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Joint hypermobility syndrome, also known as benign hypermobility syndrome, is a connective tissue disease characterized by joint instability, chronic pain, and minor skin changes. It shares many clinical features of Ehlers-Danlos syndrome, Hypermobility Type; enough so that many authorities consider them as one disease process. Approximately 3% of the general population is believed to have joint hypermobility syndrome, but despite this high prevalence, due to lack of awareness, heterogeneity of clinical presentation, and reliance on physical examination for diagnosis, it is largely overlooked by primary care physicians as well as by specialists. This leads to delayed or missed opportunities for diagnosis, and inappropriate interventions that frustrate both providers and patients. We review the literature regarding the pathophysiology, diagnosis, treatment options, and prognosis of joint hypermobility syndrome, and advocate for primary care physicians to consider it in the differential diagnosis of patients with chronic pain.
Joint hypermobility syndrome is a common cause of chronic pain and fatigue seen in at least 3% of the general population.
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Patients may also present with headaches, anxiety, orthostasis, and abdominal pain.
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Providers can use the Beighton Score and Brighton Criteria to screen for joint hypermobility syndrome.
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Establishing a diagnosis is important because lifestyle modification can help to prevent further injury and pain. Chronic use of narcotics is not recommended.
Joint hypermobility syndrome, also termed benign hypermobility syndrome, is a connective tissue disorder characterized by chronic musculoskeletal pain due to joint hyperextensibility. Occasionally considered a milder variant of Ehlers-Danlos syndrome, Hypermobility Type, it is seen in up to 3% of the general population, a prevalence rivaling fibromyalgia, gout, and rheumatoid arthritis. Despite this, it is likely underdiagnosed by physicians due to its highly variable clinical presentation, absence of a confirmatory test, and controversies regarding its etiology and pathogenesis.
The diagnosis of joint hypermobility syndrome is largely clinical and can be established in the primary care setting. Because patients have a high rate of concomitant fatigue, headaches, orthostatic hypotension, anxiety, and abdominal and genitourinary complaints, identifying these patients and providing a more appropriate, unifying diagnosis is important. Additionally, identification of joint hypermobility as a cause of chronic pain and fatigue may help guide providers toward more appropriate management strategies, including physical therapy and nonopioid pain relievers.
Epidemiology
The prevalence of joint hypermobility syndrome is estimated to be about 3%, based on a 2013 survey of 12,853 participants in the UK.
Modest association of joint hypermobility with disabling and limiting musculoskeletal pain: results from a large-scale general population-based survey.
Epidemiological studies suggest that patients of all races and age groups are affected, although it is more prevalent in children and adolescents, who tend to have greater mobility of joints.
Generalized joint hypermobility, that is, the finding of hyperextensibility in multiple joints with or without other, accompanying chronic musculoskeletal complaints, is even more prevalent. Ten to twenty percent of individuals exhibit joint hypermobility, particularly children, adolescents, females, Asians, and West Africans.
Although large-scale epidemiological studies are lacking, the rates of generalized joint hypermobility in competitive athletes may be even higher, given the inherent advantages of increased flexibility in sports such as gymnastics, swimming, and track and field.
Because of this variable clinical presentation and lack of specific biomarkers, researchers have been unable to identify a single pathophysiologic mechanism by which patients develop joint hypermobility syndrome. The fact that only a small proportion of patients with generalized joint hypermobility, that is, hypermobility found on physical examination, go on to develop varying levels of musculoskeletal pain and fatigue suggests that there are a host of genetic and environmental factors that contribute to its development.
Genetic Factors
The role of genetics in the development of joint hypermobility syndrome is controversial, and evolving with the rapid adoption of genetic testing in research and clinical settings. The vast majority of cases do not appear to be linked to any identifiable mutation, although pedigree studies have shown a weak autosomal dominant inheritance pattern with variable penetrance.
