Evolving Medical Practice

RMMJ Rambam Maimonides Medical Journal Rambam Health Care Campus 2016 October; 7(4): e0034. ISSN: 2076-9172
Published online 2016 October 31. doi: 10.5041/RMMJ.10261.
Special Issue on Rheumatology
Guest Editor: Alexandra Balbir-Gurman, M.D.

Ehlers–Danlos Syndrome—Hypermobility Type: A Much Neglected Multisystemic Disorder

Yael Gazit, M.D., M.Sc.,1* Giris Jacob, M.D., Ph.D.,1,2 and Rodney Grahame, C.B.E., M.D., F.R.C.P., F.A.C.P.3

1Internal Medicine F and the Institute of Rheumatology, Tel Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2J. Recanati Autonomic Dysfunction Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
3Hypermobility Unit, London and Centre for Rheumatology, Division of Medicine, University College London, London, UK

*To whom correspondence should be addressed. E-mail: yaelhms@gmail.com

Abstract

Ehlers–Danlos syndrome (EDS)—hypermobility type (HT) is considered to be the most common subtype of EDS and the least severe one; EDS-HT is considered to be identical to the joint hypermobility syndrome and manifests with musculoskeletal complaints, joint instability, and soft tissue overuse injury. Musculoskeletal complaints manifest with joint pain of non-inflammatory origin and/or spinal pain. Joint instability leads to dislocation or subluxation and involves peripheral joints as well as central joints, including the temporomandibular joints, sacroiliac joints, and hip joints. Soft tissue overuse injury may lead to tendonitis and bursitis without joint inflammation in most cases. Ehlers–Danlos syndrome-HT carries a high potential for disability due to recurrent dislocations and subluxations and chronic pain. Throughout the years, extra-articular manifestations have been described, including cardiovascular, autonomic nervous system, gastrointestinal, hematologic, ocular, gynecologic, neurologic, and psychiatric manifestations, emphasizing the multisystemic nature of EDS-HT. Unfortunately, EDS-HT is under-recognized and inadequately managed, leading to neglect of these patients, which may lead to severe disability that almost certainly could have been avoided. In this review article we will describe the known manifestations of the extra-articular systems.

Keywords: Disability, Ehlers-Danlos syndrome, hypermobility syndrome, joint hypermobility, multisystemic, neglect

INTRODUCTION

The Ehlers–Danlos syndromes (EDSs) constitute a group of inherited disorders of connective tissue characterized by soft hyperextensible skin and joint hypermobility, distinguished by additional connective tissue manifestations.1 The Ehlers–Danlos syndrome was first described by Ehlers in Denmark in 1898 and Danlos in Paris in 1908. They published individual case studies with common features of ligamentous laxity and skin hyperextensibility.2 Ehlers–Danlos syndrome—hypermobility type (EDS-HT) is considered to be the most common subtype of EDS3,4 and the least severe one.3 It is characterized by joint laxity, soft, stretchy, and often semi-transparent skin, and musculoskeletal complications, without severe complications of arterial dissection or bowel rupture seen in EDS-vascular type,1,5 and without hemosiderotic scars and molluscoid pseudotumors seen in the EDS-classical type.1,6 Ehlers–Danlos syndrome-HT, now considered to be indistinguishable if not identical to the joint hypermobility syndrome (JHS), manifests with musculoskeletal complaints, joint instability, and soft tissue overuse injury.3,712 Musculoskeletal complaints manifest with joint pain of non-inflammatory origin and/or spinal pain. Joint instability leads to dislocation or subluxation and involves peripheral joints as well as central joints, including the temporomandibular joints (TMJ), sacroiliac joints, and hip joints.79 Soft tissue overuse injury may lead to tendonitis and bursitis10,11,12 without joint inflammation in most cases.3,11 Although an inflammatory component is rare, EDS-HT carries a high potential for disability13 due to recurrent dislocations and subluxations and chronic pain.8,11,12,14,15 Throughout the years, extra-articular manifestations have been described, including cardiovascular and autonomic nervous system,1622 gastrointestinal,19,23 hematologic,2426 ocular,27 gynecologic,19,2831 neurologic,19,25,32,33 and psychiatric manifestations,7,8,11,19,34,35 emphasizing the multisystemic nature of EDS-HT. Unfortunately, EDS-HT is under-recognized and inadequately managed,3638 leading to neglect of these patients which may lead to severe disability that almost certainly could have been avoided.39

GENERAL CHARACTERISTICS AND MANIFESTATIONS

Joint hypermobility (JH), defined as an excessive range of joint movement taking into consideration age, gender, and ethnic background, is inherited40,41 and may pose no problem. Acquired hypermobility may also result from changes in connective tissue in other diseases such as systemic lupus erythematosus.42 Joint hypermobility is recognized by the nine-point Beighton score43 (Figure 1) and includes passive dorsiflexion of each fifth finger greater than 90°, passive apposition of each thumb to the flexor surface of the forearm, hyperextension of each elbow greater than 10°, hyperextension of each knee greater than 10°, and ability to place the palms flat on the floor with the knees fully extended.

