'The hypermobility syndrome'.

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ls ofthe Rheumatic Diseases 1990; 49: 190-200

REVIEW ARTICLE

'The hypermobility syndrome'

R Grahame

The hypermobility syndrome is characterised

by the occurrence of musculoskeletal symptoms

in hypermobile subjects in the absence of

demonstrable systemic rheumatological disease.

When the syndrome was originally described in

19671 many rheumatologists viewed it with

some scepticism-more as a clinical curiosity

than a rheumatic disease. For one thing doctors

and others are trained to examine for reduction

of joint mobility rather than for an increased

range, so that hypermobility is commonly

missed. Secondly, the absence of laboratory

abnormalities robbed the condition of scientific

plausibility. Thirdly, there were no agreed

criteria for hypermobility, merely a rather crude

set of diagnostic manoeuvres, which have come

to be known as the Beighton criteria.2 It is very

much to its credit that despite criticism over the

years, and despite various attempts to develop

more sophisticated devices, the nine point scale

has withstood the test of time and remains the

universally adopted yardstick for clinical and

epidemiological studies.

To what extent has our knowledge and

understanding of this condition advanced over

the past 22 years? The encouragingly large

number of scientific contributions published

from many countries and ranging over clinical,

epidemiological, and basic scientific aspects

attest to the substantial progress made in the

understanding of this group of disorders.

Generalised ligamentous laxity, the prerequisite

of joint hypermobility, is seen in a

substantial proportion of healthy individuals

(varying according to methodology and to the

age, sex, and ethnic origin of the population

studied), the overwhelming majority of whom

probably suffer no ill effects. On the contrary,

many derive added advantage in their pursuit of

such activities as athletics, acrobactics, and ballet

dancing, where greater flexibility is an asset.3

Mobility for a given joint follows a Gaussian

distribution,4 and within a population it is

generally those subjects whose joint range is

more than two standard deviations above the

mean who suffer musculoskeletal symptoms.5

Hypermobility diminishes markedly throughout

childhood and then more slowly during

adult life. Women generally show a greater joint

range than men, and Asians a greater range than

Negroes, who in turn are more mobile than

Caucasians. A recently established fact is that

'pauciarticular hypermobility' is even more

prevalent in otherwise healthy subjects than the

generalised variety. Among 660 North American

music students of all ages 47% of the men and

78% of the women showed at least one hypermobile

joint.6

Generalised joint laxity is a feature common

to a wide variety of heritable disorders of

connective tissue, many of which are rare. By

contrast the hypermobility syndrome, as seen in

clinical practice, is a common finding. A diagnostic

survey of 9275 new referrals to one large

general rheumatology clinic showed that the

syndrome was diagnosed more often than ankylosing

spondylitis, crystal synovitis, or psoriatic

arthritis, comprising 3-25% of all female and

0-63% of all male referrals.7

These patients present with a wide variety of

readily identifiable traumatic and overuse

lesions, such as traction injuries at tendon or

ligament insertions, joint or tendon sheath

synovitis, chondromalacia patellae, rotator cuff

lesions, or back pain due to soft tissue injury or

disc prolapse. Others suffer the effects of joint

instability, such as flat feet, recurrent dislocation,

or subluxation-notably of the shoulder patella,

metacarpophalangeal joints, or temporomandibular

joints. Others still, develop a

chronic arthritis-either a low grade inflammatory

synovitis of traumatic origin (which may

mimic and consequently be misdiagnosed as

rheumatoid or juvenile chronic arthritis) or

osteoarthritis, which is held by many authorities

(albeit on circumstantial evidence) to be a

direct complication of the hypermobility syndrome.

8 What sets the patient with the hypermobility

syndrome apart from other rheumatology

clinic attenders is the profusion and

spectrum of common lesions occurring in the

same individual and often spanning his (or more

commonly her) whole lifetime.9 More difficult

to explain in such patients is the commonly

encountered arthralgia or myalgia in the absence

of any demonstrable clinical abnormality. One

postulated mechanism is the overstimulation of

nociceptive nerve endings, which are poorly

supported by defective collagen fibrils.'0

Evidence has emerged from many centres

that extra-articular organs and tissues, which

rely for their structural integrity on the tensile

strength of normal collagen, may also become

disordered in hypermobile subjects. The skin

may be thin, soft, hyperextensible, and develop

striae. Fifty eight per cent of patients in one

series showed such skin changes, and a characteristic

facies has been described.'0 An association

between mitral valve prolapse and the

hypermobility syndrome (and vice versa) has

been reported in studies in the United

Kingdom " and in Czechoslovakia,'2 and an

increase in aortic compliance has been

recorded.'3 Weakness of the musculotendinous

supporting structures of the anterior abdominal

wall and pelvic floor no doubt explains the

Department of

Rheumatology,

Guy's Hospital,

London SEI

R Grahame

199

Grahame

reported increased finding of abdominal

hernia,'4 and of both rectal'5 and uterine

prolapse'6 in subjects with hypermobility syndrome.

Bone fragility may also be present,

resulting in an increased liability to fracture. "

Stress fractures of the metatarsal bones and of

the vertebral bodies and partes interarticulares

of the lumbar spine are particularly common,

the latter constituting additional potential

sources of low back pain in the hypermobility

syndrome. Another manifestation of bone

softening seen in the syndrome is idiopathic

protrusio acetabulae. " ' An additional feature,

the marfanoid habitus, has also been described

in patients with the hypermobility syndrome. In

one series 39% were found to have a marfanoid

habitus (defined as an upper segment:lower

segment ratio of <0 89) compared with 11l5%

of controls (p<0 05). "

It was this constellation of clinical abnormalities

observed in hypermobile subjects that

gave rise to the hypothesis that the hypermobility

syndrome was a forme fruste of a heritable

disorder of connective tissue-a (mercifully)

benign overlap syndrome which incorporated

many of the features seen in the rarer classical

hereditary disorders such as the Marfan syndrome,

the Ehlers-Danlos syndrome, and osteogenesis

imperfecta.