In fewer than 10% of cases, a mutation in the gene TNXB, coding for the extracellular matrix glycoprotein Tenascin X, has been identified. These patients tend to have more pronounced dermatologic signs, including skin hyperextensibility, velvety skin, and easy bruisability.
A host of rarer mutations have also been identified in some patients with joint hypermobility syndrome, but the clinical significance of genetic testing for these is, as of yet, unknown.
In addition to the genetic predisposition due to presumed difference in collagen structure, current theories emphasize the importance of localized biomechanical overloading and chronic soft tissue injury due to joint laxity and instability. Repetitive microtrauma may lead to altered kinematics, which, in turn, cause overload on other joints and further soft tissue injury manifesting as arthralgias and diffuse musculoskeletal pain.
Studies have also demonstrated more widespread effects on altered gait and posture. In 2 studies comparing patients with asymptomatic generalized joint hypermobility to those with joint hypermobility syndrome, it was found that patients with joint hypermobility syndrome tend to have decreased joint momenta in the lower extremities, necessitating greater force to maintain equilibrium.
However, their conclusions have been tempered by other studies that have failed to reliably demonstrate such changes, and a systematic review questioned the clinical relevance of differences in gait.
Proprioception, the ability to judge position of joints, is essential for joint stabilization; therefore, patients with joint hypermobility syndrome may be at greater risk for joint injuries, particularly in the knees bilaterally. A 2010 systematic review and meta-analysis of 18 studies concluded that there is an increased risk of knee injury, but no such finding for ankle injuries.
Additionally, starting in childhood and early adolescence, the fear of provoking pain and sustaining injury may lead to decreased levels of physical activity, leading ultimately to deconditioning and exercise intolerance.
In addition to these biomechanical perturbations, patients with joint hypermobility syndrome also have neurologic disturbances that contribute to the diffuse musculoskeletal pain. Generalized hyperalgesia is a common complaint, and is believed to be mediated by centralized sensitization.
There do not appear to be any longitudinal studies on the development of chronic musculoskeletal pain of neurologic origin, but cross-sectional studies suggest that chronic trauma reduces the pain threshold. Some authorities have even speculated that hyperalgesia may serve as a compensatory mechanism, in the absence of functional mechanisms to prevent joint instability such as intact proprioception.
Alternatively, the high prevalence of chronic pain in joint hypermobility syndrome may be attributed in part to the fact that those with chronic pain are more likely to see physicians and obtain testing than those without pain.
Less well explored are the psychosocial aspects of joint hypermobility syndrome. The higher rates of anxiety and depression are hypothesized to be due to pain-related fear and fear avoidance, but no studies have been performed specifically in joint hypermobility syndrome patients.
Even less is understood about the autonomic dysfunction seen in joint hypermobility syndrome. Patients frequently exhibit postural tachycardia syndrome (postural orthostatic tachycardia syndrome) as well as bowel and bladder dysfunction, putatively due to connective tissue abnormalities.
The role of the clinical examination in the diagnosis of joint hypermobility syndrome is critical and cannot be overstated. The history and physical examination serve 3 major goals: 1) to screen for generalized joint hypermobility; 2) to determine the extent of disease burden; and 3) to help exclude other connective tissue diseases characterized by generalized joint hypermobility.
Generalized joint hypermobility is a relatively common phenomenon, and not all patients who have generalized joint hypermobility go on to develop joint hypermobility syndrome. Only about 3.3% of women and 0.6% of men will develop chronic pain, fatigue, or other complaints that closely resemble, and may be considered, a chronic pain/fatigue syndrome in its own right. In fact, patients with generalized joint hypermobility may be advantaged in certain competitive fields, such as dance and gymnastics.
Children with generalised joint hypermobility and musculoskeletal complaints: state of the art on diagnostics, clinical characteristics, and treatment.
