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Arachnodactyly - A key to diagnosing heritable disorders of connective tissue

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Abstract and Figures

Arachnodactyly literally means spidery fingers, and describes the long, slender fingers typical of patients with Marfan syndrome (MFS). Many clinicians regard arachnodactyly as pathognomonic of MFS; however, this view is misleading as arachnodactyly is a key element of the marfanoid habitus, which is present in several heritable disorders of connective tissue (HDCTs). Other features of the marfanoid habitus include long hands and feet, increased skin stretch, joint hypermobility and characteristic changes in the physiology of the pectum. Here, we focus on the differential diagnosis of diseases with features of the marfanoid habitus. Ectopia lentis (lens dislocation) and aortic root dilation or dissection are cardinal features of MFS. Distinguishing MFS from other HCDTs has important implications for treatment, as cardiovascular and ocular complications commonly seen in patients with MFS are not seen in all HDCTs. Joint hypermobility syndrome and Ehlers-Danlos syndrome are also HDCTs, neither of which is associated with ectopia lentis or aortic changes. Some of the rarer forms of Ehlers-Danlos syndrome are associated with severe vascular, dental and skin pathologies. This Review serves as a guide for correctly diagnosing members of the HDCT family.
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Centre for
University College
Hospital London, Third
Floor Central, 250
Euston Road, London
(R.Grahame). Whipps
Cross University
Hospital, Barts Health
NHS Trust, London
E111NR, UK
Correspondence to:
R. Grahame
Arachnodactyly—a key to diagnosing
heritable disorders of connective tissue
Rodney Grahame and Alan J. Hakim
Abstract | Arachnodactyly literally means spidery fingers, and describes the long, slender fingers typical
of patients with Marfan syndrome (MFS). Many clinicians regard arachnodactyly as pathognomonic of
MFS; however, this view is misleading as arachnodactyly is a key element of the marfanoid habitus, which
is present in several heritable disorders of connective tissue (HDCTs). Other features of the marfanoid
habitus include long hands and feet, increased skin stretch, joint hypermobility and characteristic changes
in the physiology of the pectum. Here, we focus on the differential diagnosis of diseases with features of
the marfanoid habitus. Ectopia lentis (lens dislocation) and aortic root dilation or dissection are cardinal
features of MFS. Distinguishing MFS from other HCDTs has important implications for treatment, as
cardiovascular and ocular complications commonly seen in patients with MFS are not seen in all
HDCTs. Joint hypermobility syndrome and Ehlers–Danlos syndrome are also HDCTs, neither of which is
associated with ectopia lentis or aortic changes. Some of the rarer forms of Ehlers–Danlos syndrome
are associated with severe vascular, dental and skin pathologies. This Review serves as a guide for correctly
diagnosing members of the HDCT family.
Grahame, R. & Hakim, A.J. Nat. Rev. Rheumatol. advance online publication 12 March 2013; doi:10.1038/nrrheum.2013.24
Arachnodactyly—spidery fingers—is an easily recognised
physical sign that might indicate the presence of a herit-
able disorder of connective tissue (HDCT). Arachno-
dactyly should never be considered in isolation, but as a
feature of the marfanoid habitus, a range of skeletal dispro-
portions associated with increased length and decreased
breadth of long bones. Incomplete forms of the marfa-
noid habitus are commonplace and likely to be benign;
however, their presence should trigger an assessment for
features of HDCTs. Although the marfanoid habitus is
primarily associated with Marfan syndrome (MFS), MFS
is only one potential diagnosis. In particular, joint hyper-
mobility syndrome (JHS), a far more prevalent HDCT
than MFS, is also associated with the marfanoid habitus.
The HDCTs comprise a family of genetically-determined
diseases caused by mutations in genes encoding connec-
tive tissue matrix proteins (for example, collagen, elastin,
fibrillin and tenascin). Clinicians often find diagnosis
of these conditions challenging because of overlapping
symptoms and the broad spectrum of physical findings.
The aim of this article is to enable clinicians to make an
accurate diagnosis in cases where arachnodacty ly and
other signs of HDCT have been identified.
Clinical investigations of HDCTs
A number of investigations can be performed in the clinic
to identify potential HDCTs. The need for further testing
is determined by the identity of the putative HDCT.
Arachnodactyly is initially recognized by observing the
size (notably the length and slenderness) of the patient’s
hands and fingers during the course of a consultation
(Figure1a). The acid test for the confirmation of arachno-
dactyly is the performance of the tests for the Steinberg1
and Walker–Murdoch2 signs (Figure1); historically, the
metacarpal index has also been used.3
In the Steinberg test, the patient actively adducts the
thumb across the palm as far as possible and then closes
the fist, thereby enclosing the thumb. The test is positive
if it is possible to extend the thumb so that it projects
beyond the edge of the hypothenar eminence (Figure1b).
The test for the Walker–Murdoch sign requires the
patient to actively encircle their wrist with the contra-
lateral thumb and little finger. A positive test is denoted by
the ability of the two relevant fingernails to overlap by a
complete fingernail length (Figure1c). Prior to the intro-
duction of the Steinberg and Walker–Murdoch tests, the
standard approach to identifying arachnodactyly was to
calculate the metacarpal index. This calculation required
a plain radiograph of the hands; the metacarpal length is
divided by the midpoint girth for each of the digits (omit-
ting the thumb). The mean of the four ratios constitutes
the metacarpal index for that hand. Values >8.6 are con-
sidered to be indicative of arachnodactyly, whilst values
<8.0 are normal. Values between 8.0 and 8.6 do not clearly
indicate the presence or absence of arachnodactyly.
With the advent of the Steinberg and Walker–Murdoch
tests, the metacarpal index became redundant as expo-
sure to ionising radiation would no longer be justified or,
in fact,needed.
Competing interests
The authors declare no competing interests.
© 2013 Macmillan Publishers Limited. All rights reserved
The marfanoid habitus
Having confirmed the presence of arachnodactyly, the
next stage is to establish the presence of other features of
the marfanoid habitus (Supplementary Figure1). These
features are identified by careful observation supple-
mented by the calculation of four ratios. The first ratio,
the span:height ratio (SHR) is measured by asking the
patient to stand facing and in contact with a wall with
arms, hands and fingers fully extended (horizontally out-
stretched) with the tip of the middle finger of one hand
in contact with a side wall. The distance (measured with
a tape measure) from the tip of the contralateral hand to
the wall is then taken to represent the arm span. Arm span
is divided by the patient’s height to obtain the SHR. The
second and third ratios used are the hand:height ratio
(HHR) and the foot:height ratio (FHR). Hand length is
the distance between the distal palmar crease and the tip
of the middle finger; foot length is the distance between
the base of the posterior edge of the heel and the tip
of the hallux. Hand length and foot length are divided by
the patient’s height to obtain the HHR and FHR, respec-
tively. The final ratio used to determine the presence of
the marfanoid habitus is the length of the upper part of the
body to the length of the lower part of the body (upper
segment [US]:lower segment [LS] ratio; USLSR). The LS
is the distance from the midpoint of the pubic symphy-
sis to the floor with the patient standing erect. The US is
calculated by subtracting the LS from the patient’s height;
thus, USLSR = (height – LS)/LS. Based on the original data
collected by McKusick4 four decades ago, the cutoff levels
for determining the marfanoid habitus are >1.03 for SHR,
>0.11 for HHR, >0.15 for FHR and <0.89 for USLSR.
