A Framework for the Classification of Joint Hypermobility

American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 175C:148–157 (2017) ARTICLE

A Framework for the Classiﬁcation of Joint Hypermobility and Related Conditions

MARCO CASTORI,* BRAD TINKLE, HOWARD LEVY, RODNEY GRAHAME, FRANSISKA MALFAIT, AND ALAN HAKIM

In the last decade, growing attention has been placed on joint hypermobility and related disorders. The new nosology for Ehlers–Danlos syndrome (EDS), the best-known and probably the most common of the disorders featuring joint hypermobility, identifies more than 20 different types of EDS, and highlights the need for a single set of criteria to substitute the previous ones for the overlapping EDS hypermobility type and joint hypermobility syndrome. Joint hypermobility is a feature commonly encountered in many other disorders, both genetic and acquired, and this finding is attracting the attention of an increasing number of medical and non-medical disciplines. In this paper, the terminology of joint hypermobility and related disorders is summarized. Different types of joint hypermobility, its secondary musculoskeletal manifestations and a simplified categorization of genetic syndromes featuring joint hypermobility are presented. The concept of a spectrum of pathogenetically related manifestations of joint hypermobility intersecting the categories of pleiotropic syndromes with joint hypermobility is introduced. A group of hypermobility spectrum disorders is proposed as diagnostic labels for patients with symptomatic joint hypermobility but not corresponding to any other syndromes with joint hypermobility. © 2017 Wiley Periodicals, Inc.

KEY WORDS: classification; Ehlers–Danlos syndrome; joint hypermobility; nosology; terminology How to cite this article: Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A. 2017. A framework for the classiﬁcation of joint hypermobility and related conditions. Am J Med Genet Part C Semin Med Genet 175C:148–157.

INTRODUCTION by a group of experts in the field. This Society’s keyobjectives, with the support initiative was then further developed by of many experts in the field worldwide, During the first international symposium the Ehlers–Danlos National Foundation were to sponsor an update of the for the Ehlers–Danlos syndromes (EDS) and the Ehlers–Danlos Support UK, nosology for EDS, and the development in 2012 in Ghent, Belgium an initiative with other international groups, culmi- of best practice clinical guidelines. This to found the International Consortium nating in 2016 with the foundation of the article is a supplemental product of that on Ehlers–Danlos Syndromes was started Ehlers–Danlos Society. Two of the program.

Marco Castori is a Clinical Geneticist at the San Camillo-Forlanini Hospital (Rome) with focus on the diagnosis and management of hereditary connective tissue disorders, particularly Ehlers–Danlos syndromes. He is (co-)author of more than 130 papers on International journals and 14 book chapters. Brad Tinkle is a Clinical Geneticist with interests in connective tissue disorders and is Division Head of Clinical Genetics at the Advocate Children's Hospital. Howard Levy is an Associate Professor at Johns Hopkins University. He is a primary care internist and a medical geneticist, with particular interest and experience in Ehlers–Danlos syndrome and other hereditary disorders of connective tissue. Rodney Grahame is a consultant rheumatologist who specializes in the care of patients with connective tissue disorders, in particular, the Ehlers– Danlos syndrome. His first paper on EDS (with Peter Beighton), which dates back to 1969, was on the mechanical properties of skin in EDS in vivo. He is currently Honorary Professor in Division of Medicine, University College, London, UK and Affiliate Professor, School of Medicine, University of Washington, Seattle, WA, USA. Fransiska Malfait, M.D., Ph.D., is a rheumatologist and clinical geneticist. She is an Associate Professor at the Centre for Medical Genetics at the Ghent University Hospital, where she directs the research, clinical service and laboratory facility for diagnosis and genetic testing for the Ehlers–Danlos syndrome and other heritable disorders of connective tissue. She has (co-)authored over 80 papers in international journals, and 6 book chapters, andis the Chair of the medical and scientific board of the Ehlers–Danlos Society. Alan Hakim is a consultant in Rheumatology and General Medicine with a specialist interest in the diagnosis and management of hereditary connective tissue disorders. He is (co-)author of more than 100 papers in International journals, co-author and editor of 5 books, and numerous book chapters. Conflicts of interest: None. *Correspondence to: Marco Castori, M.D., Ph.D., Unit of Clinical Genetics, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87, I-00152 Rome, Italy. E-mail: [email protected] DOI 10.1002/ajmg.c.31539 Article first published online 1 February 2017 in Wiley Online Library (wileyonlinelibrary.com).

