Hypermobility of Joints

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2 Hypermobility of Joints

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4 Peter Beighton Rodney Grahame Howard Bird Hypermobility of Joints Fourth Edition

5 Peter Beighton, OMB, MD, PhD FRCP, FRSSA Department of Human Genetics University of Cape Town Cape Town South Africa Rodney Grahame, CBE, MD, FRCP, FACP Department of Rheumatolgy University College Hospital London United Kingdom Howard Bird, MA, MD, FRCP Department of Musculo-Skeletal Medicine University of Leeds Leeds United Kingdom ISBN th Edition e-isbn ISBN rd Edition ISBN nd Edition ISBN st Edition DOI / Springer London Dordrecht Heidelberg New York British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Control Number: Springer-Verlag London Limited 2012 First published 1983 Second edition 1989 Third edition 1999 Fourth edition 2012 Whilst we have made considerable efforts to contact all holders of copyright material contained in this book, we may have failed to locate some of them. Should holders wish to contact the Publisher, we will be happy to come to some arrangement with them. Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licenses issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Printed on acid-free paper Springer is part of Springer Science+Business Media (

6 Foreword to the Fourth Edition It is an honour and a pleasure to introduce the fourth edition of this remarkable book on joint hypermobility to the clinical and scientific community. The authors of this book, Peter Beighton, Rodney Graham and Howard Bird are distinguished physicians with a long and solid professional expertise in the clinical and genetic aspects of articular hypermobility. Thanks to this landmark book, the first edition of which dates from 1983, the joint hypermobility syndrome became gradually recognized as an important and heterogeneous clinical entity that may bear significant impact on the physical and psychosocial well-being of affected individuals and their families. A major strength of this work is the comprehensive approach of the subject, whereby the authors address all medical aspects of the joint hypermobility syndrome, the clinical term that refers to the symptomatic status of articular hypermobility. Based on their vast clinical experience and wisdom, they systematically review the diagnostic challenges and management issues and illustrate the important contribution of joint hypermobility to the pathogenesis of rheumatological and orthopaedic manifestations. In addition, this fourth edition elaborates more extensively on the extra-articular manifestations such as autonomic dysfunction, proprioceptive impairment and chronic pain which may significantly increase the morbidity of hypermobility conditions. Not less importantly, the authors highlight the socio-economic and psychological burden that is associated with the chronic pain and physical disabilities that may arise as consequences of the joint hypermobility syndromes, and draw attention to the multidisciplinary approach of medical management that should include a combination of medical, technical, physiotherapeutic strategies and where necessary behavioural techniques such as cognitive behavioural therapy. In addition to addressing the diagnostic, nosological and management issues, the authors also respond to the rapidly evolving scientific knowledge on the genetic and molecular basis of joint hypermobility, by including appropriate updates of the chapters on molecular collagen biology and on the expanding list of known heritable disorders in which joint hypermobility is a major clinical manifestation, such as the Ehlers Danlos syndrome. v

7 vi Foreword to the Fourth Edition Last but not least, the final chapter opens a window to future avenues for research by formulating some speculative but challenging topics for further study that will certainly keep the next generation of clinicians and scientists busy not only in trying to resolve unanswered research questions but also in translating their findings to effective therapies for the patients. And, although the authors claim that this is the last edition from their own hand, it is obvious that the hypermobility syndromes will remain a fascinating clinical and scientific field for many decades to come. A. De Paepe, M.D., Ph.D. Professor of Human and Medical Genetics Centre for Medical Genetics, Ghent University Ghent, Belgium

8 Preface It is now 28 years since the publication of the first edition of this book in 1983, and updated second and third editions appeared in 1989 and 1999 respectively. It seemed appropriate to once again re-visit this expanding and fascinating area, as urged by the late Professor Eric Bywaters in his foreword to the third edition. We are most grateful to Professor Anne de Paepe for gracing this fourth edition with a new foreword. The format is similar to that of previous monographs with the chapters on assessment, biomechanics and hypermobility in the performing arts and sports all updated. The introduction, the chapters on the molecular basis of hypermobility, illustrative case histories and the heritable hypermobility syndromes have been completely re-written. The clinical chapters have also been re-written, with specific division between articular and extra-articular features. With the expectation that this edition will be the last from our own pens, the innovative Chap. 10 speculates on future avenues for research that might provoke ideas and provide content for a future edition, probably with different editors, a decade hence. The last 10 years have seen significant advances in nosology of heritable hypermobility syndromes and, in particular, in our understanding of the molecular basis of these conditions. The latter informs on the possible pathogenesis of more heterogeneous hypermobility syndromes in the context of our increasing realisation that joints act as a surrogate for clinical features associated with joint hypermobility in other parts of the body. Translational research in the field of hypermobility may lead to real advances in this interesting group of conditions, perhaps paving the way for medical management through manipulation of cytokines connected with growth and eventually even with genetic engineering. Peter Beighton Rodney Grahame Howard Bird vii

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10 Acknowledgements The authors would like to thank the following for their contribution: Karl Ernest Kadler, B.Sc. (Hons), Ph.D. and Gillian Anne Wallis, B.Sc. (Hons), M.A., Ph.D. Faculty of Medicine and Human Sciences and Faculty of Life Sciences University of Manchester Michael Smith Building Manchester M13 9PT, United Kingdom ix

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12 Contents 1 Introduction to Hypermobility Historical Background Rheumatological Manifestations Extra-Articular Manifestations of Hypermobility Late Effects of Hypermobility Measurement of Joint Hypermobility Syndromic Associations of Joint Hypermobility Nosology of the Hypermobility Syndromes... 5 References Assessment of Hypermobility Simple Scoring Systems for Hypermobility The Brighton Criteria for Hypermobility Syndrome General Principles of More Precise Measurement at Selected Joints Back and Spinal Mobility Rotation in the Limbs Movement at the Metacarpophalangeal Joint Joint Proprioception Correlations Between Scoring Systems Used in Assessing Joint Laxity Variation of Joint Laxity Within Populations Clinical Applications of Scoring Systems Joint Hypolaxity References The Molecular Basis of Joint Hypermobility Introduction The Family of Fibril-Forming Collagens Genes Encoding Type I and V Collagens Biosynthesis of Type I and V Collagens xi

13 xii Contents 3.5 Collagen Fibril Assembly EDS and Type I Collagen EDS and ADAMTS EDS and Lysyl Hydroxylase EDS and Type V Collagen EDS and Tenascin-X EDS and Type VI Collagen Relationship Between Elastic Fibre Abnormalities, Marfan Syndrome and EDS Conclusions References Biomechanics of Hypermobility: Selected Aspects Mechanical Factors in Joint Mobility Relative Contributions of Different Factors Bony Surfaces Collagen Neuromuscular Control Proprioception Podiatric Aspects Lubrication and Stiffness Lubrication of the Synovial Membrane Measurement of Stiffness Artificial Lubricants Hypermobility and Osteoarthritis Prospects for Surgical Intervention References Musculoskeletal Features of Hypermobility and Their Management Hypermobility and Hypermobility Syndrome Impaired Healing Epidemiology of JHS The Clinical Significance of Hypermobility Musculoskeletal Features Hypermobility Syndrome in Children Epidemiology Clinical Presentation in Childhood Hypermobility in Adults Prevalence Role of Lax Ligaments Clinical Manifestations Articular Features Soft Tissue Lesions... 76

14 Contents xiii Chondromalacia Patellae Acute Articular and Peri-articular Traumatic Lesions Chronic Polyarthritis or Monoarticular Arthritis in Adults Dislocation of Joints Temporomandibular Joint Dysfunction Premature Osteoarthritis (Other Than TMJ) Spinal Complications Bone Fragility The Natural History of JHS and the Development of Chronic Pain Management of Articular Complications in the Hypermobility Syndrome General Management Specific Management Rest Local Steroid Injections Physiotherapy General Principles Passive Mobilisation Exercise Therapy Podiatry Surgical Intervention Soft Tissue Lesions Persistent Synovitis Recurrent Dislocation or Joint Instability Cervical or Lumbar Discectomy Surgery of the Foot Advanced Osteoarthritis Symptomatic Treatment Analgesic and Non-steroidal Anti-inflammatory Drugs Massage, Mobilisation, Hydrotherapy and Water Immersion Behavioural Techniques Acupuncture and Transcutaneous Neural Electrical Stimulation Denervation Procedures Support and Information References Extra-articular Manifestations of Hypermobility Introduction Weakness of Supporting Structures Including Pelvic Floor Insufficiency Mitral Valve Prolapse

15 xiv Contents Chronic Pain Proprioceptive Impairment Lack of Efficacy of Local Anaesthetics Autonomic Dysfunction Certain Psychiatric Disorders Functional Disorders of the Gastrointestinal Tract Straws in the Wind References Illustrative Case Histories Case 7.1: A 6-Year-Old Boy with EDS II/III with Grossly Unstable Hind Feet Case 7.2: Pelvic Floor Problems After Childbirth in a Patient with EDS Hypermobility Type Case 7.3: A Labral Tear and Autonomic Dysfunction Complicating Hypermobility Case 7.4: Complexities in Diagnosis and Management Case 7.5: Bony Abnormality and Complications of Subluxation Case 7.6: Arnold Chiari Malformation and Specialised Physiotherapy Case 7.7: The Performing Artist References Hypermobility in the Performing Arts and Sport Dancers Are Ballet Dancers Born or Made Is Generalised Joint Laxity an Asset or a Liability in Ballet Dancing? The Prevention of Injury Contortionists Historical Background Nosology and Semantics Training Socio-medical Implications Musicians Occupational Ills of Instrumentalists Illustrative Case Histories Repetitive Strain Syndrome Sport Joint Hypermobility in Selected Sports Joint Hypermobility in Cricket Joint Hypermobility in Yoga Hypermobility and Injury Training Methods to Improve Joint Flexibility Hormonal Aspects References

16 Contents xv 9 Heritable Hypermobility Syndromes Ehlers Danlos Syndrome General Features Nosology Diagnostic Considerations Rare Forms of the EDS Articular Manifestations Orthopaedic Management of Articular Problems Non-articular Complications Resources: Patient Support Groups Familial Articular Hypermobility Syndromes Nosology Articular Complications Other Phenotypic Manifestations Miscellaneous Joint Laxity Syndromes Joint Laxity in Inherited Connective Tissue Disorders Skeletal Dysplasias with Predominant Joint Laxity Dwarfing Dysplasias with Variable Joint Laxity Genetic Syndromes in Which Hypermobility Is Overshadowed by Other Manifestations References Future Avenues for Research Arterial Elasticity Cytokine Modulation Candidate Genes Disease Association: True or Artefactual? Neurological Aspects Podiatry Hormonal Aspects Joint Hypermobility as a Model of Accelerated Osteoarthritis References Index

17 Chapter 1 Introduction to Hypermobility 1.1 Historical Background The first clinical description of articular hypermobility is attributed to Hippocrates, who, in the fourth century B.C., described the Scythians, a race of Iranian horseriding nomads inhabiting the region that now forms the Ukraine, as having humidity, flabbiness and atony such that they were unable to use their weapons. Their main problem in warfare was that hyperlaxity of the elbow and shoulder joints prevented them from drawing their bows effectively. Thereafter, the study of joint hypermobility was ignored until the late nineteenth century, when general physicians were energetically defining medical syndromes, some of which included joint hypermobility as an important feature. Notable amongst these were Ehlers Danlos syndrome (EDS) and Marfan syndrome. The last 50 years have seen the recognition of joint hypermobility, without obvious widespread connective tissue abnormality, as a cause of orthopaedic and rheumatological symptoms. In investigations on a small number of subjects, Finkelstein 1 and Key 2 noted a familial predisposition to lax joints. Subsequently, orthopaedic surgeons recognised the importance of generalised joint laxity in the pathogenesis of dislocation of a single joint. Congenital dislocation of the hip was investigated by Massie and Howarth 3 and Carter and Wilkinson. 4 Carter and Sweetnam studied dislocation of the patella 5 and dislocation of the patella and shoulder. 6 Thereafter, generalised joint laxity was recognised as being more common than had previously been realised. This led to the introduction of simple clinical scoring systems for measuring joint laxity in affected individuals and populations. The first report of an association between joint laxity and rheumatological symptoms emanated from Sutro, 7 who described 13 young adults with effusions and pain in hypermobile knees and ankles. Similar clinical observations led Kirk et al. 8 to define the hypermobility syndrome in a group of patients with joint laxity and musculoskeletal complaints. In the absence of demonstrable systemic rheumatological disease, these authors attributed the symptoms to articular hypermobility. P. Beighton et al., Hypermobility of Joints, DOI / _1, Springer-Verlag London Limited

18 2 1 Introduction to Hypermobility Wood 9 argued from the epidemiological viewpoint that joint hypermobility should be considered as a graded trait rather than as an all or nothing syndrome. This is a simplistic concept, and there is general agreement amongst colleagues with clinical experience that the category loose-jointed persons contains not only those at the upper end of the normal spectrum but also examples of familial articular hypermobility syndromes (see Chaps. 5 and 6 ). The decade prior to the publication of the third edition of this book in 1999 brought an increased recognition of the importance of inheritance of joint laxity in the pathogenesis of a variety of rheumatological problems. Biomolecular studies 10 were then in their infancy and have advanced considerably since (see Chap. 3 ). The last decade has drawn increasing attention to the manifestations of the hypermobility syndrome at sites in the body other than the joints. Features such as compression neuropathy and involvement of the cardiovascular system have long been recognised. To this has recently been added involvement of the autonomic nervous system and the bowel. At the joints, understanding of the different factors that contribute to the observed range of joint movement has advanced with attention not just to the structure of collagen and shape of the bony articulating surfaces at each individual joint 11 but also to the nuances of neuromuscular control and their links to impairment in joint proprioception, which often occurs. In the field of translational science, hypermobility syndrome, once relatively unfashionable, is providing a fertile area for fundamental studies in many different areas of medicine (see Chap. 10 ). 1.2 Rheumatological Manifestations It is apparent that symptoms arising from lax joints may commence at any age. In their classic paper, Kirk et al. 8 described 24 patients with generalised joint hypermobility. Their symptoms started between the ages of 3 and 55 years, and threequarters had problems before the age of 15. Females were more frequently affected than males. Symptoms were mainly in the lower limbs, the commonest being pain in the knees and ankles, although joint effusions and muscle cramps also occurred. Supraspinatus and bicipital tendonitis, tennis elbow and painful Achilles tendons were also noted. In a comprehensive review, Ansell 12 mentioned that symptoms occur after, rather than during, unaccustomed exercise and diminish in later life, perhaps as the joints stiffen. Although the prognosis is good, other arthropathies must be excluded before making a diagnosis of the hypermobility syndrome. Thus, in 690 new referrals to a paediatric rheumatology unit, hypermobility was considered to be the final diagnosis in only 12 referrals. Most clinicians now, however, agree that the condition is under-diagnosed, 13 and some series from general practice have suggested that hypermobility accounts for up to one-fifth of all musculoskeletal referrals in children but also in adults (J. Dickson 2009, personal communication).

19 1.4 Late Effects of Hypermobility 3 Some persons consider themselves to be double jointed or loose limbed. There is often a family history of loose joints, and they may be talented at activities such as dance (see Chap. 8 ). By contrast, symptomatic patients are sometimes labelled as neurotic when medical practitioners who are unaware of the syndrome are unable to explain their symptoms. The hypermobile individual may be especially at risk from chronic back pain, disc prolapse and spondylolisthesis. In addition, the loose back syndrome, in which women with hypermobility develop unexplained back pain in the absence of demonstrable disc lesions and spondylitis, is now accepted as being more common than originally supposed. 14 The importance of both localised and generalised hypermobility in the pathogenesis of joint pains in children was emphasised by Lewkonia and Ansell. 15 In this context, Gedalia et al. 16 reported that 21 (66%) of 32 children with episodic arthritis had generalised joint laxity. These issues are discussed in Chap Extra-Articular Manifestations of Hypermobility The paucity of studies on extra-articular manifestations of familial hypermobility both in children 17 and adults 11 is being addressed, and this book covers recent developments in areas not previously considered to be relevant to joint hypermobility. To the strong impression that individuals with loose joints are susceptible to varicose veins, herniae and rupture of lung tissue leading to pneumothorax, have been added an increasing interest in mitral valve prolapse (floppy mitral valve syndrome), asthma, collagen structure in the bowel wall and at the sphincters and involvement of the autonomic nervous system affecting both the bowel and the vasculature (see Chap. 6 ). Dermal hyperelasticity is sometimes present in individuals with hypermobile joints, and various methods for measuring the physical properties of skin have been devised. These techniques have been used in EDS 18 19, 20 and in population studies. 1.4 Late Effects of Hypermobility Throughout the literature, it is widely held that premature osteoarthritis may be a direct consequence of hypermobility. However, final proof may only come from large and prospective long-term studies with adequate controls. In an investigation of EDS, which exhibits classical hypermobility, 16 out of a group of 22 individuals over the age of 40 had clinical osteoarthritis. The six persons without osteoarthritis had significantly less joint laxity. 21 Premature osteoarthritis was a feature of the hypermobile patients in the original studies of Kirk et al. 8 ; all affected patients were female with an age of onset of symptoms of years. The trapeziometacarpal joints and the cervical spine were the commonest sites of involvement in this group.

20 4 1 Introduction to Hypermobility In a radiological, histological and arthroscopic study, Bird et al. 22 drew attention to the way in which joint hyperlaxity apparently predisposes to a traumatic synovitis in the third decade and premature osteoarthritis in the fourth or fifth. Pyrophosphate is subsequently deposited in the unstable joint. Despite the foregoing, it is still uncertain whether loose-jointed persons have a significant propensity to develop osteoarthritis in later life. 23 We are also increasingly coming to understand the social consequences of hypermobility. Accounts from patients 24 eloquently describe the chronic difficulties often associated with this condition, not least the frequent confusion in definitive diagnosis and the dismissive attitude of the medical profession. 1.5 Measurement of Joint Hypermobility Clinicians and epidemiologists agree on the need to measure joint laxity. The first scoring system was devised by Carter and Wilkinson 4 and subsequently modified by successive authors. 25, 26 The method, which has gained general acceptance, is that derived by Beighton et al. 27 from the earlier scheme of Carter and Wilkinson. In this technique, a score of 0 9 is allocated to each individual, the highest scores denoting maximum joint laxity. Although more complex systems have been proposed, they are time-consuming and have not been widely used. Measurement of joint hypermobility in children is especially complex in view of the greater natural laxity in children compared to adults. 28 There is a substantial body of literature concerning the measurement of movements at individual joints. Methods include radiological assessment, 29 photographic techniques 30 and a pendulum machine devised by Barnett 31 for the calculation of the coefficient of resistance in the interphalangeal joints. Complicated or invasive techniques cannot be used in large population studies, and there has been some return to simple methods. Grahame and Jenkins 25 constructed a device to measure the angle of extension at the little finger when a standard force is applied. To some extent, this has been superseded by the Leeds Finger Hyperextensometer, which records the range of movement at the metacarpophalangeal joint of the index finger in response to a pre-set fixed torque. Quantitative measurements of joint mobility in adolescents were undertaken by Fairbank et al. 32 More recently, simple clinical techniques for the assessment of hypermobility have been used by Larsson et al. 33 for comparison of normal males and females, and by Wordsworth et al. 34 in a study of English Caucasians and Asian Indians. Recently, there has been some interest in measurement of neurological associations with joint hypermobility, particularly proprioception, with sophisticated devices now available for the accurate quantification of proprioception both at the knee and at the metacarpophalangeal joint. All methods of assessment are reviewed in detail in Chap. 2.

21 1.7 Nosology of the Hypermobility Syndromes Syndromic Associations of Joint Hypermobility Although no demonstrable hereditary disorder of connective tissue can be recognised in the majority of individuals with joint hypermobility, a proportion have specific genetic conditions such as EDS, familial articular hypermobility syndrome and Larsen syndrome (see Chap. 9 ). It is sometimes extremely difficult to diagnose minor forms of disorders of connective tissue. The characteristic picture of complete Marfan syndrome, with long thin limbs, ectopia lentis and dilatation of the ascending aorta, is easily recognised, but a definitive diagnosis is difficult in persons with mild manifestations. Similarly, although some varieties of EDS are easy to recognise, the hypermobility type, formerly EDS III, can closely mimic the familial articular hypermobility syndrome in both clinical presentation and mode of inheritance. 21 A survey of British consultant rheumatologists 35 demonstrated considerable confusion in the minds of these specialists as to the extent to which EDS type III could be teased apart from the less selective clinical features of benign familial hypermobility syndrome. A recent initiative from the USA 36 has suggested that for clinical purposes (and certainly for political purposes), the two conditions could be considered as the same entity, not least because treatment for each is broadly the same. It is of practical importance that joint hypermobility can occur as a secondary manifestation of inflammatory disorders such as rheumatoid arthritis. In these circumstances, the clinical picture is sometimes complicated by the presence of a neuropathy, which may accentuate joint hyperlaxity. Muscular hypotonia and drugs such as prednisolone and D-penicillamine, which alter the structure or physical properties of collagen, also influence joint laxity. The determination of the relative contributions of multiple aetiological factors, which influence the range of movements at a given joint, is a fascinating challenge to the clinician. 1.7 Nosology of the Hypermobility Syndromes Increasing interest in hypermobility has led to the subdivision of established disorders and the recognition of new entities. Problems have arisen, however, concerning syndromic boundaries, nomenclature and classification. There are considerable differences in the pathogenesis, natural history and prognosis in many of these conditions, and in these circumstances, diagnostic imprecision precludes optimal management. Similarly, the establishment of correlations between the clinical features (phenotype) and the underlying biomolecular defect is dependent upon the use of the same nosological system at both the clinical and laboratory levels. These problems first became apparent in EDS, where 11 types had been delineated and others proposed. The difficulty was accentuated when syndromes of familial articular hypermobility, without additional involvement of other tissues, were lumped together with EDS. In an attempt to bring order to this potentially chaotic situation, a Nosology Workshop was held at the Seventh International Congress of Human Genetics, Berlin,

22 6 1 Introduction to Hypermobility Table 1.1 Nosology of the Ehlers Danlos syndrome Classic (formerly EDS I and II, gravis and AD mitis type) Hypermobility (formerly EDS III, hypermobile type) AD Vascular (formerly EDS IV, arterial or AD ecchymotic type) Kyphoscoliosis (formerly EDS VI, ocular or AR scoliosis type) Arthrochalasia (formerly included in EDS VII) AD Dermatosparaxis (formerly included in EDS VII) AR Other rare forms of the EDS EDS V EDS VIII EDS X Entries now removed from the EDS classifi cation EDS IX EDS XI Source: Revised at the Villefranche Meeting, 1997, adapted C -linked type, resembles the classic type, in mild to moderate severity. Delineated in a single large family in the UK Periodontal type, resembles the classic type with the addition of fragility of the gums. Very rare. Syndromic status uncertain. AD Resembles the classic type, in mild degree, with the additional feature of abnormal platelet aggregation. Syndromic status uncertain. AR? Now termed occipital horn syndrome. C -linked disorder of copper metabolism which is allelic to the Menkes syndrome Now termed familial articular hypermobility syndrome. Resembles the hypermobility form of the EDS in September In this meeting, experts involved with genetic connective tissue conditions reached agreement upon syndromic definition and a unified nomenclature. The final proposals were published under the names of 22 authors as the International Nosology of Heritable Disorders of Connective Tissue, Berlin The continuing accumulation of clinical experience and the elucidation of the molecular defects in some forms of the EDS generated a need for reappraisal of the nosology of the disorder. For this purpose, in June 1997, a representative group of interested colleagues, convened by Petros Tsipouras, met in Villefranche-sur-Mer, France. A new nosology was formulated and the proposals were presented at the American Society of Human Genetics Congress later in the year, and subsequently published. 38 A summary is reproduced in Table 1.1, and the various forms of the EDS are further discussed in Chap. 9. Molecular heterogeneity has been recognised in the Classic type (formerly EDS I and II) and proposed in the Hypermobility type (formerly EDS III). It is likely that the nosology will be updated in the future in order to accommodate these advances.

23 1.7 Nosology of the Hypermobility Syndromes 7 Table 1.2 Familial articular hypermobility syndrome ( ) Excludes EDS group of disorders, notably the hypermobile and arthrochalasia types Skeletal dysplasias with joint hypermobility, notably the Larsen syndrome Cardinal manifestations Generalised articular hypermobility, with or without subluxation or dislocations No skin involvement Familial articular hypermobility, uncomplicated type Familial articular hypermobility, dislocating type (formerly EDS XI, familial joint instability syndrome) (The basic defect in these disorders is unknown) AD/AR AD Table 1.3 Skeletal dysplasias with predominant joint laxity Larsen syndrome Cardinal manifestations Joint laxity, especially at the knees Flattened nasal bridge Short stature Broad terminal phalanges Radiographic characteristics Supernumerary ossification centres in the carpus and calcaneus Desbuquois syndrome Cardinal manifestations Joint laxity Short stature Prominent eyes Broad terminal phalanges Supernumerary phalanges Radiographic characteristics Supernumerary carpal ossification centres Prominent lesser trochanter of femur Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL) Mild form: AD(150250) Severe form: AR(245600) AR(251450) AR(271640) AD(603546) Clinical manifestations Gross joint laxity with progressive spinal malalignment and multiple dislocations Dwarfism Variable cardiac defects and palatal clefts Radiographic characteristics Skeletal dysplasia with changes in the vertebrae, epiphyses and metaphyses The sections of the Berlin Nosology which relate to the familial articular hypermobility syndrome and the skeletal dysplasias with joint laxity are reproduced in Tables 1.2 and 1.3, and the conditions in these categories are also reviewed in Chap. 9. The numbers allocated to entities in the current online version of McKusick s Mendelian Inheritance in Man [OMIM] 39 have been cited in the titles of these disorders.

24 8 1 Introduction to Hypermobility References 1. Finkelstein H. Joint hypotonia. N Y Med J. 1916;104: Key JA. Hypermobility of joints as a sex linked hereditary characteristic. JAMA. 1927;88: Massie WK, Howarth MB. Congenital dislocation of the hip. Part II. Results of an open reduction as seen in early adult period. J Bone Joint Surg Am. 1951;33: Carter C, Wilkinson J. Persistent joint laxity and congenital dislocation of the hip. J Bone Joint Surg Br. 1964;46-B: Carter C, Sweetnam R. Familial joint laxity and recurrent dislocation of the patella. J Bone Joint Surg Br. 1958;40-B: Carter C, Sweetnam R. Recurrent dislocation of the patella and of the shoulder: their association with familial joint laxity. J Bone Joint Surg Br. 1960;42-B: Sutro J. Hypermobility of the knee due to over lengthened capsular and ligamentous tissues. Surgery. 1947;21: Kirk JA, Ansell BM, Bywaters EG. The hyper mobility syndrome. Musculoskeletal complaints associated with generalized joint hypermobility. Ann Rheum Dis. 1967;26: Wood PH. Is hypermobility a discrete entity? Proc R Soc Med. 1971;64: Child AH. Joint hypermobility syndrome: inherited disorder of collagen synthesis. J Rheumatol. 1986;13: Bird HA. Heritable collagen disorders. In: Reports on the Rheumatic Diseases (Series 5): Topical Reviews. Chesterfield: Arthritis Research Campaign; Ansell BM. Hypermobility of joints. Mod Trends Orthop. 1972;6: Grahame R. Time to take hypermobility seriously (in adults and children). Rheumatology. 2001;40: Howes RJ, Isdale IC. The loose back: an unrecognised syndrome. Rheumatol Phys Med. 1971;11: Lewkonia RM, Ansell BM. Articular hypermobility simulating chronic rheumatic disease. Arch Dis Child. 1983;58: Gedalia A, Person DA, Brewer EJ, Giannini EH. Hypermobility of the joints in juvenile episodic arthritis/arthralgia. J Pediatr. 1985;107: Adib N, Davies K, Grahame R, Woo P, Murray KJ. Joint hypermobility syndrome in childhood. A not so benign multisystem disorder? Rheumatology. 2005;44: Grahame R, Beighton P. Physical properties of the skin in the Ehlers-Danlos syndrome. Ann Rheum Dis. 1969;28: Grahame R. A method for measuring human skin elasticity in vivo with observations of the effects of age, sex and pregnancy. Clin Sci. 1970;39: Silverman S, Constine L, Harvey W, Grahame R. Survey of joint mobility and in vivo skin elasticity in London schoolchildren. Ann Rheum Dis. 1975;34: Beighton PH, Price A, Lord J, Dickson E. Variants of the ehlers-danlos syndrome. Clinical, biochemical, haematological, and chromosomal features of 100 patients. Ann Rheum Dis. 1969;28: Bird HA, Tribe CR, Bacon PA. Joint hypermobility leading to osteoarthrosis and chondrocalcinosis. Ann Rheum Dis. 1978;37: Lewkonia RM. Hypermobility of joints. Arch Dis Child. 1987;62: Gurley-Green S. Living with the hypermobility syndrome. Rheumatology. 2001;40: Grahame R, Jenkins JM. Joint hypermobility asset or liability? a study of joint mobility in ballet dancers. Ann Rheum Dis. 1972;31: Horan FT, Beighton PH. Recessive inheritance of generalized joint hypermobility. Rheumatol Rehabil. 1973;12: Beighton P, Solomon L, Soskolne CL. Articular mobility in an African population. Ann Rheum Dis. 1973;32: Bird HA. Joint hypermobility in children. Rheumatology. 2005;44:

25 References Harris H, Joseph J. Variation in extension of the metacarpo-phalangeal and interphalangeal joints of the thumb. J Bone Joint Surg Br. 1949;31-B: Troup JDG, Hood CA, Chapman AE. Measurement of the sagittal mobility of the lumbar spine and hips. Ann Phys Med. 1968;9: Barnett CH. The mobility of synovial joints. Rheumatol Phys Med. 1971;11: Fairbank JC, Pynsent PB, Phillips H. Quantitative measurements of joint mobility in adolescents. Ann Rheum Dis. 1984;43: Larsson LG, Baum J, Mudholkar GS. Hypermobility: features and differential incidence between the sexes. Arthritis Rheum. 1987;30: Wordsworth P, Ogilvie D, Smith R, Sykes B. Joint mobility with particular reference to racial variation and inherited connective tissue disorders. Br J Rheumatol. 1987;26: Grahame R, Bird H. British consultant rheumatologists perceptions about the hypermobility syndrome: a national survey. Rheumatology (Oxford). 2001;40: Tinkle BT, Bird HA, Grahame R, Lavallee M, Levy HP, Sillence D. The lack of clinical distinction between the hypermobility type of Ehlers-Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome). Am J Med Genet A. 2009;149A(11): Beighton P et al. International nosology of heritable disorders of connective tissue, Berlin, Am J Med Genet. 1988;29: Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, Am J Med Genet. 1998;77: McKusick VA (2009) Mendelian inheritance in man. Catalogs of autosomal dominant, autosomal recessive and C -linked phenotype. Online

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27 Chapter 2 Assessment of Hypermobility Adequate methods for measuring the range of movement at joints are essential for the definition of criteria used in the study of clinical problems associated with joint hypermobility. Scoring systems for hypermobility that survey a large number of joints in simple fashion are ideal for epidemiological studies in large populations. Latterly, investigators have devised sophisticated mechanical devices for the precise quantification of movement at a single joint. The greater precision afforded may be ideal for serial assessments in the same patient but this greater precision is of limited use in epidemiological work if the joint fails to mirror the status of laxity at other joints in the body. Moreover, a joint may display acquired hyperlaxity in compensation for a reduced range of movement at adjacent joints, for example in the vertebral column. A recent trend has therefore been to return to scoring systems in which a reasonably large number of joints are assessed in simple fashion. Nevertheless, there still remains uncertainty about the value of new assessments proposed. The original scoring system, first devised by Carter and Wilkinson 1 and modified by Beighton et al., 2 even now is re-emerging as the simple method of first choice, particularly for the screening of large populations. The definition of generalised joint hypermobility still remains arbitrary, and rationally should reflect both the number of joints involved and the extent to which they move. Hypermobility may represent one extreme of a Gaussian distribution of joint laxity throughout the population. Scoring systems devised for measuring joint hypermobility have proved less satisfactory in the measurement of joint hypomobility. Attention has recently been directed at the factors that contribute to the range of joint movement, not only the shape of bony articulating surfaces, the inherited collagen structure and the tone and bulk of the restraining muscle, but also recently to their neurological control, particularly in respect of proprioception, which may be impaired. It is likely that future scoring systems will concentrate even more on aetiological aspects as we attempt to separate groups of patients who may be at particular risk of osteoarthritis. P. Beighton et al., Hypermobility of Joints, DOI / _2, Springer-Verlag London Limited

28 12 2 Assessment of Hypermobility 2.1 Simple Scoring Systems for Hypermobility The first scoring system was devised by Carter and Wilkinson 1 in conjunction with their work on congenital dislocation of the hip. They defined generalised joint laxity as being present when three of the following tests were positive, provided both upper and lower limbs were involved: 1. Passive apposition of the thumb to the flexor aspect of the forearm 2. Passive hyperextension of the fingers so that they lie parallel with the extensor aspect of the forearm 3. Ability to hyperextend the elbow more than Ability to hyperextend the knee more than An excess range of passive dorsiflexion of the ankle and eversion of the foot A more complex assessment was suggested by Kirk et al., 3 but in practice this proved to be too time-consuming for routine use. The system of Carter and Wilkinson 1 was revised by Beighton and Horan 4 for the measurement of joint laxity in persons with the Ehlers Danlos syndrome (EDS). Passive dorsiflexion of the little finger beyond 90, with the forearm flat on the table, was substituted for passive hyperextension of the fingers, as the latter test had proved too severe; the range of ankle movement was replaced by measurement of forward flexion of the trunk. Patients were given a score between 0 and 5. Grahame and Jenkins 5 modified this system to include passive dorsiflexion of the ankle beyond 15. This was partly an adaptation to the particular subjects under study, half of whom are ballet dancers. Subsequently, Beighton et al. 2 amended the 1969 system for use in an epidemiological survey of bone and joint disorders in an indigenous rural South African community. They employed the same tests, but gave one point for each side of the body for the paired tests. The range of scoring was thus between 0 and 9, with high scores denoting greater joint laxity. The manoeuvres used in this scoring system are listed below and depicted in Fig. 2.1 : 1. Passive dorsiflexion of the little fingers beyond 90 (one point for each hand) two points 2. Passive apposition of the thumbs to the flexor aspects of the forearm (one point for each thumb) two points 3. Hyperextension of the elbows beyond 10 (one point for each elbow) two points 4. Hyperextension of the knee beyond 10 (one point for each knee) two points 5. Forward flexion of the trunk with knees fully extended so that the palms of the hands rest flat on the floor one point This method has found favour for the following reasons: 1. Scoring systems using hyperextension of the middle rather than the little finger exclude too many persons. 2. Scoring systems using ankle movements, although perhaps appropriate for dancers, are unlikely to show much variation between individuals in a normal population. 3. Scoring systems that include trunk and hip movement (composite joint movement) are more likely to reflect generalised articular laxity.

29 2.1 Simple Scoring Systems for Hypermobility 13 Fig. 2.1 Beighton et al.2 modification of the Carter and Wilkinson 1 scoring system In a study on 502 normal adult indigenous South Africans (168 males; 334 females), 94% of the males and 80% of the females achieved scores of 0, 1 or 2. This range of movement might be regarded as normal for adults in this population. The majority of clinicians require a minimum score in adults of between 4/9 and 6/9 before accepting the diagnosis. Laxity decreases with age and a lower level may be more appropriate to an elderly population. At any age, females are more mobile than males. In both sexes the degree of joint laxity diminishes rapidly throughout childhood and continues to fall more slowly in adult life. An alternative scoring system was then developed. Based upon work by JP Contompasis, an American podiatrist, 6 and described in detail by Poul and Fait, 7 this scoring system is more complex than the modification by Beighton et al. 2 of the Carter and Wilkinson 1 scale. A multiple-point scoring system based on six manoeuvres, five of which replicate Beighton, its scores span from the normal to the hypermobile range with a maximum total of 72. Initial studies had suggested that it was highly correlated

30 14 2 Assessment of Hypermobility with Beighton s score ( r = 0.92; p = ) in original work by the editors, and it had been claimed that it was particularly useful in the assessment of ligamentous laxity in children. The scoring system is described in detail elsewhere, 8 but greater experience produced problems in measurement, particularly in the use of foot flexibility tests, the major feature on which it differed from the Beighton score. Since the Contompasis score takes significantly longer and, in spite of the theoretical greater sensitivity, conveys little more information, the score is now only occasionally used. 9 In a seminal paper Bulbena and colleagues 10 compared Beighton s modification with the original Carter and Wilkinson 1 scoring system and the most popular scoring system used in France, 11 to find the Beighton system as effective as any in measurement. Recent studies have emphasised the difficulty in establishing joint hypermobility as a causative factor of symptoms in children whose joints in any case display an unusually large range of movement compared to adults. 12 A further study on the high prevalence of joint laxity in West Africans 13 has shown that joint hyperlaxity is substantially greater in a West African population than in almost any other population group in which it has been studied, yet is not associated with joint pain. 2.2 The Brighton Criteria for Hypermobility Syndrome Although the measurement systems so far described suit the musculoskeletal system alone (and may be of particular value in measuring serial change), it became increasingly apparent that wherever abnormal collagen was ubiquitous throughout the body other organ systems would become involved. Moreover, certain individuals, particularly in different ethnic groups, would demonstrate striking hypermobility according to a scoring system but still remain asymptomatic. It became clear that there was a need for a new scoring system that recognised all of these points. The Special Interest Group devoted to inheritable connective tissue disorders of the British Society for Rheumatology addressed this issue. As a result, criteria were proposed in Brighton in 1999, which were published the following year. 14 These are shown in Table 2.1. Incorporating the Beighton score, still felt to be the best rapid assessment of musculoskeletal hypermobility, the presence of arthralgia for more than 3 months in four or more joints was allowed equal importance. A set of minor criteria was additionally proposed and, on the basis of pilot work, a number of major or minor criteria that needed to be fulfilled were decided. The Brighton criteria have subsequently enjoyed extensive use. A study from Chile 15 using the Brighton criteria suggested that true diagnosis in the majority of patients with joint hypermobility syndrome is often overlooked, a finding replicated in the UK. 16 In the study from Chile it was noted that use of the Beighton criteria alone would have excluded 61% of patients who were identified by use of the Brighton criteria. It has been suggested that the criteria may yet benefit from further analysis and validation 17 and even the gold standards based on a consensus of experts 18 may be desirable, a point conceded by the original authors. 19 Nevertheless, there seems to be a consensus that the Brighton criteria represent a significant step forward in the quantification of hypermobility.

31 2.3 General Principles of More Precise Measurement at Selected Joints 15 Table 2.1 The Brighton criteria for joint hypermobility syndrome Major criteria A Beighton score of 4/9 or greater (either currently or historically) Arthralgia for longer than 3 months in 4 or more joints Minor criteria A Beighton score of 1, 2 or 3/9 (0, 1, 2 or 3 if aged 50+) Arthralgia (>3 months) in one to three joints or back pain (>3 months), spondylosis, spondylolysis/spondylolisthesis Dislocation/subluxation in more than one joint, or in one joint on more than one occasion Soft tissue rheumatism >3 lesions (e.g. epicondylitis, tenosynovitis, bursitis) Marfanoid habitus (tall, slim, span/height ratio >1.03, upper:lower segment ratio <0.89, arachnodactyly [positive Steinberg/wrist signs]) Abnormal skin: striae, hyperextensibility, thin skin, papyraceous scarring Eye signs: drooping eyelids or myopia or antimongoloid slant Varicose veins or hernia or uterine/rectal prolapse The joint hypermobility syndrome is diagnosed in the presence of two major criteria, or one major and two minor criteria, or four minor criteria. Two minor criteria will suffice where there is an unequivocally affected first-degree relative. Joint hypermobility syndrome is excluded by the presence of Marfan or Ehlers Danlos syndromes (other than the EDS hypermobility type (formerly EDS III) as defined by the Ghent (1996) and the Villefranche (1998) criteria respectively). Criteria Major 1 and Minor 1 are mutually exclusive as are Major 2 and Minor 2. Recently, Hakim and colleagues have also devised and validated a simple fivepoint questionnaire that can be used in general practice to alert suspicion to the presence of hypermobility General Principles of More Precise Measurement at Selected Joints A complete evaluation of a new technique for the precise measurement of movement a single joint requires the following: 1. Statements on the inter- and intra-observer error of the method 2. Consideration of the influence of age on the range of observed movement 3. A study of sex-determined differences 4. Indication of whether specialist groups have been included in the survey population (for instance, physiotherapists are often used for such studies but are likely to form a highly selected group by virtue of their training) 5. Consideration of the influence of the dominant side A hinge goniometer provides the simplest method for measuring the range of movement at a hinged joint. There are difficulties in positioning such an instrument accurately and a spirit-level device is often more appropriate. The Loebl 21 hydrogoniometer was the first such devised described. The MIE clinical goniometer (Fig. 2.2 ) is an example of a similar device that is currently manufactured. Providing the patient is correctly positioned, the instrument can be used to record the arc of movement at any joint.

