Symptomatic hypermobility in children and young people: A scoping review of clinical characteristics using a developmental framework

Abstract

OBJECTIVE:

To evaluate the literature on children and young people with symptomatic hypermobility using a developmental framework.

METHODS:

A search was conducted in EMBASE, Medline, CINAHL, Web of Science and grey literature. Full text articles reporting children and young people (birth to 24 years) with a confirmed diagnosis of symptomatic hypermobility (including Hypermobility Spectrum Disorder or hypermobile Ehlers-Danlos syndrome) using internationally recognised criteria or equivalent diagnoses were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews methodology was followed.

RESULTS:

Of the 1619 studies screened, 163 were included in the scoping review. Studies were published from 1967-2021, 30% were narrative reviews and 24% were case reports, from a range of journals. Musculoskeletal and cutaneous characteristics were common in all developmental stages. Cardiovascular characteristics including autonomic dysfunction, fatigue, and gastrointestinal issues were reported more frequently by adolescents. Young adult studies were scarce and included mostly case reports. Varied diagnostic criteria and assessment methods were identified. The Beighton Score was frequently used (93%), but rarely standardised (12%) and lacked consensus regarding the cut-off point of hypermobility.

CONCLUSIONS:

This novel systematic scoping review identifies the changing phenotype of symptomatic hypermobility from childhood to adolescence, and the unique stage of young adulthood. There is a lack of guidance regarding the utilisation of standardised tools to assess hypermobility in clinical practice and research. Numerous and inconsistent diagnostic criteria and assessment methods limit the data analysis. Case control and longitudinal studies using defined, bespoke criteria and assessments are needed.

Keywords

Joint hypermobility symptoms paediatrics adolescent health

1 Introduction

Joint hypermobility (JH) is present when a joint actively or passively moves beyond its normal range of movement [1]. It is not a diagnosis but describes a continuum and varies with age, requiring clinicians to take age-related normative data into consideration [1]. A recent systematic review reported prevalence rates of between 3.3%–65% [2]. JH also varies with gender, ethnicity, strength training, or previous injuries, which further challenges the clinician [2, 3]. JH may be present at a few joints or many which is termed generalised JH. It is often screened using the Beighton score, which is validated in children using a standardised protocol [4 –6].

The terminology used to define JH with symptoms is variable and controversial. Terms used include Hypermobility Syndrome and Joint Hypermobility Syndrome (JHS), thought to be overlapping with Ehlers-Danlos type 3 (EDS type III) and Ehlers-Danlos syndrome hypermobility type (EDS-HT) [7]. In 2017, new nosology was developed by international consensus and the term ‘hypermobile Ehlers-Danlos syndrome (hEDS)’ and ‘Hypermobility spectrum disorder (HSD)’ were proposed [3 , 8]. Recent guidelines from the British Society for Adolescent and Paediatric Rheumatology (BSPAR) use the term ‘symptomatic hypermobility’ to define symptoms understood to be related to being hypermobile [9]. The term ‘symptomatic hypermobility’ will be used in this review as an overarching term. Children and young people are defined as those from birth to 24 years of age [10].

While the association of JH with musculoskeletal symptoms was first described by rheumatologist Kirk and colleagues in 1967 [11] other symptoms, including functional gastrointestinal disorders [12], fatigue [13], cardiovascular dysautonomia [14] and headaches [15] have since been reported. The diagnosis of symptomatic hypermobility in children and young people is a clinical diagnosis of exclusion as no specific gene has been linked to HSD or hEDS [1] and there is no specific diagnostic test. Assessments must be interpreted in the context of normal variants and symptoms, such as pain [16, 17], that may be common in the general paediatric population [18].

The literature uses varied terminology, spans medical domains and settings, and includes adult and paediatric populations [19], making its interpretation difficult. This scoping review aims to systematically explore and summarise the literature reporting symptomatic hypermobility in children and young people. The objectives are to report (i) study designs and settings; (ii) population characteristics; (iii) diagnostic criteria and measurement approaches and (iv) to identify clinical characteristics in the context of developmental stages (childhood (0-9years), adolescence (10-19years), and young adulthood (20-24years)). Using a developmental framework, this review will provide clarity for clinicians and researchers assessing and managing patients.

2 Methods

A systematic scoping review (ScR) approach was used to identify and map the available evidence using an established framework [20], that was updated [21] and further clarified [22]. The research was systematically reviewed, and results presented descriptively.

2.1 Protocol and registration

The ScR protocol [23] was written using the PRISMA Extension for Scoping Reviews (PRISMA-ScR) and was registered with the Open Science Framework on 20th September 2021 (https://osf.io/m2h6q).

Table 1
Search Strategy. Search conducted on 01/12/20. Number of results from all searches = 4168. After deduplication = 1619

Database and Search Terms Results retrieved

EMBASE 1522

‘Ehlers danlos syndrome hypermobility type’/exp OR (‘ehlers danlos syndrome’/exp

AND (‘joint instability’/exp OR ‘hypermobility’/exp OR ‘joint laxity’/exp))

((ehlers–Danlos OR ‘spectrum disorder’ OR symptomatic OR syndrome) NEAR/3 hypermobil):ti,ab

(‘Hypermobile EDS’ OR ‘hEDS’ OR ‘Hypermobility spectrum disorder’ OR ‘Ehlers-Danlos syndrome hypermobility type’ OR ‘EDS-HT’ OR ‘Joint hypermobility syndrome’ OR ‘JHS’ OR ‘Ehlers-Danlos Type III’):ti,ab

(‘conference abstract’ OR ‘conference review’ OR letter):it

#1 OR #2 OR #3

#5 NOT #4

Medline 1234

Ehlers-Danlos Syndrome/ AND Joint Instability/

((Ehlers Danlos OR spectrum disorder* OR symptomatic OR syndrome) adj3 hypermobil).ti,ab.

(Hypermobile EDS OR hEDS OR Hypermobility spectrum disorder OR Ehlers-Danlos syndrome hypermobility type OR EDS-HT OR Joint hypermobility syndrome OR JHS OR Ehlers-Danlos Type III).ti,ab.

or/1-3

CINAHL 365

(MH “Ehlers-Danlos Syndrome”) AND (MH “Joint Instability+”)

TI ((Ehlers–Danlos OR “spectrum disorder” OR symptomatic OR syndrome) N2 hypermobil) OR AB ((Ehlers–Danlos OR “spectrum disorder” OR symptomatic OR syndrome) N2 hypermobil)

TI (“Hypermobile EDS” OR “hEDS” OR “Hypermobility spectrum disorder” OR “Ehlers-Danlos syndrome hypermobility type” OR “EDS-HT” OR “Joint hypermobility syndrome” OR “Ehlers-Danlos Type III”) OR AB (“Hypermobile EDS” OR “hEDS” OR “Hypermobility spectrum disorder” OR “Ehlers-Danlos syndrome hypermobility type” OR “EDS-HT” OR “Joint hypermobility syndrome” OR “Ehlers-Danlos Type III”)

S1 OR S2 OR S3

Web of Science 1047

TI=(((“Ehlers Danlos” OR “spectrum disorder” OR symptomatic OR syndrome) NEAR/2 hypermobil) OR (“Hypermobile EDS” OR “hEDS” OR “Hypermobility spectrum disorder” OR “Ehlers-Danlos syndrome hypermobility type” OR “EDS-HT” OR “Joint hypermobility syndrome” OR “Ehlers-Danlos Type III”)) OR AB=(((“Ehlers Danlos” OR “spectrum disorder” OR symptomatic OR syndrome) NEAR/2 hypermobil*) OR (“Hypermobile EDS” OR “hEDS” OR “Hypermobility spectrum disorder” OR “Ehlers-Danlos syndrome hypermobility type” OR “EDS-HT” OR “Joint hypermobility syndrome” OR “Ehlers-Danlos Type III”))

