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Hypermobility syndrome
Key Points
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Joint hypermobility as a clinical entity is difficult to define given current parameters; the Beighton score is not fit for this purpose, and a new measurement tool is required to identify patients with significant global joint laxity.
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Diagnostic criteria have changed. The 2017 International Diagnostic Criteria for Ehlers-Danlos Syndrome (EDS) has given more clarity to the various EDS types. The term benign joint hypermobility syndrome (BJHS) is no longer used. Hypermobile-EDS (hEDS) has clearly defined diagnostic criteria and replaces the previous EDS-type III and EDS-hypermobility type.
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Many of the young people reviewed will not meet the hEDS criteria and better fit primary chronic widespread pain.
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There is no current evidence for a connective tissue abnormality within hypermobile Ehlers-Danlos Syndrome (hEDS); the small subset of patients with significant joint laxity and associated problems may show an underlying causative factor as research progresses.
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There is no current evidence for the comorbidities reported with hEDS as being definitively caused by underlying pathology. There is a great deal of evidence showing that many of the comorbidities are associated with persistent pain.
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Evidence shows that interdisciplinary support with physiotherapy, occupational therapy, and psychology is effective for patients with joint laxity and pain-associated disability.
Introduction
Joint hypermobility denotes ligamentous laxity such that the movement is beyond what is considered normal for the joint according to age, sex, and race. Diagnosing a person with joint hypermobility suggests that we know what normal ranges are for that individual; this is rarely the case, so one should evaluate clinically and use best judgement.
The hereditary connective tissue diseases (HCTD) are a group of conditions in which known collagen abnormalities lie at the foundation of the symptoms and signs (osteogenesis imperfecta, Ehlers-Danlos syndrome [EDS] classical type, Marfan syndrome). Other conditions have hypermobile joints as part of more global problems (e.g., Trisomy 21). In such patients the ligamentous laxity is often profound. Mechanical sequelae are significant, and management is directed by their needs.
However, there are also significant numbers of people with joint laxity but with no underlying defined collagen abnormality. There continues to be considerable debate concerning diagnostic criteria, pathology, and associated comorbidities of such joint hypermobility. The majority of children and adults with significant joint laxity do not have pain or any other symptoms; their increased flexibility confers advantage in sport, dance, and music. The significant minority who describe musculoskeletal pain and other symptoms, however, do need the attention of health professionals. In directing rehabilitation it is important to have an understanding of the cause of their pain and any associated health conditions while not overmedicalizing or stating certainty in the absence of evidence. It is often very difficult for a health professional to differentiate between joint laxity with chronic pain and chronic pain in isolation. Both can be disabling with significant pain-associated disabilities.
Within this chapter, we explore the diagnosis of joint hypermobility further, providing readers with a balanced and current overview of diagnosis, epidemiology, associations, and management. There is still much to learn.
Epidemiology and Genetics
Most epidemiologic data sets reference the diagnosis of joint hypermobility being given to individuals who score 4 of 9 or greater on the Beighton scoring system. There is concern that this is not an ideal measurement tool (as discussed later); therefore current epidemiologic data should be viewed with some caution and an understanding that, as our knowledge and evidence in this area increases, prevalence data may alter.
Population studies show a wide variation in the prevalence of generalized joint hypermobility. In the United Kingdom, a recent large retrospective cohort study showed that 18.3% of adults self-reported a history of joint hypermobility; these individuals were more likely to be female, younger, have an active lifestyle, and smoke compared with their nonhypermobile counterparts. The authors used a postal self-report 5-point questionnaire and commented that this was subjective (depending on historical recall) and may well lead to an overdiagnosis of flexibility.
In other studies, the prevalence varies between 10% and 30% of the general adult population. As with the U.K. study, joint laxity decreases with age and is more common in those from an Asian or African descent. Indeed, in some regions, a diagnosis of hypermobility could be applied to more than 50% of the population; this underlines the importance of striving for a more meaningful measure.
No normative joint range data have yet been published for the developing skeleton. It is widely believed that younger children have a greater normative range than postpubertal adolescents. A large U.K. schoolchild cohort study ( n = 5812) showed that 19.8% of 13-year-old children had a Beighton score of 4 or greater (27.5% of girls and 10.5% of boys). More than 30% scored positively for two aspects of the Beighton measure (fifth metacarpophalangeal dorsiflexion and apposition thumbs). There was no significant difference with laterality, body mass index, maternal education, or pubertal status in this cohort.
