DISEASE CARD

Definition

Hypermobile EDS (hEDS) is a hereditary connective tissue disorder (HCTD) 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. There is no reliable/appreciable genetic etiology to test for in the vast majority of patients.

Clinical Description

EDS hypermobility type is primarily characterized by generalized joint hypermobility, affecting large and small joints. This is usually assessed using the Beighton scale, the most widely accepted grading system for the objective semi-quantification of joint hypermobility (Table 2).¹

Table 2: Beighton scale of hyermobility.

^{*As joint range of motion usually decreases with age and there is an inverse relationship between age and Beighton score, the Committee on behalf of the International Consortium on the EDS proposes adjustment of the cut-of: ≥6 for pre‐pubertal children and adolescents, ≥5 for pubertal men and women up to the age of 50, and ≥4 for those >50 years of age for hEDS2}

Joint hypermobility is rather common (8–39% of school‐age children) and should be examined whether occurring in the context of a hereditary disorder of connective tissue or of other hypermobility spectrum disorders.^{2, 3} A diagnosis of hEDS should be assigned only in those who meet all of the diagnostic criteria described below.

Primary muscular hypotonia may occur and may cause delayed gross 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, 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 hEDS 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. Those symptoms may be more burdensome than the joint symptoms, frequently restrict functionality and quality of life, and thus should always be determined during clinical encounters.

Although there is limited and contradictory data relating to bone mineral density in hEDS, affected individuals may be prone to have an increased prevalence of osteoporosis. DEXA scanning can therefore be recommended if this is suspected.⁴

Clinical Diagnostic Criteria

• Criteria I: Generalized Joint Hypermobility (GJH)

Based on Beighton Score. In individuals with acquired joint limitations (past surgery, wheelchair, amputations, etc.), the assessment of GJH may include historical information using the five‐point questionnaire (5PQ).  If the Beighton score is 1 point below the age‐ and sex‐specific cut‐off AND the 5PQ is ‘positive’ (= at least two positive items), then a diagnosis of GJH can be made.⁵

Five‐point questionnaire (5PQ)5

1. Can you now (or could you ever) place your hands flat on the floor without bending your knees?
2. Can you now (or could you ever) bend your thumb to touch your forearm?
3. As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?
4. As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?
5. Do you consider yourself “double‐jointed”?

A “yes” answer to two or more questions suggests joint hypermobility with 80–85% sensitivity and 80–90% specificity

• Criteria II: ≥2 of the following features (A–C) MUST be present
  1. Feature A: systemic manifestations of a more generalized connective tissue disorder (a total of five must be present): 1. Unusually soft or velvety skin; 2.Mild skin hyperextensibility; 3.Unexplained striae; 4.Bilateral piezogenic papules of the heel; 5.Recurrent or multiple abdominal hernia(s); 6.Atrophic scarring involving at least two sites and without the formation of truly papyraceous and/or hemosideric scars as seen in classical EDS; 7.Pelvic floor, rectal, and/or uterine prolapse in children, men or nulliparous women; 8.Dental crowding and high or narrow palate; 9.Arachnodactyly; 10.Arm span‐to‐height ≥1.05; 11.Mitral valve prolapse (MVP) mild or greater; 12.Aortic root dilatation with Z‐score > +2

1. Feature B: positive family history, with one or more first degree relatives independently meeting the current diagnostic criteria for hEDS.
2. Feature C: musculoskeletal complications (must have at least one): 1.Musculoskeletal pain in two or more limbs, recurring daily for at least 3 months; 2.Chronic, widespread pain for ≥3 months; 3. Recurrent joint dislocations or frank joint instability, in the absence of trauma

• Criteria III: All the following prerequisites MUST be met
  1. Absence of unusual skin fragility (consider other types of EDS)
  2. Exclusion of other heritable and acquired connective tissue disorders, including autoimmune rheumatologic conditions.
  3. Exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity. E.g. neuromuscular disorders (e.g., myopathic EDS, Bethlem myopathy), other HCTD (e.g., other types of EDS, Loeys–Dietz syndrome, Marfan syndrome), and skeletal dysplasias (e.g., Osteogenesis Imperfecta). Exclusion of these considerations may be based upon history, physical examination, and/or molecular genetic testing, as indicated.

The clinical diagnosis of hEDS needs the simultaneous presence of criteria 1 AND 2 AND 3.

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 hEDS. Tenascin-X is a large extracellular matrix glycoprotein, belonging to the family of tenascins. One family has been reported to carry a mutation in the COL3A1 gene.^{6, 7} An absence of proalpha2(I) collagen chains can present as a phenotype with features of mild hypermobility EDS in childhood and a cardiac valvular form of EDS during adulthood.⁸

Diagnosis

The diagnosis of hEDS 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 as well as the COL3A1 can be recommended when the symptoms are indicative for hEDS

Treatment

See article "Ehlers-Danlos-Syndrome"

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