32 16 2 Assessment of Hypermobility a b Fig. 2.2 ( a ) A clinical goniometer capable of measuring arcs of movement in any direction (manufactured by MIE Medical Research Ltd, 6 Wortley Moor Road, Leeds LS12 4JF, UK). ( b ) The goniometer in use

33 2.4 Back and Spinal Mobility 17 Recent modifications include instruments such as the Myrin goniometer, which resembles an aircraft gyrocompass; however, this instrument is expensive and lacks the sensitivity and precision of the simpler device. When surface goniometry is correlated with movement measured radiologically, goniometry frequently proves to be inadequate. The skin, fat and soft tissues may distend and cause markers on the skin to move less or more than the underlying bones. Correlation coefficients between angular bony movement at the joint determined radiologically and movement of the overlying skin are rarely provided. A comprehensive account of techniques for measuring joint movement throughout the body is described in a booklet published by the American Academy of Orthopaedic Surgeons. 22 Diagrams of suitable methods for using goniometers to determine the arcs of movement at all joints in the body are given, together with normal values, but the coefficients of variation for these measurements, both between serial assessments and in the same observer and between different observers, are not provided. A volume of Clinics in Rheumatic Disease, 23 edited by V. Wright, devotes one chapter to the measurement of movement at each major joint in the body. Available methods are compared and the most suitable selected. This is used to define the normal range of movement at each joint in males and females, usually in 10-year cohorts. Estimations of inter-observer and intra-observer variation are provided. Some additional devices have been championed for more sophisticated measurement of the range of movement. For the shoulder, an electromagnetic movement sensor has been devised and validated. 24 At the hip, a plurimeter has been devised and validated, providing a relatively inexpensive measure for the range of movement at this joint and one that might be of particular use in primary care. 25 Regular training undoubtedly affects the range of movement, due either to alteration in muscle control or to stretching of the joint capsule. Atha and Wheatley 26 showed the effect of training to be a source of greater variation in passive goniometry at larger joints; investigators therefore need to specify whether an individual is warmed up or participating in a physical training programme designed to increase the range of movement. Such changes have been further quantified in studies on athletes, 27 which drew attention to the way in which the range of joint movement could be altered by warm up and this varied according to the experience and skill of the athlete. Programmes were then introduced to stabilise unstable joints by the 28, 29 use of regular exercises. These were also shown to be effective. 2.4 Back and Spinal Mobility The spine is a complex set of joints. Restrictions of movement at one site, either inherited or acquired by disease, may result in compensatory hyperlaxity at adjacent vertebrae leaving the overall range of movement, as measured by surface techniques, unaltered. 30 Troup et al. 31 used photography to study movement of the lumbar spine and hips in a sagittal plane, and a full review appears elsewhere. 32 One-dimensional

34 18 2 Assessment of Hypermobility measures involve skin distraction techniques such as Schober s 33 method, as modified by Macrae and Wright. 34 Plumbline techniques have also been described and lumbar sagittal mobility may be measured by flexicurves. The latter method has an intra-observer and inter-observer variation of 9% and 15%, respectively. 35 A hydrogoniometer is probably the most satisfactory instrument, though more complex spondylometers 36 are available. Three-dimensional techniques include stereoradiography, vector stereography and three-dimensional optical systems. All have been reviewed recently in comprehensive fashion 37 and reference values for normal regional lumbar sagittal mobility have been published. 38 It is of interest that, although most studies at peripheral joints have clearly shown that hypermobility is more prevalent in females than in males, this does not appear to be so for the lumbar spine. Thus, Loebl 21 and Troup 31 have both shown that spinal movement is approximately equal in both sexes, while a seminal paper by Macrae and Wright 34 showed the male spinal mobility to be greater than that in females. The reason for this is not clear. In a study correlating low back symptoms with lumbar sagittal mobility (Burton and Group, unpublished results), flexicurves were used in 958 individuals aged from 10 to 84 years. Both hypermobility and hypomobility of the lumbar spine were identified as risk factors for low back trouble, though, as ascertained by questionnaire, current sufferers were more likely to be relatively hypomobile. The Polhemus Navigation Sciences 3Space Isotrak system has been used to measure the range of movement in the lumbar spine. 39 This proved valuable in detecting minor changes in spinal movement throughout the 24-h period that were attributed to the natural circadian variation. Although expensive, sophisticated, and only available in small numbers of centres, this system may provide insight into diurnal variation of symptoms arising from the spine that are a feature of subjects with hyperlaxity of the spine and also intrude on clinical practice. 2.5 Rotation in the Limbs Haskard and Silman 40 have devised fixed-torque screwdrivers that measure forearm and lower limb rotation in epidemiological studies. Inter-observer variation has been validated and is low. One such device measures forearm rotation and another leg rotation. Fairbank et al. 41 devised a goniometric assessment involving six joints. Special jigs were constructed for the measurement of hip rotation and tibial rotation. 2.6 Movement at the Metacarpophalangeal Joint The metacarpophalangeal (MCP) joint is easily accessible and also forms a component part of conventional scoring systems. Harris and Joseph 42 developed a radiological technique for measuring the range of extension at the MCP joint and

35 2.7 Joint Proprioception 19 Loebl 43 devised a mechanism for abducting the fingers to investigate movement at the MCP joints. Grahame and Jenkins 5 described a simple spring device that applied a predetermined force (2 lb (0.91 kg)) to the fifth MCP joint. Applied to the relaxed patient, this force mimicked the passive range of movement measured in the clinical scoring system. It had good reproducibility but only quantified movement to the nearest 30. The Leeds finger hyperextensometer 44 (Fig. 2.3 ) can be used for either hand. It allows greater precision in quantification of the range of movement and has good inter-observer and intra-observer reliability. The hyperextensometer applies a torque of 2.6 kgcm The device can be used in epidemiological surveys as it is portable, light and inexpensively constructed. It is of particular value in serial assessments of joint laxity in the same patient and has been used to provide the first demonstration of enhanced peripheral joint laxity prior to parturition in pregnant females. 45 An increased level of serum relaxin has been noted in pregnant women who have pelvic ligament pain. 46 Since relaxin levels are known to be high at the end of pregnancy when peripheral joint laxity was demonstrated, it remains a possibility that this hormone may be directly related to the development of rheumatological symptoms arising from hyperlax ligaments. A finger arthrograph 47 quantifies the resistance encountered when the index finger is moved in sinusoidal fashion at a constant speed through a pre-selected angle of displacement and is of value in measuring stiffness. Most recently, an electronic gravity goniometer has been developed for determining the passive range of movement of the four MCP joints by the use of preset fixed torques. 48 This may represent an improvement on the hyperextensometer. The arthrograph has also been revisited and a microprocessor-controlled arthrograph devised. In addition to the greater accuracy provided, a novel feature is the movement of the MCP joint in a lateral rather than a flexion/extension plane Joint Proprioception With increasing realisation that this is relevant to hypermobility, efforts have been directed to its accurate quantification. Ferrell and colleagues in Glasgow have designed a sophisticated rig to quantify proprioception at the knee joint and have shown in a sophisticated series of studies that this is impaired in hypermobility syndrome, 50 that enhanced proprioception ameliorates symptoms 51 and that musculoskeletal reflex function is also altered in hypermobility. 52 The rig used, however, is not portable. Parallel work has shown that proprioception is impaired both in inflammatory and degenerative arthritis and intriguingly, improved after joint replacement, probably because of surgical tightening of the capsule. A portable proprioceptometer has been devised for use in the hand 53 and is currently being used in studies of hypermobile individuals, as well as on musicians and typists. Proprioception has also recently been demonstrated to be abnormal in hypermobile children. 54

36 20 2 Assessment of Hypermobility Fig. 2.3 A finger hyperextensometer for the quantification of joint laxity. The finger of the subject is hyperextended at the metacarpophalangeal joint by the application of a pre-set fixed torque. The resultant angle of the hyperextension is read off on the dial

37 2.9 Variation of Joint Laxity Within Populations Correlations Between Scoring Systems Used in Assessing Joint Laxity A comparison has been made between the Carter and Wilkinson 1 scoring system, as modified by Beighton et al., 2 the Leeds finger hyperextensometer and a global index constructed by using goniometry to assess the range of movement at almost all the joints in the body. This comparison follows the guidelines suggested by the American Academy of Orthopaedic Surgeons 22 and sums the measured arcs of movement. 55 Individuals were selected from different sporting groups thought to reflect more generalised hyperlaxity than that seen in the normal population. Beighton et al. s modification of the Carter and Wilkinson system correlated well with the global index, endorsing the value of a simple scoring system that could be applied to large populations. 56 The hyperextensometer appeared to convey more applied information in an accurate fashion, emphasising that the range of movement at a single joint does not necessarily correlate with overall joint laxity. Silman et al. 57 have confirmed the Gaussian distribution in joint mobility that can be measured with fixed-torque measuring devices. Subsequently, a family study showed that, although the fixed-torque devices reliably reflected anticipated epidemiological findings in Asian families, the index finger hyperextensometer produced different results. They concluded that both genetic and constitutional factors affect mobility independently at certain sites. 58 Fairbank et al., 41 using goniometry at 6 different joints in a group of 446 normal adolescents, concluded that there was a weak but significant correlation between the ranges of movement at each of the different joints measured, except for elbow hyperextension. 2.9 Variation of Joint Laxity Within Populations A major development in the epidemiology of hypermobility has been the demonstration that the range of movement at a given joint is observed as a Gaussian distribution throughout the population. 59 It is no longer acceptable to consider hypermobility as an all or nothing phenomenon and it becomes logical to define hypermobile individuals as those who comprise a certain extreme proportion of the normal population. The cut-off point for hypermobility remains arbitrary, but it is our impression that the majority of musculoskeletal complaints attributable to hypermobility occur in the most supple 5% or 10% of the population. The range of normal joint movements decreases rapidly throughout childhood and more slowly in adulthood. This observation has been confirmed in children in Edinburgh, 60 in a South African population 2 and in London children. 61 Joint laxity continues to diminish throughout adult life. 3 The joints of females were found by several authors to be more lax than those of age-matched males, 2, 42, 60 though this finding has been disputed by Silverman et al. 61 and is not always seen in the spine, as previously described. Laxity may be localised to a small number of joints or a

38 22 2 Assessment of Hypermobility single joint. The concept of pauci-articular hypermobility has been reviewed in detail by Larsson et al.. 62 Although few comparative studies have been carried out, there is a strong clinical impression of a racial variation in joint mobility. For instance, Indians show more hyperextension of the thumb than Africans, who in turn have greater hyperextension than Europeans. 42 A similar result has been obtained by comparing the finger joints of different ethnic groups in Southern Africa. 63 The question of inter-ethnic variation could be resolved by large-scale comparative studies employing the techniques discussed in this chapter. A study on joint mobility among university students in Iraq has shown a relatively high prevalence of individuals scoring 4/9 on Beighton et al. s 2 modification of the Carter and Wilkinson 1 scale, the right (usually dominant) side being significantly less mobile than the left side, whatever the hypermobility score. 64 Comparable data from an age-matched group of English university students has shown a lower prevalence of hypermobility using the same scoring system. 65 When English Caucasian subjects were compared with Asian Indians and a group of patients suffering from a variety of inherited disorders, including Ehlers Danlos Syndrome (EDS) and osteogenesis imperfecta, Asian Indians were significantly more mobile than English Caucasians. Males and females with EDS were hypermobile, but only females with osteogenesis imperfecta (and female relatives of those with severe or lethal osteogenesis imperfecta) showed excess joint laxity. 66 Studies with the hyperextensometer in Europe have defined normal curves for laxity at the MCP joint in relation to age and sex and then correlated hyperlaxity with various orthopaedic diseases. 67 The frequency of occurrence of generalised ligamentous laxity has been defined in a Czechoslovakian population (Poul J and Fait M 1989, personal communication). In 890 healthy children, the Contompasis criteria 6 defined the variability of generalised ligamentous laxity in relation to age and sex. It was found that pathology was most likely to develop in subjects who exhibited two standard deviations from the mean. This study failed to show a discrete clinical abnormality of connective tissue it was felt that rheumatic or orthopaedic symptoms could occur in any individuals, providing their overall hyperlaxity exceeded a certain degree. This favours mechanical rather than biochemical aetiology for symptoms arising from joint hypermobility. A study from Yugoslavia (I. Jajic 1988, personal communication), in which 632 schoolchildren were surveyed, confirmed the greater prevalence of joint hypermobility, as measured by the Beighton et al. 2 scoring system, in schoolgirls compared to age-matched schoolboys Clinical Applications of Scoring Systems Both the Beighton 2 and Contompasis scoring systems have been used to quantify laxity in a study of 58 consecutive patients presenting to a rheumatology clinic with putative benign joint hypermobility syndrome (BJHS). There appeared to be no great prevalence of cardiac, bone, skin or eye abnormalities in this group, helping to

39 References 23 differentiate it from more serious hereditary disorders of connective tissue. 68 An epidemiological study in rheumatology clinics has evaluated 130 consecutive new patients with joint hypermobility. 69 Musculoskeletal problems were the main reason for referral, and there was a statistically significant association between diffuse joint hypermobility and osteoarthritis, supporting the hypothesis that joint hypermobility predisposes to musculoskeletal disorders, particularly osteoarthritis. More contentious is whether joint hypermobility is associated with fibromyalgia or even a cause of that condition. Criteria for fibromyalgia have recently been proposed by the American College of Rheumatology. 70 This has allowed the correlation of scoring systems for mobility with diagnostic criteria for fibromyalgia in schoolchildren, 71 which showed an apparent strong association between the two conditions, certainly in schoolchildren. In a group of adults in Oman, there was less correlation between widespread musculoskeletal symptoms in any age group and joint mobility scores 72 though specific diagnostic criteria for fibromyalgia were not sought. Other studies have suggested there may be an association between hypermobility and fibromyalgic type symptoms in adults, 73 and if further studies confirm this, exercise programmes to reduce hyperextension of joint capsules and other soft tissues may become a recognised part of the treatment of fibromyalgia. 74 The new international Nosology of heritable disorders of connective tissue from Beighton and colleagues 75 has replaced the earlier classification, first proposed in 1986, though not published until later. 76 This has defined the benign joint hypermobility syndrome as an entity quite discreet from rarer and more serious inherited abnormalities of connective tissue such as the EDS, some variants of which cause much greater involvement of body structures other than joints, particularly the blood vessels Joint Hypolaxity Restricted movement of the joint has been recognised clinically in association with certain diseases, particularly diabetes mellitus. Reduced movement has been reported in the hand, shoulder, wrist, elbow and ankle The scoring systems currently used for hyperlaxity have evolved specifically for this need and prove not to be particularly suited to the detection and measurement of joint hypolaxity. 80 References 1. Carter C, Wilkinson J. Persistent joint laxity and congenital dislocation of the hip. J Bone Joint Surg Br. 1964;46-B: Beighton P, Solomon L, Soskolne CL. Articular mobility in an African population. Ann Rheum Dis. 1973;32: Kirk JA, Ansell BM, Bywaters EG. The hypermobility syndrome. Musculoskeletal complaints associated with generalized joint hypermobility. Ann Rheum Dis. 1967;26:

40 24 2 Assessment of Hypermobility 4. Beighton P, Horan F. Orthopaedic aspects of the Ehlers Danlos syndrome. J Bone Joint Surg Br. 1969;51-B: Grahame R, Jenkins JM. Joint hypermobility asset or liability? A study of joint mobility in ballet dancers. Ann Rheum Dis. 1972;31: McNerney JE, Johnston WB. Generalized ligamentous laxity, hallux abducto valgus and the first metatarsocuneiform joint. J Am Podiatry Assoc. 1979;69: Poul J, Fait M. Generalized ligamentous laxity in children. Z Orthop Ihre Grenzgeb. 1986;124: Beighton PH, Grahame R, Bird HA. Hypermobility of Joints. 2nd ed. Berlin/Heidelberg: Springer-Verlag; Morgan AW, Bird HA. Special interest group for joint hypermobility. Br J Rheumatol. 1994;33: Bulbena A, Duro J, Porta M, Faus S, Vallescar R, Martin-Santos R. Clinical assessment of hypermobile joints: assembly criteria. J Rheumatol. 1992;19: Rotés-Querol J, Argany A. La laxité articulaire considerée comme facteur des altérations de l appareil locomoteur. Rev Rhum Mal Osteoartic. 1957;24: Gedalia A, Brewer EJ. Joint hypermobility in pediatric practice a review. J Rheumatol. 1993;20: Birrell FN, Adebajo AO, Hazleman BL, Silman AJ. High prevalence of joint laxity in West Africans. Br J Rheumatol. 1994;33: Grahame R, Bird HA, Child A, et al. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol. 2000;27: Bravo JF, Wolff C. Clinical study of hereditary disorders of connective tissues in a Chilean population: joint hypermobility syndrome and vascular Ehlers-Danlos syndrome. Arthritis Rheum. 2006;54: Grahame R, Hakim AJ. High prevalence of joint hypermobility syndrome in clinical referrals to a North London community hospital. Rheumatology (Oxford). 2004;43(Suppl 2): 90. Abs Remvig L, Jensen DV, Ward RC. Are diagnostic criteria for general joint hypermobility and benign joint hypermobility syndrome based on reproducible and valid tests? A review of the literature. J Rheumatol. 2007;34: Remvig L, Jensen DV, Ward RC. Epidemiology of general joint hypermobility and basis for the proposed criteria for benign joint hypermobility syndrome: review of the literature. J Rheumatol. 2007;34: Grahame R. The need to take a fresh look at criteria for hypermobility. J Rheumatol. 2007;34: Hakim AJ, Grahame R. A simple questionnaire to detect hypermobility: an adjunct to the assessment of patients with diffuse musculoskeletal pain. Int J Clin Pract. 2003;57: Loebl WY. Measurement of spinal posture and range of spinal movement. Ann Phys Med. 1967;9: American Academy of Orthopaedic Surgeons. Joint Motion: Method of Measuring and Recording. Edinburgh: Churchill Livingstone; Wright V, ed. Measurement of Joint Movement. Clinics in Rheumatic Diseases, vol. 9. London: WB Saunders Company Ltd; Johnson GR, Fyfe NC, Heward M. Ranges of movement at the shoulder complex using an electromagnetic movement sensor. Ann Rheum Dis. 1991;50: Croft PR, Nahit ES, Macfarlane GJ, Silman AJ. Interobserver reliability in measuring flexion, internal rotation, and external rotation of the hip using a plurimeter. Ann Rheum Dis. 1996;55: Atha J, Wheatley DW. The mobilising effects of repeated measurement on hip flexion. Br J Sports Med. 1976;10: Barton L, Bird HA, Lindsay M, Newton J, Wright V. The effect of different joint interventions on the range of movement at a joint. J Orthop Rheumatol. 1995;8:87-92.

41 References Barton L, Bird HA, Lindsay M, Newton J, Wright V. The quantification of joint hyperlaxity in athletes. J Orthop Rheumatol. 1995;8: Barton L, Bird HA. Improving pain by stabilisation of hyperlax joints. J Orthop Rheumatol. 1996;9: Hilton RC, Ball J, Benn RT. In-vitro mobility of the lumbar spine. Ann Rheum Dis. 1979;38: Troup JDG, Hood CA, Chapman AE. Measurements of the sagittal mobility of the lumbar spine and hips. Ann Phys Med. 1968;9: Anderson JAD. The thoraco-lumbar spine. Clin Rheum Dis. 1982;8: Schober P. Lendenwirbelsäul und kreuzschmerzen. Much Med Wochenschr. 1937;84: Macrae IF, Wright V. Measurement of back movement. Ann Rheum Dis. 1969;28: Burton AK. Regional lumbar sagittal mobility; measurement by flexicurves. Clin Biomech. 1986;1: Sturrock RD, Wojtulewski J, Dudley Hart F. Spondylometry in a normal population and in ankylosing spondylitis. Rheumatol Rehabil. 1973;12: Pearcy M. Measurement of back and spinal mobility. Clin Biomech. 1986;1: Burton AK, Tillotson KM. Reference values for normal regional lumbar sagittal mobility. Clin Biomech. 1988;3: Russell P, Weld A, Pearcy MJ, Hogg R, Unsworth A. Variation in lumbar spine mobility measured over a 24-hour period. Br J Rheumatol. 1992;31: Haskard DO, Silman AJ. Measuring devices for studying joint mobility in the normal population. Eng Med. 1985;14: Fairbank JC, Pynsent PB, Phillips H. Quantitative measurements of joint mobility in adolescents. Ann Rheum Dis. 1984;43: Harris H, Joseph J. Variation in extension of the metacarpophalangeal and interphalangeal joints of the thumb. J Bone Joint Surg Br. 1949;31-B: Loebl WY. The assessment of mobility in the metacarpophalangeal joints. Rheumatol Phys Med. 1972;11: Jobbins B, Bird HA, Wright V. A joint hyperextensometer for the quantification of joint laxity. Eng Med. 1979;8: Calguneri M, Bird HA, Wright V. Changes in joint laxity occurring during pregnancy. Ann Rheum Dis. 1982;41: Maclennan AH, Green RC, Nicolson R, Bath M. Serum relaxin and pelvic pain of pregnancy. Lancet. 1986;328: Jobbins B, Bird HA, Wright V. A finger arthrograph for the quantification of joint stiffness. Eng Med. 1981;10: Wagner C, Drescher D. Measuring mobility of the metacarpophalangeal joints II, III, IV and V in the dorso-volar plane. Eng Med. 1984;13: Howe A, Thompson D, Wright V. Reference values for metacarpophalangeal joint stiffness in normals. Ann Rheum Dis. 1985;44: 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: Ferrell WR, Tennant N, Sturrock RD, et al. Amelioration of symptoms by enhancement of proprioception in patients with joint hypermobility syndrome. Arthritis Rheum. 2004;50: Ferrell WR, Tennant N, Baxendale RH, Kusel M, Sturrock RD. Musculoskeletal reflex function in the joint hypermobility syndrome. Arthritis Care Res. 2007;57: Wycherley AS, Helliwell PS, Bird HA. A novel device for the measurement of proprioception in the hand. Rheumatology (Oxford). 2005;44: Fatoye F, Palmer S, Macmillan F, Rowe P, van der Linden M. Proprioception and muscle torque deficits in children with hypermobility syndrome. Rheumatology (Oxford). 2009;48: Bird HA, Brodie DA, Wright V. Quantification of joint laxity. Rheumatol Rehabil. 1979;18: Beighton P. Hypermobility scoring. Br J Rheumatol. 1988;27: Silman AJ, Haskard D, Day S. Distribution of joint mobility in a normal population: results of the use of fixed torque measuring devices. Ann Rheum Dis. 1986;45:27-30.

42 26 2 Assessment of Hypermobility 58. Silman AJ, Day SJ, Haskard DO. Factors associated with joint mobility in an adolescent population. Ann Rheum Dis. 1987;46: Wood PH. Is hypermobility a discrete entity? Proc R Soc Med. 1971;64: Wynne-Davies R. Acetabular dysplasia and familial joint laxity: two etiological factors in congenital dislocation of the hip. J Bone Joint Surg Br. 1970;52-B: Silverman S, Constine L, Harvey W, Grahame R. Survey of joint mobility and in vivo skin elasticity in London schoolchildren. Ann Rheum Dis. 1975;34: Larsson LG, Baum J, Mudholkar GS. Hypermobility: features and differential incidence between the sexes. Arthritis Rheum. 1987;30: Schweitzer G. Laxity of metacarpophalangeal joints of fingers and interphalangeal joint of the thumb: a comparative inter-racial study. S Afr Med J. 1970;44: Al-Rawi ZS, Al-Aszawi AJ, Al-Chalabi T. Joint mobility among university students in Iraq. Br J Rheumatol. 1985;24: Bird HA, Calguneri M. Joint mobility among university students. Br J Rheumatol. 1986;25: Wordsworth P, Ogilvie D, Smith R, Sykes B. Joint mobility with particular reference to racial variation and inherited connective tissue disorders. Br J Rheumatol. 1987;26: Dubs L, Gschwend N. General joint laxity. Quantification and clinical relevance. Arch Orthop Trauma Surg. 1988;107: Mishra MB, Ryan P, Atkinson P, et al. Extra-articular features of benign joint hypermobility syndrome. Br J Rheumatol. 1996;35: Bridges AJ, Smith E, Reid J. Joint hypermobility in adults referred to rheumatology clinics. Ann Rheum Dis. 1992;51: Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis Rheum. 1990;33: Gedalia A, Press J, Klein M, Buskila D. Joint hypermobility and fibromyalgia in schoolchildren. Ann Rheum Dis. 1993;52: Pountain G. Musculoskeletal pain in Omanis, and the relationship to joint mobility and body mass index. Br J Rheumatol. 1992;31: Hudson N, Starr MR, Esdaile JM, Fitzcharles M-A. Diagnostic associations with hypermobility in rheumatology patients. Br J Rheumatol. 1995;34: Klemp P. Hypermobility. Ann Rheum Dis. 1997;56: Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, Am J Med Genet. 1998;77: Beighton P, de Paepe A, Danks D, et al. International nosology of heritable disorders of connective tissue, Berlin, Am J Med Genet. 1988;29: Campbell RR, Hawkins SJ, Maddison PJ, Reckless JP. Limited joint mobility in diabetes mellitus. Ann Rheum Dis. 1985;44: Pal B, Anderson J, Dick WC, Griffiths ID. Limitation of joint mobility and shoulder capsulitis in insulin- and non-insulin-dependent diabetes mellitus. Br J Rheumatol. 1986;25: Starkman HS, Gleason RE, Rand LI, Miller DE, Soeldner JS. Limited joint mobility (LJM) of the hand in patients with diabetes mellitus: relation to chronic complications. Ann Rheum Dis. 1986;45: Bird HA. Joint and tissue laxity. In: Wright V, ed. Topical Reviews in the Rheumatic Disorders, vol. 2. Bristol: John Wright & Sons Ltd; 1983:

43 Chapter 3 The Molecular Basis of Joint Hypermobility Karl Kadler and Gillian Wallis 3.1 Introduction The ability of joints to undergo repeated and rapid movements is attributable to the unique mechanical properties of the extracellular matrix (ECM) of the joint capsule and surrounding ligaments and tendons. A delicate balance exists between stiffness and elasticity of these tissues. Stiffness comes from very long collagen fibrils that are arranged in elaborate architectures such as parallel bundles in tendon (Fig. 3.1 ), orthogonal lattices in the cornea and basket-weave in skin, depending on the mechanical requirements of the tissues in which they occur. Elasticity originates from the crimping of collagen fibrils and from elastic fibres in the ECM (Fig. 3.2 ). These elastic fibres have a unique arrangement of macromolecules that permits extension and contraction at a molecular level. An understanding of the molecular and structural basis of joint hypermobility requires a detailed knowledge of the structure, function and organisation of the collagenous and elastic polymer systems that comprise the ECM. Joint hypermobility and joint laxity are features of several heritable disorders of connective tissue. Studies of the pathway between genotype and phenotype in these disorders have provided insights into the role and interaction of components of the ECM in supporting joint function. These studies have shown that: (1) the alteration of different functional domains of an ECM component can lead to disorders that are phenotypically distinct, (2) an alteration in either the structure or the biochemical processing of an ECM component can lead to disorders that are phenotypically similar, and (3) the alteration of distinct ECM components can result in disorders that have overlapping phenotypic features as a result of the complex interplay between ECM components in tissues. Studies of the molecular basis of the Ehlers Danlos syndrome (EDS) exemplify these points and are the focus of this chapter. Several excellent reviews on EDS are available, including but not exclusively Refs. 1-3 Several reviews are also available that describe the biosynthesis, structure and organisation of collagens (e.g. Refs. 4-7 ) and elastic fibres (e.g. Refs. 8, 9 ). In this Chapter we provide an overview of collagen biosynthesis in relation to the Ehlers Danlos syndrome. P. Beighton et al., Hypermobility of Joints, DOI / _3, Springer-Verlag London Limited

44 28 3 The Molecular Basis of Joint Hypermobility Fig. 3.1 Transmission electron microscopy of tendon from a 6-week-old mouse. The collagen fibrils are closely packed in the ECM and parallel to the long axis of the tendon. Note the broad range of diameters of collagen fibrils, the close association of the cell with the fibrils and plasma membrane protrusions that increase the surface area of the cell in contact with the collagen fibrils. Scale bar, 2 m m 3.2 The Family of Fibril-Forming Collagens Collagen is the major structural protein in animals and provides a supporting framework for the attachment of cells during the formation of specialised tissues. Collagens are triple helical proteins comprised of three separate polypeptide chains with a repeating Gly-X-Y motif, where X and Y can be any amino acid but are frequently the imino acids proline and hydroxyproline, respectively. Glycine, the smallest amino acid, is required at every third residue position of each chain to allow the three chains to fold into a triple helix. At least 28 genetically distinct types of collagen exist in man which, on the basis of gene structure and protein sequence, can be classified into different families of collagens. The most abundant are the fibril-forming collagens that occur in the ECM as fibrils having a characteristic 67-nm D -periodicity (see Fig. 3.2 ). The fibrils are the largest biopolymers in animal tissues and can range in diameter ( nm) and length (from 10 m m to several millimetres) depending on tissue and stage of development 10, 11 (for review see Kadler et al. 12 and references therein). Mammals have 11 fibrillar collagen genes, which cluster phylogenetically into three distinct subclasses. 13 The corresponding polypeptide chains assemble into seven specific types that are assigned the Roman numerals I, II, III, V, XI, XXII and XXVII (for review see Kadler et al. 5 ). These collagens comprise a single uninterrupted triple helix containing ~330 contiguous Gly-X-Y triplets. Types XXII and XXVII are newly discovered

45 3.2 The Family of Fibril-Forming Collagens 29 Fig. 3.2 Transmission electron microscopy of tendon from a 6-week-old mouse showing an elastic fibre ( arrows ). The elastic fibre is in contact with the cell and is surrounded by bundles of large-diameter collagen fibrils. The elastic fibre comprises an amorphous (electron lucent) component that makes up the vast majority of the fibre and a microfibrillar component (see insert) that consists of nm microfibrils. Scale bar, 2 m m

46 30 3 The Molecular Basis of Joint Hypermobility Fig. 3.3 Schematic representation of the domain structure of the chains of type I and V collagens. The N-terminal end of each of the polypeptide chains is located at the left-hand side of the diagram. Box, PARP domain. Triangle, von Willebrand-like type C module. Oval, C-propeptides. n, approximately 330. m, 15 in type I procollagen chains and 17 in type V procollagen chains N-propeptide (Gly-X-Y)n (Gly-X-Y)m N-telopeptide C-propeptide C-telopeptide members of the fibrillar collagens and are unique in having two short interruptions in the major triple helix. A unique feature of fibril-forming collagens is that they are synthesised as precursor procollagens containing N- and C-propeptides that flank the major triple helix of the molecule. Types I and V are the most relevant collagens in the Ehlers Danlos syndrome where hypermobility is a feature and will therefore form a focus of this review. Type I collagen is the most abundant collagen and is found throughout the body, except in cartilaginous tissues. It is the predominant component of the collagen fibrils in tendon, ligament, bone and skin. Type V collagen is a minor component of several tissues where it occurs as heterotypic fibrils with type I collagen. In particular, type V collagen is thought to form the inner core of collagen fibrils comprising type I collagen in cornea, skin and ligaments and that it plays a crucial role in controlling assembly of type I/V heterotypic fibrils Genes Encoding Type I and V Collagens The organisation and intron-exon structure of the genes for type I and V collagen chains are similar. Differences in the size of the gene mostly arise from differences in the sizes of the introns (reviewed by Byers 15 ). Type I procollagen protein is comprised of two pro a 1(I) chains and a pro a 2(I) chain, which are encoded by single genes located on human chromosomes 17 (q ) and 7 (q ), respectively. The pro a 1(I) gene ( COL1A1 ) contains 18 kb and 51 exons, and the pro a 2(I) gene ( COL1A2 ) contains 40 kb and 52 exons. Forty-two exons encode the main triple helical domains of each pro a 1(I) and pro a 2(I) chain (see Fig. 3.3 for a schematic representation of the modular structure of procollagens). These exons comprise 45, 54, 99, 108 or 162 base pairs, i.e. multiples of 9 bp corresponding to Gly-X-Y triplets (commonly 54 bp). Flanking

47 3.4 Biosynthesis of Type I and V Collagens 31 these exons are exons that encode the sites of proteolytic cleavage of the N- and C-propeptides of procollagen. Three different polypeptide chains of type V collagen occur, namely pro a 1(V), pro a 2(V) and pro a 3(V). Different combinations of these chains are possible in the formation of the trimer. The most abundant form is [pro a 1(V) 2 pro a 2(V)], but homotrimers of pro a 1(V) and heterotrimers of [pro a 1(V) pro a 2(V) pro a 3(V)] have also been identified. The genes for pro a 1(V) ( COL5A1 ), pro a 2(V) ( COL5A2 ) and pro a 3(V) ( COL3A2 ) collagen chains are located on human chromosomes 9q , 16 2q and 19p13.2, 18 respectively. COL5A1 consists of 66 exons and spans ~150 kb (excluding the first intron, which itself is greater than 600 kb). Fourteen exons encode the signal peptide, the N-propeptide and the beginning of the triple helical domain. The remainder of triple helix is encoded by exons which comprise mostly of 54- and 45-bp exons. The C-propeptide is encoded by exons The final exon is identical in size (144 bp) to that of the genes encoding type I collagen. The COL5A2 gene is evolutionarily closely related to, and syntenic with, the pro a 1(III) chain of type III collagen. 19 The COL5A3 gene is closely related to the COL5A1 gene but with marked sequence difference in the N-propeptide domain and collagenous domain Biosynthesis of Type I and V Collagens The biosynthesis of type I and V procollagen molecules begins with co-translational transport of the nascent pro a chains into the endoplasmic reticulum (Fig. 3.4 ). Intracellular assembly of procollagen occurs by an initial interaction between C-propeptides followed by zipper-like folding of the triple helical domain in the C- to N-terminal direction. Recognition signals within the C-propeptides determine the selective association of individual procollagen chains. 20 Specific sequences in the C-propeptides of type I procollagen determine that two pro a1(i) chains and one pro a 2(I) chain co-assemble to generate a heterotrimeric type I procollagen molecule. The chain selection in the formation of type V collagen is more complex, and different combinations of type V and type XI collagen chains can associate in a tissue-specific manner. 18 Prior to folding of the triple helical domain, certain prolyl residues are hydroxylated at the 4 position by proline-4-hydroxylase, and certain lysyl residues are hydroxylated by lysyl hydroxylase. Both the prolyl-4-hydroxylase and lysyl hydroxylase enzymes require Fe 2+, 2-ketoglutarate, molecular oxygen and ascorbic acid as cofactors. The hydroxylation of proline is needed to produce a triple helix that is stable at body temperatures. Hydroxylation of specific lysyl residues is necessary for O -linked glycosylation (a late step in procollagen biosynthesis) and the formation of lysyl oxidase-derived crosslinks (for review see Eyre et al. 21 ). A late stage in folding involves the assembly of the trimeric N-propeptide.

48 32 3 The Molecular Basis of Joint Hypermobility Gal-O- -OH -O-Gal-Glc Hydroxylation of prolyl and hydrolysyl residues HO- -OH N-glycosylation of C-propeptides -OH -OH -OH NH 2 NH 2 NH 2 O-glycosylation of hydroxylysyl residues in the major Gly-X-Y domain NH 2 NH 2 NH 2 O-Gal-Glc OH O-Gal OH OH -s-ss-s -N-Man -s-s- Association of the C-propeptides Nucleation and propagation of the triple helix O-Gal-Glc OH -N-Man Triple helix formation OH O-Gal procollagen Fig. 3.4 Schematic representation of the intracellular events of collagen biosynthesis. The scheme is based on type I procollagen as shown by the absence of the PARP domain and the shortened N-propeptide. Ribosomes are shown on the cytoplasmic side of the endoplasmic reticulum. S-S- denotes inter-chain disulphide bonds within the C-propeptides. Intra-chain disulphide bonds occur within the C- and N-propeptides (not shown) 3.5 Collagen Fibril Assembly Procollagen cannot assemble into fibrils because of steric hindrance from the bulky C-propeptides. Removal of the C-propeptides by procollagen C-proteinases reduces the solubility of the procollagen molecule and facilitates self-assembly of the molecules into fibrils 22 (Fig. 3.5 ). Once thought to be a single enzyme with unique specificity for procollagen, it is now known that the procollagen

49 3.5 Collagen Fibril Assembly 33 type I procollagen procollagen N-proteinases (ADAMTS-2, 3, 14) procollagen C-proteinases (BMP-1/tolloid family) propeptide cleavage N-propeptides collagen C-propeptides fibril formation circular cross section fibril gap overlap 67 nm Fig. 3.5 Schematic representation of procollagen cleavage and collagen fibrillogenesis. Procollagen is shown being cleaved by procollagen N- and C-proteinases. Triple helical collagen molecules are shown assembling into fibrils in which the molecules are staggered (in register) by 67 nm. The light and dark banding pattern of the fibril (as seen by negative staining electron microscopy) arises from the gap-overlap structure of the fibril. Circle, schematic representation of the typical circular cross-section of collagen fibrils C-proteinases are the same as the BMP-1/tolloid family of astacin-like metalloproteinases that have a broad substrate specificity (for review see Greenspan 4 ). The function of the N-propeptides is unclear. They have been proposed to have a role in feedback regulation of collagen gene expression, biogenesis and maturation of type I collagen (for review see Bornstein 23 ). The N-propeptides of the pro a 1(I) chain of type I procollagen contain a cysteine-rich domain found in thrombospondins (the von Willebrand type C domain) that is homologous to the corresponding domain in the N-propeptides of type II procollagen, and which binds TGF b 1 and BMP2 during chondrogenesis. 24 It is possible, therefore, that the N-propeptides of type I procollagen have growth factor-binding abilities. In contrast to the C-propeptide, cleavage of the N-propeptides does not inhibit fibril formation. However, persistence of the N-propeptide has severe

50 34 3 The Molecular Basis of Joint Hypermobility consequences on fibril structure and tissue integrity, especially in some forms of EDS (see below). Like procollagen C-proteinase, the procollagen N-proteinase was originally considered to be a single enzyme with unique substrate specificity for procollagen. However, we now know that the N-propeptides of procollagen are cleaved by ADAMTS-2, 3 and 14, which are members of the large family of metalloproteinases that contain A D isintegrin-like A nd M etalloprotease domain (reprolysin-type) with T hrombo S pondin type I motifs (for review see Apte 25 and references therein). Removal of the N-propeptides from type I procollagen by ADAMTS2 26, 27 contributes to lowering the solubility of procollagen in the formation of collagen fibrils but has an additional role in influencing the morphology of the fibrils formed (described in more detail below). The cleavage of the N-propeptides of type V procollagen is very different to that which occurs in type I procollagen. Within the heterotrimers, pro a 1(V) N-propeptides and pro a 2(V) C-propeptides are processed by BMP-1-like enzymes, and pro a 1(V) C-propetides are processed by furin-like proprotein convertases. 31 Partial and complete processing occurs at the N-terminal end of the pro a 1(V) chain depending on whether it forms heterotrimers or homotrimers. The N-terminal domain of the pro a 2(V) chain is not processed EDS and Type I Collagen Specific mutations in the COL1A1 and COL2A1 genes that encode the chains of type I collagen are known to cause either the brittle bone disorder, osteogenesis imperfecta, or forms of EDS characterised by joint hypermobility. These contrasting phenotypic outcomes arise as a result of mutations that alter different functional domains of the collagen molecule. Further, as type I collagen is a heterotrimer, the proportion of the constituent pro a 1(I) and pro a 2(I) chains can influence either the level or nature of the trimer produced, again with different phenotypic outcomes. It is well established that heterozygosity for mutations leading to a non-functional COL1A1 allele lead to the production of half normal amounts of type I collagen and the phenotype of type I OI, which is characterised by mild to moderate bone fragility, blue sclerae and hearing loss. 33 In contrast, more recent findings have shown that homozygosity or compound heterozygosity for a non-functional COL1A2 allele leads to the production of trimers comprised only of a 1(I) chains and a variable EDS phenotype characterised by joint hypermobility, skin hyperextensibility and cardiac valvular disease. 2, 34 The mutations in this cardiac valvular form of EDS all appear to result in nonsense mediated decay of the COL1A2 transcript that leads to complete absence of pro a 2(I) synthesis. Interestingly, a total absence of a 2(I) has also been described to cause a phenotype with features of both OI and EDS but without skin or cardiovascular problems. 35 In this instance, it is surmised that a small amount of normal and abnormal protein resulting from the mutant COL2A1 allele is synthesised and hence causes the milder but overlapping OI/EDS phenotype. 34

51 3.6 EDS and Type I Collagen 35 Fig. 3.6 Arthrochalasia EDS results from mutations that cause outsplicing of exon 6 in either C OL1A1 or COL1A2. Exons are denoted as open boxes with the number of the exon indicated. Introns are represented as lines, connecting exons. ( a ) Normal splicing of exon 6. The sequences encoded by exon 6 contain the site for cleavage of the N-propeptide by the procollagen N-proteinase. ( b ) Outsplicing of exon 6 in C OL1A1 and COL1A2 in arthrochalasia EDS type A and B, respectively, caused by mutations at the intron-exon boundaries a b Similarly, it is also well established that mutations in type I collagen genes that alter the repeating Gly-X-Y structure of the triple helix affect the ability of the collagen to undergo normal mineralisation during bone formation 36 and hence cause forms of OI that range from mild to lethal. 33 Conversely, mutations in COL1A1 or COL1A2 that cause a structural change in type I procollagen and lead to the deficient processing of the N-propeptide of type I procollagen cause the arthrochalasia type of EDS (formally EDS VII). The autosomal dominant arthrochalasia EDS is distinct from other forms of EDS by virtue of severe generalised joint hypermobility, recurrent subluxations and congenital bilateral hip dislocation. The failure to process completely the N-propeptide of type I procollagen 37 results from mutations that cause the skipping of exon 6 (the exon encoding the cleavage site for ADAMTS2) during processing of pre-mrna for either the pro a 1(I) or the pro a 2(I) chain of type I procollagen 38, 39 (Fig. 3.6 ). Subsets of the arthrochalasia EDS are defined after molecular characterisation of the mutation; mutations in the COL1A1 gene cause subtype A, 40, 41 and mutations in the COL1A2 cause subtype B. 30, Again, mutations within the triple helical domain of type I collagen that are close to the N-terminal domain have features of both OI and EDS as processing of the N-propeptide is delayed as a consequence of the abnormal structure of the procollagen molecule in that region. 33 Studies of individuals with arthrochalasia EDS subtype B have shown that the collagen fibrils in their skin, bone and fascia are irregular in cross-section because of retention of the N-peptide. Analysis of type I procollagen from the cultured skin fibroblasts of these individuals showed that half of the type I procollagen secreted by the cells was cleaved normally by ADAMTS2, and half was resistant to the enzyme. The abnormally processed procollagen contained normal-sized a 1(I) chains and mutant pn a 2(I) chains. Subsequent morphological, chemical and immunochemical studies showed that the excised a 1(I) N-propeptides remained in non-covalent association with mutant pn a 1(I) ex6 chains in vivo and

52 36 3 The Molecular Basis of Joint Hypermobility in vitro. 49 In procollagen, the N-propeptide normally has a restricted conformation and is found bent back (in a hairpin conformation) on the main triple helical domain of the procollagen. 50 Partial cleavage of this domain alters it conformation and allows it to be in either a hairpin or an extended conformation. As such the abnormally processed N-propeptides can occupy gap or overlap regions of the collagen fibril and hence potentially mask binding sights for other ECM components to the fibril surface. Further, the presence of N-propeptides in a hairpin conformation forces a proportion of pncollagen molecules to be located at the fibril surface. This increases the surface area/volume ratio of the fibril and explains the irregular appearance of the fibrils in cross-section (Fig. 3.7 ). 3.7 EDS and ADAMTS2 The irregular cross-section of type I collagen fibrils in arthrochalasia EDS is reminiscent of, but not as marked as, the characteristic hieroglyphic or cauliflower-like fibrils of the dermatosparaxis type of EDS (formerly EDS type VIIC) 3 (Fig. 3.8 ). Dermatosparaxis EDS is the human equivalent of a disorder that was originally identified in cattle 51 and includes symptoms of severe skin fragility, sagging and redundant skin as well as progressive generalised joint hypermobility. Dermatosparaxis EDS is a recessively inherited condition that results from homozygosity or compound heterozygosity for mutations in ADAMTS2 that result in ablation or a significant reduction in N-proteinase activity. Hence skin extracts from affected individuals show an accumulation of pncollagen as a result of the failure to cleave the N-propeptides from the pro a 1(I) and pro a 2(I) chains in type I procollagen molecules. In this instance, the vast majority of collagen in the fibril is pncollagen, and the N-propeptides retain a hairpin conformation (as opposed to the flexible conformation of the N-propeptides of the partially processed pncollagen of the arthrochalasia -type EDS described above). The surface location of the N-propeptides forces the majority of pncollagen molecules to be located at the fibril surface with a dramatic effect on the surface area/ volume ratio of the fibril and hence the hieroglyphic appearance of the fibrils in crosssection. The altered biophysical properties of the collagen fibrils of this altered morphology presumably contribute to the fragility of skin in individuals with dermatosparaxis. Further, the difference in phenotype between arthrochalasia and dermatosparaxis EDS might arise because the different conformations of nicked and intact N-propeptides at the surface of collagen fibrils might change the way collagen fibrils bind other ECM macromolecules. This opens up the intriguing possibility that mutations in macromolecules that bind the surfaces of collagen fibrils might predispose individuals to as yet uncharacterised forms of joint hypermobility. 2 Studies of mice lacking one or more of the small leucine-rich proteoglycans (SLRP, e.g. decorin, lumican and fibromodulin) have demonstrated the importance of these extracellular macromolecules in determining the mechanical properties of connective tissues. The first SLRP knockout was decorin, which produced a mouse with fragile skin containing collagen fibrils that were abnormal in cross-section, 52 and therefore similar to the abnormal collagen fibrils seen in the tissues of

53 3.7 EDS and ADAMTS2 37 type I procollagen N-propeptides C-propeptides collagen cleavage of N-propeptides in unaffected procollagen molecules pncollagen retention of N-propeptides in procollagen molecules lacking the ADAMTS2 cleavage site or if ADAMTS2 is absent N-propeptides in bent-back conformation N-propeptides in extended conformation Fig. 3.7 Schematic representation of the abnormal cleavage of the N-propeptides in arthrochalasia EDS or dermatosparactic EDS. The cleavage of the C-propeptides occurs normally, thereby producing molecules that are competent to assemble into fibrils. The absence of ADAMTS2 N-proteinase activity (in dermatosparactic EDS) or the presence of structurally altered procollagen molecules (in arthrochalasia EDS) leads to accumulation of pncollagen molecules. The N-propeptides in structurally normal pncollagen molecules (i.e. as in dermatosparactic EDS) are in bent-back conformation. The N-propeptides in molecules in which the pro a 2(I) chain is nicked (as in arthrochalasia EDS subtype B) remain associated with the uncleaved pro a1(i) N-propeptides and can be in either bent-back or extended conformation. The retention of the N-propeptides at the surface of collagen fibrils causes an increase in the ratio [surface area]/[volume] with concomitant appearance of fibrils with irregular cross-sections individuals with EDS. Another example is joint laxity and impaired tendon development in lumican and fibromodulin-deficient mice. 53 Further studies have shown that disruption of dermatospontin, 54 mimecan 55 and thrombospondin-2 55 also results in abnormal collagen fibrillogenesis. Although no human examples have been reported for disease-causing mutations in these genes, the proteins are modulators and effectors of collagen fibrillogenesis and therefore might be expected to be phenotype modifiers.