The marfanoid habitus is not exclusively defined by
these four ratios: other features of the marfanoid habitus
Key points
Arachnodactyly is a key feature of the marfanoid habitus and thus a reliable
pointer to the presence of a heritable disorder of connective tissue (HDCT)
Joint hypermobility syndrome is the most commonly seen HDCT
The differential diagnosis of arachnodactyly is wide and extends to include
many rare genetic syndromes
Incomplete forms of the marfanoid habitus are highly prevalent and can be
benign, but should lead to an assessment for the presence of an HDCT
Neither arachnodactyly nor the marfanoid habitus on its own can be regarded
as pathognomonic of Marfan syndrome in the absence of either cardiac or
ocular involvement
are dolichocephaly (skull width/length × 100 <76%),
scolio sis (Bunnell scoliometer reading >5°), pectus
de formity (excavatum or carinatum) (Figure2a), jaw
deformities with overcrowding of teeth, a high-arched
palate (Figure2b) and long feet (often with hammer toes)
that flatten and pronate on weight-bearing. The pene-
trance of these features is variable and not all features are
required to suggest the presence of the marfanoid habitus.
In a University College Hospital London cohort of 574
patients with JHS, 82 (14.3%) had complete marfanoid
habitus, and 43 (7.5%) had an incomplete form (authors’
unpublished data).
Joint hypermobility
Joint hypermobility is the most obvious and most con-
stant outward visible feature of an HDCT and its pres-
ence should always be sought. Joint hypermobility would
be expected to be present in most conditions where the
marfanoid habitus is present, but its degree varies enor-
mously both between the different conditions and within
them, and even within individual members of the same
family. Joint hypermobility is usually recorded by means
of the Beighton score,5 which gives a maximum score of
nine out of nine (Supplementary Box1). The Beighton
score tests the ability of the subject to perform a number
of manoeuvres and the score represents, perhaps sur-
prisingly, not the degree of hypermobility, but the wide-
spread nature of the condition among a selected number
of joints. A score of four or more suggests the presence of
generalized, as opposed to localized, hypermobility. It is
also valuable, however, to look at other joints for hyper-
mobility including the temporomandibular joint, cervical
spine, thoracic spine, shoulders, hips, ankles and feet.
Hyperextensible skin
Dermal collagen represents 70% of the dry weight of
skin, and skin has the advantage of being readily acces-
sible to clinical evaluation. The recognition of increased
skin stretch (hyperextensibility) can have a pivotal role
in the recognition and clinical diagnosis of an HDCT.
The texture is often described as velvety or silky and this
texture can be a striking feature. Thickness is a reliable
indicator of the quantity of collagen (or lack thereof) in
the dermis. The skinfold thickness may be measured by
means of the Harpenden caliper;6 a reduction in thickness
denotes collagen deficiency, which is a feature of several
a cb
Figure 1 | Arachnodactyly. a | Typical appearance of arachnodactyly. b | The Steinberg test for arachnodactyly. Note that the
thumb projects beyond the hypothenar aspect of the hand without assistance or effort. c | The Walker–Murdoch test for
arachnodactyly. With the thumb and little finger encircling the contralateral wrist there is obvious overlap amounting to the
length of a fingernail.
© 2013 Macmillan Publishers Limited. All rights reserved
HDCTs. Semitransparency is manifest as ‘see-through’
skin, in which the underlying veins and tendons are
more clearly visible than normal. This feature is seen in
JHS (Box1), but more so in the vascular type of Ehlers–
Danlos syndrome (EDS–vascular type; formerly known
as EDS typeIV).
Hyperextensible skin is arguably the most consistently
reliable physical sign discriminating an HDCT from nor-
mality. In the authors’ view, the test is best performed by
raising a fold of skin overlying the third and fourth meta-
carpals of the right hand between the examiner’s thumb
and index finger and carefully observing the pattern of
stretching. In patients with an HDCT the initial stretch-
ing is seen to extend across the whole of the dorsum
of the hand and beyond. The difference in the process of
stretching between a patient with an HDCT (particularly
EDS) and one without lies in the degree of stretch that
takes place in the phase of ‘taking up slack, the first phase
of skin stretch on the stress–strain curve (Figure3); it is
greater in the former.7, 8
Striae atrophicae are stretch marks that appear during
the adolescent growth spurt. They usually appear over the
lumbosacral, thigh, knee and shoulder regions, generally
between the ages of 11 and 13years. Their appearance is
suggestive of an HDCT, and striae atrophicae are found
notably, but not exclusively, in patients with JHS.
Impaired scar formation is another manifestation of
collagen deficiency. Scars are usually pale, thin, shiny,
easily-puckered and sunken below the level of sur-
rounding skin. Such characteristic scars provide further
ev idence of the possible presence of an HDCT.
HDCTs exhibiting arachnodactyly
MFS, EDS and JHS should all be considered as possible
diagnoses when arachnodactyly is observed. A working
knowledge of the classification criteria for MFS, EDS and
JHS is important in proffering a clinical diagnosis. The
criteria for each of these diseases—the revised Ghent,9
Villefranche,10 and Brighton11 criteria, respectively—
can distinguish between the different common types of
HDCTs associated with arachno dactyly and the marfa-
noid habitus that might present to the clinician (Boxes1,
2 and 3, Table1).12
Marfan syndrome
For the clinician confronted with a patient with arachno-
dactyly or the marfanoid habitus, the first consideration
should be whether or not the patient is likely to have true
MFS—a disease that carries a considerable risk of develop-
ing a potentially fatal progressive aortic root dilatation
leading to dissection or rupture, or both. However, MFS
cannot be diagnosed in the presence of arachnodactyly
and the marfanoid habitus alone.
The classification of MFS has been refined from the
established Ghent 1996 criteria,13 which defined a set
of major and minor manifestations in the presence or
absence of an associated mutation in the gene encoding
fibrillin-1 (FBN1) or a family history of MFS. Several
conditions share certain Marfan-like (marfanoid) mani-
festations, creating the risk of inadvertent erroneous
classification as MFS. The 2010 revised Ghent criteria9
(Box2) emphasize aortic root disease (dilatation and dis-
section) and ectopia lentis (lens dislocation) as cardinal
a b
Figure 2 | Selected features of the marfanoid habitus. a | Pectus excavatum with
furrowed ribs. b | High-arched palate.
Figure 3 | Increased skin stretch in a patient with
Ehlers–Danlos syndrome during phase of taking up slack.
The identification of skin hyperextensibility by clinical
investigation can be essential to the diagnosis of heritable
disorders of connective tissues.
Box 1 | Revised Brighton 1998 criteria for joint hypermobility syndrome11
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 suffice
where there is an unequivocally affected first-degree relative. Joint hypermobility
syndrome is excluded by the presence of Marfan syndrome or EDS (other than
EDS–hypermobility type [formerly known as EDS type III]) as defined by the Ghent
199613 and the Villefranche 199710 criteria, respectively. The first major and
minor criteria are mutually exclusive, as are the second major and minor criteria.
Major criteria
Beighton score* of four or more (out of nine), either currently or historically
Arthralgia of duration >3months in four or more joints
Minor criteria
Beighton score* of 1–3 (or 0–3 if patient is age ≥50 years)
Arthralgia (duration >3months) in one to three joints or back pain (duration
>3months), spondylosis or spondylolisthesis
Dislocation or subluxation in more than one joint, or in one joint on more than
one occasion
Soft tissue rheumatism with more than three lesions (e.g. epicondylitis,
tenosynovitis or bursitis)
Marfanoid habitus, features of which include: tall, slim build; span:height ratio
>1.03; upper segment:lower segment ratio <0.89; arachnodactyly (positive
Steinberg and Walker–Murdoch signs)
Abnormal skin: striae, hyperextensibility, thin skin or papyraceous scarring
Eye signs: drooping eyelids, myopia or antimongoloid slant
Varicose veins, hernia or uterine or rectal prolapse
*The nine-point Beighton hypermobility score5 is detailed in Supplementary Box 1.
