American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 175C:48–69 (2017) ARTICLE

Hypermobile Ehlers–Danlos Syndrome (a.k.a. Ehlers–Danlos Syndrome Type III and Ehlers–Danlos Syndrome Hypermobility Type): Clinical Description and Natural History BRAD TINKLE,* MARCO CASTORI, BRITTA BERGLUND, HELEN COHEN, RODNEY GRAHAME, HANADI KAZKAZ, AND HOWARD LEVY

The hypermobile type of Ehlers–Danlos syndrome (hEDS) is likely the most common hereditary disorder of connective tissue. It has been described largely in those with musculoskeletal complaints including joint hypermobility, joint subluxations/dislocations, as well as skin and soft tissue manifestations. Many patients report activity-related pain and some go on to have daily pain. Two undifferentiated syndromes have been used to describe these manifestations—joint hypermobility syndrome and hEDS. Both are clinical diagnoses in the absence of other causation. Current medical literature further complicates differentiation and describes multiple associated symptoms and disorders. The current EDS nosology combines these two entities into the hypermobile type of EDS. Herein, we review and summarize the literature as a better clinical description of this type of connective tissue disorder. © 2017 Wiley Periodicals, Inc.

KEY WORDS: joint hypermobility; joint hypermobility syndrome; Ehlers–Danlos syndrome type III; Ehlers–Danlos syndrome hypermobility type How to cite this article: Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H, Levy H. 2017. Hypermobile Ehlers–Danlos syndrome (a.k.a. Ehlers–Danlos syndrome Type III and Ehlers–Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet Part C Semin Med Genet 175C:48–69.

INTRODUCTION cutaneous features typically observed in description of hEDS in the the classical and vascular types of EDS. Hypermobile Ehlers–Danlos syndrome Since the Villefranche nosology,the clinical medical literature has expanded (hEDS; previously known as EDS type description of hEDS in the medical IIIaccordingtotheBerlinnosology considerably to include more literature has expanded considerably to [Beighton et al., 1988] and EDS hypermo- include more features, such as chronic pain, features, such as chronic pain, bility type in the Villefranche nosology chronic fatigue, dysautonomia, and anxiety [Beighton et al., 1998]) is a heritable chronic fatigue, dysautonomia, among other associated symptoms. connective tissue disorder (HCTD) pri- and anxiety among other marily identified as having generalized joint associated symptoms. hypermobility (GJH), related musculoskel- etal manifestations, and a milder involve- Since the Villefranche mentoftheskin,whichlacksthedegreeof nosology, the clinical

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. Marco Castori is a Clinical Geneticist with focus on the diagnosis and management of hereditary connective tissue disorders, particularly Ehlers– Danlos syndromes. He is a co-author of more than 130 papers in international journals and 14 book chapters. Britta Berglund is an associated researcher in nursing research in Uppsala University, retired but active. Helen Cohen is in the Department of Rheumatology at Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex. Rodney Grahame is at Centre for Rheumatology, University College London and the Hypermobility Unit at Hospital of St John & St Elizabeth, London. Hanadi Kazkaz is in the Rheumatology Department, University College Hospital, London. 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. *Correspondence to: Brad Tinkle, M.D., Ph.D, Division of Clinical Genetics, Advocate Children's Hospital, 1875 Dempster St, Suite 285, Park Ridge, IL 60068. E-mail: [email protected] DOI 10.1002/ajmg.c.31538 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) 49

In a similar timeframe, joint hyper- attention for hEDS and to facilitate Prevalence mobility syndrome (JHS; also called scientific identification of the underly- Accurate prevalence estimation studies hypermobility syndrome or benign joint ing genetic cause(s) of the condition. are still lacking for hEDS. Steinmann hypermobility syndrome) has been fur- Accordingly, some patients meeting the et al. [2002] reported a minimum ther delineated since its original descrip- old Villefranche and Brighton criteria prevalence of 1/5,000 for all types of tion [Kirk et al., 1967; Grahame et al., will not meet the new hEDS criteria. EDS collectively. As hEDS likely rep- 2000]. The clinical spectrum of JHS is For all these individuals not showing a resents 80–90% of cases of EDS, the often clinically indistinguishable from sufficiently convincing hEDS pheno- prevalence is presumed not lower than hEDS according to an international type, some alternative labels within the 1/5,000. A much higher prevalence of panel of experts [Tinkle et al., 2009]. above-mentioned spectrum are pre- 7.5/1,000 to 20/1,000 (0.75–2%) for Subsequently, Castori et al. [2014] sented elsewhere in this issue (see “A “symptomatic” GJH has been proposed, demonstrated the evolving natural his- Framework for the Classification of considering that about 10% of individ- tory by studying multi-generational Joint Hypermobility and Related Con- uals with GJH may develop related pedigrees and applying the then current ditions” by Castori et al., this issue). symptoms in their lifetime [Hakim and diagnostic criteria for each (hEDS and Given the extreme variability Sahota, 2006]. Others confirmed such JHS) concluding that both disorders within this spectrum and the age- an estimation [Hamonet et al., 2015]. A may co-exist in the same pedigrees and influenced progression of the pheno- much higher prevalence for the associa- could not be distinguished in the familial type, some of these patients will tion of JH and widespread pain is cases. It is, therefore, the consensus of probably remain under a relaxed pro- reported by Mulvey et al. [2013] and the authors on behalf of the Interna- gram of follow-up in order to promptly Morris et al. [2016]. Based on data tional Consortium on the Ehlers– detect the possible evolution into a full- obtained from a large epidemiological Danlos Syndromes, based on the blown hEDS phenotype. study undertaken on a population of present state of our knowledge, that 12,853, 3.4% had joint hypermobility the two conditions are part of the same METHODS and widespread pain which was been clinical spectrum ranging from appar- used as a proxy for hEDS [Mulvey et al., ently symptomatic GJH to the most The Committee on hEDS of the Inter- 2013]. Accordingly, hEDS is likely the disabled individuals fitting the new national Consortium on the Ehlers– most common systemic inherited con- diagnostic criteria for hEDS. Danlos Syndromes met by telepresence nective tissue disorder in humans which Grouping all phenotypes com- or through electronic correspondence translates in approximately 2 million in prised in this spectrum under the same throughout 2015 and 2016 to discuss the the United Kingdom, 10 million in the heading may be misleading on both nosology and clinical description of United States, 17 million in Europe, and nosologic and therapeutic perspectives. hEDS. The following reflects extensive 255 million affected worldwide. How- Although it is reasonable that the literature review and the professional ever, the diagnostic criteria proposed congenitally “double-jointed” gymnast experience of the committee members herein are more selective than the and the chronically disabled hEDS as well as insights from various contribut- Villefranche nosology for EDS hyper- patient may share a strong genetic and ing members of the international effort mobility type and the Brighton criteria pathophysiological background, to date, on EDS through the Consortium. for JHS, so the prevalence of hEDS we have not any proof unequivocally under these criteria may be somewhat demonstrating that they carry the same CLINICAL DESCRIPTION lower than some of these estimates. genetic trait, unless, perhaps, they are linked by a close blood relationship. But The below sections of this paper also in this case, as the molecular bases of describing the phenotype and natural Genetics these phenotypes remain unknown, we history of hEDS are extracted by the cannot exclude that these two individu- literature available on EDS hypermobil- hEDS, for the most part, is inherited as als share a part only of the causative ity type, EDS type III and JHS (old an autosomal dominant disorder of genetic milieu (i.e., oligogenic/poly- nomenclature). To date, we are not sure connective tissue but other patterns of genic disorder) in the absence of shared that all available data will stand true for inheritance can be seen in some families; additional clinically or structurally rele- the newly defined hEDS. However, they however, this may be confounded by vant signs. are considered a good proxy for the non-penetrance, sex-influence as well as The new criteria of hEDS are delineation of the hEDS phenotype. In genetic heterogeneity. Unfortunately, stricter than the old Villefranche nosol- the following sections, the acronym unlike the other types of EDS, hEDS ogy [Beighton et al., 1988] and the hEDS is used as a substitute for EDS has no known genetic etiology respon- Brighton criteria [Grahame et al., 2000]. hypermobility type, EDS type III, and sible for any significant portion of this This is intended to define a more JHS, unless the distinction between population. JH itself is multifactorial homogeneous phenotype shared among these phenotypes is necessary for reasons with age, gender, weight, training, patients who require long-term medical of clarity. and other aspects that influence this 50 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE phenotype. Twin studies have deter- deficiency accounts for only a small children usually meeting the Ville- mined that the concordance of JH percentage of hEDS. franche criteria only and the elderly among dizygotic twins was 36% in 472 A few case reports have pointed to mostly ascertained by the Brighton female twin pairs, whereas monozygotic other genetic factors in hEDS. A criteria alone, while both diagnoses twins had a concordance rate of 60% in collagen type III (COL3A1) variant often coexisted in young adults and 483 female twin pairs suggesting a strong was found in one family without the middle-aged affected members. This genetic trait with multifactorial influ- arterial or intestinal fragility typical of implied that the mean Beighton score, ences [Hakim et al., 2004]. vascular EDS [Narcisi et al., 1994], but frequency (and distribution) of muscu- no subsequent reports of COL3A1 loskeletal pain, manifestations of skin mutation have been published in involvement, and appearance of other hEDS. More recently, a variant of the complications were strongly influenced Unfortunately, unlike the LZTS1 gene was found in four families by age. Such a phenomenon seems not other types of EDS, hEDS with a hEDS phenotype among 231 limited to the items included in the has no known genetic etiology individuals evaluated, but the causal Villefranche and Brighton criteria, but nature of these variants remains unex- also extends to other disease manifes- responsible for any significant plored [Syx et al., 2015]. It is believed by tations not originally considered, such portion of this population. JH many that the hEDS phenotype repre- as the gastrointestinal involvement sents substantial genetic heterogeneity. [Castori et al., 2015a]. itself is multifactorial with With the wider use of whole exome or In an Italian study on disease age, gender, weight, training, whole genome sequencing with strict progression with 21 hEDS patients, phenotyping, it is expected that addi- the existence of three “discrete” disease and other aspects that tional hEDS-related genes will be phases was proposed: a “hypermobility” influence this phenotype. identified. Eventual identification of phase, a “pain” phase, and a “stiffness” validated genetic etiologies will allow phase [Castori et al., 2010a]. Subsequent objective clinical testing and better observations and speculations on the Various studies have suggested that delineation of the full phenotype. same ethnic group reinforced the con- hEDS is a phenotypically and presum- cept and smoothed the rigid approach ably genetically heterogeneous disorder on three separate phases [Castori et al., The Evolving Natural History [De Wandele et al., 2013; Pacey et al., 2011a, 2013, 2015b]. The three-step 2015a]. A minority of cases have been The Villefranche criteria for EDS model can remain a prototypical de- reported to be due to a haploinsuffi- hypermobility type and Brighton crite- scription of the potential disease course, ciency of tenascin X (TNXB)[Zweers ria for JHS were originally conceived for but not every patient experiences all et al., 2003]. However, the haploin- the diagnosis of two conditions per- three phases and the rate of transition sufficiency was not penetrant in males ceived as distinct. However, they were between phases can be highly variable. and only partially in females (9 out of subsequently recognized as separate The decrease of the Beighton score in 14). TNXB lies near CYP21A2,the tools for describing a single disorder the symptomatic individual may be gene associated with congenital adrenal [Tinkle et al., 2009; Castori and considered a proxy for disease evolution hyperplasia (CAH). The region con- Colombi, 2015]. Such a dichotomy in hEDS [Castori et al., 2011a, 2015b]. tains several pseudogenes including likely reflects the protean progression In cross-sectional studies on patients those for TNXB and CYP21A2. of the same entity. Anecdotally, many with different ages at diagnosis, a Intragenic recombination and resultant families were identified that had diag- tendency of the Beighton score to turn microdeletion is a common cause of noses of EDS hypermobility type and “negative” (i.e., <5) around the fourth CAH. Merke et al. [2013] reported in JHS in various family members usually decade of life has been identified several CAH individuals, an hEDS-like segregated on age. The clinical identity [Castori et al., 2011a]. phenotype due to chromosomal micro- between EDS hypermobility type and The “hypermobility” phase domi- deletion and coined the syndrome JHS was provisionally demonstrated in nates the first several years of life with CAH-X. More recently, a novel mis- a single multiplex family with affected contortionism and propensity for sprains sense variant of TNXB was shown in individuals fitting alternatively the and dislocations. Pain is often limited to 10 individuals of seven families and was Villefranche and Brighton criteria lower limbs (i.e., persistent “growing associated with the hEDS phenotype [Hermanns-L^e et al., 2012]. pains”) but pain with fine motor or [Morissette et al., 2015]. Tenascin-X is Definitive support to such a clinical repetitive tasks such as handwriting is an extracellular matrix protein and overlap in families with EDS hypermo- also commonly encountered [Gedalia potentially can affect connective tissue bility type and JHS came from a study in et al., 1996; Murray and Woo, 2001]. in its various forms. However, the 23 Italian pedigrees [Castori et al., Easy fatigability may be a feature, exact physiologic process remains un- 2014]. In these families, the formal together with voiding dysfunction known and heterozygous tenascin-X diagnosis was influenced by age, with [Beiraghdar et al., 2013; Kajbafzadeh ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 51 et al., 2014]. Some hypermobile chil- influence of female sex hormones [Wolf, for local and generalized joint hyper- dren experience developmental dys- 2009; Shultz et al., 2012; Boyan et al., mobility—a systematic review,” Juul- praxia (or developmental coordination 2013]. hEDS is best defined as an Kristensen et al., this issue), although disorder), manifesting with mild hypo- autosomal disorder “influenced by this has major limitations in selected tonia and non-specific developmental sex,” with a predominance of symptoms populations, such as the very young and delay in gross and fine motor skills in females. It should also be recognized the elderly [Dolan et al., 2003; Castori, attainment [Adib et al., 2005; Kirby that most chronic pain syndromes also 2012]. It can be asymptomatic, and is et al., 2005; Easton et al., 2014]. have a female predominance, and this more common among dancers and elite The “pain” phase is characterized may be another contributing factor athletes where it may confer a constitu- by generalization and progressive [Wijnhoven et al., 2006]. tional advantage [Day et al., 2011; chronicity of musculoskeletal pain, The phenotype of hEDS is one that Beighton et al., 2012]; however, it which is often diagnosed as fibromyalgia evolves over time and has a gender bias may predispose to higher injury rates [Ting et al., 2012], summation of other that also changes over time. Previous [Briggs et al., 2009; Konopinski et al., forms of chronic pain, such as pelvic attempts at diagnostic criteria (Ville- 2015]. pain (in women) and headache, as well as franche and Brighton) have often not When symptomatic, it often man- exacerbation of fatigue. This phase fully accounted for the natural transition ifests in childhood or adolescence, along typically starts in the second to the from EDS hypermobility type to JHS with associated features, but is often fourth decade of life and often associates with age within the above described poorly recognized [Engelbert et al., with a variegated constellation of addi- disease evolution [Castori et al., 2013]. 2003]. Adults may recall being flexible tional complaints, such as paresthesias, Such a nosological conundrum is solved as a child, and being able to perform mixed and treatment-resistant func- by the use of unified diagnostic criteria. “party tricks” with their joints. The two tional gastrointestinal disorders, ortho- more common patterns of presentation static intolerance, and pelvic are with: (1) a limited number of painful Symptomatic Joint Hypermobility dysfunction. and/or unstable joints or (2) chronic A generalized reduction of joint Clinical problems associated with JH widespread musculoskeletal pain (which mobility dominates the “stiffness” phase, may present at any time of life. may have been diagnosed as fibromyal- in which patients usually experience Syndromic or excessive JH can be gia). In the former group, the more significant reduction in their function- difficult to diagnose in children, who common problematic or unstable joints ality due to the combination of disabling are normally more flexible than adults often presenting with recurrent sublux- symptoms (e.g., pain and fatigue) as well [Toftset al., 2009; Castori, 2012]. GJH is ations/dislocations or pain are the as motor limitations due to the coexis- often diagnosed using the Beighton shoulder, knee, and ankle [Tobias tence of reduced muscle mass and score (see also “Measurement properties et al., 2013]. Iliotibial band syndrome weakness, defective proprioception, of existing clinical assessment methods (sometimes called “snapping hip” prior injuries, and arthritis. In this phase, observed in a few adults and elderly only, the symptomatology that appeared in the “pain” phase escalates and GJH is usually not appreciated. hEDS is considered to be an autosomal dominant trait with variable expressivity. Yet, many studies point out a strong excess of affected females, at least in adults [Castori et al., 2010a]. The ratio ranges from 8–9:1 to 2:1, depending upon how patients are selected. The lowest ratio was registered in familial cases only with the inclusion of affected relatives [Castori et al., 2014]. In early childhood, the male to female ratio of affected is similar. However, in the general population, as children enter puberty, joint mobility tends to increase in females and decrease in males [Fig. 1; Figure 1. Gender and pubertal maturation status as compared to Beighton score (BHJMI) in a general population of male (N ¼ 143) and females (N ¼ 275). Beighton Quatman et al., 2008]. The reason for scores representing joint laxity increased during puberty in females and decreased in the sex bias remains incompletely males. Published with permission [Quatman et al., 2008]. understood with speculation of a greater 52 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE syndrome) is also common, and is temporomandibular joint also “Pain Management in the Ehlers– ” frequently perceived by the patient as dysfunction, sleep disturbance, Danlos Syndromes by Chopra et al., hip instability, even though the sense of this issue. motion occurs over the greater tro- as well as depression and chanters and not in the groin. In the anxiety. The specific Skin and Fascia group with chronic widespread muscu- loskeletal pain, the pain distribution and associated impairment and The Ehlers–Danlos syndromes are pri- descriptions often overlap with fibro- their severity can vary marily due to disorders of connective myalgia to such an extent that it can be markedly, and are not tissue matrix proteins, in particular, but virtually impossible to distinguish not exclusively collagen (see also “The [Ofluoglu et al., 2006; Ting et al., necessarily associated with the Ehlers–Danlos Syndromes: The New” 2012]. It is important to recognize that degree of joint laxity. by Malfait et al., this issue). It is there are many causes for both localized presumed that the genetic determinants and widespread joint or musculoskeletal of hEDS are also likely of collagen or pain, and that the presence of pain alone collagen-related genes. The dermis Pain without associated JH is insufficient to comprises 70% dry-weight collagen so establish a diagnosis of EDS. Over time, The specific underlying cause(s) and that the skin presents itself as a visible, many patients lose their former joint mechanism(s) of pain in EDS, and in palpable, and readily accessible organ for laxity, while others remain hypermobile particular hEDS, are not well under- the study of collagen-related genetic [Castori, 2012]. This reduction in JH stood, but both acute and chronic aberrations. The skin in hEDS is over time further complicates the diag- pain are common manifestations and different from normal skin and these nostic evaluation of chronic pain pa- often contribute to disability [Rombaut differences constitute an important aid tients over approximately age 40. et al., 2010, 2011a,b, 2012; Voermans to diagnosis. In hEDS, the skin texture is In common with other chronic pain et al., 2010a,b; Castori et al., 2012a; characteristically soft, silky, or velvety to syndromes, there mayalso be overlapping Murray et al., 2013]. Nociceptive pain the touch. It may be semi-transparent so diagnoses such as chronic fatigue, irrita- directly related to affected muscles, that veins and tendons are more easily ble bowel syndrome, temporomandibu- joints, and connective tissue is frequent. visible than normal, but this is subtle in lar joint dysfunction, sleep disturbance, as Neuropathic pain, characterized by allo- comparison with the skin transparency well as depression and anxiety. The dynia and/or typical quality descriptors, of vascular EDS. specific associated impairments and their such as electrical, burning, numb, or The skin in hEDS is also hyper- severity can vary markedly, and are not tingling, is also common. Anatomic extensible. The technique used is im- necessarily associated with the degree of imaging (e.g., for impingement of the portant in obtaining reliable results. The joint laxity. Higher rates of anxiety and central spine or foraminal nerve roots) stretchiness is subtle in hEDS and can depression have been noted in GJH, and functional electrodiagnostic studies easily be overlooked if the clinician is hEDS, and JHS since 1994 [Lumleyet al., (e.g., nerve conduction studies or elec- anticipating the degree of stretch seen in 1994; Mallorqui-Bague et al., 2015]. tromyography) are often negative even in classical EDS. The “rubber glove skin Distress, kinesiophobia, and individuals’ the face of subjective symptoms highly test” may distinguish between hEDS coping strategies and behavioral re- suggestive of a neuropathic etiology.Skin skin and normal, by raising a skin fold on sponses are more likely to predict biopsy may reveal reduction of intrader- the dorsum of the hand in patients with impairment and quality of life (QoL) mal nerve fiber density, suggestive of hEDS, the skin is seen to stretch over a than the intensity of pain [Celletti et al., small fiber neuropathy [Cazzato et al., much wider area than is normal, 2013]. Physical deconditioning can ex- 2016]. extending to the wrist and beyond. acerbate joint laxity, contributing to an Some potential etiologies of pain However, the clinical evaluation of skin ongoing cycle of deconditioning, weak- include spasm of muscles, tendons, and laxity follows that outlined in the new ness, joint instability, and worsening pain other connective tissue; direct trauma diagnostic criteria for hEDS (see also [Castori, 2012]. due to joint instability; and nerve “The 2017 International Classification entrapment [Granata et al., 2013]. of the Ehlers–Danlos Syndromes” by Osteoarthritis, secondary to joint in- Malfait et al., this issue). stability, is also a likely factor. Central The hEDS skin is more fragile In common with other chronic sensitization, generalized hyperalgesia, than normal, but much less so than in chronic regional pain syndrome, and the other types of EDS. Easy bruising is pain syndromes, there may similar systemic or regional pathogenic common but poorly defined. Wound also be overlapping diagnoses mechanisms may contribute in later healing may be impaired with the stages [Castori et al., 2013; Rombaut production of mildly atrophic scars, such as chronic fatigue, et al., 2015; Scheper et al., 2015, which may be wider than the original irritable bowel syndrome, 2016a; Di Stefano et al., 2016]. See wound and/or sunken below the ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 53 surface of the surrounding skin. Again, Striae atrophicae often appear dur- gravidarum may be minimal or non- the degree of atrophic scarring in ing the adolescent growth spurt usually existent in some as skin of the mature hEDS is less severe than in and usually between the ages of 11–13 years and not hEDS female is inherently stretchy so distinguishable from the other types of necessarily associated with rapid weight that the elastic limit is never reached EDS (Fig. 2). However, its occurrence gain; however, this can also be seen in despite the enlarging maternal may be exacerbated by the use of local adolescents without an underlying con- abdomen. or systemic steroids [Jacks and Zirwas, nective tissue disorder as well [Feldman Other important collagen-bearing 2016]. and Smith, 2007]. By contrast, striae tissues may also fail in hEDS due to their inherent fragility. Cerebrospinal fluid (CSF) leaks, spontaneous or induced, are a possible cause of orthostatic head- aches. One case-control study of pa- tients with spontaneous CSF leak reported a greater than expected frequency (16/50) of patients with classical EDS, hEDS, or an unclassified hereditary disorder of connective tissue [Reinstein et al., 2013], while a similar study found no increase in features of hereditary connective tissue disorders between patients with spontaneous intracranial hypotension and controls [Liu et al., 2011]. Both of the musculotendinous support of the diaphragm and the pelvic floor can fail mechanically leading to hiatal hernia [Nelson et al., 2015] or pelvic floor weakness further leading to uterine/rectal prolapse, rectocele, cys- tocele, and/or enterocele [Veit-Rubin et al., 2016]. Fascial weakness can lead to hernias in the inguinal, femoral, or umbilical areas or at sites of previous surgical incisions as after abdominal surgery [Nazem et al., 2013].