54 38 3 The Molecular Basis of Joint Hypermobility Fig. 3.8 Cauliflower-like fibrils in dermatosparactic animals. Transmission electron microscopy of skin from a normal calf ( a ) and a calf with dermatosparaxis ( b ). Note the circular appearance of fibrils in a cross-section of fibrils in normal skin, compared to the caulifl ower-like (hieroglyphic) shape of fibrils in cross-section in animals with dermatosparaxis. Fibrils with similar appearance occur in people with dermatosparactic EDS. Scale bar = 500 nm 3.8 EDS and Lysyl Hydroxylase The importance of the cross-linking of collagen to connective tissue integrity has been illustrated by studies of the autosomal recessive kyphoscoliotic type of EDS (formally EDS VIA) which is allelic to Nevo Syndrome. 56, 57 This form of EDS is characterised by severe joint hypermobility and luxations, severe muscular hypotonia, progressive kyphoscoliosis from birth, scleral fragility and rupture of the globe, and is associated with features of skin fragility with abnormal scarring, a marfanoid habitus, osteopenia and arterial rupture. This form of EDS is caused by homozygosity or compound heterozygosity for mutations in the gene, PLOD1, which encodes lysyl hydroxylase-1 (or procollagen-lysine, oxoglutarate 5-dioxygenase). Lysyl hydroxylase-1 is known to be required for the hydroxylation of specific lysine residues in X-Lys-Gly sequences of collagens I and II and is an essential precursor for subsequent cross-linking reactions. Multiple tissues are affected in kyphoscoliotic EDS, and the phenotype overlaps with other connective tissue disorders such as

55 3.9 EDS and Type V Collagen 39 Bethlem myopathy, the classic form of EDS and the vascular form of EDS that are caused by mutations in the genes encoding collagen types VI, V and III, respectively. It is yet to be elucidated if altered lysyl hydroxylation is part of the disease mechanism in these forms of EDS. Changes in the levels of hydroxylysine (and hydroxyproline) occur in the spondylocheiro dysplastic form of the Ehlers Danlos syndrome, an autosomal-recessive form of EDS caused by mutations in the zinc transporter gene SLC39A Increases in Zn 2+ in the endoplasmic reticulum are thought to compete for Fe 2+, a cofactor that is necessary for hydroxylation of lysyl and prolyl residues in collagen. Individuals with spondylocheiro dysplastic EDS exhibit a mild skeletal dysplasia with EDS-like characteristics including hyperelastic, thin and bruisable skin, hypermobility of the small joints with a tendency to contractures, protuberant eyes, hands with finely wrinkled palms, atrophy of the thenar muscles and tapering fingers. 3.9 EDS and Type V Collagen The autosomal dominant classic type of EDS is characterised by joint hypermobility, skin hyperextensibility and abnormal wound healing, with wide atrophic scars. This form of EDS was originally subdivided and designated EDS type I ( gravis ) and EDS type II ( mitis ) to represent more severe and milder forms of the disorder, respectively. However clinical evidence pointed towards there being a phenotypic continuum between EDS type I and II, and hence these two forms of EDS have been reclassified as the classic type. It is now well established that heterozygosity for mutations in COL5A1 and COL5A2 is responsible for about 50% of the cases of classic EDS.59 Mutations in COL5A3 have not however, as yet, been found to cause EDS. About 50% of the mutations identified thus far are haploinsufficient for pro a 1(V) mrna as a consequence of mutations (including nonsense mutations, splice site mutations and insertions/deletions leading to frame-shifts) that lead to nonsense-mediated mrna decay. 60 Such mutations result in half normal amounts of type V collagen being secreted into the matrix. Similarly, mutations in COL5A1 that alter the signal peptide of pre-pro a 1(V) prevent its translocation to the endoplasmic reticulum and hence its availability for trimer formation with a consequent decrease in type V collagen in the matrix. 61 In addition, mutations in COL5A1 have been identified that alter the C-propeptide of pro a 1(V) and prevent its incorporation into type V procollagen again leading to lower levels of type V collagen in the matrix. 62, 63 Surprisingly, however, mutations (splice-site mutations and glycine substitutions) that alter the structure of the collagenous domain and have an effect on triple helical formation have also been identified in both COL5A1 and COL5A2. 64, 65 By analogy with similar mutations of type I collagen that cause osteogenesis imperfecta, these mutations would exert a dominant negative effect because of the co-assembly of mutant and normal chains into procollagen trimers, and consequently abnormal type V collagen would be deposited in the matrix. There is however no evidence that this class of

56 40 3 The Molecular Basis of Joint Hypermobility mutations has a more severe phenotypic outcome than those of type V haploinsufficiency. Indeed, no distinct correlation between genotype and phenotype has been identified for mutations causing classic EDS. Further, pedigrees have been identified where affected individuals with haploinsufficiency for COL5A1 have phenotypes that range from the severe end of the classic EDS spectrum to mild localised joint hypermobility that is more consistent with hypermobility EDS. 2 It is possible that variability in the components of the ECM that interact or modify type V collagen can affect the phenotypic outcome of the primary mutation. Identification of such components may provide clues as to the molecular basis of as yet uncharacterised forms of classic and hypermobility EDS EDS and Tenascin-X Tenascin-X is a large extracellular matrix non-collagenous glycoprotein of an estimated 4,267 amino acids that has a modular structure including five N-linked glycosylation sites and multiple EGF and fibronectin type III repeats (see Bristow et al. 66 for review). In humans it is encoded by the tenascin-x gene located on chromosome 6p21.3 and comprises at least 39 differentially spliced exons. Tenascin-X is expressed predominantly in tendon sheaths, ligaments, synovium, muscle, epicardium, blood vessel adventitia, gut, skin and the vasculature Fibronectin type III repeats are capable of reversible unfolding-refolding and might act as micro-elastic modules. 70 Taking into account that tenascin-x associates with collagen fibrils, tenascin-x might act as an elastic linker between collagen fibrils. 71 A landmark study 72 of chromosomal deletions encompassing all or part of the TNX-B locus identified an affected individual with a phenotype that included hyperextensible joints and skin and easy bruising reminiscent of EDS. This led to a largescale screen of 151 patients with EDS that identified five unrelated individuals who had complete absence of tenascin-x and a phenotype of hypermobile joints, hyperextensible skin, easy bruising and tissue fragility. Mutation screening of the TNX-B gene identified either compound heterozygosity or homozygosity for truncating mutations or large deletions in these individuals. 73 This provided molecular confirmation for an autosomal recessive form of classic-like EDS that has features of the classic type but without the presence of atrophic scarring. 1 In a subsequent study, members of the families of the individuals with classiclike EDS identified above who were heterozygous for the mutations in TNX-B were examined for clinical symptoms of EDS. None of the male relatives were found to have symptoms but 65% of the female heterozygotes were found to have generalised joint hypermobility often associated with joint subluxations and chronic musculoskeletal pain. 74 This phenotype was consistent with the autosomal dominant hypermobility form of EDS (formally EDS type III). A further screen of patients with hypermobility EDS found a significant reduction in tenascin-x levels in 7.5% (all female) of those screened and the identification of a heterozygous deletion mutation in one of those individuals. These studies support that

57 3.11 EDS and Type VI Collagen 41 haploinsufficiency for tenascin-x may cause the phenotype of hypermobility EDS that is partially penetrant in females whereas absence of TNX-B expression leads to the phenotype of classic-like EDS that is penetrant in both males and females. Haploinsufficiency for TNX-B mutations however only accounts for a small subset of patients with joint hypermobility, and other candidate genes are currently been sought through both linkage and mutation screening. 1 Studies of the skin in both individuals lacking tenascin-x and in a mouse knockout model 75 show a reduction in the packing density of collagen fibrils as opposed to fibrils with an altered morphology, as seen in some forms of EDS. This indicates that tenascin-x has a role in the regulation of fibril deposition independent of collagen synthesis. There is some evidence that tenascin mediates this role through an interaction with collagen fibrils and the proteoglycan, decorin. 76 The reduction in the number of collagen fibrils and increased fibril-to-fibril spacing are likely to alter the biomechanical properties of the affected tissues making them less resistant to force EDS and Type VI Collagen One of the patients originally described by Schalkwijk and co-workers 73 (and later by Voermans et al. 77 ) who had features of EDS also had generalised muscle weakness and distal contractures. Both of these features are also characteristic of forms of myopathy associated with joint hypermobility, notably Ullrich congenital muscular dystrophy and Bethlem myopathy which both result from defects in type VI collagen (reviewed in Voermans et al. 78 ). This suggests a functional relationship between type VI collagen and tenascin. In fact, studies of tenascin-x null mice have shown that deficiency of the protein causes a decrease in the level of expression of type VI collagen. 79 Here, tenascin-x null fibroblasts show decreased cell-matrix and cell-cell adhesion, decreased mrna expression of COL6A1, COL6A2 and COL6A3 (which encode the polypeptide chains of type VI collagen), and decreased levels of the a 3(VI) chain of type VI collagen. Interestingly, the levels of type I collagen synthesised by tenascin-x null cells were also decreased, suggesting the possibility that tenascin-x has a significant role in regulating cell-cell and cell-matrix interactions as well as collagen fibrillogenesis. Such alterations in the homeostasis of the collagenous matrix are expected to have a knockon effect on the biomechanical properties of tissues such as tendon and skin in which these components occur. In further studies, Minamitani and co-workers have shown that tenascin-x binds type I collagen (although, interestingly, not type VI collagen) and markedly increased the rate of collagen fibril formation in vitro. However, combined addition of tenascin-x and type VI collagen to type I collagen had an additive effect on the rate of collagen fibril formation. These studies highlight an important correlation between the interactions of type I collagen, type VI collagen and tenascin at the genetic and protein levels, which helps to provide a molecular understanding of the overlapping phenotypes of forms of EDS and muscle myopathies.

58 42 3 The Molecular Basis of Joint Hypermobility 3.12 Relationship Between Elastic Fibre Abnormalities, Marfan Syndrome and EDS Elastic fibres are ECM structures that provide resilience and elastic recoil to deformable connective tissues (e.g. arteries, lungs, skin and ligaments) and thereby complement the tensile properties of collagen fibrils in the same tissues. Although only a few elastic fibres are present in ligaments and tendons, they are likely to be important in maintaining stability of joints. Therefore mutations that alter elastic fibre synthesis and function might be expected to generate or modify the phenotypic aspects of EDS involving skin and joint extensibility. Elastic fibres consist of elastin and fibrillin microfibrils as well as MAGP1, fibulin-4 and fibulin-5, lysyl oxidase, and latent TGF b binding protein (LTBP)-1 and LTBP-2. The fibrillin-rich microfibrils have a beaded appearance and a cross-sectional diameter of nm. 80 In addition to having a scaffolding role in elastic fibre assembly, fibrillin-1 has a pivotal role in tissue development by regulating the bioactivity of TGF b. Immunolocalisation studies show co-distribution of fibrillin-1 and fibrillin-2 in both elastic and non-elastic tissues, but fibrillin-2 appears to be preferentially accumulated in elastin-rich tissues. 81 Fibrillin-containing microfibrils also occur in tissue lacking elastin, especially ocular ciliary zonules and periodontal ligament, in which they can contribute to the elasticity of the tissue. Mutations in genes that encode elastic fibre components can cause severe, often life-threatening, disorders including the Marfan syndrome, supravalvular aortic stenosis and cutis laxa (see Kielty 9 for review). Marfan syndrome is a clinically heterogenous autosomal dominant disorder characterised by myopia and lens dislocation, tall stature, arachnodactyly and cardiovascular complications. It is caused by mutations in FBN1, which is the gene that encodes fibrillin In addition to the characteristic marfanoid habitus (tall and slender build and arachnodactyly), affected individuals can also have hyperextensibility of the skin and joint hypermobility. 83 The skin and joint involvement in the Marfan syndrome clearly overlaps with the phenotype typical of classic-like EDS caused by deficiency of tenascin-x. Interestingly, the skin of tenascin-x-deficient individuals shows abnormal elastic fibres as well as reduced collagen deposition. 84 The molecular basis for the involvement of tenascin-x in elastic fibre formation is poorly understood, but a role in fibre development 85 and anchorage to cells via integrins 86 has been proposed. An involvement of tenascin-x in elastic fibre development might help explain why some cases of hypermobility EDS have a marfanoid habitus whereas Marfan syndrome may be associated with moderate joint hypermobility (reviewed by Malfait et al. 2 ) Conclusions EDS is a clinically and genetically heterogenous connective tissue disorder characterised by joint hypermobility, skin hyperextensibility and tissue fragility. The first disease-causing mutations in EDS were located in the genes encoding collagen

59 References 43 types I and V, and the collagen-processing enzymes lysyl hydroxylase and procollagen N-proteinase. Consequently, the initial belief was that EDS was a disorder of fibrillar collagen metabolism but different from osteogenesis imperfecta in which individuals have brittle bones caused by mutations in the genes for type I collagen. However, as studies of EDS progressed, it became clear that causative mutations can reside in genes not normally associated with collagen metabolism. The best example is tenascin-x. Furthermore, studies of the Marfan syndrome, which is caused by mutations in fibrillin genes, have shown that defects in elastic fibre synthesis can also lead to joint hypermobility and skin involvement. A picture has emerged showing that a fine balance exists between normal tissue tension (attributed to the collagens) and elasticity (mostly attributed to elastic fibres) and that mutations in several genes that encode ECM macromolecules can potentially tilt this balance towards elasticity resulting in an EDS phenotype. Studies of genetic disorders have highlighted the critical importance of type I and V collagens, tenascin-x and the fibrillins in determining the normal mobility of joints. Future studies are needed to provide a detailed picture, at the atomic level, of how the different proteins and glycoconjugates in the ECM assemble into tensile and elastic networks that interact with each other to produce functional tissues. This new knowledge is a prerequisite for the development of medical strategies in the treatment of genetic and acquired diseases of joint hypermobility. Acknowledgements The work in the authors laboratories is funded by the Wellcome Trust and the Arthritis Research Campaign. Special thanks are given to Mrs. Yinhui Lu for electron microscopy. References 1. Callewaert B et al. Ehlers-Danlos syndromes and Marfan syndrome. Best Pract Res Clin Rheumatol. 2008;22(1): Malfait F et al. The genetic basis of the joint hypermobility syndromes. Rheumatology (Oxford). 2006;45(5): Beighton P et al. Ehlers-Danlos syndromes: revised nosology, Villefranche, Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998;77(1): Greenspan DS. Biosynthetic processing of collagen molecules. Top Curr Chem. 2005;247: Kadler KE et al. Collagens at a glance. J Cell Sci. 2007;120(Pt 12): Myllyharju J, Kivirikko KI. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 2004;20(1): Canty EG, Kadler KE. Procollagen trafficking, processing and fibrillogenesis. J Cell Sci. 2005;118(Pt 7): Wagenseil JE, Mecham RP. New insights into elastic fiber assembly. Birth Defects Res C Embryo Today. 2007;81(4): Kielty CM. Elastic fibres in health and disease. Expert Rev Mol Med. 2006;8(19): Craig AS et al. An estimate of the mean length of collagen fibrils in rat tail-tendon as a function of age. Connect Tissue Res. 1989;19(1): Parry DAD, Craig AS. Growth and development of collagen fibrils in connective tissues. In: Ruggeri A, Motta PM, eds. Ultrastructure of the Connective Tissue Matrix. Boston: Martinus Nijhoff; 1984:34-64.

60 44 3 The Molecular Basis of Joint Hypermobility 12. Kadler KE et al. Collagen fibril formation. Biochem J. 1996;316(Pt 1): Huxley-Jones J, Robertson DL, Boot-Handford RP. On the origins of the extracellular matrix in vertebrates. Matrix Biol. 2007;26(1): Wenstrup RJ et al. Type V collagen controls the initiation of collagen fibril assembly. J Biol Chem. 2004;279(51): Byers PH. Disorders of collagen biosynthesis and structure. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill Publishing Co; 1989: Greenspan DS et al. Human collagen gene COL5A1 maps to the q34.2 q34.3 region of chromosome 9, near the locus for nail-patella syndrome. Genomics. 1992;12(4): Emanuel BS et al. Human alpha 1(III) and alpha 2(V) procollagen genes are located on the long arm of chromosome 2. Proc Natl Acad Sci USA. 1985;82(10): Imamura Y, Scott IC, Greenspan DS. The pro-alpha3(v) collagen chain. Complete primary structure, expression domains in adult and developing tissues, and comparison to the structures and expression domains of the other types V and XI procollagen chains. J Biol Chem. 2000;275(12): Myers JC, Dion AS. Types III and V procollagens: homology in genetic organisation and diversity in structure. In: Sandell LJ, Boyd CD, eds. Extracellular Matrix Genes. New York: Academic; 1990: Lees JF, Tasab M, Bulleid NJ. Identification of the molecular recognition sequence which determines the type-specific assembly of procollagen. EMBO J. 1997;16(5): Eyre DR, Paz MA, Gallop PM. Cross-linking in collagen and elastin. Annu Rev Biochem. 1984;53: Kadler KE, Hojima Y, Prockop DJ. Assembly of collagen fibrils de novo by cleavage of the type I pc-collagen with procollagen C-proteinase. Assay of critical concentration demonstrates that collagen self-assembly is a classical example of an entropy-driven process. J Biol Chem. 1987;262(32): Bornstein P. The NH(2)-terminal propeptides of fibrillar collagens: highly conserved domains with poorly understood functions. Matrix Biol. 2002;21(3): Zhu Y et al. Type IIA procollagen containing the cysteine-rich amino propeptide is deposited in the extracellular matrix of prechondrogenic tissue and binds to TGF-beta1 and BMP-2. J Cell Biol. 1999;144(5): Apte SS. A disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif (ADAMTS) superfamily-functions and mechanisms. J Biol Chem. 2009;284(46): Colige A et al. Characterization and partial amino acid sequencing of a 107-kDa procollagen I N-proteinase purified by affinity chromatography on immobilized type XIV collagen. J Biol Chem. 1995;270(28): Colige A et al. cdna cloning and expression of bovine procollagen I N-proteinase: a new member of the superfamily of zinc-metalloproteinases with binding sites for cells and other matrix components. Proc Natl Acad Sci USA. 1997;94(6): Hulmes DJ et al. Pleomorphism in type I collagen fibrils produced by persistence of the procollagen N-propeptide. J Mol Biol. 1989;210(2): Watson RB et al. Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are not cleaved by procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface. J Mol Biol. 1998;278(1): Watson RB et al. Ehlers Danlos syndrome type VIIB. Incomplete cleavage of abnormal type I procollagen by N-proteinase in vitro results in the formation of copolymers of collagen and partially cleaved pncollagen that are near circular in cross-section. J Biol Chem. 1992;267(13): Unsold C et al. Biosynthetic processing of the pro-alpha 1(V)2pro-alpha 2(V) collagen heterotrimer by bone morphogenetic protein-1 and furin-like proprotein convertases. J Biol Chem. 2002;277(7):

61 References Gopalakrishnan B, Wang W-M, Greenspan DS. Biosynthetic processing of the Pro-alpha1(V) Pro-alpha2(V)Pro-alpha3(V) procollagen heterotrimer. J Biol Chem. 2004;279(29): Marini JC et al. Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat. 2007;28(3): Schwarze U et al. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am J Hum Genet. 2004;74(5): Nicholls AC et al. Homozygosity for a splice site mutation of the COL1A2 gene yields a nonfunctional pro(alpha)2(i) chain and an EDS/OI clinical phenotype. J Med Genet. 2001;38(2): Culbert AA et al. Substitutions of aspartic acid for glycine-220 and of arginine for glycine-664 in the triple helix of the pro alpha 1(I) chain of type I procollagen produce lethal osteogenesis imperfecta and disrupt the ability of collagen fibrils to incorporate crystalline hydroxyapatite. Biochem J. 1995;311(Pt 3): Lichtenstein JR et al. Defect in conversion of procollagen to collagen in a form of Ehlers- Danlos syndrome. Science. 1973;182(109): Eyre DR, Shapiro FD, Aldridge JF. A heterozygous collagen defect in a variant of the Ehlers- Danlos syndrome type VII. Evidence for a deleted amino-telopeptide domain in the pro-alpha 2(I) chain. J Biol Chem. 1985;260(20): Byers PH et al. Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am J Med Genet. 1997;72(1): Cole WG et al. Deletion of 24 amino acids from the pro-alpha 1(I) chain of type I procollagen in a patient with the Ehlers-Danlos syndrome type VII. J Biol Chem. 1986;261(12): Chiodo AA, Hockey A, Cole WG. A base substitution at the splice acceptor site of intron 5 of the COL1A2 gene activates a cryptic splice site within exon 6 and generates abnormal type I procollagen in a patient with Ehlers-Danlos syndrome type VII. J Biol Chem. 1992;267(9): Steinmann B et al. Evidence for a structural mutation of procollagen type I in a patient with the Ehlers-Danlos syndrome type VII. J Biol Chem. 1980;255(18): Weil D et al. Temperature-dependent expression of a collagen splicing defect in the fibroblasts of a patient with Ehlers-Danlos syndrome type VII. J Biol Chem. 1989;264(28): Weil D et al. Structural and functional characterization of a splicing mutation in the pro-alpha 2(I) collagen gene of an Ehlers-Danlos type VII patient. J Biol Chem. 1990;265(26): Weil D et al. A base substitution in the exon of a collagen gene causes alternative splicing and generates a structurally abnormal polypeptide in a patient with Ehlers-Danlos syndrome type VII. EMBO J. 1989;8(6): Weil D et al. Identification of a mutation that causes exon skipping during collagen pre-mrna splicing in an Ehlers-Danlos syndrome variant. J Biol Chem. 1988;263(18): Nicholls AC et al. Ehlers-Danlos syndrome type VII: a single base change that causes exon skipping in the type I collagen alpha 2(I) chain. Hum Genet. 1991;87(2): Vasan NS et al. A mutation in the pro alpha 2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype. Am J Hum Genet. 1991;48(2): Wirtz MK et al. In vivo and in vitro noncovalent association of excised alpha 1 (I) aminoterminal propeptides with mutant pn alpha 2(I) collagen chains in native mutant collagen in a case of Ehlers-Danlos syndrome, type VII. J Biol Chem. 1990;265(11): Holmes DF et al. Ehlers-Danlos syndrome type VIIB. Morphology of type I collagen fibrils formed in vivo and in vitro is determined by the conformation of the retained N-propeptide. J Biol Chem. 1993;268(21):

62 46 3 The Molecular Basis of Joint Hypermobility 51. Lenaers A et al. Collagen made of extended -chains, procollagen, in genetically-defective dermatosparaxic calves. Eur J Biochem. 1971;23(3): Danielson KG et al. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J Cell Biol. 1997;136(3): Jepsen KJ et al. A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice. J Biol Chem. 2002;277(38): Takeda U et al. Targeted disruption of dermatopontin causes abnormal collagen fibrillogenesis. J Invest Dermatol. 2002;119(3): Tasheva ES et al. Mimecan/osteoglycin-deficient mice have collagen fibril abnormalities. Mol Vis. 2002;8: Giunta C et al. Nevo syndrome is allelic to the kyphoscoliotic type of the Ehlers-Danlos syndrome (EDS VIA). Am J Med Genet A. 2005;133A(2): Yeowell HN, Walker LC. Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI. Mol Genet Metab. 2000;71(1 2): Giunta C et al. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome an autosomalrecessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet. 2008;82(6): Malfait F, De Paepe A. Molecular genetics in classic Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet. 2005;139C(1): Mitchell AL et al. Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS). Hum Mutat. 2009;30(6): Symoens S et al. COL5A1 signal peptide mutations interfere with protein secretion and cause classic Ehlers-Danlos syndrome. Hum Mutat. 2009;30(2):E395-E De Paepe A et al. Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II. Am J Hum Genet. 1997;60(3): Wenstrup RJ et al. A splice-junction mutation in the region of COL5A1 that codes for the carboxyl propeptide of pro alpha 1(V) chains results in the gravis form of the Ehlers-Danlos syndrome (type I). Hum Mol Genet. 1996;5(11): Richards AJ et al. A single base mutation in COL5A2 causes Ehlers-Danlos syndrome type II. J Med Genet. 1998;35(10): Giunta C et al. Homozygous Gly530Ser substitution in COL5A1 causes mild classical Ehlers-Danlos syndrome. Am J Med Genet. 2002;109(4): Bristow J et al. Tenascin-X, collagen, elastin, and the Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet. 2005;139(1): Burch GH et al. Embryonic expression of tenascin-x suggests a role in limb, muscle, and heart development. Dev Dyn. 1995;203(4): Geffrotin C et al. Distinct tissue distribution in pigs of tenascin-x and tenascin-c transcripts. Eur J Biochem. 1995;231(1): Matsumoto K et al. The distribution of tenascin-x is distinct and often reciprocal to that of tenascin-c. J Cell Biol. 1994;125(2): Oberhauser AF et al. The molecular elasticity of the extracellular matrix protein tenascin. Nature. 1998;393(6681): Elefteriou F et al. Characterization of the bovine tenascin-x. J Biol Chem. 1997;272(36): Burch GH et al. Tenascin-X deficiency is associated with Ehlers-Danlos syndrome. Nat Genet. 1997;17(1): Schalkwijk J et al. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-x deficiency. N Engl J Med. 2001;345(16): Zweers MC et al. Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome. Am J Hum Genet. 2003;73(1): Mao JR et al. Tenascin-X deficiency mimics Ehlers-Danlos syndrome in mice through alteration of collagen deposition. Nat Genet. 2002;30(4):

63 References Elefteriou F et al. Binding of tenascin-x to decorin. FEBS Lett. 2001;495(1 2): Voermans NC et al. Ehlers-Danlos syndrome due to tenascin-x deficiency: muscle weakness and contractures support overlap with collagen VI myopathies. Am J Med Genet A. 2007;143A(18): Voermans NC et al. Joint hypermobility as a distinctive feature in the differential diagnosis of myopathies. J Neurol. 2009;256(1): Minamitani T, Ariga H, Matsumoto K. Deficiency of tenascin-x causes a decrease in the level of expression of type VI collagen. Exp Cell Res. 2004;297(1): Baldock C et al. The supramolecular organization of fibrillin-rich microfibrils. J Cell Biol. 2001;152(5): Zhang H, Hu W, Ramirez F. Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J Cell Biol. 1995;129(4): Dietz HC et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352(6333): Zweers MC et al. Joint hypermobility syndromes: the pathophysiologic role of tenascin-x gene defects. Arthritis Rheum. 2004;50(9): Zweers MC et al. Deficiency of tenascin-x causes abnormalities in dermal elastic fiber morphology. J Invest Dermatol. 2004;122(4): Reinboth B et al. Molecular interactions of biglycan and decorin with elastic fiber components: biglycan forms a ternary complex with tropoelastin and microfibril-associated glycoprotein 1. J Biol Chem. 2002;277(6): Elefteriou F et al. Cell adhesion to tenascin-x mapping of cell adhesion sites and identification of integrin receptors. Eur J Biochem. 1999;263(3):

64

65 Chapter 4 Biomechanics of Hypermobility: Selected Aspects In an early paper, Sutro 1 drew attention to the biomechanical aspects of hypermobility. In a study of recurrent effusions in the knees and ankles of American army recruits, he noted an increased range of both active and passive movement in the affected joints. He argued in favour of an over-length of certain articular, capsular and ligamentous tissues, and suggested that there might be disproportion in the relative rate of growth of the bones and their attached ligaments. Two decades later, Coomes 2 made a detailed analysis of lateral instability of the knee joint. Movements were measured in 59 normal subjects and 57 patients with rheumatoid arthritis. Instability was present in rheumatoid patients with severely affected knee joints but not in those with mild disease. Instability was not present in normal knees but adolescents up to the age of 20 years displayed more lateral movement than normal adults. No change was seen in patients with ankylosing spondylitis and only moderate change in patients with psoriatic arthropathy. A biomechanical study on autopsy specimens of hip joints 3 using cryosectioning and cryodissection has shown that loading of the hips at 45 of flexion with a moderate force for 3 h results in deformation and dislocation similar to changes found at autopsy in congenital dislocation of the hip. There was no macroscopic damage to the joint. Loading at 135 of flexion (simulating breech position) also resulted in dislocation, but cartilage deformation was less pronounced than with the load applied at 45. After unloading of the dislocated hips with cartilage deformation, ligamentous joint laxity was observed. This was still present 3 h later. By implication, loads applied at critical angles can cause cartilage deformation, though ligamentous laxity, which may be of considerable duration, is a secondary phenomenon. Practical clinical studies tend to confirm the importance of these hypotheses, which are based upon detailed laboratory findings. In an investigation of injuries to knee ligaments in American professional football players, players were classified as either loose or tight. When subsequently checked for the incidence of major ligament rupture requiring surgery, an increased likelihood of ligament injury was found in players with lax joints. It was hypothesised that regular training programmes concentrating on increasing muscle tone, and thereby achieving joint stability, were likely to be of benefit in protecting players with loose ligaments from further injury. P. Beighton et al., Hypermobility of Joints, DOI / _4, Springer-Verlag London Limited

66 50 4 Biomechanics of Hypermobility: Selected Aspects 4.1 Mechanical Factors in Joint Mobility Relative Contributions of Different Factors In seminal studies performed by Johns and Wright, 5 various tissues were divided in turn at the wrist joints of anaesthetised cats. An arthrographic technique was used to determine the relative proportion contributed by each tissue layer to the joint stiffness, measured in mechanical fashion. It was argued that in the intact wrist joint of the cat, the mechanical properties were similar to those observed at the metacarpophalangeal joint in humans. Non-linear elasticity and plasticity accounted for most of the stiffness, elasticity being twice as important as plasticity. The joint capsule contributed 47% of the stiffness, passive action of the muscles 41%, the tendons 10% and the skin 2% to the total torque required to move the joint in its mid-range. Towards the extremes of joint motion, the restraining effect of tendons became more important. Clearly, many structures contribute biomechanically to the observed range of movement at a joint, and the relative proportion of tethering contributed by each of these may vary according to whether the joint is being moved close to its normal anatomical range or at an extreme of its range of function. It has been argued that, for epidemiological and clinical purposes, three main determinants of joint laxity should be considered. 6 These are: 1. The shape of the bony articulating surfaces. 2. The structure of the collagen contributing to the joint capsule, the tendon and the overlying tissues and its degree of stretch. 3. The neuromuscular tone that will tend to stabilise the joint under physiological conditions. This is derived both from the nervous system and from the muscle Bony Surfaces The range of movement is extreme for a ball and socket joint (the hip or shoulder) but non-existent in the joints that contribute to the stability of the skull. Between these two extremes, various anatomical adaptions are available to provide different ranges of movement. At the elbow, there is bony locking to prevent hyperextension, though the increased carrying angle in women allows for a greater amount of hyperextension than in males. The ankle is also a hinge joint at which lateral movement is restricted more by bony prominences than by tension in the lateral ligaments. The knee is a hinge joint, depending entirely upon ligaments for its stability (the anterior and posterior cruciate ligaments and the collateral ligaments); even at the ball and socket hip joint, some stability is provided by the ligamentum teres. In general, the shape of the articulating surfaces, determined both by bone and collagen, is likely to be hereditary. Acetabular dysplasia may lead to a marked increase in the range of movement, and it is likely that this sort of dysplasia follows

67 4.1 Mechanical Factors in Joint Mobility 51 a Gaussian distribution within the population (as described in Chap. 2 ), rather than being an all or nothing phenomenon. Up to the age of epiphyseal fusion at puberty, the shape of the bone may be influenced to some extent by external forces Collagen This is described in more detail in Chap. 3. In summary, the tensile strength of the collagen in the supporting tissues around the joint and in the joint capsule is determined by several factors. These include the chemical structure within the collagen fibres, the extent to which cross-linking has occurred between adjacent chemical chains (which increases with age), the coiling, the diameter and the density of packing of the collagen fibres. Defects in collagen formation may result from enzyme deficiencies and within the different variants of the Ehlers Danlos Syndrome (EDS), both deficiencies in collagen production and deficiencies in collagen turnover have now been recognised. 7 Most of these variations are likely to be genetically determined though the total volume of collagen and its weaving may be altered in response to external forces. Collagen fibres may suffer marked contraction when the temperature of their surroundings changes. Elastin is also present in skin and ligaments. The amino acid sequence analysis of purified elastin, the major protein in the elastic fibres, shows that it differs from collagen in containing fewer basic acidic amino acid residues. The hydroxyproline content is only one-fifth of that seen in collagen. 8 The cross-links between elastin fibres are unusual, not only joining two adjacent protein chains but also having the facility to link three or four nearby chains. With age, elastin changes as well as collagen. Above the age of 45 years, a glycoprotein becomes closely bound to elastin, producing a more brittle complex that is more readily cleaved chemically. Most studies on the tensile properties of collagen have been carried out on tendons in the tails of rats, which can be easily freed from secondary tissue. There is little slack to take up, and the shapes of the load/extension curves of collagen bundles are almost independent on the number of fibres that they contain. After an initial brief alignment of the force/extension curve, there follows an essentially linear extension, during which Hooke s law is obeyed. At a certain point, a failure of individual fibres occurs until the tendon as a whole finally ruptures. Some basic biomechanics have been performed by Silverman et al. 9 by determining the extensibility of the fifth right metacarpophalangeal joint in response to increasing loads (Fig. 4.1 ). Cases 1 and 2 were normal young subjects; case 3 was clinically hypermobile. When extensibility of the fifth metacarpophalangeal joint is related to age, a highly significant inverse correlation becomes apparent (Fig. 4.2 ). Elastic fibres, in contrast, undergo appreciable extension under the action of relatively small forces, returning to their original dimension shown when the force is removed. The properties of elastin are not maintained in older age groups, hence the change in the texture of normal skin during ageing. The physical properties of skin, which also contribute to the range of joint movement observed, have been defined

68 52 4 Biomechanics of Hypermobility: Selected Aspects Fig. 4.1 Extensibility of the fifth right metacarpophalangeal joint in response to increasing load in three subjects (Reproduced from Silverman et al., 9 with permission from BMJ Publishing Group Ltd) Case 1 Case 2 80 Nm Case Angle (degrees) 6 degrees Extensibility 10 5 Nm 5 4 Fig. 4.2 Extensibility of the fifth metacarpophalangeal joint related to age (in years) (Reproduced from Silverman et al., 9 with permission from BMJ Publishing Group Ltd.) 3 0 Age group Sample size

69 4.1 Mechanical Factors in Joint Mobility 53 Fig. 4.3 Stress (T ) versus strain ( S ) curve for intact skin from a patient suffering from Ehlers Danlos syndrome (Reproduced from Beighton et al. 73 ) 5 T (Pa 10 5 ) S Ehlers-Danlos syndrome Control subject by Grahame and Harvey 10 in terms of thickness and extensibility. The stress strain curve for intact skin from a patient suffering from EDS, measured by an in vivo suction cup method, 11, 12 is shown in Fig Neuromuscular Control In clinical terms, the premature osteoarthritis that can accompany neurological conditions as diverse as subacute combined degeneration of the cord, syringomyelia and tabes dorsalis attests to the importance of adequate joint protection by the nervous system during normal life. The wide range of movement observed at peripheral joints in patients with these neurological conditions cannot be explained on the basis of collagen or bony structure alone. That all these conditions, each involving a different part of the central nervous system, can cause osteoarthritis attests to the value of the complete integrity of the afferent proprioceptive arc and the resultant efferent control of the muscle tone. The importance of neurological servo mechanisms in allowing joint stability to be altered is well recognised by sporting coaches and forms the basis for the methods of proprioceptive neuromuscular facilitation described in more detail in Chap. 8. It follows that integrity of the Golgi tendon organs and the muscle spindles is also important in determining the range of joint movement. The quality and nature of the muscle fibres will therefore contribute both in terms of their physiological ability to stabilise the joint and in terms of their anatomical bulk, which might act to impede joint movement by creating a large muscular mass.

70 54 4 Biomechanics of Hypermobility: Selected Aspects The influence of muscles and tendons is often neglected when the frictional forces operative at synovial joints are considered. A tensile force is exerted by muscles and tendons in almost all positions of joints, irrespective of muscular contract, which would exert a further and more powerful force. It has been shown that joints are more mobile in their mid-positions than at the extremes of their ranges. 13 Studies on the wrist joints of dogs shortly after death show that an ever-increasing force is required to straighten the joint as the position of full extension is reached Proprioception There has recently been increasing interest in impaired proprioception, both in relation to joint hypermobility and osteoarthritis. Indeed, this may be one of the factors that bind these two conditions together. Anecdotally, it has been suggested for many years that joint instability is more potent than joint hypermobility alone in the pathogenesis of early premature osteoarthritis. Proprioception can be assessed clinically (though coarsely) by the estimated position of the joint when the eyes are closed, or by appropriate biomechanical devices to quantify this with more precision. Proprioception falls with age, 14 paralleling the increasing onset of osteoarthritis. It can also be impaired with inflammatory arthritis such as rheumatoid disease. 15 In animal experiments, low threshold knee joint mechanoreceptors discharge maximally towards the extremes of movement. 16 These neurones, exerting powerful reflex effects on limb muscles, act to prevent hyperextension and hyperflexion of the joint. 17 Perhaps these receptors protect the joint from potentially damaging movements at the extreme of range. Proprioception can be abnormal in knee joints prior to correction of a lesion of the medial meniscus, whereupon proprioception improves. 18 Normal shoulder proprioception alters the range of movement at that joint. 19, 20 Simple remedies such as elastic bandages 21 and knee braces 22 improve proprioception. Proprioceptive acuity is abnormal in hypermobility syndrome both at the proximal interphalangeal joint 23 and at the knee joint. 24 The sophisticated rig developed in Glasgow by Ferrell and colleagues for the precise quantification of proprioception at the knee joint 24 has provided new insights. There is some evidence that in addition to impairment of proprioception, probably mediated by the resetting of nerve receptors in the synovium, the reflex arc may also be altered. 25 In addition, physiotherapy studies, in which exercise has been given to joints with abnormal proprioception to stabilise them, have improved symptoms of hypermobility. 26 Studies are still needed to determine whether non-weight-bearing joints that are lax with impaired proprioception are less susceptible to osteoarthritis and also whether the effect is purely mechanical and anatomical or whether reduced proprioception, either on an acquired or inherited basis, is associated with altered cartilage turnover or even altered cartilage chemistry.

71 4.3 Lubrication and Stiffness Podiatric Aspects The foot is always important in maintaining gait and especially important in the hypermobile subject since balance and walking may be impaired through proprioception and the hypermobile foot may be of unusual shape and properties. The typical abnormality is flat feet but, sometimes, a high arched foot is found, analogous to the typical foot shape in the marfanoid deformity. Recent Arthritis Research Campaign funded research in Leeds has studied this in more detail with gait analysis and the provision of orthoses, predominantly designed to restore the natural arch of the flat foot. The results have been somewhat conflicting: the degree of foot abnormality (and therefore the need for correction) is not always apparent or correlating with conventional scoring systems for hypermobility (see Chap. 2 ). Preliminary analysis, however, confirms that reduced health status, greater foot pain and poorer foot health status correlate well with higher Beighton scores. Greater magnitude of mid-foot joint excursion during walking is present in the more hypermobile individuals, also correlating with greater foot pain. Arch instability rather than arch flattening may also be crucial. 27 Recent work from Stanmore has drawn attention to dysfunction of the tibialis posterior tendon as a common and treatable cause of flat foot deformity in the adult, manifested by pain and swelling in the medial hind foot. 28 Clearly, tendons extrinsic to the foot as well as those within it also play a part. 4.3 Lubrication and Stiffness Lubrication of the Synovial Membrane Although this forms a minor determinant in the observed range of joint movement, it is relevant to consider briefly why joints move so efficiently. There are a number of theories to account for the remarkably low resistance to movement observed at synovial joints, and these may also have some bearing upon the biomechanics of hyperlaxity. The oldest theory is that of hydrodynamic lubrication, first proposed by MacConaill. 29 A thick film of synovial fluid separates the articular surfaces. However, joint movement is too slow and the pressures across the surfaces are too high to allow the maintenance of a thick film of this nature. Charnley 30 postulated a monomolecular layer of hyaluronic acid protein complex that provides the so-called boundary lubrication. In this context, it is noteworthy that all known bearings depending upon boundary lubrication have a coefficient of friction 20 times as high as that present in synovial joints. The synovial joint mechanism may be more analogous to elastohydrodynamic lubrication. Here, films of viscous fluid separate rubbery surfaces. It is likely that no single mode of lubrication can fully explain the biochemical properties of synovial joints. 31 There is clear experimental evidence of fluid film

72 56 4 Biomechanics of Hypermobility: Selected Aspects lubrication, yet mathematical analysis indicates that this mechanism is not the sole factor. Fluid films require an elastohydrodynamic entraining action supplemented by squeeze film lubrication, rather than conventional hydrodynamic action alone, in order to be effective. Theoretical considerations of hydrodynamic lubrication have a bearing upon the design of new artificial joint prostheses. The artificial component provided needs to simulate the original efficient lubricating mechanism as well as provide adequate strength. If joint laxity follows a Gaussian distribution throughout the population, an artificial prosthetic joint might offer a theoretical therapeutic option for the treatment of individuals who display pathological hypolaxity, though, in practice, this procedure is at present restricted to individuals who have severe flexion contracture or flexion deformity arising from unrelated disease Measurement of Stiffness Stiffness of joints is important clinically. For instance, morning stiffness is a diagnostic criterion of rheumatoid arthritis, while articular gelling, the subjective impression of increased stiffness after a short period of immobilisation, is well known to arthritic patients. Grip strength measurements indicate that there is a circadian rhythm both in muscle strength and in joint stiffness in normal and arthritic persons. 32 Arthrographs have been used in the mechanical evaluation of stiffness at the metacarpophalangeal joint of the index finger. Similar instruments have also been designed for the evaluation of stiffness at the knee joint, but these are less easy to operate and patients with severe arthritis find difficulty in co-operating. However, important information has been gleaned regarding the muscular and skeletal factors that determine joint stiffness. Physiological variations noted include increased stiffness in the elderly and reduction in stiffness at higher temperatures. The arthrograph also allows distinction between the pathological stiffness that occurs in some diseases of joints, such as osteoarthritis and rheumatoid arthritis, and the abnormal suppleness in disorders of connective tissue, such as EDS. The principle of an arthrograph is that the joint to be studied is driven through a proportion of its normal range of movement by a motor, in sinusoidal fashion. The role of gravity needs to be considered, though this can sometimes be eliminated by measuring movement in a horizontal, rather than a vertical, plane. The resistance to movement is then measured electrically and depicted electronically on a computer screen. This results in a hysteresis loop being plotted out each time the joint is put through its predetermined range of motion. Voluntary muscular resistance can be a problem until the subject learns to relax but, in practice, this occurs early and muscular relaxation is confirmed by the reproducibility of the loops, which will assume a constant shape and position on the recorder once the subject is fully relaxed. The most recent studies have used a computerised arthrograph in which the metacarpophalangeal joint of the middle finger is moved in a horizontal plane. 33 This has allowed the demonstration of serial change as the patient s stiffness responds either to

73 4.4 Hypermobility and Osteoarthritis 57 intra-articular steroid therapy or to the use of non-steroidal anti-inflammatory drugs. Interestingly, the stiffness, as perceived by the patient and depicted on a 10-cm visual analogue scale, does not often coincide with the stiffness measured and defined in biomechanical terms. In rheumatic diseases, many patients find it difficult to distinguish stiffness from pain. We have had similar experiences when attempting to define suppleness as an index of hypermobility by the use of a postal questionnaire. The patient s perception of their own suppleness is no substitute for the adequate mechanical monitoring of the range of joint movement. Studies with selected sporting groups 34 have emphasised the importance of training techniques that enhance the range of movement at joints. This emphasises the need to determine whether suppleness is gauged by the subject before or after an appropriate warm-up period. A study on the resonant frequency at the wrist 35 showed abnormal results compared to controls in hypermobile women with damping though with normal thixotropy (the ability of a fluid or material to alter its viscosity with time or shaking). It was postulated that connective tissue in the muscles and tendons of hypermobile subjects might display enhanced compliance. A study of grip and pinch strength in the finger joints using an electronic strain gauge dynamometer (MIE Medical Research, Leeds, UK) demonstrated that symptoms of joint stiffness generally correlate with mechanical measures, providing a useful and sensitive objective index on changes occurring when intra-articular steroid injections were used to relieve stiffness Artificial Lubricants The development of the arthrograph has paved the way for a study of potential lubricants that might be injected into the synovial joints for the relief of osteoarthritis and for the enhancement of range of efficient movement. Objective arthrography has allowed the ranking of a large number of artificial chemicals that might be used in this capacity. These include polyvinyl alcohol, carbopol, manucol, polyacrylamide and polyvinyl oxide. 37 All have lubricating properties similar to those of synovial fluid, though a major pharmacological limitation in their use has been the failure of these compounds to be retained in the joint cavity. Most foreign chemicals are cleared quickly from the joint cavity and, at present, artificial lubricants do not offer a therapeutic option in the management of joint hypolaxity. By analogy, it is unlikely that a fluid selected because of properties of excessive viscosity would be of value in the management of joint hyperlaxity. 4.4 Hypermobility and Osteoarthritis It is believed that joint hyperlaxity predisposes to premature osteoarthritis. Previously, there seemed to be two possible explanations for this situation. Firstly, the particular collagen structure that contributes to hyperlaxity might be identical

74 58 4 Biomechanics of Hypermobility: Selected Aspects with that which leads to osteoarthritis. In this conceptual framework, the hyperlaxity was nothing more than a phenotypic marker of a certain genotype that predisposed to premature degeneration. Alternatively, biomechanical factors might be important in the pathogenesis of the degenerative change. In this way, any hyperlaxity, however acquired, would lead to osteoarthritis, providing it fulfilled the basic biomechanical requirements. Recently, a third suggestion that proprioception may be a causative link between hypermobility and osteoarthritis has been advocated, though the current evidence is not yet completely convincing. Thus, in a study that compared knee joint proprioception in the osteoarthritic knee and the other unaffected knee in unilateral knee joint osteoarthritis, impaired proprioception was shown not to be exclusively a local result of knee joint osteoarthritis. 38 Clearly, longitudinal studies are required to determine the true role of proprioception in osteoarthritis. Perhaps all three mechanisms contribute. Findings derived from the canine model of Pond and Nuki 39 favour the mechanical theory. Only when the cruciate ligaments were severed did sufficient lateral instability occur to initiate the earliest chemical changes in cartilage. The frequency with which osteoarthritis occurs in diseases associated with joint instability is striking. The cause of the instability may be the abnormal collagen in the ligaments, as in acromegaly, 40 or mechanical, as in some neurological diseases. The studies of the University of Leeds group have indicated that individuals indulging in sporting activity may be spared osteoarthritis. 41 It is suggested that the protective muscle tone acquired by regular training stabilises the joint and lessens the likelihood of osteoarthritis. Surveys of professional sportsmen show that osteoarthritis tends to develop in those who have had surgery or injuries to a joint, causing incongruity of the articulating surfaces or stretching of the ligaments. It may be significant that in a clinical and arthroscopic study of osteoarthritis, chondrocalcinosis and joint hyperlaxity in females, no sportswomen were found to be hyperlax. 42 By implication, those who indulged in regular exercise were spared the symptoms, if not the actual degenerative progression. Opinions still differ on whether repeated weight-bearing trauma accelerates or causes osteoarthritis. When the wrist is turned into a weight-bearing joint by the use of a stick, osteoarthritis is not more frequently found there. 43 The literature varies on the extent to which the weight-bearing joints in the lower limbs of former elite male athletes do or do not experience more osteoarthritis. 44, 45 In less selected subjects, the Framingham study has implied that habitual physical activity may influence the development of osteophytes but not of more severe or symptomatic knee joint osteoarthritis. In general, habitual physical activity was felt not to increase the risk of osteoarthritis at the knee. 46 It must also be accepted that what is conventionally termed osteoarthritis is likely to be a collection of many different conditions. On this basis, hyperlaxity would seem to be more relevant to secondary osteoarthritis at a small number of joints than to the primary or generalised osteoarthritis described by Kellgren et al. 47 The aetiology of osteoarthritis may be analogous to the current concept of seronegative inflammatory polyarthritis where the disease occurs in the context of the appropriate genetic background, such as the HLA antigen and the relevant provocative

75 4.4 Hypermobility and Osteoarthritis 59 factor, possibly infection. By analogy, joint laxity could be involved in the pathogenesis of osteoarthritis by either of these mechanisms. Osteoarthritis is not seen with increased frequency in obese individuals, but when it does occur, it is usually worse in the medial compartment of the knee. This fact is conventionally explained by bowing of the leg and a transfer of load from the lateral to the medial compartment. 48 The occurrence of this shift implies some ligamentous laxity, and the situation may therefore be analogous to the instability induced by cutting the cruciate ligament in the dog. There is considerable alteration in the biomechanics following internal derangement of the knee. 49 Fractures protect joints from excessive strains, 50 and osteoarthritis occurs only if the fracture line enters the joint cavity, leading to non-alignment of the articulating surfaces. The concept of a mechanical aetiology of osteoarthritis is also supported by a study, which showed that in meningomyelocele, articular damage occurred only in patients who retained the power of movement. 51 In the same way, there is a low incidence of osteoarthritis in limbs paralysed by poliomyelitis but used with the aid of supporting callipers, which eliminate unwanted lateral movement. 52 There remains controversy on the extent to which joint hypermobility can predispose to osteoarthritis in biomechanical terms alone. Mild degrees of joint hypermobility have not obviously been associated with premature osteoarthritis 53 providing proprioception remains intact. 54 It is also important to determine the severity of progression of osteoarthritis before attributing damage to hyperlaxity alone. 55 Evidence is still accumulating, however, that patella alignment may be crucial, 56 and the Boston osteoarthritis knee study showed site of ligament damage and therefore joint malalignment as a predisposing factor amongst others in osteoarthritis. 57 Recently, varus valgus motion has been shown to be a potent aggravating factor for osteoarthritis. 58 Biomechanical aspects apart, collagen structure may also be important (see Chap. 3 ). An accumulated number of susceptibility genes are being identified in osteoarthritis, e.g. FRZB 59 and ASPN, 60 citing specific differences in osteoarthritis and are now better understood in light of the skeletal dysplasias, which as previously discussed, is a contributing factor to hypermobility. 61 Several specific associations have been recognised, 62 thus mutations in the type II collagen gene (COL2A1) cause congenital spondyloepiphyseal dysplasia with hip osteoarthritis severe at most hyperlax joints. Recently, transforming growth factor- b (TGF-b ) has been implicated in instability-induced osteoarthritis, 63 which is of interest given the close association of this growth promoter with Marfan s syndrome. A review by Bora and Miller 64 has outlined the many links between joint pathophysiology and osteoarthritis. One hypothesis points to an excessive stress, as typified by joint laxity, imposed upon normal tissue. Another hypothesis emphasises the inadequacy of chondrocyte response, implying a basic genetically determined biochemical failure. In addition, ageing, hormones, possibly diet, crystal deposition, bone microfractures and immunological factors have all been implicated as adjuncts to the initial joint hyperlaxity.