Figure 1Figure 1
Calculation of the Beighton Score.

Ehlers–Danlos syndrome-HT, now considered to be indistinguishable if not identical to the joint hypermobility syndrome (JHS),44 is a clinical condition of JH with symptoms of joint instability, arthralgia, myalgia, soft tissue injuries, and arthritis.45,46 Diagnosis relies on the Brighton criteria (Table 1).47,48 The predominant presenting complaint is pain, which is often widespread and longstanding, with patients reporting pain ranging from 15 days to 45 years.39,49 Chronic pain may start in adolescence (with 75% of hypermobile adolescents reporting symptoms by the age of 15) or even as late as the fifth or sixth decade of life.3,39,45 Severity sometimes correlates with the degree of joint instability.3,15 Fatigue and sleep disturbance, most probably secondary to severe chronic pain, subluxations, and dislocations while changing posture during sleep, are frequently associated.3,11,12,15 Affected individuals are often misdiagnosed with chronic fatigue syndrome, fibromyalgia, depression, hypochondriasis, and/or malingering prior to recognition of joint laxity and establishment of the correct underlying diagnosis.3 Over the last three decades it has become apparent that EDS-HT has a widespread distribution and is not manifested solely in the joints (Table 2).

Table 1Table 1
Revised Diagnostic Criteria for Ehlers-Danlos Hypermobility Type, a.k.a. Joint Hypermobility Syndrome (JHS).
Table 2Table 2
Multisystemic Nature of EDS-HT.

Cardiovascular and Autonomic Nervous System Manifestations
A mild degree of aortic root dilatation has been found in up to one-third of EDS-HT patients,20,21,22 necessitating echocardiographic evaluation and surveillance. Raynaud phenomenon was found in 38% of EDS-HT patients.19 Patients with EDS-HT may suffer from palpitations, chest pain, dizziness, pre-syncope, and syncope,17 which has been attributed in the past to mitral valve prolapse (MVP). Mitral valve prolapse was originally included in the earlier version of the Brighton criteria in 1986.47 With more modern evaluation techniques clinically significant MVP has not been found to be more prevalent among EDS-HT patients.21,22,50,51 For this reason MVP was removed from the Brighton criteria in 1998.48 The frequency of MVP among EDS-HT patients was found to be 28%–67% in more recent studies,52,53 but its clinical significance is not clear. Symptoms formerly attributed to MVP are now considered to be related to autonomic dysfunction, which was found to be highly prevalent among EDS-HT patients.1618

Gastrointestinal Manifestations
Gastroesophageal reflux was found in 57% of EDS-HT patients.19,23 Chronic gastrointestinal discomfort was reported in 86% of patients with EDS-HT, attributed to dyspepsia, gastritis, or gastroesophageal reflux. Irritable bowel syndrome was found among 62% of patients. Early satiety and delayed gastric emptying are reported and exacerbated by opioids.3

Hematologic Manifestations
Easy bruising and bleeding tendency is common in all EDS types, including EDS-HT.25 It manifests with prolonged bleeding time,24,26 oral mucosa fragility with mucosal bruises,9 and menometrorrhagia.54 Since coagulation tests are normal,2426 the underlying cause is presumed to be mechanically impaired collagen too weak to afford adequate protection to the capillaries. It is important to note that small and large arterial dissections have not been reported in EDS-HT.

Ocular Manifestations
Myopia has been found in up to 50% of EDS-HT patients,54 and high myopia of more than −6.0 diopters was found in 16% of patients compared with 0% in the control group.3,27 Strabismus was found in 7% of EDS-HT pediatric patients55 (as opposed to only 2%–4% of the general pediatric population), and it is often refractory to surgical correction.56 Meyer et al. found size variations and shape abnormalities of collagen fibrils in the extra-ocular muscles that control the movement of the eye.57

Gynecologic Manifestations
Dysmenorrhea and menorrhagia are common19,28,29,54,56 and thought to be due to muscle contractions occurring with greater force given the loose connective tissue. Dyspareunia was found among 30%–57% of EDS-HT women,28,29,58 thought to be caused by small tears in the vaginal surface and lack of appropriate vaginal secretions.56 Pelvic organ prolapse is common,19,28,29,56,5962 including uterine prolapse which was found in almost 40% of women with EDS-HT.49

