children with generalised joint hypermobility and musculoskeletal complaints: state of the art on...

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Review ArticleChildren with Generalised Joint Hypermobility andMusculoskeletal Complaints: State of the Art on Diagnostics,Clinical Characteristics, and Treatment

M. C. Scheper,1,2 R. H. H. Engelbert,1,2 E. A. A. Rameckers,3,4,5 J. Verbunt,3,4

L. Remvig,6 and B. Juul-Kristensen7

! Education of Physiotherapy, Amsterdam University of Applied Sciences, Tafelbergweg "!, !!#" BD Amsterdam,$e Netherlands%Department of Rehabilitation, Academic Medical Center, University of Amsterdam, Amsterdam,$e Netherlands&Department of Rehabilitation Medicine, Maastricht University Medical Center, Maastricht,$e Netherlands'Adelante School for Public Health and Primary Care, Maastricht University,$e Netherlands"Education for Pediatric Physical$erapy, Avans University of Applied Sciences, Breda,$e Netherlands(Department of Rheumatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark)Research Unit for Musculoskeletal Function and Physiotherapy, Institute of Sports Science and Clinical Biomechanics,University of Southern Denmark, Odense M, Denmark

Correspondence should be addressed to M. C. Scheper; [email protected]

Received #! April !"#$; Revised #$ June !"#$; Accepted & July !"#$

Academic Editor: Fausto Catena

Copyright © !"#$ M. C. Scheper et al.'is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction. To provide a state of the art on diagnostics, clinical characteristics, and treatment of paediatric generalised jointhypermobility (GJH) and joint hypermobility syndrome (JHS). Method. A narrative review was performed regarding diagnosticsand clinical characteristics. E(ectiveness of treatment was evaluated by systematic review. Searches of Medline and Central wereperformed and included nonsymptomatic and symptomatic forms of GJH (JHS, collagen diseases). Results. In the last decade,scienti)c research has accumulated on all domains of the ICF. GJH/JHS can be considered as a clinical entity, which can haveserious e(ects during all stages of life. However research regarding the pathological mechanism has resulted in new potentialopportunities for treatment. When regarding the e(ectiveness of current treatments, the search identi)ed #$#* studies, from whichthree were included (JHS: ! = 2, Osteogenesis Imperfecta: ! = 1). According to the best evidence synthesis, there was strongevidence that enhancing physical )tness is an e(ective treatment for children with JHS. However this was based on only two studies.Conclusion. Based on the sparsely available knowledge on intervention studies, future longitudinal studies should focus on the e(ectof physical activity, )tness, and joint stabilisation. In JHS and chronic pain, the e(ectiveness of a multidisciplinary approach shouldbe investigated.

1. Introduction

In the last decade, increasing scienti)c research has focusedon the diagnostics and consequences of generalized jointhypermobility (GJH) and joint hypermobility syndrome(JHS), as well as the consequences of hereditary diseases ofconnective tissue, including the most serious form of theEhlers-Danlos syndrome, hypermobile type (EDS-HT) [#].GJH is de)ned from a certain number of joint mobilitytests [!] and is part of the diagnostic criteria for benignjoint hypermobility syndrome (BJHS) [$], de)ned for adults,

and for a number of serious hereditary connective tissuediseases, like Ehlers-Danlos Syndrome (EDS) and mild typesof Osteogenesis Imperfecta.'e criterion for GJH varies buthas for adults been suggested to be at least & positive tests outof + using the Beighton’s tests for joint hypermobility, equalto one of the major criteria in JHS. However, GJH can also bede)ned as at least % out of + using Beighton’s test, as in EDS-hypermobile type (EDS-HT) [&]. For children GJH is mostlyrecommended to be at least % or , out of +. 'e di(erencebetween GJH and JHS is, that JHS is a symptomatic GJHcondition, while GJH is a nonsymptomatic condition [!]. In

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a recent review the prevalence for adults varies from ! to %-%depending on age, gender, and ethnic origin [!]. For childrenthe prevalence varies from - to $,%, primarily dependingon the tests and criteria (especially the cut-o( points) usedfor diagnosing GJH [%–*]. Children may experience a greatvariety of impairments as a result of increased laxity ofthe connective tissues. 'is not only a(ects physical )tness[+], motor development [#"], and proprioception [##] butmay also include problems with di(erent organ systems [#!](e.g., skin, vessel, and internal organs) and psychologicaldistress [#$]. As a result, children may experience functionaldisability [#&], which o.en presents di/culties in normaldaily life. Increased pain intensity and decreased qualityof life were reported in children with Joint HypermobilitySyndrome (JHS) [#&]. All dimensions in the Pediatric Qualityof Life Inventory module (QoL) were decreased comparedto children without JHS, including physical and emotionalfunctioning.'is seemed to in0uence both social and schoolfunctioning, since these parameters in the QoL module alsoturned out to be poorer for the JHS versus the not JHS chil-dren. Other studies have reported proprioception andmuscletorque de)cits [##], which is also assumed to have a seriousnegative in0uence on activity as well as participation. GJHand JHS present clinicians and researchers with di/culties inproviding and developing e(ective diagnostic procedures andmultidisciplinary care. It requires a shared common language,as well as a shared framework for what constitutes a highquality intervention in terms of goals and implementation[#%].

