REPORTS ON THE RHEUMATIC DISEASES SERIES 5
Topical Reviews
An overview of current research and practice in rheumatic disease
Medical Editor: Ade Adebajo
Production Editor: Frances Mawer (arc). ISSN 1469-3097.
Published by the Arthritis Research Campaign, Copeman House,
St Mary’s Court, St Mary’s Gate, Chesterfield S41 7TD.
Registered Charity No. 207711.
February 2005
Number 5
Published 3 times a year
HERITABLE COLLAGEN
DISORDERS
INTRODUCTION
Howard A Bird
Professor of Pharmacological Rheumatology
University of Leeds
Although the first clinical description of articular hypermobility is attributed to Hippocrates, who in the
4th century BC described the Scythians as a race having
such ‘flabbiness and atony’ that they were unable to use
their weapons, the condition has only attracted rheumatological interest in the last four decades. Kirk et al1
defined the ‘hypermobility syndrome’ in 1967 in the
absence of demonstrable inflammatory rheumatological disease, attributing persistent joint symptoms to
the inherited laxity of the joints alone. Early research2
concentrated on epidemiology, biomechanics and a possible link with osteoarthritis, though recently research
has been dominated by advances in molecular biology.
In parallel, geneticists have refined a nosology for the
rarer, more severe conditions such as Ehlers–Danlos
syndrome (EDS), Marfan’s syndrome and osteogenesis
imperfecta (OI) as well as for the osteochondrodystrophies that also contribute to joint laxity through abnormal bony contour.3
• Patients with heritable collagen disorders normally present to rheumatologists because of their joint
hypermobility
• The majority will have benign joint
hypermobility syndrome (BJHS)
• Hypermobility may be generalised or
extreme at a small number of joints. It
may be associated with involvement of
other organs because of the abnormal
inherited collagen structure elsewhere
• A small number of patients will have
Ehlers–Danlos syndrome, Marfan’s
syndrome or osteogenesis imperfecta.
Each condition has characteristic
features that distinguish it from BJHS,
though there is considerable genetic
overlap between these various
conditions
The realisation that abnormal collagen in the joints
often accompanies abnormal collagen elsewhere in the
body has led to the Brighton (1998) criteria for benign
joint hypermobility syndrome,4 which essentially incorporate clinical features at sites other than the joints.
Vigorous enthusiasm amongst patients with these inherited conditions has led to the inauguration of active
patient support groups, each with their own website.
Increasingly, patients are attending clinic already well
informed but seeking clarification of precise diagnosis,
information on prognosis, and advice on the most effective management to control their persistent and widespread symptoms.
• Management for all these conditions
is mainly symptomatic, requiring a
multidisciplinary team including physiotherapists, occupational therapists and
podiatrists
1
EPIDEMIOLOGY
There is wide racial variation in collagen structure and
therefore in the ‘normal’ range of movement in different
populations. Seminal work from South Africa7 showed
that in the same environment hyperlaxity was most
marked in those of Indian descent, less marked in the
indigenous Bantu population, and least marked in the
Europeans. Pockets of localised laxity exist worldwide
(e.g. Iraq9 and possibly Mongolia). Within ethnic groups,
laxity at particular joints may predominate over others.
The hands of individuals from the Indian subcontinent
tend to be particularly lax. Moreover, discomfort arising
from lax joints does not always correlate with the joints
displaying most laxity, some ethnic groups seemingly not
experiencing any symptoms at all. Epidemiologically, the
spine often behaves separately from the limb joints and
the spine is the site of some secondary consequences
of hyperlaxity such as spondylolisthesis.10
In terms of quantification, the range of movement at a
given joint varies, with a Gaussian distribution throughout the population.5 The initial scoring system from
Carter & Wilkinson (1964)6 was modified by Beighton
et al in 19737 to provide a simple 9-point scoring system
that could be applied in a few minutes in clinic (see
Table 1 and Figure 1). Alternative, more complex systems (e.g. the Contompasis) are less practical.8
Although these scoring systems provide a rough rapid
guide, they are no substitute for the careful consideration of each joint in turn. Some joints will be disproportionately lax compared to the others, which implies
an additional abnormality such as shape of bony structure, perhaps as the result of a mild localised osteochondrodystrophy or abnormal proprioception, maybe
summating with collagen structure. Hyperlaxity that is
entirely the result of impaired collagen is likely to be
aggravated by growth spurts and hormonal changes
as in menarche and pregnancy and at the menopause.
