Hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders (2024)

Hypermobile Ehlers-Danlos syndrome (EDS) and hypermobility spectrum disorders are the most common symptomatic joint hypermobility disorders seen in clinical practice. The 2017 International Classification of Ehlers-Danlos Syndromes replaced the previous term of symptomatic joint hypermobility with hypermobile EDS and introduced the term hypermobility spectrum disorders for patients who do not meet the diagnostic criteria for hypermobile EDS. Both are diagnosed based on the 2017 diagnostic criteria, which also exclude other less common joint hypermobility disorders, such as other forms of EDS and hereditary connective tissue disorders. Hypermobile EDS is inherited in an autosomal dominant pattern, but there is no known genetic mutation present that can aid in the diagnosis. Clinical features of hypermobile EDS include joint hypermobility, skin findings, and joint pain or recurrent dislocations. Hypermobile EDS and, less commonly, hypermobility spectrum disorders may also be associated with various extra-articular symptoms, including anxiety disorders, chronic pain, fatigue, orthostatic intolerance, functional gastrointestinal disorders, and pelvic and bladder dysfunction. The central goals of therapy are to control symptoms, prevent joint damage, and educate patients about their condition. Based on limited evidence, patients with hypermobile EDS/hypermobility spectrum disorders may benefit from physical and occupational therapy, psychological support, and self-management. Primary care physicians not only play a key role in the initial recognition, diagnosis and education of patients, but through their ongoing relationship they can also help monitor and coordinate the multidisciplinary team that many of these patients require.

Hypermobile Ehlers-Danlos syndrome (EDS) and hypermobility spectrum disorders are the most common symptomatic joint hypermobility disorders seen in clinical practice.^1,2Primary care physicians play a critical role in treating patients with these conditions, from initial diagnosis to ongoing care.

"Ehlers-Danlos syndromes (EDS) ... are a group of hereditary connective tissue disorders caused by abnormalities in the structure, production and/or processing of collagen. The new classification, as of 2017, includes 13 subtypes of EDS."³ table 1describes these subtypes.^1,4,5Joint hypermobility is a feature common to many EDS subtypes and other inherited connective tissue disorders. Joint hypermobility is defined as the ability of a joint to move “beyond normal limits along physiological axes.”⁴Joint hypermobility can affect single or multiple joints and can be completely asymptomatic. Generalized joint hypermobility is more likely to be associated with a genetic syndrome than localized joint hypermobility. The exception is hypermobile EDS, the most common EDS variant, accounting for 80% to 90% of EDS cases.²with clinical features including joint hypermobility, skin findings(Figure 1)and joint pain or recurrent dislocations(Figure 2⁶Infigure 3^1,7). The 2017 classification introduced more stringent criteria for hypermobile EDS than previously available to distinguish patients with hypermobile EDS from those most likely to have a diagnosable genetic syndrome.¹For patients with symptomatic joint hypermobility who meet neither the new hypermobile EDS criteria nor another specific condition, the 2017 classification introduced hypermobility spectrum disorders.¹

Patients with hypermobility spectrum disorders differ from those with hypermobile EDS and other joint hypermobility syndromes in that their symptoms originate primarily from the musculoskeletal system; however, limited extra-articular involvement can be observed.⁴All previous terms, including EDS type III, EDS hypermobility type, hypermobility syndrome, joint hypermobility syndrome and benign joint hypermobility syndrome, should no longer be used.⁴These previously named diagnoses were previously thought to represent different entities, but later studies that found a large overlap of these older named conditions within families showed that they were the same entity.⁴In a more recent study, almost all patients with one of the earlier, now outdated diagnoses of hypermobile EDS or hypermobility spectrum disorders met the criteria.⁸Because these are the most common symptomatic hypermobility conditions, their evaluation and treatment are the focus of this article; the terms hypermobile EDS and hypermobility spectrum disorder will be used except when clarity requires reference to an older diagnostic term.

The exact prevalence of hypermobile EDS/hypermobility spectrum disorders is unknown. The best estimates of the population prevalence of these conditions are derived from national or patient register studies from Sweden and Wales, UK, using diagnostic codes for EDS and joint hypermobility syndrome, the latter a former term for hypermobile EDS, as discussed previously.^9,10The prevalence of combined hypermobile EDS/hypermobility spectrum disorders is expected to be lower than the 0.13% to 0.19% prevalence found in these two studies for all EDS and joint hypermobility syndrome codes combined.^9,10This prevalence corresponds to approximately seven to ten patients from a panel of 5,000 patients. Another estimate of the prevalence of combined hypermobile EDS/hypermobility spectrum disorders from a UK population survey found that 3.4% of adults endorsed hypermobility and chronic widespread pain using validated instruments.¹¹

Generalized joint hypermobility, a diagnostic criterion for hypermobile EDS, is more common than hypermobile EDS/hypermobility spectrum disorders because patients with generalized joint hypermobility may be asymptomatic. When assessed in student population samples using the 2017 criteria, 4% to 11% of children aged three to 19 years had generalized joint hypermobility.^12–17The percentage of people with generalized joint hypermobility who are ultimately diagnosed with hypermobile EDS/hypermobility spectrum disorders is unknown.