A panel of 21 expert geneticists from 10

countries has recently drawn up an agreed

comprehensive classification of the many syndromes

and variants of syndromes that have

been published ('The Berlin nosology'). 8 Unfortunately,

the patients with hypermobility syndrome

described above as commonly displaying

overlap features (marfanoid habitus, mitral

valve prolapse, skin hyperextensibility, and

joint laxity) do not fit comfortably into the

Berlin nosology. Neither of the two nearest

designations, the Ehlers-Danlos syndrome III

(hypermobile type) and the familial articular

hypermobility syndrome, are appropriate for

this group. The skin and joint changes seen in

the former are more florid, whereas in the latter

syndrome skin involvement and mitral valve

prolapse are reportedly absent. One hopes that

this discrepancy will be considered in future

revisions of the classification.

The multisystem pattern of the clinical

features seen in the hypermobility syndrome

points to a widespread disorder of connective

tissue. As the increased fragility of the tissues

concerned results from a loss of tensile strength

it is reasonable to assume that it is the collagen

which is at fault. Such evidence as is available

lends support to this assertion. The question

is-what defect(s)?

Skin biopsy samples showed raised ratios of

collage type III:types III+I in 14 out of 22

subjects with hypermobility syndrome,'0 indicating

a significant imbalance in the two major

collagen types present. Electron microscopic

examination of the same samples showed abnormally

small collagen fibrils with an increase in

interfibrillar matrix, elastin, and fibrocytes.

Studies of family pedigrees9 10 have provided

evidence for a dominant mode of inheritance

with sex-influenced phenotypic manifestations

in most cases of the hypermobility syndrome.

Within individual families women are more

commonly and more severely affected than

men, with a different phenotype pattern.

Women tend to present with arthralgia and

mitral valve prolapse, whereas men tend to

develop dislocations, back pain, or torn menisci

or tendons.

Although there have been recent exciting

discoveries using molecular genetic techniques

in many disorders, including variants of osteogenesis

imperfecta and the Ehlers-Danlos syndrome,'

9 the application of such techniques to

unravelling the mysteries of the hypermobility

syndrome is still in its infancy. Preliminary

work in selected families with hypermobility

syndrome using the technique of segregation

analysis suggests that the syndrome is not

caused by a mutation involving collagen types I

or III, nor the a-2 chain of type V or the a-3

chain of type VI (Brothertom, Child, Grahame,

Henney, unpublished data).

1 Kirk J H, Ansell B A, Bywaters E G L. The hypermobility

syndrome. Ann Rheum Dis 1967; 26: 419-25.

2 Beighton P H, L, Soskolne C. Articular mobility in

an african population. Ann Rheum Dis 1973; 32: 413-8.

3 Grahame R, J M. Joint hypermobility-Asset or

liability? Ann Rheum Dis 1972; 31: 109-11.

4 Wood P H N. Is hypermobility a discrete entity? Proceedings

of the Royal Society of Medicine 1971; 64: 690-2.

5 Pouk J, Fait M. Frequency of occurrence of generalised

ligamentous laxity in a population of children. Reumatologia

(USSR) (in press).

6 Larsson L-G, Baum J, Mudholkar G S. Hypermobility:

features and differential incidence between the sexes.

Arthritis Rheum 1987; 30: 1426-30.

7 Grahame R. Clinical manifestations of the joint hypermobility

syndrome. Reumatologia (USSR) 1986; 2: 20-4.

8 Grahame R. Clinical conundrum. How often, when and how

does hypermobility lead to osteoarthritis? Br J Rheumatol

1989; 28: 320.

9 Beighton P B, Grahame R, Bird H A. Hypermobility ofjoints.

2nd ed. Berlin, Heidelberg, New York: Springer, 1989.

10 Child A H. Joint hypermobility syndrome: inherited disorder

of collagen synthesis. J Rheumatol 1986; 13: 239-42.

11 Grahame R, J C, Pitcher D, Gabell A, Harvey W.

A clinical and echocardiological study of patients with the

hypermobility syndrome. Ann Rheum Dis 1981; 40: 541-6.

12 Ondrasik M, Rybar I, Rus V, et al. Joint hypermobility in

primary mitral valve prolapse patients. Clin Rheumatol

1988; 7: 69-73.

13 Child A H, Dorrance D E, Jay B, et al. Aortic compliance in

connective tissue diseases affecting the eye. Ophthalmic

PlaediatrGenet 1981; 1: 59-76.

14 Wynne-Davies R. Familial joint laxity. Proceedings of the

Royal Society of Medicine 1971; 64: 689-90.

15 Marshman D, Percy J, Fielding 1, et al. Rectal prolapse:

relationship with joint mobility. Aust NZ 7 Surg 1987; 57:

827-9.

16 Al-Rawi Z S, Al-Rawi Z T. Joint hypermobility in women

with genital prolapse. Lancet 1982; i: 1439-41.

17 Shore A, Macauley D, Ansell B M. Idiopathic protrusio

acetabulae in juveniles. Rheumatology and Rehabilitation

1981; 18: 167-9.

18 Beighton P, de Paepe A, Danks D, et al. International

nosology of heritable disorders of connective tissue, Berlin,

1986. AmJ Med Genet 1988; 29: 581-94.

19 Tsipouras P, F. Genetic disorders of collagen. J7 Med

Genet 1987; 24: 2-8.

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