Database and Search Terms	Results retrieved
EMBASE	1522
‘Ehlers danlos syndrome hypermobility type’/exp OR (‘ehlers danlos syndrome’/exp
AND (‘joint instability’/exp OR ‘hypermobility’/exp OR ‘joint laxity’/exp))
((ehlers–Danlos OR ‘spectrum disorder’ OR symptomatic OR syndrome) NEAR/3 hypermobil):ti,ab
(‘Hypermobile EDS’ OR ‘hEDS’ OR ‘Hypermobility spectrum disorder’ OR ‘Ehlers-Danlos syndrome hypermobility type’ OR ‘EDS-HT’ OR ‘Joint hypermobility syndrome’ OR ‘JHS’ OR ‘Ehlers-Danlos Type III’):ti,ab
(‘conference abstract’ OR ‘conference review’ OR letter):it
#1 OR #2 OR #3
#5 NOT #4
Medline	1234
Ehlers-Danlos Syndrome/ AND Joint Instability/
((Ehlers Danlos OR spectrum disorder* OR symptomatic OR syndrome) adj3 hypermobil*).ti,ab.
(Hypermobile EDS OR hEDS OR Hypermobility spectrum disorder OR Ehlers-Danlos syndrome hypermobility type OR EDS-HT OR Joint hypermobility syndrome OR JHS OR Ehlers-Danlos Type III).ti,ab.
or/1-3
CINAHL	365
(MH “Ehlers-Danlos Syndrome”) AND (MH “Joint Instability+”)
TI ((Ehlers–Danlos OR “spectrum disorder” OR symptomatic OR syndrome) N2 hypermobil) OR AB ((Ehlers–Danlos OR “spectrum disorder” OR symptomatic OR syndrome) N2 hypermobil)
TI (“Hypermobile EDS” OR “hEDS” OR “Hypermobility spectrum disorder” OR “Ehlers-Danlos syndrome hypermobility type” OR “EDS-HT” OR “Joint hypermobility syndrome” OR “Ehlers-Danlos Type III”) OR AB (“Hypermobile EDS” OR “hEDS” OR “Hypermobility spectrum disorder” OR “Ehlers-Danlos syndrome hypermobility type” OR “EDS-HT” OR “Joint hypermobility syndrome” OR “Ehlers-Danlos Type III”)
S1 OR S2 OR S3
Web of Science	1047
TI=(((“Ehlers Danlos” OR “spectrum disorder” OR symptomatic OR syndrome) NEAR/2 hypermobil) OR (“Hypermobile EDS” OR “hEDS” OR “Hypermobility spectrum disorder” OR “Ehlers-Danlos syndrome hypermobility type” OR “EDS-HT” OR “Joint hypermobility syndrome” OR “Ehlers-Danlos Type III”)) OR AB=(((“Ehlers Danlos” OR “spectrum disorder” OR symptomatic OR syndrome) NEAR/2 hypermobil) OR (“Hypermobile EDS” OR “hEDS” OR “Hypermobility spectrum disorder” OR “Ehlers-Danlos syndrome hypermobility type” OR “EDS-HT” OR “Joint hypermobility syndrome” OR “Ehlers-Danlos Type III”))

2.2 Research question and inclusion criteria

The Joanna Briggs institute recommended framework Population, Concept and Context (PCC) was used to formulate the research question and determine the inclusion and exclusion criteria [20]. This review was guided by the research question “What are the presenting clinical characteristics of children and young people diagnosed with symptomatic hypermobility (including HSD and hEDS and other equivalent diagnoses)?” Literature on children and young people, with a clinical diagnosis of symptomatic hypermobility, HSD, hEDS or equivalent diagnoses (EDS-HT, EDS type III and JHS) using internationally recognised criteria was included. Randomised and non-randomised controlled trials, intervention, observational studies and case reports were included. Review articles were also included when they met the inclusion criteria and captured data not seen in original articles. Bibliographies of included papers were hand searched to capture previously unidentified studies [22]. Editorials, opinion papers, abstracts, posters and papers not in the English language were excluded.

2.3 Search strategy

A systematic search was carried out from inception to June 2021. Specific search terms for each database were used so that historical articles, including seminal papers, would be included. The search strategy was drafted by an experienced subject librarian (DM) using Boolean Operators across the Cumulative Index of Nursing and Allied Health Literature, PubMed, Embase and Web of Science (Table 1). Grey literature and targeted websites were manually searched (www.opengrey.eu; www.ehlers-danlos.com; www.hedstogether.com; www.hypermobility.org). The Google search engine (www.google.com) was searched without date restriction. The first 20 hits were screened. Review articles references were hand searched to identify papers not yet captured. The final search was uploaded into Endnote and duplicates removed.

Fig.1

PRISMA-ScR flow diagram of study selection process.

2.4 Selection of sources of evidence

Papers were uploaded to Covidence software, 2016 (www.covidence.org). Title and abstract screening and full text reviewing were conducted by two independent reviewers (SW and SD). Inter-rater reliability was tested at both title and abstract and full text stages to substantial agreement (Cohen’s Kappa = 0.7) [24]. Any disagreements regarding interpretation of the criteria were discussed with the research team and clarified. Conflicts following each stage were resolved with a third independent reviewer (JD).

2.5 Data charting process

Data extraction templates for empirical studies (author, year, country, participants, methods, relevant findings), narrative reviews (author, year, diagnostic criteria, relevant findings) and systematic reviews (author, year, number of studies, relevant findings) were created. These were later categorised into clinical domains, and where possible, developmental stage. A pilot data extraction was conducted with 20 randomly selected articles between two independent reviewers (SW and SD). When consensus was achieved, one reviewer (SW) completed the data extraction process [21]. Principal authors were contacted if there was missing data, or where further information was required.

3 Results

The original search generated 4168 papers. Following deduplication, 1619 titles and abstracts were screened, and 912 full text articles were reviewed of which 150 were included in the analysis. An extended search was carried out in June 2021 and yielded a further 13 papers. The study selection process is presented as a PRISMA-ScR flow diagram (Fig. 1). In total, 163 papers were included in the scoping review and summaries of all papers, categorized by study design are presented in Appendices 1, 2 and 3.

3.1 Context

Publication dates spanned from 1967 to 2021, with 74% (n = 120) of papers dating from 2010. Journal types spanned over 25 different clinical domains including medical, surgical, psychosocial, general and specialised topics. Empirical studies (n = 108) were conducted in 26 different countries, but nearly 50% were carried out in the US (29%) or UK (20%). Italy had the most publications in Europe (9%). There was only one international collaboration, [25] and only one systematic review specific to children, but it included only two papers [26]. Of the empirical studies, 94% (n = 101) were conducted in clinical sites, mostly in specialist settings, and 6% (n = 7) were conducted in school settings. In total n = 4444 participants were included (children n = 847; adolescents n = 2553; young adults n = 50; not specified n = 994). Although critical analysis of studies was not performed [27], study designs were plotted in terms of levels of evidence. Using a simple hierarchical approach [20], study designs were predominantly of a lower level of evidence with narrative/literature reviews and case series/reports accounting for 88 (54%) of the included studies (Table 2).

Table 2
Studies by study design and date of publication

Case report/series n (%) Observational: cross sectional n(%) Observational: case control n (%) Observational: Cohort n (%) Randomised controlled trial n (%) Qualitative n (%) Narrative / literature review n (%) Systematic review n (%) Retrospective review n (%)

1967-1999 7 3 2 0 0 0 2 0 2

2000-2009 5 8 3 0 0 0 9 0 2

2010-2019 23 12 10 5 3 4 29 6 8

2020-2021 4 2 1 0 0 0 8 0 5

Total 39 (24%) 24 (15%) 16 (10%) 5 (3%) 3 (2%) 4 (2%) 49 (30%) 6 (4%) 17 (10%)

	Case report/series n (%)	Observational: cross sectional n(%)	Observational: case control n (%)	Observational: Cohort n (%)	Randomised controlled trial n (%)	Qualitative n (%)	Narrative / literature review n (%)	Systematic review n (%)	Retrospective review n (%)
1967-1999	7	3	2	0	0	0	2	0	2
2000-2009	5	8	3	0	0	0	9	0	2
2010-2019	23	12	10	5	3	4	29	6	8
2020-2021	4	2	1	0	0	0	8	0	5
Total	39 (24%)	24 (15%)	16 (10%)	5 (3%)	3 (2%)	4 (2%)	49 (30%)	6 (4%)	17 (10%)

3.2 Diagnostic criteria

Diagnostic criteria used to define symptomatic hypermobility varied. Early studies reported children who presented to rheumatology clinics with ‘musculoskeletal complaints which at the time were considered due to generalised joint laxity’ [11] or were ‘subsequently determined to have hypermobility’ as a basis for their symptoms [28]. Later studies referred to specific criteria, revised at time points over decades [29]. However, studies often differed in their interpretation of symptomatic hypermobility, for example, ‘arthralgia for three preceding months or more’ [30], ‘presence of JH and musculoskeletal pain’ [31], ‘lower limb pain and/or fatigue in the previous 4 weeks’ [32], ‘presence of multiple joint pain’ [33], and ‘musculoskeletal symptoms (arthralgia in 2 joints for 12 weeks), exercise induced pain and exercise intolerance’ [34].