Abbreviation: EDS, Ehlers–Danlos syndrome. Adapted with permission from Hypermobility,
Fibromyalgia and Chronic Pain (Eds Hakim, A., Keer, R. & Grahame, R.) Elsevier 2010.
© 2013 Macmillan Publishers Limited. All rights reserved
features of MFS; FBN1 mutations and systemic features
(Box3) also contribute to this diagnosis.
Cardiovascular complications of MFS and MFS-like
conditions can be life-threatening. Mitral valve pro-
lapse is a common feature of MFS (and some of the
rarer genetic HDCT variants), but is less common in
patients with EDS or JHS. Mitral valve prolapse can
present as atypical chest pain or symptoms suggestive
of extra or dropped beats and palpitations. Spontaneous
pneumothorax also occurs in patients with MFS but
rarely occurs in patients with EDS or JHS.
The possible presence of these pathologies should be
investigated with echocardiography, Doppler ultrasound
of the abdominal vasculature and, if there is a risk of
aortic dissection or dilation, CT angiography or mag-
netic resonance angiography of the aortic root, arch
and thoracic aorta. Annual echocardiography should be
performed, not only to exclude ‘emergent’ new patholo-
gies but also to assess known aortic dilatation and mitral
valve prolapse in MFS as both are progressive; in indivi-
duals with MFS with normal aortic diameter repeat
imaging is advisable every 2–3years. The threshold for
detailed imaging with magnetic resonance angiography
and preparation for surgical intervention is an aortic
diameter ≥4.5 cm, annual increases in aorta diameter
>0.5 cm, or a diameter at the sinus of Valsalva ≥5.0 cm,
with or without aortic valve dysfunction.
Joint hypermobility and EDS
EDS is a subfamily within the HDCTs. Several types
of EDS have been differentiated based on clinical, bio-
chemical and molecular or genetic differences. They
range from the benign ‘hypermobile’ type at one end of
the spectrum to the life-threatening ‘vascular type’ at the
other (Table1).
Many experts, the authors included, consider EDS–
hypermobility type (formerly known as EDS type III)
to be the same as JHS.14 As in JHS, therefore, the mar-
fanoid habitus is considered to be a common finding
in EDS–hypermobility type; however, the marfanoid
habitus is much less common in the other, rarer forms
of EDS. JHS is a common yet often overlooked15 condi-
tion that can manifest many physical features of HDCT.
JHS is diagnosed using the Brighton criteria (Box1).11
In addition to the signs and symptoms shown in Box1,
JHS is associated with complex systemic symptoms such
as fatigue, autonomic dysfunction, gastrointestinal dys-
motility, anxiety and phobic disorders.16–18 Although
JHS can present with considerable morbidity and signs
that overlap with other HDCTs, it is not associated with
the life-threatening vascular or ocular pathologies of
MFS, or with the more severe skin, vascular and dental
pathologies of the more rare forms of EDS.
The classification tables for EDS, MFS and JHS provide
a concise source of information upon which to build a
clinical history and physical assessment when manag-
ing patients with hypermobility (Boxes1 and 2, Table1).
From this information we have developed a ‘decision tree
that outlines investigations that should be performed to
differentially diagnose these disorders (Figure4).19
With respect to cardiovascular complications, in
EDS–vascular type there is an increased risk of rupture—
possibly concurrent with dilatation or dissection—of
medium-sized vessels such as renal and splenic arteries.
Other variants of EDS and JHS are not associated with
arterial disease. Mitral valve prolapse is rare in patients
with EDS and JHS and is usually a chance finding of
limited clinical relevance. Spontaneous pneumothorax
rarely occurs in patients with EDS or JHS.
Box 3 | Scoring* of systemic features of Marfan syndrome9
One point is given for each of the following eight features:
The presence of at least three of the following five facial features:
dolichocephaly, enophthalmus, downslanting palpebral fissures, malar
hypoplasia and retrognathia
Reduced elbow extension
Pectus excavatum or chest asymmetry (excluding carinatum, which scores two
points, as below)
Reduced upper segment:lower segment ratio and increased arm span:height
ratio in the absence of severe scoliosis
Scoliosis or thoracolumbar kyphosis
Skin striae
Mitral valve prolapse
Myopia >3 dioptres
Two points are given for each of the following five features:
Pectus carinatum
Dural ectasia
Protrusio acetabulae
Hind foot deformity (one point only is given if plain flat foot [pes planus] )
Three points are given for:
Positive Steinberg sign and Walker–Murdoch sign (one point is given if only one
of the two signs is present)
*Maximum score is 20. A score ≥7 is indicative of Marfan syndrome. Permission obtained
from BMJ Publishing Group. Loeys, B.L. etal. J.Med. Genet. 47, 476–485 (2010).
Box 2 | Revised Ghent criteria (2010) for the diagnosis of Marfan syndrome9
In the absence of a family history of Marfan syndrome, a diagnosis is made in the
presence of one of four situations:
Aortic root Z-score* ≥2 (or dissection) AND ectopia lentis, irrespective of
systemic features except where these are indicative of other conditions
Aortic root Z-score* ≥2 (or dissection) AND systemic features score§ ≥7 except
where these are indicative of other conditions
Aortic root Z-score* ≥2 (or dissection) AND a recognized FBN1 mutation
(or definite linkage to a predisposing FBN1 haplotype)
Ectopia lentis AND FBN1 mutation unequivocally associated with aortic
disease; aortic root dilatation or dissection may be absent at the time
of assessment
With a family history of Marfan syndrome (defined by any of the above), a
diagnosis is made in the presence of one of three situations:
Ectopia lentis
Systemic features score§ 7 except where these features are indicative of
other conditions
Aortic root Z-score* ≥2 (or dissection) in an individual age ≥20years, or aortic
root Z-score* ≥3 (or dissection) if age <20years
*Z-score is a measure of the aortic root (sinus of Valsalva) diameter standardized for age and
body size. The following conditions should be excluded: vascular Ehlers–Danlos syndrome,
Shprintzen–Goldberg syndrome (FBN1 mutation, craniosynostosis and mental retardation) and
Loeys–Dietz syndrome (TGFBR1 or TGFBR2 mutations, bifid uvula, cleft palate,
craniosynostosis, hypertelorism, cervical spine instability, thin velvety skin, easy bruising and
arterial tortuosity and aneur ysms). §Scoring of systemic features of Marfan syndrome is
detailed in Box1. Abbreviations: FBN1, fibrillin 1; TGFBR1, transforming growth factor β
receptor 1; TGFBR2, transforming growth factor β receptor 2. Permission obtained from BMJ
Publishing Group. Loeys, B.L. etal. J.Med. Genet. 47, 476–485 (2010).
© 2013 Macmillan Publishers Limited. All rights reserved
Rare genetic syndromes
The marfanoid habitus forms an important common
feature in a number of recently described, though seem-
ingly unrelated, rare genetic syndromes. These syn-
dromes form part of the greater family of HDCTs, and
their discovery provided much of the reasoning behind
the 2010 revision of the Ghent Criteria.9
Two syndromes, homocystinuria20 and ec topia
lentis syndrome (ELS),21 have both marfanoid features
and ectopia lentis. ELS is associated with mutations in
FBN1 and ADAMTSL4. Patients with ELS do not have
aortic root disease and can therefore be distinguished
from patients with either MFS or homocystinuria.
