Best Practice & Research Clinical Rheumatology
Vol. 22, No. 1, pp. 165–189, 2008
doi:10.1016/j.berh.2007.12.005
available online at http://www.sciencedirect.com
12
Ehlers-Danlos syndromes and Marfan
syndrome
Bert Callewaert
MD
Research Fellow
Fransiska Malfait
MD, PhD
Research Fellow
Bart Loeys
MD, PhD
Clinical Geneticist and Senior Researcher
Anne De Paepe *
MD, PhD
Professor and Head of Department
Ghent University Hospital, Centre for Medical Genetics, De Pintelaan 185, B-9000 Ghent, Belgium
Ehlers-Danlos syndromes (EDS) and Marfan syndrome (MFS) are multisystemic disorders that
primarily affect the soft connective tissues. Both disorders have benefited from recent advances
in clinical and molecular characterization, allowing improvements in clinical diagnosis and management. EDS are a heterogeneous group of conditions characterized by skin hyperextensibility,
atrophic scarring, joint hypermobility and generalized tissue fragility. The current classification
proposes six subtypes based on clinical, biochemical and molecular characteristics. However, examples of unclassified variants and ‘overlap phenotypes’ are becoming more common. Mutations
in genes encoding fibrillar collagens or collagen-modifying enzymes have been identified in most
forms of EDS, including the classic and vascular subtypes (collagen type V and III, respectively),
and the rare arthrochalasis, kyphoscoliosis and dermatosparaxis variants (type I collagen defects). To date, the genetic background of the hypermobility type of EDS remains unclear, although some new insights have been gained recently.
MFS is an autosomal-dominant disorder that affects the cardiovascular, ocular and skeletal
system with aortic root dilation/dissection, ectopia lentis and bone overgrowth, respectively.
Advances in therapeutic, mainly surgical, techniques have improved median survival significantly,
yet severe morbidity and a substantial risk for premature mortality remain associated. The disorder is caused by mutations in the FBN1 gene, encoding the microfibrillar protein fibrillin-1.
Recently, new insights in the pathogenesis changed the prevailing concept of this type 1
* Corresponding author. Tel.: þ32 9 332 36 03; Fax: þ32 9 332 49 70.
E-mail address: [email protected] (A. De Paepe).
1521-6942/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
166 B. Callewaert et al
fibrillinopathy as a structural disorder of the connective tissue into a developmental abnormality
manifesting perturbed cytokine signalling. These findings have opened new and unexpected
targets for aetiologically directed drug treatments.
Key words: Ehlers-Danlos syndromes; Marfan syndrome; clinical features; molecular pathogenesis; differential diagnosis; management.
EHLERS-DANLOS SYNDROMES
Introduction
Ehlers-Danlos syndromes (EDS) comprise a clinically and genetically heterogeneous
group of heritable disorders of connective tissue, of which the principal clinical features are due to varying degrees of tissue fragility of the skin, ligaments, blood vessels
and internal organs. The first classical description of the syndrome in the medical
literature is attributed to Tschernogubow, a Russian dermatologist who described it
in 1891. In 1901 and 1908, respectively, it was reported by the Danish and French dermatologists Ehlers and Danlos, and in the 1930s, the condition received its eponymous
title, and, by this, its scientific respectability. In the mid-20th Century, it was suggested
that a genetic defect in the collagen ‘wickerwork’ of the connective tissues accounted
for the phenotype, and not much later, the first genetic defect was identified as a deficiency of lysyl hydroxylase, a collagen-modifying enzyme. Soon thereafter, the clinical
and genetic heterogeneity of the syndrome became evident, and with the improvement of biochemical and molecular techniques, a range of defects in collagen proteins
and collagen-modifying enzymes were discovered in various forms of EDS. Early
diagnosis by means of biochemical and molecular testing is now feasible for most
EDS variants, and may prove important for adequate follow-up and genetic counselling.
This chapter gives an overview of the main clinical characteristics as well as an
update of the current insights in the molecular pathogenesis of EDS.
Epidemiology and criteria for diagnosis
The prevalence of EDS is estimated to be approximately one in 5000 births, with no racial
predisposition.1 However, the incidence rises with increased physician awareness.
The first attempts to classify EDS resulted in the Berlin nosology in 1986, in which
10 subtypes were recognized.2 Elucidation of the molecular basis of several types of
EDS resulted in refinement of this classification, which led to the 1997 Villefranche nosology.3 This classification recognizes six subtypes, based on clinical characteristics,
mode of inheritance, and biochemical and molecular findings. For each subtype, major
and minor clinical diagnostic criteria were defined. The most common types are the
classic, hypermobility and vascular types, while the kyphoscoliosis, arthrochalasis
and dermatosparaxis types are very rare. Over the past few years, it has become clear
that this classification remains insufficient and that many patients present with overlapping forms of EDS, which cannot be classified unambiguously into one of the six
recognized subtypes. Recent insights into the molecular and biochemical basis of
some EDS variants call for a refinement of the Villefranche classification, which will
likely improve genetic counselling of affected families.
Ehlers-Danlos syndromes and Marfan syndrome 167
Clinical characteristics
The main clinical characteristics of EDS, which are present to varying degrees in each
subtype, include skin hyperextensibility, delayed wound healing with atrophic scarring,
joint hypermobility, easy bruising, and generalized fragility of the soft connective
tissues.
Skin hyperextensibility is characteristic for all EDS subtypes, except the vascular
type. In contrast to the skin in cutis laxa syndromes, the skin of EDS patients is hyperelastic, which means that it extends easily and snaps back after release. The skin is often
very smooth and velvety to the touch. Wound healing is delayed and results in the formation of widened atrophic scars, so-called ‘cigarette-paper scars’, occurring mainly
over knees, elbows, shins, forehead and chin (Figure 1). In the vascular type, the
skin is not hyperextensible, but thin and transparent, showing the venous pattern
over the chest, abdomen and extremities.
Joint hypermobility (Figure 2) is usually generalized and can vary in severity. It is
generally assessed using the Beighton scale (Table 1). At birth, uni- or bilateral
Figure 1. Atrophic scarring on the knees in a patient with Ehlers-Danlos syndrome. On the shins, repetitive
trauma has led to haemosiderin deposition with dark and unaesthetic discolouration of the skin.
