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Abstract
Objective To determine if exploratory factor analysis can identify subtypes comprising recognisable clinical patterns of the presenting signs and symptoms of children with joint hypermobility syndrome (JHS).
Patients Eighty-nine children with JHS aged 6–16 years.
Methods Twelve tests comprising anthropometric, musculoskeletal and functional assessments were conducted. Signs, symptoms and family history were recorded. Exploratory factor analysis was performed, factor scores generated, and correlations calculated to identify associations.
Results Sixty-six percent of the variance in the score set could be accounted for by five JHS subtypes (Eigenvalues >1). Factor 1, ‘joint affected’ JHS, had loadings on multiple joint pain, recurrent joint instability and postural orthostatic hypotension symptoms, and factor scores were associated with worse pain (r=0.48, p<0.01), fatigue (r=−0.54, p<0.01) and reduced health-related quality of life (HRQOL) (r=−0.5, p<0.01). Factor 2, ‘athletic’ JHS, loaded on muscle endurance, balance and motor skill proficiency, and scores were associated with less fatigue (r=0.3, p<0.01) and better HRQOL (r=0.44, p<0.01). Factor 3, ‘systemic’ JHS, loaded on skin involvement, incontinence symptoms, bowel involvement and recurrent joint instability, and was associated with reduced HRQOL (r=−0.24, p=0.03). Factor 4, ‘soft tissue affected’ JHS, loaded on recurrent soft tissue injuries and reduced muscle length, and was associated with greater fatigue (r=−0.43, p<0.01) and reduced HRQOL (r=−0.44, p<0.0001). Factor 5, ‘high BMI’ JHS, had high loadings on body mass index (BMI) for age, muscle endurance and no gastrointestinal involvement, and was associated with higher pain (r=0.33, p<0.01).
Conclusions The presenting signs and symptoms of children with JHS can be summarised in five clinically recognisable subtypes.
- Joint Hypermobility Syndrome
- Ehlers-Danlos Syndrome
- Joint laxity
- factor analysis
- heritable disorder of connective tissue
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- Joint Hypermobility Syndrome
- Ehlers-Danlos Syndrome
- Joint laxity
- factor analysis
- heritable disorder of connective tissue
What is already known on this topic?
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JHS is a heterogeneous condition characterised by generalised joint hypermobility, musculoskeletal pain, variable multisystem involvement and functional disability.
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The degree of joint hypermobility in JHS is not associated with the severity of disability or organ involvement.
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Diagnosis is made on broad criteria following exclusion of other disorders, and no molecular test is available to provide a definitive diagnosis.
What this study adds?
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Five distinct subtypes of JHS have been identified: joint affected, athletic, systemic, soft tissue and high BMI.
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Children with high scores on ‘joint affected JHS’ have the most symptomatic presentation with higher pain, fatigue and reduced quality of life.
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Conversely, those scoring high on the ‘athletic JHS’ subtype have relatively lower fatigue, better quality of life and higher physical activity participation.
Introduction
Joint hypermobility syndrome (JHS) is a disorder characterised by generalised joint hypermobility, musculoskeletal pain and injuries. It is diagnosed using the Brighton criteria (table 1) following exclusion of other heritable disorders of connective tissue.1 While the Brighton criteria have not yet been validated in children, experts suggest that the criteria remain useful in the paediatric population2 and the Brighton criteria are now commonly used within paediatric research to define cohorts of children with JHS.3–5 Expert consensus considers JHS and Ehlers–Danlos Syndrome—hypermobile type (EDS-HT) to be clinically indistinguishable6 despite the differing diagnostic criteria that remain in use today. EDS-HT is diagnosed using the 1997 Villefranche criteria (table 1) in children and adults.7 Other significant systemic manifestations of JHS in children, including childhood constipation,8 reduced exercise capacity9 and diastolic dysfunction,3 are not currently included in either Brighton or Villefranche criteria. In children and adolescents, disabling fatigue,4 reduced quality of life10 and functional difficulties11 have been described. The lack of unified diagnostic criteria for this disorder, in conjunction with recent understanding of non-musculoskeletal manifestations, highlights the significant heterogeneity seen in JHS/EDS-HT.