Homocystinuria is an autosomal recessive defect in
methionine metabolism caused by a deficiency in cys-
tathionine β-synthase. This metabolic defect is also
associ ated with a deficiency in methylenetetrahydrofolate
reductase that can be assessed by measuring methio-
nine synthesis. Patients often present with nephro-
lithiasis. Characteristic features of homocystinuria
include arachnodactyly, ectopia lentis and myopia.
How ever, the vascular pathology for patients with homo-
cystinuria is thromboembolism, rather than dilatation
or dissection as seen in MFS. Mental retardation is also
a prominent feature of homocystinuria. The condition
is confirmed by finding homocystine in the serum and
urine. Homocystinuria is treated by oral administration
of vitamin B6 (pyridoxine) and a low-methionine diet.
Three syndromes have features of the marfanoid
habitus as well as some of the cardiovascular features
seen in MFS. Loeys–Dietz syndrome (familial aortic
dissection) is an autosomal dominant genetic syn-
drome, similar to Marfan syndrome, and is caused
by mutations in the genes encoding TGF-β recep-
tor type-1 or type-2 (TGFBR1 and TGFBR2, respec-
tively).22,23 Patients with Loeys–Dietz syndrome
frequently have aggressive arterial aneurysms (mean
age at death=26.1years).24 Characteristic craniofacial
features include ocular hypertelorism, bifid uvula, cleft
palate and craniosynostosis.
Table 1 | Classification of Ehlers–Danlos syndromes by the 1997 Villefranche nosology10
Type (old
classification in
Clinical manifestations IP Protein affected
(% of cases with
protein abnormality)
Major criteria Minor criteria
Classic (typeI or II) Skin hyperextensibility
Widened atrophic scarring
Joint hypermobility
Easy bruising
Smooth and velvety skin
Molluscoid pseudotumors
Subcutaneous spheroids
Muscular hypotonia
Complications of joint
Surgical complications
Positive family history
AD Type V procollagen
Generalized joint
Mild skin involvement
Recurring joint dislocations
Chronic joint pain
Positive family history
AD Tenascin-X (~5%) TNXB
Vascular (typeIV) Excessive bruising
Thin, translucent skin
Arterial, intestinal or uterine
fragility or rupture
Characteristic facial
Early-onset varicose veins
Hypermobility of small joints
Tendon and muscle rupture
Arteriovenous or carotid-cavernous
sinus stula
Pneumo (hemo)thorax
Positive family history, sudden
death in close relative(s)
AD TypeIII procollagen COL3A1
Severe muscular hypotonia
at birth
Generalized joint laxity
Kyphoscoliosis at birth
Scleral fragility and rupture
of the ocular globe
Tissue fragility, including
atrophic scars
Easy bruising
Arterial rupture
Marfanoid habitus
AR Lysyl hydroxylase 1
(type VIA)
D4ST (type VIB)
(typeVIIA or VIIB)
Severe generalized joint
hypermobility with recurrent
Congenital bilateral hip
Skin hyperextensibility
Tissue fragility, including
atrophic scars
Easy bruising
Muscular hypotonia
Mild osteopenia
AD TypeI procollagen COL1A1
Severe skin fragility
Sagging, redundant skin
Excessive bruising
Soft, doughy skin texture
Premature rupture of membranes
Large herniae
AR Procollagen I
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; IP, inheritance patter n. Reproduced from Hypermobility, Fibromyalgia and Chronic Pain
(Eds Hakim. A., Keer, R. & Grahame, R.) Elsevier 2010 with permission.
© 2013 Macmillan Publishers Limited. All rights reserved
MASS phenotype25,26 is a connective tissue disorder
named anachronistically after the clinical characteristics
seen: mitral valve prolapse, myopia, borderline and non-
progressive aortic enlargement and skin and skeletal sys-
temic features scoring ≥5 as defined in Box3 and at least
one skeletal feature. MASS phenotype is associated with
mutations in FBN1; notably, patients with MASS do not
have ectopia lentis. Mitral valve prolapse syndrome shares
many of the characteristic features of MASS; patients
with mitral valve prolapse syndrome27 carry mutations
in FBN1 and do not have ectopia lentis. MASS and mitral
valve prolapse syndrome can be distinguished by the mild
aortic root dilatation (Z-score <2) seen in patients with
mitral valve prolapse syndrome and by the extent of the
marfanoid features. Patients with mitral valve prolapse
syndrome usually have a systemic features score of <5
whereas patients with MASS have a score of ≥5.
A number of syndromes have features of the marfa-
noid habitus, but have neither ectopia lentis nor any of
the cardiovascular features associated with MFS. Some of
these syndromes have characteristic skeletal morpholo-
gies. In Shprintzen–Goldberg syndrome, cranio synostosis
is associated with severe exophthalmos, maxillary and
mandibular hypoplasia, soft tissue hypertrophy of
the palatal shelves, low-set ears with soft and pliable
au ricles, multiple abdominal hernias, arachnodactyly
and camptodactyly (fixed flexion deformity of the inter-
phalangeal joints of the little finger).28 No FBN1 or
TGFBR1 or TGFBR2 mutations have been found in
patients with Shprintzen–Goldberg syndrome. Van
Den Ende–Gupta syndrome29 (craniofacial and skeletal
manifestations with arachnodactyly) is an extremely rare
autosomal recessive disorder characterized by distinc-
tive craniofacial features, which include blepharophimo-
sis, malar hypopoplasia, maxillary hypoplasia, a narrow
and beaked nose and an everted lower lip. Other features
are arachnodactyly, camptodactyly, peculiar skeletal
abnormalities and normal development and intelligence.
Patients with Beals–Hecht syndrome (congenital contrac-
tural arachnodactyly)30,31 have marfanoid features with
joint contractures associated with mutation in the gene
encoding fibrillin-2 (FBN2).
Patients presenting with mental retardation and the
marfanoid habitus might have Lujan–Fryns syndrome.
This X-linked syndrome is also associated with psycho-
pathology with behavioural abnormalities. Lujan– Fryns
syndrome has been attributed to a missense mutation
in the gene encoding mediator of RNA polymerase II
transcription subunit 12 (MED12).32 This syndrome is
not associated with ectopia lentis or any of the cardio-
vascular features seen in MFS apart from a single case
report involving aortic root dilatation.32
Skin hyperextensibility
Joint hypermobility
Delayed wound healing
Atrophic scarring
Easy bruising
Congentital dislocation of the
Vascular fragility
Marfanoid habitus
Ectopia lentis
Aortic dilatation or dissection
Mitral valve prolapse
Spontaneous pneumothorax
Evaluation for other specic signs:
Ocular pathology
Dysmophic features
Mental retardation
Marfanoid habitus
Ectopia lentis
Mitral valve prolapse
EDS? MFS? Other syndromes?