Severe localised laxity at a single joint, perhaps a mild
osteochondrodystrophy, is more likely to be associated
with premature osteoarthritis, which may also be caused
by impaired proprioception.
BENIGN JOINT HYPERMOBILITY
SYNDROME (BJHS)
This is a multisystem disorder affecting the joints and
soft tissue, with a tendency to recurrent sprain and
dislocation, the skin, which tends to be hyperextensible,
the skeleton, which may have more specific orthopaedic
abnormalities than would normally be expected, and
TABLE 1. The 9-point Beighton scoring system for joint hypermobility scale. (Reprinted from Grahame R et al, J Rheumatol
2000;27(7):1777-9, with permission.)
The ability to
(1) Passively dorsiflex the 5th metacarpophalangeal joint to ≥90º
(2) Oppose the thumb to the volar aspect of the ipsilateral forearm
(3) Hyperextend the elbow to ≥10º
(4) Hyperextend the knee to ≥10º
(5) Place hands flat on the floor without bending the knees
R
L
1
1
1
1
1
1
1
1
1
Maximum total
9
One point may be gained for each side for manoeuvres 1–4 so that the hypermobility score will have a maximum of 9 points if all are
positive.
1
2
3
5
4
FIGURE 1. Manoeuvres used in the Beighton scoring system for joint hypermobility. Illustration © David Gifford
2
the nervous system, with neurophysiological defects.
Because inherited collagen is ubiquitous throughout
the body, other organs are involved. The diagnosis may
not be immediately apparent, particularly if laxity is restricted to a small number of joints. Neither does the
presence of hyperlaxity indicate that this is necessarily
the cause of joint symptoms. Parallel inflammatory disorders of the musculoskeletal system should always be
considered and carefully excluded before all the symptoms are attributed to hyperlaxity.
TABLE 2. 1998 Brighton revised diagnostic criteria
for benign joint hypermobility syndrome.
(Reprinted from
Grahame R et al, J Rheumatol 2000;27(7):1777-9, with permission.)
Major criteria
1. A Beighton score of 4/9 or greater (either
currently or historically)
2. Arthralgia for longer than 3 months in 4 or more
joints
Minor criteria
1. A Beighton score of 1, 2 or 3/9 (0, 1, 2, or 3 if
aged 50+)
2. Arthralgia (≥3 months) in 1–3 joints, or back
pain (≥3 months), spondylosis, spondylolysis/
spondylolisthesis
3. Dislocation/subluxation in more than one joint,
or in one joint on more than one occasion
4. Soft tissue rheumatism ≥3 lesions (e.g. epicondylitis, tenosynovitis, bursitis)
5. Marfanoid habitus: tall, slim, span:height ratio
>1.03, upper:lower segment ratio <0.89,
arachnodactyly (+ Steinberg/wrist signs)
6. Abnormal skin: striae, hyperextensibility, thin
skin, papyraceous scarring
7. Eye signs: drooping eyelids or myopia or
antimongoloid slant
8. Varicose veins or hernia or uterine/rectal
prolapse
Nevertheless, certain clues allow confidence in the diagnosis. An onset of symptoms at a time of sudden growth
or hormonal change is always suggestive. Short-lived
episodes of inflammation, providing they immediately
follow spontaneous or traumatic subluxation of a joint,
need not suggest autoimmune inflammation. Symptoms
are more marked in females and hypermobility diminishes steadily throughout adult life.11 Attention should
be given to whether the laxity has been present since
early childhood or whether it has been acquired later
by regular and persistent training, as in musicians and
dancers.12,13 Sometimes both apply.