168 B. Callewaert et al
Figure 2. Joint hypermobility in Ehlers-Danlos syndrome.
dislocation of the hip may be present. Primary muscular hypotonia may result in delayed motor development. During childhood, complications are not frequent, but subluxations and dislocations may occur from young adulthood onwards, either
spontaneously or after minimal trauma. All sites can be involved, including the extremities, vertebral column, costo-vertebral and costo-sternal joints, clavicular articulations
and temporomandibular joints. Other problems related to joint hypermobility are foot
deformities such as congenital club foot or pes planus, joint effusions and premature
osteoarthritis. Some adults may suffer from chronic musculoskeletal pain, which is distinct from the pain associated with acute dislocations. The severity of the complaints is
typically greater than expected based on physical and radiological examination, and the
impact can be devastating with disruption of sleep, work, physical activities and social
relationships.
Easy bruising is a common finding in patients with EDS, and it may even be the presenting symptom in small children. It manifests as spontaneous ecchymoses, frequently
recurring in the same areas and causing a characteristic brownish discolouration of the
Table 1. Beighton scale for joint hypermobility. A total score of at least 5 defines hypermobility.
Joint/finding
Negative
Passive dorsiflexion of the 5th finger > 90
Passive flexion of thumbs to the forearm
Hyperextension of the elbows beyond 10
Hyperextension of the knees beyond 10
Forward flexion of the trunk with knees
fully extended and palms resting on the floor
0
0
0
0
0
Unilateral
1
1
1
1
Present ¼ 1
Bilateral
2
2
2
2
Ehlers-Danlos syndromes and Marfan syndrome 169
skin, especially in exposed areas such as shins and knees. There is a tendency towards
prolonged bleeding, e.g. following brushing of the teeth, in spite of a normal coagulation status.
Other manifestations of generalized tissue fragility are observed in multiple organs
and include cervical insufficiency; inguinal, umbilical or other hernias; recurrent rectal
prolapse in early childhood; and dehiscence of sutured incisions in skin or mucosa.
Structural cardiac malformations are uncommon in most EDS types, but mitral valve
prolapse and, less frequently, tricuspid valve prolapse may occur.
The vascular type of EDS deserves special attention as this condition is associated
with an increased risk of life-threatening complications and a decreased life expectancy. Patients with vascular EDS are at risk of arterial rupture which may occur spontaneously or may be preceded by aneurysm, arteriovenous fistulae or dissection.
Other complications include spontaneous rupture of the bowel, intestine or gravid
uterus. Patients with vascular EDS who are pregnant should be followed in a highrisk obstetric programme.
In addition to these general features, some EDS subtypes are characterized by
a number of clinical manifestations which are subtype specific, and which have been
defined in the major and/or minor criteria of the nosology, as outlined in Table 2.
Differential diagnosis
EDS shows limited overlap with other heritable disorders of connective tissue, which
can usually be differentiated by distinctive clinical features. EDS should be distinguished
from Marfan syndrome (MFS), the clinical and molecular features of which are discussed below. In EDS, the skin fragility is more prominent, and joint hypermobility
is usually more severe. Although patients with the kyphoscoliosis type of EDS, and occasionally patients with the hypermobility type of EDS, can present with a marfanoid
habitus, the association with ectopia lentis and/or aortic dilatation or aneurysm is
strongly suggestive for MFS.
There is considerable clinical overlap between the vascular type of EDS and LoeysDietz syndrome type 2, a recently identified aortic aneurysm syndrome that will be
discussed in more detail below and which is caused by mutations in the genes coding
for transforming growth factor-beta (TGFb) receptor 1 and 2 (TGFBR1 or TGFBR2).4
The hyperextensible skin in EDS should be distinguished from the skin laxity observed in cutis laxa and De Barsy syndromes, in which the redundant skin hangs in
loose folds and only returns very slowly to its former position. In these syndromes,
the skin is not fragile and wound healing is normal.
EDS should also be distinguished from occipital horn syndrome (OHS), characterized by the presence of ‘occipital horns’; distinctive wedge-shaped calcifications at the
sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the
occipital bone. Occipital horns may be clinically palpable or observed on skull radiographs. Individuals with OHS also have lax skin and joints, bladder diverticulae, inguinal
hernias and vascular tortuosity. There is no easy bruising or fragility of the skin. The
serum concentrations of copper and ceruloplasmin are low. This X-linked condition is
allelic with Menkes disease and is caused by mutations in a copper transporter protein
encoded by ATP7A.5
Joint hypermobility may be the presenting feature in some other rare genetic conditions, such as pseudo-achondroplasia or Larsen syndrome, which present with other
distinctive symptoms, and in which the typical EDS skin features are absent. Distal joint
Clinical subtype
Clinical manifestations
Gene defect
Protein defect
Laboratory diagnosis
Functional deficiency
of type V procollagen
COL5A1 null allele test
Sequence analysis of
COL5A1/A2
Cardinal features
Additional features
Skin hyperextensibility
Widened atrophic
scarring
Smooth and velvety
skin
Joint hypermobility
Easy bruising
Molluscoid
pseudotumours
Subcutaneous
spheroids
Muscular hypotonia
Complications of
joint hypermobility
Surgical complications
Positive family history
COL5A1 nonfunctional allele
Mutation (mis-sense,
exon-deletion) in
COL5A1 or COL5A2
Unknown
‘Classic-like’ (AR)
Skin hyperextensibility
Easy bruising
Joint hypermobility
Smooth and velvety
skin
Complications of
joint hypermobility
Homozygous or
compound heterozygous
mutations in TNX-B
Complete deficiency
of tenascin-X
Sequence analysis of
TNX-B
Hypermobility (AD)
Generalized joint
hypermobility
Mild skin involvement
(mild skin
hyperextensibility, mild
atrophic scarring,
soft skin)
Recurring joint
dislocations
Chronic joint pain
Positive family
history
TNX-B non-functional
allele
Mis-sense mutation in
TNX-B
Synthesis of about
one-half the amount
of normal tenascin-X
Structural alteration
of tenascin-X
Functional deficiency
of type V procollagen
TNX-B null allele test
Sequence analysis
of TNX-B
Classic (AD)
COL5A1 non-functional
allele
Unknown
One locus on
chromosome 8p21
Unknown
Unknown
COL5A1 null allele test
Sequence analysis of
COL5A1/A2
170 B. Callewaert et al
Table 2. Updated Ehlers-Danlos syndrome (EDS) nosology. The presence of more than one cardinal feature is highly suggestive for the diagnosis of a specific subtype
of EDS, while the additional features contribute to the diagnosis of the specific subtype.