76 60 4 Biomechanics of Hypermobility: Selected Aspects The contribution, perhaps mild, of osteoporosis should also not be forgotten. 65 Osteoporosis, sometimes deemed to be protective for osteoarthritis, is increasingly accepted as an accompaniment to hypermobility. 65 Discussion continues on whether osteoporosis is of the conventional type with a quantitative defect in normal collagen or an inherited qualitative defect in a normal amount of collagen, which renders the bone fragile and perhaps susceptible to fracture. Whether, in turn, this might or might not respond to bisphosphonate therapy is still a matter for discussion. Osteoporosis, arguably, might confer some protection to osteoarthritis, but this might be offset by an exacerbation of pain adjacent to hypermobile osteoarthritic joints. 4.5 Prospects for Surgical Intervention Joint fusion, although time honoured, does not provide a serious surgical option for the management of extreme joint hypermobility. Conventionally, patients are instructed to stabilise the joints as far as possible by performing regular physiotherapy exercises in the hope of building up neurological control. Future research is likely to see the patients with joint hypermobility subdivided according to the factors that cause it. Rationally, patients with extreme acetabular dysplasia causing an unacceptably large range of movement might be offered a conventional replacement joint, hip arthroplasty being more refined at present than shoulder arthroplasty. Patients with generalised joint hyperlaxity mediated by inadequate neuromuscular control may be best served by attention to the nervous system. Unfortunately, pharmacological intervention has concentrated on the development of drugs that relieve spasticity rather than the development of drugs that enhance it. For those patients with generalised joint laxity secondary to abnormal inherited collagen structure, ligament tightening or ligament replacement by a surgical technique remains a theoretical option. Although not used prophylactically (see below) to any great extent, artificial ligaments have been developed for the treatment of ruptured ligaments that occur in athletics injuries. Replacement of the anterior cruciate ligament at the knee joint provides one such important example. This has practical importance because rupture of the anterior cruciate ligament is almost ten times as common as rupture of the posterior cruciate ligament in the knee joint (G.K. Sefton 1988, personal communication). It also has theoretical interest because artificial rupture of the anterior cruciate ligament in the dog produces the classic Pond-Nuki model of osteoarthritis from which much of our understanding of basic biochemistry in this condition is derived. 39 Knee injuries are the topic of increasingly sophisticated research, 66 and a link between ligamentous laxity and cruciate ligament damage has been demonstrated clearly. Loss of the collateral ligament appears to be less important 67 and can, to some extent, be compensated for by the remaining structures, especially the anterior cruciate ligament. A major surgical problem in replacement of the anterior cruciate ligament is that of fixation. Because of this, artificial ligaments that are stabilised by allowing an

77 References 61 ingrowth of bone are preferred. Three such devices exist, the carbon fibre ligament, 68, 69 the Stryker-Medox Dacron ligament 70 and the Leeds-Keio, 71 which is a polyester open-weave structure. The open-weave structure of the last named device was developed as a result of collaboration between Dr. Bahaa Seedhom, a University of Leeds bioengineer, and Professor Fujikawa, a Japanese orthopaedic surgeon. It allows the most efficient growth of new bone between the fibres of the ligament in the first few months after insertion. This leads to an even more stable bonding of the ligament to the bone than can be achieved by conventional techniques such as plugging alone. At present, the use of these ligaments has been restricted to repair of a rupture. Their use is recent so we do not yet know whether the accidental simulation of the Pond-Nuki osteoarthritic model in man can be corrected by the use of a ligament, with the resultant prevention of secondary osteoarthritis. If this proves to be the case, surgical tightening or replacement of lax ligaments in patients with genetic abnormalities of collagen such as EDS might be an attractive possibility. It would have to be shown that replacement of a single ligament, probably the anterior cruciate, produced adequate stabilisation in the presence of laxity of the posterior cruciate and collateral ligaments. In turn, mechanical devices of the sort recently developed in Leeds to quantify the component of the different knee ligaments in joint laxity may be of value. An alternative, and perhaps safer choice for such study, would be the ankle joint. Here, there is a relative bony restriction of the joint, perhaps allowing for more accurate quantification of the value, if any, of replacing the lateral ligaments of the ankle with polyester open-weave grafts. The future is likely to see increasing interest in stem cell technology. 72 Replacement joint prostheses are of limited longevity. There is a need to attain implant survival in the range of years as the population ages, with quests for biological material or tissue regeneration therapy that behaves equivalently to an autograft, a particular challenge. Training the cells to populate a scaffold remains a matter of ongoing research but, long-term, the prospects for stem cell replacement of hyperflexible ligaments in hypermobile patients, both to reduce symptoms and reduce the risk of future osteoarthritis, remains an attractive proposition. References 1. Sutro J. Hypermobility of the knee due to overstrengthened capsular and ligamentous tissues. Surgery. 1947;21: Coomes EN. Lateral instability of the knee following polyarthritis: an experimental study. Ann Rheum Dis. 1962;21: Hjelmstedt A, Asplund S. Congenital dislocation of the hip: a bio-mechanical study in autopsy specimens. J Pediatr Orthop. 1983;3: Nicholas JA. Injuries to knee ligaments: relationship to looseness and tightness in football players. JAMA. 1970;212: Johns RJ, Wright V. Relative importance of various tissues in joint stiffness. J Appl Physiol. 1962;17:

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80 64 4 Biomechanics of Hypermobility: Selected Aspects 56. Sendur OF, Gurer G, Yildirim T, Ozturk E, Aydeniz A. Relationship of Q angle and joint hypermobility and Q angle values in different positions. Clin Rheumatol. 2006;25: Hunter DJ, Zhang Y, Niu J, et al. Structural factors associated with malalignment in knee osteoarthritis: the Boston osteoarthritis knee study. J Rheumatol. 2005;32: Van der Esch M, Steultjens M, Harlaar J, Wolterbeek N, Knol D, Dekker J. Varus-valgus motion and functional ability in patients with knee osteoarthritis. Ann Rheum Dis. 2008;67: Loughlin J, Dowling B, Chapman K, et al. Functional variants within the secreted frizzled related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci USA. 2004;101: Kizawa H, Kou I, Iida A, et al. An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat Genet. 2005;37: Superti-Furga A, Unger S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet. 2007;143: Ikegawa A. Genetic analysis of skeletal dysplasia: recent advances and perspectives in the post-genome-sequence era. J Hum Genet. 2006;51: Blaney Davidson EN, Vitters EL, van der Kraan PM, van den Berg WB. Expression of transforming growth factor- b (TGFb ) and the TGF b signalling molecule SMAD-2P in spontaneous and instability-induced osteoarthritis: role in cartilage degradation, chondrogenesis and osteophyte formation. Ann Rheum Dis. 2006;65: Bora FW, Miller G. Joint physiology, cartilage metabolism and the etiology of osteoarthritis. Hand Clin. 1987;3: Stewart A, Black AJ, Reid DM. Risk factors for osteoporosis in subjects with benign joint hypermobility syndrome (BJHS): comparison to population based controls. Rheumatology. 2006;45(Supp 1):113. Abs Skinner HB, Wyatt MP, Stone ML, Hodgdon JA, Barrack RL. Exercise-related knee joint laxity. Am J Sports Med. 1986;14: Inoue M, McGurk-Burleson E, Hollis JM, Woo SL-Y. Treatment of the medial collateral ligament injury. I: the importance of anterior cruciate ligament on the varus-valgus knee laxity. Am J Sports Med. 1987;15: Weiss AB, Blazina ME, Goldstein AR, Alexander H. Ligament replacement with an absorbable copolymer carbon fiber scaffold early clinical experience. Clin Orthop Relat Res. 1985;196: Jenkins DH, Forster IW, McKibbin B, Ralis ZA. Induction of tendon and ligament formation by carbon implants. J Bone Joint Surg Br. 1977;59-B: Hoffman H. Development and evaluation of a synthetic ligament prosthesis. In: Proceedings of the Third Annual Symposium on Prosthetic Ligament Reconstruction of the Knee, Scottsdale, (1986). 71. Seedhom BB, Fujikawa K, Atkinson PJ. The Leeds-Keio artificial ligament for replacing the cruciates. In: Engineering and Clinical Aspects of Endoprosthetic Fixation. London: Mechanical Engineering Publications; 1984: Vats A, Bielby RC, Tolley NS, Nerem R, Polak JM. Stem cells. Lancet. 2005;366: Beighton P, Price A, Lord J, Dickson E. Variants of the Ehlers-Danlos syndrome. Clinical, biochemical, haematological, and chromosomal features of 100 patients. Ann Rheum Dis. 1969;28(3):

81 Chapter 5 Musculoskeletal Features of Hypermobility and Their Management 5.1 Hypermobility and Hypermobility Syndrome A common clinical error is to confuse these two terms, which are not synonymous. Hypermobility is defined as an excessive range of joint motion, taking into consideration the age, gender and ethnic origin in otherwise healthy subjects, being greater in males than females, in younger people compared with older people and in those of Asian or African origin compared to those who are Caucasian. It is characterised by an inherent increase in laxity and fragility of the connective tissues. Hypermobility is a direct consequence of ligamentous laxity, which, itself, is an expression of a genetically determined aberration of one or more of the connective tissue fibrous protein genes such as those encoding for collagen(s), fibrillin(s) or tenascin(s) (see Chap. 3 ). As an unexpected bonus, in hypermobility, the added ranges of motion turn out to favour selection into the performing arts (see Chap. 8 ). Hypermobility itself does not necessarily give rise to symptoms, but when it does, Hypermobility Syndrome is deemed to be present. Thus, hypermobility is not a diagnosis but HMS (JHS) is, and it is now classified by means of the 1998 Brighton Revised Criteria for the Benign Joint Hypermobility Syndrome (BJHS) (see below). 1 The biological price for this enhanced flexibility is tissue fragility, which underlies the musculoskeletal elements of JHS. Tissues such as tendon, ligament, bone, cartilage and skin, which rely on the considerable tensile strength of their collagen component for their physical integrity, are at greater risk of mechanical failure in hypermobile people in comparison with others. Those who engage in more demanding physical activities, such as dancers, musicians, sportspersons, etc., are at greater risk (see Chap. 8 ). Clinicians often identify hypermobility in the course of their clinical examination, but rarely attempt to make a precise clinical diagnosis, such as JHS. As a result, the patient is often left wondering what is wrong with them and why no tailor-made treatment plan has been developed for their management. 2 In clinical terms, with a resulting compromised connective tissue infrastructure comes a tendency to a variety of soft tissue injuries including ankle and other ligament strains, muscle tears, tendon bone attachment traction lesions (enthesopathies) such P. Beighton et al., Hypermobility of Joints, DOI / _5, Springer-Verlag London Limited

82 66 5 Musculoskeletal Features of Hypermobility and Their Management Fig. 5.1 An example of a typical paper-thin scar as seen in a patient with JHS. It is typically pale, shiny and thin and can easily be puckered when compressed between the examiner s index finger and thumb. It is characteristically sunken below the level of the surrounding skin. Scars arising from surgical incisions following lacerations, BCG immunisation and from chicken pox lesions are all valuable pointers to skin involvement in JHS as epicondylitis, meniscus tears, stress fractures and other overuse lesions (including chondromalacia patellae, work- and performance-related upper limb disorders), non-inflammatory spinal and joint pain and varying degrees of premature degenerative joint and spinal disease, respectively, osteoarthritis and spondylosis Impaired Healing Coupled with a general predisposition to soft tissue injury, there is in all people with JHS an impairment of the healing process, which is not only slower than normal, but may also be incomplete. Scar tissue, itself, is also collagen, which explains why scars in JHS are often of poor quality, being thin, shiny and sunken below the level of the surrounding skin. Such scars have significant diagnostic value in JHS and related disorders 1 (Fig. 5.1 ). 5.2 Epidemiology of JHS Astonishingly, up to 45% of all patients referred to general rheumatology clinics 3, 4 satisfy the Brighton criteria for JHS 1 and may therefore be said to have JHS, indicating that this is a very common at-risk phenotype in the community at large. In spite of such evidence, the rheumatological community remains largely unaware of this entity. 5.3 The Clinical Significance of Hypermobility The majority of people with lax ligaments and loose joints probably suffer no articular or peri-articular problems. For example, symptoms were not more prevalent amongst a group of 31 healthy hypermobile blood donors (average age 28 years) than in age- and sex-matched controls. 5 For most hypermobile subjects, the impression is that it is a

83 5.5 Hypermobility Syndrome in Children 67 positive attribute, which enables enhanced participation in a wide variety of physical activities (see Chap. 8 ). However, not all are so fortunate, and many do experience locomotor and other problems as a direct consequence of their hypermobility. Joint hypermobility is a feature common to most of the heritable disorders of connective tissue (HDCTs), which include the various types of the Ehlers Danlos (EDS) syndrome, the Marfan syndrome (MFS) and osteogenesis imperfecta (OI) 6 (see Chap. 9 ). It is seen in its grossest form in the classic type of EDS (formerly classified as EDS types I/II). Generally speaking, the likelihood of developing symptoms, notably arthralgia and joint instability, is directly proportional to the degree of joint laxity and hypermobility, although exceptions to this rule occur. When symptoms occur in seemingly otherwise healthy individuals, the term hypermobility syndrome (HMS) is applied. 7 In recent years, however, this term has increasingly been replaced by the preferred benign joint hypermobility syndrome (BJHS) because of the favourable prognosis, at least, as far as threat to longevity is concerned. Emerging evidence of multi-systemic complications (documented in Chap. 6 ) renders the retention of the epithet benign as of dubious veracity, and joint hypermobility syndrome (JHS) has become the most widely accepted term in common usage. Few clinicians still use an earlier term, familial articular hypermobility, which should probably now be declared obsolete. Most authorities currently acknowledge that JHS is indistinguishable from, if not identical to, the Ehlers Danlos syndrome type III (EDS III), although this remains a somewhat contentious issue Musculoskeletal Features The remainder of this chapter reviews the published data on the musculoskeletal features of JHS and its management. JHS is a condition commonly encountered in clinical practice, provided it is sought, which, sadly, is by no means commonly the case. A considerable amount of material concerning the clinical and epidemiological features of JHS has been published in the decade since the third edition of this monograph appeared in This has had the effect of reinforcing the widely held contention that JHS (at least as viewed from the clinical perspective) is a forme fruste of an HDCT with clinical features that overlap in large measure with those encountered in the MFS, EDS and OI. The question as to whether hypermobility as it exists in the community is a totally separate entity which is truly a physiological variant, merely depicting the upper range of a spectrum of normal joint movement a view favoured in the 1970s for all hypermobility, 9 is becoming increasingly untenable Hypermobility Syndrome in Children JHS often makes its presence first felt in childhood, where it can manifest in infancy as motor delay, ankle instability, flat feet, clumsiness, fidgetiness and developmental coordination disorder (dyspraxia). As in adults (see below), it may also progress to a chronic pain syndrome in later childhood. 10

84 68 5 Musculoskeletal Features of Hypermobility and Their Management Epidemiology A recent review of 13 epidemiological studies of hypermobility in children using the Beighton 9-point scale conducted in North and South America, Europe and Africa found prevalences that vary widely ranging from 6.7% in the UK to 43% in Nigeria. Because of the use of differing measurement and age criteria, these studies are difficult to interpret. In spite of this, certain clear messages emerge. Prevalences are generally higher in girls than in boys and in children compared to adults. 11 There are as yet no population studies of JHS. This may be due to the fact that the Brighton criteria have as yet not been fully validated for use in children (Hasson N, Maillard S, Woo P, Grahame R, 2006, Are the 1998 Brighton criteria for the Benign Joint Hypermobility Syndrome (BJHS) applicable to children? Unpublished Work ) Clinical Presentation in Childhood Early Features Congenital Dislocation of the Hip/Developmental Dysplasia A statistical association between hypermobility and congenital dislocation of the hip (CDH) has been known since the 1970s. 12 Its finding may be the first clinical pointer to JHS in the neonate, and the routine examination of the hip joints in all newly born infants should always be undertaken for this purpose. The finding of clicky hips at birth is an important clue to dysplasia, and an ultrasound examination should be performed in cases of doubt. 13 In a study of 125 children referred to a tertiary hypermobility clinic in London, 12% had clicky hips at birth and 4% had actual CDH. 14 Hypermobility and Motor Development Joint hypermobility is associated with motor developmental delay in infancy. 15 In a study of 59 infants, both gross and fine motor performance were significantly delayed in a group of children who exhibited joint hypermobility and motor delay in infancy. The effects of joint hypermobility resolved more frequently in children who presented normal motor development at the age of 18 months. Infants with joint hypermobility and motor delay show a less favourable motor outcome, and careful follow-up is recommended. 16 Motor delay was also observed in approximately one-third of children with generalised hypermobility in a recent Dutch series. 17 Fortunately, the motor delay diminishes as the infant develops. 15 A recent study of 29 infants from the same group reveals that this catch-up can be helped by a programme of monthly physical therapy combined with a home treatment protocol administered by caregivers. Weekly physical therapy offered no advantage over a monthly regimen. 18

85 5.5 Hypermobility Syndrome in Children 69 Fig. 5.2 Bilateral pes planus with pronation of the forefeet in a patient with JHS. Typically, the contour of the foot is normal with respect to the longitudinal arch while non-weight-bearing ( a ), and it is only on weight-bearing that the deformity is apparent ( b ) a b As well as delay in the onset of walking independently, omitting to crawl and the use of bottom shuffling or sometimes a commando crawl is seen as an alternative means of locomotion prior to independent walking. There is often also a clumsiness of movement (that may persist into adult life), as well as an irrepressible fidgetiness in affected children. This triad of bendiness, clumsiness and fidgetiness is strikingly common and may also persist into adult life. When they do commence to walk, hypermobile toddlers find walking on tiptoe, or with an in-toed or out-toed gait helpful in splinting the ankle thereby affording better hindfoot stability and support. This is often the time when parents notice easy bruising, especially on the shins. Many hypermobile children have been investigated for bruising which is a common feature in this condition. Test for bleeding diatheses is almost invariably normal, and the bruising can be explained on the basis of lack of the normal capillary support proffered by the inherently weak collagen infrastructure. The finding of spontaneous bruising in infants and children resulting from hypermobility may lead to suspicions of non-accidental injury, which may be totally unwarranted and require careful clinical evaluation and, in some cases, genetic testing to resolve. Once walking, parents often notice that their child has very flat pronated feet (Fig. 5.2 ). Reassurance along the lines that all infants are like this is misleading. Flat

86 70 5 Musculoskeletal Features of Hypermobility and Their Management pronated feet lead to an abnormal gait with features such as squinting of the patella, tibial torsion, femoral anteversion and hyperlordosis, and the provision of tailormade orthotics is an important aspect of their rehabilitation. 19 Children with JHS often have poor ball-catching skills and difficulty with using scissors due to an associated developmental coordination disorder (dyspraxia). 20 Proprioception is often impaired in hypermobility persisting into adulthood. This leads to frequent falls, and also clumsiness with walking into door frames and furniture, tripping over, and knocking objects over being common complaints. Once the infant has mastered walking, other milestones such as climbing and running are difficult due to suppleness and weakness of muscles. The gait is further disrupted as in pronation the first metatarsophalangeal joint is locked, and thus toeing off may be difficult, if not impossible, to accomplish. Much of the locomotor difficulty encountered by children with JHS derives from impairment of muscle power and proprioceptive acuity which can be detected both clinically and experimentally. In one study of 37 healthy children (mean age ± SD = 11.5 ± 2.6 years) and 29 children with JHS (mean age ± SD = 11.9 ± 1.8 years), the children with JHS had significantly poorer joint kinaesthesia, joint position sense and muscle torque than control subjects (both p < 0.001). Knee extensor and flexor muscle torque was also significantly reduced (both p < 0.001) in children with JHS compared with healthy counterparts. The authors concluded that these findings provided a rationale for the use of proprioceptive training and muscle strengthening in treatment, 21 as has been advocated clinically. 22 A recent study demonstrated in 41 hypermobile children (mean age 9 years) that only muscle strength correlated with motor performance, 23 adding yet further weight to the primacy of muscle strength and stamina in children with JHS. Arthralgia and Muscle Pain In a recent study of 125 young JHS patients attending a tertiary paediatric rheumatology referral centre, the major presenting symptoms were: joint pain, 92 (74%); back pain, 7 (6%); problems with gait, falls and coordination, 13 (10%); reduced joint movement, 12 (10%); problems with handwriting, 4 (3%); and clicky hips, 3 (2%). The most commonly affected joints (in descending order of frequency) were the knees, ankles, spine, hips, elbows, shoulders and feet. A family history of hypermobility was present in two-thirds of cases. The same study drew attention to hitherto unacknowledged degrees of morbidity and disability that can complicate JHS in children, with 14% experiencing diffuse musculoskeletal pain, 21% pain amplification, 40% handwriting problems, 48% missing physical education, 24% missing schooling and 25% using wheelchair or crutches. 14 Hypermobility in children may present as juvenile episodic arthritis/arthralgia (defined as non-specific, short-duration arthritis or arthralgia in the absence of defined rheumatic disease and with normal laboratory findings). Indeed, no less than 66% of children with this diagnosis were found to be hypermobile. 24 Following 53 hypermobile children over the course of 1 year, 40% suffered from recurrent arthralgia compared with 17% in a non-hypermobile control group. 25 Out of step with most evidence, a large Finnish study involving 1,637 schoolchildren in grades III and V (mean ages 9.8 and 11.8 years, respectively) did not

87 5.5 Hypermobility Syndrome in Children 71 Fig. 5.3 The Bunnell scoliometer manufactured by Orthopedic Systems Inc. (U.S. Patent No. 5,181,325) and supplied by the National Scoliosis Foundation confirm an association between widespread HM and joint pain. 29.9% of the hypermobile ( ³ 6/9) and 32.3% of non-hypermobile children had musculoskeletal pain at least once a week. Hypermobile children did not have more injury pain, and disability caused by musculoskeletal pain did not correlate with the Beighton score. 26 It is of interest that this large series confirms in children that the prevalence of pauci-articular hypermobility was much higher than the polyarticular form, as previously demonstrated in adults by Larsson et al. 27 JHS can also mimic juvenile chronic arthritis, in particular the pauci-articular 28 or the polyarticular variety. 29 Spinal Complications No correlation was seen between back pain and peripheral joint laxity in a group of 115 back-pain sufferers aged years. 30 A significant association has been established recently between joint laxity and idiopathic adolescent scoliosis in a population of Chinese girls in Hong Kong. In this study, the sole measure of hypermobility was the distance between the thumb tip and the volar aspect of the forearm on forced apposition. 31 Scoliosis is a frequently encountered finding in children and adults with JHS. A recent study of joint laxity using the Bunnell scoliometer 32 (Fig. 5.3 ) (which is, effectively, a modified spirit level) during scoliosis screening of 1,273 children (males 598; females 675; mean age 10.4 years) showed a correlation between the Beighton score and trunk rotation of ³7 degrees. 33

88 72 5 Musculoskeletal Features of Hypermobility and Their Management Growing Pains (GP) A common experience in childhood is joint pains for which no obvious explanation is forthcoming. Because they often occur at night, the designation Nocturnal Idiopathic Musculoskeletal Syndrome (NIMS) is widely used. This is preferable to the more conventional growing pains, which, though popular, is a misnomer. Typically, the child is disturbed at night by pain in the legs, especially in the knees. The symptoms may be quite distressing, but are often relieved by simple measures such as local heat, gentle massage, simple analgesics and comforting. Peterson defined growing pains as bilateral, intermittent non-articular pains involving the lower limbs, typically occurring during late afternoons or evenings, with a normal physical examination and normal laboratory parameters whenever performed. 34 There is a growing impression amongst clinicians that JHS provides the key to GP. This assertion is now beginning to acquire an evidence base. In a study of 433 children (219 boys and 214 girls; age range 3 9 years), 177 (41%) had JHM (Beighton ³ 5/9), and 122 (28%) satisfied Peterson s criteria for GP. Of the 177 with JHM, 75 (42%) had GP. Of the 122 with GP, 75 (62%) had JHM. Using chi-square statistical analysis, the authors found that JHM and GP were strongly associated. They also showed a particularly strong association between knee hypermobility and GP. 35 There is now increasing evidence that much of the pain experienced by patients, in particular, children with JHM, is associated with the increased muscle fatigue due to deconditioning and the increased demands falling on to muscles attempting to control joints into the hypermobile range. Ergometric testing on 32 children (mean age 12 years) revealed a significantly reduced absolute peak oxygen consumption and relative peak oxygen consumption in patients with JHS compared to control subjects Joint Instability Joint laxity predisposes a child to joint instability, leading to the possibility of joint dislocation or subluxation. Dislocation usually occurs following a traumatic episode but occasionally may be spontaneous. Shoulder and patello-femoral joints are the most frequently involved joints but the fingers, toes and ankles may also be affected. Subluxation of the first metacarpophalangeal joint, often asymmetrical (with greater instability in the non-dominant hand), is a frequent finding both in hypermobile children and adults. An unusually severe degree of this is shown in Fig Gross instability of the hindfoot may cause difficulty in walking (see Case 7.1, Chap. 7 ) Soft Tissue Lesions Sprained ankle is the most common of a range of traumatic soft tissue lesions to which hypermobile children are prone. Other examples include traumatic synovitis (especially of the fingers, wrists, knees and ankles, often provoked by overuse or by a fall), tendonitis, tenosynovitis, torn knee ligaments, torn muscles, partial or complete tendon rupture

89 5.6 Hypermobility in Adults 73 Fig. 5.4 Gross instability of the first metacarpophalangeal joint in a child with JHS (EDSHM); the joint can be dislocated (and reduced) at will or avulsion of tendon insertions and joint capsular tears. Such events are particularly likely to happen in response to vigorous sporting activities or from injuries sustained in dance or gymnastic activities (see Chap. 8 ). However, a recently published controlled study of pulled elbow in 106 girls and 94 boys aged 3 84 (mean 24) months failed to demonstrate a significant association with hypermobility Temporomandibular Dysfunction in Children and Adolescents with Hypermobility TMJ dysfunction was present in 75% of 20 children aged years with generalised joint hypermobility compared with 50% of controls. 38 Symptoms and signs of internal derangement of the temporomandibular joint were also significantly more common amongst a group of hypermobile adolescents (score ³ 5/9) than amongst controls Hypermobility in Adults Prevalence The true prevalence of JHS in the community is unknown. Generalised ligamentous laxity, the prerequisite of joint hypermobility, is seen in a substantial proportion (perhaps 10 30% ) of healthy individuals (varying according to methodology and to the age, sex and ethnic origin of the population studied). 40, 41 Individuals with asymptomatic joint laxity certainly outnumber those who experience clinical problems. Pauci-articular hypermobility is even more highly prevalent in otherwise healthy subjects than is the generalised variety. Amongst 660 North American music faculty and students of all ages in Rochester NY, USA, 47% of males and 78% of females showed at least one hypermobile joint. 25

90 74 5 Musculoskeletal Features of Hypermobility and Their Management Fig. 5.5 A positive Gorlin sign with the ability to touch the nose with the tip of the tongue. It is said that 10% of normal subjects are able to perform this manoeuvre and that in EDS, the incidence is increased fivefold It is possible to estimate the importance of hypermobility as a cause of articular morbidity by surveying the diagnoses of patients attending rheumatology clinics. Applying the Brighton criteria to consecutive routine general rheumatology hospital referrals, surprisingly high values for clinic prevalences have been recorded, up to 45% of total referrals in a London clinic. 4 A similarly high prevalence was observed in a specialist hypermobility practice in Santiago, Chile Role of Lax Ligaments Normal tight ligaments protect joints both by limiting the range of movement and by imposing stability. The lax joint is deprived of such safeguards and is, therefore, more vulnerable to the effects of injury from trauma and overuse. Many of the features of JHS are commonly seen in everyday rheumatological, orthopaedic and physiotherapy practice but occur with far greater frequency in hypermobile individuals Clinical Manifestations The spectrum of clinical manifestations in the hypermobility syndrome is wide. In most cases, the pathogenesis of the presenting lesion can be ascribed to the effects of tissue laxity and/or fragility of the collagen-rich structures ligament, skin, cartilage, bone, vascular tissues and myofascial supporting structures (pelvic floor, abdominal wall, etc.). Because of the ubiquitous nature of the connective tissue fibrous proteins throughout the body, all soft tissues may share the prevailing laxity even the tongue, giving rise to a positive Gorlin sign, the ability to touch the nose with the tip of the tongue (Fig. 5.5 )!

91 5.6 Hypermobility in Adults 75 Fig. 5.6 The absence of the lingual frenulum is seen. Based on the results of a single published study, this has been proffered as a new physical sign for EDS. The finding is yet to be confirmed in other studies Another newly discovered clinical sign in EDS is the absence of the lingual and inferior labial frenula (Fig. 5.6 ). Absence of the inferior labial frenulum is reported to have 100% sensitivity and 99.4% specificity. For the inferior labial frenulum, the equivalent results were 71.4% and 100%, respectively. 42 Considering that this study was based on a sample size of only 12 patients with classical and hypermobility types of EDS, this study is in urgent need of confirmation in other centres Articular Features Arthralgia and Myalgia Non-inflammatory joint and muscle pain, in the absence of any detectable clinical abnormality, is a frequent presentation in patients with generalised or pauci-articular joint laxity. In a population survey, the presence of arthralgia correlated significantly with the joint hypermobility score. 43 The pathogenetic mechanism is obscure, but unaccustomed physical exertion is a common pre-disposing factor. One postulated cause is the over-stimulation of sensory nerve endings, which are poorly supported by defective collagen fibrils. 44 A histochemical and electromyographic study has suggested that a primary muscle defect may be operative in such cases. 45 Many patients are able to describe aggravating and relieving factors. Changes in the climate, notably the onset of damp or cold weather, may be heralded by an exacerbation of arthralgia. A majority of female patients recognise a temporal relationship to menstruation, and although many are aware of an improvement during pregnancy, a few have noted the contrary. The most consistent precipitating factor is physical activity, which is almost invariably followed by an exacerbation of joint pain. Because patients symptoms occur in the absence of any recognisable articular abnormality, the true nature of the problem is often overlooked; they may be erroneously labelled

92 76 5 Musculoskeletal Features of Hypermobility and Their Management psychogenic. This merely adds to the frustration, which stems from the failure of the medical attendants to explain or relieve their symptoms. Not surprisingly, these patients become depressed and angry, the anger often directed to their health providers Soft Tissue Lesions A variety of soft tissue lesions which occur in everyday rheumatological practice seem to present with greater frequency amongst hypermobile individuals. Such abnormalities include tendon insertion lesions induced by overuse. Common examples are lateral and medial epicondylitis (tennis and golfer s elbow, respectively), supraspinatus and bicipital tendonitis of the shoulder and adhesive capsulitis ( frozen shoulder ). Entrapment neuropathies may also occur in relation to hypermobile joints. Examples include the carpal and tarsal tunnel syndromes, common peroneal and sciatic nerve compression. 46, 47 Soft tissue rheumatism (including fibromyalgia syndrome and bursitis/tendonitis) is figured as the most common clinical diagnosis in 50 newly referred hypermobile rheumatology patients. 48 In a study of year-old Spanish recruits undergoing military training, the occurrence of traumatic musculoskeletal lesions (notably ankle sprains) was significantly higher among the 223 hypermobile subjects ( ³ 2/5) than in the remainder. It would appear that their inherent joint laxity acted as a trauma vulnerability factor. 49 The odds ratio was calculated by March and Silman to be 3.4 (95% CI ). 50 There are clear implications here for military medicine Chondromalacia Patellae A statistically validated association between joint hypermobility and chondromalacia patellae (CMP) was recently established in a prospective study. The authors concluded that hypermobility of the knee joint may be a contributory factor in the pathogenesis of CMP. 51 Genu recurvatum (hyperextensibility of the knee), itself, may be an important pathogenetic factor for chondromalacia patellae. There is evidence that restriction of hyperextension may reduce symptoms of this disabling condition, which predominantly affects physically active adolescents and young adults Acute Articular and Peri-articular Traumatic Lesions Acute lesions include traumatic synovitis, especially of the fingers, wrists, knees and ankles, often provoked by overuse or by a fall. Tenosynovitis of long flexor tendon sheaths of fingers, torn ligaments, torn muscles, partial or complete avulsion of tendon insertions and joint capsule tears may result from overstretching. There is

93 5.6 Hypermobility in Adults 77 abundant evidence that joint laxity plays an important role in the pathogenesis of such lesions in sport and the performing arts (see Chap. 9 ) Chronic Polyarthritis or Monoarticular Arthritis in Adults Chronic arthritis is a common presentation of hypermobility in the rheumatology clinic and can give rise to diagnostic difficulties. Typically, there is soft tissue swelling with an effusion. This may be recurrent or persistent without the radiographic or laboratory features of inflammatory joint disease. The presence of a persistent knee effusion may lead to the formation of a Baker s cyst in the popliteal fossa. 53 These patients are often mistakenly diagnosed as suffering from rheumatoid arthritis and are needlessly worried by this, as well as being exposed to the possible adverse effects of anti-rheumatoid drugs Dislocation of Joints The loss of stability due to ligamentous laxity may result in recurrent dislocation after comparatively minor trauma. This is seen particularly in the patella and shoulder. A statistically significant association has been demonstrated between joint laxity and patellar dislocation. 54 Out of 104 subjects (37 men and 67 women aged years) with patellar dislocation, 67 showed generalised hypermobility using the Carter and Wilkinson 55 criteria, compared with 12 out of 110 of the controls. Some loose-jointed people are able to dislocate or sublux and reduce joints at will (a feat of dubious value!). Similarly, the ability to crack finger or other joints is almost a pathognomonic finding among hypermobile subjects. The cracking results from the sudden induction of a vacuum within the cavity of the distracted lax joints Temporomandibular Joint Dysfunction Clicking of the temporomandibular joint (TMJ) is a common symptom in hypermobile subjects. The TMJ dysfunction syndrome, which is characterised by clicking and pain in the TMJ, is associated with anteromedial displacement of the disc. Of a series of 40 patients with TMJ dysfunction syndrome, 56 no less than 21 (52.5%) showed a hypermobility score of >3, and 15 (37%) a score of >5 using the Beighton (1973) criteria. Similarly, a study using magnetic resonance imaging of the TMJs of 62 symptomatic patients and 38 asymptomatic controls revealed a significant association between the occurrence of TMJ symptoms and generalised joint laxity (>4/9) (odds ratio = 4.0 [95% CI ; p = 0.01]). 57 Westling, using a multiple stepwise regression analysis, established that hypermobility was a more important factor

94 78 5 Musculoskeletal Features of Hypermobility and Their Management in the pathogenesis of TMJ dysfunction than bruxism. 58 Thirty-eight out of 70 (58%) patients with TMJ osteoarthritis (TMJOA) satisfied the criteria for hypermobility. 59 A 30-year follow-up study of 13 hypermobile patients showed an increased radiological tendency to TMJOA compared with controls. Functionally, there was no difference between the groups. 56 Several of the authors concluded that TMJ hypermobility is a subsidiary factor in the development of TMJOA Premature Osteoarthritis (Other Than TMJ) There was for many years a strong clinical impression that hypermobility may predispose to the development of premature osteoarthritis, particularly in weight-bearing joints. Positive proof of this hypothesis awaits controlled prospective studies. Studies with dancers suggest that dancers with JHS develop premature hip OA as compared to their non-hypermobile peers (see Chap. 8 ). Scott et al. 60 compared joint mobility in a group of 50 consecutive persons aged 50 years and over with symptomatic osteoarthritis with age- and sex-matched controls. These workers demonstrated a significantly higher frequency of hypermobility amongst the patients with osteoarthritis. They conceded that hypermobility is these individuals might have been the result of the osteoarthritis rather than vice versa, but they considered this unlikely. A statistically significant association between joint hypermobility and osteoarthritis has been established amongst adults attending a general rheumatology clinic. OA was found in 12/20 (60%) hypermobile patients compared with 33/110 (30%) patients without hypermobility (chi-sq = 6.73; p < 0.01). 61 From Iceland come two studies linking hypermobility with the occurrence and severity of generalised osteoarthritis of the hand (GOA). 62 Comparing 100 GOA patients with matched controls, it was found that thumb base OA was more common, more advanced and more disabling in hypermobile patients ( ³ 2/9). Disability also correlated with the hypermobility score. The authors proposed that hypermobility-associated OA be designated as a subset of GOA of the hands. In a second study 63 by the same group, 50 consecutive female patients with clinical OA hand and thumb base symptoms were examined for hypermobility according to the Beighton score. Thirty-one out of the 50 patients had a score of >2/9 and 17 patients ³ 4/9. Corresponding numbers for the 94 matched controls were 30 ( p < 0.05) and 9, respectively ( p < 0.001). Hypermobile patients were characterised as with more severe thumb base OA and less severe OA of the interphalangeal joints, whereas in non-hypermobile patients, the converse was true Spinal Complications The spine, notably the lower cervical and lower lumbar region, is commonly affected by degenerative diseases in later life, as a result of the stresses to which it is submitted. This process is manifested by a combination of osteoarthritis of the facet joints and

95 5.6 Hypermobility in Adults 79 changes in the intervertebral discs. The onset may be acute, with herniation of the nucleus pulposus through the annulus fibrosus, leading to nerve root compression, or chronic, with osteophyte formation causing nerve root irritation. It is likely that the interspinous ligaments provide an important restraining force and prevent an excessive range of movement, which might otherwise lead to additional damage to the vertebrae, intervertebral discs or facet joints. It follows that a spine devoid of the protection provided by normal tight ligaments will be particularly vulnerable to the insults to which the back is constantly subjected in daily life. Thus, it is reasonable to assume that traumatic lesions including intervertebral disc lesions, be they in the cervical, dorsal or lumbar region, might occur with greater frequency amongst hypermobile persons. Fatigue fractures of the partes interarticularis (spondylolysis) with or without isthmic spondylolisthesis are also frequent in loose-jointed individuals. 64 Notwithstanding these recognisable structural abnormalities, low back pain does seem to occur in the absence of such identifiable lesions in otherwise healthy, hypermobile subjects. This has been termed the loose-back syndrome. 65 As with arthralgia, the mechanism for the pain in this condition is unknown. The range of spinal motion in this series was not recorded. Morgan and her colleagues found that JHS and EDS patients had a highly significantly greater incidence of history of mechanical low back pain, more painful episodes lasting more than 3 months and more radicular pain than controls. Past ability to place hands flat on the floor with knees straight or current hyperextensibility of the lumbar spine were both strongly correlated with these three outcomes. 64 Radiological anomalies of the spine, including scoliosis, transitional vertebrae at the lumbosacral junction and pars interarticularis defects, with or without spondylolisthesis, were more common amongst patients with widespread joint hypermobility. Eleven (73%) of a series of 15 patients with a hypermobility score ³5/9 showed such anomalies. The control groups (scores 3 4/9 and 0 2/9) revealed a lower incidence of anomalies of 3/9 (33%) and 3/13 (23%), respectively. The differences were statistically significant. 66 An attempt to correlate the advent of spondylolisthesis with joint laxity amongst 364 female teachers of physical education failed to produce a significant result. 63 However, this negative finding may have been due to the fact that the information was elicited by means of a postal questionnaire. Nevertheless, a higher prevalence of concomitants of joint laxity, such as flat feet, was recorded amongst the hypermobile subjects. It is of interest that the spondylolisthesis that occurred in this group was, with a single exception, of the degenerative (pseudo-spondylolisthesis) rather than the isthmic variety Bone Fragility Some hypermobile people may have a bone defect, which predisposes to fracture. Thus, in a series of 33 patients with a hypermobility score of 5 9/9, 17 (52%) gave a past history of fracture. In two age- and sex-matched control groups with

96 80 5 Musculoskeletal Features of Hypermobility and Their Management hypermobility scores of 3 4 and 0 2, the incidences of fracture were 3 (14%) and 4 (15%), respectively. 60 These findings suggest that there may be a collagen defect common to ligament and bone in JHS patients. By contrast, there was no excess of fractures in an early series of 100 patients with EDS. 67 This discrepancy might reflect differences in the nature and distribution of the fundamental abnormalities of connective tissue in these disorders. More recent studies have strengthened the link between EDS and osteoporosis 68 and between BJHS and osteopenia. 69 In the latter study, bone mineral density was measured in 40 patients compared with age-matched control subjects. On balance, although BMD was marginally reduced, the difference did not achieve statistical significance. Further light is shone on this topic in new study in 25 women said to be diagnosed with BJHS who were compared with matched controls. Total femoral and trochanteric bone mineral density and t and z scores were significantly lower in hypermobile patients compared to the control group. Ward s triangle and femoral neck z scores were also found to be significantly lower in hypermobile patients ( p < 0.05). Significant inverse correlations were found between Beighton scores and trochanteric BMD, t and z scores ( r = 0.29, r = 0.30, and r = 0.32 respectively) in hypermobility patients. Low bone mass was more frequently found among subjects with hypermobility ( p = 0.03). Hypermobility was found to increase the risk for low bone mass by 1.8 times (95% confidence interval ). The authors suggest that pre-menopausal women with joint hypermobility have lower bone mineral density when compared to the controls and furthermore, that hypermobility increases the risk for low bone density. 70 Unfortunately, as with many such studies, the authors confuse hypermobility (as judged by the Beighton scale) with JHS (classified using the Brighton Criteria) and purport to have studied JHS when, clearly, they report women with hypermobility. A similar study using patients satisfying the Brighton Criteria would possibly have produced an even more significant result The Natural History of JHS and the Development of Chronic Pain The onset of symptoms almost invariably occurs during the childhood years. In one series, out of 45 adult patients with EDS, symptoms had commenced in childhood in 40 (89%). 71 Their early years are marked by episodic soft tissue injuries, dislocations or non-inflammatory joint or spinal pain. The same seminal study established that chronic pain in EDS affecting multiple sites is progressive and unrelenting and is associated with sleep disturbance, impaired physical activity and sexual function. Abdominal pain and headaches were found to be commonplace (1 in 2 and 1 in 3, respectively). The authors refer to a severe and lifetime pain, and they also pointed out that (at that time) it was unrecognised in the medical literature. They considered that EDS should always be considered in the differential diagnosis of chronic musculoskeletal pain. 66 Chronic pain in EDS is now seen to be its greatest therapeutic challenge 72 (see Treatment Section 5.7 ).