3.3 Measurement approaches

More than 75 different measurement approaches were reported across 15 different clinical domains (Table 3). Hypermobility screening assessments were reported in 62% (n = 101) of studies. Of these, the Beighton score was most commonly used (93%, n = 94), however only 12 studies reported evidence of standardisation (goniometry or standardised positioning). Additionally, the cut-off point to determine presence of JH, was not consistent, as Beighton scores of 4 [15 , 35–37], 5 [38], and 6 [32, 39] were reported.

Table 3
Measurement approaches reported in studies on children and young people with symptomatic hypermobility

Clinical domain Measurement approach

Musculoskeletal

Joint Hypermobility screening Beighton score [78]; Beighton and Horan [79]; Bulbena score [55]; Lower Limb Assessment Scale [47]; Carter and Wilkinson [11]; Hakim and Grahame Questionnaire [80]; Contompasis [81]; Shiari-Javadi criteria [82]

Pain Pressure pain thresholds [25]; Chronic MSP standardised questionnaire [31]; Pain diary [48]; Pain VAS/NRS [36 , 51]; Peds QL Pain [47]; BAPQ [51]; Widespread Pain Index [52]; Coloured Analogue Scale [39]; PFSD [15]

Strength/Endurance Leg lift timed (Part of CMAS) [40]; Dynamometer [53, 55]

Posture/Muscle Length FPI [35, 47]; Posture assessment [41]; Hamstring length [35, 40]

Function FDI [15, 52]; Gait assessment [32]; Number of flights of stairs in 2 mins [30]; 6MWT [35 , 55]Gait analysis GAITRite [32]; 6-minute shuttle test [30]

Motor control, proprioception and balance Developmental Co-ordination Disorder Questionnaire [57]; YBT [35, 47]; BOT-2 balance subset [49]; M-ABC [55]; KTK [55]; Multiple single leg hop test [37]; Fundamental movement skills assessment [40]; Joint proprioception assessment [33, 36]; Survey motor skills and co-ordination [83]; Static/dynamic balance [37]; Postural sway [37]

Upper Limb PODCI [50]; DASH [41]

Bone densitometry Quantitative Ultrasound [34, 75]

Cardiac Primary focal hyperhidrosis assessment [82]; ECG [59 , 66]; ECHO [68 , 84]; Tissue Doppler Image [59]; CT scan [42, 70]; Autonomic testing protocol for orthostatic intolerance 10-minute standing test [60 –63]

Cutaneous Skin/superficial connective tissue stretchiness [67]; Skin extensibility/elasticity [47, 135]; Presence of scars/stretch marks [35, 47]; Skin biopsy [85]

Genetic Genetic study/ testing [64 , 87]

Ophthalmic Ophthalmic assessment [64, 67]

Neurological Neurological assessment [64 , 89]; Muscle biopsy [87]

ENT Assessment for dysphonia (video laryngoscopy) [90]

Urinary VCUG [91]; Drinking and voiding diary [64]

Gynaecological Gynaecological exam/standardised questionnaire [92,93, 92,93]

Gastrointestinal ROME criteria [63]

Psychosocial

Psychological Psychological well-being assessment [42]; Family functioning assessment [42]; The PROMIS (Pediatric Anxiety Symptoms and Depressive Symptoms short form) [52]

QOL PedsQL Generic Core [15, 39]; Child health utility 9-dimensional assessment [53]; CHQ [53,94, 53,94]; BIPQ [15]

Participation and Activity Activity Diary [49]; FPQ [49]; PAQ [35 , 95]; Physical Activity Recall Questionnaire [36, 40]

Other Clinical Areas

Fatigue The PROMIS Pediatric Fatigue (Tired) short form [52]; Peds QL Multidimensional fatigue scale questionnaire [15 , 76]

Headaches 2013 International Classification of Headaches disorder assessment [63]

Sleep SRBD [94]; ESS [94]; Home portable sleep test [94]

Somatic Symptoms Symptom Severity scale [52]

Clinical domain	Measurement approach
Musculoskeletal
Joint Hypermobility screening	Beighton score [78]; Beighton and Horan [79]; Bulbena score [55]; Lower Limb Assessment Scale [47]; Carter and Wilkinson [11]; Hakim and Grahame Questionnaire [80]; Contompasis [81]; Shiari-Javadi criteria [82]
Pain	Pressure pain thresholds [25]; Chronic MSP standardised questionnaire [31]; Pain diary [48]; Pain VAS/NRS [36 , 51]; Peds QL Pain [47]; BAPQ [51]; Widespread Pain Index [52]; Coloured Analogue Scale [39]; PFSD [15]
Strength/Endurance	Leg lift timed (Part of CMAS) [40]; Dynamometer [53, 55]
Posture/Muscle Length	FPI [35, 47]; Posture assessment [41]; Hamstring length [35, 40]
Function	FDI [15, 52]; Gait assessment [32]; Number of flights of stairs in 2 mins [30]; 6MWT [35 , 55]Gait analysis GAITRite [32]; 6-minute shuttle test [30]
Motor control, proprioception and balance	Developmental Co-ordination Disorder Questionnaire [57]; YBT [35, 47]; BOT-2 balance subset [49]; M-ABC [55]; KTK [55]; Multiple single leg hop test [37]; Fundamental movement skills assessment [40]; Joint proprioception assessment [33, 36]; Survey motor skills and co-ordination [83]; Static/dynamic balance [37]; Postural sway [37]
Upper Limb	PODCI [50]; DASH [41]
Bone densitometry	Quantitative Ultrasound [34, 75]
Cardiac	Primary focal hyperhidrosis assessment [82]; ECG [59 , 66]; ECHO [68 , 84]; Tissue Doppler Image [59]; CT scan [42, 70]; Autonomic testing protocol for orthostatic intolerance 10-minute standing test [60 –63]
Cutaneous	Skin/superficial connective tissue stretchiness [67]; Skin extensibility/elasticity [47, 135]; Presence of scars/stretch marks [35, 47]; Skin biopsy [85]
Genetic	Genetic study/ testing [64 , 87]
Ophthalmic	Ophthalmic assessment [64, 67]
Neurological	Neurological assessment [64 , 89]; Muscle biopsy [87]
ENT	Assessment for dysphonia (video laryngoscopy) [90]
Urinary	VCUG [91]; Drinking and voiding diary [64]
Gynaecological	Gynaecological exam/standardised questionnaire [92,93, 92,93]
Gastrointestinal	ROME criteria [63]
Psychosocial
Psychological	Psychological well-being assessment [42]; Family functioning assessment [42]; The PROMIS (Pediatric Anxiety Symptoms and Depressive Symptoms short form) [52]
QOL	PedsQL Generic Core [15, 39]; Child health utility 9-dimensional assessment [53]; CHQ [53,94, 53,94]; BIPQ [15]
Participation and Activity	Activity Diary [49]; FPQ [49]; PAQ [35 , 95]; Physical Activity Recall Questionnaire [36, 40]
Other Clinical Areas
Fatigue	The PROMIS Pediatric Fatigue (Tired) short form [52]; Peds QL Multidimensional fatigue scale questionnaire [15 , 76]
Headaches	2013 International Classification of Headaches disorder assessment [63]
Sleep	SRBD [94]; ESS [94]; Home portable sleep test [94]
Somatic Symptoms	Symptom Severity scale [52]

MSP Musculoskeletal Pain, VAS Pain Visual Analogue Scale, NRS Pain Numerical Rating Scale, Peds-QL Pain Paediatric Pain Questionnaire, BAPQ Bath Adolescent Pain Questionnaire, PFSD Pain-Frequency-Severity-Duration Scale; CMAS Childhood Myositis Assessment Scale, FPI Foot Posture Index, FDI The Functional Disability Inventory, 6MWT six-minute-walk-test, YBT Y-Balance Test, BOT-2 Bruininks-Oseretsky test of motor proficiency, M-ABC Movement Assessment Battery for Children, KTK Korperkoordinationstest fur Kinder PODCI The Pediatric Outcomes Data Collection Instrument, DASH Disabilitites of the Arm, Hand and Shoulder Questionnaire, ECG Electrocardiogram, ECHO Echocardiogram, CT Computed Tomography, VCUG Voiding Cysto-Urethrogram, PEDS QL Pediatric Quality of Life Inventory, CHQ Child Health Questionnaire, BIPQ Brief illness Perception Questionnaire, FPQ Frequency of Participation Questionnaire, PAQ Physical Activity Questionnaire, PROMIS Patient-Reported Outcomes Measurement Information System, SRBD Sleep-Related Breathing Disorder Scale, ESS Epworth Sleepiness Scale.