'e International Classi)cation for Child and Youth(ICF-CY) is a multidimensional model of functioning withparticipation as the key construct [#,, #-]. 'is model pro-vides a framework to describe limitations associated with achild’s functioning and identi)es in0uencing environmentalfactors. It has logical coherent content, aids in determiningclassi)cation and e(ective decision-making, and is easilyadopted in rehabilitation service [#*]. Although the ICF-CY is frequently used in providing healthcare service andpreventive care for children, it has not been described inchildren with GJH, JHS, and collagen diseases with GJH. Ineach chapter of the domains of the ICF-CY we have aimed atseparating scienti)c knowledge on )rstly children with GJH,and then JHS, in order to separate those with less from thosewith more severe conditions.

'e aim of the present paper is to provide a state of theart of diagnostics and treatment of GJH and JHS in childrenand young adults, where the ICF-CY serves as a conceptualmodel. 'e rational for this is that diagnostics as well astreatment strategies in GJH and JHS as well as in collagendiseases with GJH are sparsely evidence based, which mayeither be due to misdiagnosing or delayed diagnosing [$].'is international group of authors is collaborating to leadresearch in the )eld of GJH and JHS. 'e paper was writtenusing the current literature and up-coming future researchas the foundation. To evaluate the outcomes of treatmentstrategies regarding randomized controlled trials in GJH,JHS, and collagen diseases with GJH, a systematic review wasperformed inCentral andMedline, with critical appraisal andbest evidence synthesis.

2. Generalised Joint Hypermobility and BenignJoint Hypermobility Syndrome

Joint mobility is a continuous trait that varies with jointlocation and is strongly in0uenced by age, gender, and ethnicorigin [!]. Regardless of the type of mobility (hypo-, normo-,or hypermobility) we presume that variation in mobilitybegins in utero as part of the individual’s phenotype. Jointhypermobility has been known for centuries, but not untilrecently has it attracted a more profound and increasingscienti)c interest. 'e reason for this interest is probably ano.en observed concomitant presence of joint hypermobilityand musculoskeletal pain, giving rise to the diagnosis benignjoint hypermobility syndrome, de)ned for adults (BJHS) [#+,!"], which may include more signs than just musculoskeletalcomplaints [$]. However, hypermobility and pain are alsopart of other syndrome criteria, such as the Villefranchecriteria for the various types of Ehlers-Danlos syndrome(EDS) [&], conditions belonging to the group of hereditarydiseases of connective tissues (HDCTs).

Although the authors are aware that the primary focusof paediatric physiotherapists regarding diagnostics andtreatment strategies is the ICF-CY level of activity andparticipation, we present the current paper, including theliterature associatedwith the classi)cations of function, activ-ity, and participation. 'e problems at the level of functionmight explain the possible problems at the level of activityand participation and may guide treatment strategies. Inphysiotherapy, functional diagnostics and prognostics mightbe independent from clinical diagnosis. 'erefore, GJH andJHS with unknown origin or due to collagen diseases mightbe treated in the same way they in0uence functional de)cits.

3. Function (ICF-CY)

&.!. Generalized Joint Hypermobility. According to the Amer-icanAcademyofOrthopaedic Surgeons (AAOS), it is not pos-sible to precisely determine mean joint mobility throughoutthe body [!#]. Consequently, theAAOSdeveloped consensus-based estimates in degrees derived from statistical meansbased on reports from four committees of experts. In general,joint mobility is regarded as a graded phenomenon [!!],and a consensus has been developed that individual jointmobility follows a Gaussian distribution [!$–!%]. Abnormaljoint mobility would re0ect movements that deviate fromthe mean with ±! standard deviations. However, for prac-tical purposes, movement measurements (range of motion(ROM)) in degrees are notmanageable when testing for GJH.Instead, the Beighton tests that apply a dichotomous principleare widely used [!,]. 'e Beighton tests were describedabout &" years ago [!-], but only with photographs andshort legends accompanying )gures. A considerable variationexists in performance, at the cut-o( level for a positive testand in the criteria de)nition of GJH [!*].

'e Beighton score, consisting of )ve clinical manoeu-vres, is scored dichotomously ("/#) from which a total score,ranging from " to +, is calculated. It is a widespread beliefthat GJH is present in adults with a Beighton score of "&,

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whereas other cut-o( points for detecting the presence ofGJH have been proposed (GJH " &, GJH " %, GJH " ,,and GJH " - [$–%, !+]). Although these testing proceduresand diagnostic criteria have been in place for years and areconsidered the gold standard from infancy to old age [$"],criticism has arisen from within the rheumatological andclinical genetic community about its diagnostic and clinicalusefulness and predictive validity. Recently, standardizedprotocols have been described regarding the operationaliza-tion of the Beighton score [$#]. Currently, the Beighton testsas well as the criterion for GJH have proved to have highinter-examiner reproducibility in children as well as in adults[%, $#, $!]. In adults and children the concurrent validity alsoseemed to be acceptable as the positive Beighton tests equalnormalmeanROM+ $SD [#$, !+, $#], andGJH also has a highcorrelation to a global joint index [!+, $!]. Predictive validityof a di(erent cut-o( level for GJH has never been established.