97 5.7 Management of Articular Complications in the Hypermobility Syndrome 81 NON-INFLAMMATORY JOINT/SPINAL PAIN; RECURRENT DISLOCATIONS; TRAUMATIC SOFT TISSUE LESIONS SLOW/INCOMLETE HEALING UNACCUSTOMED PHYSICAL EXERCISE INJURY RTA WHIPLASH INEFFECITIVE ANALGESICS; PHYSICAL THERAPY INADEQUATE OR INAPPROPRIATE KINESIOPHOBIA MUSCLE DECONDITIONING FUNCTIONAL IMPAIRMENT PHYSICAL DISABILITY DEPENDENCY CHAIR/BED-BOUND REDUCED QUALITY OF LIFE LACK OF SELF-EFFICACY WORK INCAPACITY SOCIAL ISOLATION DESPAIR CHRONIC PAIN SYNDROME Fig. 5.7 Chronic pain is a frequent occurrence in the national history of JHS. Its pathogenesis is complex and incompletely understood. The early years of the syndrome are characterised by selflimited episodes of soft tissue injury, which recover, albeit slowly, but become increasingly frequent and incomplete healing may occur. Pain, in general, tends to become amplified over time, and this may be triggered by the use of ineffective physical therapy and/or analgesic medication. Other triggers to chronic pain include injury including road traffic accidents, work- or performancerelated upper limb disorder. Pain amplification invokes movement avoidance (kinesiophobia), leading to deconditioning and later weakness of muscle and progressive loss of function and diminution of quality of life Its pathogenesis is multi-factorial, and this is shown diagrammatically in Fig Management of Articular Complications in the Hypermobility Syndrome Hypermobile patients can be spared much unnecessary suffering by the establishment of the correct diagnosis. Many hapless individuals are misdiagnosed as suffering from rheumatoid arthritis (either adult or juvenile). Needlessly, they are forced to suffer the anguish of living with that diagnosis and are exposed to the dangers of the widening selection of anti-rheumatoid drugs and other potentially hazardous treatments used in its treatment. Others, in the absence of observed physical signs to

98 82 5 Musculoskeletal Features of Hypermobility and Their Management explain their symptoms (joint hypermobility is often overlooked), are labelled as neurotic. They either accept this and become resigned to a life of misery and disability, or reject it and go from one doctor to another in their quest for relief. Not surprisingly, many seek help from purveyors of complementary medicine. From the foregoing, it is self-evident that establishing a definitive diagnosis can have a profoundly beneficial effect on morale! It is, however, only just the start General Management Although the precise cause of pain in hypermobility syndrome (JHS) may be unclear, most patients can discover some key exacerbating and relieving factors. The majority recognises the adverse effects of excessive physical activity, and an individual is often able to restrict exercise to within their reasonable level of tolerance. This may entail an avoidance of strenuous sporting pursuits, a change of occupation or a modification of the manner, speed or frequency of performance of a particular job or activity. The journey to and from their place of employment may provoke more symptoms than the actual work itself. Most children with JHS can relate their symptoms to performance of specific activities or sports. Such information can form the basis for helpful advice, which may well be of therapeutic benefit. It follows that in this respect, time spent on taking a detailed history will pay dividends. There is sound epidemiological evidence that body mass may influence the development of symptoms in the hypermobility syndrome. 73 Anecdotal evidence suggests that sudden and substantial weight gain may precipitate the onset of symptoms, notably arthralgia, in previously asymptomatic hypermobile individuals. Despite the fact that no study has as yet demonstrated an improvement in symptoms following weight loss, it would seem advisable to recommend such a measure to obese adults or children with the syndrome Specific Management The reader is recommended to consult the standard texts on rheumatology, orthopaedics, physiotherapy and podiatry for a full account of the management of the wide variety of complications that may be associated with joint hypermobility. A summary of the principal methods of management is given below Rest After acute soft tissue injury, immobilisation, i.e. resting the affected part, is beneficial in the short term. Care is needed to avoid excessive rest as this may lead to loss of function. Local rest in the form of splinting combines pain relief and avoidance

99 5.7 Management of Articular Complications in the Hypermobility Syndrome 83 of contracture formation, whilst dynamic splinting permits simultaneous restoration of function. In milder cases, rest and activity avoidance should be prescribed judiciously, and patients whether adult or child should only be denied pleasurable and healthy physical activities, be they for leisure or work, if it is strictly necessary. Much distress and needless inactivity can result from such inappropriate advice Local Steroid Injections The treatment of choice in many of the soft tissue lesions associated with hypermobility is a carefully applied topical infiltration with hydrocortisone acetate or methylprednisolone with lidocaine. These entities include tennis and golfer s elbow (lateral and medial epicondylitis, respectively), bicipital and supraspinatus tendonitis, adhesive capsulitis, tenosynovitis, bursitis and ligamentous and capsular tears. The longer-acting corticosteroid preparations should be used with caution in extraarticular conditions, as they may lead to severe connective tissue atrophy with consequent weakening of collagenous tissues. 74 The injection of steroid directly into a tendon should be always avoided, as this can result in tendon damage, atrophy, weakness and even rupture. Local steroid injections are also effective in stenosing tenosynovitis the cause of trigger finger. A small volume of a potent steroid preparation, such as hydrocortisone or methylprednisolone, gives excellent results in the treatment of persistent synovitis of joints and of the carpal tunnel syndrome. In the treatment of discogenic sciatica or cruralgia, epidural corticosteroid injections given to inpatients bring relief in over two-thirds of cases, whether or not hypermobility is a predisposing factor. As outpatients, 17 (90%) of 19 patients responded to the active injection in the short term compared with 3 (19%) of 16 control patients. Two-thirds of responders retained their benefit up to the time of the 6-month assessment Physiotherapy For the bulk of patients suffering from the JHS, physiotherapy is the mainstay of treatment, both in the management of identifiable local traumatic, overuse or degenerative sequelae, but also for the less well-understood symptoms of arthralgia and myalgia (see Symptomatic Treatment, below). A wide variety of techniques are practised, ranging from ultrasound, pulsed short-wave diathermy and laser to exercise therapy and passive (Maitland s) mobilisations. As yet, although most of these treatments derive their popularity from empirical use, a number of relevant controlled trials have been published. At therapeutic levels, ultrasound has been shown experimentally to promote in vitro collagen synthesis by human fibroblasts. 76 The clinical application of this technique in JHS lies in the treatment of traumatic lesions of ligament and muscle. It is also effective in disorders of attachment of tendon to

100 84 5 Musculoskeletal Features of Hypermobility and Their Management bone, such as tennis and golfer s elbow, but is generally not as effective as a local corticosteroid injection in these conditions General Principles Physiotherapists undertaking treatment on hypermobility patients will find that they will take longer to treat the hypermobility patient than the average patient, because they often pose quite complex problems having pain at several sites. In one study, the average number of painful sites was Patients attitudes may be coloured by resentment directed towards their former therapists and doctors, whom they perceive to have failed to understand the nature of their problems or to have treated them inappropriately. For many of these patients, severe pain may have been a common everyday occurrence. 67 Their complaint is often as much stiffness as pain, and this is particularly true of the cervical and thoracic spines, which gradually become hypomobile from failure to take advantage of the hypermobile range. A full history should be taken, followed by a thorough examination. It is important to establish whether the presenting problem is an acute one, a series of chronic symptoms or an acute problem complicating a chronic one. Most acute lesions can then be treated with the usual physiotherapy modalities, taking care to progress the treatment slowly and to be content with small gains as recovery tends to take longer. The goal is to ensure that the joints can reach their natural range, no matter how excessive that may appear to be. Having attained the end of range of movement, the patient is advised to avoid sustained postures in this position. Passive mobilisations can be used to restore range both in peripheral and spinal joints. 77 If the restriction is due to pain with the joint range limited by an increase in muscle tone, then manual techniques should be very smooth, large amplitude movements in mid-range. During the performance of the technique, the muscle will suddenly relax, allowing a greater range of movement. It is important to stop treatment at this point, or the patient may experience an increase in pain following treatment or a feeling of soreness as if they have been engaging in unaccustomed exercise. If the restriction of movement is due to tightness of the ligaments and capsule around the joint, this can also give rise to pain. The amplitude of the technique is smaller but used at end of range. The range will then not be restored so dramatically. It is important to ensure that patients have muscular control throughout their range of movement, and that their natural range is restored. The latter can often be assisted and maintained by the patients themselves. If postural muscles have become elongated so that they no longer support the underlying joint range, muscle balance exercises will train the functional length and recruitment patterns of the local and global stabilisers so that they can control the movement throughout its excessive range. It is thought that the exercises facilitate slow motor recruitment to retrain the tonic-holding capacity of these muscles.

101 5.7 Management of Articular Complications in the Hypermobility Syndrome 85 These patients lack end-of-range proprioception, which could be one of the pathogenetic factors in the causation of their joint and muscle pain [see below]. It is important to teach postural awareness so that patients do not sustain or use their joints at end of range during static postures. For example, during sitting, all joints should be in a neutral position. Standing with the knees hyperextended should be avoided. Patients should, wherever possible, be taught to apply treatment themselves, e.g. rest, ice, heat, TENS machine and auto-mobilisations. They should be encouraged to work out their own problem-solving strategies such as pacing their activities and interspersing their activity periods with rest periods. Patients should also learn to understand the difference between pain and harm, so that excessive rest induced by fear does not lead to loss of joint range through inactivity, leading to atrophy, contracture and capsular fibrosis. Aids and appliances should be reserved for acute episodes of flares in a chronic one. The exception is where strapping is used as part of the retraining of good joint function Passive Mobilisation Passive mobilisation is a specialised physiotherapeutic technique requiring rigorous training. It is widely used in the treatment of a variety of conditions where restricted joint movement occurs, such as adhesive capsulitis ( frozen shoulder ) and stuck neck when cervical spine facet joints become impacted. This may happen in hypermobile subjects from partial subluxation following overstretching or later on when cervical spondylosis develops. In the latter situation, it is important to ensure that neither cord compression nor basilar insufficiency (both contra-indications to manipulative therapy of any kind) is present. In the presence of radicular symptoms and/or signs, extra care is needed to avoid damaging neural structures. Passive mobilisation is also employed for low back pain, which is not due to bony pathology or disc prolapse with nerve compression. A word of caution is needed as regards the use of forceful manipulation in hypermobile patients, as joint subluxation may result from excessive enthusiasm! Gentle mobilisation procedures, however, are very useful, particularly in those individuals in whom degenerative changes in the facet joints cause troublesome locking Exercise Therapy There is a growing evidence base verifying the value of physiotherapy in the JHS. A recent retrospective study involving 51 hypermobile children (mean age 8 years) confirmed the experience of many physiotherapists, namely that specific stabilising exercises can help to reduce symptoms in hypermobile children. 77 Exercises specifically designed to improve the stability of hypermobile joints have been shown to

102 86 5 Musculoskeletal Features of Hypermobility and Their Management reduce significantly pain emanating from the treated joint. 78 Some functions also improved, and in respect of the knee, it was possible to confirm a reduction in hyperlaxity of joints treated in this way. A clinical trial of an 8-week home-based exercise programme of closed-chain exercises aimed at improving proprioception was found to alleviate symptoms in 18 patients with JHS. Not only was proprioceptive acuity significantly improved ( p < 0.001), but there was also improvement in balance board performance and in quadriceps and hamstring strength. Symptomatic improvement also occurred in terms of both pain ( p = 0.003) and quality-of-life ( p = for physical functioning, p = for mental health) scores. 79 A recently published randomised clinical trial (RCT) in 57 children aged 7 16 years compares a targeted programme, aimed at providing symptomatic joints with stability by means of enhancing muscle retraining to achieve improved control, with a generalised one aimed at providing muscle strength and fitness. 80 Statistically significant improvement was seen in terms of parental and patient pain scores between baseline and 3-month follow-up assessments, but differences in improvement between the two groups were not significant. This is perhaps the first RCT of physiotherapy in hypermobility in children. Logistic reasons precluded the authors from acceding to their target numbers which explains why the yield in terms of finding significant differences is perhaps disappointing. Nevertheless, this is an important study which points the way for others to follow. A problem that commonly confronts hypermobile subjects is peripheral articular instability, especially of the weight-bearing joints. This is usually the result of ligamentous tears that have occurred as a consequence of pre-existing laxity. The ankle joint is especially vulnerable, and the sprained ankle is a particularly common problem in hypermobile subjects. Fortunately, the majority of these are of mild or moderate severity (grades I or II), responding to treatment with an Aircast boot for 3 weeks, which reduces swelling but at the same time allows weight-bearing. Its easy removal permits the early institution of swimming and general rehabilitation. Severe ankle sprains (grade III) in which instability occurs may require 6 weeks of immobilisation in a cast, followed by intensive rehabilitation. The most common cause of pain and swelling after treatment is residual peroneal weakness due to inadequate rehabilitation. In other situations, for example the knee, it is possible to improve the stability of a lax joint by appropriate muscle-strengthening exercises. However, care must be taken to avoid hyperextension of a lax knee with strenuous and uncontrolled quadriceps exercises, as this merely aggravates the condition. Exercise therapy, perhaps combined with electrical stimulation, can be useful after knee surgery, e.g. after anterior cruciate ligament repair. An anti-rotational brace has been found to be helpful in treating patients with anterolateral rotational instability. Also, shoulder joint instability may be relieved with the aid of a programme of muscle-strengthening exercises. In the study referred to above, specific exercises over 6 weeks reduced knee hyperextensibility as well as relieving pain in hypermobile subjects. Patients with JHS often report that their experience tells them that physiotherapy is either counterproductive or ineffective, presumably because it is either too

103 5.7 Management of Articular Complications in the Hypermobility Syndrome 87 aggressive or perhaps, in some cases, not aggressive enough. A new school of physiotherapy (still in its infancy) adapting physical therapy to the specific needs of patients with lax and fragile tissues is emerging based on sound scientific principles and with an evidence base. 81, 82 In summary, rehabilitation/physiotherapy aims to improve function and enable individuals to more effectively self-manage the condition. A comprehensive assessment identifies postural abnormalities, movement faults, muscle imbalances and weakness and balance deficits present. A specific, individualized exercise programme is developed with the patient based on the examination findings. The programme will usually be focused on functional restoration through improvement of movement control, joint stability, stretching, muscle strength and general fitness (see Hakim, Keer & Grahame 2010) Podiatry Laxity of the ankle and foot region invariably leads to flattening of the longitudinal arch (pes planus/flat foot). This is usually accompanied by pronation of the forefoot and, in severe cases, calcaneal eversion of the hindfoot. Secondary ligamentous damage, tenosynovitis of the tibialis posterior or peroneal tendon sheaths, and eventually subluxation of the ankle subtalar and adjacent joint may supervene. A podiatric assessment is advisable in all such instances, particularly when symptoms develop. A lax-jointed foot naturally adopts a flat foot shape when weight-bearing, particularly in children. When the weight is taken off the limb, the normal shape is restored (see Fig. 5.2a, b ). Such cases are mostly, but not invariably, painless and no treatment is required, and child or adult can be reassured appropriately. Where the foot is symptomatic, podiatric intervention is indicated. A podiatrist has a variety of orthotics available to help to correct the biomechanical abnormality, and thereby contain or reverse deformity, improve stability and relieve pain. Thus, the podiatrist can make an important contribution to the patient s overall treatment and improve the quality of life of hypermobile subjects Surgical Intervention Certain complications of hypermobility may require surgical measures. These are usually undertaken only after conservative treatment has failed to relieve the problem. Reconstructive procedures should be performed only after careful consideration of the risks of possible failure from recurrent stretching or tearing of the intrinsically weak tissues. For this reason, certain conditions that in patients with normal tissues would appropriately be treated surgically may, in the presence of extreme tissue laxity (as in, for example, in the EDS), be best managed conservatively.

104 88 5 Musculoskeletal Features of Hypermobility and Their Management In EDS, the skin is thinner and less robust, 83 and hence sutures are more likely to tear through. The fragility and friability of blood vessels can cause technical problems with wound closure and haemostasis, respectively, during operations. The greatest surgical hazard is in patients with EDS of vascular type (formerly EDS type IV), where the risk of serious vascular or visceral rupture is present, where the risk of wound dehiscence is greatest and where surgical mortality is high. 84 In the JHS, the skin and other tissues are also lax, hyperextensible and relatively fragile. Extra caution is advisable in order to avoid unnecessary damage to soft tissues, which are less robust. Additional sutures and their longer retention may be advisable to reduce the risk of wound dehiscence. The following categories of surgical intervention are encountered Soft Tissue Lesions Tennis and golfer s elbow, tendonitis of the shoulder and the carpal tunnel syndrome, for example, may occasionally need operation. Tenosynovitis that has failed to respond to repeated treatment with local corticosteroid injections and other measures will very occasionally require surgical management. In severe chronic tendonitis, as occurs in the flexor hallucis longus tendon in dancers, debridement of calcific nodules may be required as well as excision of the tendon sheath. Severe (grade III) ankle sprains with rupture of the lateral ligament are probably best treated by open repair. Occasionally, a chronic bursitis unresponsive to non-surgical therapy requires surgical attention. One example is refractory trochanteric bursitis (which may be associated with a snapping hip ), which responds to partial excision of the iliotibial band. Similarly, semimembranous tenosynovitis unresponsive to corticosteroid injections has been successfully treated surgically by excision of the fibrous sheath surrounding the tendon Persistent Synovitis When this occurs in a joint which has failed to respond to local steroid injections, surgical synovectomy may be required. Alternatively, if the patient is over 45 years of age, a radiation synovectomy by means of intra-articular injection of yttrium-90 or other suitable isotope may be considered. Radiation synovectomy carries a risk of causing leakage of radioactive material from the joint, with consequent exposure of the regional lymph nodes to ionising radiation. The last decades have seen the gradual decline in the use of synovectomy, both by surgery and by radiation, following the introduction of more effective topical corticosteroid preparations for intra- and peri-articular use.

105 5.7 Management of Articular Complications in the Hypermobility Syndrome Recurrent Dislocation or Joint Instability The patella, shoulder or other joint which is subject to recurrent dislocation may require surgical stabilisation to prevent further dislocation. The importance of recognising the multi-directional nature of shoulder joint instability in recurrent dislocation has been emphasised by Neer et al. 85 The Trillat procedure for recurrent anterior shoulder dislocation, introduced in 1965, in which the coracoid process is subjected to osteotomy and tilted downward so that it serves as a bone block, has given excellent results in 38 (73%), good in 5 (10%), fair in 4 (7%) and poor in only 5 (10%) of 52 cases after a mean follow-up period of 69 months. 86 Recent research has demonstrated that the application of laser energy can affect the mechanical properties of joint capsular tissues in an experimental model. Clinical results of laser-assisted thermal capsulorrhaphy in 60 patients (27 men, 32 women) with glenohumeral instability (anterior, 30; posterior, 7; anteroposterior, 4; and multi-directional (MDI), 19 were analyzed). Patients were evaluated on the basis of pain, recurrent instability, function and satisfaction. The authors conclude that laser-assisted thermal capsulorrhaphy is an effective adjunct in the treatment of anterior and posterior instability. Patients with MDI treated with this technique have high failure rates. The authors recommend caution when approaching MDI patients with this technique. 87 For an up-to-date review of the management of the unstable shoulder in JHS, the reader is referred to Jaggi and Lambert. 88 Recurrent painful dislocation of the distal interphalangeal joint of the finger can be successfully treated by arthrodesis. Chronic subluxation of a dislocating inferior radio-ulnar joint may be treated with a surgical reconstruction using the tendon of flexor carpi ulnaris. The Krogius tenoplasty introduced in 1901, for the treatment of recurrent dislocation of the patella, in which a flap of medial retinaculum is moved over the patella and attached to the lateral retinaculum is not recommended for use in patients with joint laxity in view of the high failure rate in such subjects. 89 For the same reason, pes anserinus transfer is not recommended in knee instability from rupture of the anterior cruciate ligament of the knee. Recurrent subluxation of the patella that fails to respond to conservative treatment (strengthening the quadriceps and vastus medialis, stretching the tight lateral structures) is best treated by translocating the entire quadriceps and patellar mechanism medially using the Install procedure. A report from Canada found that semitendinosus transfer to the patella with tightening of the medial retinaculum and a lateral retinacular release results in a predictable, stable patello-femoral joint. There were 26 knees (8 hypermobile); 3 boys and 19 girls; mean age at surgery, 14 years and 4 months, range years; mean follow-up, 3.2 years. On longterm follow-up, 23 of the 26 knees (88%) were asymptomatic, and the child had returned to regular activities. One child experienced recurrence of the patellar dislocation, and one child developed medial patellar subluxation. 90 Surgical repair is the treatment of choice for severe (grade III) tears of the medial collateral ligament of the knee joint in preference to conservative management. A recent review of the knee in JHS is shortly to be published. 91

106 90 5 Musculoskeletal Features of Hypermobility and Their Management Chrisman-Snook reconstruction is a surgical method for treating chronic lateral ankle instability and involves rerouting half the peroneus brevis tendon, based distally, through the lateral malleolus and anchoring it to the calcaneum. This study aims to examine the outcome and possible average follow-up period of 35.3 months, ranging from 26 to 51 months. The patients were young, and the average age was 24 years. Functional results were assessed using the Kaikkonen ankle stability score. Joint hypermobility was assessed by the Beighton score. The lateral ligaments were reconstructed. Excellent results were achieved in ten cases, good in four, and fair in one. None had poor results. Best outcomes tended to occur in patients with joint hypermobility. 92 Contrary to earlier reports, there is now good evidence to establish an association between occipito-atlantal and atlanto-axial hypermobility, Chiari malformation type I (CM-I) and HDCT, predominantly EDS, resulting in lower brain-stem symptoms. 93 CM-1 may also be associated with a further complication, namely the tethered cord syndrome with additional features which include elongation and downward displacement of the hindbrain, normal position of the CMD, tight filum terminale (FT) and reduced CSF flow in the lumbar theca. The authors present preliminary evidence that section of the FT can reverse moderate degrees of tonsillar ectopia and is appropriate treatment for cerebellar ptosis after Chiari surgery in this cohort Cervical or Lumbar Discectomy These may be indicated to remove a prolapsed or sequestered intervertebral disc. The recent trend has been away from extensive laminectomy towards the smaller minimally invasive procedures using microsurgical techniques. 95, 96 A similar approach has also been applied to decompression for spinal stenosis. 97 A recently updated Cochrane Reviews addressed the question of the efficacy of surgery in the treatment of lumbar disc prolapse. All 40 randomised controlled trials published up to January 2007 were identified. Many of the early trials were of some form of chemonucleolysis, while later studies compared either different techniques of discectomy or the use of some form of membrane to reduce epidural scarring. Discectomy produces better clinical outcomes than chemonucleolysis, which were better than placebo. Microdiscectomy gives broadly comparable results to standard discectomy. Recent trials of an interposition gel covering the dura and of fat show that they can reduce scar formation, although there is limited evidence about the effect on clinical outcomes. The evidence for other minimally invasive techniques remains unclear except for chemonucleolysis using chymopapain, which is no longer widely available. 98 Much interest now rest on the development of intervertebral disc replacement, which has the potential to retain flexibility and, at same time, obviate the additional strain posed by fusion on adjacent intervertebral discs. Basic scientific research has now developed apace, 99 and early results are encouraging. 100 However, it will some time before this intriguing new approach is suggested.

107 5.7 Management of Articular Complications in the Hypermobility Syndrome Surgery of the Foot Instability of the talus has been successfully treated with a brace or by reconstructing the inter-osseous talocalcaneal ligament both in patients with a history of trauma and in those with generalised joint laxity. 101 Hypermobility of the first ray results in insufficient weight-bearing behind the first metatarsal head. Recent research suggests that there is a direct association between hypermobility or the first metatarsophalangeal joint in extension and painful hallux valgus deformity. 102 Treatment is directed towards re-establishing stable sagittal alignment in addition to reposition of the metatarsal head over the sesamoid complex. First MTP realignment arthrodesis by regulating the elasticity of the multi-articular first ray within the sagittal plane may be the treatment of choice. Podiatric personnel undertaking surgical procedures have also been urged to undertake a thorough preoperative medical (including genetic) evaluation followed by a detailed appraisal of such aspects as anaesthetic risk, tourniquet use, tissue handling, suture techniques, post operative bandaging, etc Advanced Osteoarthritis When there is advanced osteoarthritis of the hip or knee complicating JHS or EDS, total joint replacement may be required, as in patients without hypermobility. In a Mayo Clinic study, a series of 10 patients with the EDS underwent 12 primary knee arthroplasty procedures (mean age 43.3 years, mean follow-up 65 months). The primary indications for surgery were tibio-femoral or patellar instability ( n = 8) and osteoarthritis ( n = 4). Knee Society Functional scores averaged 29.6 before surgery and 51.3 at time of interview ( p < 0.005). Knee Society Knee scores at time of follow-up evaluation averaged 70. Tibio-femoral and patello-femoral stability were significantly improved. The authors concluded that arthroplasty appears to be an effective option for knee arthritis and instability in EDS patients, although results and satisfaction were inferior to those reported for conventional arthroplasty indications Symptomatic Treatment Many of the locomotor complications of JHS can be attributed to clearly defined local lesions. Specific treatment, if appropriately applied, usually provides a satisfactory remedy. Many patients, however, suffer from arthralgia, myalgia, stiffness and/or back pain for which no overt identifiable cause is discernible. Trigger mechanisms may be recognised and, where possible, removed. For many patients, however, the only solution lies in symptomatic relief, as described below.

108 92 5 Musculoskeletal Features of Hypermobility and Their Management Analgesic and Non-steroidal Anti-inflammatory Drugs Pure analgesic drugs, such as paracetamol, dihydrocodeine or nefopam (or mixtures, such as co-dydramol), are helpful in relieving mild musculoskeletal pain. However, many patients prefer the non-steroidal anti-inflammatory drugs (NSAIDs), which seem to have a propensity for relieving locomotor-system pain whether in joint, bone tendon, ligament or muscle. A wide variety of drugs are available. 1. Salicylates aspirin in various forms 2. Pyrazoles azapropazone 3. Indene derivative indometacin, sulindac 4. Propionic acid derivatives naproxen, ketoprofen, fenoprofen, ibuprofen 5. Aryl-acetic acid derivatives diclofenac 6. Oxicam derivatives piroxicam, tenoxicam 7. Miscellaneous NSAIDs tiaprofenic acid, etodolac, nabumetone 8. Low-dose tricyclic anti-depressants amitryptiline 9. Selective serotonin reuptake inhibitors fluoxetine, sertraline, paroxetine 10. Muscle relaxants carisoprodol 11. Opioid analgesics tramadol, buprenorphine, codeine, dihydrocodeine, oxycodone, pentazocine 12. Anti-epileptic drugs gabapentin, pregabalin. Despite the large number of such drugs currently available, their usefulness in controlling pain in JHS is limited. All these drugs are capable of causing adverse reactions including skin rashes, gastrointestinal bleeding and, particularly in elderly subjects, renal impairment. The possible risk of side effects should be weighed against the need for analgesia. It is important to re-emphasise that drug therapy is not indicated for a lesion that requires primarily local treatment. Medicinal agents, however, can provide a limited level of analgesia for hypermobile patients with intractable arthralgia and/or neck or back pain. The development of chronic widespread pain poses further therapeutic challenges as analgesics (including the most potent drugs listed above), even in combination, not infrequently prove to be of little benefit. The most frequently used description of their efficacy is that at best, they merely take the edge off the pain Massage, Mobilisation, Hydrotherapy and Water Immersion Arthralgia and stiffness for no apparent reason are helped by a wide range of accessory and physiological mobilisations 77 either within the pain- and resistance-free range or just beyond it, depending on the severity of the symptoms. Myalgia sore, stiff muscles, tender on palpation and aggravated by sustained postures, e.g. holding a hair dryer often responds to sustained muscle stretch which the patient can learn and perform when required. A willing relative or friend can also be taught simple passive mobilising techniques. In this way, the need for a professional

109 5.7 Management of Articular Complications in the Hypermobility Syndrome 93 physiotherapist may be reduced to an acute exacerbation only. It is important for the patients to regain their normal hypermobile range (without exceeding it) in order to become pain-free. Extreme care is necessary in cases of recurrent dislocation. Some patients also derive symptomatic pain relief from hydrotherapy, in which exercises are performed under the supervision of a physiotherapist in a pool warmed to a temperature of 35 C. Indeed, some appear to gain more benefit from immersion in the pool than from the exercises. This apparent benefit may have a rational basis and, moreover, may go some way towards explaining the popularity of spa therapy. 105 If a hydrotherapy pool is not available, patients can be advised to soak at leisure in a warm bath Behavioural Techniques Progressive relaxation techniques or biofeedback aimed at reducing muscular tension and anxiety have become increasingly widely used in recent years in combating chronic pain. A study in 1984 showed that applied relaxation can significantly reduce chronic back and/or joint pain. 106 Cognitive behavioural therapy (CBT) for chronic pain management aims to improve physical performance and coping skills and, at the same time, transfers the control of pain and its management of its related problems back to the patient. 107 A meta-analysis of 65 studies of treatment of low back pain has shown that multidisciplinary treatments are more effective than no treatment, waiting list or singledisciplinary medical or physical treatments. 108 Not only did pain and mood improve, but behavioural variables such as return to work and use of health service facilities did so too. A randomised controlled clinical trial compared the effects of an inpatient CBT programme administered by a multi-disciplinary team to mixed chronic pain patients in comparison with a similarly constructed outpatient regimen and with a waiting list control group. While the control group did not improve, both treatment groups improved in regard to physical performance, psychological function and reduced medication use. 109 However, the inpatient group made greater gains, which they had better maintained at 1 year. They also utilised less health care. A recent review on the use of pain management programmes in the treatment of chronic pain in EDS gives an authoritative account of the state of current progress Acupuncture and Transcutaneous Neural Electrical Stimulation The use of electrical stimulation to relieve pain dates back to Ancient Greece, where the electric torpedo fish was prescribed for headaches and arthritis. Perhaps the modern equivalent is the transcutaneous nerve stimulator (TENS). A related technique, subcutaneous nerve stimulation, unfortunately has recently been shown to be no more effective in relieving pain in osteoarthritis of the hip than a placebo. 111

110 94 5 Musculoskeletal Features of Hypermobility and Their Management Acupuncture was superior to placebo in the form of detuned TENS in a small series of 13 neck pain cases. 112 Further studies are needed to assess the role of these techniques in the treatment of intractable pain Denervation Procedures When persistent low back pain originates from the facet joints, it may be reduced or abolished by means of so-called facet joint denervation. After a successful preliminary injection of local anaesthetic into the facet joint under X-ray control, the joint is denervated by radio-frequency ablation of the afferent nerves Support and Information Patient self-help and support groups now play an important role in providing information and support for their members. Their activities include the publication of leaflets, books and newsletters, holding study days and maintaining Web sites. In the UK, there are now three such groups: the Ehlers-Danlos Support Group, the Hypermobility Syndrome Association and the Marfan Association. All three are affiliated to the Coalition of the Heritable Disorders of Connective Tissue, an umbrella organisation. All three maintain contact with their sister organisations in Europe and in other parts of the world. Addresses: Ehlers-Danlos Support UK P.O. Box 748, Borehamwood WD6 9HU Tel: Hypermobility Syndrome Association 49 Orchard Crescent Oreston Plymouth PL9 7NF Marfan Association UK Rochester House 5 Aldershot Road Fleet, Hants GU13 9NG Tel: Fax:

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113 References Hudson N, Starr MR, Esdaile JM, Fitzcharles MA. Diagnostic associations with hypermobility in rheumatology patients. Br J Rheumatol. 1995;34(12): Diaz MA, Estevez BC, Sanchez-Guijo P. Joint hyperlaxity and musculoligamentous lesions: study of a population of homogenous age, sex and physical exertion. Br J Rheumatol. 1993;32(2): March L, Silman A. Joint hyperlaxity: is there a case for screening? Br J Rheumatol. 1993;32(2): al-rawi Z, Nessan AH. Joint hypermobility in patients with chondromalacia patellae. Br J Rheumatol. 1997;36(12): Walker HL, Schreck RC. Relationship of hyperextended gait pattern to chondromalacia patellae. Physiotherapy. 1978;1: Grahame R. Joint hypermobility clinical aspects. Proc R Soc Med. 1971;64(6): Runow A. The dislocating patella. Etiology and prognosis in relation to joint laxity and anatomy of patella articulation. Acta Orthop Scand. 2010;202(suppl): Carter C, Wilkinson L. Persistent joint laxity and congenital dislocation of the hip. J Bone Joint Surg Br. 1964;46: Buckingham RB, Braun T, Harinstein DA, et al. Temporomandibular joint dysfunction syndrome: a close association with systemic joint laxity (the hypermobile joint syndrome). Oral Surg Oral Med Oral Pathol. 1991;72(5): Perrini F, Tallents RH, Katzberg RW, Ribeiro RF, Kyrkanides S, Moss ME. Generalized joint laxity and temporomandibular disorders. J Orofac Pain. 1997;11(3): Westling L. Temporomandibular joint dysfunction and systemic joint laxity. Swed Dent J Suppl. 1992;81: Dijkstra PU, de Bont LG, de Leeuw R, Stegenga B, Boering G. Temporomandibular joint osteoarthrosis and temporomandibular joint hypermobility. Cranio. 1993;11(4): Scott D, Bird HA, Wright V. Joint laxity leading to osteoarthrosis. Rheumatol Rehabil. 1979;18: Bridges AJ, Smith E, Reid J. Joint hypermobility in adults referred to rheumatology clinics. Ann Rheum Dis. 1992;51(6): Jonnson H, Valtysdottir ST. Hypermobility features in patients with hand osteoarthritis. Osteoarthritis Cartilage. 1995;3(1): Jonnson H, Valtysdottir ST, Kjartansson O, Breddan A. Hypermobility associated with osteoarthritis of the thumb base: a clinical and radiological subset of hand osteoarthritis. Ann Rheum Dis. 1996;55(8): Morgan AW, Gibbon W, Bird H. A controlled study of spinal laxity in subjects with joint hyperlaxity and Ehlers-Danlos syndrome [abstract]. Br J Rheumatol. 1996;58(suppl 1), Abstract Howes RJ, Isdale IC. The loose back: an unrecognised syndrome. Rheumatol Phys Med. 1971;11: Grahame R, Edwards JC, Pitcher D, Gabell A, Harvey W. A clinical and echocardiographic study of patients with the hypermobility syndrome. Ann Rheum Dis. 1981;40(6): Beighton P, Horan F. Orthopaedic aspects of the Ehlers-Danlos syndrome. J Bone Joint Surg Br. 1969;51(3): Dolan AL, Arden NK, Grahame R, Spector TD. Assessment of bone in Ehlers Danlos syndrome by ultrasound and densitometry. Ann Rheum Dis. 1998;57(10): Mishra MB, Ryan P, Atkinson P, et al. Extra-articular features of benign joint hypermobility syndrome. Br J Rheumatol. 1996;35(9): Gulbahar S, Sahin E, Baydar M, et al. Hypermobility syndrome increases the risk for low bone mass. Clin Rheumatol. 2006;25(4): 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(2): Grahame R. Joint hypermobility syndrome pain. Curr Pain Headache Rep. 2009;13: Pountain G. Musculoskeletal pain in Omanis, and the relationship to joint mobility and body mass index. Br J Rheumatol. 1992;31(2):81-85.

114 98 5 Musculoskeletal Features of Hypermobility and Their Management 74. Harvey W, Grahame R, Panayi GS. Effects of steroid hormones on human fibroblasts in vitro. I. Glucocorticoid action on cell growth and collagen synthesis. Ann Rheum Dis. 1974;33(5): Ridley MG, Kingsley GH, Gibson T, Grahame R. Outpatient lumbar epidural corticosteroid injection in the management of sciatica. Br J Rheumatol. 1988;27(4): Harvey W, Dyson M, Pond JB, Grahame R. The stimulation of protein synthesis in human fibroblasts by therapeutic ultrasound. Rheumatol Rehabil. 1975;14(4): Maitland GD. Vertebral Manipulation. 5th ed. London: Butterworth; Barton LM, Bird H. Improving pain by stabilisation of hyperlax joints. J Orth Rheumatol. 1996;9: Ferrell WR, Tennant N, Sturrock RD, et al. Amelioration of symptoms by enhancement of proprioception in patients with joint hypermobility syndrome. Arthritis Rheum. 2004;50(10): Kemp S, Roberts I, Gamble C, et al. A randomized comparative trial of generalized vs. targeted physiotherapy in the management of childhood hypermobility. Rheumatology. 2010;49: Keer R, Grahame R, eds. Hypermobility Syndrome Recognition and Management for Physiotherapists. 1st ed. Edinburgh/London/New York/Oxford/Philadelphia/St. Louis/Sydney/ Toronto: Butterworth Heinemann; Simmonds JV, Keer RJ. Hypermobility and the hypermobility syndrome [review]. Man Ther. 2007;12(4): Grahame R, Beighton P. Physical properties of the skin in the Ehlers-Danlos syndrome. Ann Rheum Dis. 1969;28(3): Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers- Danlos syndrome type IV, the vascular type [see comment] [erratum appears in N Engl J Med 2001 Feb 1;344(5):392]. N Engl J Med. 2000;342(10): Neer CS, Craig EV, Fukuda H. Cuff-tear arthropathy. J Bone Joint Surg Am. 1983;65(9): Gerber C, Terrier F, Ganz R. The Trillat procedure for recurrent anterior instability of the shoulder. J Bone Joint Surg Br. 1988;70: Noonan TJ, Tokish JM, Briggs KK, Hawkins RJ. Laser-assisted thermal capsulorrhaphy. Arthroscopy. 2003;19(8): Jaggi A, Lambert SM. The shoulder joint. In: Hakim A, Keer R, Grahame R, eds. Hypermobility, Fibromyalgia and Chronic Pain. London: Elsevier; Bauer FC, Wredmark T, Isberg B. Krogius tenoplasty for recurrent dislocation of the patella. Failure associated with joint laxity. Acta Orthop Scand. 1984;55(3): Letts RM, Davidson D, Beaule P. Semitendinosus tenodesis for repair of recurrent dislocation of the patella in children. J Pediatr Orthop. 1999;19(6): Haddad F, Dhawan R. The knee joint. In: Hakim A, Keer R, Grahame R, eds. Hypermobility, Fibromyalgia and Chronic Pain. 1st ed. London: Elsevier; 2010: chap 12, sect iv. 92. Cheng M, Tho KS. Chrisman-Snook ankle ligament reconstruction outcomes a local experience. Singapore Med J. 2002;43(12): 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(6): Milhorat TH, Bolognese PA, Nishikawa M, et al. Association of Chiari malformation type I and tethered cord syndrome: preliminary results of sectioning filum terminale. Surg Neurol. 2009;72(1): Kotil K, Akcetin M, Bilge T. A minimally invasive transmuscular approach to far-lateral L5-S1 level disc herniations: a prospective study. J Spinal Disord Tech. 2007;20(2): Lee JY, Lohr M, Impekoven P, et al. Small keyhole transuncal foraminotomy for unilateral cervical radiculopathy. Acta Neurochir (Wien). 2006;148(9): Ikuta K, Arima J, Tanaka T, et al. Short-term results of microendoscopic posterior decompression for lumbar spinal stenosis. Technical note. J Neurosurg Spine. 2005;2(5):

115 References Gibson JN, Waddell G. Surgical interventions for lumbar disc prolapse: updated Cochrane Review. Spine. 2007;32(16): Cunningham BW. Basic scientific considerations in total disc arthroplasty. Spine. 2004; 4(6 suppl):219s-230s Zigler J. Lumbar spine arthroplasty using the ProDisc II. Spine J. 2004;4(6):S260-S Kato T. The diagnosis and treatment of instability of the sub-talar joint. J Bone Joint Surg Br. 1995;77(3): Klaue K, Hansen ST, Masquelet AC. Clinical, quantitative assessment of first tarsometatarsal mobility in the sagittal plane and its relation to hallux valgus deformity. Foot Ankle Int. 1994;15(1): Tompkins MH, Bellacosa RA. Podiatric surgical considerations in the Ehlers-Danlos patient. J Foot Ankle Surg. 1997;36(5): Rose PS, Johnson CA, Hungerford DS, McFarland EG. Total knee arthroplasty in Ehlers- Danlos syndrome. J Arthroplasty. 2004;19(2): Grahame R, Kitchen S, Hunt J. The diuretic, natriuretic and kaliuretic effects of water immersion. Q J Med. 1978;45: Linton SJ, Gotestam KG. A controlled study of the effects of applied relaxation and applied relaxation plus operant procedures in the regulation of chronic pain. Br J Clin Psychol. 1984;23: Williams de C AC, Richardson PH, Nicholas MK, Pither C, Harding V, Ridout KL. Inpatient vs. outpatient pain management: results of randomised controlled trial. Pain. 1996;66: Flor H, Fydrich T, Turk DC. Efficacy of multidisciplinary pain treatment centers: a metaanalytical review. Pain. 1992;49: Williams de C AC, Nicholas MK, Richardson PH, Pither C, Justings D, Chamberlain J. Evaluation of a cognitive behavioural programme for rehabilitating patients with chronic pain. Br J Gen Pract. 1995;43: Daniel HC. Pain management and cognitive behavioural therapy. In: Hakim A, Keer R, Grahame R, eds. Hypermobility, Fibromyalgia and Chronic Pain. Oxford: Elsevier Limited; Cottingham B, Phillips PD, Davies GE, Getty CJM. Effect of subcutaneous nerve stimulation (SCNS) on pain associated with osteoarthritis of the hip. Pain. 1985;22: Petrie JP, Langley GB. Acupuncture in the treatment of chronic cervical pain. A pilot study. Clin Exp Rheumatol. 1983;1: Gallagher J, de Petriccione de Vadi PL, Wedley J, Hamann W, Ryan P, Chikanza I. Radiofrequency facet joint denervation in the treatment of low back pain: a prospective controlled double-blind study to assess its efficacy. Pain Clin. 1994;7(3): Hakim A, Keer R, Grahame R. Hypermobility, Fibromyalgia and Chronic Pain. 1st ed. Edinburgh, London, New York, Philadelphia, St Louis, Sydney, Toronto: Churchill Livingstone Elsevier; 2010.

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117 Chapter 6 Extra-articular Manifestations of Hypermobility 6.1 Introduction Arguably, the most surprising development of the past decade has been the realisation that the effects of JHS do not lie exclusively within the confines of the musculoskeletal system. Nowadays, it is no exaggeration to state that JHS is seen as a multifacetted multi-system disorder which effectively touches virtually all medical specialties in one way or another. The original concept dates back to the original descriptions of the syndrome in the 1960s 1 when JHS was considered to be purely a mechanical problem of lax joints presenting with pain after exercise, a tendency to instability, leading ultimately to premature osteoarthritis. The affected person was seen as essentially healthy, merely lax jointed and placed at the upper end of a physiological spectrum of joint mobility. 2 Since few doctors (rheumatologists included), then as now, were trained to look routinely for hypermobility, the diagnosis was rarely sought and, thus, even more rarely found. Consequently, it was (and still is) considered to be a rare condition, which is not the case. 3 The great conceptual leap occurred in three stages. Firstly, there was the recognition in the 1970s and 1980s that JHS was itself a forme fruste of a heritable disorder on connective tissue (HDCT) with overlap features that it shared with other HDCTs such as Marfan syndrome (MFS), Ehlers Danlos syndrome (EDS) and osteogenesis imperfecta (OI) 4, 5 (Fig. 6.1 ). Secondly, the notion that what rheumatologists call JHS is indistinguishable from, if not truly identical to, what clinical geneticists term the Hypermobility type of EDS (formerly classified as EDS type III 6 ) has become more widely accepted. 7 Then, finally and slowly, over the past three decades came the realisation that patients with JHS seeking help from doctors and therapists were complaining of many symptoms that bore no obvious direct relation to joint mobility, pointing, unequivocally, to a multi-system disorder. Sadly, more often than not, their pleas initially fell on deaf ears! 8, 9 Published reports pointed (roughly in the chronological order of their appearance in the literature) to: P. Beighton et al., Hypermobility of Joints, DOI / _6, Springer-Verlag London Limited

118 102 6 Extra-articular Manifestations of Hypermobility MARFAN AORTIC DILATATION ECTOPIA LENTIS MARFANOID HABITUS EHLERS-DANLOS CLASSICAL, VASCULAR, ETC STRETCHY SKIN: TYPES PAPYACEOUS SCARS: STRIAE ATROPHICAE JOINT HYPERMOBILITY SYNDROME (=EDS III?) OSTEOPENIA OSTEOPOROSIS; FRACTURES OSTEOGENESIS IMPERFECTA Fig. 6.1 Overlap between the principal heritable disorders of connective tissue Marfan syndrome, Ehlers Danlos Syndrome (EDS) and osteogenesis imperfecta and the probable relations hip between them and the joint hypermobility syndrome (indistinguishable from the hypermobile type of EDS (EDS III)) 1. Weakness of supporting structures, in particular, the pelvic floor, diaphragm and anterior abdominal wall 2. Mitral valve prolapse 3. Chronic pain 4. Joint proprioceptive impairment 5. Lack of efficacy of local anaesthetics 6. Autonomic dysfunction 7. Certain psychiatric disorders and (most recently of all) 8. Functional disorders of the gastrointestinal tract Weakness of Supporting Structures Including Pelvic Floor Insufficiency Abdominal, thoracic and pelvic viscera may be affected as a result of weakness of supporting structures such as the anterior abdominal wall (abdominal hernia), the pelvic floor (rectal and uterine prolapse), the diaphragm (hiatus hernia) or the parietal pleura (pneumothorax).