Assessments in the musculoskeletal domain included pain (14%, n = 23) [15 , 38–54] and function (9%, n = 14) [30 , 55–58]. Cardiovascular assessments were reported in 12% (n = 19) papers [13 , 59–75]. Other clinical domains included cutaneous, genetic, urogenital, gynaecological, and gastrointestinal. Assessments relating to quality of life were reported in 8% (n = 13) of studies [15 , 76] and fatigue was assessed in 6% (n = 9) of studies [13 , 77].

3.4 Clinical characteristics

Fig.2

Studies reporting clinical characteristics for each developmental stage.

Of the 108 empirical studies, only 89 presented clinical characteristics stratified by age. Primary data were analysed with respect to developmental stage (childhood, adolescence, young adulthood) and clinical domain. A summary of findings is presented in Fig. 2.

3.5 Childhood

Clinical characteristics in children were reported in 16 studies [53 , 95–100]. Musculoskeletal characteristics were reported in 75% (n = 12) of these studies, including pain [53 , 100], exercise-induced pain [75], myalgia [71], and arthralgia [75]. Other characteristics included hyperextensible joints [79, 98], joint subluxations [79], reduced balance [57], low muscle tone [57], unstable gait [99], weakness [55], and decreased exercise capacity and participation in exercise compared to peers [55]. Cutaneous features were reported in 31% (n = 5) studies. Reports included unusually soft or velvety skin [72, 100], skin extensibility [75, 79], and easy bruising [79]. Three studies reported neurodevelopmental features including gross motor delay [100], co-ordination difficulties [53] or gross and fine motor, social and literacy problems [83]. Two studies reported cardiovascular clinical characteristics: aortic root dilatation and mitral valve prolapse [71, 72]. Two studies reported fatigue [57, 100]. One of these studies, a large retrospective review (n = 318), found 89% of participants reported a ‘sense of fatigue during or after activity’[100].

3.6 Adolescence

Clinical characteristics in adolescents were reported in 54 studies [13 , 101–117]. Musculoskeletal characteristics were reported in 85% (n = 46) of studies and included, chronic recurrent pain [34 , 118] and joint instability, sprains and dislocations [42 , 118]. Clinical characteristics from the cardiovascular domain were reported in 37% (n = 20) of studies, including valve prolapse and greater aortic root [59, 89] and dysautonomia including orthostatic intolerance [13 , 117]. Cutaneous features were reported in 35% (n = 20) studies [13 , 119] notably easy bruising [40 , 76], hyperextensibility [64 , 89], soft velvety skin [87, 108], delayed wound healing, easy scarring [35, 87], and striae [101]. Fatigue was reported in 24% (n = 13) of papers [13 , 118]. Gastrointestinal characteristics were reported in 22%, n = 12 [15 , 118]. Clinical characteristics included chronic gastritis [118], constipation [78], recurrent abdominal pain and chronic diarrhoea [35, 87], and vomiting [52]. Urogenital features were reported in 15% (n = 8) [15 , 110] including primary nocturnal enuresis and daytime symptoms of urinary urgency [64]. Sleep disorders were reported in 11% (n = 6) of studies [52 , 110] including insomnia [52, 54], obstructive sleep apnoea, circadian rhythm disorders, periodic limb movement disorder, and hypersomnia [54, 94]. Psychosocial features were reported in 11% (n = 6) of studies [15 , 104]. Characteristics included anxiety and depression [15 , 104] and eating disorders [104]. Neurodevelopmental characteristics were reported in 7% of studies [78 , 110] including relatively higher rates of learning difficulties, dyslexia and dyspraxia [78] and an association between neuropsychiatric conditions, such as attention deficit hyperactivity disorder (ADHD) and children diagnosed with HDS and hEDS [110].

3.7 Young adulthood

Nineteen studies included participants between 20 and 24 years [37 , 120–131]. Musculoskeletal characteristics were reported in 95% (n = 18) of studies, with the exception of one study [85]. Characteristics included arthralgia [41 , 128], joint instability, dislocation [43 , 128] and reduced dynamic balance [37]. Cutaneous features were reported in 42% (n = 8) of studies [41 , 130]. Characteristics included easy bruising [41, 92], soft skin [129] and striae [130]. Psychological features were reported in 26% (n = 5) of studies [41 , 129] including depression [80, 129] and anxiety [125]. Gastrointestinal characteristics were reported in 21% (n = 4) of studies, all of which were single case reports [41 , 128]. Two studies reported urogenital characteristics: stress incontinence and dysuria [80, 128].

4 Discussion

This is the first scoping review to explore the literature on children and young people with symptomatic hypermobility with a unique focus on developmental context. This review systematically clarified and interpreted the considerable quantity of diverse literature to make it more accessible to researchers and clinicians. Research on those with symptomatic hypermobility was more prolific in the last 12 years, extends over many different clinical domains, and consists largely of narrative reviews and case studies. The level of evidence of the literature on symptomatic hypermobility is predominantly of a lower hierarchy [132]. Case reports and series may represent more extreme clinical cases but were included due to the objectives of this scoping review to explore the full extent of the literature. The Beighton score was the most commonly used tool to screen for hypermobility, but there were limited details regarding how it was used. Similarities and differences in the presenting clinical characteristics across the developmental stages were identified.

This review found that musculoskeletal symptoms are the most prevalent clinical characteristics, and akin to cutaneous features, were reported across all developmental stages. Neurodevelopmental clinical characteristics were more common in children [53 , 100]. In adolescents, dysautonomia, fatigue, sleep issues, and symptoms from urogenital and gastrointestinal domains were reported more frequently. Dysautonomia is also common in those with chronic functional pain conditions and might not be a primary indicator of symptomatic hypermobility [16, 63]. The onset of puberty was reported to be associated with a worsening of symptoms in only one study [93]. Of interest, psychological characteristics such as anxiety and depression were reported in over a quarter of all young adult studies [41 , 129].

Despite the Beighton score being commonly used (n = 94), evidence of reporting of standardisation (positioning or goniometry) was documented in only 12 studies. This affects our confidence interpreting prevalence of hypermobility across different studies. A further issue of concern is that different Beighton score cut-off points were used. A large UK population study (n = 6,022) using a Beighton score cut-off point of 4/9 reported a high prevalence of hypermobility in girls (27.5%) and boys (10.6%) [133], while a study of Danish school children using a cut-off point of 6/9 resulted in a lower prevalence (9.4%) [95]. A standardised Beighton protocol has been proposed and validated in school-aged children [6] but only reported in one study in this review [57]. Barriers to its use may be a lack of awareness, equipment, or time. However, in order to accurately assess joint hypermobility, to avoid over or under diagnosis, the utilisation of standardised tools using validated protocols in clinical practice and research isessential.

Seven different assessments of function, and 11 different assessments of motor control were identified in this review. Assessments to determine cutaneous features appear to be mostly subjective. There were six different types of cardiovascular assessments, including use of echocardiography, which was recently investigated in a retrospective chart review of paediatric patients with a diagnosis of some type of EDS [69]. Authors report substantial use of echocardiography in patients with suspected hEDS but found that once other genetic conditions were ruled out, children with hEDS did not have significant aortic disease, and mitral valve prolapse occurred at the same incidence as the general population [69]. The variety of reported assessments for children and young people with symptomatic hypermobility may reflect the growing awareness of clinicians regarding the spectrum of symptoms. However, it also reflects the lack of guidance and use of specific standardised outcome measures. Additionally, it limits comparisons between studies.