&.%. Pain. GJH: generally, knee symptoms are described asthe most frequently reported symptoms among subjects withGJH [##]. 'is is supported by a recent meta-analysis whichreported that sports participants with GJH have an increasedrisk of knee joint injuries during contact sports but noaltered risk of ankle joint injury [$$]. However, an associationbetween GJH and a history of glenohumeral joint instabilityhas also recently been found [$&].

'ree population-based studies found that pain or dis-location/subluxation was not related to GJH% or GJH, in *-year-old and #"-year-old children [-, *], and in -–#%-year-oldchildren with GJH [$%].

Most of the studies describing associations between GJHand symptoms are cross-sectional [+, ##, $", $,–$+] andtherefore not able to identify causal relationships.

JHS: it is not knownwhy some childrenwithGJHdeveloppain and other symptoms, while others do not. One studyfound that children *-+ years old with JHS (for girls witha Beighton score "%, and for boys a Beighton score of "&)were more a(ected in other nonjoint related tissues (lowerultrasound values in bone, higher degradation products inurine, and higher skin extensibility) than a nonsymptomaticGJH group [#!]. 'ey also had higher values of total ROM.'is could indicate a more systemic e(ect in children withsymptomatic GJH. Comparedwith a healthy reference group,the nonsymptomatic GJH children still had larger total ROMand more profound skin extensibility [#!]. Children at +–#!years old with JHS and knee pain in the previous week furtherreported lower quality of life thanhealthy children at the sameage [#+]. One single &-year follow-up study found GJH, tobe a signi)cant predictor of recurrence of nonspeci)c painin children at #& years of age, especially in girls [,], and GJH,was also a signi)cant predictor of pain recurrence in the lowerlimb [&"].

It has been suggested that GJH is associated with prema-ture osteoarthritis [!, &#, &!], although no longitudinal studyhas shown such an association. Some of the mechanismsbehind this association could be that an increased ROMmay result in mechanical stress on parts of the cartilage ill-adapted to load, causing repetitive microtraumas, thereby

promoting development of osteoarthritis [&$–&%]. Anotherexplanation could be that GJH is an unknown connectivetissue disorder which could be the main contributor to thedevelopment of osteoarthritis [&$, &%]. A recent study foundthat adults with GJH walk with higher joint moments inthe knees and hips, which may indicate an increased risk ofdeveloping osteoarthritis [&,]. However, another study hassuggested GJH to be a protective factor for osteoarthritis,since an inverse relationship was found between hypermo-bility and hand and knee osteoarthritis [&-]. Furthermore,hypermobility was associated with lower serum cartilageoligomericmatrix protein levels, and genetic variations of thisprotein gene may account for some subgroups of JHS [&-]. Arecent study showed that children *–#, years with JHS hadsigni)cantly increased pain score, representing pain in themorning, daytime, evening, and at night, as assessed by a paindrawing [&*].

&.&. Muscle Strength, Explosive Power. GJH: reduced totalmuscle strength was seen in nonsymptomatic *- to #"-year-old children with GJH compared with a reference group [#!].Other case-control studies did not con)rm reduced isometricor isokinetic knee extension and 0exion in childrenwith non-symptomatic or symptomatic GJH [&+, %"]. Neither was therereduced hamstrings-quadriceps (H/Q) ratio in children withGJH compared with a reference group; however, girls withnonsymptomatic GJH% had reduced isokinetic normalisedPT knee extension (eccentrically) [%"].

JHS: Children with JHS between + and #$ years of age hadreduced isometric knee extension and 0exion peak torque(PT) compared with a healthy control group [##].

&.'. Proprioception. GJH: in young adults with GJH nodi(erences were found regarding joint position sense of theshoulder joint, nor di(erences in re0ex latency of upperand lower trapezius compared with a healthy control group[%#, %!].

JHS: in children +–#$ years of age with JHS (GJH ,,multiple joint pain, actual/historical), a decreased propri-oception was found during knee extension, measured aspassive joint position sense and threshold for detection of apassive movement [##].'is was partly con)rmed in anotherstudy of adolescents and adults with JHS where the re0ex inthe knee extensors was absent in &-%of #% patients, comparedwith a healthy control group in which this re0ex was presentin all subjects [%!].

&.". Balance. GJH: in a population-based study, childrenwithGJH% at * years of age had signi)cantly better static balancein “stork stand.” Furthermore, they had the same dynamicbalance, measured as agility, as the children without GJH [-].Similarly, #"-year-old children with nonsymptomatic GJHperformed just as well as a matched healthy control group indynamic one-board balance [*].

In a case-control study, *-year-old children with GJH%did not have increased muscle steadiness (poorer preci-sion) during submaximal knee 0exion and extension (!%%MVC for #% seconds) compared with children without GJH.