119 6.1 Introduction Hernia A sevenfold increase in the prevalence of hernia was seen in children with congenital dislocation of the hip and a fivefold increase in hernia in their fathers and brothers. 10 A recent postal survey undertaken among member of the Dutch Ehlers Danlos Society found that the popular concept that hernia is more common among EDS patients was upheld. 11 A recent study from neighbouring Belgium failed to detect differences between the Beighton scores in 60 adult male inguinal hernia subjects compared to controls. 12 Clearly, more research using modern methodologies and concepts is needed Rectal Prolapse The first report of rectal prolapse occurring in EDS was published by Beighton in 1969 in four children, all of whom had experienced complete remission of the symptom by the age of In a study of 21 male and 4 female patients of mean age 69.3 years with rectal prolapse, the angle of extension of the fifth metacarpophalangeal joint was significantly greater (81 ± 2.2 (S.E.M.)) than in age- and sex-matched controls (68 ± 1.7) 14 suggesting that rectal prolapse should be considered part of JHS. Further studies are needed to substantiate or refute this assertion Uterine Prolapse Amongst a group of 76 Iraqi women suffering from various degrees of uterine prolapse, 50 (66%) showed generalised joint laxity (Beighton score >3/9), compared with 14 (18%) ( p < 0.005) in age- and parity-matched female controls. 15 This initial observation has been confirmed in subsequent studies. Norton et al. (1995) found an incidence of hypermobility of 36% amongst 107 stress incontinence patients examined. Subjects with hypermobility showed a highly significantly increased incidence of rectocele, cystocele and uterine or vault prolapse than controls ( p < 0.001, p < 0.002, p < 0.002, respectively). 16 It is now widely accepted in the gynaecological literature that tissue laxity is an important factor in the pathogenesis of pelvic floor problems. In a study of 41 adult women with the EDS (mean age 41 years), genital prolapse was present in 29.3%, incontinence in 59%, endometriosis in 27%, dyspareunia in 57%, previous hysterectomy in 44% a higher incidence than expected for women in this age bracket. 17 In a recent Turkish study, 65 women who had been recommended for surgery for pelvic organ prolapse were compared with 52 age-matched healthy controls. Patients with prolapse had a significantly higher prevalence of JHM when compared with controls (53.8% vs. 9.6%). No significant correlation was demonstrated between Beighton scores and incontinence. Unfortunately, the presence or absence of JHS according to the Brighton criteria was not recorded. 18

120 104 6 Extra-articular Manifestations of Hypermobility Although pelvic floor problems are occasionally encountered in nulliparous women, they are usually considered to affect mostly multipara. In one study, 100 pairs of nulliparous and parous postmenopausal sisters were assessed for pelvic organ prolapse. High concordance of pelvic organ prolapse between nulliparous and parous sister pairs suggests a familial (possibly, even a genetic) predisposition toward developing this condition. Vaginal delivery did not appear to confer increased risk for more severe pelvic organ prolapse in later years. 19 Using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) and the Manchester Health Questionnaire, Jha et al. (2007) compared 30 JHS patients with 30 controls. They found that incontinence in the JHS group was present in 18/30 compared to 9/30 (60% vs. 30%; p = 0.037) in the control group. Twenty-three per cent (7/30) of the women with JHS had in additional anal incontinence compared to none of the controls (23% vs. 0%; p = 0.01). Thus, the prevalence of both urinary and anal incontinence appears to be significantly higher in women with JHS compared to women controls. 20 The same group also conducted a survey among 148 members of the HMSA (Hypermobility Syndrome Association), the UK-based patients self-help group (40% response rate). The survey revealed a prevalence of urinary and faecal incontinence of 68.9% and 14.9%, respectively, compared to 30% and 2.2%, respectively, as reported in the general population. 21 Self-reported data of this kind clearly need to be interpreted with caution, but admittedly, the figures are striking and further studies are necessary Mitral Valve Prolapse Mitral valve prolapse (MVP) during systole has been reported in patients suffering from hereditary disorders of connective tissue, such as MFS, 22 EDS 23 and OI. 24 Reports in the 1980s described an increased prevalence of mitral valve prolapse in persons with hypermobility. 4, 25 Using the echocardiographic technology and stricter criteria of the 1990s, Mishra et al. 5 were unable to find an increased incidence of MVP among 58 JHS patients (10%) as compared with 30 age- and sex-matched controls (7%). The MVP was minimal, and only one patient had associated mitral regurgitation. Furthermore, not a single patient showed aortic root dilatation, thereby helping to differentiate patients with JHS from those with MFS and confirming the distinct and benign nature of JHS. A recent paper from Turkey sheds a little more light on this subject. Forty-six MVP patients (with or without hypermobility) were compared with 25 healthy controls. The incidence of H/M as judged by the Beighton scale was found to be significantly higher in patients than that in the controls. Those with MVP + H/M had significantly increased anterior mitral leaflet thickness (AMLT), maximal leaflet displacement (MLD) and degree of mitral regurgitation (DMR) compared to those without hypermobility. However, the index of aortic stiffness (IAOS) was found to be lower and the aortic distensibility higher. There was a significant correlation between AMLT, MLD and DMR, and hypermobility. Had the

121 6.1 Introduction 105 authors used the Brighton criteria for JHS ( rather than solely relying on the Beighton score an index of JHM), these important new data could have clarified the situation with regard to MVP in JHS rather than in the more nebulous grouping of hypermobility Chronic Pain Chronic pain is a frequent symptom in patients attending outpatient clinics with JHS. Twenty-six per cent of 700 JHS patients attending the author s specialist hypermobility clinic at University College Hospital, London, admitted that their pain was lifedominating at the time of their first attendance (unpublished data). Surprisingly, it is only in the last decade or so that the link between JHS and chronic pain has become apparent. 27 The onset of chronic pain is usually insidious, superimposing itself on the pattern of often long-standing widespread joint and spinal pain that preceded it. Chronic pain is very different from acute pain. Unlike its acute counterpart, chronic pain cannot usually be directly traced to a specific injury; its distribution is diffuse without conforming to anatomical patterns; it may cover the whole body, half the body (top or bottom or left or right) or just a quadrant; it may be accompanied by dysaesthesiae, hyperesthesia or allodynia (seen in the tender points of fibromyalgia); and it is generally resistant to the most potent combinations of oral analgesics up to and including morphine. Most patients describe their efficacy at best, as taking the edge of it. In JHS, chronic pain is often aggravated by any body movement. Intuitively, the affected individual resorts to a strategy of movement avoidance as a means of pain avoidance, a process termed kinesiophobia. 28 This has the effect of aggravating and compounding muscle deconditioning, indeed, the very opposite effect of what is needed by a hypermobile person whose joints are inherently unstable through joint laxity. Not surprisingly, it often plunges them into a vicious downward spiral of declining function, loss of independence, self-esteem and self-efficacy. This downturn in the patient s fortune rarely occurs out of the blue and can usually be traced to either a change in lifestyle, such as a new job or leisure activity involving greater physical demands on the person s already compromised locomotor system, or a sudden traumatic event like an unaccustomed physical challenge, e.g. running in a race without appropriate prior training, undertaking over-ambitious home improvements schemes or an injury such as a whiplash injury following a road traffic accident (RTA). The intensity of all their pains is amplified. This includes not only the superimposed diffuse chronic pain, but also the pre-existing pains, be they joint, spinal or soft tissue in origin, which also increase progressively in parallel over time. The level of distress is heightened further by associated chronic fatigue (which may be just as debilitating as the pain itself and may incur an erroneous diagnosis of chronic fatigue syndrome) and depression. Sadly, for many people in this situation, their medical attendants, appear unaware of the link between JHS and this level of pain, and they are either not believed or told that it is all in the mind. 9 There is also a suggestion of an association between EDS and chronic regional pain syndrome (CRPS). 29

122 106 6 Extra-articular Manifestations of Hypermobility New interest has been added to the established association between hypermobility and fibromyalgia known to exist both in children and adults 30, 31 by the finding on dynamic MRI of the cervical spine of positional cervical cord compression in extension of the cervical spine in patients with widespread chronic pain of the fibromyalgia type and dysautonomia Proprioceptive Impairment It has been established that JHS as defined by the Brighton criteria is associated with impairment of joint proprioceptive acuity both in the finger and knee joints. 33, 34 Although it is not yet certain whether this is innate or acquired, it has been shown to be capable of being improved (even normalised) by appropriate exercise therapy 35 where it now forms part of the evidence-based rehabilitation programme (see Chap. 5 ) Lack of Efficacy of Local Anaesthetics JHS patients can often recall experiences when local anaesthetics have proved to be ineffective. In one study, the following standardised question was put to groups of JHS patients and control subjects. They were asked If you have ever had a local anesthetic injection (e.g. at the dentist, for minor surgery or epidural (spinal) anaesthesia), do you think that it was as effective as it should have been? Some 58% of the 172 JHS patients answered No as compared with 18% of the 53 controls (OR 2.85). 36, 37 It is nearly 20 years since Arendt-Nielsen and co-workers confirmed in elegant experiments that there was a true and measurable difference in responses comparing EDS patients with controls. EDS patients were not totally resistant to local anaesthetics; they merely showed a shorter duration and a reduced effect. 38 Their explanation at the time for this curious symptom, that the local anaesthetic solution diffuses away more rapidly from the micro-environment of the site of the injection because of the lax nature of the connective tissues, has not been bettered over the intervening period Autonomic Dysfunction Patients with JHS frequently complain of symptoms compatible with autonomic dysfunction. These include palpitation, dizziness, pre-syncope and syncope, and there is often an orthostatic element, similar to that seen in patients suffering from chronic fatigue syndrome (CFS) or fibromyalgia (FM). 39 Such symptoms may have in times gone by have previously been misinterpreted as stemming from mitral valve prolapse. 5 The first association between EDS and autonomic dysfunction was established in children with chronic fatigue. 40

123 6.1 Introduction 107 Gazit et al. (2003) confirmed the occurrence of autonomic symptoms in JHS, studying 48 patients and 20 controls. Symptoms including syncope, palpitations, chest discomfort, fatigue and heat intolerance were significantly more frequent among the JHS patients as compared with the controls. Furthermore, 27 patients and 21 controls underwent autonomic evaluation: including orthostatic testing of cardiovascular vagal and sympathetic function. Orthostatic hypotension (OI), postural orthostatic tachycardia syndrome (PoTS) or uncategorized orthostatic intolerance (OI) was found in 78% (21/27) of JHS patients. The authors concluded that dysautonomia is a part of the extra-articular manifestation of JHS. 41 In a study of 170 JHS patients from a specialist hypermobility clinic, Hakim and Grahame identified 41% of patients with light-headedness and other presyncopal symptoms, 26% with palpitations and shortness of breath and 37% with gastrointestinal symptoms, compared to 15%, 12% and 16% in controls, respectively. 42 Bravo and Wolfe, in a study of 1,226 JHS patients, found the prevalence of OH and OI to be especially high in adolescent girls and in adult JHS patients younger than 30 years old. Autonomic dysfunction was present in 72% of females and 44% of males in this series. 43 In a more recent study, the presence of cardiovascular autonomic dysfunction (CAD) was identified by detailed autonomic testing in symptomatic cases of JHS. Some 63% of patients had identifiable pathology (43% PoTS, 14% vasovagal syncope (VVS) and 6% both). 44 None were identified as having other pathologies such as anaemia or epilepsy that might explain their symptoms. One in three of the symptomatic cases had no identifiable autonomic pathology; a similar finding to that seen in patients with fibromyalgia and chronic fatigue syndrome. 45 A recent paper from Belgium draws attention to the overlapping relationship between chronic fatigue syndrome (CFS), chronic musculoskeletal pain and JHS and emphasises the significance of pain catastrophising as an indicator of poor exercise performance in CFS. 46 The well-established correlation between fibromyalgia (FMS) and hypermobility both in adults 30 and in children 31 has recently received further confirmation in a study of 118 FMS adult women and 118 healthy controls. Unfortunately, the investigators only measured the Beighton joint score for hypermobility (rather than the Brighton criteria for JHS), so that the true incidence of JHS in the two groups is not recorded. Using a cut-off point for hypermobility of ³ 4/9 on the Beighton scale, 46.6% of the FMS group and 28.8% of the control group were deemed to be H/M. The mean Beighton score of FM group was higher than in the controls (3.68 vs. 2.55, p < 0.001). More severe clinical findings were seen in hypermobile FMS patients compared with those who were not hypermobile, but this did not achieve statistical significance Certain Psychiatric Disorders A group of psychiatric colleagues working in Barcelona, Spain, have discovered a perplexing series of links between certain anxiety and phobic states on the one hand

124 108 6 Extra-articular Manifestations of Hypermobility and hypermobility on the other. Firstly, panic disorder, agoraphobia and simple phobias were four times more common in hypermobile patients than in controls. 48 Then, from the opposite direction, it was apparent that joint laxity was sixteen times more common in patients with panic attacks or agoraphobia than in controls. 49 Finally, a community-based study established beyond question the association between anxiety disorders and joint laxity. 50 The finding by Gratacòs et al. (2001) of an interstitial duplication on human chromosome 15 (15q24-26) (Dup 25) significantly associated with panic, agoraphobia, social phobia, joint laxity in families and with panic disorder in non-familial cases led the authors to propose that Dup 25 is a susceptibility factor for a clinical phenotype that includes both panic and phobic disorders on the one hand and joint laxity on the other. 51 In an attempt to confirm these interesting findings, a group led by Zhu et al. at NIH used two different methods to detect DUP25: high-throughput molecular gene dosage analysis and fluorescence in situ hybridization (FISH). They evaluated 56 lymphoblastoid cell lines derived from 26 unrelated patients with panic disorder obtained from several European and American populations and 30 normal controls, but could not find any cell line showing a result consistent with DUP A similar British study attempting to replicate the experimental conditions described by Gratacòs and colleagues in which fluorescence in situ hybridization was used to examine metaphase chromosomes of patients with panic disorder/social phobia and of control individuals from a southern region of the UK, the primary aim being to determine the prevalence of this chromosomal rearrangement in a geographically and ethnically distinct population. DUP25 was not observed in any of the 16 patients, nor in 40 control samples nor in 3 previously reported DUP25-positive control (Centre d Etude du Polymorphisme Humain) cell lines, indicating a highly significant difference in the frequency of DUP25 between the study by Gratacòs 51 and colleagues and the subsequent investigations in two other centres Functional Disorders of the Gastrointestinal Tract It has long been appreciated that in up to 50% of patients who present to gastroenterologists with GI symptoms, no structural or biochemical abnormality can be identified. Such patients whose symptoms are unexplained are said to be suffering from functional gastrointestinal disorders (FGIDs) (this includes so-called irritable bowel syndrome (IBS)). Because of their high prevalence, FGIDs have enormous economic consequences. There is increasing evidence to suggest that joint hypermobility is strongly implicated in the pathogenesis of the FGIDs. A recent Australian study has demonstrated an association between constipation and hypermobility defined as a Beighton score of ³ 4/9 (but not JHS) in 39 children (aged 7 17 years) with slow transit constipation (STC), a form of chronic constipation characterised with delayed colonic passage of stool, when compared with 41 controls without constipation. JHM was sought. The relationship was only statistically significant in boys. 54 In a study of 129 patients with FGIDs, no less

125 6.2 Straws in the Wind 109 than 63 (49%) were found to have either JHM or JHS. 55 Abdominal pain, bloating and constipation and/or diarrhoea, nausea and an unpleasant taste in the mouth were the commonest symptoms, and physiological studies showed features of a pan-intestinal dysmotility including gastroparesis, small bowel dysmotility and slowed colonic transit. The first evidence pointing to JHS as a factor in the pathogenesis of obstructive defecation (OD) came from a study from Australia which observed that OD, chronic constipation, JHS, chronic heavy lifting and a history of uterovaginal prolapse were significantly associated with patients with lower urinary tract (LUT) dysfunction and obstructive defecation compared to those with LUT dysfunction alone. Overall, symptoms of obstructed defecation were not more prevalent in any one urodynamic diagnostic group than in others. However, childhood constipation and current constipation were significantly more prevalent in women with voiding dysfunction than in those with other urodynamic diagnoses (16.7% vs. 5.5%, p = and 13.0% vs. 5.7%, p = 0.017). The authors concluded that women with LUT dysfunction are more likely to have symptoms of obstructive defecation than are community controls. Connective tissue disorders such as JHS were considered to be an important factor in this association. 56 A further study of rectal physiology has revealed in hypermobile subjects rectal evacuatory disorder (RED) with features of functional rectocele, occluding intussusception, megarectum and features suggestive of enterocele on proctography. Of 200 patients satisfying the criteria for JHM using a self-reported validated 5-point questionnaire, (86%) were found to have significant morphological abnormalities, compared to only 64% of the non-jhm group ( p = 0.001). 57 Thus, one-third of constipated patients presenting to a tertiary centre with symptoms of RED had evidence of JHM compared to reported prevalences of JHM in the general population of only ~5 20%. 57 The notion that the cause of the intestinal dysmotility revealed in these studies could be due to a common underlying connective defect manifesting as joint hypermobility is an intriguing one that gastroenterologists have yet to contemplate. 6.2 Straws in the Wind If fragility of connective tissue underlies such a wide variety of pathological processes, it is very likely that links between hypermobility and other diseases will come to light in years to come. A foretaste of the kind of future ramifications of hypermobility that may emerge is to be seen in orthostatic (low-pressure) headache caused by spontaneous intracranial hypotension associated with leakage of cerebrospinal fluid from the sub-arachnoid space through a rent in the dura. Of 18 patients thus presenting in one series, no less than 7 (38%) showed evidence of a connective tissue disorder including types of EDS. The authors postulate at that leakage from the dural membranes may have resulted from their inherent fragility. 58

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127 References Yazici M, Ataoglu S, Makarc S, et al. The relationship between echocardiographic features of mitral valve and elastic properties of aortic wall and Beighton hypermobility score in patients with mitral valve prolapse. Jpn Heart J. 2004;45(3): 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(2): Vlaeyen JW, Linton SJ. Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain. 2000;85(3): Stoler JM, Oaklander AL. Patients with Ehlers Danlos syndrome and CRPS: a possible association? Pain. 2006;123(1 2): Acasuso-Diaz M, Collantes-Estevez E. Joint hypermobility in patients with fibromyalgia syndrome. Arthrit Care Res. 1998;11(1): Gedalia A, Garcia CO, Molina JF, Bradford NJ, Espinoza LR. Fibromyalgia syndrome: experience in a pediatric rheumatology clinic. Clin Exp Rheumatol. 2000;18(3): Holman AJ. Positional cervical cord compression and fibromyalgia: a novel co-morbidity with important diagnostic and treatment implications. J Pain. 2008;9(7): Mallik AK, Ferrell WR, McDonald AG, Sturrock RD. Impaired proprioceptive acuity at the proximal interphalangeal joint in patients with the hypermobility syndrome. Br J Rheumatol. 1994;33(7): 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(2): Ferrell WR, Tennant N, Sturrock RD, et al. Amelioration of symptoms by enhancement of proprioception in patients with joint hypermobility syndrome. Arthritis Rheum. 2004;50(10): Hakim AJ, Grahame R. A simple questionnaire to detect hypermobility: an adjunct to the assessment of patients with diffuse musculoskeletal pain. Int J Clin Pract. 2003;57(3): Hakim AJ, Grahame R, Norris P, Hopper C. Local anaesthetic failure in joint hypermobility syndrome. J Roy Soc Med. 2005;98(2): 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(5): Hoad A, Spickett G, Ellio J, Newton J. Postural orthostatic tachycardia syndrome is an underrecognized condition in chronic fatigue syndrome. Q J Med. 2008;101(12): 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(4): Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med. 2003;115(1): Hakim AJ, Grahame R. Non-musculoskeletal symptoms in joint hypermobility syndrome. Indirect evidence for autonomic dysfunction? Rheumatology (Oxford). 2004;43(9): Bravo JF, Wolff C. Clinical study of hereditary disorders of connective tissues in a Chilean population: joint hypermobility syndrome and vascular Ehlers-Danlos syndrome. Arthritis Rheum. 2006;54(2): Hakim AJ, Mathian C, Grahame R. Outcome of cardiovascular autonomic testing in symptomatic patients with benign joint hypermobility syndrome. Rheumatology. 2009;48(4): Raj RR, Brouillard D, Simpson C. Dysautonomia among patients with fibromyalgia: a non-invasive assessment [Abstract]. J Rheumatol. 2000;27: Nijs J, Meeus M, De Meirleir K. Chronic musculoskeletal pain in chronic fatigue syndrome: recent developments and therapeutic implications [Review] [54 refs]. Man Ther. 2006;11(3): Sendur OF, Gurer G, Bozbas GT. The frequency of hypermobility and its relationship with clinical findings of fibromyalgia patients. Clin Rheumatol. 2007;26(4): Bulbena A, Duro JC, Mateo A, Porta M, Vallejo J. Joint hypermobility syndrome and anxiety disorders. Lancet. 1988;2(8612):694.

128 112 6 Extra-articular Manifestations of Hypermobility 49. Bulbena A, Duro JC, Porta M, et al. Anxiety disorders in the joint hypermobility syndrome. Psychiat Res. 1993;46(1): Martin-Santos R, Bulbena A, Porta M, Gago J, Molina L, Duro JC. Association between joint hypermobility syndrome and panic disorder. Am J Psychiat. 1998;155(11): Gratacòs M, Nadal M, M-Santos R, et al. A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders. Cell. 2001;106(3): Zhu G, Bartsch O, Skrypnyk C, et al. Failure to detect DUP25 in lymphoblastoid cells derived from patients with panic disorder and control individuals representing European and American populations. Eur J Hum Genet. 2004;12(6): Tabiner M, Youngs S, Dennis N, et al. Failure to find DUP25 in patients with anxiety disorders, in control individuals, or in previously reported positive control cell lines. Am J Hum Genet. 2003;72(3): Reilly DJ, Chase JW, Hutson JM, et al. Connective tissue disorder a new subgroup of boys with slow transit constipation? J Pediatr Surg. 2008;43(6): Zarate-Lopez N, Farmer AD, Grahame R, et al. Unexplained gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link? Neurogastroenterol Motil. 2010;22(3):252-e78. Epub Oct 15, Manning J, Korda A, Benness C, Solomon M. The association of obstructive defecation, lower urinary tract dysfunction and the benign joint hypermobility syndrome: a case-control study. Int Urogynecol J Pel. 2003;14(2): Mohammed SD, Lunniss PJ, Zarate N, et al. Joint hypermobility and rectal evacuatory dysfunction: an aetiological link in abnormal connective tissue? Neurogastroenterol Motil. 2010;22(10):1085-e283. Epub Jul 5, Schievink WI, Gordon OK, Tourje J. Connective tissue disorders with spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension: a prospective study. Neurosurgery. 2004;54(1):65-70.

129 Chapter 7 Illustrative Case Histories In all the three earlier editions of this book, published between 1983 and 1999, a chapter of Illustrative Case Histories numbering between 22 and 32 cases was included. Almost without exception they documented the variegated modes of presentation of JHS as it affected the musculoskeletal system. They illustrated how until the very end of the twentieth century, despite the evidence that was emerging over the preceding decades to the contrary, JHS was perceived exclusively as a musculoskeletal problem. With the arrival of the new millennium came the realisation that JHS is truly a multi-systemic disorder as has been recounted in Chaps. 5 and 6. To mark the occasion of this radical change of emphasis was the publication in 2000 of the Revised 1998 Brighton Criteria for the BJHS, which for the first time provided a reliable and reproducible means of classifying joint hypermobility for research purposes and clinical purposes. 1 It is as a consequence of these two developments that readers will find the current chapter on Illustrative Case Histories, whilst retaining the same name, is very different in content from its predecessors. It will attempt to demonstrate the complexity of JHS as it now manifests, as well as the often unrecognised major disabling effect that it can have on the musculoskeletal system. Case 7.1: A 6-Year-Old Boy with EDS II/III with Grossly Unstable Hind Feet M.A. did not walk until after his third birthday, prior to which he bottom-shuffled rather than crawled as a prelude to walking and thereafter had a marked tendency to fall. His very stretchy skin and joint hypermobility (Fig. 7.1 ) was first noted at the age of 2 when he was admitted to hospital for another illness. He was seen to walk on the medial aspects of his feet with marked pes planus and calcaneal eversion. His joints, especially his hands and knees, were very lax and his skin soft, velvety and very stretchy. Another relevant point in the history was the fact that he bruised easily. P. Beighton et al., Hypermobility of Joints, DOI / _7, Springer-Verlag London Limited

130 114 7 Illustrative Case Histories Fig. 7.1 The hands of a 6-year-old boy with EDS II/ III who had grossly unstable hind feet Fig. 7.2 Same patient with feet showing marked flattening and pronation on weight bearing and, in particular, pronounced calcaneal eversion He was the eldest of three siblings, all of whom showed evidence of hypermobility. There was little doubt that the condition had been inherited from their father who had been diagnosed as suffering from EDS type II by Professor Michael Pope in 1993 on the basis of scarring on the forehead, elbows and knees and the finding of cauliflower fibrils on electron microscopy of his skin collagen. M.A. was considered to manifest the EDS II/III overlap. He appeared a lively boy and extremely flexible. He walked with a hyperlordotic posture and borderline scoliosis (5 on the Bunnell scoliometer). His feet showed marked flattening and pronation on weight bearing and, in particular, pronounced calcaneal eversion (Fig. 7.2 ). Walking with the current orthotics only partially corrected the deformity. He scored 6/8 on the modified Beighton scale (only the elbows were not positive), and outside the scale, many of his other joints including shoulders, spine, small finger and toe joints, and hips were all markedly hypermobile. His

131 Case 7.2: Pelvic Floor Problems After Childbirth 115 Fig. 7.3 Same patient. His skin was very extensible (3/3) skin was very extensible (3/3) (Fig. 7.3 ). There were no scars or striae. His hands and feet appeared normal in length, but the palate was somewhat high arched and he had an obvious pectus excavatum. Initially he had been supplied with Piedro boots and later ankle/foot orthotics, which he was unable to tolerate. He walked with considerable difficulty because of the severe ankle deformities. He was referred to a podiatrist for tailor-made orthotics to good effect. Comment: This case illustrates the importance of orthotic correction of severe hind foot deformity in young children with EDS. In this instance, the child was suffering from the EDS type II/III overlap, so the deformity was unusually severe as was the walking impediment. Case 7.2: Pelvic Floor Problems After Childbirth in a Patient with EDS Hypermobility Type G.E., a 35-year-old mother of a 6-month-old daughter, presented with severe locomotor problems and widespread joint pain in the presence of hypermobility. As a child, she had been bendy, clumsy and fidgety, performing contortionist tricks, ballet and gymnastics, going on to experience so-called growing pains in her legs in her early teens. She subsequently developed pains in her wrists, knees, hips and shoulders, neck, thoracic and, during pregnancy, the low back region. Her father, paternal uncle and two first cousins on her father s side were also hypermobile. She had had a series of orthopaedic procedures mainly directed towards her knees with indifferent results. In the course of a forceps delivery of her daughter, she sustained a fourth

132 116 7 Illustrative Case Histories degree perineal tear. Post-delivery, she suffered from vaginal prolapse and lack of sensation as well as urinary urgency, frequency and leakage. She was treated with supervised intensive pelvic floor exercises supplemented with long courses of biofeedback and neuromuscular stimulation. After the birth of her daughter, she found it difficult to care for her, and this gave rise to considerable concern. Compatible with a hypermobility syndrome was the recurrent dislocation of her patellae and left shoulder, widespread joint clicking, stress incontinence since childbirth and orthostatic intolerance with syncope. Examination confirmed the presence of widespread joint laxity with a hypermobility score of 4 [historically 7/9] on the Beighton scale. By contrast, her cervical and thoracic spine movements were significantly reduced in all directions, the cervical spine particularly so and the restriction was painful. Her skin was characteristically soft and silky and showed increased stretchiness in the phase of taking up slack. A number of her operative scars were paper thin, and although she had no striae atrophicae, the absence of striae gravidarum was characteristic of the condition. The lingual frenulum was absent, another inconsistent sign of the EDS. There were no features of a marfanoid habitus. She conformed to the 1998 Brighton criteria for the joint hypermobility syndrome equivalent to the EDS hypermobility type, formerly EDS III. The nature of the condition was explained to her, in particular its genetic basis and the vulnerability it confers on soft tissue to the effects of injury and overuse. In her case, it had resulted in longstanding spinal pain and instability. Comment: Unfortunately, the emphasis in her management thus far had been along the orthopaedic route, and the results had been disappointing. She needed urgent attention to the rest of her locomotor system, in particular the axial skeleton, including a programme combining core and joint stabilising and proprioception enhancing exercises coupled with a general fitness programme to restore function and reverse the changes resulting from deconditioning, together with the use of mobilising techniques to restore areas of the spine or peripheral joints to their natural hypermobile state. She was referred to the physiotherapy department for assessment. She already attended other hospitals for her complaints and a Women s Health physiotherapist for the pelvic floor problem. A community physiotherapist visited her at home, and she also attended pain clinics at two hospitals. She found analgesics generally unhelpful, and this is a feature of the pain amplification that accompanies JHS. Case 7.3: A Labral Tear and Autonomic Dysfunction Complicating Hypermobility G.V. was a 29-year-old former mental health support worker who had not worked since her hip problem started in She was considered to have joint hypermobility syndrome. Like many hypermobile people, she walked late, experienced the so-called growing pains in her limbs, performed contortionist tricks and gymnastics in childhood,

133 Case 7.3: A Labral Tear and Autonomic Dysfunction Complicating Hypermobility 117 and went on to suffer from recurrent ankle sprains from the age of 10 years, which had persisted to the present time. She was clumsy with a tendency to trip and bump into furniture, which is also characteristic of the condition. From the age of 10 years, she complained of pain in her knees, hips and ankles, which has persisted. One day after sitting cross-legged for 3 h (as she is wont to do), she suddenly jumped up and developed an instantaneous severe left hip pain, which was excruciating and subsequently caused great difficulty in walking. From then on she managed to get about on crutches but needed a wheelchair for outdoor use. An MRI with contrast revealed a large tear of the acetabular labrum on the left. Compatible with a hypermobility syndrome were her disc prolapse at the age of 20 with left-sided sciatica and a dislocation of the left shoulder at the age of 23 when she fell downstairs, recurrent dislocations of the patellae and left 1st MCP joint. Widespread joint clicking, easy bruising, poor skin healing, history of capsulitis of the shoulder following a dislocation and right-sided costal chondritis, TMJ problems and resistance to lidocaine at the dentist and during minor surgery were other syndromic complaints. She also had osteopenia and was receiving calcium and vitamin D. She had experienced orthostatic intolerance from the age of 13 and had a history of panic attacks and claustrophobia, both of which have been linked to hypermobility. The examination revealed evidence of marked and widespread joint laxity with a Beighton score of 9/9 on the hypermobility scale. Outside the scale, her shoulders and cervical spine were also hypermobile. However, her dorsal spine showed restriction due to pain on rotation to the right. There is a 2 scoliosis on the Bunnell scoliometer but no other features of a marfanoid habitus. Her feet flattened on weight bearing. Her skin was soft and silky and showed increased stretchiness in the phase of taking up slack. There were a few small paper thin scars on her knees from childhood scrapes and striae atrophicae which had been present since the age of 14 years. The lingual frenulum was present, a normal finding. She scored relatively high (15/30) on the checklist of symptoms consistent with autonomic dysfunction commonly seen in JHS. It was not possible to confirm the presence of orthostatic hypertension or postural orthostatic tachycardia in clinic, although a rise in her pulse rate of 19 bpm on standing from lying was somewhat suggestive of the latter. She conformed to the 1998 Brighton Criteria for the Joint Hypermobility Syndrome 1 (equivalent to the EDS hypermobility type, formerly EDS III). The nature of the condition was explained to her, in particular its genetic basis and the vulnerability it confers on soft tissues to the effects of injury and overuse. In her case, it had resulted in longstanding joint pain, probably early thoracic spinal spondylosis, a past lumbosacral disc prolapse and what was, almost certainly, a labral tear associated with a dysplastic hip, and the beginnings of a chronic pain syndrome. Comment: The first priority was the need for further investigation and treatment of her autonomic symptoms and to seek orthopaedic guidance for management of the hip problem. Once this was obtained, there was the need for a programme of appropriate rehabilitation to deal with the other aspects of her condition. Physiotherapy being the mainstay of treatment, we recommended a physiotherapy programme combining core- and joint-stabilising and proprioception-enhancing exercises together with a general fitness programme to offset or reverse the tendency

134 118 7 Illustrative Case Histories to deconditioning. Where appropriate, the use of mobilising techniques to restore mobility in stiffened joints/spinal segments to their previously natural hypermobile state was also initiated. 2 She had previously found painkilling drugs ineffective and had entered a pain management programme in which a cognitive behavioural approach was used. Case 7.4: Complexities in Diagnosis and Management C.C. was first referred at the age of 24 years by a consultant rheumatologist following a succession of referrals to the clinicians. She was then a graduate in psychology, aspiring to a second degree to allow a career as a solicitor. At 5 ft 10 in., she was the tallest member of the family, the mother being much shorter and not obviously hypermobile though there was an implication that the separated father might have been hypermobile, and he was able to bite his toenails. Her paternal grandfather had a horseshoe kidney. The Beighton score was 9/9 though this only gave a modest assessment of extreme hyperlaxity which was present at certain sites, especially the fingers. She had avoided sports because of poor co-ordination and easily fulfilled the criteria for hypermobility syndrome. 1 Her scars were well healed and were not typical of EDS, the ocular lenses were not subluxed and, although her fingers and toes were long and thin, these latter features were not classical for arachnodactyly. The changes in the spine were those of a simple thoracic scoliosis rather than any of typical marfanoid deformities. Echocardiogram had shown mild prolapse of the mitral valve and no concerns in the aortic area or the aortic ring. There were concerns with vision, and an ophthalmologist had previously diagnosed swollen optic nerves ; optic neuritis had been excluded on appropriate investigation as had the Stickler syndrome. She did, however, display variation between extreme short-sightedness and extreme long-sightedness and, more recently, had developed astigmatism. There was also a family history of psoriasis (though her own skin lesions were thought to represent acne) and of possible psoriatic arthritis, though at no stage was she considered to have developed an anterior uveitis and HLA-B27 testing was negative. The gynaecological history was complex. Her periods started at 14 years, but prior to this, she was given Co-cyprindiol for skin lesions, and found that this preparation made the hyperlax joints more painful. At one point, polycystic ovary syndrome was suspected, and this has remained under review. Whilst symptoms had been present at all joints, the main practical problem was the management of the extreme hyperlaxity in the long fingers and the extreme laxity at the shoulders, both combining to cause considerable difficulties in the large amount of writing required in her second university course. Orthopaedic review in respect of the shoulders had so far avoided plication or laser capsular shrinkage and

135 Case 7.5: Bony Abnormality and Complications of Subluxation 119 it was possible the slight thoracic scoliosis was contributing to an asymmetry of symptoms at the shoulders. Management to date has been with intensive physiotherapy and guidance on thoraco-scapular tracking. Standard measures had been offered for the hands including chunky pens, three-fingered grip, elasticated gloves, spica splints by day (even when writing), and firm night rest splints ensuring the hands and wrists remained in a physiological position overnight prior to writing the next day. Both universities had been supportive with the provision of an ergonomic computer keyboard, voice recognition software and even the use of a scribe in examinations. Urinary tract symptoms including mild stress incontinence and a succession of infections were initially attributed to bladder and pelvic floor dysfunction often found in hypermobility syndrome. More recent investigation, however, has confirmed the presence of bilateral duplex kidneys. Comment: Although benign joint hypermobility syndrome provides broad cover for the many symptoms experienced by hypermobile patients, careful exclusion of alternative diagnoses is still required. Inflammatory arthritis mimicking hypermobility is unlikely to be missed, but overlap with other inherited abnormalities such as a mild variant of Marfan syndrome or even osteogenesis imperfecta needs to be kept in mind. In this case, it seemed prudent to continue with intermittent monitoring of the diameter of the aortic ring. Many patients also demonstrate clustering with other heritable disorders, in this case a condition at the eye, not fully diagnosed but thought not to be Stickler syndrome, and bilateral duplex kidney. Against this background, completion of two university courses has been challenging, but the subject is a determined optimist who has vowed to use her legal skills in the support of claimants with inherited abnormalities, hoping ultimately to specialise in this area. Case 7.5: Bony Abnormality and Complications of Subluxation J.T., first referred by her general practitioner at the age of 20 years, had also seen a succession of consultants from different specialities, including some rheumatologists, before reaching a specialised clinic devoted to inherited conditions of collagen. Most of the doctors in her local hospitals had declared themselves perplexed by her condition. A Beighton score of 9/9 only touched the surface, and a characteristic of her condition was extreme laxity at certain joints. She also fulfilled the criteria for benign joint hypermobility syndrome, though her case was far from benign. As a child, she had seen geneticists when brachydactyly type B was suggested as a cause of the shortening of some fingers. She also considered herself extremely flexible, talented at sports as a child but was aware of limitations in the back with a propensity to acute episodes of back pain and spasm, probably reflecting intermittent prolapse of a disc. Radiographs of the spine revealed a mild scoliosis of the spine complicated by a corkscrew twist and a mild degree of spina bifida occulta

136 120 7 Illustrative Case Histories around L5. The joints, whilst capable of contortion, appeared uncontrolled with poor proprioception. In childhood, she had experienced Raynaud s phenomenon, but this was normally mild, bilateral and precipitated by cold weather. During the 3 years she has been under review, a more complex picture has emerged characterised by extreme localised symptoms of vascular disturbance, analogous to reflex sympathetic dystrophy, specifically sparked by subluxation of one of her most flexible joints often, though not always, one of those displaying most bony abnormality. Nevertheless, a pattern has emerged that upon subluxation, particularly of the elbow but sometimes the shoulder, an episode of reflex sympathetic dystrophy is triggered, as often occurs after a surgical operation. A further specific feature has been the tendency for muscles around the joints that sublux to go into disproportionate spasm. In spite of intensive physiotherapy tuition in the weeks before her wedding, she still had the misfortune to sublux her right ankle on the wedding eve. Comment: The subject illustrates the greater complexity of the management of hypermobility that is disproportionately severe at certain joints. Whilst the widespread laxity at all joints of the body points to collagen structure as a cause, the disproportionately severe hyperlaxity only at certain joints is almost certainly a feature of mild bony dysplasia. Moreover, it is the dysplastic joints that seem to prompt the episodes of her presumed sympathetic dystrophy, though the tendency of these patients to exhibit a widespread autonomic neuropathy may also be a predisposing factor. Pharmacological management in her case has been complicated by the need to use muscle relaxants to counteract the spasm that is typical of her dislocations but only in doses that do not aggravate the laxity at other joints. When high doses of muscle relaxants are unavoidable, temporary extra physical protection needs to be provided for joints that will be aggravated. Case 7.6: Arnold Chiari Malformation and Specialised Physiotherapy E.B., an American citizen and university lecturer, was first seen at the age of 24 years. Her Beighton score was 5/9, and she conformed with criteria for hypermobility syndrome. Nevertheless, the skin was markedly hyperextensible at certain sites, particularly around the eyes, with a velvety texture raising the possibility of overlap with the Ehlers Danlos spectrum. Her joints had always been susceptible to subluxation, though scars had healed well. Her periods had been controlled by the fitting of a Mirena coil (a progestogen depot preparation), which she considered had not made her joints worse. As a child in the USA, she had experienced headaches from the age of 14 years. These were initially attributed to migraine, but following the development of more widespread neurological symptoms in the upper cervical core and later around the base of the brain, a Chiari malformation was suspected and confirmed on investigation. At the age of 19 years, neurosurgeons widened the foramen magnum and performed a laminectomy at C1/C2, which improved the headaches and all the

137 Case 7.7: The Performing Artist 121 symptoms that could be attributed to neurological compression at the foramen magnum. Investigations showed no syrinx in the lumbar area. At one point, bilateral carpal tunnel and bilateral cubital syndromes were suspected but these resolved spontaneously. After neurological decompression, as a good witness, she felt she became more susceptible to fainting attacks. These also were investigated; tilt table testing confirming a postural orthostatic tachycardia. An interesting feature of the joint laxity was that whilst cold, and therefore at conventional clinical examination, this was moderate with a Beighton score of 5/9. After only a brief warm up with a little stretching, this became much more pronounced with a Beighton score of 9/9. Further imaging showed that some 8 years after her surgical decompression, no recurrence of the malformation had occurred. She had, however, recently experienced bowel symptoms of increasing severity attributed by the surgeons to intermittent intussusception, sometimes complicated by rectal prolapse, and she had also experienced pelvic floor urinary tract symptoms for which she is currently being investigated. Any pelvic floor repair, which is under consideration at present, will need to attend both to bladder and bowels, possibly with surgeons working in combination. Comment: This case draws attention to the probable association between Arnold Chiari malformation and variants and patients where hypermobility is indicative of certain types of EDS. This well-informed subject considered, as so often occurs, that conventional physiotherapy practices barely helped her symptoms. She has controlled the flexibility of her joints, and the symptoms from them, by an almost obsessive dedication to her hobby, which is the practice of Ashtanga Yoga. As one of the most active variants of yoga, this combines elements of cardiovascular training, strengthening and the acquisition of flexibility. Whilst she feels it is the flexibility that most relieves symptoms, the muscular control that is required as a series of stretched asanas are built together into a sequence provides reassurance. The added complexity here has been the design of a programme that confers no extra risk in the light of the previous neurosurgery. In turn, elements of conventional physiotherapy (stretching and strengthening) are combined in the form of a hobby that is enjoyed and practised to a higher standard than might be achieved in a conventional hospital physiotherapy department. Case 7.7: The Performing Artist If the previous cases have dwelt on the disadvantages of hypermobility, this case illustrates the potential advantage of the syndrome but also the need for its precise specialised management. K.A. reached a clinic devoted to inherited complications of connective tissue through the auspices of the British Association for Performing Arts Medicine which had arranged onward referral in view of her musical prowess. First seen when she was 25 years old, she had then relinquished her ambitions to be either a professional musician or a professional dancer and, in a sea of despondency,

138 122 7 Illustrative Case Histories had taken a job as a nursing care assistant where the strain placed on her joints was making her more symptomatic. As a child and adolescent, she had sought a variety of medical opinions in the rural area where she lived, often to be given conflicting advice. Her pattern of joint laxity was predominantly that of hyperflexible hips and dislocating shoulders, though evidence of joint laxity was also present at other joints to the trained eye. Her brother, who has not been seen, was probably not hyperlax, but a younger sister, also not seen, has almost certainly had a degree of congenital dislocation of the hips. There is a tradition in the family both of sporting prowess and excellence in the performing arts. As a child and adolescent, she excelled not only at dance (ballet and contemporary) but also at music (cello and piano). She achieved at least regional standing with the award of prizes and the offer of scholarships both in music and dance with the resultant dilemma of which to select. Conflicting advice was given but in view of the flexibility of the ankles and instability of the hips a sensible decision was made to concentrate on the cello, after which over the years her shoulders and the thoracic spine became more symptomatic with a tendency for the shoulders to dislocate. When the right (bowing) wrist became symptomatic, a well-intentioned orthopaedic operation was offered, shaving the bone at the ulnar styloid and rendering the wrist less mobile, which made playing much more difficult. When first seen, x-rays of the spine showed a mild S-shaped thoracic scoliosis within a superimposed corkscrew twist and a convincing Schmorl s node on MRI scan. The Schmorl s node resulted in considerable local pain and muscular spasm necessitating the use of potent analgesics as well as some muscle relaxants. To date, further surgery has been avoided, a more suitable job has been found and a home exercise programme with adaptations to computer and chair at the workplace have enabled the subject to embark on a career as a university administrator with dancing relinquished and music teaching (piano, cello and theory) adopted as a part-time evening hobby. Comment: This case illustrates the complexity in advising and managing the hypermobile performing artist, although equal prowess in dance and the playing of an instrument and the need to choose between them is unusual (though not exceptional). The predominant factor here of restricting her career as a professional cellist is probably the well-intentioned, though problematic, attempt at stabilisation of the wrist, though the different mechanical functions to which the two subluxing shoulders are put in the playing of this particular instrument are also problematic. The slight corkscrew twist in the spine can be an asset or liability according to whether it is or is not in the direction of the slight angulatory movement required of the spine as the artist rotates forward over the cello. Ironically, early career advice towards dance rather than music might have been a safer option in pursuit of fame and excellence though this would be less sustainable as a hobby into old age.

139 References 123 References 1. Grahame R, Bird HA, Child A, et al. The revised (Brighton 1998) criteria for the diagnosis of benign joint hypermobility syndrome (BJHS). J Rheumatol. 2000;27: Keer R, Edwards-Fowler A, Mansi E. Management of the hypermobile adult. In: Keer R, Grahame R, eds. Hypermobility Syndrome: Recognition and Management for Physiotherapists. Edinburgh/London/New York: Butterworth Heinemann; 2003.

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141 Chapter 8 Hypermobility in the Performing Arts and Sport Individuals endowed with hypermobility may excel in certain artistic occupations. The professional activities of dancers, contortionists, musicians and sportsmen are all influenced by their range of joint movements. The wider implications of this situation are reviewed in this chapter. 8.1 Dancers Are Ballet Dancers Born or Made In the performance of their art, ballet dancers display impressive ranges of joint movement, which are clearly beyond the ability of lesser mortals. How much of this joint laxity is the result of painstaking regular training, often initiated in childhood, and how much is it due to an inherent laxity that may have acted in favour of recruitment to dancing? The answer is almost certainly that both factors are operative. In order to test the hypothesis that generalised hypermobility may confer positive advantage in the selection of would-be ballet dancers for training, a comparative study of joint mobility was undertaken in 53 students attending the Royal Ballet School in London and 53 student nurses at Guy s Hospital. 1 The results showed that, compared with the nurses, the ballet students showed a significantly higher incidence of hypermobility of joints, not only of the spine, hips and ankles, which would be affected by training, but also of joints such as the knee, elbow and wrist, which become unaesthetic in the hypermobile range (Fig. 8.1 ). Interestingly, 13% of the dancers but none of the nurses knew of a first-degree relative who suffered from recurrent knee effusions (a known complication of hypermobility) supporting the concept that generalised hypermobility can be inherited. There is evidence that over the age of years, female dancers retain the level of joint laxity that they enjoyed at an earlier age, while non-dancer controls show a significant reduction in Beighton et al. 2 hypermobility score over the same period. 3 P. Beighton et al., Hypermobility of Joints, DOI / _8, Springer-Verlag London Limited

142 126 8 Hypermobility in the Performing Arts and Sport Fig. 8.1 Hyperflexion of the wrist and hyperextension of the elbows produces an unaesthetic appearance Is Generalised Joint Laxity an Asset or a Liability in Ballet Dancing? On the credit side is the increased facility for undertaking the spectacular range of movement, notably of the spine, hips and ankles that is required of a ballet dancer. In the tighter-jointed individual, this can be achieved only by dint of hard work, usually with graded stretching exercises. On the debit side, generalised laxity of ligaments can pose problems for the dancer. Indeed, an enhanced range of movement may result in an unacceptable appearance. This is seen, for example, in the so-called swayback knee or genu recurvatum (Fig. 8.2 ). However, even when gross, this can be corrected satisfactorily by careful voluntary muscular control (Fig. 8.3 ). Hyperlaxity of the tarsal joints and the first tarsometatarsal joint of the great toe (Fig. 8.4 ) can create serious and even disastrous problems when one attempts to dance en pointe. To a certain extent, this lack of stability can be circumvented by improving muscular tone with exercise therapy. Hypermobile dancers are vulnerable to all the ailments to which loose-jointed persons are susceptible, but because of the greater physical demands imposed by ballet dancing they are at even greater risk.