ß 2017 Wiley Periodicals, Inc. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 149

In the last two decades, the identifi- The new nosology for EDS abolishes for the spectrum of JH-related disor- cation of over a dozen novel genes the dyadic nature of this community of ders (Fig. 2). underlying new clinical variants of EDS phenotypes (EDS-HT, JHS, and JHS þ The rationale for an evolution in enhanced our understanding of the EDS-HT) and proposes a unified set of thinking is threefold: molecular backbone of the connective criteria for a single entity called hyper- tissue, and added new tools for the mobile EDS (hEDS) (see “Hypermobile (1) Nosology: distinguishing pathogenesis diagnosis, management, and prognosis Ehlers–Danlos Syndrome (a.k.a. Ehlers– and etiology is the background for a of an increasing number of patients. Danlos Syndrome Type III and Ehlers– classification aimed at identifying Many EDS patients, however, still remain Danlos syndrome hypermobility type): Clinical more effective scientific, therapeutic, without a laboratory confirmation and Description, and Natural History” by Tinkle and healthcare strategies. this lack of knowledge contributes to the et al. [2017], this issue). However, the (2) Management: JH-related musculoskel- patients’ burden. This is mostly the case delineation of a single entity arising as the etal manifestations likely require ho- for individuals affected by the two full-blown expression of the phenotype in mogeneous rehabilitation/treatment largely overlapping conditions previously common between EDS-HT and JHS issues shared by the different genetic termed “Ehlers–Danlos syndrome, hy- leaves without an “identity” many indi- conditions, which in turn diverge for permobility type (EDS-HT)” and “joint viduals with symptomatic joint hypermo- specific extra-articular manifestations. hypermobility syndrome (JHS).” These bility (JH) and/or features of hEDS, who (3) Research: a clear separation of the JH two disorders were originally recognized do not meet the stricter criteria incorpo- secondary musculoskeletal manifesta- by different sets of diagnostic criteria, rated in the new EDS nosology. The tions from the primary pleiotropic which share many items [Beighton et al., classification of such cases requires manifestations of EDS may help in 1988; Grahame et al., 2000]. In the resolution. dissecting the intrafamilial and inter- ensuing years, the inconsistency of such a individual variability of hEDS for clinical separation emerged from expert studies aimed at deciphering its mo- AIM opinion [Tinkle et al., 2009]; a single lecular basis. segregation study formally demonstrating In this paper, the terminology of JH co-segregation of these two disorders in and related disorders is summarized. DEFINITIONS OF JOINT pedigrees with multiple affected mem- Different types of JH, its secondary HYPERMOBILITY bers with a significant proportion fitting musculoskeletal manifestations and a both criteria (i.e., JHS and EDS-HT) simplified categorization of genetic Joint hypermobility (JH) is the term [Castori et al., 2014]. syndromes featuring JH are presented. universally accepted to define the capa- We consider the spectrum of JH- bility that a joint (or a group of joints) related musculoskeletal manifestations has to move, passively and/or actively, and the range of pleiotropic manifes- beyond normal limits along physiological Many EDS patients, tations of syndromes featuring JH, axes. Hence, JH is a descriptor rather noting that these are two separate than a diagnosis. JH may exist as an however, still remain without domains that only partially overlap isolated diagnostic finding, but is often a a laboratory confirmation and (Fig. 1). We also propose a classification feature of a larger syndromic diagnosis. this lack of knowledge contributes to the patients’ burden. This is mostly the case for individuals affected by the two largely overlapping conditions previously termed “Ehlers– Danlos syndrome, hypermobility type (EDS- HT)” and “joint hypermobility syndrome Figure 1. Phenotypic ramifications of joint hypermobility. On the left, secondary musculoskeletal manifestations as summarized in four major categories. On the right, the (JHS).” pleiotropic features of hereditary connective tissue disorders featuring joint hypermobility are grouped under four major domains. 150 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