The prevalence of joint hypermobility in adults is unknown; this is in part because of the clinical difficulty in diagnosing this as an entity within generic chronic pain conditions.
In contrast, well-defined hereditary connective tissue disorders show clear prevalence and genetic data ( Table 217.1 ).
Table 217.1
Hereditary Connective Tissue Disorders a
| Condition | Prevalence (Estimated Worldwide) | Genetics (Gene and Chromosome) |
|---|---|---|
| Marfan syndrome | 1 in 5000 | FBN1 c/s 15q21 |
| Homocystinuria | 1 in 200,000 |
|
| Ehlers-Danlos syndromes (see Table 217.2 ) | 1 in 20,000–1 in 1,000,000 depending on subtype | |
| Osteogenesis imperfecta | 1 in 20,000 |
|
| Stickler syndrome | 1 in 9000 | COL2A1 (AD in 95% of cases) |
| Williams syndrome | 1 in 10,000 | ELN, CLIP2 c/s 7 |
AD , Autosomal dominant; AR , autosomal recessive.
a Hypermobility is also associated with other chromosomal abnormalities, including trisomy 21, fragile X syndrome, and Larsen syndrome.
Diagnostic Criteria for Conditions Presenting to Rheumatology With Associated Hypermobility
Diagnosing Generalized Hypermobility
Joint mobility is a continuous trait that varies with joint location and is strongly influenced by age, gender, and ethnic origin. In 1973, Beighton developed an edited version of the 1964 Carter and Wilkinson scoring system for specific joints as part of his research on articular mobility in an African population ( Fig. 217.1 ). This scoring system has long been used subsequently as the basis for defining generalized joint hypermobility if more than four of a possible nine defined joints are hypermobile. Many authors now believe that the Beighton scoring tool is not fit for purpose clinically ; it does not take into account race, gender, age, or prior physical training, all of which can affect the normative joint range. There is a need for consensus on meaningful measurement to facilitate both definition and insightful treatment.
In both children and adults, it is important to examine all joints and, taking into account known epidemiologic normative data, make a diagnosis of generalized hypermobility if widespread laxity is found.
Classification of the Ehlers-Danlos Syndromes
In March 2017, by international consensus, the classification of the Ehlers-Danlos Syndrome was changed with the release of the 2017 International Diagnostic Criteria, recognizing 13 types of EDS ( Table 217.2 ). The diagnostic criteria for the most common type, previously called EDS-Hypermobility Type (EDS-HT), was modified compared to the 1997 Villefranche nosology and renamed hypermobile-EDS (hEDS). The diagnostic checklist can be accessed on https://ehlers-danlos.com/wp-content/uploads/hEDS-Dx-Criteria-checklist-1.pdf .
Table 217.2
The 2017 International Classification on Ehlers-Danlos Syndrome (EDS)
| Name of EDS Subtype | IP a | Genetic Basis | Protein Involved |
|---|---|---|---|
| Classical EDS (cEDS) | AD | Major: COL5A1, COL5A2 | Type V collagen |
| Rare: COL1A1 c.934 C>T, p.(Arg312Cys) | Type I collagen | ||
| Classical-like EDS (cIEDS) | AR | TNXB | Tenascin XB |
| Cardiac-valvular EDS (cvEDS) | AR | COL1A2 (biallelic mutations that lead to COL1A2 NMD and absence of pro α2(I) collagen chains) | Type I collagen |
| Vascular EDS (vEDS) | AD | Major: COL3A 1 | Type III collagen |
|
Type I collagen | ||
| Hypermobile EDS (hEDS) | AD | Unknown | Unknown |
| Arthrochalasia EDS (aEDS) | AD | COL1A1, COL1A2 | Type I collagen |
| Dermatosparaxis EDS (dEDS) | AR | ADAMTS2 | ADAMTS-2 |
| Kyphoscoliotic EDS (kEDS) | AR | PLOD 1 | LH1 |
| FKBP14 | FKBP22 | ||
| Brittle cornea syndrome (BCS) | AR | ZNF469 | ZNF469 |
| PRDM5 | PRDM5 | ||
| Spondylodysplastic EDS (spEDS) | AR | B4GALT7 | β4GalT7 |
| B3GALT6 | β3GalT6 | ||
| SLC39A 13 | ZIP13 | ||
| Musculocontractural EDS (mcEDS) | AR | CHST14 | D4ST1 |
| DSE | DSE | ||
| Myopathic EDS (mEDS) | AD or AR | COL12A1 | Type XII collagen |
| Periodontal EDS (pEDS) | AD | C1R/C1S | C1r/C1s |
a Inheritance Pattern: AD , Autosomal dominant; AR , autosomal recessive.