Excessive bruising
Thin, translucent skin
Arterial/intestinal/
uterine fragility
or rupture
Characteristic facial
appearance
Acrogeria
Early-onset varicose
veins
Hypermobility
of small joints
Tendon and muscle
rupture
Arteriovenous or
carotid-cavernous
sinus fistula
Pneumo(haemo)thorax
Positive family history,
sudden death in close
relative(s)
COL3A1 mutation
COL3A1 non-functional
allele
Structural alteration
of type III collagen
Synthesis of about
one-half the amount
of normal type III
procollagen
Biochemical analysis
of type III collagen
by SDS-PAGE
COL3A1 null allele test
Sequence analysis
of COL3A1
‘Vascular-like’ (AD)
Thin, translucent skin
Joint hypermobility
Complications of
joint hypermobility
Positive family
history
COL1A1 mis-sense
mutation
R134C substitution
in a1(I) triple helical
domain
Biochemical analysis
of type I collagen by
SDS-PAGE
Sequence analysis
of COL1A1
COL1A1 mis-sense
mutation
R-to-C substitutions
in a1(I) triple helical
domain
Biochemical analysis
of type I collagen by
SDS-PAGE
Sequence analysis
of COL1A1
Homozygous or
compound heterozygous
mutations in COL1A2
Complete deficiency
of (pro)a2(I) collagen
chain
Biochemical analysis
of type I collagen by
SDS-PAGE
Sequence analysis
of COL1A2
Skin hyperextensibility
Atrophic scarring
Easy bruising
Arterial rupture
Osteopenia
Arterial rupture
‘Cardiac valvular’
(AR)
Severe cardiac valvular
disease
Skin hyperextensibility
Joint hypermobility
Atrophic scarring
Easy bruising
Blue sclerae
Increased bone
fragility
(continued on next page)
Ehlers-Danlos syndromes and Marfan syndrome 171
Vascular (AD)
Clinical subtype
Clinical manifestations
Gene defect
Protein defect
Laboratory diagnosis
HPLC
Measurement of lysyl
hydroxylase-1 activity
Sequence analysis
of PLOD1 gene
/
Cardinal features
Additional features
Severe muscular
hypotonia at birth
Generalized joint laxity
Kyphoscoliosis at birth
Scleral fragility and
rupture of the globe
Tissue fragility,
including atrophic
scars
Easy bruising
Arterial rupture
Marfanoid habitus
Microcornea
Osteopenia
Homozygous or
compound heterozygous
mutations in LH-1
(PLOD1)
Deficiency of
lysyl hydroxylase-1
Unknown
Unknown
EDS/OI overlap
syndrome (AD)
Easy bruising
Recurring joint
dislocations
Kyphoscoliosis
Chronic joint pain
Arterial rupture
Positive family
history
Mutation (exon-deletion,
mis-sense) in COL1A1 or
COL1A2 encoding the
most
amino-terminal part (w
first 80e100 amino acids)
of type I collagen triple
helical domain
Structural alteration
of type I collagen
N-anchor region,
leading to delayed
procollagen-Nproteinase processing
Biochemical analysis
of type I collagen by
SDS-PAGE
Sequence analysis
of COL1A1/A2
Arthrochalasis (AD)
Severe generalized
joint hypermobility with
recurrent subluxations
Congenital bilateral
hip dislocation
Skin hyperextensibility
Widened, atrophic
scars
Mutation leading to
deletion of exon 6 of
COL1A1 or COL1A2
Loss of procollagen
-N-proteinase cleavage
site on either proa1(I)
or proa2(I) collagen
chain
Biochemical analysis
of type I collagen by
SDS-PAGE
Detection of skipping
of exon 6 in COL1A1/
A2 by sequence analysis
Kyphoscoliotic
(AR)
Joint hypermobility
Mild skin involvement
Blue sclerae
Increased bone fragility
Easy bruising
Muscular hypotonia
Kyphoscoliosis
Mild osteopenia
172 B. Callewaert et al
Table 2 (continued)
Dermatosparaxis
(AR)
Soft, doughy
skin texture
Premature
rupture of
membranes
Progressive cigarettepaper scar formation
Progressive generalized
joint hypermobility,
delayed gross motor
development
Increased palmar
wrinkling
Bladder rupture
Rupture of diaphragm
ADAMTS-2
ProcollagenN-proteinase
Biochemical analysis of
type I collagen by SDSPAGE
Sequence analysis
of ADAMTS-2 gene
IP, inheritance pattern; AD, autosomal dominant; AR, autosomal recessive; PLOD 1, procollagen-lysine 2-oxoglutarate 5 dioxygenase-1 (lysyl hydroxylase-1);
OI, osteogenesis imperfecta; HPLC, high-performance liquid chromatography; SDS-PAGE: sodium-dodecyl polyacrylamide gele electrophoresis.
Ehlers-Danlos syndromes and Marfan syndrome 173
Severe skin
fragility
Sagging, redundant
skin
Excessive bruising
Characteristic facies
(oedema of eyelids,
downslanting palpebral
fissures, epicanthic
folds, blue sclerae,
gingival hyperplasia,
micrognathia)
Postnatal growth
deficiency, short
hands and feet
Umbilical hernia
Delayed closure
of fontanelles
174 B. Callewaert et al
hyperextensibility in combination with proximal contractures and generalized muscle
weakness is the hallmark of severe congenital muscular dystrophy, known as Ullrich
disease or scleroatonic muscular dystrophy.6 The finding of excessive distal joint laxity
is striking and often raises EDS as a diagnostic consideration. This condition, which can
be inherited autosomal dominantly or recessively, results from mutations in the genes
encoding type VI collagen.7–9
Molecular pathogenesis
EDS is extremely heterogeneous at both the clinical and the molecular level. Abnormalities in the expression or structure of the fibrillar collagen types I, III and V, as
well as enzymatic abnormalities in the post-translational modification and processing
of these collagens, have been identified in a number of EDS subtypes.