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However, even though there was no signi)cant correlationbetween steadiness during knee 0exion and extension andBeighton score, steadiness was signi)cantly worse in thechildren’s parents with GJH& [&+]. 'ese nonsymptomaticchildren with GJH% further presented with decreased muscleactivity in their knee 0exor muscles (m. biceps femoris,m. semitendinous) during submaximal knee 0exion (!%%MVC), and an increased cocontraction during knee 0exion[&*]. 'is was not seen in the knee extensor muscles (m.vastus lateralis, m. vastus medialis) during knee extension.'is illustrates a possible changed muscle activation patternin knee 0exion in children with GJH% [&+]. A recent studyof dynamic balance showed that during gait, #"-year-old chil-drenwithGJH%walkedwith a less 0exiblemovement pattern,that is, reduced lateral head stability and increased lateralhead ROM, in addition to less stable trunk segments duringenhanced balance challenges. 'e long-term consequencesof this abnormal movement pattern are, however, unknown[%$].

JHS: a recent study showed that children *–#, years withJHS had signi)cantly decreased balance, as assessed by theBruininks-Oseretsky test of motor pro)ciency [&*].

&.(. Extra-Articular Features. Numerous extra-articular fea-tures have been associated with GJH, such as chronic consti-pation and encopresis, enuresis and urinary tract infections,chronic fatigue syndrome, temporomandibular joint diseaseand )bromyalgia, although there is no universal agreementon the causal relationship [%&].

4. Activities (ICF-CY)

'.!. Motor Development. GJH: several studies indicated thatchildren with GJH have delayed and/or insu/cient motorcompetence, described as clumsiness in early childhood andpoor coordination [+, %%, %,]. One study reported that inchildren without GJH any delayed motor development dis-appeared before the second year of age, whereas in childrenwith GJH, it has been reported to continue [%-, %*]. Newerpopulation-based studies did not con)rm this associationbetween motor de)cits and GJH (with and without symp-toms) [%, -, &#], and in children between - and #% years of age,Beighton score correlated negatively with disability, meaningthat children with GJH did not experience functional limita-tions in daily activities [$%]. In fact, nonsymptomatic childrenwith GJH% and GJH, performed better in a )nger speed andreaction test [-] and so did the boys with GJH, in a )ngercoordination test [*].

JHS: in a population of children who were referred to auniversity hospital, severe delays in motor development wereobserved in approximately one third of the childrenwith JHS,whereas there was no association between the level of GJHand delay in motor development [#"].

Few objective physical performance and capacity mea-sures have been used to assess physical function in childrenwith GJH, not even as outcomes in the few treatment studiesof children with GJH. 'is is somewhat surprising, sincethe interventions all included elements of physical exercise

and performance [%+, ,"]. Instead primary outcomes inthese studies are mostly self-reported disability and pain, inaddition to injury prevalence, while physical performanceoutcomes such as muscle strength, endurance, balance, pro-prioception,motor control, posture awareness, or stability arenot measured [%+–,#], or even recommended to bemeasured[,!].

'.%. Gait Pattern. GJH: in a case-control study, children withGJH% walked with signi)cantly decreased peak momentsin their knee (0exion moment at heel strike and in mid-stance, and knee abduction moment in early push-o( phase),and in their hip (extension and abduction moment) butan increased dorsi0exion moment of the ankle. 'e anklekinematics di(ered signi)cantly between groups, while therewas no di(erence in the knee and hip kinematics [,$].However, the clinical relevance needs to be determinedthrough longitudinal investigations.

JHS: as far as the gait pattern of children with JHSis concerned, it has been written that “a combination ofhypermobile joints, reduced proprioception, weak muscles,and reduced stamina (endurance) can profoundly a(ect thegait of a child with JHS”. To correct this, the causes of theabnormalities need to be identi)ed andworked on separately,before the gait will improve [$*]. However, few studies haveactually shown this abnormal gait pattern in gait analyses. Inone study, children with JHS (GJH " ,), and multiple jointpain (currently or historically in more than one joint) had asigni)cantly lower peak knee 0exion angle both during theloading response and the swing phase, as well as an increasedknee extension in mid-stance during walking compared witha matched group of healthy children, while there was nodi(erence in gait speed between the groups [,$].

'.&. Vertical Jump. GJH: children (#" years old) with GJH%had signi)cantly higher peak vertical jump height, withouta signi)cant correlation between Beighton score and jumpheight, while there was no higher rate of force developmentin GJH% [%"]. A similar result was found in girls withGJH, who had an insigni)cantly higher vertical jump heightcompared with girls without GJH, and signi)cantly positivecorrelations between Beighton score and vertical jump height[*]. Further studies on this aspect are necessary to con)rmthese )ndings, that nonsymptomatic GJHmay produce moreexplosive power than children without GJH, and to judge thepractical implications of this, for example, as an increased riskfor future injuries.

'.'. Physical Fitness. GJH: children with GJH did not spendfewer weekly hours of physical activity than healthy referencegroups [-, *, #!, ,&]. 'is )ts well with the hypothesis thathaving nonsymptomatic GJH may even be an advantagefor selection into certain elite sports, such as ballet, dance,and gymnastics, due to the capacity for increased range ofmovement [%, ,&, ,%]. Consequently, general physical )tnessmust be adequate in children with nonsymptomatic GJH, inorder to be selected into elite sports. A recent population-based study of ,"!! children at #& years of age found a

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positive association between girls with GJH and physicalactivity, measured with accelerometry [,,]. A similar trendwas seen in a school population of -–#%-year-old children,where hypermobile children were slightly more active thannonhypermobile children, based on self-reports [$%].