Hypermobile Ehlers-Danlos Syndrome (hEDS)
The majority of the population that have significant joint laxity have no problems; their “bendiness” actually lends itself to activities where flexibility is an advantage. A significant minority, however, do have joint pain, fatigue, and other symptoms, and it is this population who were often previously given a diagnosis of joint hypermobility syndrome (JHS). This term is no longer used. Those who appear to have hypermobility-related problems but do not fulfil the stricter criteria for hEDS, and do not have a heritable disorder of connective tissue (HDCT), are sometimes given the diagnosis of hypermobility spectrum disorder (HSD). However, this label is not used widely and has not been validated in young people. It is the authors’ opinion that, without significant global laxity, this term is not meaningful and it is clinically impossible often to separate from primary chronic pain syndromes.
There is current debate concerning the criteria within the Brighton score. Arguably, these are not specific and could apply to the many patients reviewed in clinics with joint pain (and pain-related disabilities) who have no signs of joint laxity. This runs the risk of both overdiagnosis (and overmedicalization) of joint laxity and underinvestigating the few who may have significant collagen abnormalities. The Brighton criteria has been validated in adults but not in children, in whom their relevance remains unknown. With current knowledge, it is arguably not appropriate to provide a diagnosis of HSD to children.
No biochemical, molecular, or structural defect has been identified in hEDS. The role of genetics is controversial but evolving, with genetic testing increasingly available in clinical and research settings. Some pedigree studies have suggested a weak autosomal dominant inheritance pattern with variable penetrance, but most cases do not appear to be linked to an identifiable mutation. The literature shows that 5% of individuals who received a diagnosis of Ehlers-Danlos Syndrome Hypermobility Type (EDS-HT) demonstrate lower levels of tenascin X with mutations in the TNXB gene. These small case series do not indicate whether those few with the diminished levels have a more severe phenotype. The true prevalence of hEDS as currently described is not known.
Marfan Syndrome
In 2010, the Ghent diagnostic criteria for Marfan syndrome were revised to allow better specificity for this condition. The revised Ghent nosology gives more weight to the cardiovascular manifestations, particularly aortic root aneurysm, and ectopia lentis. It also considers family history, the presence of FBN1 mutation and a combination of systemic features. A scoring system has been devised to include these features. The aim of the revised Ghent nosology was to reduce the risk of premature diagnosis or misdiagnosis, particularly of relatives that arose by relying solely on the previous Berlin nosology after unequivocal diagnosis in a first-degree relative.
Clinical Musculoskeltal Associations With Joint Laxity (Known and Postulated)
Musculoskeletal Pain
Musculoskeletal pain is relatively common in the general population, reported in 30% to 50% of adults and 10% to 28% of children. Musculoskeletal pain and fatigue are often the presenting symptoms of a patient where there is underlying joint laxity. Typically, this is pain in the lower limbs during or after activity.
Pain may be attributed to excessive movement stretching the joint capsule, ligaments, or both; particularly affecting those joints under high force because of weight bearing (knee, foot, and ankle) or inherent instability (shoulder) ( Fig. 217.2 ). Poor proprioception may be observed in patients with joint laxity, and as proprioception is essential for joint stabilization, it is understandable how this may lead to increased risk of joint injury, particularly in the knees. A reduced muscle mass and strength may ensue, particularly as fear of pain (which may have been a factor from early childhood) can lead to reduced physical exercise for fear of precipitating or exacerbating discomfort. This may contribute to a general deconditioning and exercise intolerance, thus exacerbating the laxity of the joints by weakening the protective strength of the associated muscle.
A prospective cohort study following 14,000 children from birth found that children with significantly hypermobile joints (classified as Beighton score ≥6) at a mean age 13.8 showed a twofold increased risk of moderately troublesome shoulder, knee, and ankle of foot pain at a mean age of 17.8 years compared with those without hypermobile joints, particularly with knee pain in those with joint hypermobility and obesity. In this large cohort study, there was no association with increased chronic widespread pain or back pain. A recent study concluded that hypermobility and pain have an independent natural history and are probably influenced by different factors. In adults, there is a moderate association between chronic widespread pain and a Beighton score of 4 or greater, but there is no robust evidence that this is causal. Many studies are inevitably biased because they are based on self-selected clinic populations.
Management of the musculoskeletal pain that may be associated with hypermobile joints is discussed later.
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