Mutations in the COL5A1 and COL5A2 genes, encoding the a1- and the a2-chains of
type V collagen, respectively, are found in approximately 50% of individuals with the
classic type of EDS. Type V collagen is a minor fibrillar collagen which co-assembles
with type I collagen, and acts as a regulator of collagen fibril diameter through the retention of a non-collagenous amino-terminal domain of the proa1(V)-collagen chain. In
approximately one-third of all classic EDS patients, the disease is caused by a mutation
leading to a non-functional COL5A1 allele, resulting in a diminished amount of type V
collagen that is available for collagen fibrillogenesis. In a smaller proportion of patients,
a mutation in COL5A1 or COL5A2 is found, resulting in the production of a structurally
altered and functionally defective type V collagen protein.10 The relatively low detection rate for mutations in the COL5A1/A2 genes suggests genetic heterogeneity for this
condition, and this hypothesis is supported by several other findings. First, mutations
in a non-collagenous protein, tenascin-X, leading to a complete lack of serum tenascinX, have been shown to cause an autosomal-recessive phenotype with great similarities
to classic EDS, but without atrophic scars.11 Tenascin-X is a large extracellular matrix
protein that is thought to play an important role in the regulation of collagen deposition by dermal fibroblasts.11 Second, linkage studies have excluded the COL5A1 and/or
the COL5A2 gene in at least three pedigrees with classic EDS.12,13 Third, features of
classic EDS are found in patients with other variants of EDS. For example, a subgroup
of patients with the classic EDS phenotype has been observed who, in adult life, developed severe cardiac valvular problems, and in whom a complete deficiency of the proa2chain of type I collagen has been identified. This autosomal-recessive condition has been
termed the ‘cardiac valvular subtype of EDS’.14–16 Classic EDS features were also observed in a number of children with non-glycine substitutions in the type I collagen triple
helical domain.17 Recent observations showed that this phenotype evolves to a vascular
EDS-like phenotype in adult life, with increased risk for spontaneous arterial rupture.18
To date, little is known regarding the genetic defects underlying the hypermobility
type of EDS, which is by far the most common subtype. In this subtype, considerable
variability in clinical presentation, between as well as within families, hampers the use
of genetic linkage studies, although some new insights on the genetic background of
this condition have emerged recently. Family studies show that a phenotypic continuum may exist between classic and hypermobile EDS, and therefore, haploinsufficiency of the COL5A1 gene may be found in patients with the hypermobility
type of EDS, despite the fact that the skin is not severely affected. In a small subset of
patients with hypermobile EDS (5%), diminished levels of tenascin-X, due to heterozygous
mutations in the TNX-B gene, have been identified.19 In the vast majority of patients,
Ehlers-Danlos syndromes and Marfan syndrome 175
however, no molecular defects have been identified in this gene or in any of the fibrillar
collagen-encoding genes. The authors performed a genome-wide linkage scan in
a three-generation family with the hypermobility type of EDS with at least 13 affected
individuals, and were able to identify a new locus on chromosome 8p21 for this condition (Malfait et al, submitted).
The vascular type of EDS results from mutations in the COL3A1 gene, encoding the
pro-a1-chain of type III collagen. A wide spectrum of COL3A1 mutations has been identified, the majority of which are point mutations leading to substitutions for the obligatory glycine in the triple helical region of the collagen molecule.1,20
Whereas defects in the genes encoding type I collagen generally result in different
forms of osteogenesis imperfecta, one specific class of mutations, affecting either the
COL1A1 or the COL1A2 gene, leads to loss of the cleavage site for the enzyme procollagen type I amino-proteinase. As a result, the aminopropeptide of either the
pro-a1(I)- or the pro-a2(I)-collagen chain is not cleaved from the triple helical domain,
resulting in elongation of the collagen chains and disturbed fibrillogenesis. This gives
rise to the arthrochalasis type of EDS. It has recently been shown that some mutations
in the most amino-terminal part of type I collagen also interfere with removal of the
N-terminal propeptide, despite the fact that they leave the N-proteinase cleavage site
intact. These mutations result in a distinct ‘EDS/OI overlap phenotype’, characterized
by features of both EDS and osteogenesis imperfecta21,22 (Malfait et al, submitted).
Finally, homozygous or compound heterozygous mutations in genes encoding enzymes involved in collagen biosynthesis have been documented in several autosomal-recessive forms of EDS. Homozygous mutations in PLOD1 (procollagen-lysine,
2-oxoglutarate 5-dioxygenase or lysyl-hydroxylase-1) are found in patients with the
kyphoscoliotic type of EDS. Lysyl hydroxylase-1 is required for the hydroxylation of
specific lysine residues to hydroxylysines, which act as precursors for the cross-linking
process that is essential for the tensile strength of collagen. A deficient activity of procollagen-N-proteinase due to mutations in the ADAMTS-2 gene encoding this enzyme
is responsible for the dermatosparaxis type of EDS.23,24
With the recent identification of new EDS subtypes and the elucidation of their underlying molecular defects, it becomes clear that the Villefranche nosology needs updating. Table 2 gives a summary of current knowledge on the clinical characteristics of
the different EDS variants, their inheritance patterns, their underlying genetic defects,
and appropriate genetic tests.
The role of other genes in the pathogenesis of EDS
Various members of an expanding family of secreted proteoglycans, the ‘small leucinerich proteoglycans’ (SLRPs), have been shown to interact directly with fibrillar collagens,
thereby modulating fibril formation, growth and morphology in vitro. Their importance
in regulating fibrillogenesis has become clear from studies of SLRP-deficient mice, some
of which have clinical and ultrastructural features resembling human EDS.25–28 Only
DCN, the gene encoding decorin, has been linked to a human disorder, congenital
stromal dystrophy of the cornea, although no signs of generalized connective tissue
fragility were observed in affected individuals.29,30
Guidelines for management
No causal therapy is available for EDS; however, a series of ‘preventive’ guidelines are
applicable to all forms of EDS. These guidelines, although not evaluated in large series
176 B. Callewaert et al
of patients with EDS, are based on common sense and clinical experience, and are generally promoted by experts in the field of EDS.
Children with pronounced skin fragility should wear protective pads or bandages
over the forehead, knees and shins in order to avoid skin lacerations. Dermal wounds
should be closed without tension, preferably in two layers. Deep stitches should be
applied generously. Cutaneous stitches should be left in place twice as long as usual,
and additional fixation of adjacent skin with adhesive tape can help to prevent stretching of the scar.
Patients with pronounced bruising are advised to avoid contact sports and heavy
exercise. Protective pads and bandages can also be useful in the prevention of bruises
and haematomas. Supplementation of ascorbic acid, a cofactor for cross-linking of collagen fibrils, can ameliorate the tendency towards bruising in some patients.
In children with hypotonia and delayed motor development, a physiotherapeutic
programme is important. Non-weight-bearing muscular exercise, such as swimming,
is useful to promote muscular development and coordination. Sports with heavy joint
strain, such as contact sports, are discouraged. Anti-inflammatory drugs may relieve
joint pain; however, it is wise to refrain from drugs that interfere with platelet function,
such as anti-inflammatory drugs and acetylsalicylic acid, in patients with pronounced
bruising. In these instances, the use of paracetamol is preferred.1
Patients with mitral valve prolapse and regurgitation require antibiotic prophylaxis
for bacterial endocarditis. A baseline echocardiogram with aortic diameter measurement is recommended before 10 years of age, with follow-up studies timed according
to whether an abnormal measurement is found.
