through the fascia to the dermis, for example, on the medial and lateral sides of the feet when standing.
• Elastosis perforans serpiginosa: a rare skin disease of unknown etiology characterized by red or erythematous keratotic papules, some of which grow outward in a serpiginus or arcuate configuration, leaving slightly atrophic foci.
• Acrocyanosis: a painless disease caused by a narrowing or narrowing of the small blood vessels of the skin (mainly affecting the hands), in which the affected areas turn blue and become cold and sweaty; local edema may occur.
• Chills: cold injury, characterized by red, swollen skin, tender and hot to the touch, which may itch; may develop in less than two hours on skin exposed to cold.

Manifestations of generalized stretchability and brittle tissue are observed in many organs:

• Cervical insufficiency during pregnancy.
• Inguinal and umbilical hernia.
• Hiatal and postoperative hernia.
• Recurrent prolapse of the rectum in early childhood.

Joints

• Complications of hypermobility of the joints, including dislocations of the shoulder, patella, fingers, hips, radius and clavicle, can occur and usually pass spontaneously or are easily controlled by a sick person. Some people with cEDS may experience chronic pain in the joints and limbs, despite a normal radiograph of the skeleton.

Other features include hypotension with delayed motor development, fatigue and muscle cramps, as well as light bruising. Mitral valve prolapse may occur infrequently. 

Forms

Ehlers-Danlos syndrome includes a heterogeneous group of diseases that are characterized by the fragility of soft connective tissues and widespread manifestations in the skin, ligaments and joints, blood vessels and internal organs. The clinical spectrum ranges from mild skin and articular hyperlapse to severe physical disability and life-threatening vascular complications. 

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

The current classification of Villefranche 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 a deficiency of Tenascin X 
3. Type III Type of hyper mobility
4. Type VIA, Type VIB Vascular type (OMIM 225320)
5. Types VIIA and VIIB Type of Artrochalasia (OMIM 130060, 617821), Type VIIC Dermatosparaxis (OMIM 225410), Type of Progeroid
6. Type VIII Type of periodontitis, 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 of the zlers-Danlos syndrome

The scope of the survey is determined by the presence of leading clinical signs of the disease. The genealogical research and molecular genetic diagnostic methods are essential.

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

• For clinical diagnosis requires the presence of at least one large criterion. With appropriate capabilities, the presence of one or more large criteria ensures confirmation of Ehlers-Danlos syndrome at the laboratory level.
• A small criterion is a trait with a lower level of diagnostic specificity. The presence of one or more small criteria contributes to the diagnosis of a particular type of Ehlers-Danlos syndrome.
• In the absence of large criteria for establishing the diagnosis of small enough. The presence of small criteria gives reason to assume the presence of a state similar to Ehlers-Danlos syndrome, the nature of which will be clarified as its molecular basis becomes known. Since the occurrence of small criteria is significantly higher than that of large ones, in full agreement with the Villfranche revision, the presence of only small criteria provides a basis for diagnosing the ehlers-like phenotype.

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

The criteria for the diagnosis of Morphan syndrome and Ehlers-Danlos syndrome include joint hypermobility. If the relevant criteria are not met, hypermobility must be considered as an independent state.

Treatment of the zlers-Danlos syndrome

An interdisciplinary rehabilitation program that combines physical and cognitive-behavioral therapy has shown significant changes in the perception of daily activities, a significant increase in muscle strength and endurance and a significant reduction in kinesiophobia. There have been less changes in perceived pain. Participants also reported increased participation in daily life.

A protein-rich diet containing bone broths, jellies, aspic. Courses of massage, physiotherapy, physical 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 (magneV \ calcium-D3-Nycomed, magnerot), chondroitin sulfate orally and topically, Glucosamine, ossein-hydroapatite complexes (osteocare, osteogenon), trophic preparations (ATP, inosine, lecithin, coenzyme Q10). These drugs take 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 lifespan due to spontaneous rupture of a large-caliber artery (for example, the splenic artery, aorta) or perforation of internal organs. Arterial aneurysms, valve prolapse and spontaneous pneumothorax are common complications. The prognosis with this type is bad.[11]

Other types are usually not so dangerous, and people with this diagnosis can lead a healthy lifestyle. Type VI is also somewhat dangerous, although it is rare.

Children should focus on the choice of profession, not related to physical activity, work standing.