Recognising and understanding commonly co-occurring health conditions, often referred to as multimorbidity, is crucial for the delivery of targeted and coordinated interventions to affected individuals. Multimorbidity significantly impairs health-related quality of life, particularly for those with physical/mental multimorbidity, who face a disproportionately higher risk. Reference O’Loughlin, Hiscock, Pan, Devlin and Dalziel1 However, research has mainly focused on adults. Further insights on multimorbidity could shed light on disease progression and the underlying aetiopathogenetics. Reference Hu, Thomas and Brunak2 Recently there has been growing awareness of the somewhat unexpected association between joint hypermobility and neurodevelopmental problems (NDPs), both believed to emerge predominantly in childhood and adolescence.
Joint hypermobility and associated conditions
Joint hypermobility describes an increased range of motion in synovial joints, and is termed generalised joint hypermobility (GJH) when it affects multiple joints (typically at least four, depending on age and assessment tool). Reference Castori, Tinkle, Levy, Grahame, Malfait and Hakim3 GJH is estimated to affect approximately 10–20% of the general population. Reference Remvig, Jensen and Ward4 However, reported prevalence rates vary widely among studies due to factors including age, gender, race and assessment method. Reference Remvig, Jensen and Ward4 A large Swedish study from 2004 reported a prevalence of 15% in girls and 6% in boys at the age of 12 years, if the current age-specific recommendations of ≥6/9 on the Beighton score were to be applied. Reference Jansson, Saartok, Werner and Renström5 In Swedish adults, GJH rates were noted at 11% in females and 5% in males. Reference Glans, Thelin, Humble, Elwin and Bejerot6,Reference Glans, Thelin, Humble, Elwin and Bejerot7 GJH is an umbrella term that does not inherently differentiate between symptomatic and asymptomatic presentations, a distinction that remains debated and subject to evolving definitions. When systemic manifestations such as musculoskeletal issues (e.g. pain, joint instability, dislocations), cutaneous manifestation (e.g. stretchy skin, striae, atrophic scars) and varying degrees of tissue fragility (e.g. recurrent hernias, vascular aneurysms) accompany GJH, it may be part of a hereditary connective tissue disorder (HCTD) such as Ehlers–Danlos Syndrome (EDS), affecting approximately 1 in 5000 individuals. Reference Malfait, Francomano, Byers, Belmont, Berglund and Black8 For symptomatic GJH cases not meeting the diagnostic HCTD criteria, the term generalised hypermobility spectrum disorder (gHSD) is used; gHSD encompasses GJH with related musculoskeletal manifestations, such as recurring or chronic musculoskeletal pain or frequent joint dislocations. Prevalence estimates for gHSD are scarce, ranging from 0.75 to 2.0% in the general population, assuming that about 10% of individuals with GJH experience symptomatic GJH. Reference Tinkle, Castori, Berglund, Cohen, Grahame and Kazkaz9 The progression of GJH to symptomatic GJH remains uncertain, Reference Tofts, Simmonds, Schwartz, Richheimer, O’Connor and Elias10,Reference Sohrbeck-Nøhr, Kristensen, Boyle, Remvig and Juul-Kristensen11 and studies investigating the relationship between GJH and musculoskeletal pain in children have produced conflicting results. Reference Sohrbeck-Nøhr, Kristensen, Boyle, Remvig and Juul-Kristensen11–Reference Tobias, Deere, Palmer, Clark and Clinch16 For most types of EDS, responsible genes encoding for collagens and enzymes involved in their biosynthesis, or the maintenance of extracellular matrix homeostasis, have been identified. The underlying mechanisms for GJH, gHSD and hypermobile EDS (hEDS) remain unknown, but are thought to involve a similar pathogenesis. Reference Castori, Tinkle, Levy, Grahame, Malfait and Hakim3,Reference Malfait, Francomano, Byers, Belmont, Berglund and Black8 Collagens are abundant in humans, constituting approximately 25% of the body’s total protein content; as a fundamental component of the extracellular matrix, they provide structural support and shape to tissues. Additionally, they interact with cells through various receptor families, thereby regulating their proliferation, migration and differentiation throughout the body. Reference Arseni, Lombardi and Orioli17 Consequently, the increased awareness of burdens beyond the core musculoskeletal and cutaneous features of the joint hypermobility spectrum is not surprising. A recent expert consortium on children with gHSD and EDS recognised specific conditions as ‘core comorbidities’ (defined as having evidence from at least cohort studies and a prevalence greater than 10%), including chronic pain, chronic fatigue, functional gastrointestinal disorders, functional bladder disorders, dysautonomia and anxiety. It also identified several ‘emerging comorbidities’ (limited current evidence or probably low frequency), including attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and developmental coordination disorder (DCD). Reference Tofts, Simmonds, Schwartz, Richheimer, O’Connor and Elias10