JHS: however, many hours of physical activity need not beclosely related to high endurance and/or aerobic )tness.'ispoor relationship was seen in children (,–!" years) with JHSand exercise-induced pain and intolerance who actually hadreduced aerobic )tness compared with a healthy referencegroup, measured as absolute and relative (related to bodymass) peak VO! [,&].'e reason for this poor aerobic )tnesswas assumed to be due to musculoskeletal pain, resultingin inactivity and deconditioning, which could then result inexercise-induced pain and intolerance [,&].

'.". Participation (ICF-CY). JHS: children with JHS are lessactive in sports andmiss educationmore o.en in comparisonwith their healthy peers with normal joint mobility [%,]. Arecent study showed that children *–#, years with JHS hadsigni)cantly decreased participation in housework, riding abicycle, taking part in sport or outdoor games, as assessedby the Frequency of Participation Questionnaire [&*]. Alsoa higher frequency for participating in nonsporting gamesbesides a higher need to rest was reported in children withJHS [&*].

Personal communication and case reports mention thein0uence of GJH and JHS on participation, whereas theenvironmental and personal factors of childrenwithGJH andJHS have been anecdotally reported, for example, the role offamily dynamics and coping with JHS.

5. Treatment Strategies

In general, knowledge of GJH and JHS is clinically importantand tailored care should be based on the individual’s com-plaints and needs. Tailored care in terms of evidence-baseddiagnostic procedures and clinical expertise is essential inorder to construct classi)cation models as well as optimizedtreatment strategies. So diagnostics and subsequent treat-ment should be determined from evidence-based practice,clinimetrics, and clinical reasoning, eventually leading toclassi)cation and treatment strategies.

Reassurance, education, and joint care are cornerstones oftreatment strategies [%&]. In children and adults, uncontrolledstudies and therapeutic strategies have been described [,!,,-, ,*]. In a recent review Keer and Simmonds describedthat joint protection and injury prevention form a majorcomponent of a successful rehabilitation programme. 'eaims are achieved through improving posture, joint stability,and speci)c motor skills, which include pain-free, cognitiveexercise to enhance proprioception and muscle strength.Renewed con)dence in one’s own joints will lead to aresumption of a more normal level of physical activity withthe bene)ts of improved physical )tness and wellbeing. 'eoptimal form of rehabilitation tomaintain joint health in JHSis, however, questioned [,*]. Since observations are primarilybased on noncontrolled trials, we have to be cautious with theinterpretations of such literature.

A systematic review was conducted to )nd randomizedcontrolled trials focusing on interventions for GJH, JHS, andGJH in collagen diseases like EDS, Osteogenesis Imperfecta,and Marfan. Publications were retrieved from the biblio-graphic databases CENTRAL (searched in the Cochranelibrary) and MEDLINE (searched in PubMed). In PubMed,only MeSH terminology was applied combined with thesensitive Cochrane )lter for reviews on interventions andlimited to humans. In CENTRAL, only free-text terms wereapplied. 'e following keywords were combined and used:GJH, JHS, Ehlers Danlos, Osteogenesis Imperfecta (OI),Marfan Syndrome, child, treatment, and rehabilitation. Fromthese keywords MeSH headings were derived and insertedinto the electronic search. 'e references of retrieved trialsand other relevant publications including reviews and meta-analyses were examined (cross-referencing). 'e followingcriteria were used for including studies: (#) only patientswith musculoskeletal complaints, in terms of pain andfatigue, diagnosed with GJH, JHS, Ehlers-Danlos Syndrome(all types), Osteogenesis Imperfecta (all types), or MarfanSyndrome were included in the study, (!) all studies shouldonly focus on the e(ect of treatment in children, betweenthe ages of " and #* years of age, ($) only physical andcognitive oriented treatment modalities should be evaluated:medicinal, surgical, or treatment by assistive devices wereexcluded, (&) only English publications were considered forinclusion: letters, dissertations, abstracts, and case studieswere excluded.

6. Critical Appraisal of Included Studies

Two assessors (MCS and RHHE) performed retrieval ofstudies for the present review. 'e two assessors indepen-dently evaluated the identi)ed publications, classi)ed theidenti)ed studies according to predetermined criteria, andreviewed the methodological quality of each study, using thePhysiotherapy Evidence Database (PEDro) methodologicalscale [,+]. 'e PEDro scale was developed for rating qualityof RCTs and contains ## items. 'e )rst item representsexternal validity of the trial. 'is item is not included inthe total PEDro score (maximum #"); therefore, our scoreis based on items ! to ##. 'ese items represent ! aspects oftrial quality, the internal validity of the trial and whether thetrial contains su/cient statistical information. 'ese itemsare scored either yes (# point), no, or not applicable (" points).'e individual item scores and the total PEDro scores havebeen shown to be reliable [-"]. Studies with PEDro scores of& points were classi)ed as “high quality,” whereas scores of $points and below were classi)ed as “low quality” [-#]. Duringa consensus meeting, scoring disagreements were resolved.In the event that agreement could not be reached, a thirdreviewer (BJK) decided on the )nal score. Reviewers wereblinded to author(s), institution(s), or journals.