Stickler syndrome, homocystinuria,
MASS phenotype, ELS, LDS,
MVP syndrome, etc
Molecular analysis of FBN1
Vascular imaging
Radiology (e.g. spine for
Protein chemisty of collagen
type I, III, V
Molecular analysis of COL1A1,
Radiology (e.g. scoliosis, hip
Vessel imaging for
EDS–vascular type
There is no denitive test
for the diagnosis of
EDS–hypermobility type
Molecular analysis of FBN1,
Analysis for homocystine
Marfanoid habitus
Joint hypermobility
Anxiety or phobic disorders
There are no diagnostic
tests for JHS
Figure 4 | Decision tree for diagnosing patients with heritable disorders of connective tissue. Patients with arachnodactyly
can be subclassified on the basis of the presence of other features, such as joint hypermobility, marfanoid habitus, ectopia
lentis and mitral valve prolapse. These features suggest a possible diagnosis of a heritable disorder of connective tissue,
which can often be confirmed using genotyping, protein chemistry or radiology. Abbreviations: EDS, Ehlers–Danlos
syndrome; ELS, ectopia lentis syndrome; JHS, joint hypermobility syndrome; LDS, Loeys–Dietz syndrome; MASS, mitral
valve prolapse, myopia, aortic enlargement, skin and skeletal features; MFS, Marfan syndrome; MVP, mitral valve prolapse.
© 2013 Macmillan Publishers Limited. All rights reserved
Although arachnodactyly is not a typical sign of the
Stickler syndrome it is important to be aware of this
member of the HDCT family as, in particular, its ocular
presentation could easily be confused with that of MFS.
Stickler syndrome is subclassified by both ocular and
genetic findings. In most cases there are characteristic
congenital vitreous abnormalities, leading to an increased
risk of retinal detachment and haemorrhage (types I
andII); typeIII Stickler syndrome is a condition in which
the systemic features are present in the absence of ocular
pathology.33 In a recent survey by Stickler et al.,34 of 316
patients with typeI and II Stickler syndrome 95% had
ocular problems, with myopia in 90% of cases, retinal
detachment in 60% and blindness in 4%. Additionally,
90% of patients also had joint pain, usually secondary to
degenerative disease, 84% had problems with facial struc-
tures such as a flat face, cleft palate or small mandible, and
70% had some degree of hearing loss.
Arachnodactyly is an important physical sign that points
the way to the possible identification of an HDCT. It
should never be ignored or discounted until a full exami-
nation of the connective tissues has been performed and
a full clinical evaluation has been undertaken, supple-
mented by further investigations and by genetic testing
where appropriate. The differential diagnosis of arachno-
dactyly is wide-ranging and consequently should never be
regarded as being pathognomonic of Marfan syndrome.
It is hoped that with future advances in exome scan-
ning and other innovations in molecular genetics, it will
soon be possible to improve diagnostic precision by
means of genetic testing in the HDCTs. In the mean-
time, reliance must fall upon careful clinical observation
coupled with the application of existing internationally
agreed classification criteria.
Review criteria
A search for original articles published between 1953
and 2012 was performed in MEDLINE/PubMed using
the search terms “Marfan syndrome”, “Ehlers–Danlos
syndrome”, “marfanoid” and “arachnodactyly”, alone
and in various combinations. All articles identified were
English-language, full-text papers and abstracts. We
also searched the reference lists of identified articles
for further relevant papers. The reference list was last
updated in October 2012.
1. Steinberg, I. A simple screening test for the
Marfan syndrome. Am. J. Roentgenol. Radium
Ther. Nucl. Med. 97, 118–124 (1966).
2. Walker, B.A. & Murdoch, J.L. The wrist sign. A
useful physical finding in the Marfan syndrome.
Arch. Intern. Med. 126, 276–277 (1970).
3. Eldridge, R. The metacarpal index. A useful aid
in the diagnosis of the Marfan syndrome. Arch.
Intern. Med. 113, 248–254 (1964).
4. McKusick, V.A. The Marfan Syndrome. Heritable
Disorders of Connective Tissue, 4th edn 61–223
(C.V. Mosby, St Louis, 1972).
5. Beighton, P.H., Solomon, L. & Soskolne, C.
Articular mobility in an African population. Ann.
Rheum. Dis. 32, 413–417 (1973).
6. Tanner, J.M. & Whitehouse, R.H. The
Harpenden skinfold caliper. Am. J. Phys.
Anthropol. 13, 743–746 (1955).
7. Grahame, R. & Beighton, P. Physical properties
of the skin in the Ehlers–Danlos syndrome. Ann.
Rheum. Dis. 28, 246–251 (1969).
8. Farmer, A.D., Douthwaite, M.A., Gardiner, S.,
Aziz, Q. & Grahame, R. A novel in vivo skin
extensibility test for joint hypermobility.
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for the Marfan syndrome. J.Med. Genet. 47,
476–485 (2010).
10. Beighton, P., De Paepe, A., Steinmann, B.,
Tsipouras, P. & Wenstrup, R.J. Ehlers–Danlos
syndromes: revised nosology, Villefranche,
1997. Ehlers–Danlos National Foundation (USA)
and Ehlers–Danlos Support Group (UK). Am. J.
Med. Genet. 77, 31–37 (1998).
11. Grahame, R., Bird, H.A. & Child, A. The revised
(Brighton 1998) criteria for the diagnosis of
benign joint hypermobility syndrome (BJHS).
J.Rheumatol. 27, 1777–1779 (2000).
12. Beighton, P., Grahame, R. & Bird, H.A.
Hypermobility of Joints, 4th edn (Springer, London,
13. De Paepe, A., Devereux, R.B., Dietz, H.C.,
Hennekam, R.C. & Pyeritz, R.E. Revised
diagnostic criteria for the Marfan syndrome. Am.
J. Med. Genet. 62, 417–426 (1996).
14. Tinkle, B.T. et al. 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 149A, 2368–2370 (2009).
15. Ross, J. & Grahame, R. Joint hypermobility
syndrome. BMJ 342, c7167 (2011).
16. Hakim, A.J. & Grahame, R. Non-musculoskeletal
symptoms in joint hypermobility syndrome:
indirect evidence for autonomic dysfunction.
Rheumatology (Oxford) 43, 1194–1195 (2004).
17. Zarate-Lopez, N. et al. Unexplained
gastrointestinal symptoms and joint hypermobility:
is connective tissue the missing link?
Neurogastroenterol. Motil. 22, 252–262 (2010).
18. Bulbena, A. et al. Anxiety disorders in the joint
hypermobility syndrome. Psychiatry Res. 46,
59–68 (1993).
19. Malfait, F., Hakim, A.J., De Paepe, A. &
Grahame, R. The genetics of joint hypermobility
syndrome. Rheumatology (Oxford) 45, 502–507
20. Homocystinuria due to cystathionine β-synthase
deficiency. Online Mendelian Inheritance in Man
[online], (2012).
21. Familial ectopia lentis. National Marfan
Foundation [online],
marfan/2346/Familial-Ectopia-Lentis (2012).
22. Loeys, B.L. et al. Aneurysm syndromes caused
by mutations in the TGF-β receptor. N. Engl. J.
Med. 355, 788–789 (2006).
23. Van Hemelrijk, C. Renard, M. & Loeys, B. The
Loeys–Dietz syndrome: an update for the clinician.
Curr. Opin. Cardiol. 25, 546–551 (2010).
24. Loeys, B.L. & Dietz, H.C. Loeys–Dietz
syndrome. In: GeneReviews™ (eds
Pagon,R.A.et al.) [online], http://www.ncbi. (2012).
25. MASS phenotype. National Marfan Foundation
MASS-Phenotype (2012).
26. Glesby, M.J. & Pyeritz, R.E. Association of mitral
valve prolapse and systemic abnormalities of
connective tissue. A phenotypic continuum.
JAMA 262, 523–528 (1989).
27. Familial mitral valve prolapse. Online Mendelian
Inheritance in Man [online],
entry/157700 (2012).