Fatigue Fatigue is common among adolescents in general, affecting approximately one- third of the general population and can interfere with activities of daily living including school performance and at- tendance [Kizilbash et al., 2014; Sleep Working Group et al., 2014]. However, chronic fatigue defined as fatigue lasting longer than 6 months, occurs in 1% of Figure 2. Comparison between abnormal scarring and satellite cutaneous signs in adolescents in the general population hEDS and classical EDS due to mutations in COL5A1/COL5A2/COL1A1. hEDS (A–C). A: Post-traumatic mildly atrophic scarring of the knee in a boy. B: Dermal [Werker et al., 2013]. The entity chronic hypotrophy is more evident by stretching between the observer’s fingers. C: Post- fatigue syndrome (CFS) occurs more – surgical enlarged scar in a young woman. Classical EDS (D G). D: Typical papyraceous commonly in women and particularly in and hemosiderotic scar of the knee in a man. E: A milder scar in a young woman; in comparison with A and B, the atrophic nature of the scar is appreciable without passive those over 45 years of age but is often skin stretching and the surrounding skin is redundant with a cutis laxa-like appearance. underdiagnosed [Yancey and Thomas, F: The typical, though rare, subcutaneous spheroid. G: An enlarged molluscoid 2012; Wright Clayton, 2015]. It can be pseudotumor of the elbow in a man. associated with impaired memory, cog- nitive deficits, muscle pain, joint pain, 54 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE headaches, non-restorative sleep, post- Scheper et al., 2013; Pacey et al., 2015a, POTS, NMH, and orthostatic exertional malaise, as well as psycholog- b; Hershenfeld et al., 2016]. intolerance are common manifestations ical issues [Fossey et al., 2004; Nijs et al., Fatigue may also be a factor in in hEDS [Rowe et al., 1999; Gazit et al., 2006; Meeus et al., 2007]. The etiology musculoskeletal pain and injury. Exer- 2003; Mathias et al., 2011]. Head-up tilt of the chronic fatigue (syndrome) is cise to the point of physical fatigue has test may or may not establish a specific multifactorial and includes infectious been shown to alter kinematics, postural etiology, but often does not affect agents, immune dysregulation, allergies, stability, and coordination, which may therapeutic decision-making and, there- endocrinopathy, nutritional deficiency, increase the risk of direct injury and also fore, may not be necessary. See also and abnormally low blood pressure the risk of falls causing secondary injury “Guidelines on the Assessment and often associated with postural ortho- [Sparto et al., 1997; Dickin and Doan, Management of Cardiovascular Dysre- static tachycardia syndrome (POTS) or 2008]. A study of 30 EDS patients, five gulation in Ehlers–Danlos Syndrome” neurally mediated hypotension (NMH) of whom had hEDS, showed correlation by Hakim et al., this issue. [Kanjwal et al., 2010; Werker et al., between fatigue and objectively mea- Mitral valve prolapse (MVP) was 2013; Kizilbash et al., 2014]. sured muscle weakness [Voermans et al., previously considered a common feature Fatigue is one of the most com- 2011]. Exercise-induced fatigue in- of EDS and many other HCTDs, but mon complaints among those with creases knee laxity [Skinner et al., that was prior to the establishment of hEDS [Gazit et al., 2003; Maeland 1986], which may also increase the more rigorous criteria for the diagnosis et al., 2011; De Wandele et al., 2013; risk of knee injury. Fatigue is also of MVP. Since then, some studies show Murray et al., 2013]. Chronic fatigue associated with reduced ground reactive no increase in the frequency of clinically in hEDS includes bodily and mental force during gait, suggestive of de- significant MVP [Dolan et al., 1997, fatigue which only minimally improves creased proprioception [Celletti et al., McDonnell et al., 2006, Atzinger et al., with rest and often fits well into the 2012], which could also increase the risk 2011] and others show an MVP fre- diagnostic criteria of CFS [Castori for falls and injury. Severity of fatigue quency of 28–67% among hEDS pa- et al., 2011b]. In a small series of 12 also correlated with kinesiophobia in tients [Camerota et al., 2014; Kozanoglu EDS patients (six classical EDS; six hEDS and, therefore, became an activ- et al., 2016]. Increased prevalence of hEDS), Rowe et al. [1999] character- ity-limiting factor [Celletti et al., 2013]. mitral and tricuspid insufficiency has ized that all had chronic fatigue, post- In conclusion, fatigue and espe- also been reported [Camerota et al., exertional malaise, and unrefreshing cially chronic, debilitating fatigue is 2014]. Since the mitral valve relies upon sleep, whereas 92% had impaired common in hEDS. Fatigue decreases collagen for its tensile strength, and cognition/memory; 83% with polyar- muscle control and coordination, can myxomatous MVP is characterized by thralgia and headache; and 58% with inhibit physical activity, and may in- disruption of the collagen layer with muscle pain. Sore throat and lymph- crease risk for injury. The fatigue is expansion of glycosaminoglycans within adenopathy occurred in the minority at mental as well as physical, leading to the middle layer of the valve [Delling 25%. In a subsequent study of 58 impaired cognition and memory recall. and Vasan, 2014], it is reasonable to still consecutive children with CFS, Barron It is also associated with multiple consider MVP as a potential clue for et al. [2002] described GJH was comorbidities linked to pain, sleep hEDS, but the true clinical significance significantly more common in the disturbance, anxiety and depression, as is not yet known. CFS population than in healthy con- well as decreasing function and QoL. trols. In 273 EDS patients, pain and See also “Guidelines on the Assessment Gastrointestinal Disorders fatigue comprised 31% of the func- and Management of Chronic Fatigue in tional impairment with fatigue Ehlers–Danlos Syndrome” by Alan Systematic attention on gastrointestinal having a slightly greater impact overall Hakim et al., this issue. involvement in hEDS started in 2004 [Voermans et al., 2010a]. with the study by Hakim and Grahame The fatigue in hEDS, as in the [2004], who found a wide range of Cardiovascular general population, is under recognized functional complaints in adults. The [Rombaut et al., 2015] and may increase Mild dilation of the aortic root may relevance of gastrointestinal manifesta- in prevalence with age [Castori et al., develop in up to one-third of children or tions in hEDS is increasing in both 2011a]. Like in the general population, young adults [Wenstrup et al., 2002; scientific and clinical perspectives. In fatigue in hEDS is multifactorial with McDonnell et al., 2006; Atzinger et al., fact, while the link between a congenital contributing factors including pain, 2011], but is unlikely to progress and laxity of the soft connective tissue and sleep disturbance, dysautonomia, med- typically does not require any specific gut diseases is still unclear as is the role of ications, and/or allergies. It has been treatment [Atzinger et al., 2011]. Base- comorbidities and concurrent medica- associated with greater pain, functional line echocardiography is not recom- tions, its better understanding will impairment, and psychological distress mended based on these findings alone certainly help better delineate patients’ as well as decreased QoL [Voermans but depend on other symptoms and complaints, which remain without spe- et al., 2010b; Ali Zekry et al., 2013; differential diagnoses upon presentation. cific management protocols. In a recent ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 55 review on this topic, a total of 42 works report highlighting a high prevalence of intussusceptions. Systematic data are were identified exploring the relation- speech, voice, and swallowing disorders available for abdominal hernias ship between hEDS or GJH with in a heterogeneous group of EDS [Harrison et al., 2016] and rectal gastrointestinal disorders [Castori et al., patients [Hunter et al., 1998]. Zarate prolapse [Manning et al., 2003] only, 2015a]. Among them, 12 were specifi- et al. [2010] provisionally identified while all other features are described in cally addressed for better defining the dysphagia in 14.3% of their JHS patients. single reports only and their relationship spectrum of gastrointestinal symptoms Constipation with or without other with hEDS remains to be further in syndromic patients [Manning et al., features of voiding dysfunction is usually scrutinized. Abdominal hernias occur 2003; Hakim and Grahame, 2004; the earliest sign of gastrointestinal in up to one-fifth of the patients; the Castori et al., 2010b, 2011a; Zarate involvement, which tends to manifest chance of occurrence increases with age, et al., 2010; Danese et al., 2011; with multiple, sometimes severely dis- and their surgical treatment seems Mastoroudes et al., 2013a; De Wandele abling symptoms at any age. Repeated effective under standard procedures et al., 2013, 2014a; Kovacic et al., 2014; evidence indicates that gastrointestinal [Harrison et al., 2016]. Rectal prolapse Fikree et al., 2015; Pacey et al., 2015b], involvement aggregate with other is observed in more than one tenth of and various clinical reports on single chronic symptoms and, then, is more women [Mastoroudes et al., 2013b]. It complications and/or surgical treatment commonly encountered in the complex can occur in nulliparous women but its in EDS [Douglas and Douglas, 1973; patient [De Wandele et al., 2013; Fikree rate is highest in those who underwent Defuentes et al., 2004; Sardeli et al., et al., 2015; Pacey et al., 2015b]. episiotomy but has been associated with 2005; Chen and Jao, 2007; Reinstein Standard investigations are usually car- JH and pelvic floor dysfunction et al., 2012; Dordoni et al., 2013; Fogel, ried out without severe complications [Lammers et al., 2012]. The rate of 2013; Plackett et al., 2014]. in hEDS, but they often have negative rectal prolapse in men and children with or inconsistent results. Functional tests, hEDS remains unknown, as such an including esophageal manometry, 24-hr association has been reported in single pH-metry, gastric emptying study, small case reports only [Douglas and Douglas, Systematic attention on bowel manometry, and colorectal transit 1973; Chen and Jao, 2007]. See also gastrointestinal involvement study, may lead to positive results “Gastrointestinal Involvement in the although these too are sometimes inter- Ehlers–Danlos Syndromes” by Fikree in hEDS started in 2004 with mittent [Zarate et al., 2010]. et al., this issue. the study by Hakim and More recently, rectal evacuatory disorder has been confirmed by ano- Grahame [2004], who found Dysautonomia rectal manometry in 60% of the cases a wide range of functional from a mixed population of 30 classical The first evidence for a tight link between complaints in adults. The EDS, hEDS, and vascular EDS patients hEDS and autonomic dysfunction was [Nelson et al., 2015]. Treatment of published by Rowe et al. [1999], who relevance of gastrointestinal functional GI complaints in hEDS is studied eleven pediatric patients (classical manifestations in hEDS is problematic due to the absence of EDS and hEDS) all showing either POTS tailored strategies and an apparent resis- or NMH. Four years later, Gazit et al. increasing in both scientific tance to pharmacologic treatments at [2003] found orthostatic hypotension, and clinical perspectives. standard dosages/regimens. The exclu- POTS, and uncategorized orthostatic sion of common comorbidities, such as intolerance in 21 out of 27 (78%) JHS celiac disease, lactose intolerance, and adults. More specifically, this study re- Based on these publications, gas- Helicobacter pylori infection, is reasonable vealed a greater drop in systolic blood trointestinal involvement in hEDS may at first examination. Preliminary results pressure during hyperventilation and a have functional and morphological suggest an increased rate of celiac disease greater increase in systolic blood pressure manifestations, although most papers [Danese et al., 2011; Laszkowska et al., after a cold pressor test in patients were focused on the former. Collec- 2016] and eosinophilic esophagitis compared to controls. The authors sug- tively, functional features may be ob- [Abonia et al., 2013] in hEDS, but gested the existence of alpha- and beta- served in 1/3 to 3/4 of the patients with additional studies are required to deter- adrenergic hyper-responsiveness in an increasing rate by age. Manifestations mine the significance of these potential hEDS. The concept was reinforced by variably include gastroesophageal reflux, associations. Hakim and Grahame [2004], who dem- heartburn, bloating, recurrent abdomi- Morphological findings with a onstrated, for the first time, a significant nal pain, irritable bowel syndrome, presumed higher rate in hEDS com- increase of the rate of systemic dysauto- constipation, and diarrhea [Maeland pared to the general population nomic symptoms in hEDS. et al., 2011]. Dysphagia may be a further may include abdominal hernias, rectal More recently, a study focused on common complaint in hEDS, but the prolapse, ptosis of internal organs, hEDS found an increase of the physio- literature is scanty except for an early diaphragmatic hernias, and intestinal logical heart rate variability, a greater 56 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE blood pressure fall during Valsalva and arthrochalasis types of EDS as well as that hEDS is associated osteoporosis or maneuver and a smaller initial systolic the classic-like EDS with propensity to fragility fractures, especially in children. blood pressure increase during tilt in a arterial rupture [Beighton et al., 1998]. Such persons should be evaluated for cohort of 39 hEDS women compared to See also “Ehlers–Danlos Syndomes: other underlying disorders as outlined in controls [De Wandele et al., 2014b]. Rare Types” by Malfait et al., this issue. the American Academy of Pediatrics This study also highlighted POTS as the Reports of reduced bone mass in the Guideline [Flaherty et al., 2014]. The most prevalent autonomic profile in more common EDS variants, mainly bone fragility disorder, osteogenesis im- hEDS and identified sympathetic neu- classical and hypermobile types, remains perfecta, as well as the EDS/osteogenesis rogenic dysfunction as the most likely controversial. imperfecta overlap (see EDS rare types, explanation for dysautonomia in this Coelho et al. [1994] described four this issue), have JH and may be mistaken condition, although connective tissue adults with classical EDS and bone for hEDS [Castori, 2015]. laxity and vasoactive medication may mineral density (BMD) values persistently The association between GJH and also play a role. below 1 standard deviation consistent BMD was further investigated in three Cardiovascular dysautonomia can with osteopenia. In this very limited additional studies. Reduced BMD by easily explain orthostatic intolerance, series, they found that bone mass appears ultrasound and lower excretion of palpitations, tachycardia, and atypical reduced in EDS, predominantly affecting urinary hydroxylysylpyridinoline cross- chest pain, as well as a series of trabecular bone, but the degree of links and lysylpyridinoline cross-links neurological secondary manifestations, involvement is less marked than other were demonstrated in 15 children with including fatigue, dizziness, fainting, HCTDs. In the same year, Deodhar and “symptomatic” GJH compared to 95 syncope, memory, and concentration Woolf [1994] reported EDS as a diagnosis healthy prepubertal children [Engelbert troubles. A primary sudomotor involve- among seven adults referred for low bone et al., 2003]. By contrast, another study ment was recently demonstrated in density (one with classical EDS and the suggests that a high Beighton score may hEDS with a significant reduction of others with less defined phenotypes be a marker of fitness, reduced rate of sweat volume production [De Wandele which may have included hEDS). Simi- knee osteoarthritis and increased (rather et al., 2014b]; a finding than can explain larly, reduced bone mass was also demon- than reduced) hip BMD in postmeno- dry skin and mucosa. A possible wider strated at the calcaneum by ultrasound pausal women [Dolan et al., 2003]. A involvement of the autonomic nervous and previous fractures were 10 times more third study showed reduced BMD (mild system could contribute to other rela- common in EDS than general population osteopenia) in 23 premenopausal hyper- tively common features of hEDS that (86.9% vs. 8.7%) [Dolan et al., 1998]. In mobile women compared to controls by affect the gastrointestinal and urinary this work, the cause of reduced bone mass DXA at some sites but not others systems, such as gut dysmotility and in EDS was considered multifactorial [Gulbahar et al., 2006]. underactive/overactive bladder. The with a possible contribution of reduced As expected from the early litera- link between abdominal symptoms and mobility and proprioceptive defect. ture and the nosologic confusion among dysautonomia, possibly via an increased However, Carbone et al. [2000] did not EDS, GJH, and JHS, the published data visceral sensitization, still needs addi- confirm this finding in 23 hEDS adults. may be hard to apply to “pure” hEDS tional research [Farmer et al., 2014]. The authors also noted that the femoral and, then, translated in clinical practice. Dysautonomia could be also a patho- neck BMD was significantly reduced as In the above-mentioned studies, it is genic contributor to selected psycho- compared to controls but once age, unclear if hEDS is associated with logical traits of hEDS, as recently weight and activity-level were corrected osteoporosis in adults, especially pre- proposed [Eccles et al., 2015]. General for, the difference became not significant. menopausal women. An increase in assessment strategy and treatment of More recently, Mazziotti et al. fractures or risk of bone fragility POTS are available in Mathias et al. [2016] found no significant difference in fractures was not well-established. There [2011]. Minor adaptations specifically BMD among 52 EDS patients (37 hEDS). is no evidence at present to suggest that addressed for hEDS were also published However, a urrogate radiographic marker children or infants have a lower bone [Castori et al., 2012a]. See also “Guide- for vertebral fracture was more prevalent mass in hEDS nor that they are predis- lines on the Assessment and Manage- in the EDS group as compared to posed to fragility fractures. ment of Cardiovascular Dysregulation in controls. If the fractures are true (patients Ehlers–Danlos Syndrome” by Hakim only report chronic low back pain) then Osteoarthritis et al., this issue; as well as “Gastrointes- this observation is not likely due to tinal Involvement in the Ehlers–Danlos reduced BMD but mechanical stress of Osteoarthritis (OA) has been postulated Syndromes” by Fikree et al., this issue. the hypermobile spine. Critics of the as a long-term consequence of JH [Scott above-mentioned studies have speculated et al., 1979]. It is possible that an increase that those patients with EDS were often in the prevalence of OA is due to the Bone Mass less active and this should be taken into same underlying collagenopathy or by Osteoporosis and osteopenia are consid- account in comparing bone density. repetitive trauma that commonly ered features of the rare kyphoscoliotic Overall, there is no convincing evidence occurs in JH and altered joint mechanics ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 57