Diagnostic criteria for joint hypermobility syndrome (JHS) and Ehlers–Danlos Syndrome–hypermobile type (EDS-HT)
Experts recommend identification of subsets of JHS/EDS-HT incorporating the non-musculoskeletal involvement12 to allow more consistent diagnosis and tailoring of treatment strategies for individual patients. In adults with EDS-HT, three distinct subsets have been described, primarily differentiated by non-musculoskeletal symptoms.13 However, as symptomatology of this condition alters with age14 exploring the heterogeneity of children and adolescents may provide insight into early optimal management.
Factor analysis is a statistical method used to summarise the pattern of correlations between variables into a smaller number of independent factors that may correspond with different underlying disease processes and explain some of the variation within the data.15 Resulting factors can then characterise subtypes of patients with a condition. Using factor analysis, this study aims to determine if the observed clinical heterogeneity of JHS in children can be summarised into a smaller number of recognisable clinical presentations.
Methods
Patients
Children aged 6–16 years fulfilling the Brighton criteria were recruited from specialist clinics of a large tertiary paediatric service in New South Wales, Australia, and included symptomatic siblings or friends of other participants. This recruitment process resulted in the inclusion of children with JHS with varying levels of pain and disability. Potential participants were excluded if they had other significant comorbidities.
Self-reported assessments
All children underwent an assessment with an experienced physiotherapist (VP) or rehabilitation specialist (LT) with a parent present. The symptoms that were reported by parents and children and used in analyses are detailed in table 2.
Self-report and physical measures taken, method of collection and where used
Four questionnaires were also completed within this assessment, with the researcher present to assist if required. This included three Pediatric Quality of Life (Peds QL) questionnaires (see table 2). These reliable and valid instruments16–18 have been widely used to determine the health-related quality of life (HRQOL), fatigue and pain levels of healthy children and those with chronic conditions.10 ,16 ,19 All Peds QL measures employed are designed for assessing children aged 5–16 years.
The Adolescent Physical Activity Recall Questionnaire20 was also completed. This questionnaire collates the frequency and duration of all organised and non-organised physical activity undertaken, and has demonstrated acceptable reliability and validity in adolescents.20 With younger children in the present study, this questionnaire was used without difficulties. From the information obtained, the average number of minutes per week spent performing moderate and vigorous activities21 was calculated.
Objective assessments
Objective assessments taken are outlined in table 2. The Beighton score is a 9-point scale used when screening for generalised joint hypermobility, with points given based on the child's ability to touch the floor with the palms of their hands while keeping knees straight, touch the tip of their thumb to their forearm and to hyperextend their elbows, knees and fifth metacarpophalangeal joint.22 The Beighton score and Lower Limb Assessment Scale (LLAS)23 have demonstrated good reliability in the paediatric population.24 Popliteal angle measurement, taken while controlling pelvofemoral position,25 is considered to be the most reliable measure of hamstring flexibility.26
The leg lift/duration manoeuvre from the Childhood Myositis Assessment Scale is reliable in children, with normative data of healthy children demonstrating 96–100% of children aged ≥6 years can obtain the maximum score.27
The Star Excursion Balance Test (SEBT)28 composite score, consisting of the average of the anterior, posteromedial and posterolateral direction measurements, normalised for leg length, was calculated. The 6-min walk test was administered as per American Thoracic Society guidelines,29 and then normalised for leg length.30
The fundamental motor skills assessment is widely used in the local school system. Children achieve mastery of the skill if they demonstrate all components, or near-mastery if they demonstrate all but one component.21
Statistical analysis
An exploratory factor analysis using principal components analysis with varimax rotation (described in15 ,31 ,32) was undertaken using SPSS V.21, following assessment of normality for each measure. Principal components analysis has been used previously to identify clinical patterns representing the phenotypical presentations of complex disorders such as chronic fatigue syndrome33 and coagulation patterns post-trauma.32 With this method, a loading matrix is generated displaying the extent of the correlation between each of the included measures and the identified factors (subtypes). The loadings of each measure on each factor range from −1 to +1 (table 3), and estimate the extent to which each measure is weighted within an identified factor (subtype). Measures with loadings of ≥0.3 or ≤−0.3 are considered meaningful to the interpretation15 ,32 ,33 and, hence, the pattern of meaningful measures was used to name each subtype. The percentage of total variance in the measures that can be explained by each subtype is reported in table 3.
