American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 175C:158–167 (2017)

A R T I C L E

The Evidence-Based Rationale for PhysicalTherapy Treatment of Children, Adolescents,and Adults Diagnosed With Joint HypermobilitySyndrome/Hypermobile Ehlers Danlos SyndromeRAOUL H.H. ENGELBERT ,* BIRGIT JUUL-KRISTENSEN , VERITY PACEY,INGE DE WANDELE, SANDY SMEENK, NICOLETA WOINAROSKY, STEPHANIE SABO,MARK C. SCHEPER, LESLIE RUSSEK, AND JANE V. SIMMONDS

Dr. Jane SimFellow at Greatand St Elizabephysiotherapyhypermobility,

Prof. Raoul EHe is the Directtwo decades a

Professor BiDenmark, andresearcher and

Dr. Verity PaHospital at WeVerity's researc

Dr. Inge Depresence of dydisorders and

Stephanie Sadolescents. Shparticipated ininvolvement in

Nicoleta Woeducation (Machronic pain sinformation toshe is passiona

Sandy Smee(“ILC”), a natioknowledge traEhlers-Danlos

Mark Schepsciences Amsteis on disability

Dr. Leslie RuPhysical Therahypermobility,

*CorresponApplied Scienc

DOI 10.100Article first

� 2017 Wil

New insights into the phenotype of Joint Hypermobility Syndrome (JHS) and Ehlers-Danlos Syndrome-hypermobile type (hEDS) have raised many issues in relation to classification, diagnosis, assessment, andtreatment. Within the multidisciplinary team, physical therapy plays a central role in management of individualswith hypermobility related disorders. However, many physical therapists are not familiar with the diagnosticcriteria, prevalence, common clinical presentation, and management. This guideline aims to providepractitioners with the state of the art regarding the assessment and management of children, adolescents,and adults with JHS/hEDS. Due to the complexity of the symptoms in the profile of JHS/hEDS, the InternationalClassification of Functioning, Disability and Health (ICF) is adopted as a central framework whereby the umbrella

monds is Chair of the International Ehlers Danlos Syndrome Physical Therapy Clinical Guidelinesworking group. She is a Senior TeachingOrmond Street Institute of Child Health, University College London and clinical lead in the Hypermobility Unit at the Hospital of St John

th in London. Jane is an active researcher and has more than 20 years of clinical experience working with this patient group. She isadvisor to three UK patient charities and has published widely and presents regularly at international conferences in the field ofbone health and Ehlers Danlos Syndrome.ngelbert is Professor of Physiotherapy at the University of Amsterdam (AMC) where focussing on transition of care in complex patients.or of Research, Center of Research ACHIEVE, Faculty of Health, University of Applied Sciences Amsterdam and has researched for overnd published widely in the field of heritable disorders of connective tissue, hypermobility and Ehlers Danlos Syndrome.rgit Juul Kristensen is Associate Professor, Research Unit of Musculoskeletal Function and Physiotherapy, University of SouthernProfessor at the Institute of Occupational Therapy, Physiotherapy and Radiography, Bergen University College, Norway. She is an activehas published widely in the field of musculoskeletal dysfunction and hypermobility.cey is a Senior Lecturer in the Department of Health Professions, Macquarie University, and Senior Physiotherapist at The Children'sstmead, with over 10 years clinical and research experience working with children and adolescents with symptomatic hypermobility.h focuses on the assessment, treatment and quality of life of children and adolescents with connective tissue disorders.Wandele is a physiotherapist at the Center for Medical Genetics at Ghent University Hospital, Belgium. The topic of her PhD was thesautonomia in EDS. Her current clinical work and research focus on adapted physiotherapy for patients with heritable connective tissuegeneralized joint hypermobility.abo is a senior physical therapist who practices in outpatient developmental paediatrics evaluating and treating infants, children ande is the leader of the Joint Hypermobility Evidence Based Practice Team at Cincinnati Children's Hospital Medical Center. She has alsoprogram developmental for an intensive based therapy program for children with Joint Hypermobility Syndrome and EDS. She ismultiple research studies that relate to intensive therapy services and patients with EDS/Hypermobility.inarosky is a Health Resource Consultant for the Improving the Life of Children and Families Foundation (ILC), Nicoleta draws on herster's thesis on The Effects of Exercise/Physical Activity on Chronic Pain and Pain RelatedMental Health Issues), volunteer work (teachingelf-management and physical education to seniors), and experience (living with EDS and chronic pain) to provide evidence-basedhealth professionals and persons living with chronic pain syndromes including EDS. While recognizing the need for pain medications,te about the physical and psychological benefits of exercise.nk is the co-Founder and Executive Director of the Improving the Lives of Children and Families with Chronic Pain Charitable Foundationnal charity catalyzing efforts to address the burden of pain through evidence-based awareness and education, systems change andnslation. She has led substantiate initiatives to influence Ministry of Health mandated programs for people with rare diseases utilizingSyndrome (EDS) as a model of optimal care.er is a physiotherapist and clinical movement scientist. Currently working as a senior lecturer physiotherapy at the University of Appliedrdam and a researcher affiliated to the Academic Medical Center Amsterdam, department of rehabilitation. His current research focusand chronicity in children with chronic diseases, with special attention for diseases of connective tissue.ssek is an Associate Professor teaching musculoskeletal physical therapy and research courses in the Clarkson University Doctor ofpy program. She has been researching hypermobility syndrome for almost 20 years, and treats patients in her areas of specialty:fibromyalgia, and headaches.dence to: Prof. Raoul H.H. Engelbert, ACHIEVE, Centre for Applied Research, Education of Physiotherapy, Faculty of Health, University ofes Amsterdam, Amsterdam, The Netherlands. E-mail: r.h.h.engelbert@hva.nl2/ajmg.c.31545published online in Wiley Online Library (wileyonlinelibrary.com).

ey Periodicals, Inc.

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 159

term of disability is used to encompass functions, activities and participation, as well as environmental andpersonal factors. The current evidence-based literature regarding the management of JHS/hEDS is limited in sizeand quality and there is insufficient research exploring the clinical outcomes of a number of interventions.Multicenter randomized controlled trials are warranted to assess the clinical and cost-effectiveness ofinterventions for children and adults. Until further multicenter trials are conducted, clinical decision-makingshould be based on theoretical and the current limited research evidence. For all individuals diagnosed with JHS/hEDS, international consensus and combined efforts to identify risk profiles would create a better understandingof the pathological mechanisms and the potential for optimizing health care for affected individuals.© 2017 Wiley Periodicals, Inc.

KEY WORDS: physical therapy; diagnostics; treatment; guidelines; joint hypermobility syndrome/hypermobile Ehlers Danlos syndrome;international classification of functioning

How to cite this article: Engelbert RH, Juul-Kristensen B, Pacey V, deWandele I, Smeenk S, Woinarosky N,Sabo S, Scheper MC, Russek L, Simmonds JV. 2017. The evidence-based rationale for physical therapy

treatment of children, adolescents, and adults diagnosed with joint hypermobility syndrome/hypermobile Ehlers Danlos syndrome. Am J Med Genet Part C Semin Med Genet 175C:158–167.