[Bird et al., 1978; Grahame, 1989; upper body can cause widespread show a significant association of GJH Klemp, 1997]. Knee hypermobility is spasms and muscular tension leading and TMD. common among patients with knee OA to headaches as well. Temporal head- In a recent national study in Finland [Dolan et al., 2003; van der Esch et al., aches, unilateral or bilateral, may again involving 6227 participants, TMJ pain 2006; Gurer€ et al., 2016]. In a study of 34 be related to muscular dysfunction but was often associated with palpable pain patients with severe thumb (carpome- involving the temporomandibular of the neck and shoulder musculature, tacarpal) OA, 62% had generalized JH joint. Such headaches can be associated widespread pain, chronic illness, and [Jonsson and Valtysdottir, 1995]. In a also with ear symptoms such as pain, female gender [Sipil€a et al., 2011]. Given small series of 24 EDS patients with a sense of fullness, or tinnitus. Those that those with hEDS often have most if mean age of 16 years, 16% already had patients with dysautonomia, ortho- not all of the additional variables, it radiographic evidence of trapezial- static intolerance, or POTS can also would suggest that TMD in this popu- metacarpal OA [Gamble et al., 1989]. complain of intense pounding head- lation is complex, common, and must In that same study, 66% had evidence of aches. Medications and medication- use a more holistic approach to treat. subluxation and 29% with dislocation. overuse can also be responsible for The oral mucosa in hEDS is often This association adds evidence that joint headaches in this population. As in the friable and easily injured giving rise to hypermobility and presumably altered general population, individual patients episodes of painless bleeding [Hagberg joint biomechanics may increase the often suffer from more than one type of et al., 2004; Berglund and Bjorck,€ 2012]. susceptibility of such joints to OA [Wolf, headache, making both the etiology of The lingual or labial frenulum may be 2009]. the headache and the intervention less hypoplastic or altogether absent [Machet certain. et al., 2010]. Periodontitis may also be common. However, periodontal disease Headaches with early-onset and widespread tooth Temporomandibular Joint and Much like headaches in the general loss is thought to represent another form Dental Issues population, headaches in hEDS vary by of EDS, the periodontal type [Rahman type and severity [Jacome, 1999; Murray Several studies have linked temporo- et al., 2003], that has been recently et al., 2013; Neilson and Martin, 2014; mandibular joint (TMJ) hypermobility associated with defects in complement Castori et al., 2015c]. Headache itself to temporomandibular joint dysfunction type 1 [Kapferer-Seebacher et al., 2016] has been show to occur in a larger (TMD), including in children [Adair (see also “Ehlers–Danlos Syndromes: portion of EDS patients (multiple types and Hecht, 1993]. Nosouhian et al. Rarer Types” by Malfait et al., this issue). of EDS) as compared to historical [2015] characterized 69 patients with Many patients report being less respon- controls [Sacheti et al., 1997]. It is a TMJ hypermobility and found that a sive to local anesthetics during dental frequent complaint among those having maximal mouth opening (MMO) of procedures [Arendt-Nielsen et al., 1990; hEDS as well [Jacome, 1999; Maeland <55 or >65 mm, was associated with Hakim et al., 2005]. A Swedish study et al., 2011; Murray et al., 2013; more TMJ discomfort than an interme- utilizing a self-reported oral health Hamonet et al., 2015]. More specifically, diate degree of MMO. TMJ hypermo- questionnaire showed that mucosal prob- migraines were seen at a greater bility was more common in women than lems in different areas of the body were frequency and disability compared to men, and increased MMO was also reported by 206/223 (92%) women, and a control population [Hakim and correlated with more TMJ sounds that 75% of respondents with hypermo- Grahame, 2004; Bendik et al., 2011; (“clicks” or “pops”) and more pain in bility type self-reported problems with Puledda et al., 2015]. the masticatory muscles. The jaw in their oral mucosa [Berglund and Bjorck,€ Rozen et al. [2006] described new hEDS is often also hypermobile until 2012]. daily persistent headaches in a series of such time that damage occurs in the The teeth in hEDS are described 12 patients of which 11 demonstrated TMJ, which will further limit MMO. with slightly altered morphology with cervical spine hypermobility. Further Jaw sounds, locking, dislocation, brux- higher cusps and deeper fissures of the work revealed that 10 of the 11 with ism, and temporal headaches are also premolars and molars with shortened cervical spine hypermobility showed frequently described in this population. roots. Enamel hypoplasia has also been GJH. Headache due to CSF leak has Indeed, Murray et al. [2013] found that a described as well as tooth fracture been demonstrated in a few case reports significant portion of 466 adults with (unclear if fracture intrinsic to the tooth and affects a very small minority of hEDS self-reported TMD as a major or due to bruxism or similar mechanical hEDS patients but can cause significant issue. pressures) [De Coster et al., 2005]. With disability [Reinstein et al., 2013]. Cra- Westling [1992] studied 360 pa- the use of orthodontia, it is a common niocervical junction instability is tients with TMD. Among that group, a anecdotal experience that the teeth will thought to be linked to cervicogenic subset analysis of 74 females with GJH migrate faster than expected and, un- and Chiari-like headaches [Milhorat were compared to 73 age and gender fortunately, migrate back toward their et al., 2007]. This instability or simply matched controls. Using stepwise re- pre-treatment location after the removal the musculature strain throughout the gression analysis, the study was able to of the orthodontic appliance. See also 58 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