Joint hypermobility and psychiatry
With regard to psychiatry, the most robust relationship with joint hypermobility in child cohorts is for ADHD. Reference Koldaş Doğan, Taner and Evcik18–Reference Kindgren, Quiñones Perez and Knez21 Additionally, there are varying levels of evidence for a link with ASD, Reference Cederlöf, Larsson, Lichtenstein, Almqvist, Serlachius and Ludvigsson20,Reference Tedla, Asiri, Alshahrani and Gular22,Reference Shetreat-Klein, Shinnar and Rapin23 DCD Reference Adib, Davies, Grahame, Woo and Murray24–Reference Schubert-Hjalmarsson, Öhman, Kyllerman and Beckung28 and anxiety disorders. Reference Ezpeleta, Navarro, de la, Penelo and Bulbena29,Reference Javadi Parvaneh, Modaress, Zahed, Rahmani and Shiari30 In adults, anxiety disorders and ADHD have shown robust associations, with emerging evidence for ASD, mood disorders depression and eating disorders. Reference Glans, Thelin, Humble, Elwin and Bejerot6,Reference Glans, Thelin, Humble, Elwin and Bejerot7,Reference Bulbena-Cabré, Baeza-Velasco, Rosado-Figuerola and Bulbena31 NDPs rarely present with a clear and well-defined clinical picture. The ‘early symptomatic syndromes eliciting of neurodevelopmental clinical examinations’ (ESSENCE) concept recognises that early symptoms and signs of developmental deviations are non-specific, prompt further clinical evaluations and eventually align as neurodevelopmental disorders (NDDs), where ‘comorbidity’ across NDDs (e.g. ADHD and ASD) is the rule rather than the exception. Reference Gillberg32 Because ESSENCE problems are believed to be prevalent within the joint hypermobility spectrum, Reference Adib, Davies, Grahame, Woo and Murray24,Reference Baeza-Velasco, Grahame and Bravo33 GJH may serve as an additional clinical clue during health check-ups. To our knowledge, no studies have explored the link between GJH and ESSENCE in general population screening settings. Moreover, further exploration of this presumed association could provide valuable insights into disease mechanisms. Some researchers suggest that collagens, or pleiotropy in collagen-related genes, play a simultaneous role in the development and functioning of the central nervous system, in addition to their involvement in joint mobility. Reference Wasim, Suddaby, Parikh, Leylachian, Ho and Guerin34
In summary, joint hypermobility is associated with a broad range of NDPs. Further research is needed to understand how collagen abnormalities may relate to disruptions in central nervous system development and function. Moreover, enhancing our understanding of GJH, gHSD and musculoskeletal pain in children can contribute to health initiatives and scientific progress.
Aims
This study aimed to (a) determine GJH and gHSD prevalence, (b) assess the correlation between GJH and musculoskeletal pain and (c) investigate potential associations between GJH and gHSD, with a comprehensive array of NDPs at different symptom levels in 11-year-old Swedish children from the general population
Method
Participants and procedure
This cross-sectional study took place in eight schools – six public and two private – in western Sweden from 2018 and 2020, and has been reported in detail previously. Reference Landgren, Svensson, Törnhage, Theodosious, Gillberg and Johnson35 This report is part of a broad research initiative covering pupils’ basic academic skills, general health and neurodevelopment, and possible associations with important background factors. Schools were selected based on local school principals’ readiness to participate in studies of children’s health. Caregivers of all pupils attending 4th grade were invited following an oral and written presentation of the study. At each school, one or two academic years of children were recruited. Participation constituted an add-on to the existing regular health check-up conducted in the 4th grade. Data sources included medical health records, psychological assessment, physician-led physical assessment, maternal interviews, teacher and parent rating scales and national tests from the 3rd grade (Fig. 1). Following data collection, a case conference, attended by a psychiatrist, psychologist and a paediatric neurologist, was held to summarise the clinical information. Where sufficient data were available, medical conditions and psychiatric and neuropsychiatric problem areas were assigned. A detailed description of this procedure is reported elsewhere. Reference Landgren, Svensson, Törnhage, Theodosious, Gillberg and Johnson35
Fig. 1 Participant flow diagram.