7. Best Evidence Synthesis

Statistical pooling of the included studies was not feasibledue tomethodological heterogeneity in interventions, patient

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characteristics, and outcomes. 'erefore a best evidencesynthesis (BES) was applied based on the criteria of vanTulder et al. (Table #: best evidence synthesis) [-!]. 'esecriteria are based on the PEDro scale. Selected studies werecategorized into % levels of evidence: (#) strong evidence;(!) moderate evidence; ($) limited evidence; (&) indicative)ndings; and (%) no or insu/cient evidence (Table #) [-!].'e initial search identi)ed #$#* studies (Figure #). A.erselection on title and abstract %% studies were selected forfurther scrutinizing. A.er the )rst selection round, $% studieswere rejected for the following reasons: !- studies did notevaluate treatment e(ects, ! studies did not present dataon the e(ectiveness of treatment (narrative case study), %studies evaluated treatment in adult subjects, and # studywas not available in English or could be translated. In total,!" studies were digitally retrieved and were cross-referencedfor additional potential studies. Cross-referencing identi)ed# additional study. In the )nal selection round #- studieswere further rejected on the bases of the following: , studiesevaluated treatment e(ects of surgical interventions or theuse of assistive devices, * studies focused on medicinaltreatment, and $ studies did not evaluate treatmentmodalitiesincluding a physical or cognitive approach. 'at le. thepresent review with $ studies (JHS/EDS hypermobile type:! = 2, OI: ! = 1) available for critical appraisal [%+, ,#, -$].8. Critical Appraisal

Initially, disagreement was present in % out of ," scored items(*,$%), but a.er discussion total agreement was established.'e total PEDro score of the included studies ranged from $ to* and included a total population of +% children (Table !). Allincluded studies were of RCT design in which independentallocation was secured. However, in the study of Mintz-Itkinet al. [,#], no randomization method was speci)ed and thuswas found to be questionable. Only in the study of Mintz-Itkin et al. baseline comparability was established, while inthe study by Kemp et al. no statistical data was presentedin which baseline comparability was ascertained [%+]. In allincluded studies no double-blinding was applied; however,in the study by Kemp et al. therapists were blinded forsubject characteristics and disease characteristics. Only inthe study of van Brussel et al. blinding of outcome assessorswas applied, while it was unclear in the remaining studies.Loss to follow-up was reported in the study of van Brusselet al. [-$] and in the study of Kemp et al. [%+]. However thestudy by Kemp et al. failed to report of >*%% of the initiallyincluded population but did show the absence of selectiveloss to follow-up. 'e study by Mintz-Itkin et al. did notprovide complete descriptions of loss to follow-up [,#], andno intention-to-treat analysis was performed. However, invan Brussel et al. [-$] and Kemp et al. [%+], all analyses wereperformed by intention-to-treat.

9. Best Evidence Synthesis

Two studies were included evaluating the e(ectiveness ofenhancing physical )tness in children with OI and JHS

T1234 #: Best evidence synthesis.

Level of evidence

Strong evidence:Provided by statistically signi)cant)ndings in outcome measures in atleast ! high-quality RCTs with PEDroscores of at least & points

Moderate evidence:

Provided by statistically signi)cant)ndings in outcome measures in atleast one high-quality RCT and at leastone low-quality RCT ($ points onPEDro or one high-quality CCT)

Limited evidence:

Provided by statistically signi)cant)ndings in outcome measures in atleast one high-quality RCT or at least !high-quality CCTs (in the absence ofhigh-quality RCTs)

Indicative evidence:

Findings provided by statisticallysigni)cant )ndings in outcomemeasures in one high-quality CCT orlow-quality RCTs (in the absence ofhigh-quality RCTs), or !nonexperimental studies of su/cientquality (in the absence of RCTs andCCTs)

No or insu/cientevidence:

In the event that results of eligiblestudies do not meet the criteria of oneof the previously stated levels ofevidence, or in case of con0icting(statistically signi)cant positive andstatistically signi)cant negative) resultsamong RCTs and CCTs, or when noeligible studies are available, CCTsindicates controlled clinical trial.

(Table $) [%+, -$]. Both studies had PEDro scores of ",(range: ,–*) and were classi)ed as high-quality RCT studies,including +# children between the ages of - and #*. Bothstudies showed signi)cant bene)ts of enhancing physical)tness in terms of relievingmusculoskeletal complaints (painand fatigue) and reducing disability. Based on the bestevidence strategies there is strong evidence that enhancingphysical )tness in children with connective tissue diseasesis e(ective. Two studies evaluated treatments focusing onenhancingmotor control in childrenwithGJH and JHS/EDS-hypermobility type (Table $). Due to the large di(erence inage (infants versus children and adolescents), no BES wasclassi)ed for the evidence of enhancing motor control.