“Oral and Mandibular Manifestations in are not likely attributable to dysfunction have not controlled for childbirth Ehlers–Danlos Syndrome” by Mitakides at the craniocervical junction. See history or age and included patients and Tinkle, this issue. also “Neurologic Manifestations in affected by various types of EDS. the Ehlers–Danlos Syndrome” by Castori et al. [2012c] found that Henderson et al., this issue. POP represented a common late-onset Spine Similarly, laxity of the lumbar spine complication in women with hEDS. Postural kyphosis is commonly encoun- increases movement and decreases sta- Interestingly, most (90.9%) prolapses tered in those with hEDS [el-Shahaly bility. Kim et al. [2013] showed that occurred in women with positive and el-Sherif, 1991]. This is thought to young males with GJH had excessive history for episiotomy. The reason(s) as be primarily due to loose ligamentous lumbar segmental motion which was to why episiotomy associates with POP structure and poor postural ergonomics. associated with increased low back pain, in hEDS is unknown. Scoliosis is also common occurring in disability, and limited physical activity. The largest prospective case- up to half of all patients [Ainsworth and Lumbar hypermobility is also an under- control study to date to address these Aulicino, 1993; Stanitski et al., 2000; lying risk factor for degenerative disc issues was published in 2013 and Adib et al., 2005; Czaprowski, 2014; disease [Nef and Gerber, 1998] and facet involved 120 women [Mastoroudes Stern et al., 2016]. The scoliosis is fractures [Mazziotti et al., 2016]. et al., 2013a,b]. Sixty women diagnosed acquired, often mild as well as flexible with JHS, according to the Brighton and may continue to progress beyond criteria, were recruited from a tertiary Gynecologic Issues the adolescent period but most do not referral hypermobility clinic. Controls require intervention. Gynecologic complaints from patients were recruited from hospital personnel. The spine is a series of joints, the with hEDS are commonly encountered. All women in the study group were most mobile of which involves the In a study with 223 women with EDS, matched with healthy control women craniocervical junction. Multiple con- 67% self-reported mucosal problems according to age, parity and ethnicity. nective tissue disorders have been re- with their genital area [Berglund and Both groups completed specific health ported to have craniovertebral instability Bjorck,€ 2012]. Heavy menstrual bleed- and QoL questionnaires. Objective including Marfan [Herzka et al., 2000], ing (menorrhagia) was reported by assessment of POP was undertaken. Loeys-Dietz [Rodrigues et al., 2009], 26–76% of hEDS females [Ainsworth The prevalence of UI in those with and EDS [Milhorat et al., 2007]. Cervi- and Aulicino, 1993; Hugon-Rodin hEDS were significantly higher than in cal hypermobility has been associated et al., 2016]. Painful intercourse was controls (73.3% vs. 48.3%) as was with headaches and hEDS [Rozen et al., also reported by 30–57% of women with voiding difficulties. The impact of UI 2006]. In a large series of patients EDS and hEDS [McIntosh et al., 1995; on QoL was also statistically significant. presenting with signs of Chiari type I Castori et al., 2010a; Hugon-Rodin Objective findings of prolapse of the (neck pain, gait disturbance, numbness et al., 2016]. anterior vaginal wall were more severe and tingling of the hands and feet, than in controls. dizziness, dysphagia, and speech diffi- However, another recent study Pelvic Dysfunction culties), Milhorat et al. [2007] described [Derpapas et al., 2015] reported a lack nearly 13% had features consistent with Pelvic floor disorders include urinary of strong association of JH with UI or hEDS. Compared to the other patients incontinence (UI), pelvic organ pro- POP. The study involved 270 women with Chiari-like symptoms, the patients lapse (POP), and other sensory and scheduled to undergo urodynamic with hEDS were more likely to have a emptying abnormalities. Childbirth has investigations. JH was not assessed reduction of the basion-dens interval, a very substantial impact on a woman’s clinically but was based on the self- clival-axial angle, clival-atlas angle, and probability of developing pelvic floor completed five-part JH questionnaire. the atlas-axial angle as well as an disorders. It has been reported that Women underwent a full gynecologi- enlargement of the basion-dens inter- about a third of women have UI after cal history and examination. The val—all of which are concerning for childbirth [Hallock and Handa, 2016]. prevalence of reported JH in this excessive laxity or instability. There was In addition to parity, a positive family study was 31.1%; however, the re- also an increase in retro-odontoid history of prolapse increases a woman’s searchers did not find a strong pannus formation, a pathophysiologic risk of prolapse, even among nulliparous association between JH and any UI process thought to represent abnormal women [Buchsbaum et al., 2006; subtype. They reported a trend to- stress of the transverse ligament. A Buchsbaum and Duecy, 2008]. ward higher prolapse staging in portion of these patients did not have Several case-control studies in the women with JH, which becomes radiologic findings of Chiari and were past suggested that hEDS is associated significant only after adjustment for labeled as Chiari Type 0, a controversial with pelvic floor disorders [Al-Rawi and the confounding negative association label. Moreover, the Chiari-like symp- Al-Rawi, 1982; Norton et al., 1995; between age and JH. toms of headache and dysautonomia are McIntosh et al., 1996; Aydeniz et al., As childbirth has a very substantial common in hEDS and the vast majority 2010]. However, most of these studies impact on a woman’s probability of ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 59 developing pelvic floor disorders, such comparable with those in the Cauca- phenomenon occurs in women with as UI and POP, pregnancy remains a sian population. hEDS, which may lead to increased joint source of anxiety to patients and their EDS-related symptom evolution instability later in pregnancy. doctors. during pregnancy seemed unpredictable A large study was conducted to as 40% of patients reported worsening investigate the association between JH, symptoms (especially gastrointestinal obstetrical outcomes, and pelvic floor Pregnancy and Childbirth complaints, asthenia, and pain), 13% of disorders [Knoepp et al., 2013]. It Several pregnancy-related complica- patients improved, and the symptoms involved 587 parous women (partici- tions have been more commonly re- were unchanged in the remaining 47%. pants in a longitudinal cohort study of ported in women with hEDS in some Preterm delivery due to premature pelvic floor disorders after childbirth). studies but as often, not substantiated in rupture of the membrane was reported Their obstetrical histories were obtained others. In an online survey of EDS in 10% pregnancies, which is not from review of hospital records. Pelvic patients (N ¼ 497), self-reported infer- different from the general population, floor disorders were assessed using tility was more commonly encountered and none of which led to major validated questionnaires and a structured in women with hEDS [Hurst et al., complications. Rapid labor occurred examination for prolapse. JH and pelvic 2014] although this was not reproduced in more than 1/3 of the cases. floor disorders were evaluated at enroll- by others [Castori et al., 2012b; Hugon- ment (5–10 years after first delivery). Rodin et al., 2016; Sundelin et al., The main weakness of this study was the 2017]. Premature birth has been re- inclusion criteria. The researchers de- ported as more common among patients EDS-related symptom fined JH as Beighton score 4 and did with EDS than in the general popula- not use the Brighton or Villefranche tion, but this appears to be primarily evolution during pregnancy criteria. They compared obstetrical among women with classic EDS; it is seemed unpredictable as 40% outcomes and pelvic floor disorders unclear if there is an increased risk for of patients reported worsening between women with and without JH. preterm birth specifically in the hEDS JH was diagnosed in 46 women (7.8%) population as the few studies are con- symptoms (especially and was associated with decreased odds flicting [Sorokin et al., 1994; Lind and gastrointestinal complaints, of caesarean after complete cervical Wallenburg, 2002; Castori et al., 2012b; dilation or operative vaginal delivery. Hurst et al., 2014]. Some works report asthenia, and pain), 13% of In this study, anal sphincter laceration that miscarriage is increased in hEDS patients improved, and the was less likely to occur in women with [Ainsworth and Aulicino, 1993; Hurst JH and was not associated with any et al., 2014; Hugon-Rodin et al., symptoms were unchanged in pelvic floor disorder. Although this 2016] but not in other studies [Sundelin the remaining 47%. study did not address the issues related et al., 2017]. to hEDS specifically, the results are quite In a comprehensive study, Castori reassuring for women with asymptom- et al. [2012c] collected a set of The risk of intra- and post-partum atic hypermobility as JH seem to gynecological and obstetric features in hemorrhages was 1/5 irrespective to the facilitate spontaneous vaginal birth but 82 women with hEDS attending two delivery modality. They reported a high does not appear to be a risk factor for Italian centers. All patients were origi- rate of abnormal scar formation in both pelvic floor disorders in the first decade nally assessed by physical examination Caesarean and vaginal delivery with after childbirth. and questionnaire administration fo- episiotomy. In all cases, hemorrhages cused on collecting information about were always successfully managed with- Urinary System selected aspects of their gynecological out life-threatening complications and and obstetric history. Only post- no internal organ/vascular accidents De Kort et al. [2003] evaluated 89 pubertal women meeting diagnostic were registered after Caesarean. It was families of children with GJH. The criteria for the hypermobility type of reassuring that all delivery options children with GJH showed an increase EDS or JHS were included. Other showed a very limited number of local in daytime and nighttime urinary in- HCTDs were excluded clinically. The and systemic short-term complications. continence as well as urinary tract study did not include gynecological In this sample, the group did not find infections (UTIs). Voiding dysfunction examination. A total of 93 pregnancies any life-threatening complication re- was also significantly associated with were registered among the 82 women lated to local and general anesthesia. GJH in children but this is unclear if this with at least one pregnancy. In this It has long been recognized that is secondary to constipation [Kajbafza- study, fertility was overall preserved, as joint laxity increases over the course of deh et al., 2014]. Adib et al. [2005] were mean age at menarche and pregnancy, allowing the bony pelvis to evaluated 125 children with a diagnosis menopause, rate of pregnancy/woman adapt to accommodate vaginal birth of hEDS and catalogued their multisys- and of spontaneous abortion that were [Calguneri et al., 1982]. The same tem disorders. UTIs and urinary tract 60 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE dysfunction were more common in girls Mast Cell Activation Disorder gastrointestinal and autonomic). This than controls. Vesicouretal reflux was can lead to avoidance behavior, ex- Mast cell activation syndrome (MCAS) also more common in children with acerbation of dysfunction and disabil- refers to an increased number of mast hEDS as compared to the control ity, and marginalization. Resentment, cells, increased mast cell mediators population [Beiraghdar et al., 2013]. distrust, and hostility between the (e.g., histamine, tryptase, etc.), or patient, family, and healthcare team both. The clinical symptoms of may develop. To be ignored, being Sleep Disturbance MCAS include flushing, pruritis, hy- assigned a psychological and/or psy- potension, asthma, diarrhea, abdominal Sleep is a restorative process for the chiatric explanation, not being re- bloating, and cramping. The diagnosis body. During the deeper stages of non- spected and treated as an object could of MCAS is increasingly recognized in rapid eye movement sleep, the body have consequences such as mistrusting the general population [Afrin et al., regenerates tissue, builds bone and health-care and create difficulties in 2016] and is likely among those with muscle, and positively affects the im- encounters with care [Berglund et al., hEDS as well. It remains unclear if mune system. Sleep deprivation is 2010]. Equally, to ignore or avoid MCAS is more common in hEDS or considered unhealthy leading to fatigue, confronting the presence of significant perhaps represents a phenocopy of a decrease immune response, poor comorbid psychological problems can hEDS (with similar joint laxity and muscle coordination, susceptibility to lead to suboptimal treatment. See multi-system involvement). Those injury, impaired cognition and memory, “Psychiatric and Psychological Aspects with EDS report a higher incidence increased pain, moodiness, and depres- in the Ehlers–Danlos Syndromes” by of food sensitivities suggestive of hista- sion [Owens, 2014]. Insomnia can be Bulbena et al., this issue. mine reaction [Berglund, 2015]. Re- reported as delayed sleep (sleep-onset) gardless of any possible association, the or due to sleep fragmentation (sleep- presence of MCAS in hEDS might Quality of Life maintenance). Sleep deprivation due to complicate the known symptoms of sleep maintenance insomnia has been In a national cohort of 134 patients, POTS, chronic fatigue, and gastroin- related to impairment of the endoge- functional gastrointestinal disorders testinal manifestations. Elevated serum nous pain inhibitory function and correlated with a poorer QoL in EDS tryptase, a marker of MCAS, followed a therefore increases spontaneous pain patients [Zeitoun et al., 2013]. When dominant inheritance pattern that and pain amplification [Smith et al., comparing SF-36 scores as a measure of overlapped with a “hypermobile con- 2007]. QoL in EDS in a Swedish population nective tissue phenotype” in eight of Many patients with hEDS report study, the EDS group reported signifi- nine studied families [Lyons et al., poor sleep including insomnia and cantly lower scores [Berglund et al., 2014]. Subsequent evaluation of 35 unrefreshing sleep [Verbraecken et al., 2015]. Also, probable anxiety on the families with elevated serum tryptase 2001; Hakim and Grahame, 2004; Hospital Anxiety and Depression Scale showed this phenotype to be due to Murray et al., 2013]. In a study of 115 was rated as 74.8% and probable increased copy number of the alpha- patients with hEDS, Albayrak et al. depression was rated as 22.4%. Physical tryptase gene, TPSAB1 [Lyons et al., [2015] found a significant decrease in pain, psychological discomfort, and 2016]. See also “Mast Cell Activation sleep quality as compared to controls. handicap has considerable impact on Syndrome in Ehlers–Danlos Syn- Comorbid conditions such as restless health-related QoL in EDS. Adults drome” by Seneviratne et al., this issue. legs syndrome and sleep apnea have been with hEDS reporting neck and shoul- described in small series of patients with der pain had a significant association hEDS [Guilleminault et al., 2013]. Psychiatric with generalized pain and a decreased However, of the 34 patients with EDS, health-related QoL [Johannessen et al., only one was described as having hEDS Psychological dysfunction and emo- 2016]. Children with hEDS and fa- but details on the diagnostic criteria tional problems, including depression, tigue experienced poor health-related were not described. Fibromyalgia is also anxiety, affective disorder, low self- QoL [Pacey et al., 2015b]. In 38 hEDS a common comorbidity [Ofluoglu et al., confidence, negative thinking, hope- patients, baseline QoL was significantly 2006; Ting et al., 2012] and is strongly lessness, and desperation, are also reduced and worsened with experien- associated with sleep disturbance, in- common among those with EDS ces in physical therapy and iatrogenic cluding abnormal sleep architecture [Hagberg et al., 2004; Castori et al., injury [Bovet et al., 2016]. A recent [Dauvilliers and Touchon, 2001; 2010b; Baeza-Velasco et al., 2011; meta-analysis revealed significant dis- Besteiro Gonzalez et al., 2011]. Many Branson et al., 2011; Rombaut et al., ability related to pain, fatigue, and other factors may also interfere with 2011a; Berglund et al., 2015; Sinibaldi psychological distress in hEDS sleep in this population including et al., 2015; Hershenfeld et al., 2016]. [Scheper et al., 2016b]. These results pain, dysautonomia, poor sleep hygiene, These problems may exacerbate the indicate a lower quality of health in and medications [Voermans et al., pain experience, as well as other those with EDS than in the general 2010b]. organ system manifestations (especially population. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 61