Benign joint hypermobility syndrome (BJHS) 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 firstdegree relative. BJHS is excluded by the presence of
Marfan’s or Ehlers–Danlos syndrome (EDS) [other than the
EDS Hypermobility type (formerly EDS III) as defined by the
Ghent 199627 and the Villefranche 199822 criteria, respectively]. Criteria Major 1 and Minor 1 are mutually exclusive,
as are Major 2 and Minor 2.
To assist with diagnosis, the British Society for Rheumatology’s Special Interest Group devoted to inherited
abnormalities of connective tissue has devised the
Brighton criteria4 depicted in Table 2. Although these
are based on the Beighton score with the presence of
joint symptoms as a cardinal feature, they remind us
that organs may be involved.
Extra-articular features that may be present include mitral valve prolapse14 (though aortic valvular involvement
is more suggestive of Marfan’s syndrome) and varicose
veins. A frank history of sudden cardiovascular death
in early adult life suggests the vascular form of EDS
unless the event is thought to be secondary to aortic
dissection, which suggests Marfan’s. Raynaud’s phenomenon is common, although it is prudent to exclude autoimmune causes of this condition before attributing it
entirely to hypermobility.
is common and premature osteoarthritis may occur,
particularly at the joints where the laxity is most
marked16,17 or which are most unstable. Osteopenia
may be apparent on dual-energy x-ray absorptiometry
(DEXA) scanning.14
Herniae can occur at the umbilicus and in the inguinal
region. Rectal and uterine prolapse may occur as well as
cystocele and rectocele.15 In pregnancy, laxity increases
and premature rupture of membranes may occur,
though the more major problems of antepartum and
postpartum haemorrhage are not normally associated
with this condition.
Ultimately, phenotype of joint hypermobility is likely
to be multifactorial in its genetics. The isolation of a
single culprit gene is unlikely in the near future and
genetic research is best assisted by careful clinical documentation to ascribe whether the laxity results from
collagen alone or bony structure or whether it is influenced by persistent training, perhaps with alterations in neuromuscular feedback mechanisms and
proprioception.
The lack of efficacy of the topical anaesthetic effects of
lidocaine18 may be a specific pharmacogenetic test but
may also be attributed to rapid diffusion through the lax
tissues. Recently, abnormality in joint proprioception19
and dysautonomia20 have both been recognised.
Spontaneous pneumothorax may occur and there is
a tendency to asthma, perhaps reflecting abnormality
in collagenous ground substance in the lungs rather
than the more conventional explanation of tracheal
and airways collapse. In the skeleton, spondylolisthesis
Although patients often seek clarification as to whether
they have BJHS rather than one of the more serious
abnormalities of connective tissue, in view of the multi-
3
factorial genetics there is frequently some overlap. Most
specialists consider2 that there is overlap with EDS type
III, the most benign variant of EDS. Some patients with
BJHS seem particularly susceptible to spontaneous stress
fracture of the bones and some individuals appear to
have a distinct Marfanoid habitus though, on probability
alone, BJHS in a tall, thin individual is more likely than
a true Marfan’s syndrome.
EHLERS–DANLOS SYNDROME (EDS)
initial classification of five variants, and a later which
expanded these to thirteen, are now both outdated.
Table 3 is derived from a commonly used classification for EDS, based upon Beighton et al3 and Byers,21
although a more recent classification based upon the
Villefranche nosology22 has reduced this group to just
six variants. This table lists ten variants with their normal genetic inheritance and what is known of the collagen defect that causes them. The clinical features are
also summarised.
The extreme form of this condition was described by
both Ehlers and Danlos around 1900. In the last two
decades advances in collagen chemistry and in clinical diagnosis have led to several reclassifications. The
It is likely that most variants result from abnormalities
in types I, III or V collagen. The most consistent molecular correlations have been between EDS type IV
with type III collagen defects and EDS type VII with
TABLE 3. Types of Ehlers–Danlos syndrome. (Reprinted from Rheumatology, 3rd edn, Hochberg M et al (ed), ‘Heritable connective tissue
disorders’ p.2161-9, © 2003 Mosby, with permission from Elsevier.)