For the vascular and vascular-like types of EDS, some prophylactic measures are of
particular importance. Due to the pronounced vascular and tissue fragility, it is prudent for individuals with these conditions to avoid contact sports or isometric exercises (weightlifting), and to refrain from drugs that interfere with platelet function
and anti-coagulation. Invasive vascular procedures such as arteriography and catheterization should also be avoided because of the risk for life-threatening vascular rupture.31,32 Surgical interventions are generally discouraged because of increased
vascular fragility, and conservative therapy is recommended. If surgery is unavoidable,
manipulation of vascular and other tissues should be done with extreme care.
Although no effective preventive treatment yet exists in vascular EDS, the use of
b-blockers is now under study.
Finally, emotional support and behavioural and psychological therapy can be useful
in all subtypes of EDS in order to facilitate the process of coping with the drawbacks of
the condition. In this respect, joining a patient support group can be beneficial.
MARFAN SYNDROME
Introduction
Over 100 years ago, the French paediatrician Antoine-Bernard Marfan described a 5year-old girl, Gabrielle, with long slender digits, long bone overgrowth and muscle
hypoplasia.33 Since then, clinical research has further delineated this condition and identified it as a systemic disorder of the connective tissue, with severe manifestations in
the cardiovascular, ocular and skeletal system impelling a multidisciplinary approach
for both diagnosis and management. Since the identification of FBN1 as the causal
gene, ongoing research is unravelling the pathophysiology underlying the pleiotropic
Ehlers-Danlos syndromes and Marfan syndrome 177
manifestations observed in MFS. Recent insights in the pathogenesis have changed the
prevailing concept of this type 1 fibrillinopathy as a structural disorder of the connective
tissue into a developmental abnormality manifesting perturbed cytokine signalling, and
opening new and unexpected targets for drug treatments.
Epidemiology and criteria for diagnosis
MFS occurs worldwide with an estimated incidence of one in 5000, affecting both
sexes equally.34 The disease demonstrates autosomal-dominant inheritance with
high penetrance and marked inter- and intrafamilial variability. MFS is caused by mutations in the FBN1 gene, encoding an important extracellular matrix protein, fibrillin-1.
The clinical and molecular diagnosis of MFS can be hampered by several factors. First,
MFS is a clinically evolving phenotype that is not always easily recognizable at a young
age, especially in the absence of a familial history. Second, although the major symptoms comprise the ocular and cardiovascular system, the diagnosis is often triggered
by skeletal involvement that, at the mild end of the spectrum, overlaps with normal
variation. Third, although most, if not all, patients harbour mutations in the FBN1
gene, a diagnostic molecular test is neither commonly nor rapidly available.
In 1986, a first set of clinical criteria was defined by expert opinion in the Berlin
nosology.2 With the discovery of the molecular basis of MFS in 1991 identifying
FBN1 mutations as the underlying cause of the disease35, it became clear that more
stringent criteria were needed to avoid the danger of overdiagnosis. In 1996, these
shortcomings were addressed in the revised Ghent nosology, which also acknowledged the contribution of molecular analysis to the diagnosis.36 In the Ghent nosology,
major and minor criteria in the skeletal, ocular, cardiovascular, dural, integument and
pulmonary systems have been defined. The major manifestations include a combination
of four out of eight major skeletal features, ectopia lentis, aortic root dilatation/dissection, dural ectasia and a positive familial history and/or presence of an FBN1 mutation.
The diagnosis of MFS in a sporadic patient requires major involvement of at least two
different organ systems and minor involvement of a third system. In the presence of an
FBN1 mutation known to cause MFS or a positive familial history, one major and one
minor system involvement is sufficient to make the diagnosis. This nosology stresses
that a family history is only contributory as a major criterion when a first-degree relative is diagnosed independently on the basis of clinical criteria alone. In the absence of
a family history, molecular confirmation of an FBN1 defect also constitutes a major
criterion.
The Ghent criteria have proven to work well, and with improving techniques, molecular confirmation of the diagnosis is possible in over 90% of MFS patients.37 However, these diagnostic criteria define an entity within the wider clinical spectrum of
type 1 fibrillinopathies and, as such, the diagnosis is what we define it to be. Therefore,
a few drawbacks should be considered in a new nosology. For example, it is of concern
that in the absence of aortic dilation, patients may carry the diagnosis as a social stigma
restricting their career aspirations and possibilities towards life insurance rather than
as a guarantee for optimal medical care. A new expert panel on Marfan nosology is
currently addressing this issue by making the criteria more patient centred and evidence based. Although the use of major and minor organ involvement is helpful, several
hinge points within the Ghent nosology have not been validated. Moreover, they do not
necessarily make a fundamental difference in patient management. For example, does the
presence of dural ectasia ever make a difference in the diagnostic decision-making
178 B. Callewaert et al
process, and does it carry predictive value towards the development of aortic root
dilatation?
Also, there is a clear need for better definitions of ectopia lentis syndrome, mitral
valve prolapse, myopia, mild non-progressive aortic root dilation, and marfanoid skeletal and skin features (MASS phenotype), and mitral valve prolapse syndrome. Finally,
the criteria should be complemented with management and follow-up guidelines for
patients that do not yet fulfill the diagnostic criteria.
Unavoidably, in some cases, FBN1 mutation analysis will remain helpful, especially in
families with marked intrafamilial variability, in children that present with evolving
Marfan phenotypes and in the context of prenatal or pre-implantation diagnosis38, although it remains difficult, if not impossible, to predict severity on the basis of a mutation alone. Since mutation screening is expensive, time consuming and has
incomplete mutation detection rates, advantages and disadvantages have to be considered for each patient.
Clinical characteristics
Skeletal system
Long bone overgrowth contributes to the most striking observations in MFS, leading
to disproportionately long limbs and anterior chest deformities due to rib overgrowth.
Other major manifestations include arachnodactyly, elbow contractures, scoliosis or
spondylolisthesis, protrusio acetabulae (detected by x-ray) and calcaneal displacement
resulting in pes planus with hindfoot valgus. Arachnodactyly is often a subjective finding
but requires the thumb sign (when the fully adducted thumb extends beyond the ulnar
border of the palm) and wrist sign (when the distal phalanges of the thumb and fifth
finger fully overlap when grasping the contralateral wrist). Patients may present with
typical facial characteristics including downslanting palpebral fissures, enophthalmia,
retrognathia and a high arched palate with tooth crowding. Joint hypermobility may
predispose to ligamentous injury, dislocations, chronic joint pain and premature arthrosis. Other troublesome locomotor symptoms include muscle hypoplasia and myalgia, resulting in fatigue and spinal pain. These symptoms increase with age and affect
up to 98% of adult patients.39 It has been suggested that MFS patients have more fractures due to osteopenia, but this remains to be confirmed (Figure 3).
