Ehlers-Danlos Syndrome, Hypermobility Type

DISEASE CARD

Disease group Connective tissue disorders
DISEASE NAME EHLERS-DANLOS SYNDROME, HYPERMOBILITY TYPE
Synonymous Ehlers-Danlos syndrome III
Estimated prevalence 1 - 5 / 10.000
OMIM 130020, 606408
Inheritance Autosomal dominant, Autosomal recessive
Gene (s) TNXB (600985), COL3A1 (120180)

Definition

The term Ehlers-Danlos syndrome (EDS) does not describe a specific disease but a group of connective tissue disorders that share the clinically manifestations of skin hyperextensibility, articular hypermobility and tissue fragility [1]. In the “Villefranche” classification, the formerly used Roman numerals were replaced by six descriptive main types (Table 1). Besides the six main types, EDS also includes a series of “other” types, that are either not clearly classified or poorly characterized [2, 3].

EDS hypermobility type (hEDS) is a connective tissue disorder characterized by generalized joint hypermobility and joint instability causing recurrent subluxations and dislocations and chronic musculoskeletal pain. Skin abnormalities are usually mild and include a soft and mildly hyperextensible skin and easy bruising. The genetic basis of EDS hypermobility type is largely unknown, but in a minority of patients haplo-insufficiency of tenascin-X was identified [4].

One patient has been reported to carry a mutation in the COL3A1 gene [5].

Table 1: Villefranche classification of the six main types of EDS.

Descriptive type Numerical type Genes
Classic type EDS I (Gravis)
EDS II (Mitis)
COL5A1
COL5A2
COL1A1
Hypermobility type EDS III TNXB
COL3A1*
Vascular type EDS IV COL3A1
Kyphoscoliosis type EDS VI PLOD1
Arthrochalasia type EDS VIIA
EDS VIIB
COL1A1
COL1A2
Dermatosparaxis type EDS VIIC ADAMTS2

*Only one patient has been reported to carry a mutation in the COL3A1 gene.

Clinical Description

EDS hypermobility type is primarily characterized by generalized joint hypermobility, affecting large and small joints [2]. This is usually assessed using the Beighton scale, the most widely accepted grading system for the objective semi-quantification of joint hypermobility (Table 2).

Table 2: Beighton scale of hyermobility.

Joint/Finding Negative Unilateral Bilateral
Passive dorsiflexion of the 5th finger >90° 0 1 2
Passive flexion of thumbs to the forearm 0 1 2
Hyperextension of the elbows beyond 10° 0 1 2
Hyperextension of the knees beyond 10° 0 1 2
Forward flexion of the trunk with knees fully extended and palms resting on the floor 0 1
A total score of at least 5 defines hypermobility

Primary muscular hypotonia may occur and may cause delayed motor development, problems with ambulation, and mild motor disturbance. During childhood however complications are not frequent and the joint hypermobility may even be an asset for performing sports, dance or music.

From young adulthood on subluxations and dislocations are common. They may occur spontaneously or with minimal trauma and can be acutely painful. Reduction often occurs spontaneously or can be accomplished by the affected individual or a friend/family member. Even in the absence of clinically obvious subluxation, instability and excessive joint motion is evident on routine activity. All sites can be involved, including the extremities, vertebral column, costo-vertebral and costo-sternal joints, clavicular articulations, and temporomandibular joints. Other problems related to the joint hypermobility are foot deformities such as congenital clubfoot or pes planus, joint effusions, and osteoarthritis.

Some adult individuals may suffer from chronic musculoskeletal pain[6], which is distinct from the pain associated with acute dislocations. The severity is typically greater than expected based on physical and radiological examination, and the impact can be devastating with disruption of sleep, work physical activities and social relations. Affected individuals are often diagnosed with chronic fatigue syndrome, fibromyalgia or depression prior to recognition of joint laxity and establishment of the underlying diagnosis. This chronic pain may be attributable to repeated microtrauma to the vulnerable connective tissues, and to myofascial spasms which occur in response to chronic joint instability. Many patients also suffer from neuropathic pain, which may be the result of nerve compression, e.g., by the subluxed joints or the spasmed connective tissues.

The skin is often soft or velvety and may be mildly hyperextensible. Cigarette paperscars, as seen in the classic type of EDS are absent, although some mildly atrophic scars can be seen, especially over pressure points. Easy bruising is common.

Other extra-articular features that are often present in EDS hypermobility type include autonomic dysfunction, with orthostatic hypotension, positional orthostatic tachycardia syndrome (POTS) and (pre-)syncope; functional bowel disorders, with gastro-esophageal reflux and gastritis, irritable bowel syndrome and delayed gastric emptying; nociceptive defects, with an inadequate response to local anesthetic; and diminished proprioception.