Because joint hypermobility syndrome is a diagnosis of exclusion, it is of utmost importance to identify other signs of potential disease and to carefully solicit a family history for connective tissue disorders. In particular, Marfan syndrome and Ehlers-Danlos syndrome, Vascular Type (although this type is not typically associated with generalized hypermobility) need to be ruled out because, unlike joint hypermobility syndrome, these are associated with sudden demise. Although establishing the diagnosis of Ehlers-Danlos syndrome and other heritable connective tissue diseases is beyond the scope of this article, recognition of associated congenital abnormalities listed in Table 1 is essential in determining which cases need referral to medical genetics for further testing and counseling.
Joint hypermobility syndrome has a highly variable presentation but most patients come to attention because of their joint complaints. Although joint hypermobility syndrome manifests itself in childhood, symptoms may appear at any age. Therefore, the role of the history and physical examination are paramount because there are no laboratory or radiographic tests to confirm the diagnosis, and generalized joint hypermobility may be seen in many other connective tissue diseases.
Generalized Joint Hypermobility
Because generalized joint hypermobility is a prerequisite for the diagnosis of joint hypermobility syndrome, providers should perform a thorough history and physical examination to identify any symptoms and signs of hypermobility.
Primary care providers can be aided by a 5-point questionnaire devised by Hakim et al
for the detection of joint hypermobility; positive responses to 2 of these 5 questions had a sensitivity of 84% and specificity of 85% in 2 cohorts of 382 patients (Table 2). Because range of motion decreases with advancing age, this questionnaire may be particularly helpful in older patients who may have once been hypermobile but no longer appear to be so.
Selected differential diagnoses of joint hypermobility in adults. Please note that this is not an exhaustive list and that many of the above-mentioned conditions are highly variable in presentation.
∗ Selected differential diagnoses of joint hypermobility in adults. Please note that this is not an exhaustive list and that many of the above-mentioned conditions are highly variable in presentation.
Table 2Questions to Ask Patients with Suspected Joint Hypermobility
Adapted from Hakim AJ, Cherkas LF, Grahame R, et al. The genetic epidemiology of joint hypermobility: a population study of female twins. Arthritis Rheum. 2004;50(8):2640-2644.
• Can you now (or could you ever) place your hands flat on the floor without bending your knees?
• Can you now (or could you ever) bend your thumb to touch your forearm?
• As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?
• As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?
Positive responses to 2 of these questions have a sensitivity of 84% and specificity of 85% for joint hypermobility syndrome (JHS), as characterized by the Brighton Criteria for JHS.
The degree of hypermobility can be assessed and documented by the Beighton Score, which incorporates 5 simple maneuvers to calculate a score between 0 and 9 (Figure 1). A Beighton Score ≥4, in addition to arthralgias for longer than 3 months in 4 or more joints, constitutes the major criteria for the Brighton Criteria (Figure 2).
The Beighton Score should be used in the context of the Brighton Criteria, because the Beighton Score only documents the degree of hypermobility.
Figure 1Maneuvers used to calculate the Beighton Score. The Beighton Score is calculated by adding the points obtained through each maneuvers, yielding a total maximum score of 9. A Beighton Score of 4 or higher is a major criterion for the Brighton Criteria (Figure 2).
Figure 2The Revised Brighton Criteria. In order to establish the diagnosis of joint hypermobility syndrome, the individual must satisfy any one of the following: 1) 2 major criteria; 2) 1 major and 2 minor criteria; 3) 4 minor criteria; or 4) 2 minor criteria and unequivocally affected first-degree relative in the family.
Figure adapted from Grahame R, Bird HA, Child A. The revised (Brighton 1998) Criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol. 2000;27(7):1777-1779.
Additionally, joints should be examined for tenderness, swelling, redness, and deformities in addition to assessing range of motion in major joints. While frank swelling is rare, some patients may have small noninflammatory effusions resulting from meniscal or cartilaginous irritation. Similarly, the presence of correctable deformities like swan neck deformities of the fingers may also resemble conditions like rheumatoid arthritis.