Type
Name
Genetics
Aetiology
Clinical
EDS I
Gravis
AD
30% of cases caused by null allele
for COL5A1 or COL5A2
Soft skin with scars
Hypermobile joints
Easy bruising
EDS II
Mitis
AD
30% of cases caused by null allele
for COL5A1 or COL5A2
Less severe form of type I EDS
EDS III
Hypermobile
AD
Unknown
Soft skin without scars
Marked mobility of large and
small joints
EDS IV
Vascular
AD (AR)
Defects of type III collagen
Translucent skin
Marked bruising
Ruptured arteries, uterus, bowel
Normal joint mobility
EDS V
X-linked
XL
Unknown
Similar to EDS II
EDS VI
Ocular-scoliotic
VI-A-decreased lysyl
hydroxylase type
VI-B-decreased lysyl
hydroxylase type
AR
EDS VII
Unknown
Skin soft and extensible
Scoliosis
Ocular fragility
Hypermobile joints
Defects in lysyl hydroxylase
Arthrochalasis multiplex
congenita
VIIA-α1 (I) type
VIIB-α2 (I) type
VIIC-enzyme deficiency
AD
AD
AR
α1(I) DE6
α2(I) DE6
Deficient procollagen N-proteinase
Congenital hip dislocation
Hypermobile joints
Skin soft without scars
EDS VIII
Periodontitis type
AD
Unknown
Generalized periodontitis
Skin soft and extensible
Easy bruising
Hypermobile joints
EDS IX
(Vacant)
EDS X
Fibronectin
Soft, lax skin
Bladder diverticula and rupture
Bony occipital horns
AR
Fibronectin
AD autosomal dominant; AR autosomal recessive; EDS Ehlers–Danlos syndrome; XL X-linked
4
Mild joint hypermobility
Easy bruising
Abnormal platelet aggregation
type I collagen defects. Some defects are similar to
those seen in OI but others have been point mutations
causing aberrant splicing of one or more exons. Classical
EDS types I and II have been demonstrated to have
defects in type V collagen, but only in 30% of patients.23
Recently, deletion of tenascin-X has been identified in
a family with EDS.24 The defects may not be restricted
to collagen alone as conventionally taught.
Genetic and clinical features have been delineated.26
There is an autosomal dominant inheritance and the
approximate prevalence of 1 in 20,000 is similar to the
prevalence of the more severe variant of EDS. There is
no racial or geographical susceptibility.
The Ghent nosology,27 defining the major criteria, is
shown in Table 4. For diagnosis, major findings are
required in two out of the three main systems affected (heart; eyes; skeleton) as well as involvement of
a third organ system. Very few patients match up to
these strict criteria. Conventional rheumatological investigations (such as a metacarpal index >8.4) are of
limited relevance.
There is little risk of mistaking EDS type I with the full
picture of hypermobile joints supplemented by quite
characteristic elasticity of the skin and abnormal papyraceous scars together with a varying number of orthopaedic deformities such as talipes, kyphoscoliosis and
severe spondylolisthesis. EDS type II is simply a milder
variant and the main diagnostic difficulty comes in attempting to separate type III from BJHS. Since the risk
of vascular catastrophe in EDS type III appears to be
minimal and treatment for the two conditions is the
same with no prophylactic prevention for EDS, distinction is probably academic and most patients accept this
when it is explained to them. A papyraceous scar or
extreme laxity of the skin would sway towards EDS.
Typical musculoskeletal features26 include limbs disproportionately long for the trunk, scoliosis (in particular pectus excavatum or carinatum), and a high-arched
narrow palate with laxity of the joints.
The cardiovascular features are the most important diagnostically, with mitral valve prolapse and, particularly,
dilatation of the ascending aorta. Aortic regurgitation
may develop. Histologically, the aorta demonstrates cystic medial necrosis. Progressive dilatation of the aorta
is symmetric, commencing at the sinus of Valsalva and
predisposing to rupture and dissection.
