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Aims
In this chapter joint hypermobility syndrome is
seen as one of the heritable disorders of,
connective tissue, and its similarities to and
differences from the other diseases in this
category are highlighted in terms of clinical
features, nosological criteria and underlying
molecular genetic bases. Guidelines are also
provided on when it would be desirable for a
physiotherapist to refer for specialist medical
advice and/or for genetic testing. This chapter
will attempt to place the hypermobility syndrome
within the general framework of disordered
connective tissue.
16 HYPERMOBILITY SYNDROME
Figure 2.1 The pathophysiology that pertains in all heritable disorders of connective tissue. Genetic aberrations affecting
fibrous proteins give rise to biochemical variations, then in turn to impairment of tensile strength, resulting in enhanced mobility
but at a cost of increased fragility, ultimately risking mechanical tissue failure
Cardinal features
Symptoms
Effects
Joint
Hypermobility
Arthralgia
Instability
Skeleton
Marfanoid habitus
Dislocation
Slender extremities
Pectus deformities
Skin
Hyperextensibility
Thinning
Striae atrophicae
Papyraceous scars
Easy bruising
Eyes
Ectopia lentis
Visual problems
Vascular
Aortic dilatation
Mitral valve
Aneurysm
Prolapse
Sub-acute bacterial
endocarditis (SBE)
Table 2.2 Clinical features in the Ehlers-Danlos syndrome classic type (EDS I and II) (reproduced with kind
permission of the editor and publishers of the Archives of Diseases of Childhood)
Cardinal features
Symptoms
Effects
Joint
Hypermobility
Arthralgia
Instability
Skeleton
Osteoporosis
Dislocation
Scoliosis
Fracture
Skin
Hyperextensibility
Thinning
Striae atrophicae
Molluscoid pseudotumours
Vascular
Mitral valve
Intracranial (EDS IV)
Prolapse
Aneurysm
SBE
Subarachnoid haemorrhage
Muscle
Laxity
Hernia
Intestinal/bladder diverticulae
Rectal/uterine prolapse
Neuromyopathy
Site
Eyes
Cardinal features
Symptoms
Effects
Joint
Hypermobility
Arthralgia
Instability
Skeleton
Osteoporosis
Dislocation
Fracture
Skin
Hyperextensibility
Thinning
Striae atrophicae
Papyraceous scars
Easy bruising
Eyes
Blue sclera
Vascular
Mitral valve
Prolapse
SBE
Table2.4 Clinical features in the benign joint hypermobility syndrome/EDS III (reproduced with
kind permission of the editor and publishers of the Archives of Diseases of Childhood)
Effects
Site
Cardinal features
Symptoms
Joint
Hypermobility
Arthralgia
Instability
Skeleton
Marfanoid habitus
Osteoporosis (low BMD)
Dislocation
Slender extremities
Pectus deformities
Fracture
Skin
Hyperextensibility
Thinning
Striae atrophicae
Papyraceous scars
Easy bruising
Eyes
Lid laxity
Blue sclera (occasionally)
Vascular
Varicose veins
Muscle
Laxity
Hernia
Rectal/uterine
prolapse
Table 2.5
New
Former
OMIM Inheritance
Classical type
Gravis EDS 1
Mitis EDS II
H/mobile EDS III
Ecchymotic EDS IV
130000
130010
130020
130050
(225350) (225360)
(225400) (229200)
130060
AD
AD
AD
AD
225410
AR
305200
130080
225310
147900
130070
XL
AD
Hypermobility
Vascular
Kyphoscoliosis
Arthrochalasia
Dermatosparaxis type
Other forms: X-linked EDS
Periodontitis type EDS VIII
Fibronectin-deficient EDS
Familial h/mob syndrome
Progeroid EDS
Unspecified forms
AR
?
AD
The 'Villefranche Nosology'(Beightonet al. 1998) replacedits predecessor, the 'Berlin Nosology'(Beighton et al. 1988) and,
in so doing, simplifiedthe classification of EDS, replacing the earlier numeral system with appropriate descriptiveterms.(Types
I and II were amalgamated to form the classic type, type III becamethe hypermooility type and type IV the vasculartype.)The
so-called familial articular hypermobility syndrome(FAHS), which previouslycarried the designationEDS type XI, is the one
that bears the closest relationto JHS.However, it excludes skin hyperextensibility, whichtherefore invalidates it as a description of
JHS (see Chapter 1).The numbersgiven refer to the OMIM classification (Online Mendelian Inheritancein Man NationalCenter
for Biotechnology Information, websitehttp://www.ncbi.nlm.nih.gov/Omimlsearchomim.html).AD. autosomaldominant pattern
of inheritance; AR, autosomalrecessive pattern of inheritance. AmericanJournal of Medical Genetics 1998, 77, 31-37.