Furthermore, these patients may also have scoliosis, lordosis, pes planus, genu valgum, patellar subluxation, marfanoid habitus, varicose veins, rectal or uterine prolapse, or thin skin.
Children with generalised joint hypermobility and musculoskeletal complaints: state of the art on diagnostics, clinical characteristics, and treatment.
Many of these are considered minor criteria in the Brighton Criteria.
Musculoskeletal Pain
There does not appear to be a specific pattern of joint involvement, and some patients may have generalized and symmetric polyarthralgias closely resembling inflammatory arthritis. The pain is typically described as dull, and may be self-limited or constant. Weight-bearing joints like the knees and ankles appear to be more commonly involved. Unlike classic descriptions of inflammatory arthritis, the joint pain in joint hypermobility syndrome seems to be exacerbated by repetitive use or physical activity. As a result, prolonged morning stiffness (lasting >30 minutes) is rare, and the pain usually occurs later in the day.
In fact, the fatigue can be so substantial that it can meet criteria for chronic fatigue syndrome. Although the underlying cause is unclear, muscle weakness is believed to be a key factor, because this fatigue is associated with worsening with activity, delayed recovery from physical exertion, and alterations in gait.
With advancing disease, postexertional malaise and exercise intolerance become more of a background sensation of fatigue; over 90% of adults over the age of 40 complain of fatigue, compared with only 28% in the second decade of life.
Additionally, there may be other contributors, including sleep disturbance, concentration problems, and symptomatic cardiovascular dysautonomia. Sleep disturbance is a particularly common complaint in patients with joint hypermobility syndrome, and may be linked to nocturnal musculoskeletal pain, as well as periodic limb movement and restless leg syndrome. While obstructive sleep apnea has not been reported in joint hypermobility syndrome, in other, related connective tissue diseases such as Ehlers-Danlos syndrome and Marfan syndrome, hypotonia of the upper respiratory passages may lead to upper airway resistance, predisposing to hypopneic episodes.
Although previously underappreciated, the decreased quality of life due to severe dysautonomia can be as high as in patients with congestive heart failure.
Evidence suggests that there is increased sympathetic tone, but decreased sympathetic reactivity to stimuli. As a result, patients tend to have orthostatic intolerance, gastrointestinal discomfort (such as early satiety, bloating, postprandial nausea/vomiting), and secretomotor complaints, including Raynaud phenomenon, abnormal sweating, and sicca-like symptoms.
Therefore, practitioners should solicit any history of orthostatic symptoms, such as lightheadedness immediately after rising from a seated position or an inability to remain in an upright posture, and elicit objective signs in the clinic for orthostasis.
While the cause of this dysautonomia remains uncertain, speculation rests on peripheral neuropathy, increased vascular distensibility leading to orthostasis, concurrent depression, and low-level pain-induced sympathetic arousal as potential causes.
Headache is a particularly troublesome symptom experienced by patients with joint hypermobility syndrome, with 75% of female patients suffering from migraines. This may be due to intracranial vasculopathy causing reversible cerebral vasoconstriction.
However, patients tend to have a host of other primary and secondary headaches, including those due to tension, temporomandibular joint dysfunction, unilateral myofascial pain, idiopathic cerebrospinal fluid leak, Chiari malformation, cervicogenic headache, and neck-tongue syndrome. Pain amplification, local muscle hyperalgesia, and neck motion are also contributors to persistent chronic headache.
Both dysautonomia, as mentioned above, and laxity in collagen comprising the gastrointestinal tract, may underlie increased pain generation. Iturrino et al
demonstrated that up to 25% of variation in gas and pain sensation in healthy subjects could be associated with colonic compliance. Due to the reduced pain thresholds in patients with joint hypermobility syndrome, this gas and pain sensation may be further amplified.
Abdominal and pelvic pain also might be due to other causes. Abnormal laxity may cause pelvic prolapse as well; the rate of joint hypermobility in females with pelvic prolapse has been reported to be as high as 54%.