Ocular system
Ocular lens dislocation of any degree should promptly trigger further assessment for
MFS. It occurs in approximately one-half to two-thirds of all patients. Final diagnosis of
ectopia lentis can only be made by slit lamp examination. High myopia, retinal detachment, cataract or glaucoma occur and may cause significant visual impairment or even
blindness.40
Cardiovascular system
While other systems may be severely impaired in MFS, cardiovascular pathology remains the leading cause of mortality and morbidity with aortic root dilatation, dissection and rupture being life-threatening manifestations. Dilatation is generally greatest
at the sinuses of Valsalva. Measurements should be normalized to body surface area
and age.41 Aortic root aneurysms occur in an age-dependent manner with high variability among individuals, prompting life-long follow-up. While in severe cases, the
Ehlers-Danlos syndromes and Marfan syndrome 179
Figure 3. Clinical features in a 12-year-old boy with Marfan syndrome. Note the pectus excavatum and long
bone overgrowth (A); a beginning scoliosis at the onset of growth acceleration (B); and arachnodactyly and
hypermobility of the small joints (C).
onset of dilation occurs early in life, some individuals will never need aortic root replacement. The majority of fatal events associated with untreated MFS occur in early
adult life. However, timely recognition and appropriate medical and surgical management of the disease increased the mean survival age to 72 years.42 The improved
life expectancy in MFS has revealed that patients are also prone to more distally occurring aortic manifestations, especially after aortic root replacement, requiring appropriate imaging.43 Pulmonary artery diameters are significantly larger in MFS and
may become apparent before aortic root dilatation, revealing potential diagnostic
value, especially in children.44
Two-thirds of patients have mitral valve dysfunction, with valve prolapse, insufficiency and calcification often associated with myxomatous valve thickening.45 In contrast, aortic valve insufficiency usually results from aortic root dilation. At the extreme
end of presentation, infants with neonatal MFS manifest severely impaired valve dysfunction, leading to congestive heart failure, pulmonary hypertension and even early
death.46
Primary progressive myocardial dysfunction is usually mild, but may be aggravated
by b-adrenergic blockade or valve insufficiency.47
180 B. Callewaert et al
Dura
Dural ectasia is a common observation, with a prevalence of up to 92% in Marfan patients. It may be detected in young children.48 Unfortunately, many other conditions,
including neurofibromatosis, Loeys-Dietz syndrome and EDS, manifest dural ectasia,
and its precise specificity and sensitivity is not established. Moreover, it requires specific imaging of the lumbosacral region, with computed tomography (CT) or magnetic
resonance imaging (MRI) reducing its accessibility. In some patients, it causes discomfort as low back pain, headaches and irradiating leg pains.49
Skin/pulmonary system
Due to low specificity, skin and pulmonary involvement are only defined as minor criteria. Striae distensae independent of marked weight gain or pregnancy occur in up to
two-thirds of all patients.50 Recurrent inguinal or surgical hernias are common and
need special attention. Pneumothorax, pulmonary emphysema and dysfunction, partly
due to alveolar septation defects, represent rare but disabling manifestations. Restrictive lung disease may result from severe pectus deformities. In view of the long bone
overgrowth, pulmonary function should be normalized to sitting height rather than
body surface area.51
Differential diagnosis
The differential diagnosis of MFS is extensive, comprising other connective tissue disorders and metabolic diseases with skeletal, ocular and/or cardiovascular involvement
(Table 3).
Cardiovascular system
As in MFS, thoracic aortic root dilatation (TAA) presenting with no or minor systemic
involvement is progressive, and the risk for dissection or rupture depends mainly on
aortic measurements. Importantly, aortic aneurysms in TAA can also occur distally
from the sinuses of Valsalva, requiring imaging of the entire aorta. About 20% of patients with TAA have a positive family history, with predominantly autosomal-dominant segregation and decreased penetrance.52 Genetic mapping studies have
revealed large genetic heterogeneity in TAA53,54, and therefore it is not possible to
perform comprehensive genetic screening, mandating follow-up of first-degree family
members. Occasional FBN1 mutations are identified in patients with TAA who often
show limited skeletal and skin involvement. Recently, mutations in TGFb receptor 2
(TGFBR2) gene have been implicated as a rare cause (5%) in familial TAA, with more
widespread vascular disease and aneurysms and dissections of the descending aorta
and middle-sized arteries.55
Bicuspid aortic valve, the most common cardiac malformation with a prevalence of
1–2% in the general population, is frequently associated with aortic root dilation that
often occurs above the sinuses of Valsalva. Increasing evidence suggests a common genetic defect underlying both the valve abnormalities and the aortic dilatation.56 Counselling in first-degree relatives is complicated by incomplete penetrance of this
dominant condition.
Some EDS (as described above), mainly the vascular and kyphoscoliotic types, may
show overlap with MFS, but can usually be differentiated on the skin findings.
Ehlers-Danlos syndromes and Marfan syndrome 181
Table 3. Conditions to be considered in the differential diagnosis of Marfan syndrome.
Main feature
Aortic root
dilation/
dissection
Ectopia lentis
Marfanoid
habitus
Additional symptoms
None or minor systemic
involvement
Patent ductus arteriosus
Bicuspid aortic valve
Thin skin, atrophic scars,
joint hypermobility
Hypertelorism, bifid uvula,
cleft palate, widespread
arterial involvement
Think of .
Genetic defect
TAA
FBN1, TGFBR1/2, other
TAA/PDA
BAV
EDSIV - LDS2
MYH1, TGFBR1/2
NOTCH1, KCNJ2, other
COL3A1 - TGFBR1/2
LDS1
TGFBR1/2
Stocky stature, brachydactyly
Mental retardation,
marfanoid habitus
None or mild systemic
features
WMS
Homocystinuria
ADAMTS10 (AR)/FBN1 (AD)
Cystathionine beta-synthase
Familial EL
FBN1, other
Mitral valve prolapse,
stable and mild (<2.5 SD)
aortic root dilation, absent EL
Crumpled ears, contractures,
absence of EL
Atrophic scars, velvety skin,
severe hypermobility
Mental retardation, tall
stature (X-linked)
Mental retardation (X-linked)
Mental retardation,
craniosynostosis
Long face, protruding ears
Camptodactyly, hearing loss
Mental retardation,
ectopia lentis
MASS
FBN1 (?)