A second diagnostic difficulty is whether a family history of premature death from cardiovascular causes
can reliably be attributed to hereditary factors predisposing to atheroma and thrombosis (the more likely
probability) or whether it suggests haemorrhagic disease from rupture of aneurysm or arterial wall, which
would be in keeping with EDS type IV. Whatever the
clinical suspicion, it is often not possible to obtain postmortem findings or case notes from long-dead relatives
that would clarify this.
Subluxation of the lens because of laxity of the suspensory ciliary ligament is present in about 60% of cases,
TABLE 4. Ghent nosology of Marfan’s syndrome27:
major criteria.
Skeletal system (four or more of)
• Pectus carinatum
• Pectus excavatum
• Span to height >1.05
• Wrist and thumb signs
• Scoliosis >20˚
• Elbow extension <170˚
• Pes planus
• Protrusio acetabulae
The other variants of EDS are relatively rare, though
most patients with EDS type I share some features of
EDS types VI, VII or VIII.
MARFAN’S SYNDROME
Dura
• Lumbosacral dural ectasia by CT or MRI
Described by Marfan in 1896, this was the first heritable disorder of connective tissue to be reported. Conventionally considered to be a ‘collagen disorder’, the
syndrome is now linked to mutations in fibrillin-1, a
350 kDa glycoprotein discovered in 1986 and widely
distributed in the aortic media, ciliary zone of the eye,
periosteum and skin. Decreased microfibrils were demonstrated in Marfan’s patients, and mutation screening
of all 65 exons of the FBN-1 chain, detecting a majority
of mutations, is available, though expensive and not
widely accessible.25 Several hundred mutations have
now been delineated, the genotype/phenotype correlations not straightforward. Normality in a second fibrillin gene on chromosome 5 is linked to cases of congenital contracture arachnodactyly.
Ocular system
• Ectopia lentis
Cardiovascular system
• Dilatation of ascending aorta involving at least
sinuses of Valsalva
• Dissection of ascending aorta
Family/genetic history
• First degree relative with Marfan’s syndrome
• Presence of FBN-1 mutation
For index case: Diagnosis requires major criteria in at
least two different organ systems and involvement of a
third organ system
For a relative of an index case: Major criterion in one
organ system and involvement of a second organ system
CT computerised tomography; MRI magnetic resonance imaging
5
normally bilateral and presenting and associated with
severe myopia because of increased axial length of the
cornea from childhood onwards.
The abnormality in OI is now well understood.32 Type I
collagen is a heterotrimer composed of two α1(I) chains
and one α2(I) chain twisted around each other in a long
right-handed helix. The formation and modification
of type I collagen requires a series of enzymatic steps.
Linkage analysis of pedigrees with the dominantly inherited mild type I and moderate type IV forms have
consistently demonstrated segregation of COL1A1 or
COL1A2 markers with the disease. Those cases of mild
OI type I are caused by premature chain termination.
Moderate OI type IV is associated with structural mutations of either collagen chain. Those cases of OI
type III are caused by structural defects in one of two
chains of type I collagen, and OI type II, like type IV,
is normally associated with structural defects in the
chains of type I collagen that result in overmodification
of the helices.
Marfan’s syndrome is now best managed in a specialist tertiary centre by an interdisciplinary team with a
cardiologist and, possibly, a cardiothoracic surgeon as
important members. Cardiovascular care often includes
annual echocardiography until the aortic root exceeds
45 mm, when echocardiography may be required more
frequently. The aortic root dilates progressively with age,
though not in all patients. Some consider dilatation is
maximal at middle age. For advanced aortic dilatation
avoidance of strenuous exercise and management with
β-adrenergic blockers may both be indicated. Elective
aortic surgery may need to be considered. The Bentall
procedure when dilatation is about 55 mm uses a composite graft to replace both ascending aorta and aortic
valve.28 Eighty-eight per cent of patients have a >5-year
surgical survival in experienced hands. Pregnancy causes
high cardiac and aortic risk.