Additionally, females with joint hypermobility syndrome are more likely to have polycystic ovaries, endometrial cysts, uterine leiomyomas, endometrial hypertrophy, and endometriosis.
The relationship between joint hypermobility syndrome and mitral valve prolapse is a matter of contention. Some of the earlier studies did suggest an association,
Regardless, cardiology consultation should be considered for patients with suspected mitral valve prolapse and joint hypermobility syndrome, because many other connective tissue diseases can present with mitral valve prolapse.
Psychosomatic Features
Evidence also suggests a strong psychosomatic component to joint hypermobility syndrome. Patients with joint hypermobility syndrome are 4 times more likely to develop anxiety or depression, and nearly 7 times more likely to have a panic disorder, compared with those without joint hypermobility syndrome. This may partly be due to the fear and anxiety associated with potential re-injury, but the nature of this relationship remains largely uncharacterized.
Establishment of the diagnosis of joint hypermobility syndrome is important because, unlike many other causes of chronic musculoskeletal pain, joint hypermobility syndrome is a nonprogressive and noninflammatory condition. Because joint laxity decreases with advancing age, some symptoms may attenuate later on in life.
However, patients should be aware that there are sequelae to joint hypermobility syndrome. The increased joint laxity may predispose patients to premature osteoarthritis, but this association has not been consistently demonstrated.
Lifestyle modification is considered the most important intervention, although rigorous studies evaluating the efficacy of any particular intervention is lacking. Patients should be advised that excessive joint movement may aggravate symptoms and lead to joint, meniscal, and cartilage injury. Regular exercise is important, but overtraining, poor pacing, and excessive focus on joint flexibility may also lead to injury. Low-cost interventions, like neuromuscular taping and bracing, may help to prevent injury and improve gait.
Importantly, patients should consider strengthening programs for periarticular musculature in order to stabilize joints.
Prior to strenuous activity, stretching techniques to isolate tight muscles without stressing the joints may improve balance and control. For those who engage in athletic competition, nonsteroidal anti-inflammatory drugs prior to physical activity may help reduce symptoms.
Because some patients may have extreme fear and anxiety of provoking re-injury, cognitive behavioral therapy may be required in certain cases.
Nutritional supplementation has also been proposed as an important modality in the treatment of joint hypermobility syndrome, but there is a lack of any studies investigating its role specifically in joint hypermobility syndrome. Vitamin C may be useful in addressing some cutaneous features, and vitamin D supplementation may be required in those with reduced bone mineral density.
Importantly, there is no evidence available regarding the use of opioids for the treatment of chronic pain due to hypermobility. Because the pathogenesis of pain in hypermobility relates more to chronic stresses, it does not stand to reason that opioids will help promote long-term alleviation of pain. Moreover, because opioid medications carry very significant risks, including the development of central pain sensitization, dependency, and the potential for abuse, these should not substitute for physical therapy and lifestyle modification.
Conclusion
Joint hypermobility syndrome is a relatively common cause of chronic pain in the general population. Because its diagnosis requires a high level of clinical suspicion and the performance of specific physical examination maneuvers, it is often overlooked by providers. This is unfortunate, because establishment of the diagnosis allows for more appropriate management and care. In addition to providing an explanation to patients about their disease process, patients with joint hypermobility syndrome can also be counseled about ways to protect their joints and to undergo lifestyle modification in order to prevent further damage. Providers should be cognizant that patients with chronic musculoskeletal pain may have joint hypermobility and that it may be related to a series of other, seemingly unrelated symptoms such as headache, abdominal pain, fatigue, and anxiety.
References
Mulvey M.R.
Macfarlane G.J.
Beasley M.
et al.
Modest association of joint hypermobility with disabling and limiting musculoskeletal pain: results from a large-scale general population-based survey.
Children with generalised joint hypermobility and musculoskeletal complaints: state of the art on diagnostics, clinical characteristics, and treatment.
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