Measures
Exposures
GJH
GJH was measured and rated according to the Beighton score Reference Beighton, Solomon and Soskolne36 (range 0–9), as part of a structured physical examination that included a neuromotor and dysmorphological assessment. Assessors received training in the structured neurodevelopmental examination from a paediatric neurologist (M.L.), and the protocol encompassed written instructions detailing the criteria for the Beighton score. Joint hypermobility was assessed by four clinicians. A goniometer was not used. Participants did not warm up prior to the examination. The recommended age-adapted cut-off score of ≥6/9 on the Beighton score was used as the criterion for GJH. Reference Tofts, Simmonds, Schwartz, Richheimer, O’Connor and Elias10 To facilitate comparisons with prior research employing lower thresholds, and to address potential dimensional considerations, supplementary analyses were conducted using thresholds of ≥5/9 and ≥4/9, and also with total Beighton score as a continuous variable.
HSDs
A proxy variable for gHSD was defined for individuals displaying GJH along with self-reported musculoskeletal pain (described below). To meet the criteria for gHSD, participants were required to exhibit GJH (based on the employed Beighton score cut-off), along with musculoskeletal pain reported weekly.
Outcomes
Musculoskeletal pain
As a component of the systematic physical examination, participants were interviewed using questions that specifically addressed pain in the legs, arms and joints. We ensured that participants understood the distinctions and provided clarification through visual feedback. The participants were provided with three choices for answering. The first option, ‘Often’, referred to pain that occurred more than once a week and was assigned a value of 2 points. The second option, ‘Sometimes’, referred to pain that occurred a few times per month and was assigned a value of 1 point. The third option, ‘Never’, referred to pain that either never or rarely occurred and was assigned a value of 0 points. This allowed for the calculation of a ‘pain score’ ranging from 0 to 6. Analyses of pain encompassed assessment of the relationship between GJH and any reported weekly pain, as well as examination of the correlation between total pain score and total Beighton score. Additionally, responses were utilised to establish the aforementioned proxy variable for gHSD. In this case, the response ‘often’ in any location (pain, leg or arm) was deemed to indicate significant musculoskeletal pain.
NDPs
In the case conference summarising clinical information, an emphasis was placed on symptoms of NDDs. For this purpose we scrutinised all available data as reported previously in detail. Reference Landgren, Svensson, Törnhage, Theodosious, Gillberg and Johnson35 The shared polygenetic origins of NDDs, and the frequent co-occurrence of symptoms from multiple diagnostic groups (e.g. autistic traits are common among patients with attention-deficit/hyperactivity disorder), are well established and warrant viewing as dimensional traits rather than discrete entities. Reference Taylor, Martin, Lu, Brikell, Lundström and Larsson37 We therefore chose to incorporate a global assessment of the NDPs (i.e. NDD symptoms irrespective of diagnostic status) displayed by each participant. This allowed us not only to categorise individuals who might fall below a clinical diagnostic threshold, but also to take into account the total burden of symptoms for each participant.
For each participant, the overall severity of symptoms/degree of functional impairment from NDPs was rated using the ordinal scale Clinical Global Impression-Severity instrument (CGI-S, range 1–7). Reference Busner and Targum38 The CGI rating thus took into account multiple functional areas (e.g. cognition, hyperactivity/inattention, autistic traits, coordination problems) and rated the symptoms and impairment irrespective of whether a diagnostic cut-off was met or not. In a clinical setting based on our experience, participants with CGI 1–3 would not be referred for regular healthcare, while those with CGI 4–7 would probably indicate symptoms/impairments warranting clinical attention and likely diagnosis.