INTRODUCTION

In the last decade, scientific research in thearea of hypermobility related disordershas grown. Scientific exploration has notonly provided new insights into thephenotype of Joint HypermobilitySyndrome (JHS) and Ehlers-DanlosSyndrome-hypermobility type (hEDS),but it has also raisedmany issues in relationto classification, diagnosis, assessment,and treatment. We will refer to theseoverlapping/indistinguishable clinical en-tities [Tinkle et al., 2009; Remvig et al.,2011], in this paper as JHS/hEDS.Withinthe multidisciplinary team, physical ther-apy plays a central role in management ofindividuals with hypermobility relateddisorders [Simmonds and Keer, 2007;Grahame and Hakim, 2008; Scheperet al., 2013, 2016a]. The reportedprevalence of JHS/hEDS in adult physicaltherapy outpatient musculoskeletal set-tings has been reported to be between30% [Connelly et al., 2015] and 55%[Clarke and Simmonds, 2011]. Despitethe relatively high incidence of JHS/hEDS, recent research has found thatmany physical therapists and other clini-cians are not familiar with the diagnosticcriteria, prevalence, or common clinicalpresentation of affected individuals[Billings et al., 2015; Lyell et al., 2016;Russek et al., 2016], whereas cliniciansalso experience a lack of awareness of thiscondition [Billings et al., 2015; Rombautet al., 2015a;Terry et al., 2015; Lyell et al.,2016]. This guideline aims to providephysical therapists and other clinicianswith the state of the art regarding theassessment and management of children,

adolescents, and adults with JHS/hEDS.In preparing the guideline, the quality ofevidence is graded according to theGRADE criteria (Grading of Recom-mendations Assessment, Developmentand Evaluation) [Balshem et al., 2011].The paper has been written based on asynthesis of best evidence available andconsensus opinion of an internationalgroup of researchers, clinicians, andpatient representatives. Evidenced-basedassessment and treatment strategies shouldbe used where available. In the absence ofthese, therapists should be guided byclinical reasoning and assessment andtreatment should be tailored to theindividual patient’s needs.

Due to the complexity of thesymptoms in the profile of JHS/hEDS,the International Classification of Func-tioning, Disability and Health (ICF) isadopted as an overarching framework[Atkinson and Nixon-Cave, 2011].Disability, according to the WorldHealth Organization, is an umbrellaterm covering functions, activities andparticipation, as well as environmentaland personal factors [WHO, 2015]. Inchildren, adolescents and adults withJHS/hEDS, impairments in the ICFdomain body and function may result indecreased functional capacity and re-strictions in participation.

The Beighton tests for assessinggeneralized joint hypermobility (GJH)arewidely used andwere described about40 years ago, but only with photos andunclear legends accompanying [Beightonet al., 1973].Considerable variation existsin the utilization of this tool, the cut-off

level used for a positive test and in thecriteria definition of GJH [Remvig et al.,2007]. The Beighton score, consisting offive clinical maneuvers, is scored dichot-omously (0/1) from which a total score,ranging from 0 to 9, is calculated. It is awidespread belief that GJH is present inadults with a Beighton score of �4 asdescribed in the diagnostic Brightoncriteria [Grahame et al., 2000] and forhEDS �5 [Beighton et al., 1998]. Othercut-off points for detecting the presenceofGJHhave beenproposed, especially forchildren, among others �6, �7, and �8[Jansson et al., 2004]. Although thesetesting procedures and diagnostic criteriahave been in place for years and areconsidered the gold standard from in-fancy to old age [Adib et al., 2005],criticism has arisen from clinicians andresearchers about its diagnostic andclinical usefulness and predictive validity[Juul-Kristensen et al., 2017]. Beyond theBeighton scale, other assessment mea-sures should be utilized within eachdomain of the ICF and clinical reasoningshould underpin where appropriate, andwhere possible evidence-based, tailoredtreatment strategy.

Beyond the Beighton scale,other assessment measures

should be utilized within eachdomain of the ICF andclinical reasoning should

underpin where appropriate,

160 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

and where possible evidence-based, tailored treatment

strategy.

Figure

JHS/hEDS IN CHILDHOOD

Children with JHS/hEDS may experi-ence multiple impairments as a result ofincreased laxity of the connective tissues,incorporating complaints in all domainsof the ICF as illustrated in Figure 1[Pacey, 2014].

Pain and Health Related Quality ofLife

In JHS/hEDS pain is often present. It isnot known why some children developpain and other symptoms, whileothers do not. The primary hypothesis

1. Proposed ICF model for JHS

regarding the development of musculo-skeletal complaints is localized bio-mechanical overload during activity,with a high risk of repetitive trauma.Generalized joint instability may causethe occurrence ofmicro-traumas in jointsurfaces, leading toward adaptation andcompensation of movement patterns,consequently causing overload in otherareas of the musculoskeletal system[Ferrell et al., 2004]. Pain exacerbatedby activity is a distinguishing feature ofJHS/hEDS. Eighty-one percent of chil-dren with JHS attending a rheumatologyservice reported that their pain wasexacerbated by exercise [Adib et al.,2005]. All of these children reportedexperiencing pain in the 24 hr followingexercise: 65% immediately post exercise,59% later that evening, and 50% thefollowing morning. The knee, a weight-bearing joint of the lower limb, and the

in children by Pacey [2014].

shoulder, are the most commonly af-fected sites of pain in children with JHS/hEDS [Adib et al., 2005; Pacey et al.,2015a]. Parent and child self-reportedpain intensity is highly correlated [Paceyet al., 2015b], although parents havebeen shown to underestimate theirchild’s perception of pain [Kemp et al.,2010]. Recently it was shown thatchildren and adults diagnosed withJHS/hEDS are not only characterizedbyGJH, and chronic pain, but also by thepresence of generalized hyperalgesia(GHA) [Scheper et al., 2016b]. Thepresence of GHA may indicate involve-ment of the central nervous system in thedevelopment of chronic pain and maynot only provide insights as to thephenotype of GJH related disorders,but also indicates diagnostic qualitiesthat may be useful in clinical practice[Scheper et al., 2016c].

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 161

Children aged 9–12 years old withJHS/hEDS and knee pain report lowerHealth Related Quality of Life (HRQL)than healthy children at the same age[El-Metwally et al., 2005; Fatoye et al.,2011]. Children with JHS/hEDS expe-rience poor HRQL and disablingfatigue, with parent scores providing agood proxy. Pain, fatigue, and thepresence of stress incontinence symp-toms have been demonstrated to havethe greatest impact on their HRQL[Pacey et al., 2015a].

Dysfunction in JHS/hEDS can bethe result of chronic pain but also due toinvolvement of multiple systems, psy-chological distress and related disability.How chronic pain and systemic deficitscome into effect and interact with eachother is currently unknown. The spe-cific problems related to the GJH relatedsyndromes as compared with otherchronic pain syndromes are still chal-lenging for most clinicians and scientistsdue tomany issues surrounding etiology,disease classification, diagnostics, andtreatment [Scheper et al., 2015].