28. Greally, M.T. et al. Shprintzen–Goldberg
syndrome: a clinical analysis. Am. J.Med. Genet.
76, 202–12 (1998).
29. Van den Ende–Gupta syndrome. Online
Mendelian Inheritance in Man [online], http://
syndrome%20den (2012).
30. Putnam, E.A., Zhang, H., Ramirez, F. &
Milewicz,D.M. Fibrillin-2 (FBN2) mutations result
in the Marfan-like disorder, congenital contractural
arachnodactyly. Nat. Genet. 11, 456–458 (1995).
31. Callewaert, B.L. et al. Comprehensive clinical
and molecular assessment of 32 probands with
congenital contractural arachnodactyly: report of
14 novel mutations and review of the literature.
Hum. Mutat. 30, 334–341 (2009).
32. Van Buggenhout, G. & Fryns, J.P. Lujan–Fryns
syndrome (mental retardation, X-linked, marfanoid
habitus). Orphanet J. Rare Dis. 1, 26 (2006).
33. Rose, P.S. et al. Stickler syndrome: clinical
characteristics and diagnostic criteria. Am. J.
Med. Gen. A 138, 199–207 (2005).
34. Stickler, G.B., Hughes, W. & Houchin, P. Clinical
features of hereditary arthro-ophthalmopathy
(Stickler syndrome): a survey. Genet. Med. 3,
192–196 (2001).
The authors would like to thank their patients whose
photographs have been used in this article.
Author contributions
R. Grahame and A.J. Hakim made substantial
contributions to discussions of content and review/
editing of the manuscript before submission, and
R.Grahame researched data for the article and wrote
the article.
Supplementary information is linked to the online
version of the paper at
© 2013 Macmillan Publishers Limited. All rights reserved
... 5). Также среди 13-14-летних было больше подростков с арахнодактилией, а с гипермобильностью Таблица 2. Клиническая характеристика групп подростков, включенных в исследование (собственные данные) ,7) 68 (14,8) 2,3 (1,9) Плоскостопие 126 (16,8) 46 (10,0) 1,7 (1,31) Вегетососудистая дистония 101 (13,5) 33 (7,2) 1,9 (1,29-2,74) Миопия 146 (19,5) 54 (11,7) 1,7 (1,22) Заболевания органов пищеварения 229 (30,5) 104 (22,6) 1,4 (1,11-1,65) Дискинезия желчевыводящих путей 110 (14,7) 38 (8,2) 1,8 (1,25-2,53) Частые острые респираторные вирусные инфекции 104 (13,9) 43 (9,3) 1,5 (1,06-2,08) ...
... 5). Также среди 13-14-летних было больше подростков с арахнодактилией, а с гипермобильностью Таблица 2. Клиническая характеристика групп подростков, включенных в исследование (собственные данные) ,7) 68 (14,8) 2,3 (1,9) Плоскостопие 126 (16,8) 46 (10,0) 1,7 (1,31) Вегетососудистая дистония 101 (13,5) 33 (7,2) 1,9 (1,29-2,74) Миопия 146 (19,5) 54 (11,7) 1,7 (1,22) Заболевания органов пищеварения 229 (30,5) 104 (22,6) 1,4 (1,11-1,65) Дискинезия желчевыводящих путей 110 (14,7) 38 (8,2) 1,8 (1,25-2,53) Частые острые респираторные вирусные инфекции 104 (13,9) 43 (9,3) 1,5 (1,06-2,08) ...
... В ходе исследования обнаружено, что арахнодактилия характерна для подростков 13-14 лет. Высокая частота встречаемости арахнодактилии у подростков в старшем возрасте представляется закономерной, так как многие авторы называют данный маркер ключевым элементом в диагностике наследственных нарушений соединительной ткани [13]. ...
Full-text available
Early detection of the connective tissue dysplasia (CTD) is hampered as the used diagnostic criteria are complex and subjective. The aim of the study is to examine the incidence and clinical profile of the adolescent CTD by means of the screening checklist. Methods. The study included the pupils at the age of 10–14 years. The questionnaire designed to reveal the 7 CTD’s signs (thin skin, skin hyperelasticity, keloid cicatrix, blue sclera, soft auricles, arachnodactylia, joints hypermobility), containing 12 illustrated questions with explanation for the parents, was performed as a screening method. The conditionally healthy group (the absence of CTD) consisted of the adolescents with below 12 points total and CTD group was presented by the adolescents with 13 and more points. The physical development was appreciated according to the centile tables, Quetelet index and Vargui index. The health status analysis was based on the out-patient medical records. Results. 1560 pupils were the participants of the study: 752 boys (48.2%) and 808 girls (51.8%). CTD signs were observed in 965 (61.9%) children. The adolescents with CTD’s signs demonstrated the following characters more often than the adolescents without CTD’s signs: soft auricles — 788 (81.7%) against 277 (46.6%), skin hyperelasticity — 685 (71%) against 93 (15.6%), joints hypermobility — 665 (68.9%) against 203 (34.1%), blue sclera — 665 (68.9%) against 184 (30.9%), arachnodactylia — 534 (55.3%) against 57 (9.6%). The disharmonious physical development because of the underweight body took place in 430 (52.3%) adolescents with CTD. Compared to the conditionally healthy group the most of the adolescents with CTD had the pathology of the musculoskeletal system (scoliosis, flatfoot), myopia, vegetative-vascular dystonia, digestive apparatus diseases. The CTD is associated with greater probability of the development of above mentioned pathologies, that can be indicative of the contribution of the anomalies of the connective tissue development into the etiopathogenesis of the these diseases. Conclusion. It is established that there is the high prevalence of the CTD signs among the adolescents (pupils) at the age of 10–14 years.
... Marfanoid features are present in several heritable disorders of connective tissue, mimicking some of the changes of Marfan syndrome but not accompanied by luxation of lens, and aneurysm of aorta. Incomplete forms of the marfanoid habitus are commonplace and likely to be benign; however, their presence should trigger an assessment for another feature of heritable disorders of connective tissue (6). ...
... The marfanoid habitus is an important common feature in a number of genetically heritable disorders of connective tissue syndromes and isn't pathognomonic of MS (6). Current Ghent and marfanoid habitus criteria (6,7) allow to distinguishing MS patient from marfanoid habitus patients in our study with high sensitivity and specificity. ...
... The marfanoid habitus is an important common feature in a number of genetically heritable disorders of connective tissue syndromes and isn't pathognomonic of MS (6). Current Ghent and marfanoid habitus criteria (6,7) allow to distinguishing MS patient from marfanoid habitus patients in our study with high sensitivity and specificity. The most important finding of the present investigation was that the early contractile injury seen in marfanoid habitus patients with normal global contractile function is regionally distributed in the LV septum and inferior wall. ...
... The weight given to deformities of the hands and feet when calculating the systemic score for MFS reflects the importance of these features as a part of the phenotype; in total, 5 points can be scored if all the characteristic signs are observed. In the hand, the wrist and thumb signs complement each other, scoring 3 points when present concurrently, or 1 point if only one is found [5,6]. In the foot, 2 points are awarded for a hindfoot deformity, specifically "hindfoot valgus in combination with forefoot abduction and lowering of the midfoot", whilst simple pes planus (flatfoot), considered to be relatively common among the general population, scores only 1 point. ...