For analysis, we chose the total score and hyperactivity subscore from the Strength and Difficulties Questionnaire (SDQ). Reference Malmberg, Rydell and Smedje39 This choice was made due to the broad validation of SDQ as a measure of NDDs in research. Reference Mulraney, Arrondo, Musullulu, Iturmendi-Sabater, Cortese and Westwood40 Additionally, SDQ has been utilised in prior studies on ADHD, a neurodevelopmental condition linked to GJH. Reference Glans, Thelin, Humble, Elwin and Bejerot6 We also considered SDQ as a complement to our own global measure.
Statistics
We used percentages for displaying proportions in descriptive statistics. Continuous variables were reported with the mean and standard deviation. In instances of small groups and non-normal distributions following visual inspection, median and interquartile range were reported. Anthropometric variables were converted to z-scores that denote the distance of the raw score from that of the reference mean, and were handled as continuous variables.
Prevalence rates and 95% confidence intervals for GJH and HSD were estimated according to the Clopper–Pearson exact method. We conducted separate analyses by gender, and at three different cut-offs on the Beighton score. Because sample size was not contingent upon the current objective, we examined the statistical power for the present hypotheses. Applying an alpha of 0.05 and a beta of 0.8, the hypothesis comparing GJH at the 95th percentile with those below, regarding binary variables, suggested power to detect only large effect sizes (∼0.8). To mitigate type II errors (false negatives), we also designed analyses for continuous variables because the sample size provided sufficient power to identify even minor effects for these (∼0.2).
We split the cohort into high- and low-score groups regarding Beighton score, with a cut-off of ≥6. The same was applied to gHSD, which was defined as weekly pain in combination with Beighton score ≥6. We used Fisher’s test to compare groups for binary variables, and the Mann–Whitney U-test to compare continuous variables. Spearman’s rank correlation analysis was used to investigate relationships between Beighton score and specific factors of interest that could be analysed as dimensional variables (pain score, SDQ score and CGI ratings of NDPs).
As sensitivity analyses we analysed high- and low-score groups, and the gHSD definition with additional cut-offs (≥4, ≥5). We also investigated associations between Beighton score and CGI-S, the measure of global burden of NDPs, while adjusting for the impacts of gender and body mass index (BMI). This was performed with Beighton score, gender and BMI as predictor, and CGI-S as outcome, in a linear regression. Analyses were conducted in R version 4.2.3 for Windows, (Posit Software, PBC, Boston, MA, USA; http://www.posit.co/) using the packages binom, pwr and glm. The manuscript was prepared using Microsoft Word, version 16 (2021; Microsoft Corporation, Redmond, WA, USA; https://www.microsoft.com/microsoft-365/word running on macOS 11 Big Sur (2020; Apple Inc., Cupertino, CA, USA; https://www.apple.com/macos/big-sur).
Results
Characteristics
Of 348 eligible students, 223 consented to participation and 207 had been assessed by a physician and could be included in the study (Fig. 1). The participants exhibited slightly greater height and weight compared with the reference values, with boys showing a somewhat greater difference (Table 1).
Table 1 Participant characteristics
BMI, body mass index.
Prevalence rates of GJH and gHSD
Table 2 presents the distribution and cumulative percentage of Beighton score, along with gender-stratified rates of GJH and gHSD based on various cut-off levels on the Beighton score. Overall, the median Beighton score was 1 (interquartile range 0–2) and did not differ significantly between genders (Wilcoxon test P = 0.17; Fig. 2). With the recommended cut-off of ≥6/9 on the Beighton score, 1 participant met the criteria for gHSD. Lowering the cut-off to ≥5/9 and ≥4/9 resulted in 2 and 6 individuals meeting the gHSD criteria, respectively.
Table 2 Distribution and cumulative percentage of joint hypermobility
a . Generalised joint hypermobility according to different cut-off scores in the Beighton scoring system.
b . Generalised hypermobility spectrum disorder was operationalised as pain (complaints of weekly pain in arms, legs or joints) combined with the specified cut-off in the Beighton scoring system.
Fig. 2 Beighton score stratified by gender. M, male; F, female.