Item loadings of the 5 joint hypermobility syndrome (JHS) subtypes identified from the retained factors
All measures were standardised by conversion to Z-scores, and the sum of all measures which had meaningful loadings for each factor (subtype) was calculated to create a set of ‘factor scores’ for each child, one score for each subtype. These factor scores were then correlated with measures of self-reported symptoms, markers of physical activity participation and the intrinsic characteristics of the child (table 4). Correlations of r=0.1 were considered as weak, r=0.3 moderate and r≥0.5 strong.34 Because factor analysis techniques result in each child having a set of scores on the identified factors (subtypes), they do not exclusively fit every child into one identified subtype.15 While the highest factor score obtained for each child best determines the subtype they are most likely a member of, moderate factor scores can be achieved on multiple subtypes.
Correlation between JHS subtypes and intrinsic characteristics, physical activity and symptoms
Results
Eighty-nine children (50 girls) with JHS aged 6–16 years were assessed between August 2011 and July 2012. Sixty-one participants (80%) seeking professional healthcare for JHS-associated musculoskeletal complaints were recruited from the following specialist paediatric services—connective tissue dysplasia management service incorporating geneticists and musculoskeletal rehabilitation physicians (42%), rheumatologist (15%), sports physician (11%), physiotherapist (9%), orthopaedic surgeon (2%) and podiatrist (1%). The remaining 18 participants (20%) were friends or siblings of participants not currently seeking specialist-level healthcare services for their hypermobility symptoms. The sample recruited by this process was, therefore, generalisable to the wider population of children with JHS.
Table 5 describes the characteristics of the included children, with the SD and range for each measure indicating the variability within the cohort. Non-musculoskeletal involvement was present in 91% of children—(gastrointestinal (54%), skin (78%), eye (28%), cardiovascular (42%), incontinence (26%) and hernia (12%)). Musculoskeletal symptoms were present in all children, with 61% reporting recurrent joint instability episodes and chronic pain, 8% reporting recurrent joint instability only, and the remaining 31% of children reporting chronic pain only.
Characteristics of the participating children with joint hypermobility syndrome (n=89)
Factor analysis and identification of subtypes
Five clinically interpretable subtypes (factors) with eigenvalues >1 and minimal overlap of meaningfully weighted measures were identified following inspection of the scree plot, accounting for 65.8% of the total variance (table 3). A 6-factor model was rejected due to an eigenvalue <1.15 Subtype 1, labelled ‘Joint Affected JHS’, was characterised by a high number of painful joints, recurrent joint instability episodes and orthostatic hypotension symptoms. Subtype 2 was distinguished by better muscle endurance, balance and leaping proficiency, and was designated ‘Athletic JHS’. Subtype 3, called ‘Systemic JHS’, was described by two unique symptoms, skin involvement and urinary stress incontinence symptoms, as well as the overlapping complaints of recurrent joint instability and gastrointestinal involvement. Subtype 4 was characterised by recurrent soft tissue injuries and reduced hamstring muscle length and was thus called ‘Soft Tissue Affected JHS’. Subtype 5 was the only factor with high BMI centile for age, and also had high loadings for having no gastrointestinal involvement and better muscle endurance. Hence, subtype 5 was named ‘High BMI JHS’.