Proprioception, Muscle Strength,and Balance

Another important factor within thebiomechanical pathway in JHS/hEDSpatients may be reduced proprioceptiveacuity, which has been suggested to beimportant for the occurrence of gaitabnormalities and musculoskeletal pain[Smith et al., 2013]. Decreased kneejoint proprioception in combinationwith decreased knee flexor and extensormuscle strength has also been reportedin children with JHS/hEDS [Fatoyeet al., 2009]. This was partly confirmedin another study of adolescents andadults with JHS/hEDS where the reflexin the knee extensors was absent in 47%of 15 patients, compared with a healthycontrol group in which this reflex waspresent in all subjects [Ferrell et al.,2007]. Decreased muscle strength isassociated with activity limitations inJHS/hEDS patients. Joint propriocep-tion has been found to influence thisassociation and should be considered inthe development of new treatmentstrategies for patients with JHS/hEDS

[Scheper et al., 2016a]. Children be-tween 8 and 16 years of age with JHS/hEDS assessed by the balance sub-section of the Bruininks–Oseretsky testof motor proficiency (2nd edition), havebeen found to have significantly reducedbalance [Schubert-Hajlmarsson et al.,2012].

Decreased muscle strength isassociated with activity

limitations in JHS/hEDSpatients. Joint proprioceptionhas been found to influence

this association and should beconsidered in the developmentof new treatment strategies forpatients with JHS/hEDS.

Joint Instability

Dislocations or subluxations in morethan one joint, or in one joint on morethan one occasion, form part of thediagnostic criteria for JHS/hEDS. Con-sequently, recurrent joint instabilityepisodes are commonly reported bychildren with JHS/hEDS, with theknee, ankle, and shoulder as the mostaffected joints [Pacey et al., 2015b].

Extra-Articular Features

In children with JHS/hEDS involve-ment of not only the skin and joints butalso other organ systems consisting ofdifferent types of collagen, for example,bone and blood vessels, indicates a moresystemic rather than local involvement.In children 8–9 years old with JHS/hEDS, lower ultrasound values in bone,higher degradation products in urine,higher skin extensibility, and lowerblood pressure have been observed incomparison with a non-symptomatichypermobile group [Engelbert et al.,2003]. High levels of urinary inconti-nence are reported in children withJHS/hEDS [Pacey et al., 2015a], wheresuch systemic concerns cause significant

discomfort and impacts significantly onfunction and quality of life, a referral to apediatrician or system specialist is re-quired [de Kort et al., 2003].

A relationship between JHS/hEDSand a characteristic neurodevelopmentalprofile affecting coordination is emerg-ing.Common symptoms sharedbetweenchildren with JHS/hEDS and those withdevelopmental coordination disorder(DCD) have been highlighted [Kirbyand Davies, 2007]. Multiple clinicalfeatures of JHS/hEDS, such as “dou-ble-jointedness,” joint pain, flat feet, easybruising and dysautonomic symptoms,have been found to be significantly morefrequent in children with DCD than inchildren without [Kirby and Davies,2007]. Among children with JHS pre-senting to health care services, 36%report poor coordination and 48% reportclumsiness, and problems with gait, falls,and coordination are the second mostcommon presenting complaint [Adibet al., 2005]. Overall gross motor abilitieshave been shown to be reduced in 22%ofchildren (mean 8 years of age) with JHS/hEDS measured with the MovementAssessment Battery for Children[Hanewinkel-van Kleef et al., 2009].

Symptoms of gastrointestinal dys-function (GID) and dysautonomia maycommence very early in a child’s life.The most common GID symptomsinclude gastrointestinal reflux, abdomi-nal pain, and slow transit constipation orlong standing intractable diarrhea; how-ever, abnormalities from the mouth tothe anus have been reported [Aboniaet al., 2013].

Psychological Symptoms

Children and adolescents with JHS/hEDS aged 8–15 years report signifi-cantly poorer emotional functioningon the Pediatric Quality of LifeInventory compared to their non-hypermobile peers [Pacey et al.,2015b]. Furthermore, self-esteem, be-havior, and psychosocial functioning ofchildren with JHS/hEDS have beenshown to be significantly lower thanpopulation norms prior to commenc-ing a treatment program [Pacey et al.,2013].

162 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

Activities: Motor Development,Gait Pattern, Physical Fitness

The medical history often revealsdevelopmental delay during earlychildhood and DCD may coexist[Kirby et al., 2005; Kirby and Davies,2007]. Congenital hypotonia or“floppy infant” syndrome and jointhypermobility (JH) have been recog-nized by a number of researchers[Mintz-Itkin et al., 2009]. Late walkingand clumsiness are characteristics com-monly reported by parents [Adib et al.,2005]. In JHS/hEDS, non-physiologi-cal gait-patterns (absolute comparisons:spatio-temporal, kinematics, and ki-netics) have been demonstrated inchildren. These patterns were notconsistent and a high variability withinpatients was present [Fatoye et al.,2011], and children with JHS/hEDSand multiple joint pain, had signifi-cantly decreased knee flexion in theswing phase, as well as increased kneeextension in mid-stance during walk-ing. Also, decreased lateral joint stabil-ity and different stabilization strategies(kinetic patterns) in children and adultswith GJH have been shown [Falkerslevet al., 2013].

As far as the gait pattern ofchildren with JHS/hEDS is concerned,it has been reported that “hypermobilejoints, reduced proprioception, weakmuscles, and reduced stamina (endur-ance) can profoundly affect the gait of achild with JHS/hEDS. To correct this,the causes of the abnormalities need tobe identified and worked on separately,before the gait will improve” [Murray,2006]. Problems with gait, falls andcoordination are the second mostcommon presenting complaint of chil-dren with JHS/hEDS presenting to anoutpatient rheumatology clinic [Adibet al., 2005].

In children with JHS/hEDS, arelationship was found with exerciseinduced pain and reduced aerobic fitnessand physical capacity fitness comparedwith a healthy reference group, mea-sured as absolute and relative (related tobody mass) peak VO2 [Engelbert et al.,2006], and also when assessed witha sub-maximal 6min walk test

[Hanewinkel-van Kleef et al., 2009].The reason for this poor aerobic fitnesswas assumed to be due to musculoskel-etal pain, resulting in inactivity anddeconditioning, which could then resultin exercise-induced pain andintolerance.

Participation: Hobbies, Sport, andSocial Activities

Children with GJH are less active insports and miss education more often incomparison with their healthy peerswith normal joint mobility [Janssonet al., 2004]. Qualitative research withchildren with JHS/hEDS and theirparents has identified “difficulties atschool” as being one of the six mainthemes, when discussing symptomsprior to commencing a treatmentprogram [Birt et al., 2014]. A retrospec-tive chart audit also showed that 40% ofaffected children report handwritingdifficulties, 24% report “problems atschool,” 41% report missing time fromschool, and 48% were unable to partici-pate in physical education classes as aresult of their condition [Adib et al.,2005]. A recent study showed thatchildren 8–16 years with JHS/hEDShad significantly decreased participationin housework, riding a bicycle, takingpart in sport or outdoor games, asassessed by the Frequency of Participa-tion Questionnaire, in conjunction witha higher frequency of participation innon-sporting games and a higher needto rest [Schubert-Hajlmarsson et al.,2012]. Withdrawal from physical activ-ity due to their condition has also beenreported by children and their parents[Birt et al., 2014].

Qualitative research withchildren with JHS/hEDS andtheir parents has identified“difficulties at school” asbeing one of the six mainthemes, when discussing

symptoms prior to

commencing a treatmentprogram.

It is essential therefore for cliniciansto explore and understand the impact ofthe child’s problems on school, homeand social life. Some children have poorschool attendance records due to recur-rent injury, pain, and systemic issues.Many children reduce physical activityand stop participating in physical edu-cation due to fear of re-injury or pain.