Urologic Manifestations
In children with hypermobility constipation and fecal soiling were found to be more common in boys, and urinary tract infection and urinary incontinence more common among girls.63 In another pediatric series 13% of girls and 6% of boys suffered from urinary tract infections.64 Stress urinary incontinence was found in 40%–70% of women with EDS-HT,28,58,65 often earlier in life, thought to be due to a weakened pelvic floor, which may be worsened to bladder prolapse.56 Fecal incontinence was found in up to almost 15% of EDS-HT patients, as compared to only 2.2% of the general population.65 Rectal prolapse may also be found among EDS-HT patients.66 Furthermore, Dordoni et al. reported on two EDS-HT family members who suffered from visceroptosis, including bilateral kidney prolapse, gastric ptosis, liver prolapse, and ovarian and heart prolapse.67

Obstetric Manifestations
While labor and delivery might be rapid (shorter than 4 hours),19,29 and premature rupture of membranes is common,54,68,69 pregnancy in women with EDS-HT is generally normal with good maternal and neonatal outcome.30,70 However, joint laxity and pain may increase during pregnancy.3,29,30,54,70 Pelvic pain and instability necessitate the use of pelvic belt, crutches, and/or bed rest in 26% of women with EDS, the majority being EDS-HT (compared to only 7% among non-affected women).56,70 Varicose veins in the legs and the vulva are more common among pregnant women with EDS-HT.56

Dysautonomia, characterized by lightheadedness, dizziness, fainting, etc., may worsen during pregnancy,56 and when postural orthostatic tachycardia syndrome (POTS) is present a blood pressure fall was reported.71 Women with EDS-HT are more prone to postpartum hemorrhage (19% versus 7%) and complicated perineal wounds (8% versus none).70 Premature delivery was found to be more related to EDS-HT of the infant (40%), and was less prevalent if the mother had EDS-HT (21%).70

Neurologic Manifestations
A total of 40% of children with EDS-HT72 and 50% of adults14 suffer from headaches, characterized as chronic recurrent headaches in the absence of structural, congenital, or acquired central nervous system lesions that correlate with their symptoms.73 Many complain of headaches related to the neck or facial pain that might be related to jaw or TMJ problems.56 Headaches may also be part of dysautonomia, which was found in 78% of EDS-HT patients versus 10% of controls,17 characterized by dizziness/ lightheadedness and pre-syncopal episodes, which were found in 88% and 83% of patients, respectively. Partial or complete failure of local anesthesia was described during biopsies and dental or obstetric procedures.74,75 Hakim and Grahame found local anesthesia resistance in 58% of EDS-HT patients versus 21% of controls.32 Proprioceptive acuity has been found to be impaired among EDS-HT adult patients76,77 and pediatric patients.78 Postural instability and balance and gait impairment, resulting in increased frequency of falls, were found among EDS-HT patients as compared to matched healthy controls.79 Impaired proprioceptive acuity is thought to influence muscle strength. Therefore, improving muscle strength on the basis of proprioceptive impairment may be more important for reducing activity limitations than just improving muscle strength.80 Chiari 1 malformation type 1 was found in 4.7% of EDS-HT patients19 and may be associated with cranio-cervical instability and/or the tethered cord syndrome.

Psychiatric Manifestations
Fear of joint pain and/or instability may lead to avoidance behavior (kinesiophobia) and exacerbate dysfunction and disability.3,7 Depression and anxiety are more common among EDS-HT patients7,19,34 and are exacerbated by fatigue and pain.11,15

GENERAL REMARKS

The multisystemic nature of EDS-HT results in patients having difficulty coping with the syndrome, as well as medical personnel failing to understand the true nature of the condition. This may adversely affect the therapeutic relationship, giving rise to skepticism, resentment, distrust, and hostility on the part of the patient.3,7

Although EDS-HT is the most common type and the least severe type of EDS, it tends to be underdiagnosed and mistreated, sometimes leading to severe disability that may have been preventable if diagnosed and treated properly.64,81,82 A survey among physiotherapists in the UK found that only 32% of respondents received formal training in EDS-HT management.83 Patients perceive a lack of awareness of the syndrome among health professionals and describe delays in diagnosis and access to appropriate health care services.84 Many patients reported lengthy diagnosis trajectories and treatment for individual symptoms rather than EDS-HT as a whole. Receiving a correct diagnosis is necessary in order to access appropriate care pathways, for example, referral for physiotherapy for EDS-HT rather than for an acute single joint problem.84 A study conducted among military personnel found misdiagnosis of EDS-HT has a disabling impact on military personnel with EDS-HT who are exposed to strenuous physical activities.85 Significant neuromuscular and motor development problems have been found among a pediatric population, and delay in diagnosis resulted in poor control of pain and disruption of normal home life, schooling, and physical activities.64 Furthermore, they conclude that knowledge of the diagnosis and appropriate interventions are likely to be highly effective in reducing the morbidity and cost to the health and social services.64

DIAGNOSIS

Diagnosis relies on the revised Brighton criteria, but it is important to rule out other connective tissue disorders, especially Marfan syndrome and other types of EDS. Unfortunately, no genetic defect has been found, and for such a prevalent and complex genetic disorder multiple genes might be involved.