Joint hypermobility and musculoskeletal pain burden
Prevalence rates of self-reported weekly pain are reported in Table 3. No significant difference was observed between those with and without GJH. The proportion endorsing weekly pain was insignificantly higher in girls (n = 42, 48%) than in boys (n = 43, 37%; Fisher’s test P = 0.15). There was no significant correlation between total Beighton score and musculoskeletal pain burden (Fig. 3).
Table 3 Low- compared with high-scoring participants at Beighton score cut-off ≥6 for generalised joint hypermobility
CGI, Clinical Global Impression (range 1–7); ESSENCE-Q, early symptomatic syndromes eliciting of neurodevelopmental clinical examinations (ESSENCE) questionnaire (range 0–24); GJH, generalised joint hypermobility; NDPs, neurodevelopmental problems.
a . The Strength and Difficulties Questionnaire ranges from 0 to 40 in total score and 0–10 in the hyperactivity subscale.
b . P-values for Fisher’s exact test and Wilcoxon signed-rank test for binary and continuous variables, respectively.
Fig. 3 Spearman’s rank correlation between Beighton score and musculoskeletal pain.
Joint hypermobility and NDPs
GJH
Participant characteristics stratified as non-GJH or GJH according to Beighton score ≥6 are shown in Table 3. There were no differences between the groups regarding gender and internalising symptoms or occurrence of weekly pain. No difference in any neurodevelopmental measures was observed. Adjusting the cut-off to either ≥5 (n = 17 scoring ≥5) or ≥4 (n = 40 scoring ≥4) showed no significant differences between the groups (data not shown).
To further explore potential GJH associations of a dimensional nature, we analysed the correlation between total Beighton and total SDQ-scores, but no significant correlation was found (Fig. 4).
Fig. 4 Spearman’s rank correlation between Beighton scores and Strengths and Difficulties Questionnaire (SDQ) scores. (a) Teacher-rated. (b) Parent-rated.
To examine potential confounding influences from gender and BMI on the association of GJH and NDPs, we performed a sensitivity analysis; NDP, as rated by CGI-S, was selected as the outcome, and GJH adjusted for gender and BMI as the predictors. No significant association was found for either GJH (estimate 0.04, P = 0.32) or gender (estimate 0.19, P = 0.31), but a significant association of BMI with NDPs was noted (estimate 0.18, P = 0.003). However, taken together, the variance explained by the model was not practically relevant (R 2 = 0.05, 95% CI: 0–0.11, P = 0.01).
HSDs
To investigate the potential impact of symptomatic GJH, we operationalised gHSD as the presence of GJH plus weekly musculoskeletal pain. With the recommended cut-off of ≥6/9 on the Beighton score, 1 participant met the criteria for gHSD. Lowering the cut-off to ≥5/9 and ≥4/9 resulted in 2 and 6 individuals meeting the gHSD criteria, respectively; of these 6, 2 had a CGI rating of 4, indicating clinically relevant NDPs. The limited number of individuals meeting the criteria for the gHSD variable prevented meaningful analyses of the association between gHSD and NDPs.
Discussion
To our knowledge, this study is the first to explore potential associations between joint hypermobility and a comprehensive array of ESSENCE/NDPs in a community sample of middle school-aged children. Employing a cross-sectional design, we measured GJH through physical examination and conducted a thorough evaluation of both subclinical and clinical NDPs by a multidisciplinary team. Our analyses revealed no significant links between GJH and any level of NDP, suggesting that individuals with GJH at this age generally follow typical developmental patterns, thus cautioning against using GJH as a biomarker for NDPs in this age group.
In our cohort, the prevalence rate of GJH was 5.6% for girls and 6.8% for boys. These rates align with the notion that GJH should be assigned to only the most extreme end of the population, and validate the age-dependent recommended cut-off point of ≥6/9 on the Beighton score. We found no association between GJH and musculoskeletal pain. Signs of HSD were uncommon in our sample, affirming its impact on only a subset of individuals and typical emergence later in life. Nevertheless, a significant 42% of the total sample experienced weekly pain, meriting further investigation into its occurrence and impact.