143 8.1 Dancers 127 Fig. 8.2 The swayback knee Fig. 8.3 The same knee corrected by voluntary muscular control

144 128 8 Hypermobility in the Performing Arts and Sport Fig. 8.4 Instability of the first metacarpophalangeal joint precludes the possibility of dancing en pointe Not surprisingly, back, knee and foot complaints figure prominently amongst hypermobile dancers, many of whom are forced to abandon their career prematurely. 4 Miller et al. 5 compared the problems of the professional ballet dancer with those of a vigorous athlete, and cited osteochondral fractures, fatigue fractures, sprains, chronic ligamentous laxity of the knee, meniscal tears, degenerative arthritis of multiple joints and low back pain as problems which were frequently encountered. In a systematic radiological survey of 28 members of the Cincinnati Ballet Company, evidence of stress fractures was seen by the weight-bearing bones of the lower limbs. 6 These were recognised in the femoral necks, anterior aspects of the mid-shafts of the tibiae and the lower half of the fibulae. In the feet, cortical thickening was present in the first, second or third metatarsal shafts in 23 out of 28 dancers but there were no fractures. A postal survey of injuries sustained in dancing, conducted throughout the USA and some other countries, revealed that ligamentous injuries were by far the commonest lesions. 7 These occurred in the knee, ankle and foot, in descending order of frequency. Fractures constituted the second most frequent injury and the majority of these were in the metatarsals and phalanges.

145 8.1 Dancers 129 Fig. 8.5 Radiograph of the foot of a ballet dancer who complained of pain in the second right metatarsal shaft. There is hypertrophy of the cortex but no fracture A hypermobility score of 4 or more by the Beighton et al. criteria was present in 36 (9.5%) of 377 ballet dancers studied by Klemp et al. 8 Forward flexion correlated significantly with the duration of dance training, indicating an acquired training effect with regard to this movement, whilst the high prevalence of joint hypermobility in dancers families indicated a strong hereditary influence on generalised laxity. Injuries were significantly more numerous in the hypermobile dancers than in the non-hypermobile ones. Scintigraphy has been used to bring to light stress lesions in dancers presenting with pain and tenderness in the bones of the foot with normal appearance on radiography. 9 Such a case is illustrated in Figs. 8.5 and 8.6, when little is shown on conventional radiography, although there is increased uptake in the scan in an area corresponding to the shaft of the second right metatarsal. This 16-year-old ballet student had experienced pain in the affected region for the previous 18 months and had been precluded from doing her pointe work. After a 3-month rest, her symptoms remitted and a repeat bone scan was normal. Similar findings have been reported in athletes. 10 If generalised joint laxity represents one aspect of a multisystem heritable connective tissue disorder, it is conceivable that fractures, at least in some dancers, may be a further facet of the same problem. Another factor favouring the development of fractures is osteoporosis associated with oestrogen deficiency in adolescent female dancers with delayed menarche and/ or amenorrhoea. 11, 12 Such problems appear to be a combination of the degree of exercise and self-imposed dietary deficiency. 13

146 130 8 Hypermobility in the Performing Arts and Sport Fig. 8.6 A scintiscan using technetium-99m diphosphonate. Increased uptake of the isotope on the region of the second right metatarsal is indicative of a stress lesion (Reproduced with permission from Grahame et al. 9 ) The Prevention of Injury Attention at dance schools has recently been directed to the screening of pupils and the prevention of injury. Applicants with joint hyperlaxity may sometimes be recommended to undertake a course of strengthening exercises before commencing the arduous routine inherent in professional dancing. Two recent articles have reviewed the prevalence and treatment of injury with comments on perception of causes. Although factors such as being overtired, overworked, unsuitable flooring, inadequate warm-up and difficult choreography all figure as causes of injury, many of the injuries described were those classically associated with hypermobile subjects. One quarter of all injuries occur at the foot or ankle, problems of the patella dominating knee complaints. Male dancers, with less laxity, have problems analogous to weight lifters, such as acute and chronic back and shoulder injuries. Female dancers were particularly susceptible to foot and ankle injuries, especially when these joints were relatively lax. Overuse injuries figure as prominently amongst dancers as amongst musicians. Imbalance or stress such as occurs between the plantar and dorsiflexors of the feet 17 is increasingly recognised as a factor predisposing to injury. A Swedish study 18 drew attention to the way in which poor training accounts for increased musculoskeletal complaints amongst 147 professional dancers.

147 8.2 Contortionists 131 A spondylolysis and spondylolisthesis, both common associations with joint hypermobility, are frequently found as causes of back pain in dancers. The incidence of spondylolysis in dancers has long been known to be four times that in the general population 19 ; although this is sometimes attributed to the increased flexion extension inherent in dancers, an alternative explanation is that hyperlax subjects, favoured at audition, already have such an abnormality. Oblique radiographs or computer tomography may demonstrate stress fractures. 20 Trunk strength as well as pilates exercises are helpful, and early diagnosis is important. Spondylolisthesis is also common amongst dancers. A grade 1 spondylolisthesis is not a contraindication to dance, and it is possible to dance with spondylolisthesis of even greater severity. 8.2 Contortionists Historical Background Contortionists were certainly active 4,000 years ago, as evidenced by an engraving on the hilt of the sword, which now rests in a museum at Heraklion, on the island of Crete. This depicts a lithe youth in the Palace of Knossos, balancing himself on the tips of his toes and the crown of his head, which arched over the point of the blade. Extreme joint laxity seems to have excited interest in many cultures. During mediaeval times, contortionists performed in fairgrounds, attracting an audience by their peculiar abilities. When a crowd gathered, their assistants would sell patent remedies such as slippery worm oil, claiming that it was efficacious in the treatment of sore and stiff joints. The contortionist s performance was obvious proof of the benefits to be obtained from regular applications of the oil! These acts were the forerunners of America s nineteenth-century travelling medicine show wagons. Further information is available at The Contortion Home Page at contortionhomepage.com Nosology and Semantics There has been much confusion in the past as to the differences, from a professional point of view, between the India Rubber Man and the Elastic Lady. Although these terms were more or less interchangeable in the circus world, the India Rubber Man was usually a joint-bending contortionist, while the Elastic Lady was a skinstretching exhibitionist. The elastic people could take hold of the skin of their face or trunk and pull it out for several inches. On release, it would immediately spring back to its former position. These individuals had Ehlers Danlos syndrome (EDS), which is a familial disorder of connective tissue (see Chap. 9 ). Articular hypermobility is also a feature of EDS, and the elastic people were therefore equipped to

148 132 8 Hypermobility in the Performing Arts and Sport Fig. 8.7 A professional contortionist demonstrating her prowess (From Beighton 71 ) perform contortions. However, in view of their cutaneous fragility and unstable joints, it is doubtful whether they indulged in this activity. The contortionist s act is centred around the ability to hyperextend or hyperflex the spine. In circus terminology, the performer is either a front bender or back bender, and all the facets of the act are built on these movements. Many contortionists have considerable athletic prowess, and they may be able to indulge in such variations as placing their feet around their necks, whilst standing on one hand. The forward bending is usually the funny man, as he can take up ludicrous positions and perform amusing feats. In contrast, the backward bender or posturer has a more serious act. The posturer is often an attractive young woman who can perform speciality acts, or incorporate her abilities into a graceful dance routine Training Many contortionists develop their skills by rigorous training. This must begin in childhood, and the French author, Guy de Maupassant, described how mountebanks would steal children for this purpose. Legislation to preventing training of children in Great Britain was enacted at the beginning of the present century. Contortionists who have acquired their joint laxity by years of training must practise for several hours each day, and even a week of inactivity will result in a marked stiffening of the joints. In the same way, a long warming-up period is required before the performance. However, some contortionists have inherent articular laxity, and these individuals are in a much more fortunate situation, as they require very little in the way of training or warming-up. They are usually able to perform forward and backward bending with equal facility, and inactivity does not lead to loss of joint mobility (Figs ). On the other hand, their joints may be unstable, and they may be unable to perform feats of strength. Although able to roll up into a tiny ball, they cannot do this while balanced on their fingers! This type of joint laxity is often a genetic trait, and these individuals may have familial

149 8.3 Musicians 133 Fig. 8.8 and Fig. 8.9 A contortionist with inherent articular laxity is usually able to perform forward and backward bending with equal facility (From Beighton 71 ) hypermobility (see Chap. 9 ). The disorder is usually inherited as an autosomal dominant, and a number of affected persons are members of well-known circus families Socio-medical Implications It is a surprising fact that osteoarthritis does not seem to affect elderly contortionists, and indeed, many of them retain hypermobility in old age. Ferry the Frog could still wrap his feet around his head at the age of 72 years, and he attributed his good health to his professional activity. Dad Witlock was performing in an American circus when he was 79 years old, and Norwood, the Flexible Fellow, retained much of his flexibility in his 80s (Fig ). Perhaps the secret of their continuing health is their good nature and their readiness to please other people. In the theatrical world, it is axiomatic that the Elastic Ladies are always prepared to stretch a point, while the India Rubber people are renowned for their willingness to bend over backwards to be of assistance! 8.3 Musicians Manual dexterity is essential to the handling of many orchestral instruments, and hypermobility may be an asset. Dancers and contortionists tend to use both halves of the body equally. In musicians, the requirements of the instrument may dictate

150 134 8 Hypermobility in the Performing Arts and Sport Fig Norwood the Flexible Fellow a professional contortionist in the days of the music halls quite separate uses of the two sides; this is most pronounced in string players. Such musicians act as their own control, adding interest to the study of this group of players. Nicolo Paganini ( ) is frequently quoted as having extreme hand hypermobility. Contemporary accounts describe his tall, thin frame and spider-like features associated with a chest deformity and striking laxity of the hands, endowing him with a technical prowess, which enabled him to play his difficult compositions. Some have suggested that he had Marfan s syndrome.

151 8.4 Occupational Ills of Instrumentalists 135 Attention has recently been directed to the increasing digital skill, particularly with respect to the neglected fifth digit, that is inherent in the development of instrumental music over the centuries as both instruments and techniques have become more complex. 21 Unilateral laxity of one hand is particularly helpful in classical guitarists. 22 It has recently been argued that several composer pianists, including Liszt and Rachmaninov, were endowed with joint hypermobility in the hands, enabling them to compose and then play their extremely difficult works. Plaster of Paris casts of Liszt s hands show them to be relatively large, and pupils of Rachmaninov who still survive attest to the considerable lateral laxity of the middle fingers in his hands that allow him to play stretched chords with great facility. Such chords figure prominently in his piano writing. It does not follow that a composer such as Mozart had hypomobile hands the technical limitations of the instrument of his time, together with contemporary taste, also have influence on the final composition. The laxity of hands has been determined in 650 individuals at a music school. Hypermobility was found to be predominantly a female characteristic in this population. Age differences, as anticipated, were demonstrated. Attention was drawn to the way in which hypermobility could affect only a small number of joints (or even in a solitary joint), this pauci-articular hypermobility being more prevalent than the generalised variety in musicians. Whether this was acquired as a result of musical training or reflects selection of musicians by virtue of hyperlaxity in the hands remains unanswered Playing instruments can certainly cause music-related upper limb pain, 26 probably through overuse, though this study did not determine whether the frequency of pain was specifically associated with joint hyperlaxity. 8.4 Occupational Ills of Instrumentalists The spectrum of rheumatic complaints seen in a music clinic has been outlined in considerable detail from several countries. Hochberg et al. 27 describe their experience with 100 musicians presenting to an American clinic, and Fry 28 describes patterns of overuse seen in 658 instrumental musicians, mainly from Australia. One review based on the Eastman School of Music, University of Rochester, New York, devotes particular attention to the influence of joint hypermobility on musical injuries. 23 Additional reviews available include those by Hoppman and Patroni 29, Lambert 30 and Greer and Panush. 31 Ironically, musicians are not matched anatomically and physiologically to instruments at the start of their training. This means that some individuals devote many years of practice to instruments for which they are anatomically unsuited. Inevitably, when they come to pursue a professional career, musculoskeletal difficulties occur, leading to much anxiety and sometimes loss of employment. In woodwind players, the main difficulty is holding a relatively heavy instrument (in the case of the oboe and clarinet) at a position of mechanical disadvantage for long periods of time. This leads to musculoskeletal problems in the shoulders, and difficulties can also occur with the mouth and lips. Pianists also develop bilateral

152 136 8 Hypermobility in the Performing Arts and Sport problems concentrated at the wrists and the fingers. The span required between fingers may be greater than the lesser spans required for the key systems of woodwind instruments, so hand hypermobility may be advantageous for pianists, particularly in interpretation of works of the late romantic era. Pianists with relatively stiff hands may be advised to concentrate on earlier composers. With players of stringed instruments, considerable differences in function are required between the two arms. Players of the double bass and cello may also have back and seating problems, particularly affecting the lower back muscles, whereas woodwind players need postural support of the upper body, particularly if the instrument is held sideways, as with the flute. Particular problems are seen with cellists who have a slight curvature of the spine, particularly if this is a corkscrew twist. The natural position for cello playing requires a slight rotation towards the instrument. If a cellist has a slight spinal rotation in the opposite direction, overuse problems often ensue. By contrast, a slight spinal twist in the direction appropriate for the instrument confers advantages. Additional problems have been seen in classical cellists who convert to the electric cello, which requires the use of a foot pedal. This can upset the alignment of the spine, especially if there is a slight scoliotic twist prior to the transition. For violin and viola players, one hand holds the bow and is subject to musculoskeletal strain, particularly at the shoulder and elbow. The other hand stops the strings, so lateral laxity of the fingers may be advantageous, enabling the hand to span a long distance on the sounding board. The greatest divergence of function occurs with the guitar. The hand that plucks the strings has a relatively easy task. The hand that spans the sounding board benefits from considerable hand hypermobility, the stretches required being greater than those in the violin or viola. It is tempting to hypothesise that in string players, especially those who have practised for many years, proprioception might be enhanced in the left hand, the fingers of which require precise positioning on the strings compared to the right hand where the function of the fingers is largely supportive of the bow with no great need for enhanced position sense. Studies of this sort, using the Leeds Proprioceptometer (see Chap. 2 ), are in progress. In the Rochester assessment of 660 individuals from a music school, musicians were examined for laxity of the thumbs, fingers, elbows, spine and knees. Of these, 178 (27%) had one lax joint, and only 20 (3%) possessed all five features. The proportion of women to men displaying two features was 2:1, the ratios for the occurrence of three, four and five features being 4:1, 8:1 and 3:1, respectively. Joint laxity declined with age though not to a statistically significant degree. In males, the decline started in the mid-20s, but in women, joint laxity persisted unaltered through the mid-40s. The authors did not attempt a correlation of patterns of joint laxity with the playing of individual instruments, so the question of whether the hyperlax individuals represented a normal occurrence within the population or whether they acquired their hypermobility by regular training from an early age remains unanswered. The Gaussian distribution of observed joint laxity was confirmed in this population. Additional surveys of instrumental musicians with overuse syndromes and with other musculoskeletal problems are available in the literature. Lederman and Calabrese 32 have reviewed overuse syndrome in instrumentalists as seen in American musicians. Fry 38 has described overuse syndrome in musicians as seen in Australia.

153 8.4 Occupational Ills of Instrumentalists 137 Fig The left wrist of the guitarist exhibiting traumatic synovitis (Reproduced with permission from Bird and Wright 34 ) His subsequent articles review patterns of overuse in 658 affected instrumental musicians 28 and treatment of overuse syndrome in 175 patients Illustrative Case Histories Musicians attending a rheumatology clinic in Leeds fall into three main categories: 1. Those with hypermobility of the hands 2. Those with normal laxity of the hands but with overuse syndromes 3. Those who have acquired systemic rheumatic diseases but who still wish to continue their playing The overuse syndromes now account for the most referrals. Typical case histories are presented from each of these three groups Hypermobility: Traumatic Synovitis in a Classical Guitarist PD, a 31-year-old male, was a student of the classical guitar. He practised for up to 5 h each day for the last 10 years and was an advanced performer with a national reputation. In June 1978, he noticed pain at the back of the left wrist associated with swelling, exacerbated by practising the guitar. It was not present in the other hand, and no other joints were involved. In December 1978, he sought the advice of his general practitioner, and a cystic swelling on the dorsum of the left wrist was ascribed to traumatic synovitis (Fig ). He considered himself to be

154 138 8 Hypermobility in the Performing Arts and Sport double-jointed in comparison with other members of the class, and there was an unusual degree of joint laxity present in both hands. In May 1979, he was seen in the rheumatology clinic at Leeds. The swelling of the dorsal aspect of the left wrist had persisted, but his symptoms were controlled by indomethacin 25 mg three times daily. There was no early morning stiffness and no other symptoms apart from possible intermittent swelling of some proximal interphalangeal joints. His father had regarded himself as double-jointed, and a maternal aunt and grandmother were both said to have had rheumatoid arthritis. Although his score for generalised hypermobility was on 4/9, he had marked hypermobility in both hands. There was no clinical evidence of rheumatoid disease at the metacarpal or metatarsal heads or at the ulna styloid. All other joints were normal. Routine haematological and serological investigations yielded normal results, and radiographs of the hands and feet revealed no abnormality. He was treated with a single local injection of steroid and a short period of rest. This produced immediate and lasting improvement in spite of a subsequent return to regular guitar practice. He had only minimal symptoms for a period of 2.5 years; these did not require further steroid injections and were controlled by indomethacin capsules, which were taken as required, two or three before a concert. He was then lost from the clinic. The apparent association between the patient s joint laxity, his occupation and the synovitis prompted study of other members of the guitar class. 34 Details were collected of age, sex and duration of guitar playing. Hyperextension of the metacarpophalangeal joint of the left index finger was measured by the Leeds Finger Hyperextensometer (35 ; see Chap. 2 ) and assessment of the lateral laxity of the fingers made by eye and graded +, ++, +++. The finger hyperextensometer was also used to assess laxity of the same joint in 100 normal people, drawn at random from a Caucasian population. The degree of joint laxity found in the other members of the guitar class (11 male, 3 female) was in no instance as marked as in this particular individual. Overall, the females exhibited slightly more laxity than did the males. Hand laxity did not correlate with the duration of guitar playing, and the observations suggested that hereditary factors were more important than regular training in producing the observed laxity. Even when an allowance was made for the age differences, the only member of the class who exhibited synovitis (PD) had by far the most striking laxity in the hands. This was not only in an antero-posterior plane, but also in a lateral plane. Indeed, PD was the only member of the class who could reasonably be described as double-jointed. It is of interest that guitar players overall have a lower degree of hyperextension than normal members of the population. This possibly reflects their greater muscular control since studies on athletes confirm that the range of movement at other joints in the body is reduced by regular athletic training (see below). In the case of PD, there was a strong history of joint hypermobility on his father s side of the family and it seems that his hypermobility was inherited. Only the stretched hand developed a synovitis and it is in this hand that he has had the majority of musculoskeletal symptoms associated with benign hypermobility. Lateral instability

155 8.4 Occupational Ills of Instrumentalists 139 in the loaded joint may be the most important factor on the aetiology of traumatic synovitis Overuse Syndromes: Synovial Trauma in a Violinist PN, a 27-year-old violinist had performed to a high standard for almost 10 years, often playing for up to 8 h a day. His symptoms had always been confined to the left hand and wrist, and he attributed this to the greater stress placed upon this hand by his playing. He did not consider himself to be double-jointed, and there was no evidence of generalised joint hypermobility. The history was of 4 weeks of pain in the left wrist, most pronounced when he flexed the joint and accentuated by rapid finger work. Like many patients with overuse syndrome, he had identified a critical threshold above which symptoms occurred. He had noticed that if he was able to rearrange his work schedule (which was difficult with his appointment) so that the critical threshold was never exceeded, the symptoms abated over a period of a few days. Examination showed no general or localised hypermobility, though there was a localised point on the extensor tendon expansion over the left wrist at which pain could be reproduced. A diagnosis of overuse syndrome was made, and the patient was advised to immobilise the joint for 4 days. The symptoms disappeared, and this schedule was then changed for a compromise between immobilisation and playing that did not exceed the trigger threshold. The localisation of symptoms to one hand strongly supports the mechanical aetiology of overuse syndrome. In many patients, chronicity develops and anxiety can exacerbate symptoms as well Acquired Systemic Disease: Generalised Osteoarthritis in a Violinist Mrs. EM, aged 68 years, had been Leader (Concert Master) of a respected local orchestra for 20 years. She played the violin regularly for 50 years and had also taught this instrument. There was a family history of progressive generalised osteoarthritis, and examination confirmed this diagnosis with the presence of Heberden s nodes and typical osteoarthritic deformity. There is no evidence of rheumatoid disease in the form of muscle wasting, vasculitis, nodule formation or synovial proliferation. Nevertheless, a remarkable degree of osteoarthritic deformity existed in her joints, possibly attributable to the additional mechanical insult of playing her instrument over many years. She had never considered her hands to be hypermobile, though examination confirmed the presence of an unusual degree of joint hypermobility for a 68-yearold woman. In part, this may be attributed to her earlier treatment with a small dose of oral prednisolone. Management has been with analgesics, anti-inflammatory agents and as required and the occasional increase in the dose of prednisolone to enable her to perform well at an important concert. Musicians are often of high intelligence, and it is remarkable how

156 140 8 Hypermobility in the Performing Arts and Sport they learn to adapt their playing technique in the face of arthritic deformity. Even patients with rheumatoid arthritis are often able to continue pursuing their musical hobby Repetitive Strain Syndrome This accounts for most maladies experienced by musicians. 36 It is characterised by pain and loss of function in muscles and joint ligaments of the upper limb but can affect other muscles, for example the mouth and soft palate in wind players. 37 Physical signs of tenderness can often be elicited in affected structures, and the condition is typically brought on by an increase in the duration and intensity of 38, 39 practice or playing. Opinions vary on treatment, which ranges from absolute immobility at one extreme to a more cautious approach integrating periods of rest with a gentle return to playing. 40 The syndrome has been a major cause of litigation in Australia. 41 If the condition is mechanical in aetiology and if joint hypermobility behaves as a graded trait with a Gaussian distribution throughout the population, research is likely to be directed to seeking possible correlations between these two common conditions. The anecdotal impression that repetitive playing of an instrument is more likely to invoke discomfort in hands that are hypermobile, rather than nonhypermobile, is a strong one. There is also an impression that in violin players, symptoms of repetitive strain are more likely to be present in the left hand, whether this is dominant or non-dominant, compared to the right, reflecting the quite different hand function in the two arms. It has been claimed that the repetitive strain syndrome is characterised by an increase in type 1 muscle fibres and a decrease in type 2 fibres, with mitochondrial changes and other ultrastructural abnormalities in a controlled study of muscle biopsy in this condition. 42 Overall, the frequency of this condition appears to be reducing particularly in certain countries such as Australia where an apparent epidemic of 5 years ago was felt partly to be attributable to the wide number of conditions, with vague definition, for which industrial compensation was available. Musicians, unlikely to benefit from litigation in view of the parlous financial state of orchestras and music schools, do not illustrate such trends, and in general, the percentage of musicians experiencing overuse syndromes such as repetitive strain disorder has remained relatively constant. 8.5 Sport All sportspeople attest to the need for flexibility, a useful attribute, which is said by coaches to improve performance in a wide variety of sports. There is a Gaussian distribution of flexibility throughout the population and in sports; this natural variation may be altered by regular training. A stiff person may become more supple but may never reach the level achieved by individuals who have greater natural endowment.

157 8.5 Sport 141 The range of movement at any given joint depends upon a variety of actions, including muscular tone, laxity of the ligaments and joint capsules and the shape of bony contours. In the hip, for example, either acetabular dysplasia or ligamentous laxity may produce an abnormally wide range of movement. Individuals must be considered on their own merits according to their sport, and different joints within the same person are likely to respond to different training programmes. For example, all the best hurdlers may have a small degree of acetabular dysplasia, which enables them to achieve the wide range of lateral movement at the hip joint that is required in this sport. Regular training of the individual without this particular bone structure may never achieve the range of movement required, no matter how much attention is given to the factors which may be altered, such as muscle tone and ligamentous stretching. In Eastern European countries, the selection of individuals who are suitable for particular sports reached a high level of sophistication. Schoolchildren were screened for their body attributes and directed into the sport in which they were most likely to succeed. This selection was followed by a lengthy and detailed training programme at specialist state-subsidised schools. The range of movement that can be achieved at joints varies not only between persons but also between different joints in the same individual. Flexibility may not always be of value to the sportsperson. Joint hypermobility at the elbow, a feature deliberately sought on the Carter and Wilkinson 43 scoring system, may be a severe disadvantage to a gymnast who has to stand on his or her hands. The elbows may give way under the weight of the body, and regular training is required to increase the muscle tone around the elbow joint in order to achieve stabilisation. Similarly, hyperextension of the knee joint, a feature also sought in the Carter and Wilkinson scoring system, places runners at a disadvantage, particularly when running downhill. Conversely, the ability to hyperextend the knee confers a mechanical advantage in uphill running. The virtue of evaluating joint laxity in sport is to enable individuals to be directed towards the sport for which their joints are most suited. Thereafter, where necessary, training programmes should be directed at improving the performance of the joints in terms of the requirements of that particular sport. This may involve either inducing hypermobility in a stiff person or stabilising laxity in an individual who is initially too supple. Certain sports where hypermobility is especially relevant, or to which the author s attention has been directed, are reviewed below Joint Hypermobility in Selected Sports Gymnasts have much in common with ballet and hypermobility would at first sight be deemed an advantage. A wide range of movement at the lumbar spine, hips and shoulders is required. Although parts of women s gymnastics place emphasis on suppleness at many joints, marks are also rewarded for tumbling which requires considerable momentum of a stable body. Instability of the elbows would be a disadvantage in performing a handstand, and strength is needed in the sub-sport of

158 142 8 Hypermobility in the Performing Arts and Sport acrobatics where human pyramids are built. Gymnastics coaches prefer a relatively stiff newcomer to a novice who is too supple. Appreciation of each individual s attributes is required. Thus, the crab or backbend position can be achieved in several ways. Provided that a total sum of 180 of hyperextension is achieved, the precise joints that hyperextend can be varied according to the individual s ability. Some will hyperextend the back; others will compensate for a stiff back with hyperextension of the shoulders and hips. 44 It has been suggested that idiopathic scoliosis may be more frequently encountered in gymnasts than in other sportspersons and that, in turn, a degree of hypermobility that might be beneficial in gymnastics has actually predisposed to the presence of a scoliosis. 45 Swimmers are aware of the beneficial effects of practising in warm water, which enhances the range of movement at joints. Many swimmers cite a particular stroke as their preferred one and this is often based upon anatomical attributes. Thus, the butterfly stroke requires the greatest flexibility of all at the shoulders, though considerable strength as well and is tiring, requiring power in the legs. The back stroke requires slightly less (though still substantial) flexibility in the shoulders and is less tiring on the body. The crawl (freestyle) occupies an intermediate position requiring only modest flexibility of the shoulders and reasonable strength in the legs. For these reasons, it is the most popular stroke and most frequently encountered. The breaststroke is compatible with relative stiffness in the shoulders but requires substantial flexibility in the hips and knees to adopt the frog position that is required for it. Diving combines the attributes of swimming and gymnastics 46 especially from the highest board. In athletics, a small physique is suited to long-distance running whereas the taller individual will excel at the long jump. For high jumping and hurdling, flexibility of the spine and hip, respectively, may be advantageous. Javelin throwers need flexibility at the shoulder. Racquet sports require flexibility of the shoulder, though neuromuscular co-ordination with good reflexes and good eyesight may be more important attributes in the selection of students. In team sports such as soccer, rugby and hockey, joint hypermobility will not contribute extensively to the individual s sporting performance, though it may influence the pattern of sports injuries the player is likely to sustain. The same applies to cricket, though laxity of the fingers may help spin bowlers to impart a greater rotation on the ball as it leaves the hand. Work from Leeds 47 quantified the range of joint movement using hydrogoniometry at a wide selection of joints in an athletic population selected for joint hyperlaxity. This included gymnasts competing at national club level, divers and dancers as well as non-specialised physical education students who acted as controls. The greater laxity of females in youth was confirmed and the influence of training recorded. A graded increase in laxity from controls through novice gymnasts, divers, dancers, to competitive gymnasts was observed in that order. A group of patients recruited because of their symptoms had an even higher degree of laxity recorded on a Carter and Wilkinson scale as measured by a postal questionnaire.

159 8.5 Sport Joint Hypermobility in Cricket If a single sport were to be selected as being most closely entwined with hypermobility, it would probably be cricket with the arm actions required of the bowlers. It also provides an interesting example of inter-ethnic aptitude. In general, the elbows, wrists and fingers of Caucasians are relatively inflexible. Genetic mutation would probably be required to give them the prowess enjoyed by competing ethnic groups. As might be expected, West Indians of Afro-Caribbean descent tend to have a little more hyperlaxity than their Caucasian competitors (see Chap. 2 ). Asymptomatic hypermobility, especially of the fingers, seems to be a trait of individuals from the Indian subcontinent, particularly the southern part, which probably accounts for the prowess of spin bowlers from India. Lateral laxity of the fingers is required both to hold the ball and to impart the spin. If strength is acquired in the index and ring fingers, the ball can be held between the two, the middle finger depressed such that not only is the ball spun but also it is virtually impossible for the batsman to read the direction of the spin procured (The Doosra). By contrast, anatomical variation in the elbow, arguably particularly pronounced in the northern part of the Indian subcontinent (characterised politically as Pakistan), has led to attempts to rewrite the rules of cricket. If natural hyperextension of the elbow occurs in fast bowlers, the force of the action will cause the hyperextension to be pronounced, leading to the criticism of throwing. This is clearly a quirk of natural selection in individuals so endowed and would therefore not necessarily carry any implication of cheating. The philosophy of whether extreme natural selection is compatible with fair play also intrigues. Much ink has been spilt on the importance of chromosome testing in athletes with the implication that the resultant differential concentration of male and female sex hormones might confer unfair advantage. By contrast, Afro- Caribbeans, with their explosive power in sprint events or hyperlaxity of the spine conferring an advantage in tall, thin, high jumpers, would not attract such criticism. The distinction between selecting individuals for sports deliberately by virtue of their anatomical endowment and then implying that this confers unfair advantage, analogous to cheating, would seem to be a fine one Joint Hypermobility in Yoga Although not strictly a sport, yoga also raises intriguing issues both ethnic and therapeutic. That yoga may have originated on the Indian subcontinent where individuals are often endowed with asymptomatic hyperlaxity may not have arisen by chance. Legend sometimes has it that those who devoted unlimited time to religious practices had ample time to refine the art form. Philosophical implications apart, there exists a wide variety in the anatomical and physiological requirements for each of the many yoga styles. At one extreme

160 144 8 Hypermobility in the Performing Arts and Sport are the philosophical variants where time is spent observing a candle burn, which may in itself provide relaxation analogous to cognitive behavioural therapy that has sometimes been claimed to be helpful in the management of hypermobility syndromes. At the opposite extreme are the severely physical, even acrobatic, types of yoga with Ashtangar yoga as the most obvious example. A little less severe than Ashtangar and concentrating deliberately on an exact balance of agonist and antagonist movements around a given joint is Miyengar yoga. All have their advocates, not least in the treatment of hypermobility syndromes. This raises the extent to which yoga is beneficial in hypermobility and, indirectly, whether physiotherapy routines should concentrate on strengthening or stretching or aim to combine both. This last is probably the most appropriate, and discussion with yoga teachers attending or assisting in our own clinics devoted to hypermobile patients suggests that a combination of two-thirds strengthening and one-third stretching may well be optimum for patients, though there is considerable variation between individuals and ideally a programme should be tailor-made to the attributes of each individual set of joints. 8.6 Hypermobility and Injury Injuries rarely occur in yoga but are more frequently seen in competitive contact sports such as American football. In one large study, 48 American footballers were divided into stiff-jointed and loose-jointed individuals. The former were particularly susceptible to tearing injuries, and the latter were susceptible to stretching injuries. Physiotherapy programmes and training schedules were modified accordingly so that hypermobile joints were stabilised by enhanced muscle power. The injury rate declined. These general findings have been confirmed whenever other sports are studied. Although injury patterns in gymnasts follow this general rule, 44 most injuries result from falls or even from faulty apparatus rather than from joint hypermobility. 49 In a study to determine whether injury-prone gymnasts could be identified using simple test procedures, 22 with relatively high body weight were found to be most susceptible to injury. As a result, an injury score that could be applied to trainee gymnasts in the field was devised. Of the injuries, 70% could be predicted from consideration of weight, height, mesomorphy, lumbar posture and age. 50 That ligamentous laxity makes a relatively minor contribution to injury is confirmed in a study in which 166 American footballers and 116 basketball players were compared to 400 normal age-matched subjects not involved in interscholastic sports. No correlation could be found between ligamentous laxity and the occurrence or type of injury. 51 With renewed social interest in keep-fit programmes, it should be recalled that individuals who are unaccustomed to regular training develop rheumatic symptoms, particularly in hypermobile joints, after performing aerobics. 52 Knee injuries have been the subject of research. A physiological study to examine the hypothesis that excessive training of the knees by exercises led to acquired increased ligamentous laxity

161 8.6 Hypermobility and Injury 145 that might predispose to injury showed a significant increase in joint laxity ( p = 0.02) after an appropriate exercise programme. 53 Females may be particularly susceptible in view of the increased knee joint laxity inherent in a normal female population. It has been argued that female athletes may be better protected by vigorous training regimes, and the degree of potential knee laxity should be considered when females are selected for serious training in different sports. 54 In a study of basketball-related injuries in 76 females, the knee was the most common site of injury and anterior cruciate ligament rupture accounted for 25% of all injuries seen. This injury was more common in female than in male basketball players, and joint laxity, along with a weak quadriceps mechanism, player position and hormonal background were postulated as reasons for the difference between sexes. 55 Joint laxity has also contributed to injuries at a variety of joints in soccer players. 56 The role of knee meniscus injury also merits attention. Medial meniscectomy often predisposes to osteoarthritis. 57, 58 Whether this is because the operation leads to altered joint mechanics, or whether individuals who require operation already display a genetic susceptibility to osteoarthritis mediated by the presence of faulty collagen that causes the initial damage, is not clear. In a radiological survey of physical education teachers, premature osteoarthritis was not seen significantly more frequently than in an age-matched control population but, on the odd occasion when it occurred, usually after meniscectomy, it was severe in the physical educationalists. 59 When stress radiography for antero-posterior mobility of the knees was performed on 17 patients who had undergone medial meniscectomy and 10 patients who had undergone later meniscectomy, an increase in varus mobility following medial meniscectomy was primarily attributed to compression of the medial compartment space. Anterior and total antero-posterior mobility were bilaterally greater in patients with medial meniscectomy compared with lateral meniscectomy and were also greater than values obtained with 28 normal knees. On this evidence, the biomechanical joint laxity induced by the operation may be the greatest risk factor, and individuals who already have hyperlax joints might benefit from counselling prior to operation and more intensive physiotherapy after it. 60 A graded exercise programme, individualised for each subject, providing strengthening exercises around joints that were particularly lax and providing stretching exercises around joints that were particularly stiff has been shown to be effective in improving performance. This stabilisation of hypermobile joints, in particular, was pronounced and maintained using the standard method favoured by sports physiologists advising sporting coaches Training Methods to Improve Joint Flexibility It may be advantageous for the athlete and coach to increase the range of joint movement. A variety of methods have been validated for this. Massage and warming-up are beneficial 61, and static stretching exercises and stationary

162 146 8 Hypermobility in the Performing Arts and Sport cycling both proved equally effective in increasing the range of movement of the hip joint, retaining the increase for a 15-min period in a controlled environment. 62 Stretching by jogging is less helpful in increasing mobility than simple stretching exercises. 63 One of the most effective methods of enhancing the range of joint movement is proprioceptive neuromuscular facilitation (PNF). This hypothetically induces relaxation of the muscle to be stretched through spinal reflexes. 64, 65 Studies show that a static contraction preceding muscle stretch facilitates stretching activity through lingering after discharge in the afferent limb of the stretch reflex. A muscle is initially more resistant to change in length after a static contraction. In an electromyographic investigation of muscle stretching techniques in which static, contraction/relaxation cycles and PNF were compared in 21 female gymnasts, hamstring stretch produced the greatest increase in range of joint movement and was associated with significantly greater hamstring length. 66 Although the efficacy of PNF is not doubted, the long-term risk of its use on muscles and ligaments, if any, still has to be determined. Experience from North America, where the method has been used for many years and where the results of its use are well documented, does not at present cause undue anxiety. A small pilot study in which plain stretching, ballistic stretching and PNF were compared in a group of medical students who were amateur dancers suggests that both ballistic stretching and PNF are superior to ordinary passive stretching in procuring extra flexibility. However, since the benefits from PNF, although most pronounced, were also normally short-lived, ballistic stretching under appropriate careful supervision was judged to be the most effective. This would also conform with the view of many sports coaches. More comprehensive details of the many methods available for improving the 67, 68 range of joint movement for athlete pursuits are to be found elsewhere Hormonal Aspects That dancers and, perhaps, other sportspersons for whom a small frame is considered advantageous might also have implications in relation to hypermobility is something that has not so far attracted much attention. In the management of hypermobility syndromes, evidence is accumulating that progestogens tend to make previous asymptomatic hypermobile joints symptomatic, while oestrogens tend to stabilise and reduce symptoms. With menarche sometimes delayed in the case of dancers and young female gymnasts, there may be implications for joint laxity as well as for bone strength. In the case of male football players, maturity, defined as the difference between chronological age and skeletal age, plus training and playing hours, together in a formula, predict injury in schoolboy footballers 69. Joint mobility was not measured in this study but may also have contributed. Epidemiologically, the ratio of finger length between the second and fourth fingers has been championed as a predictor of sporting prowess in females. 70 The

163 References 147 reason is unclear and probably depends upon the diverse gender and hormonal related traits, including cognitive ability, disease susceptibility and sexuality. A relationship with testosterone has also been postulated, perhaps influencing joint laxity, as well as muscular strength. Clearly, a variety of factors may have relevance of which joint laxity is only one. References 1. Grahame R, Jenkins JM. Joint hypermobility asset or liability? a study of joint mobility in ballet dancers. Ann Rheum Dis. 1972;31: Beighton P, Solomon L, Soskolne CL. Articular mobility in an African population. Ann Rheum Dis. 1973;32: Poul J, Fait M, Bajerova J. Zjistovani generalizovani ligamentosni laxicity u studujicich baletu. Rheumatologia (CSSR). 1988;4: Huwyler J. Bedeutung der flexibilität bei klassichen tänzerinnen und tänzern. Orthopade. 1984;13: Miller EH, Schneider HJ, Bronson JL, McLain D. A new consideration in athletic injuries. The classical ballet dancer. Clin Orthop Relat Res. 1975;111: Schneider HJ, King AY, Bronson JL, Miller EH. Stress injuries and developmental change of lower extremities of ballet dancers. Radiology. 1974;113: Washington EL. Musculoskeletal injuries in theatrical dancers: site, frequency, and severity. Am J Sports Med. 1978;6: Klemp P, Stevens JE, Isaacs S. A hypermobility study in ballet dancers. J Rheumatol. 1984;11: Grahame R, Saunders AS, Maisey M. The use of scintigraphy in the diagnosis and management of traumatic foot lesions in ballet dancers. Rheumatology. 1979;18: Saunders AJS, El Sayed TF, Hilson AJW, Maisey MN, Grahame R. Stress lesions of the lower leg and foot. Clin Radiol. 1979;30: Warren MP. The effects of exercise on pubertal progression and reproductive function in girls. J Clin Endocrinol Metab. 1980;51: Warren MP, Brooks-Gunn J, Hamilton LH, Warren LF, Hamilton WG. Scoliosis and fractures in young ballet dancers. Relation to delayed menarche and secondary amenorrhea. N Engl J Med. 1986;314: Anonymous (leading article). Bionic ballerinas. Lancet. 1985;326: Bowling A. Injuries to dancers: prevalence, treatment, and perceptions of causes. Br Med J. 1989;298: Hald RD. Dance injuries. Primary Care. 1992;19: Schon LC, Weinfeld SB. Lower extremity musculoskeletal problems in dancers. Curr Opin Rheumatol. 1996;8: Micheli LJ, Gillespie WJ, Walaszek A. Physiologic profiles of female professional ballerinas. Clin Sports Med. 1984;3: Ramel E, Moritz U. Self-reported musculoskeletal pain and discomfort in professional ballet dancers in Sweden. Scand J Rehabil Med. 1994;26: Roche MB, Rowe GG. The incidence of separate neural arch and coincident bone variations. J Bone Joint Surg Am. 1952;34: Micheli LJ. Back injuries in dancers. Clin Sports Med. 1983;2: O Donovan DK. The role of the fifth digit in music: discussion paper. J R Soc Med. 1992;85: Bird HA. Occupational illnesses in classical guitarists. Eur Guitar Teachers Assoc. 1991;2:

164 148 8 Hypermobility in the Performing Arts and Sport 23. Larsson LG, Baum J, Mudholkar GS. Hypermobility: features and differential incidence between the sexes. Arthritis Rheum. 1987;30: Larsson L-G, Baum J, Mudholkar GS, Kollia GD. Benefits and disadvantages of joint hypermobility among musicians. N Engl J Med. 1993;329: Grahame R. Joint hypermobility and the performing musician. N Engl J Med. 1993;329: Fry HJ, Rowley GL. Music related upper limb pain in schoolchildren. Ann Rheum Dis. 1989;48: Hochberg FH, Leffert RD, Heller MD, Merriman L. Hand difficulties among musicians. JAMA. 1983;249: Fry HJ. Patterns of over-use seen in 658 affected instrumental musicians. Int J Music Educ. 1988;11: Hoppmann RA, Patrone NA. A review of musculoskeletal problems in instrumental musicians. Semin Arthritis Rheum. 1989;19: Lambert CM. Hand and upper limb problems of instrumental musicians. Rheumatology. 1992;31: Greer JM, Panush RS. Musculoskeletal problems of performing artists. Baillieres Clin Rheumatol. 1994;8: Lederman RJ, Calabrese LH. Overuse syndromes in instrumentalists. Med Probl Perform Art. 1986;1: Fry HJ. The treatment of overuse syndrome in musicians. Results in 175 patients. J R Soc Med. 1988;81: Bird HA, Wright V. Traumatic synovitis in a classical guitarist: a study of joint laxity. Ann Rheum Dis. 1981;40: Jobbins B, Bird HA, Wright V. A joint hyperextensometer for the quantification of joint laxity. Eng Med. 1979;8: Bird HA. Overuse injuries in musicians. Br Med J. 1989;298: Bird HA. When the body takes the strain. New Sci. 1990;1724: Fry HJ. Overuse syndrome in musicians: prevention and management. Lancet. 1986;328: Fry HJ. Prevalence of overuse (injury) syndrome in Australian music schools. Br J Ind Med. 1987;44: Bird HA, Rathbone J, Nixon PGF. Over-use syndromes in musicians. Lancet. 1986;328: Littlejohn GO. Repetitive strain syndrome: an Australia experience. J Rheumatol. 1986;13: Dennett X, Fry HJ. Overuse syndrome: a muscle biopsy study. Lancet. 1988;332: Carter C, Wilkinson J. Persistent joint laxity and congenital dislocation of the hip. J Bone Joint Surg Br. 1964;46-B: Bird HA, Walker A, Newton J. A controlled study of joint laxity and injury in gymnasts. J Orthop Rheum. 1988;1: Meyer C, Cammarata E, Haumont T, et al. Why do idiopathic scoliosis patients participate more in gymnastics? Scand J Med Sci Sports. 2006;16: Brodie DA, Bird HA, Wright V. Joint laxity in selected athletic populations. Med Sci Sports Exerc. 1982;14: Barton L, Bird HA, Lindsay M, Newton J, Wright V. The quantification of joint hyperlaxity in athletes. J Orthop Rheumatol. 1995;8: Nicholas JA. Injuries to knee ligaments: relationship to looseness and tightness in football players. JAMA. 1970;212: Silver JR, Silver DD, Godfrey JJ. Injuries of the spine sustained during gymnastic activities. Br Med J. 1986;293: Steele VA. Injury Amongst Female Olympic Style Competitive Gymnasts [M.Sc., thesis]. Salford: Physical Education Section, University of Salford; 1984.

165 References Grana WA, Moretz JA. Ligamentous laxity in secondary school athletes. JAMA. 1978;240: Hull RG. Articular hypermobility presenting after aerobic exercise. Clin Exp Rheumatol. 1985;3: Skinner H, Wyatt MP, Stone ML, Hodgdon JA, Barrack RL. Exercise-related knee joint laxity. Am J Sports Med. 1986;14: Beck JL, Wildermuth BP. The female athlete s knee. Clin Sports Med. 1985;4: Gray J, Taunton JE, McKenzie DC, Clement DB, McConkey JP, Davidson RG. A survey of injuries to the anterior cruciate ligament of the knee in female basketball players. Int J Sports Med. 1985;6: Keller CS, Noyes FR, Buncher CR. The medical aspects of soccer injury epidemiology. Am J Sports Med. 1987;15: Serafini-Fracassini A, Smith JW. The Structure and Biochemistry of Cartilage. Edinburgh: Churchill Livingstone; Tapper EM, Hoover NW. Late results after meniscectomy. J Bone Joint Surg Am. 1969;51: Bird HA, Hudson A, Eastmond CJ, Wright V. Joint laxity and osteoarthrosis: a radiological survey of female physical education specialists. Br J Sports Med. 1980;14: Sturup J, Iversen BF, Lauersen N. Abnormal knee mobility and meniscal injury. Acta Orthop Scand. 1987;58: Wiktorsson-Möller M, Oberg B, Ekstrand J, Gillquist J. Effects of warming up, massage, and stretching of range of motion and muscle strength in the lower extremity. Am J Sports Med. 1983;11: Hubley CL, Kozey JW, Stanish WD. The effects of static stretching exercises and stationary cycling on range of motion at the hip joint. J Orthop Sports Phys Ther. 1984;6: Williford HN, East JB, Smith FH, Burry LA. Evaluation of warm up for improvement in flexibility. Am J Sports Med. 1986;14: Holt LE, Travis TM, Okita T. Comparative study of three stretching techniques. Percept Mot Skills. 1970;31: Knott M, Voss DE. Proprioceptive Neuromuscular Facilitation: Patterns and Techniques. 2nd ed. New York: Harper and Rowe; Moore MA, Hutton RS. Electromyographic investigation of muscle stretching techniques. Med Sci Sports Exerc. 1980;12: Anderson R. Stretching: Exercises for Everyday Fitness and for Twenty-Five Individual Sports. London: Pelham Books; De Vries HA. Physiology of Exercise. Dubuque: Brown & Co; Johnson A, Doherty PJ, Freemont A. Investigation of growth, development, and factors associated with injury in elite schoolboy footballers: prospective study. Br Med J. 2009;338:b Paul SN, Kato BS, Hunkin JL, Vivekanandan S, Spector TD. The big finger the second to fourth digit ratio (2d:4d) is a predictor of sporting ability in females. Rheumatology. 2006;45(supp 1):Abs 283, Beighton P. The Ehlers-Danlos Syndrome. London: William Heinemann Medical Books Ltd; 1970.

