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25 YEARS 1985-2010

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EDNF 25 BENIGN JOINT HYPERMOBILITY: IS IT REALLY EDS AFTER ALL? – “Or How, after 42 years 2 diseases became 1” RODNEY GRAHAME UNIVERSITY COLLEGE LONDON SCHOOL OF MEDICINE U. WASHINGTON

EDNF 25 BENIGN JOINT HYPERMOBILITY: IS IT REALLY EDS AFTER ALL? – Or How, after 42 years 2 diseases became 1! RODNEY GRAHAME UNIVERSITY COLLEGE LONDON SCHOOL OF MEDICINE U. WASHINGTON

HMS 1967 (KIRK et al)

EDS III 1968 (BEIGHTON)

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25 YEARS 1985-2010

All presentations are for personal use by members only; copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

“THE HYPERMOBILITY SYNDROME”

“Musculoskeletal symptoms in the presence of generalised joint laxity in otherwise normal subjects”. Kirk JA, Ansell BM, Bywaters EGL.

Ann Rheum Dis. 1967; 26: 419-25

1967

JOINT HYPERMOBILITY JOINT HYPERMOBILITY

+ SYMPTOMS +

SYMPTOMS (PAIN &/OR=INSTABILITY)

JOINT HYPERMOBILITY = THE HYPERMOBILITY SYNDROME SYNDROME [HMS]

HMS 1967 (KIRK et al)

EDS III 1968 (BEIGHTON)

RHEUMATOLOGISTS JOINTS

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25 YEARS 1985-2010

All presentations are for personal use by members only; copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

HMS 1967 (KIRK et al) RHEUMATOLOGISTS JOINTS

EDS III 1968 (BEIGHTON) GENETICISTS GENETICS

FIBROUS PROTEINS • • • • •

COLLAGEN(S) ELASTIN(S) FIBRILLIN(S) TENASCIN(S) OTHER(S)

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25 YEARS 1985-2010

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COLLAGEN • THE TOUGHEST PROTEIN IN THE BODY AND THE MOST WIDELY DISTRIBUTED. • MAJOR COMPONENT OF: TENDON, SKIN LIGAMENT, SCLERA, HEART VALVES. • INFRASTRUCTURE OF BONE, CARTILAGE, MUSCLE

Modulus of Elasticity (Pa) • • • • • • •

SMOOTH MUSCLE ELASTIC FIBRES RUBBER COLLAGEN FIBRES WOOD -WILLOW WOOD - OAK STEEL

6 x 10-2 3 x 100 4 x 101 1 x 103 5 x 104 1 x 105 2 x 106

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®

All presentations are for personal use by members only;

25 YEARS 1985-2010

copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

HMS 1967

EDS III 1968

(KIRK et al)

(BEIGHTON)

RHEUMATOLOGISTS

GENETICISTS

JOINTS

GENETICS HDCTs

GENETIC ANOMALY

BIOCHEMICAL ABNORMALITY

FRAGILITY

INJURY

+

BIOMECHANICAL DEFECT

TISSUE LAXITY

IMPAIRED HEALING

HERITABLE DISORDERS OF CONNECTIVE TISSUE • MARFAN SYNDROME [MFS] • EHLERS-DANLOS SYNDROME [EDS] • OSTEOGENESIS IMPERFECTA [OI]

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25 YEARS 1985-2010

All presentations are for personal use by members only; copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

HMS 1967 (KIRK et al) RHEUMATOLOGISTS JOINTS OVERLAP WITH HDCTs

EDS III 1968 (BEIGHTON) GENETICISTS GENETICS HDCTs

Grahame and Jenkins 1972 53 Royal Ballet School students 53 Guy’s Hospital student nurses “Ballet students showed a significantly higher incidence of hypermobile joints including knee, elbow, wrist, which are not affected by training”. [INFERENCE: H/M A +VE SELECTION FACTOR IN RECRUITMENT INTO DANCE] Ann Rheum Dis 39: 109-11, 1972

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25 YEARS 1985-2010

copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

[GRAHAME et al ARD 1981]