MEDICAL MANAGEMENT

Treatment requires multidisciplinary co-operation and consulting with a cardiologist with echocardiogram monitoring every 2–5 years, orthopedic surgeon with a follow-up once a year, oral and maxillofacial surgeon for temporomandibular joint involvement, gastroenterologist when gastrointestinal manifestations are present, ophthalmologist to rule out other connective tissue diseases and when ocular manifestations are present, urologist and urogynecologist when urologic manifestations are suspected, neurologist and neurosurgeon when prolonged headache is present to rule out Chiari 1, and psychiatry when anxiety and/or depression are suspected. Allergologic consultation may also be needed when there are multiple drug reactions and/or food allergies. An autonomic nervous system specialist should be consulted when signs and symptoms of POTS or other autonomic nervous system manifestations are present. Management includes physiotherapy and hydrotherapy aimed at symmetric and generalized muscle strengthening and proprioception acuity improvement, including deep connective tissue manipulations after each session, occupational therapy when wrists and fingers are involved, and cognitive behavioral therapy for proper adjustment to the chronic nature of the condition. Nutrition has an important role in treating EDS-HT, and nutritional deficiencies should be sought out and treated.

CONCLUSION

Ehlers–Danlos syndrome-HT is a complex hereditary disorder which is multisystemic, probably due to the prevalence of connective tissue in all body systems. Its gene defect has yet to be found and might be of multigenetic nature, but until then we have to think about the possibility of EDS-HT in every chronic pain patient, and look for joint hypermobility as well as other multisystemic manifestations of this prevalent syndrome.

Abbreviations

EDS Ehlers–Danlos syndrome
HT hypermobility type
JH joint hypermobility
JHS joint hypermobility syndrome
MVP mitral valve prolapse
TMJ temporomandibular joints

Footnotes

Conflict of interest: No potential conflict of interest relevant to this article was reported.