Finding out about hobbies, ambi-tions, and sports that a child enjoys isvery helpful in driving the manage-ment plan. Physical therapists andparents have difficulty when searchingfor sports and hobbies that suit thechild, because many sports involvemovement or activities with high riskof injuries in unstable joints. Contactsports for example have been suggestedto be an injury risk factor for kneeinjuries amongst individuals with GJH[Pacey et al., 2010]. In reality manychildren with JHS/hEDS cannot keepparticipating in their preferred hobbies,sports and activities, despite theirhypermobility originally being consid-ered an asset. It can therefore be verychallenging to find activities whichyoung people like and which do notexacerbate pain and joint instability

JHS/EDS-HT INADULTHOOD

Pain, Fatigue, and Health RelatedQuality of Life

Adults diagnosed with JHS/hEDS oftenexperience joint pain in multiple joints,which can vary from localized towidespread pain, in nature and severity[Remvig et al., 2011; Connelly et al.,2015]. Chronic widespread pain isfrequently present in patients with theJHS/hEDS. In half of the patient group, apredominantly neuropathic pain com-ponent was present [Rombaut et al.,2011a]. This study provides evidence forthe existence of hyperalgesia even inasymptomatic areas (generalized second-ary hyperalgesia). The GHA (generalised

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 163

hyperalgesia) may represent the involve-ment of a sensitized central nervoussystem, which requires an adapted painmanagement approach for this patientgroup [Rombaut et al., 2015b].

Fatigue symptoms are heteroge-neous in nature and can vary frommild to severe. However, patients oftenreport fatigue symptoms as the mostdisabling complaint. In addition, neu-rologically oriented symptoms (propri-oceptive deficits, central mediatedhyperalgesia), psychological dysfunction(anxiety, depression), and systemic com-plaints (organ dysfunction, dysautono-mia) are often highly prevalent in JHS/hEDS [Voermans and Knoop, 2011; DePaepe and Malfait, 2012].

Fatigue symptoms areheterogeneous in nature andcan vary from mild to severe.However, patients often reportfatigue symptoms as the most

disabling complaint.

Muscle Strength, Proprioception,and Balance

Rombaut et al. [2012] demonstratedseverely reduced quantitative musclefunction and impairment in physicalfunction in patients with JHS/hEDScompared to age- and sex-matchedcontrols. The muscle weakness may bedue to muscle dysfunction rather thanreduced muscle mass. Whether musclestrength and endurance can be improvedby appropriate exercise programs needsevaluation in further studies. Comparedwith healthy participants, individualswith JHS/hEDS showed significantlyimpaired balance, reflected by increasedsway velocity, mediolateral and ante-roposterior sway excursion, and swayarea during modified Clinical Test ofSensory Interaction on Balance(mCTSIB) and the Tandem Stance test(TS). Gait velocity, step length, andstride length were significantly smallerduring all walking conditions, and a

significant dual-task-related decrementwas found for gait velocity, step andstride length, and cadence in the JHS/hEDS subjects compared with thecontrol group. Ninety-five percent ofthe patients fell during the past year, andsome fear of fallingwas further measured[Rombaut et al., 2011b]. DCD maypersist into adulthood. In a case controlstudy, 56% of those with JHS/EDS-HTmet the criteria for adult DCD [Clarket al., 2014]. Proprioception has beenshown to be impaired in a number ofstudies [Smith et al., 2013].

Extra-Articular Features

Dysautonomia, defined as a term forvarious conditions in which the auto-nomic nervous system does not workcorrectly, provides a complex challengefor the multidisciplinary team. Dysau-tonomia consisting of cardiovasculardysfunction is found to be present inJHS/hEDS. Neuropathy, connectivetissue laxity, and vasoactive medicationare likely to play a role in its develop-ment [De Wandele et al., 2014].Gastrointestinal symptoms are also com-monly reported [Zarate et al., 2010],impact significantly on quality of life andare managed in a variety of ways.Specialist medical referral may be nec-essary. Constipation requires activetreatment usually including dietary ad-vice, however sustained use of laxativesis often required. Adult women withJHS/hEDS have an increased rate ofincontinence. Both case-control andcross-sectional studies consistently re-port that 60–73.3% of adult womenwith JHS/hEDS have urinary inconti-nence, compared with only 30–48.3%in non-affected women [Mastoroudeset al., 2013]. The increased rate seen inwomen with JHS/hEDS is present withvarious types of incontinence, includingurgency incontinence, nocturnal enure-sis, and intercourse incontinence [Nijset al., 2000]. Other symptoms of lowerurinary tract dysfunction includingnocturia (waking one or more timesat night to void), urgency, bladderpain, urinary tract infections, andvoiding difficulties (poor stream,straining, incomplete bladder emptying,

postmicturition dribble) have also beenreported to be significantly more preva-lent in women with JHS/hEDS[Mastoroudes et al., 2013]. No studieshave yet investigated incontinence orother lower urinary tract symptoms inadult men with JHS/hEDS.

Impaired bone health in adults withJHS/hEDS has been demonstrated bysignificant reductions in volumetricbone density measured at the distalradius site using peripheral quantitativecomputed tomography in comparisonwith age and gender matched peers[Nijs et al., 2000]. However, in contrastCarbone et al. [2000] found that aftercorrection for height, weight, andamount of physical activity, no signifi-cant differences between bone densitymeasured by dual energy absorptiome-try was found in adults with JHS/hEDSand controls.

Activities and Participation

Significant disability has been shown inpatients with JHS/hEDS in ambulation(walking, running, stair climbing), ac-tivities of daily living (personal hygiene,self-care) and sports activities, influenc-ing quality of life. The high number andseverity of complaints in JHS/hEDSresult in substantial care and treatmentseeking. In a group of 78 adults withJHS/hEDS registered as patients in arehabilitation medicine department,92.4% were medication consumers,70.9% had underwent several surgicalinterventions, and 51.9% had receivedphysiotherapy treatment [Rombautet al., 2011a]. The main objective ofrehabilitation is to reduce disability andto improve quality of life, however,evidence concerning effectiveness oftreatment for reducing disability islimited, as are the actual factors relatedto disability. A recent meta-analysisshowed that pain, fatigue, and psycho-logical distress had a significant impacton disability [Scheper et al., 2016b].

Psychological Symptoms

A systematic review has demonstratedthat compared with their non-affectedpeers, adults with JHS/hEDS have

164 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

greater risk of anxiety, depression andpanic disorders [Smith et al., 2014a]. Anationwide population-based cohortstudy showed a high incidence ofpsychiatric disorders including anxiety,depression, attention deficit hyperactiv-ity disorder, and autism spectrum disor-der in the JHS/hEDS patient population[Cederl€of et al., 2016].

PRINCIPLES OFMANAGEMENT OFINDIVIDUALS WITH JHS/EDS-HT IN CHILDHOOD,ADOLESCENCE, ANDADULTHOOD

In children and adults with JHS/hEDSwith symptomatic joints or intestinaland systemic problems, differential di-agnostics have to be performed toexclude other diseases or disorders thatare characterized by GJH. In individualswith GJH, easy bruising and frequentfracturing, the presence of a collagendisease such as osteogenesis imperfectaor osteopenia due to vitamin D defi-ciency should be considered. WhenGJH and musculoskeletal complaints aswell as a Marfanoid habitus is present,Marfan or Loeys-Dietz syndromeshould be considered. Severe collagendiseases, such as the other types of EDSshould be excluded. In case of progres-sive muscle weakness central of periph-eral neurological conditions includingmyopathies should be ruled out. Addi-tionally, rheumatology conditionsshould also be considered and ruled out.