MANAGEMENT fatigue), as well as primary non-opioid oral analgesics should be maximized first, including both acet- Assessment of a person with or sus- and secondary prevention of aminophen and either a non-steroidal pected of having hEDS is based on acute and chronic anti-inflammatory (NSAID) or cyclo- symptoms. Musculoskeletal symptoms oxygenase-2 (COX2) inhibitor. should be approached conservatively. complications. NSAIDs may be helpful after episodes Physical therapy, education, and pacing of dislocation or subluxation or as an are paramount [Simmonds and Keer, addition during flares of pain. Topical 2007]. “The Evidence-Based Rationale Pain agents such as lidocaine, NSAIDs and/ for Physical Therapy Treatment of Primary prophylaxis and treatment of or custom compounded creams can also Children, Adolescents and Adults Diag- nociceptive pain relies upon physical be helpful. Where allowed by law, nosed with Joint Hypermobility Syn- approaches to improve joint stability and cannabinoids can be considered, but drome/Hypermobile Ehlers Danlos prevent or reduce myofascial spasm. the treatment effect must be measured Syndrome” by Engelbert et al., this Although there is only limited evidence, against potential long-term consequen- issue. Frank joint instability should be avoidance of joint hyperextension may ces [Mandelbaum and de la Monte, evaluated by orthopedics or other well- not be necessary [Pacey et al., 2013]. 2017]. Muscle relaxants may help to qualified personnel. Symptoms of or- High impact and resistance exercise reduce myofascial spasm and nociceptive thostatic intolerance, tachycardia with should be minimized, but regimens pain [Abdel Shaheed et al., 2017; Chou palpitations, and/or near-syncope need to be individualized and this is et al., 2016]. Benzodiazepines can be should be also treated conservatively not a strict contraindication. Myofascial considered for cautious short-term by fluid and salt intake along with release, stretching, and other mechanical muscle relaxation, but are poor choices education and the appropriate exercise. techniques to reduce spasm can provide for long-term use due to loss of muscle- Syncope should be evaluated further by up to 24 hr of pain reduction. Joint relaxing effect over time, in addition to specialists such as neurology or cardiol- stabilization is best achieved by working problems with tolerance, dependency, ogy for concerns of arrhythmia, seizure on muscle tone (the resting state of and sometimes addiction. Neuropathic disorder, cardiomyopathy, and so on. muscle contraction) and propriocep- pain often requires one or more of The management of hEDS includes tion, with only gentle attention to a tricyclic antidepressant, serotonin- treatment of acute/emergency manifes- strength (voluntary force exerted at norepinephrine reuptake inhibitor, tations (e.g., dislocations), attenuation of will) [Simmonds and Keer, 2007; and/or an anti-epileptic drug. Topical chronic symptoms (e.g., pain and fa- Palmer et al., 2014]. Exercises should lidocaine and capsaicin may also provide tigue), as well as primary and secondary be low resistance, with very gradual some benefit. Opioids are rarely needed prevention of acute and chronic com- increase in repetitions but not resistance. for the treatment of chronic musculo- plications. Acute complications are Water-based exercise is often a good skeletal pain [NGC, 2013] and are no usually managed far away from the choice for some individuals because higher than third line agents for neuro- reference center and treatment follows water reduces effective body weight pathic pain [Finnerup et al., 2015]. guidelines and procedures applied in the and protects against impact. Exercise Opioids and tramadol are best reserved general population. As many patients regimens are often initiated with formal for acute pain episodes or for patients with hEDS have multiple symptoms, a physical therapy, but once learned by the whose pain is inadequately managed on coordinated effort is required as other patient, can and should be continued all of the above medications, require specialists (if needed) are incorporated indefinitely, independent of formal in- close monitoring, and should be added into the medical team. The approach struction or supervision. It is important on to the above regimen in the lowest should be holistic focusing on the to understand that physical therapy possible doses rather than replacing the complications, the desire(s) of the should be done by experienced and above medications. There are particular patient, QoL and functionality, as well learned professionals as many patients concerns regarding the risks of co- as the psychological aspects. commonly report increased pain and prescribing opioids and benzodiazepines decreased QoL with improper exercise [Babalonis and Walsh, 2015]. Recent regimens [Bovet et al., 2016]. It often guidance by the Centers for Disease takes several months of routine toning Control recommends that providers The management of hEDS exercise to halt progressive deterioration should prescribe opioids only when includes treatment of acute/ in pain, and it may be several years benefits outweigh expected risks and before substantial reduction in pain is that they should avoid prescribing emergency manifestations recognized. opioids and benzodiazepines concur- (e.g., dislocations), Scheduled use of multiple medica- rently whenever possible [Dowell et al., attenuation of chronic tions together is often more effective 2016]. than as-needed use of one or There is theoretical risk and anec- symptoms (e.g., pain and two medications at a time. Systemic dotal description that muscle relaxant 62 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE medications and/or too much stretching questionnaires should be used for diag- delay in wound closure and tissue repair. can exacerbate joint instability and nosis and ongoing monitoring. Fatigue, Hence, surgical procedures should be ultimately increase nociceptive pain, much like pain, often responds to carried out with gentle dissection and but many patients tolerate these modal- treatment such as exercise therapy but use of mild lateral force during incisions, ities well and treatment should be only very slowly over time [Edmonds retraction and suturing. Skin closure tailored to each individual’s response. et al., 2004]. See “Chronic Fatigue in should be performed in two layers with NSAIDs and COX2 inhibitors may Ehlers–Danlos Syndromes” by Hakim minimal tension, sufficient amount of exacerbate gastritis, bleeding and/or et al., this issue. sutures, deep stitches, and the support of bruising, but are often well-tolerated. steri-strips, by using proper distance to Chronic high dose NSAID therapy may the incision in order to avoid sutures Orthostatic Intolerance also increase the risk of coronary artery cutting through the fragile tissue, and disease and renal insufficiency; this risk Non-pharmacologic management in- without the use of skin clips. Finally, needs to be weighed against the severity cludes avoidance of rapid orthostatic sutures should be left twice as long as of the patient’s pain and the patient change or prolonged upright posture, normally recommended in order to should be encouraged to make his or her lower extremity compression garments, avoid wound re-opening [Burcharth own choice about these risk and and supplementation of water and and Rosenberg, 2012]. benefits. Many of the above pain electrolytes to maximize blood volume. Anesthesia and perioperative man- medications increase serotonin levels, Routine low resistance exercise in- agement may also deserve special care in so patients should be monitored for signs creases both skeletal muscle and vascular hEDS. This is mostly influenced by some and symptoms of serotonin syndrome. tone, improving venous return to the primary disease features, including mu- Many patients with hEDS may heart. Beta adrenergic blockade often cosal fragility, propensity to ecchymosis, develop chronic generalized pain which improves symptoms, perhaps by slowing and the risk of hemorrhage (that are, becomes their primary problem. This the heart rate or perhaps by reducing however, usually limited in hEDS), the type of presentation should be consid- autonomic sympathetic activity. Beta risk of orthostatic headache due to spinal ered as a centralized pain state belonging blockade is not strictly contraindicated anesthesia, but also by several common to the spectrum of chronic widespread in patients with low resting blood comorbidities, such as autonomic dys- pain, with additional superimposed pressure, but does require close moni- function, occipitoatlantoaxial joint insta- musculoskeletal components. Some pa- toring in such patients. Some additional bility, and spondylosis. A freely tients who continue to struggle to cope medication options include midodrine, downloadable summary of recommen- with their pain may need consideration fludrocortisone, and pyridostigmine dations concerning pre-surgical evalua- of a multidisciplinary pain management [Mathias et al., 2011]. See also “Auto- tion, patient monitoring and positioning, program [Bathen et al., 2013]. nomic Dysregulation in Ehlers–Danlos airway management, circulatory and The overall goal should be to Syndromes,” by Hakim et al., this issue. bleeding issues, pharmacology, use of maintain adequate control of pain to a tourniquets, central venous catheteriza- tolerable level, not to completely elimi- tion, obstetrical, regional and local Neuropsychiatric nate pain. Such expectation manage- anesthesia, and other aspects, is available ment can help to reduce the overall Management starts with validation of at the OrphanAnesthesia website subjective pain experience, even when the patient’s symptoms and efforts to (http://www.orphananesthesia.eu/en/ objective somatic pain cannot be establish rapport and trust with the rare-diseases/published-guidelines/cat_ completely controlled. See “Pain Man- patient. Psychological counseling view/61-rare-diseases/60-published-gui agement in Ehlers–Danlos Syndrome” should focus on accepting and coping delines/89-ehlers-danlos-syndrome. by Chopra et al., this issue. with chronic pain and chronic disease. html) or in the work by Wiesmann et al. Cognitive behavioral therapy is particu- [2014]. In both works, recommendations lar beneficial, if the patient is willing to are offered for EDS in general, therefore, Fatigue actively engage in the process [Bathen specific considerations for hEDS should Both mental and physical fatigue are as et al., 2013]. Distraction, hypnosis, and be carefully extracted by the reader. commonly encountered as pain in judicious use of anti-depressant medica- hEDS [Castori et al., 2011b]. It is tion can also help. FUTURE DIRECTIONS often multifactorial. Stimulant medica- tions are often effective for very short hEDS is a common clinical entity that Surgery and Anesthesia periods of time. However, the various affects many disciplines of healthcare. contributors of fatigue should be con- In hEDS, surgical risks are generally The precise description both in the sidered such as anemia, nutritional lower that other EDS variants due to the diagnostic criteria as well as the natural deficiencies, deconditioning, medica- only minor fragility of skin, vessels, and history of hEDS need a great deal of tions, sleep disturbance, dysautonomia, internal organs. The greatest surgery further refinement. Management of this and/or psychological aspects. Screening related issue of hEDS is the possibility of disorder has drawn many parallels to ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 63 other disorders as few large-scale studies separation of these sub-groups, efforts However, many questions remain in- have been performed in this patient to define this group under a diagnosis of cluding validation of physical therapy in population. The areas of future interest hEDS may complicate studies on an the treatment of EDS. See “The Evi- represent a limited partial set but those of exomic or genomic basis. Last, as several dence-Based Rationale for Physical higher priority. factors play into the phenotype presen- Therapy Treatment of Children, Ado- tation such as gender, training, pain lescents and Adults Diagnosed with threshold, etc. multiple genetic and Joint Hypermobility Syndrome/Hyper- hEDS Diagnostic Criteria non-genetic factors may be contribut- mobile Ehlers–Danlos Syndrome” by The new nosology will have to be ing. It is obvious that there needs to be a Engelbert et al., this issue. applied to all populations and be deter- broader recognition and recording of mined where deficiencies and gaps lie the features of hEDS (such as in a Craniocervical Junction within the criteria. This includes the database registry) so that phenotypic evaluation of and validation of the patterns may emerge that can help the As the cervical spine, and most especially modified Beighton scoring system. design and interpretation in the pursuit the craniocervical junction, comprise a Formulation of such questions and of the genetic etiology(ies). joint(s), it is also believed to be addressing these concerns will need to susceptible to the same strain and be an ongoing mission. injuries as seen in other joints in EDS. Dysautonomia As joint hypermobility is common As these joints protect the central in many disorders and may be the The presence of orthostatic intolerance nervous system, it is plausible that presenting sign, differentiating hEDS and POTS or NMH in the hEDS neurologic symptoms might also occur. from other HDCTs, especially those population needs further and large-scale Which symptoms, the proper imaging with vascular involvement, is important. validation. A full descriptive inventory (and measurements) as well as manage- As hEDS is a clinical diagnosis, refine- of all of the dysautonomic symptoms ment are not well-established. Although ment of the diagnostic criteria is even also is in need. The link between upright MRI reproduces a more physi- more important as is the search for a abdominal symptoms and dysautono- ologic strain on the craniocervical genetic cause. In a systematic approach mia, possibly via an increased visceral junction, its routine use has not been to pursuing a molecular diagnosis, sensitization, still needs additional vali- recommended [Health Quality Ontario, Weerakkody et al. [2016] found 28 dation [Farmer et al., 2014]. 2015]. Further studies about the preva- patients with pathogenic variants in- lence as well as the symptoms, imaging, cluding one with suspected hEDS and management are needed. Bone Density emphasizing the need for a systemic diagnostic approach to EDS that will Due to a few small case reports and series, Mast Cell Activation Syndrome need to be further refined. there is some concern for possible loss of bone density with hEDS. This has been MCAS can complicate management of popularized through social media and in dysautonomia and may contribute to Molecular Basis the courts as a defense against charges of fatigue and decreased QoL. Further hEDS remains the sole EDS major type child abuse in the case of an infant with studies of MCAS in the hEDS popula- without a known molecular defect. multiple fractures of unknown etiology. tion are needed to detail the possible Such a lack of knowledge is likely due There is no credible studies demonstrat- comorbidity and its impact on disease to various complexities. First, although ing bone fragility fractures in hEDS. manifestation and management. hEDS is inherited as a dominant trait, Subsequently, hEDS is not considered that is, sex-influenced, this inheritance one of the bone fragility syndromes and SUMMARY model may not explain all cases. Locus the diagnosis of hEDS is far too subjective heterogeneity is very likely which may to rely on in these situations. Those hEDS is a heritable connective tissue explain some of the cases with apparent infants with features of a connective disorder without a clear etiology. It is different inheritance patterns. Second, tissue disorder and multiple unexplained common, representing up to 1–3% of the current diagnostic criteria are gen- fractures, should be considered for the general population. It is multi- erally broad to cover what is suspected to genetic testing [Byers et al., 2006; systemic with primary musculoskeletal be various phenotypic sub-groups. Flaherty et al., 2014]. Larger and well- manifestations but various other comor- Therefore, the diagnosis of one individ- controlled studies of bone density in bidities exist such as pain, fatigue, ual may be ultimately attributable to a hEDS are needed at all ages. orthostasis, sleep disturbance, anxiety, mutation of a particular gene while in and a poorer health-related quality of another person with a similar or differ- life. Much work in the area of diag- Physical Therapy Management ent phenotypic presentation may be due nostics, prevalence of hEDS, and the to mutation of another gene altogether. Physical therapy is considered the associated comorbidities as well man- Without recognition and eventual mainstay of management in hEDS. agement specific to hEDS is needed. 64 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

ACKNOWLEDGMENTS hypermobility in Turkish women. Arch Bird HA, Tribe CR, Bacon PA. 1978. Joint Gynecol Obstet 281:301–304. hypermobility leading to osteoarthrosis We want to thank the many interna- Baeza-Velasco C, Gely-Nargeot MC, Bulbena and chondrocalcinosis. Ann Rheum Dis Vilarrasa A, Bravo JF. 2011. Joint hypermo- 37:203–211. tional experts and patient group repre- bility syndrome: Problems that require Bovet C, Carison M, Taylor M. 2016. Quality sentatives that have contributed to this psychological intervention. Rheumatol Int of life, unmet needs, and iatrogenic process of defining and refining hEDS. 31:1131–1136. injuries in rehabilitation of patients with Babalonis S, Walsh S. 2015. Warnings unheeded: Ehlers-Danlos syndrome hypermobility We also acknowledge the contributions The risks of co-prescribing opioids and type/joint hypermobility syndrome. Am of many from multiple specialties as well benzodiazepines. Pain Clinical Updates J Med Genet A 170:2044–2051. as the patients and their families that 23:1–7. Boyan BD, Hart DA, Enoka RM, Nicolella DP, Barron DF,Cohen BA, Geraghty MT, Violand R, Resnick E, Berkley KJ, Sluka KA, Kwoh have significantly contributed to our Rowe PC. 2002. Joint hypermobility is CK, Tosi LL, O’Connor MI, Coutts RD, understanding of this common disorder. more common in children with chronic Kohrt WM. 2013. Hormonal modulation of fatigue syndrome than in healthy controls. connective tissue homeostasis and sex differ- J Pediatr 141:421–425. ences in risk for osteoarthritis of the knee. REFERENCES Bathen T, Hangmann AB, Hoff M, Andersen LO, Biol Sex Diff 4:3. Rand-Hendriksen S. 2013. Multidisciplin- Branson JA, Kozlowska K, Kaczynski KJ, Roesler Abdel Shaheed C, Maher CG, Williams KA, ary treatment of disability in Ehlers-Danlos TA. 2011. Managing chronic pain in a young McLachlan AJ. 2017. Efficacy and tolerabil- syndrome hypermobility type/hypermobil- adolescent girl with Ehlers-Danlos syn- ity of muscle relaxants for low back pain: ity syndrome: A pilot study using a drome. Harv Rev Psychiatry 19:259–270. Systematic review and meta-analysis. Eur J combination of physical and cognitive- Briggs J, McCormack M, Hakim AJ, Grahame R. Pain 21:228–237. behavioral therapy on 12 women. Am J 2009. Injury and joint hypermobility syn- Abonia JP,Wen T, Stucke EM, Grotjan T, Griffith Med Genet Part A 161A:3005–3011. drome in ballet dancers—A 5-year follow- MS, Kemme KA, Collins MH, Putnam Beighton P, de Paepe A, Danks D, Finidori G, up. Rheumatol 48:1613–1614. PE, Franciosi JP, von Tiehl KF, Tinkle BT, Gedde-Dahl T, Goodman R, Hall JG, Buchsbaum GM, Duecy EE, Kerr LA, Huang LS, Marsolo KA, Martin LJ, Ware SM, Hollister DW, Horton W, McKusick VA, Perevich M, Guzick DS. 2006. Pelvic organ Rothenberg ME. 2013. High prevalence Opitz JM, Pope FM, Pyeritz RE, Rimoin prolapse in nulliparous women and their of eosinophilic esophagitis in patients with DL, Sillence D, Spranger JW, Thompson E, parous sisters. Obstet Gynecol 108: inherited connective tissue disorders. Tsipouras D, Viljoen D, Winship I, Young I, 1388–1393. J Allergy Clin Immunol 132:378–386. Reynolds JF. 1988. International Nosology Buchsbaum GM, Duecy EE. 2008. Incontinence Adair SM, Hecht C. 1993. Association of of Heritable Disorders of Connective Tissue, and pelvic organ prolapse in parous/nullipa- generalized joint hypermobility with his- Berlin, 1986. Am J Med Genet 29:581–594. rous pairs of identical twins. Neurourol tory, signs and symptoms of temporoman- Beighton P, De Paepe A, Steinmann B, Tsipouras Urodyn 27:496–498. dibular joint dysfunction in children. Pediatr P, Wenstrup RJ. 1998. Ehlers-Danlos syn- Burcharth J, Rosenberg J. 2012. Gastrointestinal Dent 15:323–326. dromes: Revised nosology, Villefranche, surgery and related complications in patients Adib N, Davies K, Grahame R, Woo P, Murray KJ. 1997. Ehlers-Danlos National Foundation with Ehlers-Danlos syndrome: A systematic 2005. Joint hypermobility syndrome in child- (USA) and Ehlers-Danlos Support Group review. Dig Surg 29:349–357. hood. A not so benign multisystem disorder? (UK). Am J Med Genet 77:31–37. Byers PH, Krakow D, Nunes ME, Pepin M. Rheumatology (Oxford) 44:744–750. Beighton P, Grahame R, Bird HA. 2012. 2006. Genetic evaluation of suspected Afrin LB, Butterfield JH, Raithel M, Molderings Hypermobility of joints, 4th edition. Lon- osteogenesis imperfecta (OI). Genet Med GJ. 2016. Often seen, rarely recognized: don, UK: Springer. 8:383–388. Mast cell activation disease—A guide to Beiraghdar F, Rostami Z, Panahi Y, Einollahi B, Calguneri M, Bird HA, Wright V. 1982. Changes diagnosis and therapeutic options. Ann Med Teimoori M. 2013. Veisocuretheral reflux in in joint laxity occurring during pregnancy. 48:190–201. pediatrics with hypermobility syndrome. Ann Rheum Dis 41:126–128. Ainsworth SR, Aulicino PL. 1993. A survey of Nephrouro Mon 5:924–927. Camerota F, Castori M, Celletti C, Colotto M, patients with Ehlers-Danlos syndrome. Clin Bendik EM, Tinkle BT, Al-shuik E, Levin L, Amato S, Colella A, Curione M, Danese Orthop Relat Res 286:250–256. Martin A, Thaler R, Atzinger CL, Rueger J, C. 2014. Heart rate, conduction and Albayrak I, Yilmaz H, Akkurt HE, Salli A, Karaca Martin VT. 2011. Joint hypermobility ultrasound abnormalities in adults with G. 2015. Is pain the only symptom in syndrome: A common clinical disorder joint hypermobility syndrome/Ehlers- patients with benign joint hypermobility associated with migraine in women. Ceph- Danlos syndrome, hypermobility type. syndrome? Clin Rheumatol 34:1613–1619. alalgia 31:603–613. Clin Rheumatol 33:981–987. Ali Zekry O, Ali Ahmed M, Ali Elsayed Abd Berglund B, Mattiasson A-C, Randers I. 2010. Carbone L, Tylavsky FA, Bush AJ, Koo W,Orwoll Elwahid H. 2013. The impact of fatigue on Dignity not fully upheld when seeking E, Cheng S. 2000. Bone density in health related quality of life in adolescents health-care: Experiences expressed by indi- Ehlers-Danlos syndrome. Osteoporos Int with benign joint hypermobility syndrome. viduals suffering from Ehlers-Danlos syn- 11:388–392. Egypt Rheumatol 35:77–85. drome. Disabil Rehabil 32:1–7. Castori M, Camerota F,Celletti C, Grammatico P, Al-Rawi ZS, Al-Rawi ZT. 1982. Joint hypermo- Berglund B, Bjorck€ E. 2012. Women with Ehlers- Padua L. 2010a. Ehlers–Danlos syndrome bility in women with genital prolapse. Danlos syndrome experience low oral hypermobility type and the excess of affected Lancet 1:1439–1441. health-related quality of life. J Orofacial females: Possible mechanisms and perspec- Arendt-Nielsen L, Kaalund S, Bjerring P, Høgsaa. Pain 26:307–314. tives. Am J Med Genet Part Part A 1990. Insufficient effect of local analgesics in Berglund B, Pettersson C, Pigg M, Kristiansson P. 152A:2406–2408. Ehlers Danlos type III patients (connective 2015. Self-reported quality of life, anxiety Castori M, Camerota F, Celletti C, Danese C, tissue disorder). Acta Anaesthesiol Scand and depression in individuals with Ehlers- Santilli V, Saraceni VM, Grammatico P. 34:358–361. Danlos syndrome (EDS): A questionnaire 2010b. Natural history and manifestations of Atzinger CL, Meyer RA, Khoury PR, Gao Z, study. BMC Musculoskelet Disord 16:89. the hypermobility type Ehlers–Danlos syn- Tinkle BT. 2011. Cross-sectional and lon- Berglund B. 2015. Food hypersensitivity in drome: A pilot study on 21 patients. Am J gitudinal assessment of aortic root dilation individuals with EDS: A common problem. Med Genet Part A 152A:556–564. and valvular anomalies in hypermobile and Nord J Nurs Res 35:10–12. Castori M, Sperduti I, Celletti C, Camerota F, classic Ehlers-Danlos syndrome. J Pediatr Besteiro Gonzalez JL, Suarez Fernandez TV, Grammatico P. 2011a. Symptom and joint 158:826–830. Arboleya Rodriguez L, Muniz J, Lemos mobility progression in the joint hypermo- Aydeniz A, Dikensoy E, Cebesoy B, AltindagO, Diraldez S, Alvarez Fernandez A. 2011. bility syndrome (Ehlers–Danlos syndrome, Gursoy S, Balat O. 2010. The relation Sleep architecture in patients with fibromy- hypermobility type). Clin Exp Rheumatol between genitourinary prolapse and joint algia. Psicothema 23:368–373. 29:998–1005. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 65