Pathogenesis

To date, the genetic basis of joint hypermobility remains largely unknown. Mutations in a non-collagenous molecule, tenascin-X, have been identified in a small subset of patients with EDS, hypermobility type [4]. Tenascin-X is a large extracellular matrix glycoprotein, belonging to the family of tenascins. One patient has been reported to carry a mutation in the COL3A1 gene [5].

Diagnosis

The diagnosis of EDS hypermobility type is based entirely on clinical evaluation and family history. A serum-based screening assay to detect tenascin X deficiency as well as molecular sequence analysis of the TNXB gene is available on a research basis.

Treatment

The Ehlers-Danlos syndrome hypermobility type requires a multidisciplinary approach with a therapy plan that is tailored to the patient’s problems. Joint stability may be improved by low-resistance exercise to increase muscle tone. Examples include walking, bicycling, swimming or water exercise, and simple range-of-motion exercise without added resistance. It may take months or years for significant progress to be recognized.

Joint hyperextension must be avoided. Individuals with EDS hypermobility type usually need to be educated about the normal range of joint extension and cautioned not to exceed it.

High impact sports, such as football and fighting sports are discouraged because they increase the risk of acute subluxation/dislocation of joints, chronic pain, and osteoarthritis.

Braces, including braces for knees and ankles, shoulder and hips, ring splints for the interphalangeal joints and wrist-thumb braces, are useful to improve joint stability. A soft neck collar, if tolerated, may help with neck pain and headaches. There is no contraindication to joint surgery, but the surgeon should be aware of the possibility of delayed wound healing or prolonged bleeding. Orthopedic interventions may include arthroscopic debridement, tendon relocations, capsulorraphy, and arthroplasty. The degree of stabilization and pain reduction and duration of improvement are variable, but results are usually disappointing. Therefore orthopedic surgery should be delayed in favour of physical therapy and bracing. Temporomandibular joint laxity and dysfunction are difficult to treat. There are no specific interventions of proven benefit. Intra-oral devices are sometimes helpful. Oral rest (minimization of chewing and talking), local myofascial release, and muscle relaxant medications may be beneficial for acute flares. Surgical intervention is often disappointing and should be considered only as a last resort.

Analgesic drugs are widely used in patients with EDS hypermobility type. Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs), including the selective COX-2 inhibitors can be helpful for acute pain. If necessary, tramadol can be added. When used alone, analgesics and NSAIDs are disappointingly ineffective in treating chronic pain, and patients should be made aware of their low efficacy in this condition. Other potentially effective drugs include low-dose tricyclic antidepressants, which are often effective for neuropathic pain, with additional benefits of mild sedation (sleep is often difficult) and a little mood elevation. Patients with depression may also have a good effect from a selective serotonin reuptake inhibitor (SSRI). The use of potent opioids in musculoskeletal disorders is generally not advised and, if necessary, is reserved as long as possible.

Gastritis and reflux symptoms may require intensive therapy, including proton pump inhibitor, H2-blocker and over-the-counter acid-neutralizing agents. Delayed gastric emptying should be treated with promotility agents (e.g., erythromycin, metoclopramide). Irritable bowel syndrome is treated with antispasmodics, anti-diarrheals, and laxatives as needed. Validation of the affected individual's symptoms can be immensely helpful, as many with EDS hypermobility type have been diagnosed with primary psychiatric disorders by previous physicians. Depression is a common result of the chronic pain and other complications. Psychological and/or pain-oriented counseling can improve adaptation to and acceptance of these issues and the physical limitations. Many individuals initially resist a diagnosis of or therapy for depression because of concern that their problems are being written off as purely psychiatric.

References

1
Beighton P. The Ehlers-Danlos syndromes. In: Beighton P. (ed.) : McKusick's Heritable Disorders of Connective Tissue. 5th ed. St. Louis: Mosby 1993. Pp. 189-251.

2
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. (1998) Ehlers-Danlos Syndromes: Revised Nosology, Villefranche, 1997. Am J Med Genet 77:31-37.

3
Byers PH, Murray ML. (2012) Heritable Collagen Disorders: The Paradigm of the Ehlers-Danlos Syndrome. J Invest Dermatol 132(E1):E6-E11.

4
Zweers MC, Bristow J, Steijlen PM, Dean WB, Hamel BC, Otero M, Kucharekova M, Boezeman JB, Schalkwijk J. (2003) Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome. Am J Hum Genet 73(1):214-217.

5
Narcisi P, Richards AJ, Ferguson SD, Pope FM. (1994) A family with Ehlers-Danlos syndrome type III/articular hypermobility syndrome has a glycine 637 to serine substitution in type III collagen. Hum Mol Genet 3(9):1617-1620.

6
Sacheti A, Szemere J, Bernstein B, Tafas T, Schechter N, Tsipouras P. (1997) Chronic pain is a manifestation of the Ehlers-Danlos syndrome. J Pain Symptom Manage 14(2):88-93.