Kemp et al. [2010] performed thefirst prospective randomized controlledtrial (RCT) in children comparing a6-week generalized program, improvingmuscular strength and fitness, with atargeted program aimed at correctingmotion control of symptomatic joints. Itwas demonstrated in 57 children thatsignificant improvements in both thechildren’s and parental pain scores werereached in both groups. A recent RCTstudy of children with JHS/hEDS andhypermobile knees found an increasedeffect on psychosocial/self-esteem in thegroup that performed knee exercisesinto the hypermobile range of motion(ROM) compared with the control

group performing knee exercises intoneutral ROM. Both groups improvedknee strength and reduced knee pain[Pacey et al., 2013]. Evidence-basedguidelines suggest that children withflexible flat foot presenting with pain orimpaired function, particularly in thepresence of GJH, such as that commonlyseen in children with JHS/hEDS,should use orthotics and/or sensiblefootwear [Evans and Rome, 2011].Preliminary findings of a small RCTsuggests that use of orthotics mayimprove the efficiency of gait of childrenwith GJH and DCD [Morrison et al.,2013].

Kemp et al. performed thefirst prospective randomizedcontrolled trial (RCT) in

children comparing a 6-weekgeneralized program,

improving muscular strengthand fitness, with a targetedprogram aimed at correcting

motion control of symptomaticjoints. It was demonstrated in57 children that significantimprovements in both the

children’s and parental painscores were reached in both

groups.

Only one RCT study of adults withJHS/hEDS has been performed, show-ing reduced knee pain and increasedproprioception, in the group receivingexercises of proprioception, balance andplyometrics, compared with a matchedcontrol group receiving no exercises[Sahin et al., 2008].

A number of cohort/uncontrolledclinical studies of JHS/hEDS in childrenand adults report positive effects ofstrength, core stability and endurancetraining in addition to education in painmanagement [Bathen et al., 2013],

different intensity of resistive trainingalone [Ferrell et al., 2004; Møller et al.,2014], and education in pain manage-ment alone [Rahman et al., 2014];however, these reports need to befurther evidenced with more rigorousresearch designs. Existing consensusbased hospital and UK paediatric rheu-matology guidelines may also offerhelpful advice and treatment strategiesto clinicians [The British Society forPediatric and Adolescent Rheumatol-ogy, 2013; Cincinnati Children’s Hos-pital Medical Center, 2014]. Qualitativeinterviews with 28 families with chil-dren with JHS/hEDS (5–17 years) onprerequisites for the best adherence toexercise is reported to be parentalmotivation adapting family routines,making exercise a family activity andseeing the benefit [Birt et al., 2014]. Onthe other hand are factors for non-adherence to exercise for these children,lower levels of parental supervision, notunderstanding the treatment, not seeingthe benefit and not having specific timeto dedicate for doing exercises [Birtet al., 2014].

There is someevidence for that JHS/hEDS improveswith exercise, but there isno convincing evidence for specific typesof exercise or that exercise is better thancontrol [Smith et al., 2013; Palmer et al.,2014]. Both reviews recommend thatlonger term, rigorous high-qualitymulti-centre RCT’s are warranted for childrenand adults with JHS/hEDS.

Education, reassurance, manualtherapy, tape, hydrotherapy, and relaxa-tion training are used by physicaltherapists [Lyell et al., 2015; Palmeret al., 2015; Rombaut et al., 2011b,2015b; Billings et al., 2015] and clinicalexperts recommend these strategies[Russek, 2000; Simmonds and Keer,2007; Keer and Simmonds, 2011], basedon clinical experience and some evi-dence of their efficacy from otherpatient groups. Currently there are noRCT’s or comparative trials to supportthe efficacy of these strategies in indi-viduals with JHS/hEDS. Therapiesshould be individualized [Simmondsand Keer, 2007, 2008; Simmondset al., 2016a] and applied carefully toavoid exacerbation of pain as peripheral

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 165

and central sensitization is commonlyobserved [Rombaut et al., 2011b].Although Adib et al. [2005] refer to25% of children using mobility aids in aselected population and splints aresometimes recommended, limited effectof these aids, and splinting for hands/wrists in individuals with JHS/hEDS hasbeen found [Smith et al., 2013].

Cardiovascular, musculoskeletaland physical fitness training parametersshould be encouraged in both childrenand adults according to the criteria ofthe National Strength and ConditioningAssociation (NSCA) and AmericanCollege of Sports Medicine (ACSM)[Faigenbaum et al., 2009; Faigenbaumand Myer, 2010; Garber et al., 2011]. Ingeneral, specialists recommend a care-fully graduate exercise training prescrip-tion, underpinned by motor learningtheory [Smith et al., 2014b] to avoidinjury and overtraining as this may leadto loss of confidence in the physicaltherapist. Pain, fatigue, and fear of injuryare commonly reported barriers toexercise [Simmonds et al., 2016b]. Agraduated return to higher levels of sportor dance is recommended, and trainingloads should be observed to ensureadequate recovery.

Patients with JHS/hEDS have nu-merous complaints and an impairedfunctional status that strongly determinetheir high rate of treatment consump-tion. The outcome of surgical andphysical therapy treatment is largelydisappointing, which illustrates theneed for a stronger evidence base[Rombaut et al., 2011a]. Education forhealth professionals [Billings et al., 2015;Rombaut et al., 2015b; Terry et al.,2015; Lyell et al., 2016; Russek et al.,2016] is paramount in order to optimizephysical therapy provision. A recentfeasibility study of a six session packageof treatment demonstrates future poten-tial [Palmer et al., 2016a,b] and furtherresearch is required to explore thespecific therapeutic actions of physicaltherapy for managing JHS/hEDS. Re-cently, a meta-analysis revealed that fortreatment of adults, a significant painreduction was achieved by a variety ofphysical and cognitive approaches. Ac-tive modes of physical therapy are the

recommended approach. However, theeffectiveness on disability still needs tobe established [Scheper et al., 2016c].

In cases where significant systemicsigns and symptoms are observed andreported by individuals, such as cardiacdysautonomia, gastrointestinal, urinaryand bladder dysfunction, referral tospecialist medical teams is indicated.Readers are referred to care guidelinesin these specialist areas. Physiotherapistsplay an important role in managementthrough exercise prescription and pa-tient education for many of theseconditions. Relatively recent developedmasterclass courses, papers, and sympo-sia provide clinicians with informationon how to adapt and apply therapies[Simmonds and Keer, 2007, 2008;Simmonds et al., 2016c].

CONCLUSION

Children, adolescents, and adults suf-fering from JHS/hEDS frequentlypresent with complex symptoms andare therefore challenging for physicaltherapists to manage effectively. Basedon the ICF, a literature overview hasbeen presented for the assessment andmanagement based on the best evi-dence available to help guiding clini-cians. The current evidence-base forthe physical therapy assessment andmanagement of JHS/hEDS is limitedin size and quality.