... However, this ratio was found to be rather nonspecific and become obsolete following the widespread adoption of the wrist and thumb signs, which are far more convenient Fig. 2 Plain X-rays demonstrating arachnodactyly of the toes and fingers. The metacarpal index is calculated as a ratio of length and width of the metacarpals (white lines) which in this case is 9.5 to evaluate clinically and avoid unnecessary radiation exposure [6,8,9]. Arachnodactyly is often easy to spot clinically (Fig. 3A). ...
Full-text available
Purpose of Review Marfan syndrome (MFS) is an autosomal dominant heritable disorder of fibrillin-1 (FBN1) with predominantly ocular, cardiovascular, and musculoskeletal manifestations that has a population prevalence of approximately 1 in 5–10,000 (Chiu et al. Mayo Clin Proc. 89(1):34–42, 146, Dietz 3, Loeys et al. J Med Genet. 47(7):476–85, 4). Recent Findings The vascular complications of MFS still pose the greatest threat, but effective management options, such as regular cardiac monitoring and elective surgical intervention, have reduced the risk of life-threatening cardiovascular events, such as aortic dissection. Although cardiovascular morbidity and mortality remains high, these improvements in cardiovascular management have extended the life expectancy of those with MFS by perhaps 30–50 years from an estimated mean of 32 years in 1972 (Dietz 3, Gott et al. Eur J Cardio-thoracic Surg. 10(3):149–58, 147, Murdoch et al. N Engl J Med. 286(15):804–8, 148). The musculoskeletal manifestations of MFS, which to date have received less attention, can also have a significant impact on the quality of life and are likely to become more important as the age of the Marfan syndrome population increases (Hasan et al. Int J Clin Pract. 61(8):1308–1320, 127). In addition, musculoskeletal manifestations are often critically important in the diagnosis of MFS. Summary Here, we review the main clinically relevant and diagnostically useful musculoskeletal features of MFS, which together contribute to the “systemic features score” (referred to hereafter as systemic score), part of the revised Ghent nosology for MFS. We discuss current treatment strategies and highlight the need for a multidisciplinary approach to diagnosis and management. Finally, we review new pharmacological approaches that may be disease modifying and could help to improve the outcome for individuals with this syndrome.
... However, the locomotor system of the child with JH, already in the first year of life, may present characteristics that signal implications in neuropsychomotor development (17)(18)(19). Signs may include motor and cognitive deficits, benign motor delay (20), frequent falls (21)(22)(23)(24), "flying bird" hand sign, Steinberg sign, and Walker-Murdoch sign (19,(25)(26)(27). ...
Full-text available
Objectives To identify psychosocial and motor aspects related to joint hypermobility (JH) in a sample from almost all Brazilian states by age range and sex; to characterize JH by the Beighton total score ≥4, ≥5, and ≥6 according to sex and age and atypicality in the sitting position and in the hands; identify, in the total sample, manifestations of “growing pain” and its location, fatigue, attention deficit, anxiety, insomnia, drowsiness, apathy, depression, delay in walking, not crawling or crawling differently, school performance, spatial orientation and/or temporally impaired, social isolation, and being stigmatized as “lazy/clumsy/apathetic”. Methods This retrospective, observational, quantitative, and cross-sectional study used data obtained through analyses of descriptive and inferential crossings between 2012 and 2020 of 482 medical records of individuals between 1 and 76 years of age, from most Brazilian states. All patients previously diagnosed with “joint hypermobility syndrome” (JHS) and “Ehlers-Danlos syndrome hypermobility type” (EDS-HT) had their medical records reassessed, following the guidelines established in 2017. The analysis of GJH was performed using the updated method by Beighton method; atypical characteristics were investigated in the hands and the ability to sit in the “W” and the “concave” positions. The characteristics and manifestations of “growing pain” and its location were analyzed in the total sample, fatigue, insomnia, drowsiness, apathy, depression, social isolation, attention deficit, anxiety, stigmatization as “lazy,” clumsy/restless, impaired school performance, and spatial and/or temporal orientation. Descriptive and inferential statistical methods were used, such as Mean, Median, Mode, Standard Deviation, Standard Error, Maximum Value, Minimum Value, Komolgorov-Smirnov , Significance, Relative Value, Absolute Value, Mann-Whitney U , and Correlation of Spearman . Results JH in the total sample predominated in the upper limbs, the majority were women, represented by 352 (73.02%), 15 years old or older with 322 (66.80%), 312 (64.73%) had a Beighton total score ≥6, which decreased as the age increased. Always sitting in the “concave” position was represented by 54.15% and the ability to sit in the “W” position by 39.21%; signs on the hands totaled between 27.59 and 44.19% with a significant correlation between the variables. Among the characteristics, fatigue predominated, followed by an awkward/clumsy/restless individual, attention deficit, anxiety and stigmatized as “lazy,” insomnia, drowsiness, apathy, depression, impaired spatial and/or temporal orientation, and social isolation. From the total sample, pain in the lower limbs was reported by 55.81% and having or having had “growing pain” was reported by 36.93%, delay in walking occurred in 19.92%, 15.35% did not crawl or crawled differently, and for 12.86%, school performance was impaired. Higher Beighton total scores showed a trend towards motor implications and correlation between variables. Ability to still sit in the “concave” position was possible for 54.15% and to sit in the “W” position for 39.21%. Conclusion In the total sample, the JH characteristic prevails in the upper limbs of female children, adolescents and adults, with a total Beighton score ≥6. Most sit in the “concave” position and less than half also sit in the “W” position and with atypical hand postures. The higher Beighton scores, which include the upper limbs, show a tendency to not crawl or crawl differently, delayed ambulation, and impaired school performance. The predominance of JH in the upper limbs is suggestive of a justification for not crawling or crawling differently. Characteristics of atypical motor performance in hands and sitting posture, in addition to fatigue, pain since childhood, anxiety, apathy, depression, sleep disorders, stigmatization, attention deficit, spatial and/or temporal orientation impairment, and social isolation are characteristics. suggestive of psychosocial implications at different ages. Future studies with motor and psychosocial aspects of people with JH will help to identify the phenotype of this population and consequent guidance for clinical management based on the motor and psychosocial aspects of people with JH.
... Arachnodactyly, or spider fingers, is also common in Marfanoid habitus and a sign of connective tissue disorders. 93 The Steinberg sign, also known as the thumb sign, in which the thumb extends past the palm of the hand in a closed fist and Walker-Murdoch, or wrist sign, in which the thumb and fifth finger overlap around the wrist are typically used to asses arachnodactyly. The Beighton criteria was designed to be a nonsubjective measurement of joint hypermobility but is often criticized for not including other relevant joints where hypermobility may be present. ...
Full-text available
The Ehlers Danlos Syndromes (EDS) are a group of heritable, connective tissue disorders characterized by joint hypermobility, skin hyperextensibility and tissue fragility. There is phenotypic and genetic variation among the thirteen subtypes. The initial genetic findings on EDS were related to alterations in fibrillar collagen, but the elucidation of the molecular basis of many of the subtypes revealed several genes not involved in collagen biosynthesis or structure. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. hEDS is the most common type of EDS and involves generalized joint hypermobility, musculoskeletal manifestations, and mild skin involvement along with the presence of several co-morbid conditions. Variability in the spectrum and severity of symptoms and progression of patient phenotype likely depend on age, gender, lifestyle and expression domains of the EDS genes during development and postnatal life. In this review, we summarize the current molecular, genetic, epidemiologic and pathogenetic findings related to Ehlers-Danlos Syndromes with a focus on the hypermobile type. This article is protected by copyright. All rights reserved.