Hypermobile EDS is the only EDS subtype for which a genetic mutation has not yet been discovered. Hypermobile EDS is believed to be inherited in an autosomal dominant manner with incomplete penetrance. The pathogenesis of hypermobile EDS and hypermobility spectrum disorders is still being unraveled, but involves muscle and tendon laxity,¹⁸reduced proprioception,¹⁹significantly disrupted connective tissue structure and changes in gene expression.²⁰

Hypermobile EDS and hypermobility spectrum disorders present a complex array of signs and symptoms of varying degrees and combinations that make these conditions difficult to recognize.Common features of hypermobile EDS are listed intable 2.^1,2,21The prevalence of generalized joint hypermobility decreases with age,²and this decrease is taken into account in the 2017 hypermobile EDS criteria by including historical questions for patients with subthreshold joint hypermobility.^1,7The strongest systemic findings associated with hypermobile EDS include anxiety disorders, chronic pain, fatigue, orthostatic intolerance, functional gastrointestinal disorders, and pelvic and bladder dysfunction.^22–26 table 3describes the symptoms and physical findings commonly associated with hypermobile EDS.^{2,22,23,26–38}

The diagnosis of hypermobile EDS should be considered in patients with clinical features noted intable 2.^1,2,21Patients with systemic manifestations(table 3^{2,22,23,26–38})and a history of joint hypermobility or arthralgia can also lead to hypermobile EDS or a related condition that was overlooked or previously misdiagnosed.¹A British patient survey found that the average time to diagnosis was 10 years.³⁹

The diagnosis of hypermobile EDS/hypermobility spectrum disorders is made based on medical history, physical examination, and exclusion of other conditions associated with musculoskeletal hypermobility.^2,40,41Diagnostic criteria for hypermobile EDS are listed inFigure 2.⁶ table 1outlines criteria for hypermobility spectrum disorders when patients do not meet the criteria for hypermobile EDS, nor any other specific condition.^1,4,5A differential diagnosis for joint hypermobility is shown inTable 4.^1,4,21,42It is important to take a careful family history, asking about joint hypermobility, musculoskeletal symptoms, aneurysms, and genetic disorders. When hypermobile EDS is suspected,The doctor should determine the degree and pattern of hypermobility using a validated instrument known as the Beighton score^1,40,41,43 (Table 5^1,44). The Beighton score involves five maneuvers to calculate a score between 0 and 9. The 2017 criteria for hypermobile EDS inFigure 2specify that if the Beighton score is one point below the age- and sex-specific cutoffs for generalized joint hypermobility, the next step is to administer a validated five-part questionnaire to help determine whether the patient has generalized joint hypermobility, a necessary criterion for the diagnosis of hypermobility EDS.^6,7Patients without generalized joint hypermobility may still have hypermobility spectrum disorders.figure 3suggests an evaluation strategy for patients suspected of hypermobile EDS or hypermobility spectrum disorders.^1,7

If generalized joint hypermobility is confirmed in patients with suspected hypermobile EDS, the remainder of the hypermobile EDS criteria is sought¹ (Figure 2⁶). This means that the patient is asked about a history of musculoskeletal complaints, an abdominal hernia and prolapse of organs and mitral valves; examination of the skin; testing for arachnodactyly; and measuring the ratio of arm span to height.Figure 1shows a typical atrophic scar.

There is no confirmatory test, so hypermobile EDS and hypermobility spectrum disorders remain clinical diagnoses.²Laboratory tests and radiographs to evaluate for acquired connective tissue disorders or suspected bone or joint injuries are based on the clinical history and physical examination. The presence of marfanoid features requires differentiation between hypermobile EDS and Marfan-related syndromes.Table 4lists characteristics that can help distinguish between these conditions.^1,4,21,42Screening echocardiography should be performed to evaluate for aortic root dilation or mitral valve prolapse in patients with possible hypermobile EDS. Specific genetic testing should be performed for other EDS variants, Marfan and Loeys-Dietz syndrome, and other genetic disorders if suspected(Table 4).^1,4,21,42Multiple visits are often required to complete a diagnostic evaluation. Many patients who do not meet the hypermobile EDS criteria and do not have clear evidence of another specific syndrome will meet the criteria for hypermobility spectrum disorders. If the diagnosis remains unclear, referral to a genetics specialist may be necessary for further investigation.eTabel Acontains resources that support the diagnosis and treatment of hypermobility syndromes.