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Minorcriteria
Fat cornea
Mitral valve prolapse
Pneumothorax
Striae
Majorcriteria
Minorcriteria
Pectus carinatum
Moderate pectus
Pectus excavatum
excavatum
Joint hypermobility
requiring surgery
High arched palate with
Reduced upper:lower
teeth crowding
segment ratio
Facial appearance
Span:height > 1.05
(dolichocephaly, malar
Positive wrist and thumb
hypoplasia, enophthalmos,
(Steinberg) test
0
downslanting
Scoliosis > 20 or
palpebral fissures)
spondylolisthesis
retrognathia
Reduced elbow extension
to less than 170 0
Medial displacement of
medial malleolus to produce
pes planus
Protrusio acetabulae of any
degree (ascertained on
radiographs)
Requirements for diagnosis of the Marfan syndrome:
For index case: Major criteria in '" two organ systems
and involvement of a third
For relative of an index case: one major criterion +
involvement of a second organ system.
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Box 2.3
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HYPERMOBILITY SYNDROME
In spite of improvements in medicine and surgery, many patients with MFS die needlessly and
prematurely because their condition has not been
identified; their true diagnosis has gone by default
and appropriate therapeutic action not been taken.
Because the physiotherapist may be the first health
professional to come into professional contact
with such a patient, it behoves him or her to be
alert to the possibility of undiagnosed MFS.
At the same time, it is important to appreciate
that marfanoid habitus is not pathognomonic
for MFS, as it is seen as part of many phenotypically related HDCTs, including JHS patients,
among whom it is present in about one-third of
cases (Grahame et al. 1981). The pivotal role of
echocardiography and slit-lamp examination of
the eye in clarifying the diagnosis of MFS is
illustrated in Figure 2.4.
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Unlike other types, the rarer vascular type (formerly EDS type IV) carries a poor prognosis as
it may give rise to arterial, bowel or uterine
rupture, with attendant dire consequences. These
complications tend to occur between the ages of
20 and 40 years. It results from mutations in the
gene for type III procollagen (COL3Al). In a recent
study of 220 biochemically proven patients and
199 of their affected relatives, the median survival was 48 years (Pepin et a1. 2000). Most deaths
resulted from arterial rupture.
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HYPERMOBILITY SYNDROME
Figure 2.8
In EDS classic type the degree of skin stretch (hyperextensibility) (a) is greater than that seen in JHS/EDS
hypermobility type (b)
Joint hypermobility syndrome (JHS) is the commonest of all the HOCTs and the one that occurs
most frequently in clinical practice. JHS shares
overlap features with the other HOCTs, including joint hypermobility, hyperextensible skin,
impaired scar formation and striae atrophicae,
the marfanoid habitus and, sometimes, osteopenia (Fig. 2.4) (Table 2.4). This has led to the notion
that JHS is itself an (albeit mild) form of HOCT
and that it and the hypermobile form of EOS (formerly known as EOS type III) are one and the
same (Grahame 2000a). Unlike some of the betterknown (though rarer) HOCTs it does not reduce
life expectancy, but it carries with it the greatest
burden of pain and disability (Grahame 2000b). It
is considered in depth in Chapter 1.
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HYPERMOBILITY SYNDROME
GENETIC TESTING
At present there is a limited availability of
laboratory tests that are of practical use in
delineating the HDCTs or in distinguishing one
from another. These investigations are labourintensive and expensive, and few laboratories in
the UK are suitably equipped to perform them.
Most work is undertaken under the auspices of
research grants and diagnostic applications are
considered a secondary issue at best. Genetic
testing for the HDCTs is in its infancy. The exciting discovery barely 15 years ago that mutations
in the fibrillin-l (FBN1) gene were the cause of
Marfan syndrome, and the early promise of a
simple diagnostic test for the disease, gave place
to bitter disappointment when it became clear
that over 200 such mutations were discovered in
Marfan syndrome - almost one for every family
investigated. However, in families with known
mutations it is possible to use this knowledge to
test family members in order to ascertain whether
a particular individual has the mutation. No doubt
as the science of molecular biology advances, the
prospects for a laboratory-based diagnosis for the
HDCTs using genetic methods will improve. In
the meantime diagnosis rests on the use of
validated clinical criteria (Heighton et al. 1988a,
De Paepe et al. 1996;Heighton and De Paepe 1996,
Grahame et al. 2000).
REFERENCES
Beighton, P.,De Paepe, A., Steinmann, B. et al. (1998)
Ehlers-Danlos syndromes: revised nosology,
Villefranche, 1997. American Journal of Medical
Genetics, 77, 31-7.
Beighton, P.,De Paepe, A., Danks, G. et al. (1988)
International nosology of heritable disorders of
connective tissue, Berlin 1986. American Journal of
Human Genetics, 29, 581-94.
Burrows, N.P., Nicholls, A.c., Yates, J.R. et al. (1997)
Genetic linkage to the collagen alpha 1 (V) gene
(COLSA1) in two British Ehlers-Danlos syndrome
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