The fracture susceptibility is extremely variable33 but
the skeleton is characterised by osteopenia secondary to
osseous matrix abnormality. Bowing of the long bones
and compression of the vertebral bodies, with a characteristic triangular facies, are secondary features to this.
Sclerae are blue (caused by decreased scleral thickness)
which is common in all types of OI though may be seen
in other inherited abnormalities, including some cases
of EDS. Dentition34 may be imperfect and hearing loss
is a common feature in some 50% of patients. Mitral
OSTEOGENESIS IMPERFECTA (OI)
The term osteogenesis imperfecta was first used by
Vrolik in 1849. The 1979 Sillence genetic classification,29
shown in Table 5, is now that most widely accepted.
Recently, it has been demonstrated that OI is caused
by abnormalities in type I collagen synthesis.30,31
TABLE 5. Sillence classification of osteogenesis imperfecta (OI) syndromes. (Reprinted from Rheumatology, 3rd edn,
Hochberg M et al (ed), ‘Heritable connective tissue disorders’ p.2161-9, © 2003 Mosby, with permission from Elsevier.)
Type
Genetics
Description
I
Autosomal dominant
Mildest form of OI
Mild-to-moderate bone fragility without deformity
Associated with blue sclerae, early hearing loss, easy bruising
May have mild-to-moderate short stature
Type 1A: dentinogenesis imperfecta absent
Type 1B: dentinogenesis imperfecta present
II
Autosomal dominant
or recessive
Perinatal lethal or recessive
Extreme fragility of connective tissue, multiple in utero fractures, usually
intrauterine growth retardation
Soft, large cranium
Micromelia, long bones crumped and bowed, ribs beaded
III
Autosomal dominant
or recessive
Progressive deforming phenotype
Severe fragility of bones, usually have in utero fractures
Severe osteoporosis
Relative macrocephaly with triangular facies
Fractures heal with deformity and bowing
Associated with white sclerae and extreme short stature, scoliosis
IV
Autosomal dominant
Skeletal fragility and osteoporosis more severe than type I
Associated with bowing of long bones; light sclerae
± moderate short stature, ± moderate joint hyperextensibility
Type IVA: dentinogenesis imperfecta absent
Type IVB: dentinogenesis imperfecta present
6
valve prolapse may be present, representing another
overlap with the other conditions.
autoimmune rheumatic disease. The extent to which an
inherited abnormality might influence the progression
of later acquired disease has not been fully studied but
it seems likely that rheumatoid arthritis, for example,
may be more mutilating in an individual whose joints
are already unstable prior to its onset. Recently, sensitive MRI scanning has allowed realisation that the
site of joint damage in rheumatoid joints and in joints
affected by seronegative spondyloarthritis may be influenced by the ligamentous tension, suggesting that
biomechanical factors may be locally important in
determining the site of joint damage in rheumatoid
arthritis.39 It is possible that hydrodynamic factors
contribute in a similar fashion to the distribution of
vasculitis in some blood vessels. There is also some
evidence that the clinical onset of ankylosing spondylitis may be masked in a patient who has inherited a
supple spine, though the progression of disease at the
sacroiliac joint is unlikely to be altered.
Children with OI are typically treated by paediatricians,
and rheumatologists are likely to see the less severe
cases that reach adult life. Management will be as with
other inherited abnormalities, but in this condition
there is more experience with orthopaedic procedures
involving the spine, possibly because fragility of the
skin and subcutaneous tissues is less marked and therefore does not act as a deterrent. Intramedullary rod fixation may be appropriate for improving limb appearance and correcting deformities prior to weightbearing.
Scoliosis of moderate to severe OI does not respond
to Milwaukee braces, and when scoliosis exceeds 40˚
spinal fusion with Harrington instrumentation is normally recommended.
There is currently debate about the role of bisphosphonate drugs for the medical management of this condition.35 Intravenous pamidronate has been shown to
reduce the frequency of fracture in severe OI and to
enhance healing. Whether oral bisphosphonates may
have a role in the long-term prevention of fracture in
milder cases is currently under study.