In future directions longer term,rigorous multicenter randomized con-trolled trials are warranted to assess theclinical and cost-effectiveness of in-terventions for children and adultswith JHS/hEDS. There is a need forfurther identification and validationof suitable outcome measures. Untilfurther multicenter trials are con-ducted, clinical decision-makingshould be theoretically applied based,underpinned by the available evidencewhere available. In patients diagnosedwith JHS/hEDS international consen-sus and combined efforts to identifypatient risk profiles would create abetter understanding of the patholog-ical mechanisms with the possibilityof optimizing health care for affectedindividuals.

REFERENCES

Abonia JP, Wen T, Stucke EM, Grotjan T,Griffith MS, Kemme KA, Collins MH,Putnam PE, Franciosi JP, von Tiehl KF,Tinkle BT, Marsolo KA, Martin LJ, WareSM, Rothenberg ME. 2013. High preva-lence of eosinophilic esophagitis in pa-tients with inherited connective tissuedisorders. J Allergy Clin Immunol 132:378–386.

Adib N, Davies K, Grahame R, Woo P, MurrayKJ. 2005. Joint hypermobility syndrome inchildhood. A not so benign multisystemdisorder? Rheumatol 44:744–750.

Atkinson HL, Nixon-Cave K. 2011. A tool forclinical reasoning and reflection using theinternational classification of functioning,disability and health (ICF) framework andpatient management model. Phys Ther91:416–430.

Balshem H, Helfand M, Sch€unemann HJ,Oxman AD, Kunz R, Brozek J, Vist GE,Falck-Ytter Y, Meerpohl J, Norris S,Guyatt GH. 2011. GRADE guidelines: 3.Rating the quality of evidence. J ClinEpidemiol 64:401–406.

Bathen T, Hångmann AB, Hoff M, AndersenandL, Rand-Hendriksen S. 2013. Multidisci-plinary treatment of disability inehlers-danlos syndrome hypermobilitytype/hypermobility syndrome: A pilot studyusing a combination of physical and cogni-tive-behavioral therapy on 12 women. Am JMed Genet Part A 161A:3005–3011.

Beighton P, Solomon L, Soskolne CL. 1973.Articular mobility in an African population.Ann Rheumatic Dis 32:413–418.

Beighton P, De Paepe A, Steinmann B, Tsipour-asand P, Wenstrup RJ. 1998. Ehlers-Danlossyndromes: Revised nosology, villefranche,1997. Ehlers-Danlos National Foundation(USA) and Ehlers-Danlos Support Group(UK). Am J Med Genet 77:31–37.

Billings S, Deane JA, Bartholomew J, SimmondsJV. 2015. Knowledge and perceptions ofjoint hypermobility syndrome amongstpediatric physiotherapists. J Physiother PractRes 36:33–51.

Birt L, PfeilM,MacGregor A, ArmonK, Poland F.2014. Adherence to home physiotherapytreatment in children and young people withjoint hypermobility: A qualitative report offamily perspectives on acceptability andefficacy. Musculoskel Care 12:56–61.

Carbone L, Tylavsky FA, Bush AJ, KooW,OrwollE, Cheng S. 2000. Bone density in Ehlers-Danlos syndrome. Osteoporos Int11:388–392.

Cederl€of M, Larsson H, Lichtenstein P, AlmqvistC, Serlachius E, Ludvigsson JF. 2016.Nationwide population-based cohort studyof psychiatric disorders in individuals withEhlers-Danlos syndrome or hypermobilitysyndrome and their siblings. BMC Psychia-try 16:207.

Clark C, Khattab A, Carr E. 2014. Chronicwidespread pain and neurophysiologicalsymptoms in Joint Hypermobility Syn-drome. Int J Ther Rehab 21:60–68.

Clarke C, Simmonds JV. 2011. An exploration ofthe prevalence of hypermobility syndromein Omani women attending an outpatientdepartment. Musculoskel Care 9:1–10.

166 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

Connelly E, Hakim A, Davenport HS, SimmondsJV. 2015. A Study exploring the prevalenceof Hypermobility Syndrome in a musculo-skeletal triage clinic. Physiother Res Pract36:43–53.

de Kort LM, Verhulst JA, Engelbert RH,Uiterwaal CS, de Jong TP. 2003. Lowerurinary tract dysfunction in children withgeneralized hypermobility of joints. J Urol170:1971–1974.

De Paepe A, Malfait F. 2012. The Ehlers-Danlossyndrome, a disorder with many faces. ClinGenet 82:1–11.

De Wandele I, Rombaut L, Leybaert L, Van deBorne P, De Backer T,Malfait F, De Paepe A,Calders P. 2014. Dysautonomia and itsunderlying mechanisms in the hypermobil-ity type of Ehlers—Danlos syndrome. SeminArthritis Rheum 44:93–100.

El-Metwally A, Salminen JJ, Auvinen A,Kautiainen H, Mikkelsson M. 2005. Lowerlimb pain in a preadolescent population:Prognosis and risk factors for chronicity—Aprospective 1- and 4-year follow-up study.Pediatrics 116:673–681.

Engelbert RH, Bank RA, Sakkers RJ, Helders PJ,Beemer FA, Uiterwaal CS. 2003. Pediatricgeneralized joint hypermobility with andwithout musculoskeletal complaints: A lo-calized or systemic disorder? Pediatrics 111:e248–e254.

Engelbert RH, van Bergen M, Henneken T,Helders PJ, Takken T. 2006. Exercisetolerance in children and adolescents withmusculoskeletal pain in joint hypermobilityand joint hypomobility syndrome. Pediatrics118:e690–e696.

Evans AM, Rome K. 2011. ACochrane review ofthe evidence for non-surgical interventionsfor flexible pediatric flat feet. Eur J PhysRehabil Med 47:69–89.

Evidence based Care Guideline for Managementof Pediatric Joint Hypermobility GuidelineCopyright © 2014. Cincinnati Children’sHospital Medical Center, James M. Ander-son Center for Health Systems ExcellenceEvidence Based Care Guideline Identifica-tion and management of Pediatric JointHypermobility In children and adolescentsaged 4 to 21 years old Publication Date:October 21, 2014.

Faigenbaum AD, Kraemer WJ, Blimkie CJ,Jeffreys I, Micheli LJ, Nitka M, RowlandTW. 2009. Youth resistance training: Up-dated position statement paper from thenational strength and conditioning associa-tion. J Strength Cond Res 23:S60–S79.

Faigenbaum AD, Myer GD. 2010. Resistancetraining among young athletes: Safety,efficacy and injury prevention effects. Br JSports Med 44:56–63.

Falkerslev S, Baagø C, Alkjær T, Remvig L,Halkjær-Kristensen J, Larsen PK, Juul-Kristensen B, Simonsen EB. 2013. Dynamicbalance during gait in children and adultswith Generalized Joint Hypermobility. ClinBiomech (Bristol Avon) 28:318–324.

Fatoye F, Palmer S,Macmillan F, Rowe PP, van derLindenM. 2009. Proprioception andmuscletorque deficits in children with hypermobil-ity syndrome. Rheumatol 48:52–57.

Fatoye FA, Palmer S, van der Linden ML, RowePJ, Macmillan F. 2011. Gait kinematicsand passive knee joint range of motion in

children with hypermobility syndrome. GaitPost 33:447–451.