MARFAN

EHLERS-DANLOS

AORTIC DILATATION ECTOPIA LENTIS

CLASSICAL, VASCULAR, ETC TYPES

MARFANOID HABITUS

STRETCHY SKIN: PAPYACEOUS SCARS: STRIAE ATROPHICAE

JOINT HYPERMOBILITY SYNDROME (=EDS III?) OSTEOPENIA OSTEOPOROSIS; FRACTURES OSTEOGENESIS IMPERFECTA

HERITABLE DISORDERS OF CONNECTIVE TISSUE • • • •

MARFAN SYNDROME [MFS] EHLERS-DANLOS SYNDROME [EDS] OSTEOGENESIS IMPERFECTA [OI] [BENIGN] JOINT HYPERMOBILITY SYNDROME [(B)JHS]

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25 YEARS 1985-2010

All presentations are for personal use by members only; copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

HERITABLE DISORDERS OF CONNECTIVE TISSUE EDS type GENETICS • MARFAN SYNDROME [MFS] • EHLERS-DANLOS } SYNDROME [EDS] } • OSTEOGENESIS IMPERFECTA [OI] • BENIGN JOINT HYPERMOBILITY SYNDROME [BJHS]

HMS 1967 (KIRK et al) RHEUMATOLOGISTS JOINTS OVERLAP WITH HDCTs

I/II IV

FBN 1 COL5a1/2 COL3A1 COL1A1/2

III

(TNXB)

EDS III 1968 (BEIGHTON) GENETICISTS GENETICS HDCTs BERLIN (1986) VILLEFRANCHE (1997)

HMS 1967 (KIRK et al) RHEUMATOLOGISTS JOINTS OVERLAP WITH HDCTs BRIGHTON (1998)

EDS III 1968 (BEIGHTON) GENETICISTS GENETICS HDCTs BERLIN (1986) VILLEFRANCHE (1997)

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25 YEARS 1985-2010

All presentations are for personal use by members only; copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

Revised “1998 Brighton” diagnostic criteria for the Benign Joint Hypermobility Syndrome MAJOR CRITERIA MINOR CRITERIA • Beighton score of 1,2, 3/9 (0, if aged 50+) • Arthralgia in 1-3 joints/ back pain/spondylosis/ spondylolysis/’olisthesis. • Dislocation in >1 joint, or in 1 joint on >1 x • > 3 soft tissue lesions • Marfanoid habitus • Skin: striae, thin, stretchy, abnormal scarring. • Eye signs: drooping eyelids or myopia • Varicose veins/hernia/ uterine/rectal prolapse

• Beighton score > 4/9 or (currently/historically) • Arthralgia > 3 months in >4 joints The BJHS is diagnosed with: 2 major criteria or 1 major and 2 minor criteria or 4 minor criteria. 2 minor + 1° degree relative. BJHS is excluded by presence of Marfan or Ehlers-Danlos syndromes (other than the EDS Hypermobility type formerly EDS III) as defined by the Ghent 1996 and Villefranche 1998 criteria respectively

APPLICATIONS OF BRIGHTON CRITERIA • DEFINING THE PHENOTYPE • SELECTING PATIENTS FOR CLINICAL STUDIES • EPIDEMIOLOGY OF JHS • CLINICAL DIAGNOSIS

INFLUENCE OF GENDER AND ETHNIC BACKGROUND ON CLINIC PREVALENCE OF JHS PHENOTYPE 70 60 50 40 % JHS 30 20 10 0 NON-CAUCASIAN FEMALES [183] NON-CAUCASIAN MALES [94] CAUCASIAN FEMALES [140] CAUCASIAN MALES [89]

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25 YEARS 1985-2010

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ROYAL BALLET SCHOOL REVISTED AFTER 30 YEARS

[Journal of Rheumatology 2004; 31(1):173-178]

•Royal Ballet School (lower 86; upper 64; controls 36) •Royal Ballet Company (dancers 71; controls 31) •BJHS (Brighton criteria) highly prevalent (cf controls): •Male as well as female •Junior school as well as senior •Professionals as well as students •Corps de ballet > soloists > principals (0) •Recurrent dislocations, Multiple soft tissue injuries, and a marfanoid habitus were features seen more often in dancers than controls •Implications for selection/training in individuals with BJHS.