Castori M, Celletti C, Camerota F,Grammatico P. joint hypermobility syndrome/Ehlers- New insights into disease progression, 2011b. Chronic fatigue syndrome is com- Danlos syndrome, hypermobility type. Am genetics, and molecular basis. Circulation monly diagnosed in patients with Ehlers- J Med Genet Part C 169C:43–53. 129:2158–2170. Danlos syndrome hypermobility type/joint Castori M, Morlino S, Ghibellini G, Celletti C, Deodhar AA, Woolf AD. 1994. Ehlers Danlos hypermobility syndrome. Clin Exp Rheu- Camerota F, Grammatico P. 2015c. Con- syndrome and osteoporosis. Ann Rheum matol 29:597–598. nective tissue, Ehlers-Danlos syndrome(s), Dis 53:841–842. Castori M. 2012. Ehlers–Danlos syndrome, and head and cervical pain. Am J Med Genet Derpapas A, Cartwright R, Upadhyaya P, Bhide hypermobility type: An underdiagnosed Part C 169C:1–14. AA, Digesu AG, Khullar V. 2015. Lack of hereditary connective tissue disorder Cazzato D, Castori M, Lombardi R, Caravello F, association of joint hypermobility with with mucocutaneous, articular, and sys- Bella ED, Petrucci A, Grammatico P, urinary incontinence subtypes and pelvic temic manifestations. ISRN Dermatol Dordoni C, Colombi M, Lauria G. 2016. prolapse. BJU Int 115:639–643. 2012:751–768. Small fiber neuropathy is a common feature De WandeleI, Rombaut L, Malfait F,De Backer T, Castori M, Morlino S, Celletti C, Celli M, of Ehlers-Danlos syndromes. Neurology De Paepe A, Calders P. 2013. Clinical Morrone A, Colombi M, Camerota F, 87:155–159. heterogeneity in patients with the hyper- Grammatico P. 2012a. Management of Celletti C, Galli M, Cimolin V, Castori M, mobility type of Ehlers-Danlos syndrome. pain and fatigue in the joint hypermobility Albertini G, Camerota F.2012. Relationship Res Dev Disabil 34:873–881. syndrome (a.k.a. Ehlers-Danlos syndrome, between fatigue and gait abnormality in joint De Wandele I, Calders P,Peersman W,Rimbaut S, hypermobility type): Principles and proposal hypermobility syndrome/Ehlers-Danlos De Backer T, Malfait F, De Paepe A, for a multidisciplinary approach. Am J Med syndrome hypermobility type. Res Develop Rombaut L. 2014a. Autonomic symptom Genet Part A 158A:2055–2070. Disabil 33:1914–1918. burden in the hypermobility type of Ehlers- Castori M, Morlino S, Dordoni C, Celletti C, Celletti C, Castori M, La Torre G, Camerota F. Danlos syndrome: A comparative study with Camerota F, Ritelli M, Morrone A, 2013. Evaluation of kinesiophobia and its two other EDS types, fibromyalgia, and Venturini M, Grammatico P, Colombi M. correlations with pain and fatigue in joint healthy controls. Semin Arthritis Rheum 2012b. Gynecologic and obstetric implica- hypermobility syndrome/Ehlers-Danlos 44:353–361. tions of the joint hypermobility syndrome syndrome hypermobility type. BioMed De Wandele I, Rombaut L, Leybaert L, Van de (a.k.a. Ehlers-Danlos syndrome hypermo- Res Intl 2013:580460. Borne P,De Backer T,Malfait F,De Paepe A, bility type) in 82 Italian patients. Am J Med Chen CW, Jao SW. 2007. Images in clinical Calders P. 2014b. Dysautonomia and its Genet Part A 158A:2176–2182. medicine. Ehlers-Danlos syndrome. N Engl underlying mechanisms in the hypermobil- Castori M, Morlino S, Dordoni C, Celletti C, J Med 357:e12. ity type of Ehlers-Danlos syndrome. Semin Camerota F,Ritelli M, Morrone A, Venturini Chou R, Deyo R, Friedly J, Skelly A, Hashimoto Arthritis Rheum 44:93–100. M, Grammatico P, Colombi M. 2012c. R, Weimer M, Fu R, Dana T, Kraegel P, Dickin DC, Doan JB. 2008. Postural stability in Gynecologic and obstetric implications of Griffin J, Grusing S, Brodt E. 2016. altered and unaltered sensory environments the joint hypermobility syndrome (a.k.a. Noninvasive treatments for low back pain following fatiguing exercise of lower ex- Ehlers–Danlos syndrome hypermobility [Internet]. AHRQ Comparative Effective- tremity joints. Scand J Med Sci Sports type) in 82 Italian patients. Am J Med Genet ness Reviews, Report 16-EHC004-EF. 18:765–772. Part A 158A:2176–2182. Rockville (MD): Agency for Healthcare Di Stefano G, Celletti C, Baron R, Castori M, Di Castori M, Morlino S, Celletti C, Ghibellini G, Research and Quality (US). PMID: Franco M, La Cesa S, Leone C, Pepe A, Bruschini M, Grammatico P, Blundo C, 26985522. Cruccu G, Truini A, Camerota F. 2016. Camerota F. 2013. Re-writing the natural Coelho PC, Santos RA, Gomes JA. 1994. Central sensitization as the mechanism history of pain and related symptoms in the Osteoporosis and Ehlers-Danlos syndrome. underlying pain in joint hypermobility joint hypermobility syndrome/Ehlers- Ann Rheum Dis 53:212–213. syndrome/Ehlers-Danlos syndrome, hyper- Danlos syndrome, hypermobility type. Am Czaprowski D. 2014. Generalised joint hypermo- mobility type. Eur J Pain 20:1319–1325. J Med Genet Part A 161A:2989–3004. bility in Caucasian girls with idiopathic Dolan AL, Mishra MB, Chambers JB, Grahame R. Castori M, Dordoni C, Valiante M, Sperduti I, scoliosis: Relation with age, curve size, and 1997. Clinical and echocardiographic survey Ritelli M, Morlino S, Chiarelli N, Celletti curve pattern. Scientific World Journal of the Ehlers-Danlos syndrome. Br J C, Venturini M, Camerota F, Calzavara- 2014:370134. Rheumatol 36:459–462. Pinton P,Grammatico P,Colombi M. 2014. Danese C, Castori M, Celletti C, Amato S, Lo Dolan AL, Arden NK, Grahame R, Spector TD. Nosology and inheritance pattern(s) of joint Russo C, Grammatico P, Camerota F. 2011. 1998. Assessment of bone in Ehlers Danlos hypermobility syndrome and Ehlers-Danlos Screening for celiac disease in the joint syndrome by ultrasound and densitometry. syndrome, hypermobility type: A study of hypermobility syndrome/Ehlers-Danlos Ann Rheum Dis 57:630–633. intrafamilial and interfamilial variability in syndrome hypermobility type. Am J Med Dolan AL, Hart DJ, Doyle DV, Grahame R, 23 Italian pedigrees. Am J Med Genet Part A Genet Part A 155A:2314–2316. Spector TD. 2003. The relationship of joint 164A:3010–3020. Dauvilliers Y, Touchon J. 2001. Sleep in hypermobility, bone mineral density, and Castori M. 2015. Ehlers-Danlos syndrome(s) fibromyalgia: A review of clinical and osteoarthritis in the general population: The mimicking child abuse: Is there an impact polysomnographic data. Neurophysiol Chingford Study. J Rheumatol 30:799–803. on clinical practice? Am J Med Genet Clin 31:18–33. Dordoni C, Ritelli M, Venturini M, Chiarelli N, 169:289–292. Day H, Koutedakis Y, Wyon MA. 2011. Hyper- Pezzani L, Vascellaro A, Calzavara-Pinton P, Castori M, Colombi M. 2015. Generalized joint mobility and dance: A review. Int J Sports Colombi M. 2013. Recurring and general- hypermobility, joint hypermobility syn- Med 32:485–489. ized visceroptosis in Ehlers-Danlos syn- drome and Ehlers-Danlos syndrome, hyper- De Coster PJ, Martens LC, De Paepe A. 2005. drome hypermobility type. Am J Med mobility type. Am J Med Genet Part C Oral health in prevalent types of Ehlers- Genet Part A 161A:1143–1147. 169C:1–5. Danlos syndromes. J Oral Pathol Med Douglas BS, Douglas HM. 1973. Rectal prolapse Castori M, Morlino S, Pascolini G, Blundo C, 34:298–307. in the Ehlers-Danlos syndrome. Aust Grammatico P. 2015a. Gastrointestinal and Defuentes G, Damiano J, Moulin O, Hervouet M, Paediatr J 9:109–110. nutritional issues in joint hypermobility Zing E, Berets O. 2004. Colite diverticulaire Dowell D, Haegerich TM, Chou R. 2016. CDC syndrome/Ehlers-Danlos syndrome, hyper- droite revelatrice d’un syndrome d’Ehlers- guideline for prescribing opioids for mobility type. Am J Med Genet Part C Danlos. Presse Med 33:1591–1592. chronic pain—United States, 2016. JAMA 169C:54–75. De Kort LM, Verhulst JA, Engelbert RH, 315:1624–1645. Castori M, Dordoni C, Morlino S, Sperduti I, Uiterwaal CS, de Jong TP. 2003. Lower Easton V, Bale P, Bacon H, Jerman E, Armon K, Ritelli M, Valiante M, Chiarelli N, Zanca urinary tract dysfunction in children with Macgregor AJ. 2014. A89: The relationship A, Celletti C, Venturini M, Camerota F, generalized hypermobility of joints. J Urol between benign joint hypermobility syn- Calzavara-Pinton P, Grammatico P, 170:1971–1974. drome and developmental coordination Colombi M. 2015b. Spectrum of mucocu- Delling FN, Vasan RS. 2014. Epidemiology and disorders in children. Arthritis Rheumatol taneous manifestations in 277 patients with pathophysiology of mitral valve prolapse: 66:S124[poster]. 66 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