... The role of Marfanoid habitus was early recognized and included in the Brighton criteria [Grahame et al., 2000]. More recently, emphasis has been put on arachnodactyly as a powerful marker for heritable connective tissue disorders in the routine rheumatologic clinic [Grahame and Hakim, 2013]. Habitus is not included in the Villefranche criteria for EDS-HT and the original habitus item from the Brighton criteria does not offer any guidance on the relative weight that dolichostenomelia and arachnodactyly carry in the attribution of the criterion. ...
Full-text available
Joint hypermobility syndrome (JHS) and Ehlers–Danlos syndrome, hypermobility type (EDS–HT) are two overlapping heritable disorders (JHS/EDS–HT) recognized by separated sets of diagnostic criteria and still lack a confirmatory test. This descriptive research was aimed at better characterizing the clinical phenotype of JHS/EDS–HT with focus on available diagnostic criteria, and in order to propose novel features and assessment strategies. One hundred and eighty-nine (163 females, 26 males; age: 2–73 years) patients from two Italian reference centers were investigated for Beighton score, range of motion in 21 additional joints, rate and sites of dislocations and sprains, recurrent soft-tissue injuries, tendon and muscle ruptures, body mass index, arm span/height ratio, wrist and thumb signs, and 12 additional orthopedic features. Rough rates were compared by age, sex, and handedness with a series of parametric and non-parametric tools. Multiple correspondence analysis was carried out for possible co-segregations of features. Beighton score and hypermobility at other joints were influenced by age at diagnosis. Rate and sites of joint instability complications did not vary according to age at diagnosis except for soft-tissue injuries. No major difference was registered by sex and dominant versus non-dominant body side. At multiple correspondence analysis, selected features tend to co-segregate in a dichotomous distribution. Dolichostenomelia and arachnodactyly segregated independently. This study pointed out a more protean musculoskeletal phenotype than previously considered according to available diagnostic criteria for JHS/EDS–HT. Our findings corroborated the need for a re-thinking of JHS/EDS–HT on clinical grounds in order to find better therapeutic and research strategies.
The Marfan syndrome is inherited as an autosomal dominant trait, but there is often incomplete penetrance of the gene resulting in a variable phenotype. This variability leads to problems in diagnosis when one is faced with a tall gangly individual with minimal ocular or cardiovascular involvement. In order to confirm the clinical impression of arachnodactyly in patients with the Marfan syndrome, Steinberg1 in 1966 popularized the thumb sign, which was first described by Parker and Hare2 in 1945. This sign is elicited by having the patient make a fist over the clenched thumb. When the result is positive the thumb extends significantly beyond the ulnar margin of the hand (Fig 1). Unfortunately this sign is negative in a sufficiently high proportion of patients with the Marfan syndrome as to reduce its usefulness when used alone (Table). It is also positive in a small proportion of normal children (1.1%
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)
More than half of all patients evaluated in our clinic for the possible diagnosis of a heritable disorder of connective tissue could not be classified in the current nosology, yet they had considerable clinical evidence of a systemic defect of the extracellular matrix. As a group, these patients share many manifestations of the Marfan syndrome including long limbs, deformity of the thoracic cage, striae atrophicae, mitral valve prolapse, and mild dilatation of the aortic root. Clinical clustering did not emerge when patients were stratified by mitral valve prolapse or aortic dilatation. The clinical phenotype of patients with mitral valve prolapse constitutes a continuum, from Marfan syndrome at one extreme to isolated mitral valve prolapse due to myxomatous proliferation of the valve leaflets. In the absence of biochemical or DNA markers, discerning whether a patient with mitral valve prolapse and mild aortic root dilatation (in the absence of ectopia lentis or a family history) has Marfan syndrome, or another heritable disorder of connective tissue, will continue to be a clinical challenge. Until subclassification based on refined clinical, genetic, and laboratory investigations is possible, the patients we describe are best seen as having an "overlap" heritable connective-tissue disorder. We suggest the acronym "MASS phenotype" to emphasize involvement of the mitral valve, aorta, skeleton, and skin. (JAMA. 1989;262:523-528)
Early diagnosis of the Marfan syndrome may permit modification of the often lethal cardiovascular changes and alleviation of the more disabling ocular and musculoskeletal complications.1-3 Given the classical triad of long, thin, and loosely jointed bones, dislocation of the crystalline lens with tremulous irides, and dilatation of the ascending aorta with aortic valve insufficiency, the diagnosis of the Marfan syndrome is easily made, especially if relatives are known to have similar changes. But in cases where only equivocal features are present a firm diagnosis can be difficult, if not impossible, to make. The ocular and cardiovascular changes are highly suggestive of the Marfan syndrome; but it is the musculoskeletal involvement that most frequently brings the diagnosis to mind. Indeed, in the first cases reported, only the skeletal abnormalities were noted. Marfan, in 1896, described a five-year-old girl with unusually long, slender arms and legs whose long, thin fingers were
Categorization of the Ehlers-Danlos syndromes began in the late 1960s and was formalized in the Berlin nosology. Over time, it became apparent that the diagnostic criteria established and published in 1988 did not discriminate adequately between the different types of Ehlers-Danlos syndromes or between Ehlers-Danlos syndromes and other phenotypically related conditions. In addition, elucidation of the molecular basis of several Ehlers-Danlos syndromes has added a new dimension to the characterization of this group of disorders. We propose a revision of the classification of the Ehlers-Danlos syndromes based primarily on the cause of each type. Major and minor diagnostic criteria have been defined for each type and complemented whenever possible with laboratory findings. This simplified classification will facilitate an accurate diagnosis of the Ehlers-Danlos syndromes and contribute to the delineation of phenotypically related disorders. Am. J. Med. Genet. 77:31–37, 1998. © 1998 Wiley-Liss, Inc.
Shprintzen-Goldberg syndrome (SGS) is characterized by craniosynostosis (involving the coronal, sagittal, or lambdoid sutures), distinctive craniofacial features, skeletal changes (dolichostenomelia, arachnodactyly, camptodactyly, pes planus, pectus excavatum or carinatum, scoliosis, joint hypermobility, or contractures), neurologic abnormalities, mild-to-moderate intellectual disability, and brain anomalies (hydrocephalus, dilatation of the lateral ventricles, and Chiari 1 malformation). Cardiovascular anomalies (mitral valve prolapse, mitral regurgitation, and aortic regurgitation) may occur, but aortic root dilatation is most likely not found. Minimal subcutaneous fat, abdominal wall defects, cryptorchidism in males, and myopia are also characteristic findings. The diagnosis of SGS is suspected in individuals with characteristic clinical findings and radiographic findings showing C1-C2 abnormality, wide anterior fontanel, thin ribs, 13 pairs of ribs, square-shaped vertebral bodies, and osteopenia. The gene in which SGS-causing mutations occur is unknown. Treatment of manifestations: Surgical repair of abdominal hernias, physiotherapy for joint contractures, and placement in special education programs. Prevention of secondary complications: Subacute bacterial endocarditis (SBE) prophylaxis is recommended for dental work or other procedures for individuals with cardiac complications. Surveillance: As indicated by a cardiologist. The mode of inheritance of SGS is unknown. Familial recurrences are rare. Germline mosaicism for a new autosomal dominant mutation, autosomal recessive inheritance, or a cryptic structural abnormality of a chromosome may explain familial recurrence with unaffected parents. The risk to sibs of a proband is small, but greater than that of the general population. To date, all offspring of individuals diagnosed with Shprintzen-Goldberg syndrome have been unaffected. Prenatal diagnosis is not possible at this time.