Prevalence rates of GJH and gHSD
Data on prevalence rates of GJH and gHSD are significant for research, public health policies and raising public awareness. In our study cohort, GJH was identified in 5.6% (95% CI: 1.8–12.6) of girls and 6.8% (95% CI: 3.0–12.9) of boys. Comparing these findings with a 2004 Swedish study involving 12-year-old children, the rates observed among boys were similar but notably lower than those among girls. In the 2004 study, 15% of the girls would have met the criteria for GJH if the current recommended cut-off of ≥6/9 had been applied. Reference Jansson, Saartok, Werner and Renström5 Discrepancies between the two studies may be attributed to hormonal changes and the onset of puberty, probably more pronounced in the 2004 study because participants were 1 year older than in our cohort. These factors are believed to influence joint hypermobility, with an expected increase in prevalence with age among girls and a decrease among boys. Reference Jansson, Saartok, Werner and Renström5,Reference Quatman, Ford, Myer, Paterno and Hewett41 Unfortunately, we did not collect data on puberty or biological maturity, which prevents further analysis in this regard. Many researchers and clinicians argue that GJH should signify an anomaly, advocating for setting the cut-off value on the Beighton score to 2 standard deviations above the mean, or within the top 5%, for each age, gender and race category. Reference Jansson, Saartok, Werner and Renström5,Reference Tofts, Simmonds, Schwartz, Richheimer, O’Connor and Elias10,Reference Singh, McKay, Baldwin, Nicholson, Chan and Burns42 The prevalence rates found in our study validate the use of a cut-off of ≥6/9 on the Beighton score, while also confirming a similar prevalence of GJH between genders in this age group.
GJH, combined with self-reported weekly pain, was used as a proxy variable for gHSD, deviating from the standardised gHSD assessment. These analyses are thus preliminary. With the ≥6/9 cut-off for GJH on the Beighton score, only 1 participant of 207 (0.5%) met the classification for gHSD. Lowering the cut-off to ≥5/9 and ≥4/9 resulted in 2 and 3 individuals meeting the gHSD criteria, respectively. Limited data exist on gHSD prevalence and progression, but the clinical progression of hEDS is believed to unfold in three phases: the hypermobility phase, characterised by hypermobility and frequent joint sprains/strains; the pain phase, marked by widespread chronic pain; and the stiffness phase, with a notable decline in hypermobility. Reference Castori, Sperduti, Celletti, Camerota and Grammatico43 This pattern may extend to gHSD, supported by the limited number of participants in our cohort manifesting coexisting GJH and pain.
Joint hypermobility and musculoskeletal pain
Although not within the scope of our primary investigation, the significant prevalence of weekly pain observed in our cohort deserves mention. In this cohort, 42% of the children experienced weekly musculoskeletal pain, with no discernible difference between genders. This exceeds the figure reported in a nationwide Swedish study from 2007, where only 5% of girls and 9% of boys reported weekly musculoskeletal pain. Reference Brun Sundblad, Saartok and Engström44 However, studies on childhood pain yield varied results, with a Norwegian study reporting frequent bodily pain in 30% of children in this age group. Reference Smedbråten and Natvig45 Discrepancies may arise from variations in assessment methods, criteria for defining pain or characteristics of the study population. Musculoskeletal pain in children and adolescents correlates with impaired health-related quality of life, Reference Paananen, Taimela, Auvinen, Tammelin, Zitting and Karppinen46 while also predicting health and social difficulties in later life. Reference Eckhoff, Straume and Kvernmo47 In the present study we did not assess the potential negative impacts of pain. Nevertheless, the significant occurrence observed in our cohort warrants further investigation to deepen our understanding and enable effective detection and prevention.