REFERENCES
1.
Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998;77:31–7. https://doi.org/10.1002/(SICI)1096-8628(19980428)77:1%3C31::AID-AJMG8%3E3.0.CO;2-O.
2.
Grahame R. Ehlers-Danlos syndrome. S Afr Med J. 2016;106:S45–6. https://doi.org/10.7196/SAMJ.2016.v106i6.10991.
3.
Levy, HP. Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 1993–2016 [accessed October 7, 2016]. Ehlers Danlos Syndrome, Hypermobility Type. Updated March 31, 2016. Available at: http://bit.ly/2ePdTyk.
4.
De Paepe A, Malfait F. The Ehler-Danlos syndrome, a disorder with many faces. Clin Genet. 2012;82:1–11. https://doi.org/10.1111/j.1399-0004.2012.01858.x.
5.
Pepin, MG.; Murray, ML.; Byers, PH. Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 1993–2016 [accessed October 7, 2016]. Vascular Ehlers-Danlos Syndrome. Updated Nov 19, 2015. Available at: http://bit.ly/2fiszsr.
6.
Malfait, F.; Wenstrup, R.; De Paepe, A. Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 1993–2016 [accessed October 7, 2016]. Ehlers-Danlos Syndrome, Classic Type. Updated Nov 19, 2015. Available at: http://bit.ly/2dL9wGW.
7.
Branson JA, Kozlowska K, Kaczynski KJ, Roesler TA. Managing chronic pain in a young adolescent girl with Ehlers-Danlos syndrome. Harv Rev Psychiatry. 2011;19:259–70. https://doi.org/10.3109/10673229.2011.614484.
8.
Hagberg C, Berglund B, Korpe L, Andersson-Norinder J. Ehlers-Danlos syndrome (EDS) focusing on oral symptoms: a questionnaire study. Orthod Craniofac Res. 2004;7:178–85. https://doi.org/10.1111/j.1601-6343.2004.00288.x.
9.
De Coster PJ, Martens LC, De Paepe A. Oral health in prevalent types of Ehlers-Danlos syndromes. J Oral Pathol Med. 2005;34:298–307. https://doi.org/10.1111/j.1600-0714.2004.00300.x.
10.
Rombaut L, Malfait F, Cools A, De Paepe A, Calders P. Musculoskeletal complaints, physical activity and health-related quality of life among patients with the Ehlers-Danlos syndrome hypermobility type. Disabil Rehabil. 2010;32:1339–45. https://doi.org/10.3109/09638280903514739.
11.
Rombaut L, Malfait F, De Paepe A, et al. Impairment and impact of pain in female patients with Ehlers-Danlos syndrome: a comparative study with fibromyalgia and rheumatoid arthritis. Arthritis Rheum. 2011;63:1979–87. https://doi.org/10.1002/art.30337.
12.
Rombaut L, Malfait F, De Wandele I, et al. Medication, surgery, and physiotherapy among patients with the hypermobility type of Ehlers-Danlos syndrome. Arch Phys Med Rehabil. 2011;92:1106–12. https://doi.org/10.1016/j.apmr.2011.01.016.
13.
Voermans NC, Knoop H. Both pain and fatigue are important possible determinants of disability in patients with the Ehlers-Danlos syndrome hypermobility type. Disab Rehabil. 2011;33:706–7. https://doi.org/10.3109/09638288.2010.531373.
14.
Sacheti A, Szemere J, Bernstein B, Tafas T, Schechter N, Tsipouras P. Chronic pain is a manifestation of the Ehlers-Danlos syndrome. J Pain Symptom Manage. 1997;14:88–93. https://doi.org/10.1016/S0885-3924(97)00007-9.
15.
Voermans NC, Knoop H, Bleijenberg G, van Engelen BG. Pain in ehlers-danlos syndrome is common, severe, and associated with functional impairment. J Pain Symptom Manage. 2010;40:370–8. https://doi.org/10.1016/j.jpainsymman.2009.12.026.
16.
Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY, Geraghty MT. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatr. 1999;135:494–9. https://doi.org/10.1016/S0022-3476(99)70173-3.
17.
Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med. 2003;115:33–40. https://doi.org/10.1016/S0002-9343(03)00235-3.
18.
Mathias CJ, Low DA, Iodice V, Owens AP, Kirbis M, Grahame R. Postural tachycardia syndrome--current experience and concepts. Nat Rev Neurol. 2011;8:22–34. https://doi.org/10.1038/nrneurol.2011.187.
19.
Castori M, Camerota F, Celletti C, et al. Natural history and manifestations of the hypermobility type Ehlers-Danlos syndrome: a pilot study on 21 patients. Am J Med Genet A. 2010;152A:556–64.
20.
Wenstrup RJ, Meyer RA, Lyle JS, et al. Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet Med. 2002;4:112–17. https://doi.org/10.1097/00125817-200205000-00003.
21.
McDonnell NB, Gorman BL, Mandel KW, et al. Echocardiographic findings in classical and hypermobile Ehlers-Danlos syndromes. Am J Med Genet A. 2006;140:129–36. https://doi.org/10.1002/ajmg.a.31035.
