Hypermobility, the Ehlers-Danlos syndromes and chronic pain D. Syx, I. De Wandele, L. Rombaut, F. Malfait Center for Medical Genetics, ABSTRACT the nature and mediators of chronic Ghent University and Ghent Chronic widespread pain is a common pain are needed in order to potentially University Hospital, Ghent, Belgium. complaint among individuals affected identify novel targets for therapeutic in- Delfien Syx, PhD by generalised joint hypermobility. In tervention and optimise treatment. Inge De Wandele, PT, PhD the absence of other conditions that Lies Rombaut, PT, PhD cause chronic pain, these individuals Hypermobility, joint hypermobility Fransiska Malfait, MD, PhD are usually diagnosed with joint hyper- syndrome and Ehlers-Danlos Please address correspondence to: mobility syndrome (JHS). JHS is a mul- syndromes Dr Fransiska Malfait, Center for Medical Genetics, tifactorial trait with a strong genetic Joint hypermobility (JH) implies a Ghent University Hospital, basis, but no specific genetic markers. range of joint movement that exceeds De Pintelaan 185, Clinical overlap of JHS is seen with what is considered to be normal for that 9000 Ghent, Belgium. heritable connective tissue disorders, joint, taking into account the individu- E-mail: [email protected] particularly with the Ehlers-Danlos al’s age, gender and ethnicity. JH can be Received and accepted on September 8, syndrome, hypermobile type (hEDS). limited to one or a few joints (localised 2017. The Ehlers-Danlos syndromes (EDS) JH), but when present at multiple sites Clin Exp Rheumatol 2017; 35 (Suppl. 107): comprise a heterogeneous group of rare the term generalised JH (GJH) is pre- S116-S122. monogenic conditions that are charac- ferred (1). The presence of GJH tradi- © Copyright CLINICAL AND terised by joint hypermobility, skin and tionally is defined by a score of at least EXPERIMENTAL RHEUMATOLOGY 2017. vascular fragility and generalised con- 5 on the nine-point Beighton scale, nective tissue friability, and are caused a standardised test consisting of five Key words: joint hypermobility, by genetic defects in an array of extra- clinical maneuvers (described in Ta- Ehlers-Danlos syndrome (EDS), pain cellular matrix genes. The genetic basis ble I) (2, 3). JH is a multifactorial trait of hEDS remains however unknown, in with a strong genetic basis: in a female contrast to other well-described EDS twin study, the heritability of JH was subtypes. In view of the considerable estimated to be 70% (4). A review arti- clinical overlap with JHS, many con- cle reports prevalence of GJH between sider it and hEDS to be a single clini- 6 and 57% for women and 2–35% for cal entity. Clinical experience and a men of varying ages and ethnicities (5). limited number of clinical studies show Besides gender, age and ethnicity, envi- that chronic pain also is common in ronmental factors that influence JH in- EDS patients, especially in hEDS. The clude weight, training, trauma, surgery specific underlying causes and mecha- and various medical conditions. nisms of pain in JHS and EDS remain JH does not necessarily lead to symp- poorly understood. Factors likely con- toms, and is not a disease, nor a perma- tributing to the generation and chro- nent diagnosis. The first comprehensive nicity of pain include nociceptive pain, description of symptomatic JH in the directly based on structural changes rheumatological literature is attributed in affected joints, muscle and connec- to Kirk, Ansell and Bywaters in 1967. tive tissue; neuropathic pain; impaired They coined the term ‘hypermobility proprioception and muscle weakness; syndrome’ (HMS) and defined it as ‘the and central sensitisation. These mecha- occurrence of musculoskeletal symp- nisms are not mutually exclusive, and toms in a hypermobile, but otherwise likely more than one mechanism may be healthy person’ (6). Later, the recogni- present. Furthermore, anxiety, depres- tion of the relatively benign prognosis sion, and other variables may influence of HMS in terms of life-threatening the phenotype. Chronic pain in JHS and Funding: This work was supported by complications led to the use of the term a Methusalem Grant 08/01M01108 from EDS patients often is inadequately con- ‘benign joint hypermobility syndrome’ the Ghent University, and a grant from trolled by traditional analgesics and (BJHS) or briefly, ‘joint hypermobility Association Française des Syndromes physical therapy. In view of the high syndrome’ (JHS) (7). A set of clinical d’Ehlers-Danlos (AFSED). prevalence of these underrecognised diagnostic criteria, the ‘Brighton Crite- Competing interests: none declared. conditions, future studies addressing ria’ was established, the major criteria S-116 Clinical and Experimental Rheumatology 2017 Hypermobility, the