or more), the term generalized joint hypermobility (GJH) is preferred. The- oretically, GJH is the presence of JH appreciable simultaneously at the four limbs and axial skeleton. Given this, it is not necessarily straightforward as to whether an individual has GJH or not. Also, ROM of most joints and the distribution of JH at the different sites is strongly influenced by age, sex, and ethnicity [Remvig et al., 2007]. There- fore, the identification of a standardized procedure applicable in all circumstances is challenging. Over the years, a handful of clinical tools have been used to define GJH, with some validated in different populations. The Beighton score [Beighton et al., 1973] is the most commonly used and, perhaps, the most reliable tool for assessing GJH (see “Measurement Properties of Clinical Assess- ment Methods for Classifying Generalized Joint Hypermobility—a Systematic Review,” by Juul-Kristensen et al. [2017], this issue). Figure 2. Schematization of the novel terminology introduced by the new nosology However, all of them have limitations – of Ehlers Danlos syndrome and joint hypermobility. The two-dimensional variability is and the attribution of GJH as a feature represented by the vertical (pathogenesis) and horizontal (etiology) lines. In the middle, the relationships between the domains of asymptomatic joint hypermobility(ies) remains partly influenced by the exam- and Ehlers–Danlos syndrome. Generalized joint hypermobility and hypermobile iner’s professional experience and rec- – Ehlers Danlos syndrome are highlighted as the closest phenotypes, within the ognition of the need to look at all the corresponding domains. Pleiotropy is the concept bridging the two domains. Below them, the “realm” of the hypermobility spectrum disorders as outlined in the present joints (certainly at least those in the paper. Hypermobility spectrum disorders group together all those phenotypes presenting context of the clinical presentation) and joint hypermobility plus one or more of its secondary manifestations, but not satisfying the not simply those assessed in these tools. criteria for any Ehlers–Danlos syndrome variant, also comprising the hypermobile type. Above the two domains, the wide spectrum of joint hypermobility-related co-morbidities Unlike LJH, GJH is more often a that may occur in all the phenotypes laying beneath. Joint hypermobility-related co- congenital, possibly an inherited trait. morbidities comprehend an expanding groups of common disorders (i.e., psychological Acquired forms of GJH also exist and distress, functional gastrointestinal disorders, cardiovascular dysautonomia, and pelvic prolapses—not otherwise defined), that show a statistical association with joint include widespread inflammatory or hypermobility, but their etiopathogenesis is complicated by a variety of acquired factors. degenerative diseases of the joints, – EDS, Ehlers Danlos syndrome (various types); FGDs, functional gastrointestinal musculoskeletal tissues and nerves, and disorders; G-HSD, generalized hypermobility spectrum disorder; GJH, generalized joint hypermobility; hEDS, hypermobile Ehlers–Danlos syndrome; JH, joint hypermobility hypothyroidism and other endocrine (various types); H-HSD, historical hypermobility spectrum disorder; L-HSD, localized disorders. Furthermore, malnutrition hypermobility spectrum disorder; P-HSD, peripheral hypermobility spectrum disorder; might also be a source of secondary POTS, postural orthostatic tachycardia syndrome. GJH in children [Hasija et al., 2008]. Further classifications of JH, LJH, and GJH are speculative. However, clini- Synonyms of JH include joint laxity and When JH is observed at one or a few cal practice and the literature prompt double-jointedness. In general terms, types of joints (usually fewer than five) it speculation as to the existence of two joint hyperlaxity is often considered a may be defined as localized joint hyper- additional clinical manifestations of JH. further synonym of JH. Establishing mobility (LJH). Typically, LJH affects a Peripheral joint hypermobility (PJH) is a whether a joint is hypermobile or not single small or large joint and may be potentially discrete form of JH that is is a relatively easy task and it is carried out bilateral (e.g., bilateral genu recurvatum appreciable at the hands and/or feet only. by (i) using professional tools, such due to knee hyperextensibility). LJH It is not defined as localized due to as the orthopedic goniometer; (ii) fol- may be inherited, but it may be an involvement of the four limbs, but, at the lowing specific procedures (e.g., [Juul- acquired trait related to, for example, past same time, PJH is distinguished from GJH Kristensen et al., 2007]); and (iii) trauma, joint disease, surgery, or training by the absence of large and axial joint comparing the measured range of mo- (e.g., spine hypermobility). In individu- involvement. It is common in infants, tion (ROM) with normal parameters. als with JH at multiple sites (usually five toddlers, and children, in whom it is ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 151 usually non-pathological or only mild in SECONDARY JH [Castori, 2016]. Preliminary studies impact.However,inselectedcircum- MANIFESTATIONS OF suggest the existence of hyperalgesia as a stances, PJH may