22.
Atzinger CL, Meyer RA, Khoury PR, Gao Z, Tinkle BT. Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome. J Pediatr. 2011;158:826–30.e1.
23.
Levy HP, Mayoral W, Collier K, Tio TL, Francomano CA. Gastroesophageal reflux and irritable bowel syndrome in classical and hypermobile Ehlers Danlos syndrome (EDS). Am J Hum Genet. 1999;65:A69.
24.
Anstey A, Mayne K, Winter M, Van de Pette J, Pope FM. Platelet and coagulation studies in Ehlers-Danlos syndrome. Br J Dermatol. 1991;125:155–63. https://doi.org/10.1111/j.1365-2133.1991.tb06063.x.
25.
De Paepe A, Malfait F. Bleeding and bruising in patients with Ehlers-Danlos syndrome and other collagen vascular disorders. Br J Haematol. 2004;127:491–500. https://doi.org/10.1111/j.1365-2141.2004.05220.x.
26.
Mast KJ, Nunes ME, Ruymann FB, Kerlin BA. Desmopressin responsiveness in children with Ehlers-Danlos syndrome associated bleeding symptoms. Br J Haematol. 2009;144:230–3. https://doi.org/10.1111/j.1365-2141.2008.07446.x.
27.
Gharbiya M, Moramarco A, Castori M, et al. Ocular features in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type: a clinical and in vivo confocal microscopy study. Am J Ophthalmol. 2012;154:593–600.e1. https://doi.org/10.1016/j.ajo.2012.03.023.
28.
McIntosh LJ, Mallett VT, Frahm JD, Richardson DA, Evans MI. Gynecologic disorders in women with Ehlers-Danlos syndrome. J Soc Gynecol Investig. 1995;2:559–64.
29.
Castori M, Morlino S, Dordoni C, et al. Gynecologic and obstetric implications of the joint hypermobility syndrome (a.k.a. Ehlers – Danlos syndrome hypermobility type) in 82 Italian patients. Am J Med Genet Part A. 2012;158A:2176–82. https://doi.org/10.1002/ajmg.a.35506.
30.
Volkov N, Nisenblat V, Ohel G, Gonen R. Ehlers-Danlos syndrome: insights on obstetric aspects. Obstet Gynecol Surv. 2007;62:51–7. https://doi.org/10.1097/01.ogx.0000251027.32142.63.
31.
Dutta I, Wilson H, Oteri O. Pregnancy and delivery in ehlers-danlos syndrome (hypermobility type): review of the literature. Obstet Gynecol Int. 2011;2011:306413. https://doi.org/10.1155/2011/306413.
32.
Hakim AJ, Grahame R, Norris P, Hopper C. Local anaesthetic failure in joint hypermobility syndrome. J R Soc Med. 2005;98:84–5. https://doi.org/10.1258/jrsm.98.2.84.
33.
Milhorat TH, Bolognese PA, Nishikawa M, McDonnell NB, Francomano CA. Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and chiari malformation type I in patients with hereditary disorders of connective tissue. J Neurosurg Spine. 2007;7:601–9. https://doi.org/10.3171/SPI-07/12/601.
34.
Baeza-Velasco C, Gély-Nargeot MC, Bulbena Vilarrasa A, Bravo JF. Joint hypermobility syndrome: problems that require psychological intervention. Rheumatol Int. 2011;31:1131–6. https://doi.org/10.1007/s00296-011-1839-5.
35.
Bulbena A, Duro JC, Porta M, et al. Anxiety disorders in the joint hypermobility syndrome. Psychiatry Reserve. 1993;46:59–68. https://doi.org/10.1016/0165-1781(93)90008-5.
36.
Grahame R. Time to take hypermobility seriously (in adults and children). Rheumatology (Oxford). 2001;40:485–7. https://doi.org/10.1093/rheumatology/40.5.485.
37.
Gurley-Green S. Living with the hypermobility syndrome. Rheumatology (Oxford). 2001;40:487–9. https://doi.org/10.1093/rheumatology/40.5.487.
38.
Keer, R.; Grahame, R. Hypermobility Syndrome—Recognition and Management for Physiotherapists. London: Butterworth-Heinemann; 2003.
39.
Simmonds JV, Keer RJ. Hypermobility and the hypermobility syndrome. Man Ther. 2007;12:298–309. https://doi.org/10.1016/j.math.2007.05.001.
40.
Child AH. Joint hypermobility syndrome: inherited disorder of collagen synthesis. J Rheumatol. 1986;13:239–43.
41.
Beighton, P.; Grahame, R.; Bird, HA. Genetic Aspects of the Hypermobility Syndrome. In: Beighton P, Grahame R, Bird HA. , editors. Hypermobility of Joints. 2nd ed. Berlin, Germany: Springer; 1989. pp. 55–66. https://doi.org/10.1007/978-1-4471-3900-3_5.
42.
Beighton, P.; Grahame, R.; Bird, HA. Clinical Features of Hypermobility Syndrome. In: Beighton P, Grahame R, Bird HA. , editors. Hypermobility of Joints. 2nd ed. Berlin, Germany: Springer; 1989. pp. 67–84. https://doi.org/10.1007/978-1-4471-3900-3_6.
43.