There is a strong clinical impression that patients with
hypermobility of joints may be susceptible to overuse
syndrome at the joints that are most hyperlax. In simple
terms, additional effort is required to stabilise the joints
in a position of reasonable (if not optimum) function
before the additional force of the muscle serves to
move them. There is also a strong clinical impression
that joints that are most hyperlax may be susceptible
to premature osteoarthritis, though whether this reflects the proximity of genes for collagen structure and
osteoarthritis or whether it implies a biomechanical
cause is not certain.
SKELETAL DYSPLASIAS
This term refers to a large number of inherited disorders associated with structural abnormalities of the
skeletal system, particularly the bones and cartilage.
Such conditions have been recognised since antiquity,
often associated with short stature. Classification criteria
have been devised based on clinical, radiographic and
molecular approaches.36–38 Some are associated with glycosaminoglycan processing abnormalities; others are
recognised as collagenopathies.
Drugs that are used in inflammatory arthritis may also
affect collagen structure. D-penicillamine enhances
joint laxity by qualitative effects on collagen structure.
Steroids enhance laxity by reducing the total amount
of collagen and, for this reason, intra-articular steroids
should be used very sparingly and with great care, if
at all, in these inherited conditions.
Plain radiographs remain important in diagnosis but
computed tomography and magnetic resonance imaging
(MRI) are required to determine the extent to which
cartilage as well as bone is abnormal in contour.
MANAGEMENT
In turn, abnormal localised bone growth or malalignment may lead to mechanical stretching of the joint
capsule with consequent later joint instability presenting as joint hyperlaxity. It is possible that mild forms of
these conditions contribute whenever laxity is unduly
pronounced at a single or small number of joints.
Unfortunately, management remains supportive and
symptomatic rather than curative. With the possible important exceptions of the cardiological care required in
Marfan’s patients and the orthopaedic care and possible
use of bisphosphonates in OI patients, treatment is
similar throughout the whole group of conditions.
INTERACTION WITH OTHER
DISEASES OF THE MUSCULOSKELETAL SYSTEM
Education is very important. Many patients will have
seen a variety of medical specialists without receiving
either a firm diagnosis or clarification as to whether the
symptoms can be attributed exclusively to an inherited
condition. It is useful to give patients a copy of the arc
information booklet ‘Joint Hypermobility’ (revised edn.
Patients with inherited abnormalities of connective
tissue are as susceptible as any others to inflammatory
7
Arthritis Research Campaign; 2005. www.arc.org.uk/
about_arth/booklets/6019/6019.htm), which as well as
helpful practical advice contains full contact details of
the various patient support groups. Patients may or
may not find contact and membership of such a group
helpful. Each of the groups produces its own literature
so patients can select the pamphlets or booklets that
they most need. Understanding the diagnosis can allay
anxiety and there is normally relief when it is explained
that progressive inflammatory disease is not present,
symptoms of hyperlaxity are likely to improve with age
and, where appropriate, premature osteoarthritis may
not occur.
be preferred unless the pain is only associated with a
period of post-traumatic inflammatory effusion after
dislocation, when the use of NSAIDs is more rational.
Patients with the more severe conditions have substantial pain, necessitating quite potent oral analgesics.
There may be a role for topical application of counterirritants or even potent analgesics such as fentanyl in
topical application. Nocturnal tricyclics in doses lower
than those conventionally used for depression may
also be helpful.
Surgery is more contentious. Patients with these abnormalities are susceptible to bleeding at operation,
difficulties with haemostasis, post-operative bruising
and infection, and poor skin healing.50,51 For all these
reasons, operation should only be considered if absolutely necessary. A variety of procedures are available for
instability of the patella or shoulder, two of the most
common problem sites. More recently, laser capsular
shrinkage has been under study for both the knee and
the shoulder joints.
There is epidemiological evidence that lean body mass
reduces symptoms40 and that weight gain, growth spurts
and hormonal factors can all aggravate them. If certain
sports or activities aggravate specifically41 these should
be avoided. Rest may also be helpful, particularly if
there is traumatic inflammation following a dislocation,
but this group of patients may be more susceptible to
osteopenia and disuse atrophy if rest is prolonged.42
Patients are often avid for information on specific topics.