Previous studies have suggested that there is a changing phenotype, characterised by a progressive worsening from childhood to adulthood [134]. One of only two longitudinal cohort studies identified in this review reported that an increased incidence of multisystem complaints was more predictive of functional decline [35]. This ScR categorised clinical characteristics according to specific developmental stages, comprehensively reporting evidence of a changing clinical presentation. However, to advance our understanding of children and young people with symptomatic hypermobility, future well-designed case control and longitudinal cohort study designs are required to observe such clinical characteristics that develop and/or change with age, so that health care professionals will be able to offer them optimum care over their lifespan.

Unlike systematic reviews, scoping reviews can be used when literature exhibits a heterogenous nature which is not as amenable to a systematic review [36]. The broad systematic search strategy was conducted by an experienced librarian and guided by expert clinicians and research team members with expertise across clinical and research spheres. There was an attempt to reduce some of the methodological heterogeneity by scrutinising literature, in particular the definitions of diagnosed symptomatic hypermobility, to ensure that studies of children with asymptomatic hypermobility were not included. Extraction of data for participants who were 24yrs presented significant challenges in the review and there were studies whereby data could not be extracted, which could be seen as a limitation.

5 Conclusion

This review presents a synthesis of the diverse research on symptomatic hypermobility in children and young people in a developmental context. Given the changing temporal pattern of symptoms, longitudinal studies and large case control studies are warranted to provide better understanding of symptomatic hypermobility in this population. Such studies should have bespoke criteria and use standardised assessment protocols so that findings from different studies can be compared and data can be pooled for analysis.

The comprehensive reporting of symptoms, extending beyond the musculoskeletal system into wide-ranging clinical domains presents the consideration of alternative care pathways for children and young people, whereby not all require referral to traditional settings of tertiary rheumatology and genetic clinics. With clearer guidance for health care professionals, patients with clinically relevant hypermobility could be recognised earlier and managed locally, to address the broad symptomatology with appropriate support. Those who require onward assessment and referral to tertiary services could be identified. This can only be achieved if clinicians in primary and community care are guided regarding bespoke assessment and diagnostic criteria with a background knowledge of paediatric conditions which present similarly.

Author contributions

SW, SD, JD, JS and EMD conceived the study, and formulated the research question. The search strategy was drafted by DM. SW and SD conducted screening and reviewing, whilst conflicts were resolved by JD. SW and SD drafted the review. All authors were involved in the revisions to the paper and approved the final text for submission.

Conflict of interest

The authors have no conflict of interest to report.

Funding

Supported by the National Children’s Research Centre (NCRC), Dublin, Ireland (grant number –D/19/5 to SW). The NCRC has been in existence for more than 50 years and has been funded since its inception by the Children’s Health Foundation Crumlin, Dublin, Ireland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Supplementary materials

Appendices 1, 2 and 3 are available in the electronic version of this article: https://dx.doi.org/10.3233/PPR-220699.

References

Castori

. Joint hypermobility in children: a neglected sign needing more attention. Minerva Pediatrica. 2020;72:123–33.

Sobhani-Eraghi

, Motalebi

, Sarreshtehdari

, Molazem-Sanandaji

, Hasanlu

. Prevalence of joint hypermobility in children and adolescents: A systematic review and meta-analysis. J Res Med Sci. 2020;25:104.

Malfait

, Francomano

, Byers

, Belmont

, Berglund

, Black

, et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):8–26.

Remvig

, Kümmel

, Kristensen

, Boas

, Juul-Kristensen

. Prevalence of generalized joint hypermobility, arthralgia and motor competence in 10-year-old school children. International Musculoskeletal Medicine. 2011;33:137–45.

Juul-Kristensen

, Schmedling

, Rombaut

, Lund

, Engelbert

. Measurement properties of clinical assessment methods for classifying generalized joint hypermobility-A systematic review. Am J Med Genet C Semin Med Genet. 2017;175:116–47.

Smits-Engelsman

, Klerks

, Kirby

. Beighton score: a valid measure for generalized hypermobility in children. J Pediatr. 2011;158:11923:e1–4.

Castori

, Tinkle

, Levy

, Grahame

, Malfait

, Hakim

. A framework for the classification of joint hypermobility and related conditions. Am J Med Genet C Semin Med Genet. 2017;175:148–57.

Tinkle

. Symptomatic joint hypermobility. Best Pract Res Clin Rheumatol. 2020;34:101508.

Council AMmoBS. Guidance for Management of Symptomatic Hypermobility in Children and Young People - A Guide for Professionals managing Children and Young People with thei condition June 2019 [Available from: https://www.rheumatology.org.uk/Portals/0/Documents/Guidelines/Pediatric%20guidelines/Guidance_management_symptomatic_hypermobility_CYP_June 2019-06-24-134 243-607. Accessed June 13, 2021.

10.

Society for Adolescent H, Medicine. Young Adult Health and Well-Being: A Position Statement of the Society for AdolescentHealth and Medicine. J Adolesc Health. 2017;60:758–9.

11.

Kirk

, Ansell

, Bywaters

. The hypermobility syndrome. Musculoskeletal complaints associated with generalized joint hypermobility. Ann Rheum Dis. 1967;26(5):419–25.

12.

Beckers

, Keszthelyi

, Fikree

, Vork

, Masclee

, Farmer

, et al. Gastrointestinal disorders in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type: A review for the gastroenterologist. Neurogastroenterol Moti. 2017 29 (8).

13.

Rowe

, Barron

, Calkins

, Maumenee

, Tong

, Geraghty

. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatr. 1999 135(4).

14.

De Wandele

, Calders

, Peersman

, Rimbaut

, De Backer

, Malfait

, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: a comparative study with two other EDS types, fibromyalgia, and healthy controls. Semin Arthritis Rheum. 2014;44:353–61.

15.

, Muriello

, Clemens

, Wang

, Smith

, Tran

, et al. Factors affecting quality of life in children and adolescents with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders. Am J Med Genet A. 2019;179(4):561–9.

16.

Armon

. Musculoskeletal pain and hypermobility in children and young people: is it benign joint hypermobility syndrome? Arch Dis Child. 2015;100(1):2–3.

17.

Michaleff

, Kamper

, Stinson

, Hestbaek

, Williams

, Campbell

, et al. Measuring Musculoskeletal Pain in Infants, Children, and Adolescents. J Orthop Sports Phys Ther. 2017;47(10):712–30.

18.

Foster

, Cabral

. Is musculoskeletal history and examination so different in paediatrics? Best Pract Res Clin Rheumatol. 2006;20(2):241–62.

19.

Castori

, Hakim

. Contemporary approach to joint hypermobility and related disorders. Curr Opin Pediatr. 2017;29(6):640–9.

20.

Peters

MDJ

, Godfrey

, McInerney

, Munn

, Trico

, Khalil

. Chapter 11: Scoping Reviews. JBI Manual for Evidence Synthesis. 2020.

21.

Levac

, Colquhoun

, O’Brien

. Scoping studies: advancing the methodology. Implement Sci. 2010;5(69).

22.

Arksey

, O’Malley

. Scoping studies: towards a methodological framework. Int J Soc Res Methodol. 2005;8(1):19–32.

23.

Ward

, MacDermott

, Deane

, Simmonds

, Mockler

, Dockrell

. Clinical Characteristics of Symptomatic Hypermobility in Children and Young People: A Scoping Review Protocol. Physiother Pract Res. 2022: 43 (1)63–69.

24.

McHugh

. Interrater reliability: the kappa statistic. Biochem Med (Zagreb). 2012;22(3):276–82.

25.

Scheper

, Pacey

, Rombaut

, Adams

, Tofts

, Calders

, et al. Generalized Hyperalgesia in Children and Adults Diagnosed With Hypermobility Syndrome and Ehlers-Danlos Syndrome Hypermobility Type: A Discriminative Analysis. Arthritis Care Res. 2017;69(3):421–9.

26.