Beighton PH, Solomon L, Soskolne CL. Articular mobility in an African population. Ann Rheum Dis. 1973;32:413–18. https://doi.org/10.1136/ard.32.5.413.
44.
Grahame, R. Hypermobility and Hypermobility Syndrome. In: Keer R, Grahame R. , editors. Hypermobility Syndrome—Recognition and Management For Physiotherapists. London, UK: Butterworth-Heinemann; 2003. pp. 1–14. https://doi.org/10.1016/B978-0-7506-5390-9.50005-8.
45.
Kirk JA, Ansell BM, Bywaters EL. The hypermobility syndrome. Ann Rheum Dis. 1967;26:419–25. https://doi.org/10.1136/ard.26.5.419.
46.
Grahame R. Joint hypermobility: clinical aspects. Proc R Soc Med. 1971;64:32–4.
47.
Beighton P, De Paepe A, Danks D, et al. International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986. Am J Med Genet. 1988;29:581–94. https://doi.org/10.1002/ajmg.1320290316.
48.
Grahame R, Bird HA, Child A. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol. 2000;27:1777–9.
49.
El-Shahaly HA, el-Sherif AK. Is the benign joint hypermobility syndrome benign? Clin Rheumatol. 1991;10:302–7. https://doi.org/10.1007/BF02208695.
50.
Dolan AL, Mishra MB, Chambers JB, Grahame R. Clinical and echocardiographic survey of the Ehlers-Danlos syndrome. Br J Rheumatol. 1997;36:459–62. https://doi.org/10.1093/rheumatology/36.4.459.
51.
Mishra MB, Ryan P, Atkinson P, et al. Extra-articular features of benign joint hypermobility syndrome. Br J Rheumatol. 1996;35:861–6. https://doi.org/10.1093/rheumatology/35.9.861.
52.
Camerota F, Castori M, Celletti C, et al. Heart rate, conduction and ultrasound abnormalities in adults with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. Clin Rheumatol. 2014;33:981–7. https://doi.org/10.1007/s10067-014-2618-y.
53.
Kozanoglu E, Coskun Benlidayi I, Eker Akilli R, Tasal A. Is there any link between joint hypermobility and mitral valve prolapse in patients with fibromyalgia syndrome? Clin Rheumatol. 2016;35:1041–4. https://doi.org/10.1007/s10067-015-3024-9.
54.
Ainsworth SR, Aulicino PL. A survey of patients with Ehlers-Danlos syndrome. Clin Orthop Rel Res. 1993;286:250–256. https://doi.org/10.1097/00003086-199301000-00037.
55.
Pemberton JW, MacKenzie Freeman H, Schepens CL. Familial retinal detachment and the Ehlers-Danlos syndrome. Arch Ophthalmol. 1966;76:817–24. https://doi.org/10.1001/archopht.1966.03850010819007.
56.
Tinkle, BT. A Guide for the Issues & Management of Ehlers-Danlos Syn-drome Hypermobility Type and The Hypermobility Syndrome. Niles, IL: Left Paw Press, LLC; 2010. Joint Hypermobility Handbook.
57.
Meyer E, Ludatcher RM, Zonis S. Collagen fibril abnormalities in the extraocular muscles in Ehlers-Danlos syndrome. J Pediatr Opthalmol Strabismus. 1988;25:67–72.
58.
Castori M, Camerota F, Celletti C, Grammatico P, Padua L. Quality of life in the classic and hypermobility types of Ehlers-Danlos syndrome. Ann Neurol. 2010;67:145–7. https://doi.org/10.1002/ana.21934.
59.
Al-Rawi ZS, Al-Rawi ZT. Joint hypermobility in women with genital prolapse. Lancet. 1982;1:1439–41. https://doi.org/10.1016/S0140-6736(82)92453-9.
60.
Norton PA, Baker JE, Sharp HC, Warenski JC. Genitourinary prolapsed and joint hypermobility in women. Obstet Gynecol. 1995;85:225–8. https://doi.org/10.1016/0029-7844(94)00386-R.
61.
Carley ME, Schaffer J. Urinary incontinence and pelvic organ prolapsed in women with Marfan or Ehlers Danlos syndrome. Am J Obstet Gynecol. 2000;182:1021–3. https://doi.org/10.1067/mob.2000.105410.
62.
Aydeniz A, Dikensoy E, Cebesoy B, Altinadaq O, Gursoy S, Balat O. The relation between genitourinary prolapsed and joint hypermobility in Turkish women. Arch Gynecol Obstet. 2010;281:301–4. https://doi.org/10.1007/s00404-009-1103-3.
63.
de Kort LM, Verhulst JA, Engelbert RH, Uiterwaal CS, de Jong TP. Lower urinary tract dysfunction in children with generalized hypermobility of joints. J Urol. 2003;170:1971–4. https://doi.org/10.1097/01.ju.0000091643.35118.d3.
64.
Adib N, Davies K, Grahame R, Woo P, Murray KJ. Joint hypermobility syndrome in childhood A not so benign multisystem disorder. Rheumatology (Oxford). 2005;44:744–50. https://doi.org/10.1093/rheumatology/keh557.
65.
Arunkalaivanan AS, Morrison A, Jha S, Blann A. Prevalence of urinary and faecal incontinence among female members of the Hypermobility Syndrome Association (HMSA). J Obstet Gyneacol. 2009;29:126–8. https://doi.org/10.1080/01443610802664747.