be a clue of vascular JOINT HYPERMOBILITY possible form of pain sensitization in EDS, as it is classically associated with JH patients with EDS and chronic pain JH is frequently a symptomless trait. limited to the small joints (see “Vascular [Rombaut et al., 2015; Di Stefano et al., However, a relatively robust amount of Ehlers–Danlos Syndrome,” by Byers et al. 2016] (see also “Pain Management in data supports the existence of a series of [2017], this issue). Ehlers–Danlos Syndrome” by Chopra musculoskeletal symptoms and compli- The effect of age negatively im- et al. [2017], this issue). The recent cations that may be interpreted as bona pacting the ROM of many joints has observation of a high rate of small fiber fide secondary manifestations of JH. prompted some researchers to hypothe- neuropathy in adults with common EDS size the possibility of chronic musculo- subtypes (i.e., classical, hypermobile, and skeletal symptoms (see below) in older Trauma vascular) [Cazzato et al., 2016] may lead adults who have progressively lost their one to speculate on a direct relationship The hypermobile joint may be predis- GJH. The five-point questionnaire was between an impaired connective tissue posed to an excess of macro- and introduced as a rapid screening tool to function and abnormal pain processing. microtrauma. Macrotrauma (i.e., dislo- investigate historical joint hypermobil- An alternative or complementary hy- cations, subluxations, and other soft- ity (HJH) in adults who presumably have pothesis is the existence of a common tissue injuries—that is, any form of lost their GJH [Hakim and Grahame, pathogenesis shared by other forms of damage of muscles, ligaments, tendons, 2003]. Although this hypothesis is chronic musculoskeletal pain (e.g., synovium, and cartilage) is most likely reasonable and some cross-sectional acquired connective tissue disorders and the result of isolated or recurrent trauma studies have tried to support it [Castori idiopathic osteoarthritis), that may due to excessive joint movement et al., 2011], prospective research tracing develop in a way independent from the along non-physiological axes, poten- the natural history of GJH in individuals discrete causes of the primary joint tially compounded by joint instability. is lacking. disease [Castori et al., 2013]. Macrotrauma typically leads to acute pain, loss of function, and often the need JOINT INSTABILITY for acute treatment. Microtrauma is subtle/silent injury typically not per- Joint instability (JI) has in the past been Occasional and recurrent ceived by the individual or practitioner used as a synonym of JH. However, JI by musculoskeletal pain is a as it occurs. However, over time it might inference is a prelude to detrimental effect predispose to recurrent or persistent quite common immediate on the involved joint(s), while JH is a pain and potentially to early joint neutral term often defining a benign trait. manifestation of JH as the degeneration (i.e., early osteoarthritis). Hypermobile joints may also be unstable, While JH is largely accepted as predis- natural consequence of but JI is not a mandatory consequence of posing to recurrent musculoskeletal JH. Also, the reverse is true: not all predisposition to trauma. The pain, neither chronic pain nor early unstable joints are hypermobile. osteoarthritis is a uniform obligate development of chronic pain is Instability arises from a number of complication of JH. Repetitive micro- sometimes a long-term pathologies including laxity in the sup- trauma and occasional/recurrent mac- porting soft tissue structures; congenital complication of JH. rotrauma may lead to regional joint or acquired abnormality of the joint disorders, for example, temporoman- Preliminary studies suggest articulation; muscle disorders (inherent dibular joint dysfunction [De Coster or acquired weakness, and biomechanical the existence of hyperalgesia et al., 2005] (see also “Oral and imbalance); and musculoskeletal dys- Mandibular Manifestations in Ehlers– as a possible form of pain function as a result of neurological Danlos Syndrome,” by Mitakides and disorders. The lack of support puts an sensitization in patients with Tinkle [2017], this issue), or labral tear individual at increased risk of joint EDS and chronic pain. of the hip [Groh and Herrera, 2009]. dislocations (luxations and subluxations), and articular and soft-tissue injuries. While JH is frequently a consequence Chronic Pain Disturbed Proprioception of (either congenital or acquired) ligamentous (hyper-) laxity,the pathogenesis Occasional and recurrent musculoskele- In the symptomatic patient, it is not of JI is wider, as the propensity to joint tal pain is a quite common immediate uncommon to find JH coupled with dislocations, joint pain, and soft-tissue manifestation of JH as the natural reduced proprioception in selected joints traumas may arise from a number of consequence of predisposition to trauma. [Smith et al., 2013] and with muscle hereditary and acquired muscle and bone The development of chronic pain is weakness [Rombaut et al., 2012; Scheper disorders. sometimes a long-term complication of et al., 2016]. Reduced proprioception and 152 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE muscle strength significantly influence straightforward. In these