Peterson

, Coda

, Pacey

, Hawke

. Physical and mechanical therapies for lower limb symptoms in children with Hypermobility Spectrum Disorder and Hypermobile Ehlers-Danlos Syndrome: a systematic review. J Foot Ankle Res. 2018;11:59.

27.

Khalil

, Peters

, Tricco

, Pollock

, Alexander

, McInerney

, et al. Conducting high quality scoping reviews-challenges and solutions. J Clin Epidemiol. 2021;130:156–60.

28.

Biro

, Gewanter

, Baum

. The hypermobility syndrome. Pediatrics. 1983;72(5):701–6.

29.

Malfait

, Castori

, Francomano

, Giunta

, Kosho

, Byers

. The Ehlers–Danlos syndromes. Nat Rev Dis Primers. 2020 6 (1).

30.

Kemp

, Roberts

, Gamble

, Wilkinson

, Davidson

, Baildam

, et al. A randomized comparative trial of generalized vs targeted physiotherapy in the management of childhood hypermobility. Rheumatology. 2010;49(2):315–25.

31.

Zapata

, Moraes

, Leone

, Doria-Filho

, Silva

. Pain and musculoskeletal pain syndromes related to computer and video game use in adolescents. Eur J Pediatr. 2006;165(6):408–14.

32.

McDermott

, Wolfe

, Lowry

, Robinson

, French

. Evaluating the immediate effects of wearing foot orthotics in children with Joint Hypermobility Syndrome (JHS) by analysis of temperospatial parameters of gait and dynamic balance: A preliminary study. Gait Posture. 2018;60:61–4.

33.

Fatoye

, Palmer

, Macmillan

, Rowe

, van der Linden

. Proprioception and muscle torque deficits in children with hypermobility syndrome. Rheumatology. 2009;48(2):152–7.

34.

Engelbert

, van Bergen

, Henneken

, Helders

, Takken

. Exercise tolerance in children and adolescents with musculoskeletal pain in joint hypermobility and joint hypomobility syndrome. Pediatrics. 2006;118(3):e690–6.

35.

Scheper

, Nicholson

, Adams

, Tofts

, Pacey

. The natural history of children with joint hypermobility syndrome and Ehlers-Danlos hypermobility type: a longitudinal cohort study. Rheumatology. 2017;56(12):2073–83.

36.

Pacey

, Adams

, Tofts

, Munns

, Nicholson

. Proprioceptive acuity into knee hypermobile range in children with joint hypermobility syndrome. Pediatr Rheumatol Online J. 2014;12:40.

37.

Iatridou

, Mandalidis

, Chronopoulos

, Vagenas

, Athanasopoulos

. Static and dynamic body balance following provocation of the visual and vestibular systems in females with and without joint hypermobility syndrome. J Bodyw Mov Ther. 2014;18 (2): 159–64.

38.

Pacey

, Tofts

, Adams

, Munns

, Nicholson

. Exercise in children with joint hypermobility syndrome and knee paA randomised controlled trial comparing exercise into hypermobile versus neutral knee extension. Pediatric Rheumatology 2013 11 (1).

39.

Fatoye

, Palmer

, Macmillan

, Rowe

, van der Linden

. Pain intensity and quality of life perception in children with hypermobility syndrome. Rheumatology International. 2012;32(5):1277–84.

40.

Pacey

, Adams

, Tofts

, Munns

, Nicholson

. Joint hypermobility syndrome subclassification in paediatrics: a factor analytic approach. Arch Dis Child. 2015;100(1):8–13.

41.

Quarrier

. Is hypermobility syndrome (HMS) a contributing factor for chronic unspecific wrist pain in a musician? If so, how is it evaluated and managed? Work. 2011;40(3):325–33.

42.

Branson

, Kozlowska

, Kaczynski

, Roesler

. Managing chronic pain in a young adolescent girl with Ehlers-Danlos syndrome. Harv Rev Psychiatry. 2011;19(5):259–70.

43.

Schoorl

, Nguyen

NTV

, van Noort

, Alta

TDW

, Sanchez-Sotelo

. Capsulorraphy with Achilles Allograft Augmentation for Shoulder Instability in Patients with Ehlers-Danlos Syndrome. J Shoulder Elbow Surg. 2021;30(4):865–70.

44.

Scheper

, Keer

, Engelbert

RHH

. Clinical profiling and tailorednon-pharmacological treatment in hypermobility spectrumdisorders/hypermobile Ehlers-Danlos syndrome. Jacobs JWG, Cornelissens LJM, Veenhuizen MC, Hamel BCJ, editors. 2018;311–29.

45.

van Meulenbroek

, Huijnen

IPJ

, Simons

, Conijn

AEA

, Engelbert

RHH

, Verbunt

. Exploring the underlying mechanism of pain-related disability in hypermobile adolescents with chronic musculoskeletal pain. Scand J Pain. 2020;31:31.

46.

Zekry

, Ahmed

, Elwahid

HAEA

. The impact of fatigue on health related quality of life in adolescents with benign joint hypermobility syndrome. Egyptian Rheumatologist. 2013;35(2):77–85.

47.

Nicholson

, Adams

, Tofts

, Pacey

. Physical and Psychosocial Characteristics of Current Child Dancers and Nondancers With Systemic Joint Hypermobility: A Descriptive Analysis. J Orthop Sports Phys Ther. 2017;47(10):782–91.

48.

Sperotto

, Balzarin

, Parolin

, Monteforte

, Vittadello

, Zulian

. Joint hypermobility, growing pain and obesity are mutually exclusive as causes of musculoskeletal pain in schoolchildren. Clin Exp Rheumatol. 2014;32(1):131–6.

49.

Schubert-Hjalmarsson

, Ohman

, Kyllerman

, Beckung

. Pain, balance, activity, and participation in children with hypermobility syndrome. Pediatr Phys Ther. 2012;24(4):339–44.

50.

Shotwell

, Moore

. Assessing reliability and validity of a functional outcome measure for adolescents with hypermobility spectrum disorder. Disabil Rehabil. 2020;1–6.

51.

Revivo

, Amstutz

, Gagnon

, McCormick

. Interdisciplinary Pain Management Improves Pain and Function in Pediatric Patients with Chronic Pain Associated with Joint Hypermobility Syndrome. Pm & R. 2019;11(2):150–7.

52.

Tran

, Jagpal

, Koven

, Turek

, Golden

, Tinkle

. Symptom complaints and impact on functioning in youth with hypermobile Ehlers–Danlos syndrome. J Child Health Care. 2020;24(3):444–57.

53.

Bale

, Easton

, Bacon

, Jerman

, Watts

, Barton

, et al. The effectiveness of a multidisciplinary intervention strategy for the treatment of symptomatic joint hypermobility in childhood: a randomised, single Centre parallel group trial (The Bendy Study). Pediatr Rheumatol Online. 2019;17(1):2.

54.

Domany

, Hantragool

, Smith

, Xu

, Hossain

, Simakajornboon

. Sleep disorders and their management in children with Ehlers-Danlos syndrome referred to sleep clinics. J Clin Sleep Med. 2018;14(4):623–9.

55.

Hanewinkel-van Kleef

, Helders

, Takken

, Engelbert

. Motor performance in children with generalized hypermobility: the influence of muscle strength and exercise capacity. Pediatr Phys Ther. 2009;21(2):194–200.

56.

Russek

, Stott

, Simmonds

. Recognizing and Effectively Managing Hypermobility-Related Conditions. Phys Ther. 2019;99(9):1189–200.

57.

Moore

, Rand

, Simmonds

. Hypermobility, developmental coordination disorder and physical activity in an Irish paediatric population. Musculoskeletal Care. 2019;17(2):261–9.

58.

Simmonds

, Keer

. Hypermobility and the hypermobility syndrome. Manual Therapy. 2007;12(4):298–309.

59.

Balli

, Aydin

, Gerdan

, Ece

, Oflaz

, Kibar

, et al. Evaluation of cardiac functions of patients with benign joint hypermobility syndrome. Pediatr Cardiol. 2014;35(2):374–9.

60.

Boris

, Bernadzikowski

. Demographics of a large paediatric Postural Orthostatic Tachycardia Syndrome Program. Cardiol Young. 2018;28(5):668–74.

61.