HMS 1967 (KIRK et al) RHEUMATOLOGISTS JOINTS OVERLAP WITH HDCTs BRIGHTON (1998)

EDS III 1968 (BEIGHTON) GENETICISTS GENETICS HDCTs BERLIN (1986) VILLEFRANCHE (1997) CHRONIC PAIN (Sacheti 1997)

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25 YEARS 1985-2010

All presentations are for personal use by members only; copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

Chronic pain is a manifestation of EDS Sacheti et al (1997 )Jl of Chronic Pain 14(2): 88-93

• • • • • •

51 EDS pts; 32 f; mean age 34 (9-70) 6 <20 structured interview 20-60 min age, gender, EDS type, onset, progression chronic pain (0-10); quality impact: physical, sex, social, job pain control strategies: medication, physical therapy, orthotics, etc..

Chronic pain is a manifestation of the EDS Sachetti et al (1997 )Jl of Chronic Pain 14(2): 88-93

»46/51 (90%) chronic pain > 6 months »Mean number of painful sites 8 + 3.3 »Mean intensity of pain 5.3 + 1.5 »Progressive pain 43/51 (84%)

Chronic pain is a manifestation of the EDS Sachetti et al (1997 )Jl of Chronic Pain 14(2): 88-93

»Frequent headaches 1/2 »Intermittent abdominal pain 1/3 »40/45 adults symptoms began in childhood or adolescence »Sleep disturbance »Impaired physical activity »Impaired sexual function

70% 70% 45%

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25 YEARS 1985-2010

All presentations are for personal use by members only; copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

HMS 1967 (KIRK et al) RHEUMATOLOGISTS JOINTS OVERLAP WITH HDCTs BRIGHTON (1998)

EDS III 1968 (BEIGHTON) GENETICISTS GENETICS HDCTs BERLIN (1986) VILLEFRANCHE (1997) CHRONIC PAIN (Sacheti 1997) AUTONOMIC DYSFUNCTION (Rowe 1999)

HMS 1967 (KIRK et al) RHEUMATOLOGISTS JOINTS OVERLAP WITH HDCTs BRIGHTON (1998)

EDS III 1968 (BEIGHTON) GENETICISTS GENETICS HDCTs BERLIN (1986) VILLEFRANCHE (1997) CHRONIC PAIN (Sacheti 1997) AUTONOMIC DYSFUNCTION (Rowe 1999) GASTROINTESTINAL DISORDERS (Levy et al 1999)

HMS 1967 (KIRK et al) RHEUMATOLOGISTS JOINTS OVERLAP WITH HDCTs BRIGHTON (1998) ANXIETY & PHOBIAS (Bulbena 1988-)

EDS III 1968 (BEIGHTON) GENETICISTS GENETICS HDCTs BERLIN (1986) VILLEFRANCHE (1997) CHRONIC PAIN (Sacheti 1997) AUTONOMIC DYSFUNCTION (Rowe 1999) GASTROINTESTINAL DISORDERS (Levy et al 1999)

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25 YEARS 1985-2010

All presentations are for personal use by members only; copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

ASSOCIATION BETWEEN PANIC, PHOBIAS AND JOINT LAXITY BULBENA et al 1988; BULBENA et al 1993; MARTIN-SANTOS 1998

• Panic disorder, agoraphobia, simple phobias 4 x more common in hypermobile patients than in controls • Joint laxity 16 x more common in patients with panic/agoraphobia than in controls • Community study association between anxiety disorders and joint laxity

A POLYMORPHIC GENOMIC DUPLICATION ON HUMAN CHROMOSOME 15 IS A SUSCEPTIBILITY FOR PANIC AND PHOBIC DISORDERS. Gratacos et al. Cell 2000; 106: 367-379

• “We have studied the molecular basis of the concurrence of panic and phobic disorders with joint laxity. • We have identified an interstitial duplication on human chromosome 15 (15q24-26), which is significantly associated with panic/agoraphobia/social phobia/joint laxity in families and with panic disorder in non-famililial cases. • We propose that Dup 25 is a susceptibility factor for a clinical phenotype that included panic and phobic disorders and joint laxity.”