FerrellWR, Tennant N, Baxendale RH, KuselM,Sturrock RD. 2007. Musculoskeletal reflexfunction in the joint hypermobility syn-drome. Arthr Care and Res 57:1329–1333.

Ferrell WR, Tennant N, Sturrock RD. 2004.Amelioration of symptoms by enhancementof proprioception in patients with jointhypermobility syndrome. Arthr Rheum50:3323–3328.

Garber CE, Blissmer B, Deschenes MR, FranklinBA, Lamonte MJ, Lee IM, Nieman DC,Swain DP. 2011. American College of SportsMedicine position stand. Quantity andquality of exercise for developing and main-taining cardiorespiratory, musculoskeletal,and neuromotor fitness in apparently healthyadults: Guidance for prescribing exercise.Med Sci Sports Exerc 43:1334–1359.

Grahame R, Hakim AJ. 2008. Hypermobility.Curr Opin Rheumatol 20:106–110.

Grahame R, Bird HA, Child A. 2000. The revised(Brighton 1998) criteria for the diagnosis ofbenign joint hypermobility syndrome(BJHS). J Rheumatol 27:1777–1779.

Guidelines for Management of Joint Hypermobil-ity Syndrome in Children and Young People.2013. The British Society for Pediatric andAdolescent Rheumatology. Available onlinehttps://www.google.co.uk/?gws_rd¼ssl#q¼bsparþforþhypermobility.Publication Date: 20. 6.2013.

Hanewinkel-van Kleef YB, Helders PJ, Takken T,Engelbert RH. 2009.Motor performance inchildren with generalized hypermobility:The influence of muscle strength andexercise capacity. Pediatr Phys Ther21:194–200.

Jansson A, Saartok T,Werner S, Renstrom P. 2004.General joint laxity in 1845 Swedish schoolchildren of different ages: Age- and gender-specific distributions. Acta Pardiatr93:1202–1206.

Juul-Kristensen B, Schmedling K, Rombaut L,Lund H, Engelbert RH. 2017. Measure-ment properties of clinical assessment meth-ods for diagnosing generalised jointhypermobility—A systematic review. Am JMed Genet part C submitted, in press.

Keer R, Simmonds JV. 2011. Joint protection andphysical rehabilitation of the adult withhypermobility syndrome. Cur OpinionsRheumatol 23:131–136.

Kemp S, Roberts I, Gamble C, Wilkinson S,Davidson JE, Baildam EM, Cleary AG,McCann LJ, Beresford MW. 2010.A randomized comparative trial of general-ized vs targeted physiotherapy in themanagement of childhood hypermobility.Rheumatol (Oxford) 49:315–325.

Kirby A, Davies R. 2007. Developmental coordi-nation disorder and joint hypermobilitysyndrome—Overlapping disorders? impli-cations for research and clinical practice.Child Care Health Dev 33:513–519.

Kirby A, Davies R, Bryant A. 2005. Hypermobil-ity syndrome and developmental coordina-tion disorder: Similarities and features. Int JTher Rehabil 12:431–443.

Lyell M, Simmonds JV, Deane J. 2015. Physi-otherapists’ knowledge and management ofadults with hypermobility and joint hyper-mobility syndrome in the UK; A nationwide

survey. Poster, WCPT May, Singapore.Physiotherapy 101:e919.

Lyell M, Simmonds JV, Deane JA. 2016. Future ofeducation in hypermobility and hypermo-bility syndrome. J Physiother Pract and Res37:101–109.

Mastoroudes H, Giarenis I, Cardozo L, SrikrishnaS, Vella M, Robinson D, Kazkazand H,Grahame R. 2013. Lower urinary tractsymptoms in women with benign jointhypermobility syndrome: A case-controlstudy. Int Urogynecol J 24:1553–1558.

Mintz-Itkin R, Lerman-Sagie T, Zuk L, Itkin-Webman T, Davidovitch M. 2009. Doesphysical therapy improve outcome in infantswith joint hypermobility and benign hypo-tonia? J Child Neurol 24:714–719.

Morrison SC, Ferrari J, Smillie S. 2013. Assess-ment of gait characteristics and orthoticmanagement in children with Developmen-tal Coordination Disorder: Preliminaryfindings to inform multidisciplinary care.Res Dev Disabil 34:3197–3201.

Møller MB, Kjær M, Svensson RB, Andersen JL,Magnusson SP, Nielsen RH. 2014. Func-tional adaptation of tendon and skeletalmuscle to resistance training in three patientswith genetically verified classic EhlersDanlos Syndrome. Muscles Ligaments Ten-dons J 4:315–323.

Murray KJ. 2006. Hypermobility disorders inchildren and adolescents. Best Pract ResClin Rheumatol 20:329–351.

Nijs J, Van Essche E, De Munck M, Dequeker J.2000. Ultrasonographic, axial, and periph-eral measurements in female patients withbenign hypermobility syndrome. CalcifTissue Int 67:37–40.

Pacey V, Nicholson L, Adams R, Munn J, MunnsC. 2010. Generalised joint hypermobilityand injury risk of lower limb injury duringsport. Am J Sports Med 38:1487–1497.

Pacey V. 2014. PhD thesis: Joint HypermobilitySyndrome in Children, University of Syd-ney, Sydney, Australia.

PaceyV,AdamsRD,Tofts L,MunnsCF,NicholsonLL. 2015a. Joint hypermobility syndromesubclassification in paediatrics: A factoranalytic approach. Arch Dis Child 100:8–13.

Pacey V, Tofts L, Adams RD, Munns CF,Nicholson LL. 2015b. Quality of lifeprediction in children with joint hypermo-bility syndrome. J Paediatr Child Health51:689–695.

Pacey V, Tofts L, Adams RD, Munns CF,Nicholson LL. 2013. Exercise in childrenwith joint hypermobility syndrome andknee pain: A randomised controlled trialcomparing exercise into hypermobile versusneutral knee extension. Pediatr RheumatolOnline J11:30.

Palmer S, Bailey S, Barker L, Barney L, Elliott A.2014. The effectiveness of therapeuticexercise for joint hypermobility syndrome:A systematic review. Physiotherapy100:220–227.

Palmer S, Cramp F, Lewis R, Shahid M, Clark E.2015. Diagnosis, management and assess-ment of adults with joint hypermobilitysyndrome: A UK-Wide survey of physio-therapy practice. Musculoskeletal Care13:101–111.

Palmer S, Terry R, Rimes KA, Clark C,Simmonds J, Horwood J. 2016a.

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 167

Physiotherapy management of joint hyper-mobility syndrome—A focus group study ofpatient and health professional perspectives.Physiother 102:93–102.

Palmer S, Cramp F, Clark E, Lewis R, Brookes S,HollingworthW,WeltonN, ThomN, TerryR, Rimes KA, Horwood J. 2016b. Thefeasibility of a randomised controlled trial ofphysiotherapy for adults with joint hyper-mobility syndrome. Health Technol Assess20:1–264.

Rahman A, Daniel C, Grahame R. 2014. Efficacyof an out-patient pain management pro-gramme for people with joint hypermobilitysyndrome. Clin Rheumatol 33:1665–1669.

Remvig L, Jensen DV, Ward C. 2007. Arediagnostic criteria for general joint hyper-mobility andbenign joint hypermobilitysyndrome based on reproducible and validtests? A reviewof the literature. J Rheumatol34:798–803.