Boris

, Bernadzikowski

. Prevalence of joint hypermobility syndromes in pediatric postural orthostatic tachycardia syndrome. Auton Neurosci. 2021;231:102770.

62.

Boris

, Huang

, Shuey

, Bernadzikowski

. Family history of associated disorders in patients with postural tachycardia syndrome. Cardiol Young. 2020;30(3):388–94.

63.

Chelimsky

, Kovacic

, Simpson

, Nugent

, Basel

, Banda

, et al. Benign Joint Hypermobility Minimally Impacts Autonomic Abnormalities in Pediatric Subjects with Chronic Functional Pain Disorders. J Pediatr. 2016;177:49–52.

64.

Cunha

, Matias

, Marques

. Ehlers-Danlos syndrome presenting with primary nocturnal enuresis. BMJ Case Re. 2020;13(2):04.

65.

Handler

, Child

, Light

, Dorrance

. Mitral valve prolapse, aortic compliance, and skin collagen in joint hypermobility syndrome. Heart. 1985;54(5):501–8.

66.

McDonnell

, Gorman

, Mandel

, Schurman

, Assanah-Carroll

, Mayer

, et al. Echocardiographic findings in classical and hypermobile Ehlers-Danlos syndromes. Am J Med Genet A. 2006;140(2):129–36.

67.

Mishra

, Ryan

, Atkinson

, Taylor

, Bell

, Calver

, et al. Extra-articular features of benign joint hypermobility syndrome. Rheumatology (Oxford). 1996;35(9):861–6.

68.

Paige

, Lechich

, Tierney

ESS

, Collins

, 2nd . Cardiac involvement in classical or hypermobile Ehlers-Danlos syndrome is uncommon. Genet Med. 2020;22(10):1583–8.

69.

Rauser-Foltz

, Starr

, Yetman

. Utilization of echocardiography in Ehlers-Danlos syndrome. Congenital Heart Disease. 2019;14(5):864–7.

70.

Rubio-Agusti

, Kojovic

, Chandrashekar

, Edwards

, Bhatia

. Cervical dystonia and joint hypermobility syndrome: a dangerous combination. Mov Disord. 2012;27(2):203–4.

71.

Shiari

, Vaziri

, Javaherizadeh

, Zahmatkesh

, Torabizadeh

, Zadkarami

, et al. Association of benign joint hypermobility syndrome with mitral valve prolapse in Iranian children. Hong Kong J Paediatr. 2012;17(2):115–8.

72.

Tiller

, Cassidy

, Wensel

, Wenstrup

. Aortic root dilatation in Ehlers-Danlos syndrome types I, II and III. A report of five cases. Clin Genet. 1998;53(6):460–5.

73.

Winship

. Ehlers-Danlos syndrome in the Western Cape. S Afr Med J. 1985;67(13):509–11.

74.

Wong

, Javid

. Bilateral femoral hernias in a male child as the initial presentation of Ehlers-Danlos syndrome. J Pediatr Surg Case Re. 2020;62.

75.

Engelbert

, Bank

, Sakkers

, Helders

, Beemer

, Uiterwaal

. Pediatric generalized joint hypermobility with and without musculoskeletal complaints: a localized or systemic disorder? Pediatrics. 2003;111(3):248–54.

76.

Pacey

, Tofts

, Adams

, Munns

, Nicholson

. Quality of life prediction in children with joint hypermobility syndrome. J Paediatr Child Health. 2015;51(7):689–95.

77.

Scheper

, Engelbert

, Rameckers

, Verbunt

, Remvig

, Juul-Kristensen

. Children with generalised joint hypermobility and musculoskeletal complaints: state of the art on diagnostics, clinical characteristics, and treatment. Biomed Res Int. 2013;121054.

78.

Adib

, Davies

, Grahame

, Woo

, Murray

. Joint hypermobility syndrome in childhood. A not so benign multisystem disorder? Rheumatology. 2005;44(6):744–50.

79.

Gamble

, Mochizuki

, Rinsky

. Trapezio-metacarpal abnormalities in Ehlers-Danlos syndrome. J Hand Surg Am. 1989;14(1):89–94.

80.

Folci

, Capsoni

. Arthralgias, fatigue, paresthesias and visceral pacan joint hypermobility solve the puzzle? A case report. BMC Musculoskelet Disord. 2016;17:58

81.

McCormack

, Briggs

, Hakim

, Grahame

. Joint laxity and the benign joint hypermobility syndrome in student and professional ballet dancers. J Rheumatol. 2004;31(1):173–8.

82.

Parvaneh

, Shahvaladi

, Rahmani

, Yekta

, Gorji

, Shiari

, et al. Correlation between benign joint hypermobility syndrome and primary focal hyperhidrosis in children: a novel concept. BMC Musculoskelet Disord. 2020;21(1):268.

83.

Kirby

, Davies

, Bryant

. Hypermobility syndrome and developmental coordination disorder: similarities and features...including commentary by Wilson PH, Visser J, and Adib N. Int J Ther Rehabil. 2005;12(10):431–7.

84.

Ritter

, Atzinger

, Hays

, James

, Shikany

, Neilson

, et al. Natural history of aortic root dilation through young adulthood in a hypermobile Ehlers-Danlos syndrome cohort. Am J Med Genet A. 2017;173(6):1467–72.

85.

Reinstein

, Pariani

, Bannykh

, Rimoin

, Schievink

. Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: A prospective study. Eur J Med Genet. 2013;21(4):386–90.

86.

Morlino

, Dordoni

, Sperduti

, Venturini

, Celletti

, Camerota

, et al. Refining patterns of joint hypermobility, habitus, and orthopedic traits in joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type. Am J Med Genet A. 2017;173(4):914–29.

87.

Ghibellini

, Brancati

, Castori

. Neurodevelopmental attributes of joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type: Update and perspectives. Am J Med Genet C Semin Med Genet. 2015;169C (1) 107–16.

88.

Celletti

, Castori

, Galli

, Rigoldi

, Grammatico

, Albertini

, et al. Evaluation of balance and improvement of proprioception by repetitive muscle vibration in a 15-year-old girl with joint hypermobility syndrome. Arthritis Care Res. 2011;63(5):775–9.

89.

Galan

, Kousseff

. Peripheral neuropathy in Ehlers-Danlos syndrome. Pediatr Neurol. 1995;12(3):242–5.

90.

Rimmer

, Giddings

CEB

, Cavalli

, Hartley

BEJ

. Dysphonia-A rare early symptom of Ehlers-Danlos syndrome? Int J Pediatr Otorhinolaryngol 2008;72(12):1889–92.

91.

Beiraghdar

, Rostami

, Panahi

, Einollahi

, Teimoori

. Vesicourethral reflux in pediatrics with hypermobility syndrome. Nephrourology Monthly. 2013;5(4):924–7.

92.

Krapf

, Goldstein

. Two case presentations of profound labial edema as a presenting symptom of hypermobility-type Ehlers-Danlos syndrome. J Sex Med. 2013;10(9):2347–50.

93.

Hugon-Rodin

, Lebegue

, Becourt

, Hamonet

, Gompel

. Gynecologic symptoms and the influence on reproductive life in 386 women with hypermobility type ehlers-danlos syndrome: a cohort study. Orphanet J Rare Dis. 2016;11(1):124.

94.

Stoberl

, Gaisl

, Giunta

, Sievi

, Singer

, Moller

, et al. Obstructive Sleep Apnoea in Children and Adolescents with Ehlers-Danlos Syndrome. Respiration. 2019;97(4):284–91.

95.

Juul-Kristensen

, Kristensen

, Frausing

, Jensen

, Rogind

, Remvig

. Motor competence and physical activity in 8-year-old school children with generalized joint hypermobility. Pediatrics. 2009;124(5):1380–7.

96.

Martinez-Coronado

, Torres-Alvarez

, Castanedo-Cazares

. Goose skin in a girl with Ehlers-Danlos syndrome. J Community Hosp Intern Med Perspect. 2015;5(4):28216.

97.

Kerr

, Macmillan

, Uttley

, Luqmani

. Physiotherapy for children with hypermobility syndrome. Physiotherapy. 2000;86(6):313–7.

98.

Shanmugapriya

, Subashini

, Brindha

, Shobhana

. A ‘benign’ condition masquerading as arthritis. BMJ Case Rep. 2013;05:05.

