Ehlers-Danlos syndrome

Ehlers-Danlos syndrome is a group of inherited disorders that weaken the connective tissues supporting skin, bones, blood vessels, and organs. It is characterized by joint hypermobility, skin elasticity, and tissue fragility.

Overview and Classification

Ehlers-Danlos syndrome (EDS) is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in these tissues cause signs and symptoms ranging from mildly loose joints to life-threatening complications.

The classification of Ehlers-Danlos syndrome has evolved over time:

• Originally, 11 forms were named using Roman numerals (type I, type II, etc.).
• In 1997, the Villefranche nomenclature simplified the classification to six types with descriptive names.
• In 2017, the classification was updated to describe 13 distinct types of Ehlers-Danlos syndrome, incorporating newly identified rare forms.

Symptoms and Types

The signs and symptoms of Ehlers-Danlos syndrome vary significantly depending on the specific type:

Joint Hypermobility

An unusually large range of joint movement (hypermobility) occurs in most forms of EDS and is the hallmark of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay motor skills like sitting, standing, and walking. Loose joints are unstable, painful, and prone to dislocation. In the arthrochalasia type, infants are born with severe hypermobility and dislocations of both hips.

Skin Elasticity and Fragility

Many affected individuals have soft, velvety skin that is highly stretchy (elastic) and fragile. Easy bruising and abnormal scarring are common. People with the classical form experience wounds that split open with little bleeding, leaving characteristic wide scars. The dermatosparaxis type is characterized by severely fragile skin that sags and wrinkles, often with extra folds of skin.

Vascular and Organ Fragility

The vascular type of EDS is associated with unpredictable tearing (rupture) of blood vessels and organs, which can cause internal bleeding, intestinal perforation, stroke, or uterine rupture during pregnancy. Rupture of blood vessels can also occur in the kyphoscoliotic, classical, and classical-like types.

Other Systemic Features

• Cardiac-valvular type: Causes severe problems with the valves that control blood flow through the heart.
• Kyphoscoliotic type: Features severe, progressive spine curvature that can restrict lung expansion and interfere with breathing.
• Brittle cornea syndrome: Characterized by thinness of the cornea and other eye abnormalities.
• Spondylodysplastic type: Features short stature and skeletal abnormalities like bowed limbs.
• Musculocontractural and myopathic types: Characterized by muscle abnormalities, hypotonia, and permanently bent joints (contractures).
• Periodontal type: Causes abnormalities of the teeth and gums.

Frequency

The combined prevalence of all types of Ehlers-Danlos syndrome is estimated to be at least 1 in 5,000 individuals worldwide. The hypermobile and classical forms are the most common. The hypermobile type may affect 1 in 5,000 to 20,000 people, while the classical type occurs in approximately 1 in 20,000 to 40,000 people. Other forms of EDS are extremely rare.

Causes and Genetic Factors

Variants (mutations) in at least 20 genes have been found to cause the Ehlers-Danlos syndromes. Many of these genes provide instructions for making or processing collagen, a protein that gives structure and strength to connective tissues throughout the body.

Associated Genes

• COL5A1, COL5A2, and COL1A1: Associated with the classical type.
• TNXB: Causes the classical-like type and is found in a small percentage of hypermobile cases (though the cause of most hypermobile cases remains unknown).
• COL1A2 and COL1A1: Associated with the cardiac-valvular and arthrochalasia types.
• COL3A1: Causes most cases of the vascular type.
• ADAMTS2: Causes the dermatosparaxis type.
• PLOD1 and FKBP14: Result in the kyphoscoliotic type.
• Other genes associated with rare types of EDS include AEBP1, B3GALT6, B4GALT7, C1R, C1S, CHST14, COL12A1, DSE, PRDM5, SLC39A13, and ZNF469. Some of these genes have functions unrelated to collagen, and it is not yet clear how they lead to the symptoms of EDS.

Inheritance Pattern

The inheritance pattern of EDS depends on the specific type:

• Autosomal Dominant: The classical, vascular, arthrochalasia, periodontal, and likely hypermobile types are inherited in an autosomal dominant pattern, meaning one copy of the altered gene in each cell is sufficient to cause the disorder. These can be inherited from an affected parent or result from new (de novo) mutations.
• Autosomal Recessive: The classical-like, cardiac-valvular, dermatosparaxis, kyphoscoliotic, spondylodysplastic, and musculocontractural types, as well as brittle cornea syndrome, are inherited in an autosomal recessive pattern, requiring two altered copies of the gene. Parents of an affected individual are typically unaffected carriers.
• Myopathic Type: Can be inherited in either an autosomal dominant or autosomal recessive pattern.

Other Names for This Condition

• EDS
• Ehlers Danlos disease