Ehler Danlos Syndrome

Ehlers-Danlos syndrome
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Ehlers-Danlos Syndrome
Classification and external resources

Ehlers-Danlos syndrome (EDS) (also known as "Cutis hyperelastica"[1]) is a group of inherited connective tissue disorders, caused by a defect in the synthesis of collagen (a protein in connective tissue). The collagen in connective tissue helps tissues to resist deformation (decreases its elasticity). In the skin, muscles, ligaments, blood vessels, and visceral organs collagen plays a very significant role and with increased elasticity, secondary to abnormal collagen, pathology results. Depending on the individual mutation, the severity of the syndrome can vary from mild to life-threatening. There is no cure and treatment is supportive, including close monitoring of cardiovascular system.

The syndrome is named after two doctors, Edvard Ehlers of Denmark, and Henri-Alexandre Danlos of France, who identified it at the turn of the 20th century.[2]

Individual with EDS displaying hypermobile joints.
Signs vary widely based on which type of EDS the patient has. In each case, however, the signs are ultimately due to faulty or reduced amounts of Type III collagen. EDS most typically affects the joints, skin, and blood vessels, the major signs and symptoms include:

Highly flexible fingers and toes
Loose, unstable joints that are prone to: sprains, dislocations, subluxations (partial dislocations), hyperextension (double jointedness) [3]
Flat feet
High and narrow palate, a sign, resulting in dental crowding
Easy bruising
Fragile blood vessels resulting from cystic medial necrosis with tendency towards aneurysm (even abdominal aortic aneurysm)
Velvety-smooth skin which may be stretchy
Abnormal wound healing and scar formation
Low muscle tone and Muscle weakness
Early onset of osteoarthritis
Cardiac effects: Dysautonomia typically accompanied by Valvular heart disease (such as mitral valve prolapse, which creates an increased risk for infective endocarditis during surgery, as well as possibly progressing to a life-threatening degree of severity of the prognosis of mitral valve prolapse) [4]
Other, less common signs and complications may include:

Osteopenia (low bone density)
Talipes equinovarus (club foot), especially in the Vascular type
Deformities of the spine, such as: Scoliosis (curvature of the spine), Kyphosis (a thoracic hump), Tethered spinal cord syndrome, Occipitoatlantoaxial hypermobility [5], Arnold-Chiari malformation [6]
Functional bowel disorders (functional gastritis, irritable bowel syndrome)
Nerve compression disorders (carpal tunnel syndrome, acroparesthesia, neuropathy) [7]
Vascular skin conditions: Raynaud's phenomenon, Livedo reticularis
Fibromyalgia symptoms: Myalgia and arthralgia [8]
otosclerosis (hearing loss) [9]
Premature rupture of membranes during pregnancy
Platelet aggregation failure (platelets do not clump together properly) [10]
Infants with hypermobile joints often appear to have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking
Arterial/intestinal/uterine fragility or rupture
Because it is often goes undiagnosed in childhood, some instances of Ehlers-Danlos syndrome have been mischaracterized as child abuse.[11] The pain, a symptom, associated with this condition is a serious complication.

Classification
In the past, there were more than 10 recognized types of Ehlers-Danlos syndrome. In 1997, researchers proposed a simpler classification that reduced the number of major types to six and gave them descriptive names.[12] These six major types are listed here. Other types of the condition may exist, but they have been reported only in single families or are not well characterized. Except for hypermobility, the specific mutations involved have been identified and they can be precisely identified by genetic testing; this is valuable due to a great deal of variation in individual presentation of symptoms which may confuse classification of individuals on purely symptomatic basis. In order of prevalence in the population, they are:

Name Number Description OMIM Gene(s)
Hypermobility type 3 Affects 1 in 10,000 to 15,000 and is caused by an autosomal dominant or autosomal recessive mechanism. Mutations in either of two separate genes (which are also involved in Vascular EDS and Tenascin-X deficiency EDS, respectively) may lead to this variant. Extreme flexibility is the hallmark of this type. 130020 COL3A1, TNXB
Classical types 1 & 2 Affects approximately 2 to 5 in 100,000 people. It is caused by autosomal dominant mechanism and affects type-V collagen, as well as type I. Type 1 typically presents with severe skin involvement, and type 2 presents with mild to moderate skin involvement. 130000, 130010 COL5A1, COL5A2, COL1A1
Vascular type 4 Is an autosomal dominant defect in the type-III collagen synthesis; affecting approximately 1 in 100,000 to 250,000 people. The vascular type is considered one of the more serious forms of Ehlers-Danlos syndrome because blood vessels and organs are more prone to tearing (rupture). Patients with EDS type 4 often express a characteristic facial appearance (large eyes, small chin, thin nose and lips, lobeless ears), have a small stature with a slim build, and typically have thin, pale, translucent skin (veins can usually be seen on the chest and abdomen). About one in four people with vascular type EDS develop a significant health problem by age 20 and more than 80 percent develop life-threatening complications by age 40. 130050 COL3A1
Kyphoscoliosis type 6 Is an autosomal dominant defect due to deficiency of an enzyme called lysyl hydroxylase; it is very rare, with fewer than 60 cases reported. The kyphoscoliosis type is characterised by progressive curvature of the spine (scoliosis), fragile eyes, and severe muscle weakness. 225400, 229200 PLOD1
Arthrochalasis types 7A & B Is also very rare, with about 30 cases reported. It affects type-I collagen. The arthrochalasia type is characterised by very loose joints and dislocations involving both hips. 130060 COL1A1, COL1A2
Dermatosparaxis type 7C Also very rare, with about 10 cases reported. The dermatosparaxis type is characterised by extremely fragile and sagging skin. 225410 ADAMTS2

Other types
Although the above classifications are well defined, it is rare for a case to fit neatly in a single category, and cross-over symptoms lead to under-diagnosis or mis-diagnosis. So patients should not rely on the "fact" of having a certain type of EDS if cross-over symptoms are evident and might be life-threatening.

"The large number of distinct types of the Ehlers-Danlos syndrome that have already been identified indicates great heterogeneity, but clearly that heterogeneity is not exhausted by the present classification." [8] Forms of EDS within this category may present with soft, mildly stretchable skin, shortened bones, chronic diarrhea, joint hypermobility and dislocation, bladder rupture, or poor wound healing. Inheritance patterns within this group include X-linked recessive, autosomal dominant, and autosomal recessive. Examples of types of related syndromes other than those above reported in the medical literature include