99.

Yen

, Lin

, Chen

, Niu

. Clinical features of Ehlers-Danlos syndrome. J Formos Med Assoc. 2006;105(6):475–80.

100.

Di Mattia

, Fary

, Murray

, Howie

, Smith

, Morris

. Two subtypes of symptomatic joint hypermobility: a descriptive study using latent class analysis. Arch Dis Child. 2019;104(11):1099–101.

101.

Kaalund

, Hogsaa

, Grevy

. Coxa saltans in patients with Ehlers-Danlos syndrome, type III. Scand J Rheumatol. 1988;17(3):229–30.

102.

Khocht

, Calem

, Deasy

. Use of anti-inflammatory medications in managing atypical gingivitis associated with hypermobile Ehlers-Danlos syndrome: a case report. J Periodontol. 2004;75(11):1547–52.

103.

Syx

, Symoens

, Steyaert

, De Paepe

, Coucke

, Malfait

. Ehlers-Danlos Syndrome, Hypermobility Type, Is Linked to Chromosome 8p22-8p21. 1 in an Extended Belgian Family. Dis Markers. 2015;828970.

104.

Baeza-Velasco

, Van den Bossche

, Grossin

, Hamonet

. Difficulty eating and significant weight loss in joint hypermobility syndrome/Ehlers–Danlos syndrome, hypermobility type. Eat Weight Disord. 2016;21(2):175–83.

105.

Bamber

, Evans

. The value of decision tree analysis in planning anaesthetic care in obstetrics. Int J Obstet Anesth. 2016;27:55–61.

106.

Fatoye

, Palmer

, van der Linden

, Rowe

, Macmillan

. Gait kinematics and passive knee joint range of motion in children with hypermobility syndrome. Gait Posture. 2011;33(3):447–51.

107.

Gharbiya

, Moramarco

, Castori

, Parisi

, Celletti

, Marenco

, et al. Ocular features in joint hypermobility syndrome/ehlers-danlos syndrome hypermobility type: a clinical and in vivo confocal microscopy study. Am J Ophthalmol. 2012;154(3):593 600e1.

108.

Giordano

, Del Vecchio

, Scaraggi

, Cardinale

, Moretti

, Lassandro

, et al. Hemarthrosis due to a rare cause of hemorrhagic diathesis: Ehlers-Danlos syndrome. Pediatr Hematol Oncol. 2008;25(3):205–9.

109.

Kazkaz

, Grahame

. The rheumatological heritable disorders of connective tissue. Medicine (United Kingdom). 2018;46(4):256–60.

110.

Kindgren

, Quinones Perez

, Knez

. Prevalence of ADHD and Autism Spectrum Disorder in Children with Hypermobility Spectrum Disorders or Hypermobile Ehlers-Danlos Syndrome: A Retrospective Study. Neuropsychiatr Dis Treat. 2021;17:379–88.

111.

Krishna

, Diwan

, Singh

, Desai

. Hypermobility syndrome. J Assoc Physicians India. 2014;62(8):710–3.

112.

Nash

, Liu

, Maestas

, Layugan

, Culver

, King

, et al. Chest Pain From Hypermobility Responding to Physical Therapy in an Adolescent. Am J Phys Med Rehabil. 2017;96(12):e219–e22.

113.

Patzkowski

. Peripheral nerve blocks in patients with Ehlers-Danlos syndrome, hypermobility type: a report of 2 cases. J Clin Anesth. 2016;29:50–3.

114.

Scharf

, Nahir

. Case report: hypermobility syndrome mimicking juvenile chronic arthritis. Rheumatology & Rehabilitation. 1982;21(2):78–80.

115.

Sperotto

, Brachi

, Vittadello

, Zulian

. Musculoskeletal pain in schoolchildren across puberty: a 3-year follow-up study. Pediatr Rheumatol Online J. 2015;13:16.

116.

Terry

, Palmer

, Rimes

, Clark

, Simmonds

, Horwood

. Living with joint hypermobility syndrome: patient experiences of diagnosis, referral and self-care. Fam Pract. 2015;32(3):354–8.

117.

Zarate

, Farmer

, Grahame

, Mohammed

, Knowles

, Scott

, et al. Unexplained gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link? Neurogastroenterol Motil. 2010;22(3):252–e78.

118.

Celletti

, Castori

, Galli

, Rigoldi

, Grammatico

, Albertini

, et al. Evaluation of balance and improvement of proprioception by repetitive muscle vibration in a 15-year-old girl with joint hypermobility syndrome. Arthritis Care Res (Hoboken). 2011;63(5):775–9.

119.

Hakim

, Grahame

. A simple questionnaire to detect hypermobility: an adjunct to the assessment of patients with diffuse musculoskeletal pain. Int J Clin Pract. 2003;57(3):163–6.

120.

Echaniz-laguna

, Saint-Martin

, Lafontaine

, Tasch

, Thomas

, Hirsh

, et al. Bilateral Focal Polymicrogyria in Ehlers-Danlos syndrome. Arch Neurol. 2000;57:123–127.

121.

Boudreau

, Steiman

, Mior

. Clinical management of benign joint hypermobility syndrome: a case series. Journal of the Canadian Chiropractic Association. 2020;64(1):43–54.

122.

Clement

, Forster

, Logemann

. Focal linear elastosis in a patient with joint hypermobility syndrome. Dermatol Online J. 2018;24(1):15.

123.

Krijgh

, Harley

, Hovius

, Coert

, Walbeehm

. Surgical technique: hemi-extensor carpi radialis brevis tenodesis for stabilizing the midcarpal joint in Ehlers-Danlos syndrome. J Hand Surg Am. 2014;39(10):2071–4.

124.

Larson

, Stone

, Grossi

, Giveans

, Cornelsen

. Ehlers-Danlos Syndrome: Arthroscopic Management for Extreme Soft-Tissue Hip Instability. Arthroscopy. 2015;31(12):2287–94.

125.

Lee

, Strand

. Ehlers–Danlos syndrome in a young woman with anorexia nervosa and complex somatic symptoms. Int J Eat Disord. 2018;51(3):281–4.

126.

Palmer

, Cramp

, Clark

, Lewis

, Brookes

, Hollingworth

, et al. The feasibility of a randomised controlled trial of physiotherapy for adults with joint hypermobility syndrome. Health Technol Assess. 2016;20(47):1–264.

127.

Sætre

, Eik

. Flexible bodies—Restricted lives: Aqualitative exploratory study of embodiment in living with jointhypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. Musculoskeletal Care. 2019;17(3):241–8.

128.

Smith

, Hussain

, Seth

, Kazkaz

, Panicker

. Stress urinary incontinence as the presenting complaint of benign joint hypermobility syndrome. JRSM Short Reports. 2012;3(9):66.

129.

Stoler

, Oaklander

. Patients with Ehlers Danlos syndrome and CRPS: a possible association? Pain 2006;123(1-2):204–9.

130.

Strunk

. Multimodal Chiropractic Care for Pain and Disability in a Patient Diagnosed With Ehlers-Danlos Syndrome-Hypermobility Type: A Case Report. Journal of Chiropractic Medicine. 2017;16(2):147–55.

131.

Zhou

, Rewari

, Shanthanna

. Management of chronic pain in Ehlers–Danlos syndrome: Two case reports and a review of literature. Medicine. 2018;97(45).

132.

JBI Levels of Evidence and Grades of Recommendation Working Party*. Supporting Document for the JBI Levels of Evidence and Grades of Recommendation. JBI. 2014. https://jbi.global The Joanna Briggs Institute Levels of Evidence and Grades of Recommendation Working Party. Accessed June 2021.

133.

Clinch

, Deere

, Sayers

, Palmer

, Riddoch

, Tobias

, et al. Epidemiology of generalized joint laxity (hypermobility) in fourteen-year-old children from the UK: a population-based evaluation. Arthritis Rheum. 2011;63(9):2819–27.

134.

Castori

, Sperduti

, Celletti

, Camerota

, Grammatico

. Symptom and joint mobility progression in the joint hypermobility syndrome (Ehlers-Danlos syndrome, hypermobility type). Clin Exp Rheumatol. 2011;29(6):998–1005.