circumstances, secondary effects mediated by each other and might generate a vicious the reduction in bone mass is typically the JH and other factors. circle of increasing limitation of activities milder, not clearly associated with in- of daily living in those with EDS. The creased fracture risk, and may be multi- mechanisms underlying the relationship factorial [Dolan et al., 2003; Gulbahar In the recent consensus paper on between reduced/lack of proprioception, et al., 2006] and partly related to the lack of general terminology in Medical Genet- weakness, and JH in adults are incom- proprioception, muscle weakness, and ics by Hennekam et al. [2013], a pletely understood, but their co-existence reduced activity that often characterize (genetic) syndrome is defined as “a should be considered in rehabilitation GJH independently from the underlying pattern of anomalies, at least one of plans [Scheper et al., 2016]. cause. which is morphologic, known or In other ways, the combination of JH thought to be causally (etiologically) and its neuromuscular attributes may also related.” Therefore, the term “syn- PATHOGENESIS AND influence performance in children. Some drome” should be used to name multiple PLEIOTROPY evidence suggests a significant association features that share the same underlying between GJH and developmental co- As previously emphasized, JH does not cause (etiology) rather than a common ordination disorder [Ghibellini et al., always rise to the level of a clinical pathogenesis. Pleiotropy is the biologi- 2015], a more inclusive term also com- disorder, as it is often asymptomatic. cal mechanism underlying genetic syn- prising developmental dyspraxia. The Practitioners usually recognize JH dromes, that is, patterns of anomalies pathophysiology is unknown but the when it runs in association with each caused directly by a defective gene interplay between poor proprioception additional musculoskeletal manifesta- simultaneously (and independently) af- and muscle weakness during the develop- tions. Those musculoskeletal manifes- fecting the development/functions of ment of motor schema may be one tations are likely due to pathogenic different tissues/organs/structures. mechanism. effects of the underlying JH (patho- For all these reasons, the presence of genesis). Accordingly, patterns of pre- JH in combination with secondary Other Musculoskeletal Traits sentation of JH-related musculoskeletal musculoskeletal anomalies does not features are highly variable and strongly suffice for the delineation of a genetic Individuals with GJH often present a related to modifier factors (e.g., sex, syndrome. The appellation “syndrome series of minor musculoskeletal physical mechanical forces, lifestyle habits, job, with JH” should be restricted to genetic traits, which may be the result of the accidents), which are causally indepen- conditions featuring JH together with interactions between “softer” musculo- dent from JH and may manifest at the primary involvement of at least a skeletal tissues and mechanical forces different ages. Thus, they are not second tissue/structure (e.g., skin in- (e.g., recumbent preferred position, directly due to the underlying cause volvement in classical EDS and hEDS). body weight, gravity, lateralization, of the JH, but instead are secondary Intrafamilial phenotypic variability is a sport activities) during growth and effects mediated by the JH and other feature of most genetic syndromes. development. Such traits, commonly factors. Hence, within the same pedigree, the encountered in individuals with GJH “ ” involvement of the various systems may include: pes planus (of the flexible be not straightforward in all affected type), valgus deformity of elbows, hind- individuals. However, an objective JH feet and halluces, scoliosis (not congen- Accordingly, patterns of ¼ > should be a highly penetrant trait within ital, of mild to moderate degree 7° presentation of JH-related and between families, as also emphasized using the Bunnel scoliometer [Bunnell, in the new criteria for hEDS. 1993]), accentuated dorsal kyphosis and musculoskeletal features are lumbar lordosis, and deformational highly variable and strongly plagiocephaly [Tinkle, 2010; Morlino related to modifier factors GENETIC SYNDROMES et al., 2016]. WITH JOINT Some genetic syndromes that feature (e.g., sex, mechanical forces, HYPERMOBILITY GJH are associated with severe reduction lifestyle habits, job, in bone mass and the propensity to Hereditary Disorders of the Soft fractures, and long bone deformities. In accidents), which are causally Connective Tissue these conditions, the pleiotropic effect of independent from JH and may thecausativegenemasksanypathogenic These are well known genetic syndromes correlation between GJH and a defective manifest at different ages. featuring JH. In particular, EDS is bone mass. This may not hold true for Thus, they are not directly probably the default diagnosis (or sus- milder phenotypes in which GJH asso- pected diagnosis) of many patients with ciates with a milder reduction of the bone due to the underlying cause of multiple manifestations combined with mass and a pleiotropic effect is not the JH, but instead are JH (for a full description of the new nosology of ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 153