The analyses on GJH and musculoskeletal pain revealed no significant differences in pain experience between individuals with and without GJH. Additionally, when treating pain and joint hypermobility as dimensional variables, no correlation was observed. These findings align with a systematic review and meta-analysis conducted in 2012, encompassing 15 cross-sectional studies. This meta-analysis revealed no significant correlation between GJH and musculoskeletal pain within Caucasian populations but indicated a link in African Asian populations. Reference McCluskey, O’Kane, Hann, Weekes and Rooney13 Two subsequent cross-sectional studies also predominantly reported no associations. Reference Sohrbeck-Nøhr, Kristensen, Boyle, Remvig and Juul-Kristensen11,Reference Morris, O’Sullivan, Murray, Bear, Hands and Smith14 However, an Australian study noted a relationship for boys when employing the ≥6/9 cut-off on the Beighton score. Reference Morris, O’Sullivan, Murray, Bear, Hands and Smith14 While cross-sectional studies have limitations in detecting progression of pain, longitudinal studies provide some support for GJH in childhood as a risk factor for developing musculoskeletal pain in adolescence. Reference Scheper, Pacey, Rombaut, Adams, Tofts and Calders12,Reference El-Metwally, Salminen, Auvinen, Kautiainen and Mikkelsson15,Reference Tobias, Deere, Palmer, Clark and Clinch16 Joint instability is often cited as a contributor to musculoskeletal pain in GJH, Reference Tofts, Simmonds, Schwartz, Richheimer, O’Connor and Elias10 while central nervous system hypersensitisation is implicated in chronic widespread pain. Reference Scheper, Pacey, Rombaut, Adams, Tofts and Calders12 Consequently, the aforementioned prospective studies could infer that any potential effects of GJH on joint instability or perceived pain emerge later in life. In conclusion, our study supports the growing evidence of no relationship between GJH and musculoskeletal pain in prepubertal children. However, prospective studies are needed to explore potential changes over time and their relation to biological maturation.
GJH and NDPs
The present study revealed no significant associations between joint hypermobility and any type of NDP at any level. We evaluated the relationship for two basic variables, GJH and HSD, with a broad spectrum of measures of NDPs/ESSENCE and without confining ourselves to the diagnostic boundaries of DSM-5. This approach offers advantages, given the significant symptom overlap between NDDs and their presumed dimensional nature. Reference Taylor, Martin, Lu, Brikell, Lundström and Larsson37 Unlike specific genetic syndromes, GJH probably displays considerable variability among individuals in terms of the underlying mechanisms and associated characteristics. Therefore, it is intriguing that numerous studies have identified robust associations between GJH and various extra-articular conditions. Of note, these associations span the entire joint hypermobility symptom spectrum (i.e. GJH/HSD/EDS), not merely confined to recognised genetic syndromes such as classical EDS or Marfan syndrome. Regarding NDPs on the other hand, it is unknown whether the presumed associations extend across the clinical and non-clinical continuum, because previous studies have predominantly focused on clinical cohorts. To our knowledge, only one study has evaluated the link between joint hypermobility and subclinical NDPs. This study, with a large sample (n = 1039) of adults from the general population, found no association between GJH and signs of ADHD, ASD or DCD. Reference Glans, Bejerot and Humble48
Our results from analysis of subclinical NDPs align with the aforementioned observations in adults. Reference Glans, Bejerot and Humble48 It is plausible that mechanisms underlying subclinical neurodevelopmental phenotypes are more heterogeneous than those driving more severe pathology, thus diluting the hypothesised influence of collagen abnormality.
However, when assessing more pronounced NDPs, our results deviate from those of previous studies. The relatively low prevalence of GJH (approximately 5%) poses a risk of type 2 errors, particularly in analyses of variables involving fewer participants such as those at higher symptom severity. Nevertheless, it is conceivable that the presumed link between joint hypermobility and NDPs does not apply to children of this age. Recognising the shift within the hypermobile cohort around puberty, marked by a notable influx of females and outflow of males, may be pivotal. Post-pubertal cohorts encompass a notably distinct group of individuals compared with those in prepubertal cohorts. While no prospective studies are available, a Swedish cross-sectional study on hEDS individuals showed an increased ADHD prevalence with age: 35% in 15- to 16-year-olds and 46% in 17- to 18-year-olds, compared with 23% across ages 6–18 years. Reference Kindgren, Quiñones Perez and Knez21 Whether this reflects increased evaluation time and awareness of adolescent ADHD, or signals a phenotype shift within the hypermobile cohort around puberty, remains uncertain. There is also a possibility that a hitherto uncharacterised factor (e.g. environmental triggers, personality or lifestyle factors) mediates an association of NDPs and GJH in adulthood. Prospective studies are needed to investigate this matter further. Moreover, because puberty affects hypermobility differently in boys and girls, future studies should consider performing gender-stratified analyses.