Eccles JA, Owens AP, Mathias CJ, Umeda S, benign joint hypermobility syndrome syndrome are frequent, diverse and strongly Critchley HD. 2015. Neurovisceral pheno- (BJHS). J Rheumatol 27:1777–1779. associated with pain. Rheumatol Int 36: types in the expression of psychiatric Granata G, Padua L, Celletti C, Castori M, 341–348. symptoms. Front Neurosci 9:4. Saraceni VM, Camerota F. 2013. Entrap- Herzka A, Sponseller PD, Pyeritz RE. 2000. Edmonds M, McGuire H, Price J. 2004. Exercise ment neuropathies and polyneuropathies in Atlantoaxial rotatory subluxation in patients therapy for chronic fatigue syndrome. joint hypermobility syndrome/Ehlers- with Marfan syndrome. A report of three Cochrane Database Syst Rev 3:CD003200. Danlos syndrome. Clin Neurophysiol cases. Spine 25:524–526. el-Shahaly HA, el-Sherif AK. 1991. Is the benign 124:1689–1694. Hugon-Rodin J, Lebegue G, Becourt S, Hamonet joint hypermobility syndrome benign? Clin Guilleminault C, Primeau M, Chiu H, Yuen C, Gompel A. 2016. Gynecologic symptoms Rheumatol 10:302–307. KM, Leger D, Metlaine A. 2013. Sleep- and the influence on reproductive life in 386 Engelbert RH, Bank RA, Sakkers RJ, Helders PJ, disordered-breathing in Ehlers-Danlos syn- women with hypermobility type of Ehlers- Beemer FA, Uiterwaal CS. 2003. Pediatric drome (a genetic model of obstructive sleep Danlos syndrome: A cohort study. Orphan J generalized joint hypermobility with and apnea). Chest 144:1503–1511. Rare Dis 11:124. without musculoskeletal complaints: A lo- Gulbahar S, Sahin E, Baydar M, Bircan C, Kizil R, Hunter A, Morgan AW, Bird HA. 1998. A survey calized or systemic disorder? Pediatrics 111: Manisali M, Akalin E, Peker O. 2006. of Ehlers-Danlos syndrome: Hearing, voice, e248–e254. Hypermobility syndrome increases the risk speech and swallowing difficulties. Is there Farmer AD, Fikree A, Aziz Q. 2014. Addressing for low bone mass. Clin Rheumatol 25: an underlying relationship? Br J Rheumatol the confounding role of joint hypermobility 511–514. 37:803–804. syndrome and gastrointestinal involvement Gurer€ G, Bozbas GT, Tuncer T, Unobol AI, Ucar Hurst BS, Lange SS, Kullstam SM, Usadi RS, in postural orthostatic tachycardia syndrome. UG, Memetoglu OI. 2016. Frequency of Matthews ML, Marshburn PB, Templin Clin Auton Res 24:157–158. joint hypermobility in Turkish patients with MA, Merriam KS. 2014. Obstetric and Feldman K, Smith WG. 2007. Idiopathic striae knee osteoarthritis: A cross sectional multi- gynecologic challenges in women with atrophicae of puberty. Can Med Assoc J center study. Int J Rheum Dis July 27 [ePub Ehlers-Danlos syndrome. Obstet Gynecol 176:930–931. ahead of print]. 123:506–513. Fikree A, Grahame R, Aktar R, Farmer AD, Hagberg C, Berglund B, Korpe L, Andersson- Jacks SK, Zirwas MJ. 2016. Abnormal wound Hakim AJ, Morris JK, Knowles CH, Aziz Q. Norinder J. 2004. Ehlers-Danlos Syndrome healing related to high-dose systemic corti- 2015. A prospective evaluation of undiag- (EDS) focusing on oral symptoms: A costeroid therapy in a patient with Ehlers- nosed joint hypermobility syndrome in questionnaire study. Orthod Craniofac Res Danlos syndrome benign hypermobility patients with gastrointestinal symptoms. 7:178–185. type. Cutis 98:E20–E23. Clin Gastroenterol Hepatol 27:569–579. Hakim AJ, Grahame R. 2004. Non-musculoskel- Jacome DE. 1999. Headache in Ehlers-Danlos Finnerup NB, Attal N, Haroutounian S, McNicol etal symptoms in joint hypermobility syn- syndrome. Cephalalgia 19:791–796. E, Baron R, Dworkin RH, Gilron I, drome. Indirect evidence for autonomic Jonsson H, Valtysdottir ST. 1995. Hypermobility Haanp€a€a M, Hansson P, Jensen TS, dysfunction? Rheumatology (Oxford) features in patients with hand osteoarthritis. Kamerman PR, Lund K, Moore A, Raja 43:1194–1195. Osteoarthritis Cartilage 3:1–5. SN, Rice ASC, Rowbotham M, Sena M, Hakim AJ, Cherkas LF, Grahame R, Spector TD, Johannessen EC, Reiten HS, Løvaas H, Maeland S, Siddall P, Smith BH, Wallace M. 2015. MacGregor AJ. 2004. The genetic epidemi- Juul-Kristensen B. 2016. Shoulder dysfunc- Pharmacotherapy for neuropathic pain in ology of joint hypermobility. A population tion, pain and health related quality of life in adults: A systematic review and meta- study of female twins. Arthrit Rheumat adults with joint hypermobility syndrome/ analysis. Lancet Neurol 14:162–173. 50:2640–2644. Ehlers-Danlos syndrome-hypermobility Flaherty EG, Perez-Rossello JM, Levine MA, Hakim AJ, Grahame R, Norris P, Hopper C. type. Disabil Rehabil 38:1382–1390. Hennrikus WL, American Academy of 2005. Local anaesthetic failure in joint Kajbafzadeh AM, Sharifi-Rad L, Seyedian SS, Pediatrics Committee on Child Abuse and hypermobility syndrome. J Royal Society Mozafarpour S, Paydary K. 2014. General- Neglect; Section on Radiology, American Med 98:84–85. ized joint hypermobility and voiding dys- Academy of Pediatrics; Section on Endocri- Hakim AJ, Sahota A. 2006. Joint hypermobility function in children: Is there any nology, American Academy of Pediatrics; and skin elasticity: The hereditary disorders relationship? Eur J Pediatr 173:197–201. Section on Orthopaedics, American Acad- of connective tissue. Clin Dermatol 24: Kanjwal K, Saeed B, Karabin, Kanjwal Y, Grubb emy of Pediatrics; Society for Pediatric 521–533. BP. 2010. Comparative clinical profile of Radiology. 2014. Evaluating children with Hallock JL, Handa VL. 2016. The epidemiology postural orthostatic tachycardia patients fractures for child physical abuse. Pediatrics of pelvic floor disorders and childbirth: An with and without joint hypermobility 133:e477–e489. update. Obstet Gynecol Clin North Am syndrome. Indian Pacing Electrophysiol J Fogel S. 2013. Surgical failures: Is it the surgeon or 43:1–13. 10:173–178. the patient? The all too often missed Hamonet C, Gompel A, Mazaltarine G, Brock I, Kapferer-Seebacher I, Pepin M, Werner R, diagnosis of Ehlers-Danlos syndrome. Am Baeza-Velasco C, Zeitoun JD, Bienvenu B. Aitman TJ, Nordgren A, Stoiber H, Surg 79:608–613. 2015. Ehlers-Danlos syndrome or disease? Thielens N, Gaboriaud C, Amberger A, Fossey M, Libman E, Bailes S, Blatzan M, J Syndrome 2:5. Schossig A, Gruber R, Giunta C, Bamshad Schondorf R, Ansel R, Fichten CS. 2004. Harrison B, Sanniec K, Janis JE. 2016. Collage- M, Bjorck€ E, Chen C, Chitayat D, Sleep quality and psychological adjustment nopathies-implications for abdominal wall Dorschner M, Schmitt-Egenolf M, Hale in chronic fatigue syndrome. J Behav Med reconstruction: A systematic review. Plast CJ, Hanna D, Hennies HC, Heiss- 27:581–605. Reconstr Surg Glob Open 24:e1036. Kisielewsky I, Lindstrand A, Lundberg P, Gamble JG, Mochizuki C, Rinsky LA. 1989. Health Quality Ontario. 2015. Positional mag- Mitchell AL, Nickerson DA, Reinstein E, Trapeziometacarpal abnormalities in Ehlers- netic resonance imaging for people with Rohrbach M, Romani N, Schmuth M, Danlos syndrome. J Hand Surg 14A:89–94. Ehlers-Danlos syndrome or suspected cra- Silver R, Taylan F, Vandersteen A, Gazit Y, Nahir AM, Grahame R, Jacob G. 2003. niovertebral or cervical spine abnormalities: Vandrovcova J, Weerakkody R, Yang M, Dysautonomia in the joint hypermobility An evidence-based analysis. Ont Health Pope FM; Molecular Basis of Periodontal syndrome. Am J Med 115:33–40. Technol Assess Ser 15:1–24. EDS Consortium. 2016. Periodontal Eh- Gedalia A, Press J, Buskila D. 1996. Diffuse Hermanns-L^e T, Reginster MA, Pierard-Franchi- lers–Danlos syndrome is caused by mutations musculoskeletal pain syndromes in pediatric mont C, Delvenne P,Pierard GE, Manicourt in C1R and C1S, which encode subcom- practice. J Clin Rheumatol 2:325–330. D. 2012. Dermal ultrastructure in low ponents C1r and C1a of complement. Am J Grahame R. 1989. How often, when and how Beighton score members of 17 families Hum Genet 99:1005–1014. does joint hypermobility lead to osteoar- with hypermobile-type Ehlers-Danlos syn- Kim HJ, Yeom JS, Lee DB, Kang KT, Chang BS, thritis. Br J Rheumatol 28:320. drome. J Biomed Biotechnol 2012:878107. Lee CK. 2013. Association of benign joint Grahame R, Bird HA, Child A. 2000. The revised Hershenfeld SA, Wasim S, McNiven V,Parikh M, hypermobility with spinal segment motion (Brighton 1998) criteria for the diagnosis of Majewski P, Faghfoury H, So J. 2016. and its implication in active young males. Psychiatric disorders in Ehlers-Danlos Spine 38:e1013–e1019. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 67

Kirby A, Davies R, Bryant A. 2005. Hypermobility Wilson TM, Tucker S, Zhang Y, McElwee Meeus M, Nijs J, Merleir KD. 2007. Chronic syndrome and developmental coordination JJ, Pao M, Glover SC, Rothenberg ME, musculoskeletal pain in patients with chronic disorder: Similarities and features. Int J Ther Hohman RJ, Stone KD, Caughey GH, fatigue syndrome: A systematic review. Eur J Rehabil 12:431–436. Heller T, Metcalfe DD, Biesecker LG, Pain 11:377–386. Kirk JA, Ansell BM, Bywaters EGL. 1967. The Schwartz LB, Milner JD. 2016. Elevated Merke DP, Chen W, Morissette R, Xu Z, Van hypermobility syndrome. Musculoskeletal basal serum tryptase identifies a multisystem Ryzin C, Sachdev V,Hannoush H, Shanbhag complaints associated with generalized disorder associated with increased TPSAB1 SM, Acevedo AT, Nishitani M, Arai AE, joint hypermobility. Ann Rheum Dis copy number. Nat Genet 48:1564–1569. McDonnell NB. 2013. Tenascin-X haploin- 26:419–425. Machet L, Huttenberger B, Georgesco G, Dore C, sufficiency associated with Ehlers-Danlos Kizilbash SJ, Ahrens SP, Bruce BK, Chelimsky G, Jamet F, Bonnin-Goga B, Giraudea B, syndrome in patients with congenital adrenal Driscoll SW,Harbeck-Weber C, Lloyd RM, Maruani A, Laure B, Vaillant L. 2010. hyperplasia. Eur J Med Genet 54:112–117. Mack KJ, Nelson DE, Ninis N, Pianosi PT, Absence of inferior labial and lingual frenula Milhorat TH, Bolognese PA, Nishikawa M, Stewart JM, Weiss KE, Fischer PR. 2014. in Ehlers-Danlos syndrome: A minor diag- McDonnell NB, Francomano CA. 2007. Adolescent fatigue, POTS, and recovery: A nostic criterion in French patients. Am J Syndrome of occipitoatlantoaxial hypermo- guide for clinicians. Curr Probl Pediatr Clin Dermatol 11:269–273. bility, cranial settling, and Chiari malforma- Adolesc Health Care 44:108–133. Maeland S, Assmus J, Berglund B. 2011. Subjec- tion type I in patients with hereditary Klemp P. 1997. Hypermobility. Ann Rheum Dis tive health complaints in individuals with disorders of connective tissue. J Neurosurg 56:573–575. Ehlers-Danlos syndrome: A questionnaire Spine 7:601–609. Knoepp LR, McDermott KC, Munoz A, Blom- study. Int J Nurs Stud 48:720–724. Morissette R, Chen W, Perritt AF, Dreiling JL, quist JL, Handa VL. 2013. Joint hypermo- Mallorqui-Bague N, Bulbena A, Roe-VellveN, Arai AE, Sachdev V,Hannoush H, Mallappa bility, obstetrical outcomes, and pelvic floor Hoekzema E, Carmona S, Barba-Muller€ A, Xu Z, McDonnell NB, Quezado M, disorders. Int Urogynecol 24:735–740. E, Fauquet J, Pailhez G, Vilarroya O. Merke DP. 2015. Broadening the spectrum Konopinski M, Graham I, Johnson MI, Jones G. 2015. Emotion processing in joint hyper- of Ehlers Danlos syndrome in patients with 2015. The effect of hypermobility on the mobility: A potential link to the neural congenital adrenal hyperplasia. J Clin En- incidence of injury in professional football: bases of anxiety and related somatic docrinol Metab 100:E1143–E1152. A multi-site cohort study. Phys Ther Sport symptoms in collagen anomalies. Eur Morris SL, O’Sullivan PB, Murray KJ, Baer N, 21:7–13. Psychiatry 30:454–458. Hands B, Smith AJ. 2016. Hypermobility Kovacic K, Chelimsky TC, Sood MR, Simpson P, Mandelbaum DE, de la Monte SM. 2017. Adverse and musculoskeletal pain in adolecents. Nugent M, Chelimsky G. 2014. Joint structural and functional effects of marijuana J Pediatr 16:31044–31047. hypermobility: A common association on the brain: Evidence reviewed. Pediatr Mulvey MR, Macfarlane GJ, Beasley M, Sym- with complex functional gastrointestinal Neurol 66:12–20. mons DP, Lovell K, Keeley P, Woby S, disorders. J Pediatr 165:973–978. Manning J, Korda A, Benness C, Solomon M. McBeth J. 2013. Modest association of joint Kozanoglu E, Coskun Benlidayi I, Eker Akilli R, 2003. The association of obstructive defeca- hypermobility with disabling and limiting Tasal A. 2016. Is there any link between joint tion, lower urinary tract dysfunction and the musculoskeletal pain: Results from a large- hypermobility and mitral valve prolapse in benign joint hypermobility syndrome: A scale general population-based survey. Ar- patients with fibromyalgia syndrome? Clin case-control study. Int Urogynecol J Pelvic thritis Care Res (Hoboken) 65:1325–1333. Rheumatol 35:1041–1044. Floor Dysfunct 14:128–132. Murray B, Yashar BM, Uhlmann WR, Clauw DJ, Lammers K, Lince SL, Spath MA, van Kempen Mastoroudes H, Giarenis I, Cardozo L, Srikrishna Petty EM. 2013. Ehlers-Danlos syndrome, LC, Hendriks JC, Vierhout ME, Kluivers S, Vella M, Robinson D, Kazkaz H, hypermobility type: A characterization of KB. 2012. Pelvic organ prolapse and Grahame R. 2013a. Lower urinary tract the patients’ lived experience. Am J Med collagen-associated disorders. Int Urogyne- symptoms in women with benign joint Genet Part A 161A:2981–2988. col J 23:313–319. hypermobility syndrome: A case-control Murray KJ, Woo P. 2001. Benign joint hypermo- Laszkowska M, Roy A, Lebwohl B, Green PH, study. Int Urogynecol 24:1553–1558. bility in childhood. Rheumatology Sundelin HE, Ludvigsson JF. 2016. Nation- Mastoroudes H, Giarenis I, Cardozo L, Srikrishna 40:489–491. wide population-based cohort study of S, Vella M, Robinson D, Kazkaz H, Grahame Narcisi P, Richards AJ, Ferguson SD, Pope FM. celiac disease and risk of Ehlers-Danlos R. 2013b. Prolapse and sexual function in 1994. A family with Ehlers-Danlos syn- syndrome and joint hypermobility syn- women with benign joint hypermobility drome type III/articular hypermobility drome. Dig Liver Dis 48:1030–1034. syndrome. BJOG 120:187–192. syndrome has a glycine 637 to serine Lind J, Wallenburg HC. 2002. Pregnancy and the Mathias CJ, Low DA, Iodice V, Owens AP, Kirbis substitution in type III collagen. Hum Mol Ehlers-Danlos syndrome: A retrospective M, Grahame R. 2011. Postural tachycardia Genet 3:1617–1620. study in a Dutch population. Acta Obstet syndrome-current experience and concepts. National Guideline Clearinghouse (NGC). 2013. Gynecol Scand 81:293–300. Nat Rev Neurol 8:22–34. Guideline summary: Assessment and man- Liu FC, Fuh JL, Wang YF, Wang SJ. 2011. Mazziotti G, Dordoni C, Doga M, Galderisi F, agement of chronic pain. In: National Connective tissue disorders in patients Venturini M, Calzavara-Pinton P, Maroldi Guideline Clearinghouse (NGC) [Web with spontaneous intracranial hypotension. R, Giustina A, Colombi M. 2016. High site]. Rockville (MD): Agency for Health- Cephalalgia 31:691–695. prevalence of radiologic vertebral fractures care Research and Quality (AHRQ). [cited Lumley MA, Jordan M, Rubenstein R, Tsipouras in adult patients with Ehlers-Danlos syn- 2017 Jan 21]. Available: https://www. P,Evans MI. 1994. Psychosocial functioning drome. Bone 18:88–92. guideline.gov in the Ehlers-Danlos syndrome. Am J Med McDonnell NB, Gorman BL, Mandel KW, Nazem M, Mottaghi P, Hoseini A, Khodadadi H. Genet 53:149–152. Schurman SH, Assanah-Carroll A, Mayer 2013. Benign joint hypermobility syndrome Lyons JJ, Sun G, Stone KD, Nelson C, Wisch L, SA, Najjar SS, Francomano CA. 2006. among children with inguinal hernia. J Res O’Brien M, Jones N, Lindsley A, Komarow Echocardiographic findings in classical and Med Sci 18:904–905. HD, Bai Y, Scott LM, Cantave D, Maric I, hypermobile Ehlers-Danlos syndromes. Am Nef W, Gerber NJ. 1998. Hypermobility syn- Abonia JP, Rothenberg ME, Schwartz LB, J Med Genet Part A 140A:129–136. drome. When too much activity causes pain. Milner JD, Wilson TM. 2014. Mendelian McIntosh LJ, Mallett VT, Frahm JD, Richardson Schweiz Med Wochenschr 128:302–310. inheritance of elevated serum tryptase DA, Evans MI. 1995. Gynecologic disorders Neilson D, Martin VT. 2014. Joint hypermobility associated with atopy and connective tissue in women with Ehlers-Danlos syndrome. and headache: Understanding the glue that abnormalities. J Allergy Clin Immunol J Soc Gynecol Investig 2:559–564. binds the two together—Part 1. Headache 133:1471–1474. McIntosh LJ, Stanitski DF, Mallett VT, Frahm JD, 54:1393–1402. Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, Richardson DA, Evans MI. 1996. Ehlers- Nelson AD, Mouchli MA, Valentin N, Deyle D, Ho N, Zhao M, Liu Y, O’Connell MP, Danlos syndrome: Relationship between Pichurin P,Acosta A, Camilleri M. 2015. Ehlers Trivedi NN, Nelson C, DiMaggio T, Jones joint hypermobility, urinary incontinence, Danlos syndrome and gastrointestinal manifes- N, Matthews H, Lewis KL, Oler AJ, Carlson and pelvic floor prolapse. Gynecol Obstet tations: A 20-year experience at Mayo Clinic. RJ, Arkwright PD, Hong C, Agama S, Invest 41:135–139. Neurogastroenterol Motil 27:1657–1666. 68 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