Remvig L, Engelbert RH, Berglund B, BulbenaA, Byers PH, Grahame R, Juul-KristensenB, Lindgren KA, Uitto J, Wekre LL. 2011.Need for a consensus on the methods bywhich to measure joint mobility and thedefinition of norms for hypermobility thatreflect age, gender and ethnic-dependentvariation: Is revision of criteria for jointhypermobility syndrome and Ehlers-Danlossyndrome hypermobility type indicated?Rheumatol 50:1169–1171.

Rombaut L, ScheperM,DeWandele I, DeVries J,Meeus M, Malfait F, Engelbert RH, CaldersP. 2015a. Chronic pain in patients with thehypermobility type of Ehlers-Danlos syn-drome: Evidence for generalized hyper-algesia. Clin Rheumatol 34:1121–1129.

Rombaut L, Deane J, Simmonds J, De Wandele I,De Paepe A, Malfait F, Calders P. 2015b.Knowledge, assessment, and management ofadults with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility typeamong Flemish physiotherapists. Am J MedGenet C Semin Med Genet 169C:76–83.

Rombaut L, Malfait F, DeWandele I, Taes Y, ThijsY, De Paepe A, Calders P. 2012. Musclemass, muscle strength, functional perfor-mance, and physical impairment in womenwith the hypermobility type of Ehlers-Danlos syndrome. Arthritis Care Res(Hoboken) 64:1584–1592.

Rombaut L, Malfait F, De Wandele I, Thijs Y,Palmans T, De Paepe A, Calders P. 2011a.Balance, gait, falls, and fear of falling inwomen with the hypermobility type ofEhlers-Danlos syndrome. Arthr Care Res(Hoboken) 63:1432–1439.

Rombaut L, Malfait F, De Wandele I, Cools A,Thijs Y, De Paepe A, Calders P. 2011b.Medication, surgery, and physiotherapy

among patients with the hypermobilitytype of Ehlers-Danlos syndrome. ArchPhys Med Rehabil 92:1106–1112.

Russek L. 2000. Examination and treatment of apatient with hypermobility syndrome. PhysTher 80:386–398.

Russek LN, LaShomb EA,Ware AM,Wesner SM,Westcott V. 2016. United States physicaltherapists’ knowledge about joint hypermo-bility syndrome compared with fibromyalgiaand rheumatoid arthritis. Physiother Res Int21:22–35.

Sahin N, Baskent A, Cakmak A, Salli A, Ugurlu H,Berker E. 2008. Evaluation of knee proprio-ception and effects of proprioception exercisein patients with benign joint hypermobilitysyndrome. Rheumatol Int 28:995–1000.

Scheper MC, Engelbert RH, Rameckers EA,Verbunt J, Remvig L, Juul-Kristensen B.2013. Children with generalised joint hy-permobility andmusculoskeletal complaints:State of the art on diagnostics, clinicalcharacteristics, and treatment. Biomed ResInt 2013:121054.

Scheper MC, de Vries JE, Verbunt J, EngelbertRH. 2015. Chronic pain in hypermobilitysyndrome and Ehlers—Danlos syndrome(hypermobility type): It is a challenge.J Pain Res 20:591–601.

Scheper MC, Juul-Kristensen B, Rombaut L,Rameckers EA, Verbunt J, Engelbert RH.2016a. Disability in adolescents and adultsdiagnosed with hypermobility related dis-orders: A meta-analysis. Arch Phys MedRehabil 97:2174–2187.

Scheper MC, Pacey V, Rombaut L, Adams RD,Tofts L, Calders P, Nicholson LL, EngelbertRH. 2016b. Generalized Hyperalgesia inchildren and adults diagnosed with Hyper-mobility Syndrome and Ehlers-Danlos Hy-permobility type: A discriminative analysis.Arthr Care Res 15:1–7.

Scheper MC, Rombaut LL, de Vries JE, deWandele I, Esch van M, Calders P,Engelbert RH. 2016c. Factors of activityimpairment in adult patients with EhlersDanlos Syndrome hypermobility type):Muscle strength and proprioception. Dis-abil Rehabil 24:1–7.

Simmonds JV, Keer RJ. 2007. Hypermobility andthe hypermobility syndrome. MasterclassMan Ther 12:298–309.

Simmonds JV, Keer RJ. 2008. Hypermobility andthe hypermobility syndrome. Masterclass.Illustrated via case studies, part II. Man Ther13:e1–e11.

Simmonds J, Herbland A, Hakim A, Ninis N,Lever W, Aziz Q, Cairns M. 2016a.Attitudes, beliefs and behaviours towardsexercise amongst individuals with jointhypermobility syndrome/Ehlers Danlos

syndrome—hypermobility type IFOMPTProceedings. Man Ther 25:335336.

Simmonds JV, Pacey V, Keer RJ, Castori MM.2016b. Advancing practice in hypermobilitySyndrome/Ehlers Danlos syndrome—hypermobility type focused symposium.IFOMPT, glasgow, UK. Man Ther 25:e21–e22.

Simmonds JV, Herbland A, Hakim A, Ninis N,Lever W, Aziz Q, Cairns M. 2016c.Attitudes, beliefs and behaviours towardsexercise amongst individuals with jointhypermobility syndrome/Ehlers Danlossyndrome—hypermobility type IFOMPT,Glasgow, UK. Man Ther 25:e35–e36.

Smith TO, Jerman E, Easton V, Bacon H, ArmonK, Poland F,Macgregor AJ. 2013. Do peoplewith benign joint hypermobility syndrome(BJHS) have reduced joint proprioception?A systematic review and meta-analysis.Rheumatol Int 33:2709–2716.

Smith TO, Easton V, Bacon H, Jerman E, ArmonK, Poland F, Macgregor AJ. 2014a. Therelationship between benign joint hypermo-bility syndrome and psychological distress: Asystematic review and meta-analysis. Rheu-matol (Oxford) 53:114–122.

Smith TO, Bacon H, Jerman E, Easton V, ArmonK, Poland F, Macgregor AJ. 2014b. Physio-therapy and occupational therapy interven-tions for people with benign jointhypermobility syndrome: A systematic re-view of clinical trials. Disabil Rehabil36:797–803.

Terry RH, Palmer ST, Rimes KA, Clark CJ,Simmonds JV, Horwood JP. 2015. Livingwith joint hypermobility syndrome: Patientexperiences of diagnosis, referral and self-care. Fam Pract 32:354–358.

Tinkle BT, Bird HA, Grahame R, Lavallee M,Levy HP, Sillence D. 2009. The lack ofclinical distinction between the hypermo-bility type of Ehlers-Danlos syndrome andthe joint hypermobility syndrome (a.k.a.hypermobility syndrome). Am J Med GenetPart A 149A:2368–2370.

Voermans NC, Knoop H. 2011. Both pain andfatigue are important possible determinantsof disability in patients with the Ehlers-Danlos syndrome hypermobility type. Dis-abil Rehabil 33:706–707.

World Health Organization. 2015. InternationalClassification for Functioning Disability andHealth. http://www.who.int/classifications/icf/en/ [Accessed April 2016].

Zarate N, Farmer AD, Grahame R, MohammedSD, Knowles CH, Scott SM, Aziz Q. 2010.Unexplained gastrointestinal symptoms andjoint hypermobility: Is connective tissuethe missing link? Neurogastroenterol Motil22:252–278.