HMS 1967 (KIRK et al) RHEUMATOLOGISTS JOINTS OVERLAP WITH HDCTs BRIGHTON (1998) ANXIETY & PHOBIAS (Bulbena 1988-) AUTONOMIC DYSFUNCTION (Gazit 2003)

EDS III 1968 (BEIGHTON) GENETICISTS GENETICS HDCTs BERLIN (1986) VILLEFRANCHE (1997) CHRONIC PAIN (Sacheti 1997) AUTONOMIC DYSFUNCTION (Rowe 1999) GASTROINTESTINAL DISORDERS (Levy et al 1999)

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25 YEARS 1985-2010

All presentations are for personal use by members only; copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

Dysautonomia in the Joint Hypermobility Syndrome Gazit Y, Nahir M, Grahame R, Jacob G 2003 Amer Jl Med 2003;114:33-40

• 48 JHS patients; 20 controls responded to ANS-linked questions: Syncope, pre-syncope, palpitations, chest discomfort, fatigue and heat intolerance were significantly more common among JHS patients. • 27 patients and 21 controls underwent autonomic evaluation: orthostatic test, cardiovascular vagal and sympathetic function. Orthostatic hypotension (OH), postural orthostatic tachycardia syndrome (POTS), and uncategorized orthostatic intolerance (UOI) was found in 78% of JHS patients cf.10% controls. • dysautonomia is part of the extra-articular manifestations of BJHS

175 BJHS consecutive patients % of patients reporting: • • • • • • • •

PAIN FATIGUE FAINTS HEADACHE MOOD GAST/INT CARD/RESP CONFUSION

No 95 76 68 67 58 53 52 51

HMS 1967 (KIRK et al) RHEUMATOLOGISTS JOINTS OVERLAP WITH HDCTs BRIGHTON (1998) ANXIETY & PHOBIAS (Bulbena 1988-) AUTONOMIC DYSFUNCTION (Gazit 2003) GASTROINTESTINAL DYSMOTILITY (Zarate 2010)

% 67 46 48 23 33 33 24 33

EDS III 1968 (BEIGHTON) GENETICISTS GENETICS HDCTs BERLIN (1986) VILLEFRANCHE (1997) CHRONIC PAIN (Sacheti 1997) AUTONOMIC DYSFUNCTION (Rowe 1999) GASTROINTESTINAL DISORDERS (Levy et al 1999)

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25 YEARS 1985-2010

All presentations are for personal use by members only; copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

GASTROINTESTINAL DYSMOTILITY • • • •

49% [63/129] OF FG-IDs PATIENTS HAD JHM/BJHS MOST UNAWARE OF THEIR HYPERMOBILITY HYPERMOBILITY NOT SOUGHT BY PHYSICIANS SYMPTOMS COMPRISE: REFLUX; VOMITING; ABDOMINAL BLOATING;CONSTIPATION>DIARRHOEA • TESTS SHOW ‘SLUGGISH BOWEL’ • IS CONNECTIVE TISSUE THE MISSING LINK? Zarate-Lopez N, Farmer AD, Grahame R, Mohammed S, Knowles CH, Scott S, et al. Unexplained Gastrointestinal Symptoms and Joint Hypermobility: Is Connective Tissue the Missing Link? Neurogastroenterology and Motility 2010;22:252-62.