66.
Grahame R. Pain, distress and joint hyperlaxity. Joine Bone Spine. 2000;67:157–63.
67.
Dordoni C, Ritelli M, Venturini M, et al. Recurring and generalized visceroptosis in Ehlers-Danlos syndrome hypermobility type. Am J Med Genet A. 2013;161A:1143–7. https://doi.org/10.1002/ajmg.a.35825.
68.
Taylor DJ, Wilcox I, Russell JK. Ehlers-Danlos syndrome during pregnancy: a case report and review of the literature. Obstet Gynecol Surv. 1981;36:277–81. https://doi.org/10.1097/00006254-198106000-00001.
69.
De Vos M, Nuytinck L, Verellen C, De Paepe A. Preterm premature rupture of membranes in a patient with the hypermobility type of the Ehlers-Danlos syndrome. A case report. Fetal Diagn Ther. 1999;14:244–7. https://doi.org/10.1159/000020930.
70.
Lind J, Wallenburg HC. Pregnancy and the Ehler-Danlos syndrome: a retrospective study in a Dutch population. Acta Obstet Gynecol Scand. 2002;81:293–300. https://doi.org/10.1034/j.1600-0412.2002.810403.x.
71.
Jones TL, Ng C. Anaesthesia for caesarean section in a patient with Ehlers-Danlos syndrome associated with postural orthostatic tachycardia syndrome. Int J Obstet Anesth. 2008;17:365–9. https://doi.org/10.1016/j.ijoa.2008.04.003.
72.
Mato H, Berde T, Hasson N, Grahame R, Maillard S. A review of symptoms with benign joint hypermobility syndrome in children. Ped Rheumatol. 2008;6(Suppl 1):P155. https://doi.org/10.1186/1546-0096-6-S1-P155.
73.
Jacome DE. Headache in Ehlers-Danlos syndrome. Cephalalgia. 1999;19:791–6. https://doi.org/10.1046/j.1468-2982.1999.1909791.x.
74.
Kaalund S, Hogsaa B, Grevy C, Oxlund H. Reduced strength of skin in Ehlers-Danlos syndrome type III. Scand J Rheumatol. 1990;19:67–70. https://doi.org/10.3109/03009749009092623.
75.
Arendt-Nielsen L, Kaalund S, Bjerring P, Hogsaa B. Insufficient effect of local analgesics in Ehlers-Danlos type III patients (connective tissue disorder). Acta Anaesth Scand. 1990;34:358–61. https://doi.org/10.1111/j.1399-6576.1990.tb03103.x.
76.
Mallik AK, Ferrell WR, McDonals AG, Sturrock RD. Impaired proprioceptive acuity at the proximal interphalangeal joint in patients with the hypermobility syndrome. Br J Rheumatol. 1994;33:631–7. https://doi.org/10.1093/rheumatology/33.7.631.
77.
Hall MG, Ferrell WR, Sturrock RD, Hamblen DL, Baxendale RH. The effect of the hypermobility syndrome on knee joint proprioception. Br J Rheumatol. 1995;34:121–5. https://doi.org/10.1093/rheumatology/34.2.121.
78.
Fatoye F, Palmar S, Macmillan F, Rowe P, van der Linden M. Proprioception and muscle torque deficits in children with hypermobility syndrome. Rheumatology (Oxford). 2009;48:152–7. https://doi.org/10.1093/rheumatology/ken435.
79.
Rombaut L, Malfait F, De Wandele I, et al. Balance, gait, falls, and fear of falling in women with the hypermobility type of Ehlers-Danlos syndrome. Arthritis Care Res (Hoboken). 2011;63:1432–9. https://doi.org/10.1002/acr.20557.
80.
Scheper M, Rombaut L, de Vreis J, et al. The association between muscle strength and activity limitations in patients with the hypermobility type of Ehlers-Danlos syndrome: the impact of proprioception. Disabil Rehabil. 2016 Jun 24;:1–7. [Epub ahead of print].
81.
Grahame R. Joint hypermobility: emerging disease or illness behavior? Clin Med (Lond). 2013;13(Suppl 6):s50–2. https://doi.org/10.7861/clinmedicine.13-6-s50.
82.
Wolf JM, Cameron KL, Owens BD. Impact of joint laxity and hypermobility on the musculoskeletal system. J Am Acad Orthop Surg. 2011;19:463–71. https://doi.org/10.5435/00124635-201108000-00002.
83.
Palmar S, Cramp F, Lewis R, Muhammad S, Clark E. Diagnosis, management and assessment if adults with joint hypermobility syndrome: a UK-wide survey of physiotherapy practice. Musculoskeletal Care. 2015;13:101–11. https://doi.org/10.1002/msc.1091.
84.
Terry RH, Palmer ST, Rimes KA, Clark CJ, Simmonds JV, Horwood JP. Living with joint hypermobility syndrome: patient experience of diagnosis, referral and self-care. Fam Pract. 2015;32:354–8. https://doi.org/10.1093/fampra/cmv026.
85.
Mullick G, Bhakuni DS, Shnmuganandan K, et al. Clinical profile of benign joint hypermobility syndrome from a tertiary care military hospital in India. Int J Rheum Dis. 2013;16:590–4. https://doi.org/10.1111/1756-185x.12024.