Association of JHS subtypes with self-reported symptoms
The ‘joint affected’ subtype was found to be the most symptomatic, with children achieving high factor scores on this subtype also experiencing more pain (r=0.48, p<0.001), more fatigue (r=−0.54, p<0.0001) and lower HRQOL (r=−05, p<0.0001) (table 4). The children with high scores on the ‘high BMI’ subtype experienced more pain (r=0.33, p=0.002), and those with high scores on the ‘soft tissue affected’ subtype experienced worse fatigue (r=−0.43, p<0.0001) and HRQOL (r=−0.44, p<0.0001). Children with high factor scores on the ‘systemic’ subtype had a weak-moderate association with worse HRQOL (r=−0.24, p=0.03). ‘Athletic’ JHS was the only subtype where high factor scores were significantly related to having less fatigue (r=0.3, p=0.006) and better HRQOL (r=0.44, p<0.0001).
Association of JHS subtypes with physical activity participation and proficiency
Children with high factor scores on the ‘athletic’ subtype were significantly associated with higher exercise capacity (r=0.4, p<0.0001), higher physical activity participation (r=0.39, p<0.0001) and better proficiency of all gross motor skills (r=0.28–0.53, all p≤0.01). Children with high scores on the ‘high BMI’ subtype were weakly to moderately associated with higher physical activity participation (r=0.23, p=0.04). High factor scores on the ‘joint affected’ (r=−0.26, p=0.02) and ‘soft tissue affected’ (r=−0.32, p=0.003) subtypes were both associated with lower exercise capacity.
Association of JHS subtypes with and intrinsic characteristics of the child
The only significant association with having a hypermobile parent was found for the children with high factor scores for the ‘joint affected’ JHS (r=0.21, p=0.05). Having a high factor score for ‘soft tissue affected’ JHS was associated with the extent of joint hypermobility and laxity, with the significant negative association (r=−0.27, p=0.01) being because less laxity corresponds to a lower score as measured by the LLAS. The Beighton score was not associated with any of the subtypes. The ‘joint affected’ (r=0.48, p<0.0001), ‘soft tissue affected’ (r=0.33, p=0.001) and ‘high BMI’ (r=0.23, p=0.04) subtypes were all age-related, with increasing age associated with higher factor scores on the nominated subtypes.
Discussion
This study identifies five distinct, clinically recognisable subtypes of JHS derived from a statistical analysis of objective physical measurements and reported symptoms. The factor score correlations with self-reported pain, fatigue and HRQOL delineate which clinical presentations are likely to be most symptomatic, and together with the features associated with the factors, thereby provide insight into possible treatment strategies for individual patients based on their most likely subtype.
‘Joint affected’ JHS accounted for the greatest variance in the employed measures and was the most symptomatic subtype. Postural orthostatic hypotension and postural orthostatic tachycardia syndrome have been reported in adolescents with JHS/EDS-HT.35 ,36 However, the cause of these symptoms in this population remains unknown. It may be due to: lax connective tissue in dependent blood vessels resulting in pooling in response to normal hydrostatic pressures,35 primary autonomic system dysfunction37 or deconditioning from chronic pain.38 Comparatively older age and reduced exercise capacity were both associated with this subtype.
Comparatively older age was significantly associated with higher scores on all three most symptomatic subtypes of JHS—‘joint affected’, ‘soft tissue affected’ and ‘high BMI’. There were no associations of factor scores with relatively younger age, indicating that while children of all ages with JHS can remain ‘well’, symptoms are more likely to occur in adolescents. ‘Joint affected’ and ‘Soft tissue affected’ JHS subtypes both demonstrated lower functional exercise capacity. Importantly, a problem cascade is often seen in children with JHS in the clinical setting, where previously well children experience an injury or insidious intractable pain that leads to deconditioning and/or weight gain, resulting in exacerbation of symptoms and reduced HRQOL. Early identification of at-risk children prior to cascade onset may allow for appropriate preventative strategies to be implemented. However, longitudinal studies are needed to confirm if children's factor scores and, hence, their clinical presentations, move between these subtypes as they get older.