This sometimes needs to be handled with sensitivity.
Women and obstetricians frequently enquire about the
hazards of pregnancy. Patients often seek counselling
on the likely affect of their condition on their progeny,
in which situation examination of the other parent is
advised. Children and adolescents often experience difficulty at school because of the fragility of their joints
and their pain. They may be subject to bullying, and
the spontaneous bruising that can occur on minimal
trauma sometimes raises the possibility of child abuse.
Where a potentially lethal condition such as the vascular
variant of EDS is suspected formal counselling may be
required, particularly since at present no preventative
treatment is available.
Physiotherapy remains extremely important.43 A wide
range of techniques is practised, including exercise therapy, passive mobilisation, hydrotherapy, ultrasound,
pulsed short-wave diathermy and laser therapy. Some
patients benefit from acupuncture. Ultrasound in particular promotes collagen synthesis44 and may also be
important locally after injury.
Exercises are particularly beneficial and should concentrate on core support and the stabilisation of the
most lax joints by increasing muscle tone around
them.45 Recent studies have demonstrated the benefit of exercise programmes in stabilising joints and
thereby relieving symptoms.46,47 Some patients benefit
from passive mobilisation, and if proprioception is
impaired, proprioceptive enhancement is likely to be
beneficial.48
CONCLUSION
Heritable collagen disorders continue to provide both
a clinical challenge and also valuable examples of the
molecular genetics of disease. Their study is likely to
contribute significantly to our understanding of disease
pathogenesis.
Ergonomic assessment, often performed by occupational therapists, is also important. Hyperlax fingers
have difficulty holding pens, and adaptations are required. Lightweight splints might assist at work, providing they do not restrict function, and if fatigue is
occurring at hyperlax joints the use of protective firmer
rest splints, perhaps overnight, may stabilise for use
during the following day – though excessive wearing of
splints over long periods may promote disuse atrophy.
Feet in particular are often ignored and podiatry is of
benefit. Orthoses are likely to be helpful49 and their use
is currently the subject of an arc-funded trial.
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This issue of ‘Topical Reviews’ can be downloaded as html or a PDF file from the Arthritis
Research Campaign website (www.arc.org.uk/about_arth/rdr5.htm and follow the links).
Hard copies of this and all other arc publications are obtainable via the on-line ordering
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arc Publications for People with Arthritis
As well as publications written specifically for medical practitioners the Arthritis
Research Campaign (arc) publishes over 80 booklets, mind maps, fold-out guides and
information sheets aimed at people with arthritis and their carers. These publications
provide information about specific types of arthritis and treatments and offer practical
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below) or as html or PDF at www.arc.org.uk/about_arth/patpubs.asp.
The publications are regularly revised to incorporate the latest information. As well as
the seventeen information sheets on drugs and arthritis, which are updated annually,
the following were all revised in 2004/5:
•
•
•
•
•
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A Beginner’s Guide to the Internet
Blood Tests and X-Rays for Arthritis
Fibromyalgia
Joint Hypermobility
Lupus (SLE)
Pain in the Neck
Osteoarthritis
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Osteoarthritis of the Knee
Osteoporosis
Pseudogout and Calcium Crystal Diseases
Psoriatic Arthritis
Raynaud’s Phenomenon
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As part of arc’s educational work these resources are provided free of charge
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to: arc Trading Ltd, James Nicolson Link, Clifton Moor, York YO30 4XX.
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NEW
Information on osteomalacia
in five Asian languages
The Arthritis Research Campaign (arc) has recently published information sheets
on osteomalacia in five Asian languages:
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Each sheet includes the English text alongside the Asian one. An audio CD containing spoken versions of the text in the same languages and English is also
available.
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within the UK. You can order on-line at www.arc.org.uk/orders or by writing to:
arc Trading Ltd, James Nicolson Link, Clifton Moor, York YO30 4XX.
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