10. Discussion

Observational studies have been performed to describethe clinical characteristics in GJH and JHS. Whether GJHand JHS are separate or related entities is not clear, sinceprospective follow-up studies in GJH children leading to JHSare scarce. Although many case reports have been writtenregarding interventions for GJH and JHS, few randomizedcontrolled trials have been performed. Future randomized

BioMed Research International -

Initial search:n = 1318 studies

Selected forinclusion:n = 55 studies

duplicates

n = 1263 studies

Excluded

Digital retrieval

n = 20 studies

Excluded

JMS/EDSIII

2 studies

OI

1 study

EDS othertypes

0 studies

MFS

0 studies

and !nal selection

n = 3 studies

∙ Surgical treatment (n = 6)

∙ Did not evaluate physical or

cognitive oriented treatment (n = 3)

∙

∙

∙ Did not present data on the

e"ectiveness of treatment (narrative

case study) (n = 2)

∙ No evaluation of treatment (n = 27)

∙ Medicinal treatment (n = 8)

Excluded on title, abstract, and

Cross-referencing

Included adult subjects (n = 5)

Was not available in English

nor was there a translation (n =1)

F56784 #: Flow diagram of the selection process of included studies.

controlled trials are indicated to study the e(ects of stand-alone (an)aerobic, strength and stability, as well as coordina-tion training in di(erent combinations. Until these )ndingshave been published it will not be possible to developevidence-based treatment protocols and guidelines for train-ing JHS. 'ese interventions may be based on the trainingprinciples for healthy children and children with chronicdiseases. Over the last decade, children’s training has beendiscussed from the perspective of physical )tness in physicaltherapy. 'e focus on physical )tness has increased, due tothe decreased physical )tness of normal developing children[-&], along with the e(ects of training on children withdi(erent diagnoses [-%]. Both cardiovascular and strengthtraining are important aspects of physical )tness. Guidelinesfor cardiovascular and strength training in children aredescribed in Strength &Conditioning Professional Standardsand Guidelines and the Position Statements published bythe National Strength and Conditioning Association (NSCA)[-,, --]. In the guidelines for strength training (NCSA), thetraining principles are described: the frequency of training #–$ times a week, for at least * weeks, but preferably #! weeks,the advised load (repetition maximum (RM)) *–#! RM, andthe preferable method Progressive Resistance Training (PRE)

[-*]. Strength training should be performed only a.er the ageof - years and ideally under supervision.

In a recent systematic review, the e(ectiveness of pro-prioceptive and coordination training in preventing sportsinjuries was described [-+]. Results of seven method-ologically well-conducted studies were presented. Multi-intervention training was e(ective in reducing the risk oflower limb injuries, acute knee injuries, and ankle spraininjuries. Balance training alone resulted in a signi)cant riskreduction of ankle sprain injuries [-+]. However, the e(ect ofthis training on children as well as adolescents with JHS isnot known. It is concluded in the NCSA position statementsthat school-aged youth should participate daily in ,"minutesor more of moderate to vigorous physical activity that isenjoyable, appropriate to their stage of development, andinvolve a variety of activities. Not only is regular physicalactivity essential for normal growth and development, butalso a physically active lifestyle during the pediatric yearsmayhelp to reduce the risk of developing some chronic diseaseslater in life. Resistance training can o(er unique bene)tsfor children and adolescents when appropriately prescribedand supervised. Combined comprehensive school-based pro-grammes are speci)cally designed to enhance health-relatedcomponents of physical )tness including muscular strength[-,, --].

JHS: based on the literature, it would be ideal if arandomized controlled trial was performed in JHS children,assessed with instruments with high psychometric qualities,and also with objective measurements, with an interven-tion period of at least #! weeks and a progressive trainingintervention of a minimum of $ times a week, in which thedose of training intervention is e(ective, based on the above-mentioned training principles.

GJH: little is known about the children with GJH whodevelop eventually JHS. Although pain is more common inchildren and adolescents with GJH as compared with theirnonhypermobile peers, only a minority of children with painwill eventually develop a chronic pain syndrome. However,for these children, pain can have a huge impact on their lifeand development, interfering with school and leisure timeactivities. Chronic pain syndromes, like complex regionalpain syndrome [*"] or chronic widespread pain syndrome[,, *#], have increasingly been associated with underlyingligamentous laxity in both adult and paediatric populations.

A traditional biomedical approach with a single focus onphysical impairment is in most cases insu/cient to explainthe total impact of chronic pain and its associated disability.Studies among children with chronic pain [*!] suggestthat behavioural and psychosocial factors contribute to thedevelopment and maintenance of chronic pain. Recently,increasing evidence came available con)rming a central roleto the concept of pain-related fear in children/adolescentswith chronic pain [#", *$]. In the fear avoidancemodel, one ofthe most prominent explanatory models for disability in painresearch, it is stated that a subgroup of persons will, a.er anacute pain problem, interpret their pain as threatening [*$].For these individuals, expectations of adverse consequencesof physical activity, such as a further increase in pain or(re)injury, will be a reason for avoiding physical activity [*&].

* BioMed Research International

T1234 !: Study characteristics and study results.

Author(year)

Diagnosis(age, rangein years)

Sample sizeDesign/time-intervals

(weeks a.er#0)Experimentaltreatment(w/f /i)

Controltreatment(w/f /i)

Outcomedomains(ICF-CY)

Results Authorsconclusions

van Brusselet al.,(!""*) [-$]

OI(*–#*)

$ = 34(E: #,/C: #-)

RCT#1: #!#2: !&#3: $,Physicaltraining(#!/$/&%)

Usualcare(?/?/?)