EDS, see the Malfait et al. [2017], this recent review pointed out the increasing An Annotation on hEDS issue). Other hereditary disorders of the list of hereditary myopathies which Molecular discoveries have allowed the soft connective tissue with JH as a major typically show JH and, among them identification of an increasing number of feature include Marfan syndrome and Bethlem myopathy, Ullrich congenital uncommon, rare, and ultra-rare syn- related disorders, Loeys–Dietz syn- myopathy, COL12A1-related myopathy dromes with JH. For patients affected by dromes, Beals syndrome, arterial tortu- (or Ehlers–Danlos syndrome/myopathy such conditions, molecular testing is osity syndrome, lateral meningocele overlap), SEPN1-andRYR1-related usually the ultimate tool for reaching syndrome, and various hereditary cutis myopathies, MYH7-andTTN-related the correct diagnosis. However, for the laxa syndromes [Colombi et al., 2015; core myopathies, and limb girdle muscular hypermobile variant of EDS, there is no Mohamed et al., 2015]. dystrophy type 2E with joint hyperlaxity known genetic marker. One of the major and contractures [Donkervoort et al., goals of the revised nosology of EDS was 2015]. The underlying cause of JH in Other Genetic Syndromes to identify a single term, within the EDS these conditions is thought to be multi- nomenclature, for these patients and the An increasing number of skeletal dysplasias factorial, including the muscle/tendon term “hypermobile Ehlers–Danlos syn- also present with JH and its musculoskele- complex, the joint capsule and other drome (hEDS)” was elected as the tal consequences, such as joint pain and extracellular matrix components [Don- preferred one. The identified new set of dislocations [Bonafe et al., 2015]. Exam- kervoort et al., 2015]. JH may also be seen clinical criteria for the diagnosis is stricter ples include Larsen syndrome, Desbuquis in some forms of mitochondrial myopa- than the Brighton criteria for JHS and the syndrome, CST3-andgPAPP-related thy [Sugimoto et al., 2000]. Villefranche nosology for EDS-HT. The chondrodyplasias, spondyloepimetaphy- Practice also indicates that some rationale supporting these new criteria seal dysplasia with joint laxity, spondyloe- chromosomal and genomic disorders reflects (i) the need to place more emphasis pimetaphyseal dysplasia with leptodactyly, may frequently show JH, a feature that on the use of the term “syndrome” and in diastrophic dysplasia, and trichorhinopha- can also impact the overall rehabilitation doing so also highlights the pleiotropic langeal syndromes. plan of affected individuals. Down syn- nature of the disorder; and (ii) the drome is a prototype, and in which JH may opportunity to maintain coherence strongly influence gait performance and within the EDS nosology according to may be associated with atlantoaxial insta- the original description of the disease. bility [Galli et al., 2014; Siemionow and An increasing number of Many researchers and practitioners Chou, 2014]. This association extends to with experience on JH and related skeletal dysplasias also present other aneuploidies, in particular of the sex conditions perceive that the boundaries chromosomes (47,XXY and 47,XXX), with JH and its separating the continuous spectrum of and various microdeletion and micro- JH-related musculoskeletal manifesta- musculoskeletal consequences, duplication syndromes [e.g., Ciaccio tions and the true pleiotropic phenotype such as joint pain and et al., 2016]. However, the impact that (i.e., hEDS) are not always straightfor- JH may have on the management of these dislocations. Examples include ward and sometimes arbitrary. While the conditions remains undetermined, except, identification of stricter criteria for Larsen syndrome, Desbuquis perhaps, the link between GJH and co- hEDS, which more genuinely reflect ordination troubles commonly observed in syndrome, CST3- and the original description of the disease, children with selected sex chromosome gives more order to the nosology,it leaves gPAPP-related aneuploidies [Tartaglia et al., 2010; out many “non-syndromic” patients Samango-Sprouse et al., 2014]. chondrodyplasias, who suffer with the various secondary Finally, JH is also a commonly spondyloepimetaphyseal manifestations of JH. These patients do encountered feature in many multiple indeed have real medical needs even if dysplasia with joint laxity, congenital anomalies/intellectual dis- they do not meet criteria for hEDS or ability disorders, such as selected RA- spondyloepimetaphyseal another syndrome, and there is need for a Sopathies (e.g., Noonan, Costello, and logical framework of diagnostic terms to dysplasia with leptodactyly, cardio–facio–cutaneous syndromes) adequately describe their manifestations. diastrophic dysplasia, and [Detweiler et al., 2013; Vegunta et al., 2015; Rauen, 2016], Kabuki syndrome CLASSIFYING JOINT trichorhinophalangeal [Kawame et al., 1999], and Fragile-X HYPERMOBILITY syndromes. syndrome [Saul and Tarleton, 2012]. The rate and extent of JH in these We propose that individuals with JH conditions is probably underestimated may be classified as follows: The hereditary myopathies are a third due to the relatively small impact that group of genetic conditions which may this feature may have on the long-term (1) Subjects with asymptomatic, non- present with clinically significant JH. A management of these patients. syndromic/isolated LJH, PJH, or 154 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