Ehlers-Danlos syndromes and chronic pain / D. Syx et al. Table I. Beighton score used for the evaluation of joint hypermobility. biochemical and/or molecular defects in fibrillar collagen types I, III and V, Negative Unilateral Bilateral or in their modifying enzymes, mak- Passive dorsiflexion of the 5th finger >90° 0 1 2 ing EDS an exemplary heritable colla- Passive flexion of the thumbs to the forearm 0 1 2 gen disorder (11). With the advent of Hyperextension of the elbows >10° 0 1 2 next generation sequencing techniques, Hyperextension of the knees >10° 0 1 2 molecular defects have recently been Forward flexion of the trunk with knees fully 0 Present identified in a variety of extracellular extended and palms resting on the floor 1 matrix (ECM) molecules, gradually expanding the list of distinct EDS sub- Table II. Brighton Criteria for Joint Hypermobility Syndrome (JHS) (8) and Villefranche types, and increasing our understand- Criteria for Hypermobile EDS (hEDS) (11). ing of the underlying pathogenetic ba- Brightoni Criteria (JHS) Villefranche Critera for hEDS sis of EDS. These studies have recently led to a revision of the EDS classifica- Major Criteria Major Criteria tion, which now includes 13 distinct - Beighton score ≥ 4/9 (currently or historically) - Beighton score ≥ 5/9 clinical EDS subtypes, for which mo- - Arthralgia > 3 months in > 4 joints - Skin involvement (hyperextensibility and/or smooth, velvety skin) lecular defects have been identified in Minor Criteria 19 different genes (Table III). Besides - Beighton score of 1-3 Minor Criteria defects in fibrillar collagens (collagen - Arthralgia in 1-3 joints or back pain, spondylosis, - Recurring joint dislocations spondylolysis or spondylolisthesis - Chronic joint/limb pain (> 3 months) types I, III and V), their modifying en- - Dislocations/subluxations in more than 1 joint, or - Positive family history zymes (ADAMTS-2, lysylhydroxylase in 1 joint on more than one occasion 1 (LH1)), and molecules involved in - Soft tissue rheumatism ≥ 3 lesion A major criterion has high diagnostic collagen folding (FKBP22), defects (e.g. epicondylitis, tenosynovitis, bursitis) specificity and the presence of one or - Marfanoid habitus more major criteria is either necessary for have now also been identified in other - Skin striae, hyperextensibility, thin skin, papyra- clinical diagnosis or highly indicative. constituents of the ECM (e.g. Tenas- ceous scarring A minor criterion is a sign of lesser diag- cin-X, collagen type XII), enzymes - Eye signs: drooping eyelids or myopia or anti- nostic specificity. The presence of one or involved in glycosaminoglycan bio- mongolid slant more minor criteria contributes to the di- - History of varicose veins, hernias, uterine/rectal agnosis. However, in the absence of major synthesis (galactosyltransferase I and prolapses criteria they are not sufficient to establish II (β4GalT7 and β3GalT6), dermatan the diagnosis 4-O-sulfotransferase-1 (D4ST1), der- For a diagnosis of JHS, the presence of both ma- matan sulfate epimerase (DSE)), (pu- jor criteria, one major and two minor, four minor, or two minor criteria plus one or more first-degree tative) transcription factors (ZNF469, affected relative(s) is needed. The diagnosis of PRDM5), components of the comple- JHS needs clinical and/or molecular exclusion of ment pathway (C1r, C1s) and an intra- overlapping heritable connective tissue disorders. cellular Zinc transporter (ZIP13) (12). Despite advances in our understanding being the presence of GJH and chronic clinical characteristics of EDS include of the genetic basis of EDS, one of the musculoskeletal pain (8). Besides GJH skin hyperextensibility and fragility; initially recognised and most preva- and pain, it was recognised that JHS vascular fragility with easy bruisability lent EDS subtypes, hypermobile EDS patients show mild signs of connec- and a variable bleeding tendency; joint (hEDS), remains molecularly unex- tive tissue fragility and laxity, including hypermobility (usually generalised) plained. hEDS shows considerable clini- skin hyperextensibility, hernia, vari- and manifestations of generalised con- cal overlap with JHS, as reflected in the cose veins, uterine or rectal prolapse nective tissue fragility (10). Depending two sets of diagnostic criteria that have and marfanoid habitus (Table II). As on the EDS subtype and the underly- been used over the past two decades (Ta- such, JHS shows overlap with several ing genetic defect, these manifestations ble II) (8, 11). The similarities between heritable connective tissue disorders and their consequences may vary from these conditions have created the notion (HCTD), such as Marfan syndrome and almost subclinical to severely debilitat- that JHS and hEDS may constitute