(i) Physical)tness(ii) Fatigue(iii) Perceivedcompetence(iv) HRqOL

Improvementswere found on alloutcomes in favorof E at #1. At #2and #3 scoresdeteriorated

Supervisedprogram improvesphysical )tness andreduces fatiguesafely ande(ectively

Mintz-Itkinet al.,(!""+) [,#]

GJH("-#)

$ = 29(E: #%/C: #&)

RCT#1: $,#2: &*#3: ,"#4: -!Monthly,Bobath

treatment(?/?/?)

Weekly,Bobath

treatment(?/?/?)

(i) Gross motordevelopment(ii) Achievementmotormile-stones

Motor catch-upwas achieved inboth groups, (nosigni)cantbetween-groupdi(erence)

Monthly physicaltherapy combinedwith homeexercises issu/cient toachieve motorcatch-up

Kemp et al.,(!""+) [%+]

JHS/EDSIII(-–#,)

$ = 57(E: $"/C: !-)

RCT#1: ,#2: #!Enhancingjoint control

ofsymptomatic

joints(,/#/$")

Physicaltraining(,/#/$")

(i) Physical)tness(ii) Pain scores(iii) Disability

Both groupsimproved inperceived pain andfunctional ability,(nobetween-groupdi(erence)

Both interventionsdemonstratedsigni)cant painreduction, (nobetween-groupsdi(erence)

OI: Osteogenesis Imperfecta, GJH: generalized joint hypermobility, JHS: joint hypermobility syndrome, EDSIII: Ehlers-Danlos hypermobile type, E:experimental group, C: control group, RCT: randomized clinical trial,w: weeks of treatment, f : frequency per week, i: intensity inminutes per session, ICF-CY:International Classi)cation of Functioning for Child and Youth.

Over the long term, avoidance behaviour will thus result ina combination of negative health consequences: disability,depression, and disuse, the last of which may be de)nedas a decreased level of physical activity in daily living [*%].In adults, numerous studies have con)rmed the role of fearof pain/reinjury in explaining pain related disability [*,].In children and adolescents, recently more evidence cameavailable con)rming the applicability of the fear avoidancemodel in children/adolescents [*$, *-]. Parent perceptions of,and responses to, pain have been identi)ed as important addi-tional factors contributing to pain-related disability amongchildren and adolescents with chronic pain [**].

Whether fear of movement/(re)injury accounts for anadditional disabling in0uence in children and adolescentswith disabling GJH is currently still unknown. However,the high incidence of GJH in paediatric populations andthe need for multidisciplinary care for their pain problem[$*] seem to indicate the multidimensionality of their painproblem. It can be hypothesized that, in children with JHS,the role of fear of movement is even more pronounced thanin children with pain without hypermobility, since recentstudies have shown that JHS appears to be associated witha higher risk of developing anxiety disorders [*,]. Andsince previous research has shown that anxiety sensitivityis strongly associated with fearful appraisals of pain, theoccurrence of pain related fear in JHS can be expected to behigher as compared to that in children/adolescents with painwithout hypermobility [*+].

As a consequence, an acute pain problem, such as amusculoskeletal complaint or (sub)luxation in a child with

GJH may therefore have a disabling impact on its own, but,in those with a high level of pain-related fear, it may also leadto a downward spiral by avoiding further activities. Since theJHS has been indicated as one of the most frequent causesof musculoskeletal symptoms in children and adolescentsaged between #$ and #+ years of age [+"], this populationseems more prone to developing chronic pain syndrome ascompared with those children without JHS.

A recent systematic review identi)ed a positive e(ectof behavioral treatment in children with chronic pain as asingle psychological treatment [+#]. For those with disablingchronic pain, currently no studies in a randomized design areavailable to con)rm the e(ect of multidisciplinary treatment,although studies in a prepost design do support its value [+!].In addition, whether themost e(ective treatment for childrenand adolescents withGJH and JHSwould be graded exposuretreatment, which is a multidisciplinary treatment speci)callytargeting pain and disability-related problems, is currentlystill unclear.

11. Conclusions

Generalised joint hypermobility (GJH) with and withoutmusculoskeletal complaints is frequently observed in chil-dren and young adults. Based on a narrative and a systematicreview, knowledge on function and activity in GJH and JHS isavailable, and knowledge on participation, personal and envi-ronmental factors recently showed a signi)cantly decreasedparticipation in housework, taking part in sport or outdoorgames, as well as a higher frequency for nonsporting games.

BioMed Research International +

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#" BioMed Research International

If and why children with GJH eventually develop JHS isnot known, due to lack of prospective, longitudinal studies.

Based on the sparsely available knowledge of interventionstudies, future longitudinal studies should focus on the e(ectof physical activity and )tness, as well as muscle strengthand stabilisation in general, and in the hypermobile jointsin particular. In JHS and chronic pain, the e(ectiveness of amultidisciplinary approach should be investigated.

Abbreviations

JHS: Joint hypermobility syndromeEDSIII: Ehlers-Danlos hypermobile typeOI: Osteogenesis ImperfectaEDS: Ehlers DanlosMFS: Marfan syndrome.

Conflict of Interests

'e authors declare they have no con0ict of interests.

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