HMS 1967

EDS III 1968

(KIRK et al)

(BEIGHTON)

RHEUMATOLOGISTS

GENETICISTS

JOINTS

GENETICS

OVERLAP WITH HDCTs

HDCTs

BRIGHTON (1998)

BERLIN (1986)

ANXIETY & PHOBIAS (Bulbena 1988-)

VILLEFRANCHE (1997) CHRONIC PAIN (Sacheti 1997)

AUTONOMIC DYSFUNCTION (Gazit 2003) GASTROINTESTINAL DYSMOTILITY (Zarate 2010)

AUTONOMIC DYSFUNCTION (Rowe 1999) TINKLE et al 2009 ‘INDISTINGUISHABLE FROM ONE ANOTHER’

GASTROINTESTINAL DISORDERS (Levy et al 1999)

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 Part A 2009 149A:2368–2370. “It is our collective opinion that BJHS/HMS and EDS hypermobility type represent the same phenotypic group of patients that can be differentiated from other HCTDs but not distinguished from each other. Clinically, we serve this population better by uniting the two diagnostic labels. With this approach, we can strive to better define the phenotype and improve measurable outcomes of this patient population. Furthermore, we recognize that it is important that, in those hypermobility patients who develop potentially debilitating symptoms of chronic fatigue or polyarthralgia, whatever the underlying cause, there should be prompt and appropriate intervention [Keer and Grahame, 2003]”.

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25 YEARS 1985-2010

copyright is retained by the authors and presenters, and copies cannot be distributed or made without express permission of the original copyright holder. By downloading any presentation, you automatically agree to these terms.

JOINT HYPERMOBILITY SYNDROME [JHS] IN 2010 • • • • • •

CONNECTIVE TISSUE MATRIX PROTEINS CAUSED BY GENE DEFECTS CONSEQUENCES ARE BIOMECHANICAL PATHOLOGY OF TRAUMA/OVERUSE WIDE-RANGING CLINICAL FEATURES NEUROPHYSIOLOGICAL DEFECTS? – PROPRIOCEPTIVE IMPAIRMENT; – RESISTANCE TO LIDOCAINE;

ENHANCED PAIN PERCEPTION AUTONOMIC DYSFUNCTION

• PAN-GASTROINTESTINAL DYSMOTILITY • COMPLEX CLINICAL PICTURE • NEGLECTED BY HEALTH PROFESSIONALS

JOINT HYPERMOBILITY SYNDROME CLINICAL FEATURES JOINT

SOFT TISSUE

SPINE

EXTRAARTICULAR

HIP DYSPLASIA LATE WALKING

LIGAMENT/MUSCLE/ MENISCUS TEAR

“LOOSE-BACK SYNDROME”

“GROWING PAINS”

EPICONDYLYTIS

DISC PROLAPSE

ARTHRALGIA/ MYALGIA TENDONITIS/ CAPSULITIS DISLOCATION/ SUBLUXATION

STRETCHY SKIN THIN SCARS HERNIA

PARS DEFECTS VARICOSE VEINS FRACTURES

TENOSYNOVITIS SPONDYLOLYSIS UTERINE/ RECTAL ENTRAPMENT NEUROPATHY -OLISTHESIS PROLAPSE SPINAL ANOMALIES

G.I. DYSMOTILITY

CHONDROMALACIA PATELLAE

JOINT SYNOVITIS BAKER’S CYST

SPINAL STENOSIS S.I. JT INSTABILITY

OSTEOARTHRITIS

FIBROMYALGIA

DYSAUTONOMIA

CHRONIC PAIN SYNDROME DEPRESSION/ ANXIETY

NATURAL HISTORY OF SEVERE JHS – MUSCULOSKELETAL TISSUE LAXITY • NON-INFLAMMATORY JOINT/SPINAL PAIN; • DISLOCATIONS/SUBLUXATIONS • LIGAMENT, MUSCLE, TENDON, ENTHESIS INJURY/OVERUSE, FLAT FEET • PELVIC FLOOR; HERNIAE; VARICOSE VEINS

– NON-ARTICULAR • • • •

PAIN AMPLIFICATION; ‘KINESIPHOBIA’; DECONDITIONING WIDESPREAD CHRONIC PAIN [‘FIBROMYALGIA’] FATIGUE ORTHOSTATIC INTOLERANCE; POSTURAL TACHYCARDIA.

– PSYCHOSOCIAL SEQUELLAE • ANXIETY/DEPRESSION; OBESITY; WORK INCAPACITY; ISOLATION; RESENTMENT; ANGER

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Grahame2010EDNF