The central goals of therapy are to control symptoms, prevent joint damage, and educate patients about their condition.^45–48Based on limited evidence and expert opinion, the pillars of treatment for hypermobile EDS and hypermobility spectrum disorders include patient education, physical and occupational therapy, psychological support, and self-management. Symptoms of hypermobility spectrum disorders may resolve with therapy, persist, or progress to hypermobile EDS. Hypermobile EDS is treated as a lifelong condition because there are currently no curative treatments.

Treatment strategies differ due to the many different systems that may be involved.Patients with hypermobile EDS may benefit from a multidisciplinary team consisting of physicians, nurses, physiotherapists, occupational therapists, orthopedic surgeons, nutritionists and/or lifestyle coaches, psychologists, and community and online support.Specialist care can help treat skin, joint, cardiovascular and gastrointestinal complications and chronic pain. General practitioners play a key role in monitoring and coordinating the complex care that many patients with hypermobile EDS require.

The treatment of musculoskeletal disorders includes conservative treatments such as physical activity, paracetamol and non-steroidal anti-inflammatory drugs, heat and/or cold application, improved ergonomics and posture, relaxation techniques, massage, hydrotherapy and joint stabilization techniques with bracing and/or taping.^47,49,50Medications that reduce platelet function should generally be avoided in patients with hypermobile EDS who bruise easily. Physiotherapists must adapt their training in strength exercises, proprioceptive exercises and joint protection.⁵¹Occupational therapists can help strengthen the muscles of the upper extremities and hands, improve activities of daily living, and introduce patients to adaptive writing instruments and other adaptive aids. Tai chi has shown benefits in patients with osteoarthritis, fibromyalgia and lower back pain.⁵²although it has not been studied in people with hypermobile EDS/hypermobility spectrum disorders. The use of splints and orthoses may help selected patients.

Educating patients about lifestyle changes, treatment options and expectations is one of the most important interventions. Encouraging optimal sleep, joint protection through the right amount of regular exercise (low impact and low resistance), weight management, avoiding drug use (e.g. alcohol, nicotine) and eating a healthy diet can reduce and support pain, injury and fatigue the mobility and mobility. functionality. Orthostatic intolerance can be reduced by drinking more fluids, increasing salt intake and using compression stockings.

Qualitative studies describe patients' experience of pain and disability with hypermobile EDS, which is often minimized or eliminated in their social circles and even in medical contexts because the patients are perceived as 'normal' or the condition goes unrecognized.^53–55The complexity of hypermobile EDS/hypermobility spectrum disorders and the lack of knowledge among clinicians may lead them to ignore or be skeptical of patients' experiences with their EDS conditions, potentially having lasting negative consequences for patients.⁵⁶Qualitative data strongly support the idea that earlier diagnosis and empathetic, informed clinical care are strongly desired by patients.^53–55but further research is needed to confirm whether earlier diagnosis and expert, caring support improve outcomes beyond patient satisfaction. The risks and benefits of invasive tests and procedures should be carefully assessed in patients with all forms of EDS because bleeding complications, inadequate response to regional and local anesthesia, and iatrogenic injury are common.⁵⁷

Finally, clinicians must be aware of and empathetic to the cognitive deficits, negative emotions, and changes in activity that can complicate this challenging condition.³⁷More research is needed, but three small studies of a multidisciplinary approach involving physical, occupational and cognitive behavioral therapy have shown reduced anxiety, depression, catastrophizing and kinesiophobia (fear of pain due to movement) with improved physical functioning and self-efficacy in treated patients. patients.^32,58,59A comparable multidisciplinary intervention without cognitive behavioral therapy showed no benefit.⁴⁵

A three-phase natural history of hypermobile EDS has been proposed based on a large Italian case series.⁴⁹In this series, patients progressed from generalized joint hypermobility alone with or without joint pain in childhood to musculoskeletal pain, falls, mixed headaches, and functional gastrointestinal disorders in the second and third decades of life. In the third to fourth decades of life, patients developed inflexibility, widespread pain, and disabling fatigue. The prognosis of hypermobile EDS/hypermobility spectrum disorders varies widely and is difficult to predict for individual patients. A convenience sample of children diagnosed with a precursor to hypermobile EDS in a tertiary care hospital, followed for three years, found four factors that predicted disease severity and modestly predicted disability development over the course of predicted time: multisystem involvement, pain, fatigue, and postural control.⁶⁰However, variable results were the rule. In adults, chronic pain, gastrointestinal and genitourinary problems, fatigue, limited mobility and frequent injuries were most often associated with the functional outcomes of reduced perceived quality of life and reduced participation in daily activities.^30,53,61

The authors would like to thank our medical librarians at the Gundersen Health System-La Crosse campus and Drs. Karyn Laursen and Kerry Jedele for their reviews and assistance with the manuscript.