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167 Chapter 9 Heritable Hypermobility Syndromes The heritable hypermobility syndromes are a group of disorders in which joint laxity is a prominent feature. In some of these conditions, the loose joints predispose to a wide variety of articular complications and, despite their rarity, they are of considerable rheumatological importance. The best-known disorders of this type are Ehlers Danlos syndrome (EDS) and Familial Articular Hypermobility syndrome (FAHS). Joint laxity is also a feature of several inherited connective tissue disorders, such as Marfan syndrome and osteogenesis imperfecta, together with certain dwarfing skeletal dysplasias and other genetic entities. These conditions are reviewed here from the rheumatological standpoint, and a selective bibliography is provided. 9.1 Ehlers Danlos Syndrome The Ehlers Danlos syndrome is an inherited disorder of connective tissue which is characterised by the clinical triad of articular hypermobility, dermal extensibility and cutaneous scarring. 1, 2 The manifestations are very variable, although usually fairly consistent within any kindred, and it has become increasingly evident that the EDS is very heterogeneous. The joint laxity in EDS leads to a wide variety of rheumatological complications which are outlined in this chapter. Detailed accounts of the condition can be found in the following books: The Ehlers-Danlos Syndrome, Beighton (1970) 3 McKusick s Heritable Disorders of Connective Tissue, Beighton (1993) 4 Connective Tissue and Its Heritable Disorders, Royce and Steinmann (1993) 5 Articles in the online GeneReviews series, which are regularly updated, provide expert overviews of the various forms of the EDS. P. Beighton et al., Hypermobility of Joints, DOI / _9, Springer-Verlag London Limited

168 152 9 Heritable Hypermobility Syndromes EDS Classic Type (Wenstrup and De Paepe 2008) 6 EDS Hypermobility Type (Levy 2007) 7 EDS Vascular Type (Pepin and Byers 2006) 8 EDS Kyphoscoliotic Type (Yeowell and Steinmann 2008) 9 EDS is of topical interest because of the protean nature of its clinical complications, the unfolding heterogeneity and the ongoing elucidation of the biomolecular determinants. The level of attention that is being given to the EDS can be obtained from the fact that in 1991, the world literature concerning the condition comprised about 500 articles. By 2009, this figure had risen to over In 1966, the combined population frequency of all forms of the EDS in southern England was estimated at about 1 in 150,000, while the current estimates for the USA are as high as 1 in 5,000. The latter figure is indicative of increasing awareness of the condition, together with diagnostic accuracy and medical interest. The development of lay associations for affected families, the availability of information on the internet and the establishment of dedicated Hypermobility clinics are other relevant factors General Features There is considerable variation in the extent to which individuals may be affected by EDS, and the clinical manifestations and complications are by no means consistent. Nevertheless, the components of the diagnostic triad of extensible skin, loose joints and fragile tissues are always present in some degree (Figs ). The skin splits on minor trauma, forming gaping lacerations. These heal slowly and wide papyraceous scars develop which are often darkly pigmented and are typically found over the knees and elbows. Raisin-like swellings known as molluscoid pseudotumours are present in scarred areas and hard calcified subcutaneous spheroids may be palpated in the forearms and shins. The joint laxity predisposes to instability, sprains, subluxations and dislocations. Pes planus and hallux valgus are frequent, while spinal malalignment is a less common complication. Limb and joint pains of uncertain pathogenesis are an inconsistent but important problem. Complications are encountered in virtually every system of the body; these have a common basis in connective tissue extensibility and fragility. In the minority of affected persons with the Vascular form (previously EDS IV), sudden death can occur from rupture of large arteries, dissection of the aorta or gastrointestinal perforation and bleeding Nosology Heterogeneity was initially suspected on clinical and genetic grounds. 10, 11 Further delineation was achieved by the recognition of the basic biochemical

169 9.1 Ehlers Danlos Syndrome 153 Fig. 9.1 Dermal extensibility is a prominent feature of EDS. On release, the skin springs back to take up its former position (From Beighton 3 ) Fig. 9.2 Thin pigmented scars over the bony prominences result from trivial trauma (From Beighton 3 )

170 154 9 Heritable Hypermobility Syndromes Fig. 9.3 Articular hypermobility is variable in degree, but often very marked (From Beighton 3 ) abnormality in some affected individuals and nine major forms of EDS were eventually proposed. A nomenclature and subclassification of EDS, together with information concerning the mode of inheritance, was subsequently promulgated as the Berlin Nosology. 11a The continuing elucidation of biochemical and molecular defects and the widening of clinical experience soon necessitated expansion. 12 In 1997, a new version of the Nosology was compiled at Villefranche-sur-Mer, France, under the auspices of the Ehlers-Danlos Support Group (UK) and the Ehlers-Danlos National Foundation, USA. 12 This simplified version, which listed six major types of the EDS, is presented in Chap. 1. It has emerged that about 50% of families with the comparatively common EDS types I and II have defects of the pro a 1 or pro a 2 chains of type V collagen determined by the COL5A1 and COL5A2 genes; these conditions are now lumped together as the Classic type of the EDS. The former EDS III is retained as the Hypermobility type, in which the basic defect is still unknown, although the glycoprotein tenascin-x has been implicated in a few instances. 13 EDS IV, in which type III collagen is defective, is now codified as the Vascular type. The uncommon EDS VI, previously known as the Ocular or Scoliosis form, is characterised by major spinal problems, while the eyes are often normal. For this reason, it is now termed the Kyphoscoliosis type; the basic defect is deficiency of the collagen-modifying enzyme, lysyl oxidase. The former EDS VII was an incompletely delineated category, which has now been subdivided on a biomolecular basis. The new Arthrochalasia type is an autosomal dominant condition with predominant joint laxity and extensible skin which results from a defect in type I procollagen, due to a skipping mutation of exon 6 in the COL1A1 gene. The other former component of EDS VII, an autosomal recessive disorder with skin laxity and fragility which is now termed the Dermatosporaxis type, is the consequence of deficiency of

171 9.1 Ehlers Danlos Syndrome 155 procollagen 1 N -terminal peptidase in collagen type I. The clinical manifestations of these two rare entities are very disparate. The former EDS V, VIII and X are now regarded as private syndromes or of doubtful syndromic status, while EDS IX and XI have been reclassified. Further discussion is outside the scope of this review but details of the biomolecular defects in the EDS can be found in Chap. 3 and in articles referenced at the end of this chapter. In clinical practice, the majority of affected persons have the Classical type of EDS (formerly EDS I gravis and II mitis). Another large group of individuals have the Hypermobility type (formerly EDS III) and as discussed elsewhere, this category is frequently overdiagnosed. In the uncommon potentially lethal Vascular type (formerly EDS IV), the propensity for arterial and bowel rupture overshadows the other conventional syndromic manifestations. The remaining forms of the EDS are rare Diagnostic Considerations The initial diagnosis of the various forms of the EDS is usually made on a basis of the clinical manifestations and pedigree data. It must be emphasized, however, that there is considerable phenotypic overlap and precise categorisation is often very difficult. In these circumstances, it may be possible to obtain an objective diagnosis by biochemical studies involving cultured fibroblasts or by molecular investigations. Histological and electron microscopical investigations of skin biopsy specimens yield conflicting results and they are not of great diagnostic value. A firm diagnosis facilitates accurate prognostication and meaningful genetic counselling. Related issues such as prenatal diagnosis, pre-implantation diagnosis and carrier detection may arise, and in these situations, the identification of a specific mutation by molecular techniques is necessary. The banking of DNA for future studies is another issue which warrants consideration. In view of the increasing sophistication of laboratory technology and the rapid accumulation of knowledge, it is anticipated that routine molecular genetic testing in the EDS will be increasingly available. The practical implications of the common forms of the EDS and the current status of biomolecular testing in these conditions are summarised below: 1. Classical form (OMIM :130015) The Classical form of the EDS is the archetype of the disorder and affected persons have the characteristic skin and articular features in greater or lesser degree. Autosomal dominant inheritance is well established and large affected families have been documented. The geographical distribution is wide and a population prevalence of 1 in 20,000 has been estimated for the USA. In the premolecular era, the electron microscopical cauliflower configuration of collagen fibrils in skin biopsy specimens was used as a diagnostic indicator. These changes have proved to be inconsistent, and this test has fallen into disuse. Biochemical investigations are unhelpful but molecular studies have proved to be of value.

172 156 9 Heritable Hypermobility Syndromes Mutations in the COL5A1 gene identified by sequence analysis are present in about 45% of affected families and in the COL5A2 gene in 5% of families In the remainder, the determinant genes have not been identified. 17 In clinical practice, molecular investigations for the COL5A1 and COL5A2 genes are widely available in Europe and the USA. 2. Hypermobility form (OMIM ) Articular laxity in the absence of other syndromic manifestations is a common problem in the rheumatological setting. In this situation, diagnostic distinction between the Hypermobility form of the EDS, the Familial Articular Hypermobility syndrome and persons at the end of the normal spectrum of joint mobility can be a difficult matter. 17a The molecular basis of the Hypermobility form is the focus of considerable current interest. The usual mode of inheritance is autosomal dominant, but in a rare autosomal recessive variety, deficiency of the glycoprotein tenascin-x encoded by the TNXB gene at the chromosomal locus 6p21.3 has been implicated. 18, 19 Some heterozygotes in an affected family had joint laxity. 20 In a separate group of 80 sporadic persons with joint laxity, 6 had deficiency of tenascin-x and the corresponding gene mutation was identified in 2 of them. 21 These observations have considerable potential implications for diagnostic categorization, but it must be emphasized that at the present time, tenascin deficiency has been detected in only a very small minority of persons with articular laxity. These tests are not currently available on a routine basis. 3. Vascular form (OMIM ) The potentially lethal Vascular form of the EDS is uncommon, and a population prevalence of about 1 in 250,000 has been estimated for the USA. Despite this low frequency, reports of dramatic arterial and visceral complications and their management predominate in the literature. The surgical management of spontaneous bowel perforation was discussed by Fuchs and Fisherman. 22 and Hawk et al. 23 The occurrence of spontaneous carotid cavernous fistulae was reviewed by Chuman et al. and the surgical management of this complication was outlined by Hollands et al. 24 Naidu et al. 25 reported percutaneous embolisation of a lumbar pseudoaneurysm. The hazards of surgical intervention have been emphasised by Freeman et al. 26 and Oderich et al. 27 and a review of 400 affected persons provided objective information concerning the natural history of the condition. 28 In view of the unfavourable prognosis, diagnostic confirmation in the Vascular form is routinely obtained by biomolecular investigations on blood or skin biopsy specimens. The conventional approach is biochemical demonstration of abnormal type III collagen in proteins synthesised in cultured skin fibroblasts, followed by molecular analysis of the COL3A1 gene.29, 30 These tests are readily available in Europe and North America. 4. Kyphoscoliotic form (OMIM ) The autosomal recessive Kyphoscoliotic form of the EDS is most often encountered in Greece, Turkey and the Middle East, and it is uncommon in Western Europe and the USA. The condition resembles the Classic form of the EDS with the additional features of a propensity to early onset progressive

173 9.1 Ehlers Danlos Syndrome 157 kyphoscoliosis, arterial rupture and occasional spontaneous perforation of the ocular sclera. The diagnosis is made by biochemical assessment of the activity of the enzyme lysyl hydroxylase I indirectly in urine specimens 31 or directly in cultured fibroblasts. 32 Determinant mutations in the PLOD-1 gene at the locus 1p36.3 p36.2 can be identified by molecular sequencing or deletion-duplication analysis. 33 Diagnostic confirmation and gene carrier detection is available in specialised laboratories Rare Forms of the EDS For the sake of completion, rare forms of the EDS are summarised below. These conditions are unlikely to be encountered in routine rheumatological practice EDS Arthrochalasis Type (Formerly EDS VIIA and B) Congenital dislocation of the hip is a presenting feature of this rare autosomal dominant form of the EDS. Skin extensibility, a mild scarring propensity and marked articular laxity are other manifestations. 34 Mutations in the COL1A1 or COL1A2 genes underlie mrna deletions of exon 6. Investigation of collagen fibril ultrastructure may be of diagnostic value EDS Dermatosparaxis Type (Formerly EDS VIIC) Skin fragility and laxity are the major manifestations of this autosomal recessive condition. Joint laxity is minimal but short stature, stubby digits and blue sclerae are syndromic concomitants. Activity of the enzyme procollagen- N -proteinase is deficient EDS Progeroid Type In addition to joint laxity and dermal extensibility, affected persons have an aged appearance, with thin wrinkled skin and fine hair. The basic defect in this rare autosomal recessive disorder is defective activity of galactose transferase 7 due to homozygosity for mutations in the B4GALTZ gene EDS Cardiac Valvular Type In this autosomal recessive disorder, the manifestations of the Classic form of the EDS are accompanied by significant abnormalities of the valves of the heart. Mutations in COL1A2 gene have been implicated. 37

174 158 9 Heritable Hypermobility Syndromes Classic EDS with Arterial Rupture A few individuals with the Classic EDS phenotype plus a propensity to arterial rupture have been documented. 38 This autosomal dominant disorder results from a mutation in the COL1A1 gene Spondylocheiro Dysplastic form of the EDS This unusual autosomal recessive entity is the consequence of homozygosity for mutations in the zinc transporter gene SLC39A EDS: Osteogenesis Imperfecta phenotype There have been a few reports of persons with a combined EDS-Osteogenesis Imperfecta phenotype. The basic defect has been documented as partial duplication of the COL1A2 gene, 40 and as a specific cysteine substitution in type I collagen Occipital Horn Syndrome (Formerly EDS IX) This X-linked disorder is no longer classified as a form of the EDS, but it is included in this section for the sake of completion. It is characterised by articular hypermobility, and skin which is lax but not fragile. Palpable occipital protuberances or horns are a pathognomonic feature. Diagnosis is confirmed by biochemical detection of disordered copper transportation Articular Manifestations Hypermobility of the joints is a cardinal manifestation of EDS and articular problems are frequently encountered. The complications which were present in a series of 100 patients of all ages have been reviewed. 42 The majority of these individuals had the former EDS I and II, which are now grouped together as the Classical type. The general implications of articular laxity are similar in the various forms of the EDS. The Classical and Hypermobility types are by far the most common in rheumatological practice, and the details set out below pertain to either. In general, these facts also hold true for the other rarer forms of the EDS in which the joints are lax, and for the Familial Articular Hypermobility Syndrome Disclocations The degree of articular hypermobility and the incidence of dislocations are closely related, although in some persons a surprising range of joint movement can occur without causing

175 9.1 Ehlers Danlos Syndrome 159 Fig. 9.4 In some persons with EDS, articular laxity may be extreme and it is not surprising that a large variety of musculoskeletal complications may occur clinical problems. The joints most frequently affected are those of the digits, elbows, shoulders and patella, while dislocation of the sternoclavicular joints has also been recorded. Congenital dislocation of the hips is well documented but infrequent. 43 Recurrent 44, 45 temporomandibular joint subluxations are more common than previously supposed. Dislocations are often recurrent and may be spontaneous, but reduction is usually easy and often spontaneous, particularly in the digital and shoulder joints. The degree of hypermobility and the incidence of dislocations often lessen with ageing although musculoskeletal disability does not usually decrease Joint Instability The more hypermobile persons are frequently troubled by instability of the joints, particularly the ankles and knees (Figs. 9.4 and 9.5 ). For this reason, such activities as running or the wearing of high heels may be impossible. Instability of the finger joints may also be a problem and simple actions such as typing or unscrewing bottle tops can be very difficult.

176 160 9 Heritable Hypermobility Syndromes Fig. 9.5 An affected girl with instability of the knee and ankle. Her shins bear the characteristic scars It must be stressed that not all affected individuals have articular problems. Amongst persons known to have EDS were a racing cyclist, a weight-lifter and an amateur boxing champion. The implications for athletic activity in individuals with the EDS have been reviewed by Schroeder and Lavallee Joint Effusions Persistent or recurrent effusions are commonly encountered. The usual site is the knee joint, but the ankles, elbows and digits may also be affected. These effusions are related to activity and often appear at the end of the day. Haemarthroses may occur in a minority of patients in whom the bleeding tendency is severe Hypotonicity Many affected individuals have muscular hypotonicity, which is probably directly associated with their lax joints. In infancy, the recognition of EDS may be very

177 9.1 Ehlers Danlos Syndrome 161 difficult, particularly as all babies are somewhat hypermobile. The EDS should certainly be considered in the differential diagnosis of any floppy infant. It is relevant that misdiagnoses of a variety of neuromyopathies have been made in neonates with the EDS. The Kyphoscoliotic form which presents with severe neonatal hypotonia is vulnerable in this respect Spinal Abnormalities Spinal malalignment of greater or lesser degree is present in a proportion of affected persons and it is the hallmark of the Kyphoscoliotic form of the EDS. Thoracolumbar scoliosis is the commonest abnormality of this type, and vertebral wedging may occur at the apex of the kyphotic element of the curve when a severe scoliosis is present. Spondylolisthesis is an uncommon complication. 49 The fact that spinal changes are uncommon in affected children suggests that scoliosis in adults is caused by the strains imposed by the upright stance on vertebral joints which have lax ligaments Thoracic Asymmetry Asymmetry of the thorax and sternal depression may occur, particularly in conjunction with spinal malalignment. When severe, the thoracic deformity may cause displacement of the heart, which in turn can lead to a cardiac murmur and an abnormal electrocardiogram. It is relevant, however, that a floppy mitral valve is more common in the EDS than previously suspected Foot Involvement Talipes equinovarus is present at birth in a proportion of persons with EDS. As intrauterine malposition is a causative factor in the pathogenesis of the club foot, it is reasonable to postulate that individuals with abnormally mobile joints would be at an unusually high risk for this complication. Pes planus is a frequent abnormality in the EDS. During childhood, the longitudinal arch frequently appears to be normal when no weight is being borne, but by the age of 30 years, the majority of persons with flat feet show both static and dynamic pes planus deformity. The most severe flat feet usually give no pain, and difficulty in fitting shoes is the main problem. Hallux valgus, claw toes and plantar keratomata are other common problems in the feet. The extensible skin may contribute to an appearance of moccasin feet where the affected individual seems to be wearing an oversize pair of ankle socks. Pain on weight bearing can result from the presence of piezogenic papules on the margins of the soles of the feet. These pea-shaped lumps result from herniation of globules of fibro-fatty tissue through the dermis.

178 162 9 Heritable Hypermobility Syndromes The implications of foot pain and disability in the EDS upon daily life activities have been reviewed by Berglund et al Osteoarthritis It seems likely that the development of osteoarthritis is related directly to the magnitude of hypermobility and the frequency and degree of trauma to which a particular joint is exposed. Nevertheless, there is a lack of consensus in this matter and the issue has not been settled. Osteoarthritis in the EDS and FAHS has been observed in the hands, knees, ankles and shoulders, but involvement of the hip joint is uncommon Bursae Bursae may develop in association with the Achilles tendon, hallux valgus and in the olecranon and prepatellar regions. It is sometimes difficult to distinguish these bursae from haematomata or from molluscoid pseudotumours, which also occur at these sites. The results of excision of these bursae are usually good Limb Pain A considerable proportion of persons with the EDS experience cramps in the leg muscles. These usually occur at night and are most severe during childhood, often resolving in adult life. In addition, ill-defined muscular pain is relatively common and may cause considerable handicap. 52 The pathogenesis is unknown, but it is possible that the pains are caused by the overstretching of the muscles which is permitted by the abnormal range of movements of the lax joints. In addition to cramps and muscle pains, non-specific discomfort may also involve the joints. This symptom is occasionally severe and may warrant consideration in the differential diagnosis of any child with polyarthralgia. Limb pain is a major reason for referral to special Hypermobility Clinics and a great deal of effort has gone into the elucidation of this problem. Protocols for management include sophisticated physiotherapy and psychological support. The pathogenesis and management of limb and joint pain in the EDS and the Hypermobility syndrome is discussed in detail in Chap Peripheral Circulatory Phenomena Acrocyanosis occurs in many affected persons, while a minority experience the Raynaud phenomenon.

179 9.1 Ehlers Danlos Syndrome Bony Abnormalities A variety of bony features have been encountered in isolated instances, including radioulnar synostosis, lack of development of the proximal phalanx of the little finger, syndactyly, spina bifida occulta and abnormalities of cranial ossification. It is unlikely, however, that these changes are directly related to EDS, as a majority of affected persons do not have any significant primary bony abnormality. The incidence of fractures is no higher than in normal individuals, and bone healing is uneventful. There is no increased liability to musculoskeletal neoplasia Handshake Affected individuals have a characteristic handshake. The musculoskeletal structure of the hand seems to collapse on pressure and the hands feel like a bag of bones Gait Persons with EDS can often be recognised by their gait. The feet are placed firmly and flatly upon the ground. The hips are hyperextended during weight-bearing to counteract the genu recurvatum, thus enabling the pelvis to remain balanced with respect to the feet. This gait is accentuated by the concomitant pes planus, and resembles that of tabes dorsalis Orthopaedic Management of Articular Problems The orthopaedic management of the EDS is determined by the strict application of basic principles. It is an important practical point that surgical procedures may be complicated by the fragility of the tissues. Sutures often cut out, and closure of operation sites may be difficult. Surgeons have aptly described attempts at skin suture as being like trying to sew porridge. 53 Similarly, angiographic procedures have caused major lacerations of the femoral artery. Nevertheless, the majority of affected persons do not have operative problems of this magnitude. A bleeding tendency may be present in some individuals. Although the majority of patients have trouble-free operations, massive haemorrhage has occurred in a few instances. The bleeding diathesis has been variously ascribed to changes in the coagulation mechanism, vessel walls or perivascular connective tissues, but no consistent abnormality has been demonstrated. 54 Postoperative haematoma formation may delay wound healing. The alteration of normal tissue elasticity, which would usually prevent the expansion of such haematomata is probably significant.

180 164 9 Heritable Hypermobility Syndromes Due to the tissue fragility, a small skin incision may extend spontaneously to become a gaping wound. Fine suture material, the avoidance of tension and a meticulous technique increase the chances of satisfactory operative results. Healing is often slow and wounds may reopen when sutures are removed. Surgical scars are usually thin and they may widen and distract with the passage of time, even when initial healing has been satisfactory. In some affected persons, especially those with the Kyphoscoliosis type of EDS, spinal malalignment may require correction. 55 In view of the potential surgical problems, it would be prudent for a major procedure of this type to be undertaken only after due consideration. Despite the potential problems in orthopaedic intervention in the EDS, total knee arthroplasty has been successfully accomplished. 56 Likewise, sternoclavicular joint stabilization 57 and orthoscopic tendon arthroplasty have been undertaken. 58 Anaesthetic techniques need to be chosen with cognisance of the syndromic manifestations and potential complications. The Vascular form of the EDS is especially important in this respect. 59, 60 Local anaesthesia may be ineffective in the EDS and the hypermobility syndrome. The basis of this problem has not yet been elucidated. Lax joints are generally best left lax as stabilisation procedures, apart from fusion, are rarely successful. The quote I was doing well before they operated on me is often apt A Patient s Viewpoint of His Articular Problems A young man with EDS wrote the following excellent description of certain aspects of his condition. My skin is rather loose and my knee joints will extend about 2 inch further back than a normal person s knees. If I stand with my knees straight I have to use my leg muscles to hold them there. If I let my knees extend backwards to their locked position it doesn t take long until they ache from the awkward position which they are in. The weight of my body rests on my knees at a slight angle from the vertical, which results in a strain being put upon them. Not only is my skin loose but the supporting tissue under the skin is soft. Although I am a construction electrician and work with my hands, I do not form callous on them. Sometimes when I lift something heavy I feel the tissue give way between the bones of my fingers and the object that I am lifting Non-articular Complications Apart from the articular complications, a wide variety of problems in other systems may arise from the underlying connective tissue abnormality. These are briefly reviewed below.

181 9.1 Ehlers Danlos Syndrome Cardiovascular Structural cardiac defects were initially thought not to be a primary feature of EDS, but with the introduction of sophisticated investigation techniques, a variety of cardiac abnormalities have been recognised. 61, 62 As in other inherited disorders of connective tissue, a floppy mitral valve is fairly common and mild dilation of the aortic root may occur. Cardiac assessment of all affected persons is warranted and if cardiac abnormalities are detected, annual cardiological surveillance is recommended. The potentially lethal complications of dissection of the aorta and spontaneous rupture of large arteries are virtually confined to the Vascular form of the EDS. These problems have been reviewed by Pepin et al Abdominal Structural anomalies of the gastrointestinal tract result form the undue tissue laxity. These abnormalities include hiatus hernia, gastric, duodenal and colonic diverticulae, and rectal prolapse. Inguinal, femoral and umbilical herniae are also common, and urinary bladder diverticulae may occur. Gastrointestinal haemorrhage, with or without perforation, is a feature of the Vascular form of the EDS. These events may be spontaneous, or follow minor trauma, and several deaths have been reported Neurological Intracranial vascular abnormalities are uncommon but dangerous complications of EDS. They are probably due to distensibility and fragility of the walls of the blood vessels, and the problems which arise can be compounded by a bleeding tendency. Aneurysms of the internal carotid arteries, carotid cavernous sinus fistulae and subarachnoid haemorrhage have all been reported. Angiographic investigations of intracranial lesions of this type are hazardous. Haematomata may compress peripheral nerves and the occurrence of recurrent neuropathy in the EDS has been documented. Spinal malalignment can result in cord compression, but this complication is rare Ophthalmological Involvement of the scleral connective tissue permits distortion of the eyeball leading to myopia and divergent strabismus. Uncomplicated convergent squint is common, due to laxity of the tendons of the extrinsic muscles of the eye. Scleral perforation and potential visual loss are features of the Kyphoscoliosis form of the EDS.

182 166 9 Heritable Hypermobility Syndromes Epicanthic folds and redundant skin on the upper eyelid may produce undesirable cosmetic effects. In this context, Méténier s sign (ease of eversion of the upper eyelid) is one of the minor diagnostic features of EDS Obstetric Although there are many potential complications in pregnancy, the majority of women with the Classic form of the EDS do not experience any difficulties. Nevertheless, antenatal surveillance and hospital delivery are desirable. One aspect of the EDS which is regarded as advantageous is the fact that striae gravidarum do not usually develop during pregnancy. Antepartum and postpartum haemorrhage are not infrequent, and it may be difficult to achieve haemostasis. Precipitate labour, severe lacerations of the perineum and uterine prolapse are relatively common. 64 If the foetus has in herited the condition, the amniotic and chorionic membranes will be fragile. These may rupture at an early stage, causing premature labour. The sequelae of pregnancy include uterine prolapse leading to dyspareunia and urinary incontinence. The vascular form of the EDS is especially liable to serious obstetrical complications. The tissue fragility and bleeding tendency pose special hazards during pregnancy, and expert antenatal care and delivery is essential. In one horrific episode, forceps delivery in an affected woman resulted in extraction of the infant, together with the uterus, bladder and ureters Dental Tissue fragility in the EDS can lead to damage to the gums on brushing the teeth, with consequent gingival periodontitis. 65, 66 Dental extraction may also be complicated by this fragility, with the additional hazard of abnormal bleeding, especially in EDS IV. 67 Articular hypermobility underlies pain and instability of the temporomandibular joints, and accidental dislocation can occur during extraction of teeth from the mandible. Numerical and structural abnormalities of the teeth are uncommon and inconsistent Breast Mammography Routine mammographic screening for neoplasia of the breasts has revealed that tissue calcification is a feature of the Classical form of the EDS. 69, 70, 71 This abnormality is probably analogous to the subcutaneous spheroids found in the limbs. Breast calcification may arouse suspicion of neoplasia, and awareness that it can be a syndromic complication in the EDS can avert an unnecessary mastectomy.

183 9.2 Familial Articular Hypermobility Syndromes Resources: Patient Support Groups Ehlers-Danlos Support Group PO Box 337 Aldershot Surrey GU12 6WZ UK Phone: Ehlers-Danlos National Foundation 3200 Wilshire Boulevard Suite 1601 South Tower Los Angeles CA Phone: ; Fax: Canadian Ehlers-Danlos Association 88 De Rose Avenue Bolton ON L7E 1AB Canada Phone: Fax: Association Francaise des Syndrome d Ehlers Danlos 34 rue Léon Joulin Tours France m.h.boucand@wanadoo.fr Familial Articular Hypermobility Syndromes The familial hypermobility syndromes are a heterogeneous group of disorders in which generalised joint laxity is the primary clinical manifestation. The EDS and other rare genetic conditions which have additional non-articular stigmata are excluded from this category. Semantic confusion still occurs, since the term hypermobility syndrome is often employed in a clinical context for any patient with articular symptoms which are the consequence of lax joints, in the absence of a specific syndromic diagnosis. The major problem lies in distinguishing between individuals who are at the upper end of the spectrum of the normal range of joint movements and those who have an inherited connective tissue disorder which presents with articular laxity (i.e. the familial articular hypermobility syndrome). This problem is discussed at length in Chap. 2.

184 168 9 Heritable Hypermobility Syndromes It is probable that the general category of loose-jointed persons with articular symptoms comprises a very heterogeneous group of simple and complex genetic conditions. The limits of syndromic resolution at a clinical level have been reached and further delineation will depend upon the recognition of specific biochemical or molecular markers. The identification of deficiency of the glycoprotein tenascin-x in a small proportion of persons with the Hypermobility form of the EDS may be a precursor to future molecular categorisation Nosology Early accounts of familial hypermobility were given by Key 72 and Sturkie. 73 The generation-to-generation transmission of loose-jointedness in association with multiple dislocations was documented by Hass and Hass 74 under the designation arthrochalasis multiplex congenita. The patients reported in this article included individuals with EDS and no attempt was made to differentiate the separate entities. Carter and Sweetnam 75, 76 and Carter and Wilkinson 77 drew further attention to the association of familial generalised joint laxity and dislocations. In addition to the generalised hypermobility syndromes, familial joint laxity is sometimes localised to a single site. For instance, Whitney 78 described autosomal dominant inheritance of hypermobility which was confined to the interphalangeal joint of the thumb, whilst a kindred with joint laxity in four generations and a propensity to recurrent dislocation of the patella was reported by Shapiro et al. 79 Beighton and Horan 80 documented two kindreds in which joint laxity was transmitted as an autosomal dominant trait and introduced the designation Familial Generalised Articular Hypermobility (Figs. 9.6 and 9.7 ). The first was a family of contortionists who had experienced few orthopaedic problems during their professional activities, while the second family had multiple dislocations and deformities which were attributable to their hypermobility. A further family with autosomal dominant generalised joint laxity and multiple dislocations was described by Horton et al. 81 These authors reviewed the literature and proposed the designation familial joint instability syndrome for the condition. Thereafter, the Berlin Nosology listed separate uncomplicated and dislocating types of the familial articular hypermobility syndrome (see Chap. 1 ). The autosomal dominant Familial Articular Hypermobility Syndrome differs from the Hypermobile type of EDS (formerly EDS III) only by virtue of additional dermal extensibility in the latter disorder. If this manifestation is of minor degree, exact diagnostic categorisation may be impossible. The problem is compounded by the fact that an ill-defined velvety texture to the skin and minimal cutaneous extensibility may be present in both conditions. It is possible that involvement of the tenascin-x gene could explain the similarity of these disorders. 20

185 9.2 Familial Articular Hypermobility Syndromes 169 Fig. 9.6 A young woman with familial generalised articular hypermobility (From Beighton 3 ) Fig. 9.7 She was able to maintain her joint laxity without any special training (From Beighton 3 )

186 170 9 Heritable Hypermobility Syndromes Fig. 9.8 Spontaneous dislocation of the right shoulder in the familial hypermobility syndrome (From Beighton 3 ) Autosomal recessive inheritance of familial articular hypermobility was recognised in two sisters born in a consanguineous French-Canadian kindred. 82 Both had gross generalised joint laxity and a soft, velvety skin. The younger sister had experienced numerous orthopaedic problems but the elder was asymptomatic. With hindsight, it seems possible that the former could have been homozygous for Tenascin-X deficiency, while the latter might have been heterozygous. This concept, however, is speculative. The genetic basis of the articular hypermobility syndromes has been reviewed by Malfait et al Articular Complications The Familial Articular Hypermobility syndrome and the common, apparently nonfamilial Hypermobility syndrome are very variable in severity. In clinical practice, they may be indistinguishable and the range of their potential complications is probably identical. In some hypermobile families, a wide spectrum of dislocations and subluxations may occur, while in others, there is a predisposition to dislocation or subluxation of a particular joint (Fig. 9.8 ). Following the reports of Carter and Sweetnam, 75, 76 recurrent dislocation of the patella and shoulder has been repeatedly recorded in families with hypermobility. Shapiro et al. 79 mentioned recurrent dislocations of the patella in four generations of a loose-jointed kindred.

187 9.3 Miscellaneous Joint Laxity Syndromes 171 The occurrence of hip dislocation in families with hypermobility has been documented by Carter and Wilkinson, 77 Wynne-Davis 84, 85 and Bjerkreim and van der Hagen. 86 Fredensborg 87 described an unusual patient with unilateral congenital dislocation of the hip and joint laxity which was present only on the same side. Apart from recurrent dislocations and subluxations, hypermobile individuals, familial or otherwise are liable to develop other orthopaedic complications due to their joint laxity. These include sprains, effusions, spinal malalignment and pes planus. Hallux valgus may also occur. 88 It has been shown that hypermobility is associated with osteoarthritis at the base of the thumb but not in the interphalangeal joints. 89 The issue as to whether or not hypermobility is related to the common forms of degenerative osteoarthropathy remains unsettled Other Phenotypic Manifestations Inguinal herniae are often encountered in hypermobile individuals and it seems likely that they are a genuine complication of the syndrome. In view of the underlying generalised connective tissue abnormality, this propensity for hernia is not unexpected. A link with the carpal tunnel syndrome and an association with mitral valve prolapse has been recognised. 91 There are few, if any, other structural non-articular complications. 92 The occurrence of non-specific limb and joint pains in hypermobile persons has attracted considerable attention. The clinical implications and management of Hypermobility are discussed in Chaps. 5 and Miscellaneous Joint Laxity Syndromes In addition to EDS and the familial articular hypermobility syndrome, joint laxity is present in a number of inherited disorders. In some it is a major feature, while in others the hypermobility is overshadowed by other syndromic components Joint Laxity in Inherited Connective Tissue Disorders Hypermobility is a clinically important facet of a few well-established connective tissue disorders, the most important of which are Marfan syndrome and osteogenesis imperfecta. A full description of these conditions and related disorders can be found in Heritable Disorders of Connective Tissue 96 and Connective Tissue and Its Heritable Disorders. 5

188 172 9 Heritable Hypermobility Syndromes Fig. 9.9 A boy with Marfan syndrome; arachnodactyly and thoracic asymmetry are evident Marfan Syndrome [154700] (See also Chap. 3 ) The Marfan syndrome is relatively common, with a population frequency of about 1 in 5,000 10,000 individuals. The hallmarks of Marfan syndrome are disproportionate limb length in relation to the trunk and arachnodactyly (long slim digits). The establishment of a firm clinical diagnosis of the Marfan syndrome is often difficult and partial examples are frequent. 97, 98 The most common of these are the mitral valve prolapse syndrome (MVP) and the MASS phenotype (myopia, mitral valve prolapse, mild aortic root dilation and variable skin and skeletal abnormalities). In addition, a marfanoid habitus, including lax joints, are a feature of several rare syndromic entities. These include familial aortic aneurysm, familial ectopic lentis, the Shprintzen Goldberg syndrome and the Loeys Dietz syndrome. Other well-established conditions which can be confused with the Marfan syndrome include the EDS, congenital contractural arachnodactyly, homocystinuria and the Stickler syndrome. The promulgation of diagnostic criteria for the Marfan syndrome has been helpful in clarifying this situation. 98a In the Marfan syndrome, thoracic asymmetry and spinal malalignment are sometimes present and dislocation of the ocular lenses and aortic and mitral valvular disease are additional features (Fig. 9.9 ). Aneurysmal dissection of the aorta in adulthood is a common mode of death. Joint laxity is maximal in the wrists, but other joints may be hypermobile to some degree (Fig ). Orthopaedic complications which are related to the laxity include recurrent dislocation, especially of the shoulder and patella, spinal malalignment, pes planus and hallux valgus.

189 9.3 Miscellaneous Joint Laxity Syndromes 173 Fig Articular laxity is maximal in the wrist joint in Marfan syndrome (Reproduced with permission from Beighton et al. 12 ) Inheritance is autosomal dominant but phenotypic expression is very variable and mildly affected persons may be difficult to distinguish from normal individuals. The identification of the chromosomal locus of the Marfan gene represented a major advance in the elucidation of the disorder. Molecular sequencing has revealed considerable intragenic heterogeneity. Diagnostic confirmation can be obtained by molecular investigation of the FBN-1 gene on 15q21.1 which encodes the protein fibrillin The clinical manifestations, management and pathogenesis of the Marfan syndrome have been comprehensively reviewed by Dietz Osteogenesis Imperfecta [120150] Osteogenesis imperfecta (OI) is a well-known genetic disorder in which bone fragility is associated with blue sclerae and wormian bones in the skull (Figs and 9.12 ). Hypermobility of digits is present in some affected persons, and in a minority, joint laxity may be widespread. In a review of the historical background of OI, Weil 101 drew attention to several reports in the early literature of hypermobility and recurrent dislocations. Ligamentous laxity probably plays a significant role in the development of the spinal deformities which occur in a small proportion of individuals with OI. In affected persons, joint mobility and muscle strength are significant factors in functional ability and rehabilitation. 102 The effective treatment of affected children with bisphosphanates has revolutionised the medical management of OI. 103 A rare form of OI, the Bruck syndrome, is characterised by articular rigidity rather than joint laxity. 104

190 174 9 Heritable Hypermobility Syndromes Fig A young man with osteogenesis imperfecta, showing severe deformity of the long bones (Reproduced with permission from Beighton et al. 12 ) A detailed account of OI has been presented online in the series in GeneReviews Other Bone Fragility-Joint Laxity Syndromes In the osteoporosis-pseudoglioma syndrome [259770], the radiological appearance of the skeleton and the presence of wormian bone are reminiscent of OI. These features are associated with mild mental retardation and potential blindness in infancy due to pseudogliomatous retinal detachment and the other ocular complications. 106 Ligamentous laxity is present but does not cause clinical problems. Using the designation OI associated with the Ehlers Danlos syndrome Biering and Iverson 107 reported the occurrence of gross generalised osteoporosis, articular laxity with dislocations, dermal extensibility and blue sclerae. There have been a few additional reports of this unusual condition (see EDS section ).

191 9.3 Miscellaneous Joint Laxity Syndromes 175 Fig The digits are sometimes lax in osteogenesis imperfecta A family with autosomal recessive inheritance of blue sclerae, keratoconus, deafness and spondylolisthesis was described by Greenfield et al. 108 Biglan et al. 109 reported five patients from two families with a similar disorder in which keratoglobus, blue sclerae, hearing loss, mottling of the teeth and generalised joint laxity were the main features. Inheritance was autosomal recessive. Robertson 110 detected hypermobility in 50% of a series of 44 patients with keratoconus and made a reasonable suggestion that the ocular and ligamentous abnormalities shared a common pathogenesis Skeletal Dysplasias with Predominant Joint Laxity Joint laxity is a major feature of a few uncommon genetic skeletal dysplasias and malformation syndromes. In these conditions, multiple dislocations may result from alteration in the mechanical properties of ligaments and joint capsules. Moreover, disordered growth may lead to alteration of bony contours in the joints, thereby

192 176 9 Heritable Hypermobility Syndromes Fig A girl with Larsen syndrome, showing epicanthus and the characteristic broad flat nasal bridge increasing the liability to dislocation. If ligamentous laxity is a significant syndromic component, this propensity is greatly enhanced. In these circumstances, concomitant dysplasia of the odontoid peg and marked joint laxity can render the cervical spine unstable and predispose to atlanto-axial subluxation and potentially lethal spinal cord compression. Articular hypermobility with or without subluxation and dislocation of single joints is a frequent but inconsistent feature of numerous malformation syndromes. In this context, joint laxity is not an important diagnostic indicator. It is also relevant that unilateral congenital dislocation of the hip is the most frequent abnormality in this category. Bilateral dislocation of multiple joints, notably the hips and elbows, is strongly suggestive of syndromic identity, and the more important conditions of this type are outlined below. In these disorders, lack of full extension and rotation of the elbows may be present; this paradoxical situation is the result of dislocation of the radial heads and it can be misleading in the clinical context Larsen Syndrome [150250; ] Larsen syndrome is characterised by marked generalised hypermobility in association with stunted stature, mid-facial hypoplasia, flattening of the nasal bridge and spatulate digits (Figs and 9.14 ). Joint laxity is maximal in the knees, and genu

193 9.3 Miscellaneous Joint Laxity Syndromes 177 Fig In the Larsen syndrome, the digits are lax and their tips are spatulate recurvatum and instability commonly occur. Initial presentation is as a floppy infant and other complications include dislocation of the hips and radial heads, and talipes equinovarus. 111 In later childhood, the ligamentous laxity predisposes to spinal malalignment, which may be progressive and difficult to manage. 112, 113 Distinct mild autosomal dominant and severe autosomal recessive forms of the Larsen syndrome have been documented. 114, 115 The basic defect in the latter is carbohydrate sulfotransferase 3 deficiency Desbuquois Syndrome [251400] Desbuquois syndrome is a rare autosomal disorder in which joint laxity is associated with stunted stature, broad terminal phalanges, polydactyly and protuberant eyes. Supernumerary ossification centres are present in the carpus and there is a characteristic prominence of the lesser trochanter of the femur. 117 Desbuquois syndrome is potentially lethal 118 but survival time is very variable Spondyloepimetaphyseal Dysplasia with Joint Laxity and Severe Progressive Kyphoscoliosis (SEMDJL) [271640] More than 20 children with a syndrome comprising skeletal dysplasia, gross generalised joint laxity and severe spinal malalignment have been documented in South

194 178 9 Heritable Hypermobility Syndromes Fig A boy with spondyloepimetaphyseal dysplasia with joint laxity (SEMHJL) in which dwarfism, gross kyphoscoliosis and articular laxity are the major features Africa (Fig ). The skin is rubbery and extensible but not fragile. Numerous orthopaedic problems are related to the hypermobility, including dislocation, subluxation, genu valgum, genu recurvatum, talipes equinovarus and pes planus. 120, 121 Inheritance is autosomal recessive. 122 The biomolecular defect has not yet been elucidated in this disorder Spondyloepimetaphyseal Dysplasia with Leptodactyly [603546] The leptodactylic type or Hall type of SEMDJL has been documented in Europe 123 and the USA. 124 The term leptodactyly pertains to the length and slender configuration of the tubular bones of the hands and feet. The clinical and radiological manifestations of both forms of SEMDJL are otherwise similar. 125 In distinction to the South African form of SEMDJL, however, the leptodactylic type is inherited as an autosomal dominant trait Dwarfing Dysplasias with Variable Joint Laxity Pseudoachondroplasia [177170] Pseudoachondroplasia is a comparatively common dwarfing skeletal dysplasia in which joint laxity is a variable component (Fig ). The digits are often stubby, with an impressive range of movement. In some affected persons

195 9.3 Miscellaneous Joint Laxity Syndromes 179 Fig Pseudoachondroplasia; short-limbed dwarfism and genu varum are the major stigmata. Loose stubby digits are characteristic of some forms of this heterogeneous disorder the hypermobility is sufficiently severe to cause dislocation, deformities and spinal malalignment, while in others the range of articular movement is 127, 128 normal Morquio Syndrome [253000] The eponymous designation Morquio is sometimes applied to any dwarfing syndrome in which spinal malalignment is a major feature, but in the strict sense, the term pertains to Mucopolysaccharidosis type IV (MPS IV). Dwarfism, thoracic deformity, aortic incompetence and progressive corneal clouding are the major clinical features, and the diagnosis may be confirmed by demonstration of the radiographic changes of dysostosis multiplex and excessive excretion of keratan sulphate in the urine. In distinction to the other Mucopolysaccharidoses, the joints are lax in MPS IV. This feature is most obvious in the digits, but the hypermobility predisposes to orthopaedic complications including genu valgum, spinal malalignment and pes

196 180 9 Heritable Hypermobility Syndromes Fig A boy with MPS IV showing the typical barrel chest, short neck and spinal malalignment. The digital laxity which is present in this condition is a useful diagnostic discriminant from the other mucopolysaccharidoses planus (Fig ). 129 It is of special clinical importance that the odontoid process is often hypoplastic in MPS IV, as the combination of this defect and joint laxity places affected persons at risk of subluxation of the cervical vertebrae and spinal cord compression Metaphyseal Chondrodysplasia Type McKusick [250500] This condition, also known as cartilage-hair hypoplasia, is characterised by fine hair, disproportionate dwarfism and lax stubby digits. Affected persons have a propensity to Hirschsprung disease and severe varicella. The disorder has been extensively studied among the inbred Amish community of Pennsylvania 131 and in the population of Finland Hypochondroplasia [146000] Hypochondroplasia is a relatively common dwarfing dysplasia, in which the clinical and radiographic features are similar to, but milder than, those of Achondroplasia. There may be some generalised joint laxity in hypochondroplasia, but this rarely causes clinical problems. 133