Limitations
This study has several strengths. GJH assessment in all study participants by physical examination ensures high diagnostic accuracy. We explored a wide array of NDPs, extending beyond DSM diagnostic boundaries. This enhanced sensitivity in detecting atypical development, contributing to a comprehensive understanding of these frequently overlapping conditions. Our multidisciplinary team, including psychiatrists, psychologists and paediatric neurologists, enhances reliability and validity. Analysis of NDPs across various symptom levels makes this study unique because it incorporates dimensional aspects of the hypothesised associations. Recruitment during routine school health check-ups facilitated accessibility, inclusivity and data collection efficiency, reducing selection bias.
Our findings should also be considered in light of limitations. No sample size estimation was performed, and assessing variables with low prevalence increases the risk of type 2 errors. The study’s cross-sectional design hinders drawing conclusions about temporal associations. The lack of information about biological maturity or puberty impedes our ability to evaluate potential influences. In addition, joint hypermobility was assessed by multiple clinicians without formal evaluation of interrater reliability, which may have introduced variability in scoring. The attrition rate was substantial and, as previously noted, we interpret the elevated prevalence of NDPs in our cohort as being due to a selection of schools with significant socioeconomic disadvantage, along with a bias towards study participation of families of children with unmet needs who are pursuing an evaluation for NDPs. Reference Landgren, Svensson, Törnhage, Theodosious, Gillberg and Johnson35 Consequently, the sample may have had a higher proportion of NDPs than would be expected in the general population. While this may not directly hinder the capacity to discover genuine associations, it needs to be factored in. The Beighton score primarily focuses on upper limb hypermobility, potentially overlooking hypermobility in joints not included in the Beighton protocol. Despite its limitations, the Beighton score remains the standard assessment method for GJH in both clinical practice and research studies. Lastly, the use of a proxy variable for gHSD and an unvalidated pain score renders these analyses preliminary.
In conclusion, our study on 11-year-old Swedish children showed GJH prevalence rates of 5.6% for girls and 6.8% for boys. These rates align with the notion of capturing 5% of the population, thereby corroborating the current age-dependent recommendations for GJH in the Beighton score.
There was no association between joint hypermobility and musculoskeletal pain, adding to the growing body of evidence that disputes such a link in this age group. Furthermore, our study found that indicators of gHSD were infrequent, confirming that it affects a certain group of individuals with GJH and usually develops at a later stage in life. However, a substantial 42% of the total sample experienced weekly musculoskeletal pain. This significant occurrence merits further investigation to explore potential negative impacts and facilitate detection and prevention.
Finally, our study found no association between joint hypermobility and NDPs, contrasting with previous studies. Based on the age of our study participants, we hypothesise that the absence of such an association could be attributed to significant changes in hypermobility that occur during puberty. Our findings are noteworthy because they suggest that individuals with GJH at this age generally follow typical development trajectories, cautioning against the use of GJH as a biomarker for NDPs in this age group.
Data availability
The data that support the findings of this study are available from the corresponding author, M.R.G., upon reasonable request.
Author contributions
M.R.G.: conceptualisation, study design, data analysis and interpretation and primary contributor to manuscript writing. A.A.: data analysis and interpretation, manuscript writing contribution. E.K.: interpretation and critical manuscript revision. R.K.: conceptualisation, study design, data acquisition, interpretation and critical manuscript revision. M.L.: conceptualisation, study design, data acquisition and manuscript revision. V.L.: conceptualisation, study design, data acquisition, data analysis and interpretation and critical manuscript revision.
Funding
Funding was provided by grants from Research and Development of Region Västra Götaland (no. VGSKAS-931754) and the research fund at Skaraborg Hospital (nos VGSKAS-967692, VGSKAS-939541, VGSKAS-101174).
Declaration of interest
None.
Ethical standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation, and with the Helsinki Declaration of 1975 as revised in 2013. All procedures involving human subjects/patients were approved by the ethical board at Gothenburg University (no. 852-17). Furthermore, all caregivers and children signed informed consent.
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