GJH. Asymptomatic JH may occur in patients’ classification. HSDs are also from families with other relatives with multiple individuals from the same intended to identify discrete subtypes a previous diagnosis of hEDS (accord- pedigree (i.e., familial asymptomatic filling the full gap between asymptom- ing to the new criteria), a “relaxed” JH) and, theoretically, might also atic JH and hEDS. follow-up in clinical genetics services occur as an isolated trait in healthy There might be a scenario where may be scheduled due to a potential relatives of patients with a full-blown the diagnosis of HSD is given to an future revision of the diagnosis to hEDS. individual with a family history of hEDS hEDS or potentially another JH- (2) Individuals with a well-defined syn- (i.e., relatives with an independent related syndrome. drome with JH, also comprising hEDS diagnosis of hEDS). Such a presentation In line with the previously delin- (i.e., new diagnostic criteria met). might suggest the same underlying eated types of JH, four different HSDs (3) In individuals with symptomatic JH genetic trait with variable expression. may be identified: but not satisfying the criteria/diagno- However, from a classification perspec- sis for a syndrome, the term hypermo- tive, the diagnosis of hEDS is established (1) Generalized (joint) HSD (G-HSD): bility spectrum disorder(s) (HSDs) is by the presence of a positive Beighton GJH objectively assessed (e.g., by the proposed. score (i.e., GJH) plus two or more Beighton score) plus one or more among musculoskeletal criteria, sys- secondary musculoskeletal manifesta- temic involvement, and positive family tions as previously identified. In these HYPERMOBILITY history (as specifically defined in the patients, the pattern and severity of the SPECTRUM DISORDERS new nosology). Hence, the addition of a involvement of the musculoskeletal HSDs are a group of clinically relevant family history alone should not be system should be carefully assessed in conditions related to JH and are insufficient to change a diagnosis from order to explore the possibility of a tended as descriptive and exclusion HSD to hEDS according to the new full-blown hEDS. In this category diagnoses. They are distinguishable criteria. One recognizes this in other usually fall most patients with GJH from hEDS and the other syndromes areas of musculoskeletal medicine where and additional musculoskeletal mani- with JH because the phenotypic do- the same principle applies. For example, festations but do not meet the full mains of HSDs are usually limited to the there may be a family history of diagnostic criteria for hEDS. musculoskeletal system. The involve- rheumatoid arthritis (RA) (as defined (2) Peripheral (joint) HSD (P-HSD): JH ment of the musculoskeletal system is by accepted international criteria), but limited to hands and feet plus one or intended as the presence of one or more the individual presents with some clini- more secondary musculoskeletal man- of the secondary manifestations of JH as cal features to suggest an autoimmune ifestations as previously identified. reported above (i.e., trauma, pain, rheumatic disease but has insufficient (3) Localized (joint) HSD (L-HSD): JH at degenerative joint and bone disease, clinical and biological markers to define single joints or group of joints plus one neurodevelopmental manifestations, or- RA. The term “sero-negative inflam- or more secondary musculoskeletal thopedic traits) (Fig. 1). In these matory arthropathy” might apply. This manifestations regionally related to the patients’ category, a limited extension individual would be managed on the hypermobile joint(s). to other organs and tissues, particularly basis of their presenting complaint and (4) Historical (joint) HSD (H-HSD): self- in form of JH-related co-morbidities followed to determine whether their reported (historical) GJH (e.g., by the (see below), is possible, but the overall condition changed in any way that five-point questionnaire) with nega- clinical picture does not fit the criteria might then lead to a diagnosis of RA. tive Beighton score plus one or more for one of the various EDS types. HSD should be considered in the same secondary musculoskeletal manifesta- Therefore, HSDs are mostly intended way, including the possibility of clinical tions as previously identified; in these as alternative labels for patients with evolution and transition to another cases, physical examination aimed at symptomatic JH who do not have any rare diagnosis (e.g., hEDS). excluding the alternative diagnoses of type of EDS and do not meet the criteria for Although HSDs share JH with the G-HSD, P-HSD, and L-HSD as well hEDS in terms of severity/pattern of other conditions and, in particular with as other rheumatologic conditions is musculoskeletal involvement and/or due to EDS, at present it is premature to a mandatory. the absence of the other necessary criteria (as priori define HSDs as Mendelian The literature is full of case-control reported in the new EDS nosology—this disorders of the soft connective tissue. studies showing a significant association issue). In many circumstances, the HSDs In fact, their molecular basis remains between GJH (usually assessed by the will become the updated diagnosis for all unknown and they may occur sporadi- Beighton score) and specific extra-artic- those individuals who met the previous cally, may segregate within families as ular disorders. To date, the strongest criteria for EDS-HT or JHS but do not Mendelian traits (dominant, recessive associations are with anxiety disorders match the new hEDS criteria. However, or X-linked) or they may aggregate in [Sinibaldi et al., 2015], orthostatic tachy- HSDs are not limited solely to substi- families as multifactorial or polygenic cardia [Mathias et al., 2011], a variety of tuting the “old” Brighton criteria, that traits. In selected cases and, particularly, functional gastrointestinal disorders should not yet be considered for modern in some children and in individuals [Zarate et al., 2010], and pelvic and ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 155 bladder dysfunction [de Kort et al., 2003; are with anxiety disorders, genetic mutation). Therefore, these com- Veit-Rubin et al., 2016]. These associ- orthostatic tachycardia, a plications, when encountered in patients ations are often real (i.e., easily confirmed belonging to one of the above-mentioned by clinical practice) and clinically relevant variety of functional categories of JH, should be defined as JH- as these additional manifestations may be gastrointestinal disorders, and related co-morbidities. The concurrence commonly encountered in conditions of JH and one or more of its co- with JH, in particular hEDS, and might pelvic and bladder morbidities does not exclude an accurate impact seriously on the quality of life and dysfunction. differential diagnosis for the other causes management of affected individuals. underlying such co-morbidities. From Hence, their prompt recognition is useful this perspective, the presence of one or and the concurrence with GJH should be However, at the moment, it does not more JH-related co-morbidities aggra- emphasized also for therapeutic issues (see seem prudent to consider the combina- vates the overall phenotype and usually the many additional papers in this issue). tion of GJH and anxiety (or any other indicates the need of a multidisciplinary strongly associated extra-articular disor- therapeutic approach. Whether the de- ders) a syndrome per se, at least from the velopment of chronic pain is a late Medical Genetics perspective. In fact, consequence of JH or rather it should The literature is full of case- these satellite manifestations may compli- be considered a JH-related co-morbidity cate a variety of phenotypes, including is still a matter of debate and further control studies showing a isolated JH, syndromes with JH and research is needed to clarify this point. significant association between HSDs, and the burden may be strongly influenced by acquired factors (e.g., THE SPECTRUM GJH (usually assessed by the psychological distress). According to Beighton score) and specific such an assumption, it is too premature While Mendelian syndromes with JH can extra-articular disorders. To to consider such manifestations primary be clearly separated by molecular testing (i.e., pleiotropic) clinical expressions of from the other JH-related phenotypes, date, the strongest associations the underlying etiological factor (i.e., this is not the case for asymptomatic JH,