CCA
FBN2
EDSVI
PLOD1
Lujan-Fryns
syndrome
MED12
SGS
ZDHHC9
FBN1 (?)
FRA-X
CATSHL
Homocystinuria
FMR1
FGFR3
Cystathionine beta-synthase
TAA, thoracic aortic aneurysm; PDA, patent ductus arteriosus; BAV, bicuspid aortic valve; EDS, EhlersDanlos syndromes; LDS, Loeys-Dietz syndrome; WMS, Weill-Marchesani syndrome; AR, autosomal
recessive; AD, autosomal dominant; EL, ectopia lentis; MASS, mitral valve prolapse, myopia, aortic
root dilation, skeletal and skin features; CCA, congenital contractural arachnodactyly; SGS, Shprintzen-Goldberg syndrome; FXS, fragile X syndrome; CATSHL, camptodactyly, tall stature, hearing loss.
Loeys-Dietz syndrome is a novel autosomal-dominant aortic aneurysm syndrome
characterized by the triad of hypertelorism, bifid uvula/cleft palate, and arterial tortuosity with ascending aortic aneurysm/dissection, caused by heterozygous loss-of-function mutations in the TGFBR1 or TGFBR2 gene.57 The main differences with MFS are
the absence of significant long bone overgrowth or lens dislocation, and the presence
of multiple other findings, including craniosynostosis, Chiari malformation, club feet,
patent ductus arteriosus, and aneurysms/dissection throughout the arterial tree. In
contrast to this typical presentation, referred to as Loeys-Dietz syndrome type 1,
some patients show less craniofacial abnormalities but prominent skin and joint manifestations, more reminiscent of vascular EDS.4 This subset of patients (Loeys-Dietz
182 B. Callewaert et al
syndrome type 2) is characterized by a velvety and translucent skin, easy bruising,
widened atrophic scars, uterine rupture, severe peripartal bleedings, and arterial aneurysm/dissections throughout the arterial circulation. Importantly, the natural history of
patients with TGFBR1/2 mutations is far more aggressive than in MFS or even vascular
EDS, with a mean age at death of 26.1 years. Aortic dissections occur in young childhood and/or at smaller aortic dimensions (<40 mm), and the incidence of pregnancyrelated complications is high.4
Ocular system
In contrast to MFS, Weill-Marchesani patients present with a stocky stature,
brachydactyly and stiff joints in conjunction with anterior chamber anomalies including ectopia lentis. Both recessive and dominant inheritance have been
described.58,59
Homocystinuria is a recessively inherited metabolic disorder characterized by ectopia lentis, long bone overgrowth, mental retardation, and a high predisposition to
thrombo-embolism and coronary artery disease in the absence of aortic root dilation.
Diagnosis is based on the presence of elevated concentrations of homocystine in urine
or plasma.60
In several families, isolated ectopia lentis has been shown to segregate as a dominant
trait. Although mild marfanoid skeletal features may be present, these patients do not
meet diagnostic criteria for MFS. However, lifelong follow-up by echocardiography is
advised as aortic root dilatation occurs later in life in some patients.
Skeletal system
In many individuals evaluated for MFS who do not meet the diagnostic criteria,
a varying constellation of mitral valve prolapse, myopia, mild non-progressive aortic
root dilation, and marfanoid skeletal and skin features is depicted (MASS phenotype).61
This phenotype may segregate as a dominant trait and remain stable over time. In rare
instances, FBN1 mutations have been identified.62
Another rare autosomal-dominant syndrome showing considerable overlap with
MFS is congenital contractural arachnodactyly. Cardinal clinical features are crumpled
ears, arachnodactyly, congenital contractures of small and large joints, and usually
progressive scoliosis. Recently, mild aortic root enlargement has been reported in
a few patients, but progression to dissection or rupture remains unclear.63 Congenital
contractural arachnodactyly is caused by mutations in the fibrillin-2 gene (FBN2),
which is closely related to FBN1.64
Mental retardation syndromes with a marfanoid habitus
When patients present with mental retardation in addition to systemic features of
MFS, other conditions, including Lujan-Fryns, Shprintzen-Goldberg (SGS), CATSHL
(camptodactyly, tall stature, hearing loss) and even fragile X-syndrome, should be considered. Shprintzen-Goldberg syndrome typically comprises craniosynostosis, hypertelorism and (rarely) aortic root dilatation. Although FBN1 mutations were found in two
Shprintzen-Goldberg patients65, the underlying defect remains unexplained in the majority of cases. Recently, mutations in ZDHHC9 and MED12 have been identified in patients, reminiscent of Lujan-Fryns syndrome.66,67
Ehlers-Danlos syndromes and Marfan syndrome 183
Molecular pathogenesis
Fibrillin 1, the protein mutated in MFS, is a 350-kDa extracellular glycoprotein that is
highly conserved between different species. Most mutations affect predictably spaced
cysteine residues in the calcium binding epidermal growth factor-like domains needed
for proper folding and stabilization of the protein. Fibrillins polymerize extracellularly
as parallel bundles of head-to-tail monomers, and form macro-aggregates, called
‘microfibrils’, in association with other proteins such as latent TGFb binding proteins.
Microfibrils provide force-bearing structural support and can associate with elastin to
form elastic fibres providing elasticity in a time- and tissue-dependent manner.68 For
a long time, it was believed that the pathophysiology of MFS was entirely based on
severely reduced and fragmented elastic fibres in affected tissues. This observation
led to the hypothesis that structural deficiency of the fibrillin-1 protein was the
most important factor in the aetiology of MFS. While this hypothesis offered an explanation for aortic pathology, it did not reconcile the observation of other clinical
features such as long bone overgrowth, thickening of the cardiac valves or muscle
hypoplasia.
The study of fibrillin-1 mutant mouse lines that recapitulate human MFS has
recently challenged this ‘mechanistic’ view. Indeed, mouse models have shown that
structural fibrillin-1 deficiency leads to increased activation of the sequestered cytokine, TGFb69,70, which has a pivotal role in development and maintenance of several
tissues. Enhanced activation of the TGFb pathway was shown to contribute to the
development of emphysema, aortic aneurysms and muscle hypoplasia seen in MFS.