The ‘Athletic’ JHS subtype accounted for the second largest amount of variance in the collected measures within this cohort, and identification of this subtype may provide insights into possible treatment strategies. Maintenance of gross motor skills, balance and muscular endurance, while continuing participation in physical activity, may be protective against pain, fatigue and reduced HRQOL in JHS. However, conversely, these children may be the ones who are better able to participate in physical activity as a result of their lower pain levels.
Obesity in the presence of joint hypermobility significantly increases the risk of pain in weight-bearing joints affected by mechanical forces.39 Interestingly, while having a high factor score on the ‘high BMI’ subtype was associated with higher pain levels, high scorers on this subtype also participated in more physical activity and their HRQOL was unaffected. Physical activity may be protective for children with JHS, suggesting that high scorers on this subtype have a disposition to be better copers with pain.
The possibility that some of these subtypes represent a yet-to-be-defined genetic condition is noteworthy. Currently, JHS/EDS-HT cannot be diagnosed by molecular testing, and new heritable disorders of connective tissue involving joint hypermobility within their diagnostic criteria are continually being described. ‘Joint affected’ JHS was associated with having an affected parent, representing a likely autosomal dominant condition. ‘Systemic’ JHS demonstrated association with multisystem involvement, indicating a likely more global connective tissue defect. The disorder in the ‘soft tissue affected’ subtype appears to be limited to the musculoskeletal system.
It is also of note that the LLAS, but not the Beighton score, was associated with the ‘soft tissue affected’ JHS subtype. The LLAS incorporates measures of joint laxity in accessory planes of movement (ie, knee rotation and ankle anterior drawer), muscle length (ie, hip abduction and ankle dorsiflexion) and joint hypermobility in physiological planes of movement (ie, knee hyperextension, metatarsophalangeal extension).23 While only assessing the lower limbs, this provides a more comprehensive assessment of the effect of JHS/EDS-HT on the musculoligamentous system than the Beighton score, and is a useful tool in the clinical and research setting.
The present study is the first of this kind in children with JHS. Similar to the findings from cluster analysis performed with adults with EDS-HT,13 a high level of non-musculoskeletal symptoms was seen in our cohort. However, we were able to identify a subtype of children with JHS who were relatively asymptomatic (‘athletic’ JHS). The use of objective physical measures within our analysis, and the robust statistical technique of factor analysis, adds significant strength to our findings. Longitudinal studies will provide evidence as to whether children demonstrating a particular clinical presentation can move from a symptomatic subtype to a relatively asymptomatic subtype. Randomised controlled trials assessing treatment efficacy will determine whether treatment prioritisation based on subtype is an effective management strategy.
Conclusion
The major proportion of clinical heterogeneity seen in children with JHS can be accounted for by five distinct clinical subtypes, each impacting differently on the child's HRQOL, pain and fatigue. Greater recognition of the common clinical presentations of the musculoskeletal and systemic manifestations of this condition may assist clinicians and researchers in identifying appropriately tailored treatment techniques.
Acknowledgments
We wish to acknowledge the contribution of Melanie Ryan, physiotherapist, for her assistance with data collection, and the children and families for participation in this study. VP is supported by The Menzies Foundation Sir Robert Menzies Memorial Research Scholarship in the Allied Health Sciences.
References
Footnotes
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Competing interests VP is supported by The Menzies Foundation Sir Robert Menzies Memorial Research Scholarship in the Allied Health Sciences.
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Ethics approval The study was approved by The Children's Hospital at Westmead and The University of Sydney Human Ethics Committees.
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Patient consent Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.