TABLE I. Phenotypes Belonging to “the spectrum”

Beighton Musculoskeletal Phenotype score involvement Notes Asymptomatic Positive Absent – GJH Asymptomatic Usually Absent – PJH negativea Asymptomatic Negativeb Absent – LJH G-HSD Positive Present – P-HSD Usually Present – negativea L-HSD Negativeb Present – H-HSD Negative Present Historical presence of joint hypermobility (e.g., positive 5-point questionnaire) hEDS Positivec Possible Plus positive family history (first-degree relatives) and/or specific systemic manifestations (see new criteria)

GHD, generalized hypermobility disorder; G-HSD, generalized hypermobility spectrum disorder; hEDS, hypermobile Ehlers–Danlos syndrome; L-HSD, localized hypermobility spectrum disorder; LJH, localized joint hypermobility; P-HSD, peripheral hypermobility spectrum disorder; PJH, peripheral joint hypermobility. All these phenotypes request accurate exclusion of the other acquired and hereditary, partially overlapping disorders. aPeripheral joint hypermobility is typically limited to hands and/or feet; Beighton score is usually negative. bLocalized joint hypermobility is limited to single joints or body parts; Beighton score is negative. cSee the new criteria for the operational definition of “generalized joint hypermobility” as mandatory feature/criterion of hypermobile Ehlers–Danlos syndrome. 156 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE hEDS, and HSDs. In fact, their clinical isolated JH could be one of the future Sangiorgi L, Savarirayan R, Sillence D, Spranger J, Superti-Furga A, Warman M, manifestations are variable, but largely goals of the scientific community, espe- Unger S. 2015. Nosology and classification overlapping, as seen in extended pedigree cially in the fields of Human and Medical of genetic skeletal disorders: 2015 revision. study and the identification of family Genetics. This knowledge will surely ease Am J Med Genet Part A 167A:2869–2892. ’ Bunnell WP. 1993. Outcome of spinal screening. members belonging to all three pheno- patients classification and prognostication, Spine (Phila Pa 1976) 18:1572–1580. types with variable degree of disability. and, perhaps, will better rationalize medi- Byers P,Belmont J, Black J, De Backer J, Frank M, Therefore, from a clinical perspec- cal and economic resources. At the same Jeunemaitre X, Johnson D, Pepin M, Robert L, Sanders L, Wheeldon N. 2017. tive, asymptomatic JH, HSDs, and hEDS time, exploring the pathogenetic links Diagnosis, natural history, and management can be brought back to a single continu- connecting JH and its secondary muscu- in vascular Ehlers Danlos syndrome. Am J ous spectrum ranging from isolated JH to loskeletal manifestations, as well as the Med Genet Part C Semin Med Genet (in full-blown hEDS passing through the mechanisms underlying the JH-related co- press). Castori M, Dordoni C, Valiante M, Sperduti I, various HSDs. The nosologic distinction morbidities is the greatest challenge for the Ritelli M, Morlino S, Chiarelli N, Celletti among them is summarized in Table I. various disciplines involved in the daily C, Venturini M, Camerota F, Calzavara- The existence of this spectrum is the management of patients with JH. Pinton P,Grammatico P,Colombi M. 2014. Nosology and inheritance pattern(s) of joint rationale supporting the dynamic nature hypermobility syndrome and Ehlers–Danlos of such a classification and the possibility syndrome, hypermobility type: A study of of phenotype transition due to the intrafamilial and interfamilial variability in 23 Italian pedigrees. Am J Med Genet Part A changing pattern of JH-associated man- Dissecting the molecular basis 164A:3010–3020. ifestations. The follow-up of these of hEDS, HSDs, and isolated Castori M, Morlino S, Celletti C, Ghibellini G, patients may be relevant also for diagnos- Bruschini M, Grammatico P, Blundo C, Camerota F. 2013. Re-writing the natural tic accuracy, especially for patients at risk JH could be one of the future history of pain and related symptoms in the of developing a phenotype consistent goals of the scientific joint hypermobility syndrome/Ehlers–Dan- with the new criteria for hEDS, but also los syndrome, hypermobility type. 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