In murine models, these changes can be effectively blocked by the administration of
TGFb antibodies.69,71,72
Further evidence of perturbed TGFb signalling in aortic aneurysm came from the
identification of the Loeys-Dietz syndrome, caused by loss-of-function mutations in
the TGFBR1 and TGFBR2 genes.57
Guidelines for management
Diagnosis and management require a multidisciplinary approach by geneticists, cardiologists, orthopaedic surgeons and ophthalmologists with experience in this field.73
Cardiovascular follow-up should include serial evaluation with echocardiography or
CT/MRI angiography when visibility of the aortic root and ascending aorta is limited.43
Evaluation frequency should be tailored based upon aortic dimensions, the rate of aortic growth and family history. Beta-adrenergic blockade, titrated to physiological response, is a standard treatment to slow aortic growth, mainly by virtue of its
antihypertensive and negative inotropic effects.74 If beta-blockade is contra-indicated
(asthma, Raynaud phenomenon, psoriasis, depression, fatigue), calcium antagonists
or angiotensin converting enzyme inhibitors may be used although no randomized
studies exist. Surgical repair of the aorta is indicated once the maximal diameter exceeds 5 cm in adults, when the rate of aortic growth exceeds >0.5–10 mm/year or in
the presence of significant aortic regurgitation. In case of proper aortic valve function,
the preferred technique is the valve-sparing procedure avoiding lifelong anticoagulant
therapy, especially in females in their fertile period. Although the superiority of
this technique in comparison with the composite graft has not been established, the
10-year experience is very promising.75 After surgical repair of the aortic root, imaging
of the whole aorta is warranted for timely detection of aortic graft pseudo-aneurysms,
184 B. Callewaert et al
more distally occurring aneurysms and coronary artery aneurysms.73 While most TAA
patients may benefit from the same cardiovascular management guidelines as in MFS,
recent studies warned about the aggressive nature of the disease in patients harbouring TGFb receptor mutations warranting earlier surgical repair and more extensive
imaging.4
During pregnancy, the risk for aortic complications increases with aortic root
dimensions before pregnancy, but is regarded to be low below 4 cm.73 Therefore,
pregnancy should be followed intensively, with special care peripartum, through
a high-risk obstetric clinic.
Orthopaedic complications mainly involve anterior chest and vertebral column
deformities that should be followed carefully, especially during and just after puberty.
Since extreme pectus deformities have little impact on pulmonary function, surgery is
considered as a cosmetic issue. Correction, preferably using the minimal invasive Nuss
procedure, should not be done before the age of 11 years76, as earlier intervention
might lead to recurrent deformity due to continued rib growth. In contrast, severe
(kypho-)scoliosis has a major impact on quality of life, needing surgical stabilization
as bracing often remains inadequate.77 Protrusio acetabulae is often asymptomatic
in young adults, and the benefit of surgery is questioned.78 Hormone therapy is
indicated if predicted final height is unacceptable.79
Diffraction anomalies due to lens subluxation, flat cornea or myopia can easily be
corrected by eyeglasses or contact lenses. Lens extraction for manifest ectopia lentis
or cataract severely increases the pre-existing risk for retinal detachment and glaucoma which causes significant visual impairment. Yearly examination by an experienced
ophthalmologist is highly recommended for every Marfan patient.
Finally, lifestyle modifications may promote cardiovascular and psychosocial health,
and prevent or relieve many locomotor inconveniences including arthrosis, fatigue,
myalgia and chronic joint pains. Patients should avoid competitive sport, straining or
isometric exercise as these increase blood pressure and cause considerable dynamic
stress on the aortic root. Additionally, contact sports should be avoided as these
may precipitate aortic dissection.80 Activity guidelines are available on the National
Marfan Foundation website (http://www.marfan.org/).
New therapeutic strategies, based upon the physiopathology in MFS, propose
losartan as an antihypertensive agent attenuating TGFb signalling. In murine models,
losartan has been shown to stop aortic growth and induce regression of emphysematous changes in the lung, even in adult life.69,72 Currently ongoing randomized trials are
focusing on this new treatment possibility in MFS, which may also be beneficial in
related conditions.71 This beautifully illustrates how insights gained in the pathophysiology of monogenic multisystem connective tissue disorders may lead to insights and
new treatment options for other, more common disorders.
Practice points
diagnosis of EDS is based on a combination of clinical, biochemical and ultrastructural examinations that guide molecular analysis of relevant gene(s)
in case of suspicion of vascular EDS, biochemical analysis of type III collagen
extracted from cultured skin fibroblasts is mandatory to confirm the diagnosis
phenotypic overlap exists between different EDS subtypes; some form a phenotypic continuum
Ehlers-Danlos syndromes and Marfan syndrome 185
several ‘unclassified’ EDS phenotypes confirm wide clinical and genetic heterogeneity within the EDS spectrum
while aortic and ocular involvement are usually the most disabling and lifethreatening manifestations of MFS, the diagnosis is often triggered by skeletal
abnormalities that merge with the normal population in the mild end of the
spectrum
multisystem manifestations in MFS require a multidisciplinary approach for
diagnosis and management
the diagnosis of MFS still tends to stigmatize patients, and careful consideration
is needed in the absence of (a familial history) aortic root dilation. Nevertheless, aortic follow-up is always strongly advised
management guidelines in MFS are mainly based on expert opinion, and experience is needed to tailor these recommendations to the individual patient
Research topics
in the classic and hypermobility types of EDS, further studies are needed to elucidate the underlying molecular mechanisms. The search for genetic causes of
EDS should extend beyond fibrillar collagens to other molecules that are
involved in regulation and modulation of type I collagen fibrillogenesis
many EDS variants cannot be classified into one of the existing categories. Better insight into their phenotype, natural history and the underlying biochemical
and genetic defects will improve early recognition and diagnosis, lead to a more
logical classification and hopefully allow development of more effective
therapies
the recent progress in identification of new molecular defects and recognition
of new EDS variants necessitates an update of the Villefranche nosology
the promising results seen in murine models for MFS treated with losartan
should be confirmed in humans with randomized clinical trials to document
carefully the benefits and side-effects in MFS patients. These results can serve
as a basic document to engage in further trials
re-evaluation of the Ghent criteria is needed after 10 years of experience in
order to define which criteria have worked well and which criteria need further evidence-based foundation
ACKNOWLEDGEMENTS
The authors are indebted to Paul Coucke and Sofie Symoens for supervision of the
molecular and biochemical analyses, and to Petra Van Acker and Karen Wettinck
for technical assistance. This work is supported by Grant G.0171.05 and Grant
G.0094.06 from the fund for Scientific Research-Flanders (to ADP), a GOA Research
Grant from the Ghent University (to ADP) and by the Geneskin Consortium within
the Sixth Framework Programme of the European Commission.
186 B. Callewaert et al
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