Nijs J, Meeus M, De Meirleir K. 2006. Chronic Reinstein E, Pariani M, Bannykh S, Rimoin DL, RH. 2016a. Generalized hyperalgesia in musculoskeletal pain in chronic fatigue Schievink WI. 2013. Connective tissue children and adults diagnosed with hyper- syndrome: Recent developments and thera- spectrum abnormalities associated with mobility syndrome and Ehlers-Danlos syn- peutic implications. Manl Ther 11:187–191. spontaneous cerebrospinal fluid leaks: A drome hypermobility type: A discriminative Norton PA, Baker JE, Sharp HC, Warenski JC. prospective study. Eur J Hum Genet analysis. Arthritis Care Res Aug 2 [Epub 1995. Genitourinary prolapse and joint 21:386–390. ahead of print]. hypermobility in women. Obstet Gynecol Rodrigues VJ, Elsayed S, Loeys BL, Dietz HC, Scheper MC, Juul-Kristensen B, Rombaut L, 85:225–228. Yousem DM. 2009. Neuroradiologic man- Rameckers EZ, Verbunt J, Engelbert RH. Nosouhian S, Haghighat A, Mohammadi I, ifestations of Loeys-Dietz syndrome type 1. 2016b. Disability in adolescents and adults Shadmehr E, Davoudi A, Badrian H. AJNR Am J Neuroradiol 30:1614–1619. diagnosed with hypermobility-related dis- 2015. Temporomandibular joint hypermo- Rombaut L, Malfait F, Cools A, De Paepe A, orders: A meta-analysis. Arch Phys Med bility manifestation based on clinical obser- Calders P. 2010. Musculoskeletal com- Rehab 97:2174–2187. vations. J Intl Oral Health 7:1–4. plaints, physical activity and health-related Scott D, Bird H, Wright V. 1979. Joint laxity Ofluoglu D, Gunduz OH, Kul-Panza E, Guven Z. quality of life among patients with the leading to osteoarthritis. Rheumatol Reha- 2006. Hypermobility in women with fibro- Ehlers-Danlos syndrome hypermobility bil 18:167–169. myalgia syndrome. Clin Rheuamtol 25: type. Disabil Rehabil 32:1339–1345. Shultz SJ, Wideman L, Montgomery MM, 291–293. Rombaut L, Malfait F, De Paepe A, Rombaut S, Beasley KN, Nindl BC. 2012. Changes in Owens J. 2014. Insufficient sleep in adolescents Verbruggen G, De Wandele I, Calders P. serum collagen markers, IGF-I, and knee and young adults: An update on causes and 2011a. Impairment and impact of pain in joint laxity across the menstrual cycle. consequences. Pediatr 134:e921. female patients with Ehlers-Danlos syn- J Orthop Res 30:1405–1412. Pacey V, Tofts L, Adams RD, Munns CF, drome: A comparative study with fibromy- Simmonds JV, Keer RJ. 2007. Hypermobility and Nicholson LL. 2013. Exercise in children algia and rheumatoid arthritis. Arthritis the hypermobility syndrome. Man Ther with joint hypermobility syndrome and Rheum 63:1979–1987. 12:298–309. knee pain: A randomized controlled trial Rombaut L, Malfait F, De Wandele I, Cools A, Sinibaldi L, Ursini G, Castori M. 2015. comparing exercise into hypermobile versus Thijs Y, De Paepe A, Calders P. 2011b. Psychopathological manifestations of joint neutral knee extension. Pediatr Rheumatol Medication, surgery, and physiotherapy hypermobility and joint hypermobility Online 11:30. among patients with the hypermobility syndrome/Ehlers-Danlos syndrome, hy- Pacey V, Adams RD, Tofts L, Munns CF, type of Ehlers-Danlos syndrome. Arch permobility type: The link between con- Nicholson LL. 2015a. Joint hypermobility Phys Med Rehabil 92:1106–1112. nective tissue and psychological distress syndrome subclassification in paediatrics: Rombaut L, Malfait F,De Wandele I, Taes Y,Thijs revised. Am J Med Genet C Semin Med A factor analytic approach. Arch Dis Child Y, De Paepe A, Calders P. 2012. Muscle Genet 169C:97–106. 100:8–13. mass, muscle strength, functional perfor- Sipil€a K, Suominen AL, Alanen P, Heliovaara€ M, Pacey V, Tofts L, Adams RD, Munns CF, mance, and physical impairment in women Tittanen P, Kon€ onen€ M. 2011. Association Nicholson LL. 2015b. Quality of life with the hypermobility type of Ehlers- of clinical findings of temporomandibular prediction in children with joint hypermo- Danlos syndrome. Arthritis Care Res disorders (TMD) with self-reported muscu- bility syndrome. J Paediatr Child Health (Hoboken) 64:1584–1592. loskeletal pains. Eur J Pain 15:1061–1067. 51:689–695. Rombaut L, Scheper M, De WandeleI, De Vries J, Skinner HB, Wyatt MP, Stone ML, Hodgdon JA, Palmer S, Bailey S, Barker L, Barney L, Elliot A. Meeus M, Malfait F,Englebert R, Calders P. Barrack RL. 1986. Exercise-related knee 2014. The effectiveness of therapeutic 2015. Chronic pain in patients with the joint laxity. Am J Sport Med 14:30–34. exercise for joint hypermobility syndrome: hypermobility type of Ehlers-Danlos syn- Sleep Working Group and Committee on Ado- A systematic review. Physiotherapy 100: drome: Evidence for hyperalgesia. Clin lescence, and Council on School Health. 220–227. Rheumatol 34:1121–1129. 2014. American Academy of Pediatrics PlackettTP,KwonE,GaglianoRAJr.,Oh Rowe PC, Barron DF,Calkins H, Maumenee IH, Policy Statement: School start times for RC. 2014. Ehlers-Danlos syndrome- Tong PY, Geraghty MT. 1999. Orthostatic adolescents. Pediatrics 134:642–649. hypermobility type and hemorrhoids. intolerance and chronic fatigue syndrome Smith MT, Edwards RR, McCann UD, Case Rep Surg 2014:171–180. associated with Ehlers-Danlos syndrome. Haythornwaite JA. 2007. The effects of sleep Puledda F, Vigano A, Celletti C, Petolicchio B, J Pediatr 135:494–499. deprivation on pain inhibition and spontane- ToscanoM, Vicenzini E, Castori M, Laudani Rozen TD, Roth JM, Denenberg N. 2006. ous pain in women. Sleep 30:494–505. G, Valente D, Camerota F, Di Piero V. 2015. Cervical spine hypermobility as a predispos- Sorokin Y,Johnson MP,Rogowski N, Richardson A study of migraine characteristics in joint ing factor for the development of new daily DA, Evans MI. 1994. Obstetric and gyne- hypermobility syndrome a.k.a. Ehlers- persistent headache. Headache 45:828–829. cologic dysfunction in the Ehlers-Danlos Danlos syndrome, hypermobility type. Sacheti A, Szemere J, Bernstein B, Tafas T, syndrome. J Reprod Med 39:281–284. Neurol Sci 36:1417–1424. Schechter N, Tsipouras P. 1997. Chronic Sparto PJ, Parnianpour M, Reinsel TE, Simon S. Quatman CE, Ford KR, Myer GD, Paterno MV, pain is a manifestation of the Ehlers-Danlos 1997. The effect of fatigue on multijoint Hewett TE. 2008. The effects of gender syndrome. J Pain Symptom Manage 14: kinematics, coordination, and postural and pubertal status on generalized joint 88–93. stability during a repetitive lifting test. laxity in young athletes. J Sci Med Sport Sardeli C, Axelsen SM, Bek KM. 2005. Use of J Orthopaedic Sport Phys Therap 25:3–12. 11:257–263. porcine small intestinal submucosa in the Stanitski DF, Nadjarian R, Stanitski CL, Bawle E, Rahman N, Dunstan M, Teare MD, Hanks S, surgical treatment of recurrent rectocele in a Tsipouras P. 2000. Orthopaedic manifesta- Douglas J, Coleman K, Bottomly WE, patient with Ehlers-Danlos syndrome type tions of Ehlers-Danlos syndrome. Clin Campbell M, Berglund B, Nordenskjold€ III. Int Urogynecol J Pelvic Floor Dysfunct Orthop Relat Res 376:213–221. M, Forssell B, Burrows N, Lunt P, Young I, 16:504–505. Steinmann B, Royce PM, Superti-Furga A. 2002. Williams N, Bignell GR, Futreal A, Pope Scheper MC, de Vries JE, de Vos R, Verbunt J, The Ehlers-Danlos syndrome. In: Royce FM. 2003. Ehlers-Danlos syndrome with Nollet F, Engelbert RHH. 2013. General- PM, Steinmann B, editors. Connective severe early-onset periodontal disease (EDS- ized joint hypermobility in professional tissue and its heritable disorders, 2nd edition. VIII) is a distinct, heterogeneous disorder dancers: A sign of talent or vulnerability? New York (US): Wiley-Liss. pp 431–524. with one predisposition gene at chromo- Rheumatol 52:651–665. Stern CM, Pepin MJ, Stoler JM, Kramer DE, some 12p13. Am J Hum Genet 73:198–203. Scheper MC, de Vries JE, Verbunt J, Engelbert Spencer SA, Stein CJ. 2016. Musculoskeletal Reinstein E, Pimentel M, Pariani M, Nemec S, RH. 2015. Chronic pain in hypermobility conditions in a pediatric population with Sokol T, Rimoin DL. 2012. Visceroptosis of syndrome and Ehlers-Danlos syndrome Ehlers-Danlos syndrome. J Pediatr 3476: the bowel in the hypermobility type of (hypermobility type): It is a challenge. 31212–31214. Ehlers-Danlos syndrome: Presentation of a J Pain Res 20:591–601. Sundelin HE, Stephansson O, Johansson K, rare manifestation and review of the litera- Scheper MC, Pacey V, Rombaut L, Adams RD, Ludvigsson JE. 2017. Pregnancy outcome ture. Eur J Med Genet 55:548–551. Tofts L, Calders P, Nicholson LL, Engelbert in joint hypermobility syndrome and ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 69

Ehlers-Danlos syndrome. Acta Obstet Verbraecken J, Declerck A, Van de Heyning P, Westling L. 1992. Temporomandibular joint Gynecol Scand 96:114–119. De Backer W, Wouters EF. 2001. Evalua- dysfunction and systemic joint laxity. Swed Syx D, Symoens S, Steyaert W, De Paepe A, tion for sleep apnea in patients with Dent J Suppl 81:1–79. Coucke PJ, Malfait F. 2015. Ehlers-Danlos Ehlers-Danlos syndrome and Marfan: Wiesmann T, Castori M, Malfait F,Wulf H. 2014. syndrome, hypermobility type, is linked to A questionnaire study. Clin Genet Recommendations for anesthesia and chromosome 8p22-8p21.1 in an extended 60:360–365. perioperative management in patients with Belgian family. Dis Mark 2015:828970. Voermans NC, Knoop H, van de Kamp N, Hamel Ehlers-Danlos syndrome(s). Orphanet J Ting TV, Hashkes PJ, Schikler K, Desai AM, BC, Bleijenberg G, van Engelen BG. 2010a. Rare Dis 9:109. Spalding S, Kashikar-Zuck S. 2012. The role Fatigue is a frequent and clinically relevant Wijnhoven HA, de Vet HC, Picavet HS. 2006. of benign joint hypermobility in the pain problem in Ehlers-Danlos syndrome. Semin Explaining sex differences in chronic mus- experience in juvenile fibromyalgia: An Arthritis Rheum 40:267–274. culoskeletal pain in a general population. observational study. Pediatr Rheumatol Voermans NC, Knoop H, Bleijenberg G, van Pain 124:158–166. Online J 10:16. Engelen BG. 2010b. Pain in Ehlers-Danlos Wolf JM. 2009. Influence of ligamentous laxity Tinkle BT, Bird HA, Grahame R, Lavallee M, syndrome is common, severe, and associated and gender: Implications for hand surgeon. Levy HP, Sillence D. 2009. The lack of with functional impairment. J Pain Symp- J Hand Surg 34A:161–163. clinical distinction between the hypermo- tom Manag 40:370–378. Wright Clayton E. 2015. Beyond myalgic bility type of Ehlers-Danlos syndrome and Voermans NC, Knoop H, Bleijenberg G, van encephalomyelitis/chronic fatigue syn- the joint hypermobility syndrome (a.k.a. Engelen BG. 2011. Fatigue is associated with drome. An IOM report on redefining an hypermobility syndrome). Am J Med Genet muscle weakness in Ehlers-Danlos syn- illness. JAMA 313:1101–1102. Part A 149A:2368–2370. drome: An explorative study. Physiotherapy Yancey JR, Thomas SM. 2012. Chronic fatigue TobiasJH, Deere K, Palmer S, Clark EM, Clinch J. 97:170–174. syndrome: Diagnosis and management. Am 2013. Joint hypermobility is a risk factor for Weerakkody RA, Vandrovcova J, Kanonidou C, Fam Physician 86:741–746. musculoskeletal pain during adolescence. MuellerM,GampawarP,IbrahimY, Zarate N, Farmer AD, Grahame R, Mohammed Findings of a prospective cohort study. Norsworthy P, Biggs J, Abdullah A, SD, Knowles CH, Scott SM, Aziz Q. 2010. Arthrit Rheumat 65:1107–1115. Ross D, Black HA, Ferguson D, Cheshire Unexplained gastrointestinal symptoms and ToftsLJ, Elliot EJ, Munns C, Pacey V,Sillence DO. NJ, Kazkaz H, Grahame R, Ghali N, joint hypermobility: Is connective tissue 2009. The differential diagnosis of children Vandersteen A, Pope FM, Aitman TJ. the missing link? Neurogastroenterol Motil with joint hypermobility: A review of the 2016. Targeted next-generation sequenc- 22:252–e78. literature. Pediatr Rheumatol Online 7:1. ing makes new molecular diagnoses and Zeitoun JD, Lefevre JH, de Parades V,Sejourne C, van der Esch M, Steultjens M, Knol DL, Dinant H, expands genotype-phenotype relationship Sobhani I, Coffin B, Hamonet C. 2013. Dekker J. 2006. Joint laxity and the relation- in Ehlers-Danlos syndrome. Genet Med Functional digestive symptoms and quality ship between muscle strength and functional 18:1119–1127. of life in patients with Ehlers-Danlos ability in patients with osteoarthritis of the Wenstrup RJ, Meyer RA, Lyle JS, Hoechstetter L, syndromes: Results of a national cohort knee. Arthritis Rheum 55:953–959. Rose PS, Levy HP, Francomano CA. 2002. study on 134 patients. PLoS ONE 8:e80321. Veit-Rubin N, Cartwright R, Singh AU, Digesu Prevalence of aortic root dilation in the Zweers MC, Bristow J, Steijlen PM, Dean WB, GA, Fernando R, Khullar V. 2016. Associa- Ehlers-Danlos syndrome. Genet Med 4: Hamel BC, Otero M, Kucharekova M, tion between joint hypermobility and 112–117. Boezeman, Schalkwijk J. 2003. Haploinsuf- pelvic organ prolapse in women: A systemic Werker CL, Nijhof SL, van de Putte EM. 2013. ficiency of TNXB is associated with hyper- review and meta-analysis. Int Urogynecol J Clinical practice. Chronic fatigue syndrome. mobility type of Ehlers-Danlos syndrome. 27:491–493. Eur J Pediatr 172:1293–1298. Am J Hum Genet 73:214–217.