Prevalence of aortic root dilation in the Ehlers-Danlos syndrome.
ABSTRACT To determine the prevalence of proximal aortic abnormalities in patients with Ehlers-Danlos syndrome (EDS).
In a prospective cohort study, aortic measurements by two-dimensional echocardiography were performed on consecutive EDS patients.
Twenty-eight percent (20 of 71) had aortic root dilation (ARD) (> +2 SD above population based norms). Fourteen of 42 individuals with the classical form of EDS (types I/II) and 6 of 29 individuals with the hypermobile form (type III) had ARD, with no gender differences.
ARD is a common finding in EDS. Longitudinal studies are indicated to determine progression of ARD and its clinical significance.
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ABSTRACT: Joint hypermobility syndrome (JHS) and Ehlers-Danlos syndrome, hypermobility type (EDS-HT) are two clinically overlapping heritable connective tissue disorders strongly associating with pain, fatigue and other secondary aspects. Though not considered a diagnostic criterion for most EDS subtypes, cardiovascular involvement is a well-known complication in EDS. A case-control study was carried out on 28 adults with JHS/EDS-HT diagnosed according to current criteria, compared to 29 healthy subjects evaluating resting electrocardiographic (ECG), 24-h ECG and resting heart ultrasound data. Results obtained in the ECG studies showed a moderate excess in duration of the PR interval and P wave, an excess of heart conduction and rate abnormalities and an increased rate of mitral and tricuspid valve insufficiency often complicating with "true" mitral valve prolapse in the ecocardiographic study. These variable ECG subclinical anomalies reported in our sample may represent the resting surrogate of such a subnormal cardiovascular response to postural changes that are known to be present in patients with JHS/EDS-HT. Our findings indicate the usefulness of a full cardiologic evaluation of adults with JHS/EDS-HT for the correct management.Clinical Rheumatology 04/2014; · 2.04 Impact Factor
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ABSTRACT: Recent advances in Kawasaki disease have included attempts to define genes involved in its pathogenesis. There have been recent advances in the studies of rheumatic carditis, leading to a better understanding of the mechanism of the disease. Histologic evaluation of patients with neonatal lupus erythematosus has revealed fibrosis with collagen deposition and calcification of the atrioventricular node. Therapy for cardiac involvement in systemic juvenile idiopathic arthritis should involve treatment of the underlying disease and systemic inflammatory state, and typically includes nonsteroidal antiinflammatory drugs, corticosteroids, disease-modifying drugs, and biologic therapies targeting tumor necrosis factor-alpha, interleukin-1, and interleukin-6.Rheumatic diseases clinics of North America 02/2014; 40(1):61-85. · 2.59 Impact Factor
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ABSTRACT: Long thought to be two separate syndromes, Ehlers-Danlos syndrome hypermobility type (EDS-HT) and benign joint hypermobility syndrome (BJHS) appear on close examination to represent the same syndrome, with virtually identical clinical manifestations. While both EDS-HT and BJHS were long thought to lack the genetic loci of other connective tissue disorders, including all other types of EDS, researchers have discovered a genetic locus that accounts for manifestations of both EDS-HT and BJHS in a small population of patients. However, given the modest sample size of these studies and the strong correlation between serum levels of tenascin-X with clinical symptoms of both EDS-HT and BJHS, strong evidence exists for the origins of both types of hypermobility originating in haploinsufficiency or deficiency of the gene TNXB, responsible for tenascin-X. Tenascin-X regulates both the structure and stability of elastic fibers and organizes collagen fibrils in the extra-cellular matrix (ECM), impacting the rigidity or elasticity of virtually every cell in the body. While the impacts of tenascin-X insufficiency or deficiency on the skin and joints have received some attention, its potential cardiovascular impacts remain relatively unexplored. Here we set forth two novel hypotheses. First, TNXB haploinsufficiency or deficiency causes the range of clinical manifestations long identified with both EDS-HT and BJHS. And, second, that haploinsufficiency or deficiency of TNXB may provide some benefits against adverse cardiovascular events, including heart attack and stroke, by lowering levels of arterial stiffness associated with aging, as well as by enhancing accommodation of accrued atherosclerotic plaques. This two-fold hypothesis provides insights into the mechanisms underlying the syndromes previous identified with joint hypermobility, at the same time the hypothesis also sheds light on the role of the composition of the extracellular matrix and its impacts on endothelial sheer stress in adverse cardiovascular events.Medical Hypotheses 07/2013; · 1.18 Impact Factor
Prevalence of aortic root dilation in the Ehlers-
Richard J. Wenstrup, MD1, Richard A. Meyer, MD2, Jennifer S. Lyle, BS1, Leah Hoechstetter, MS1, Peter S. Rose, MD3,
Howard P. Levy, MD3, and Claire A. Francomano, MD3
Purpose: To determine the prevalence of proximal aortic abnormalities in patients with Ehlers-Danlos syndrome
(EDS). Methods: In a prospective cohort study, aortic measurements by two-dimensional echocardiography were
performed on consecutive EDS patients. Results: Twenty-eight percent (20 of 71) had aortic root dilation (ARD) (?
?2 SD above population based norms). Fourteen of 42 individuals with the classical form of EDS (types I/II) and
6 of 29 individuals with the hypermobile form (type III) had ARD, with no gender differences. Conclusion: ARD is
a common finding in EDS. Longitudinal studies are indicated to determine progression of ARD and its clinical
significance. Genet Med 2002:4(3):112–117.
Key Words: Ehlers-Danlos, echocardiogram, aorta, aortic dilation
The Ehlers-Danlos syndromes (EDS) are a genetically, bio-
mon.1–3Prior classifications of EDS have included up to 11
disorders. Recently a simplified classification came into use
that takes into account increasing clinical experience and ad-
vances in our understanding of the molecular pathogenesis of
these disorders. Table 1 provides the new Villefranche classifi-
cation and its relationship to the most recent prior classifica-
tion in 1988.2,4Of these, the classical (EDS types I, II), hyper-
mobile (EDS type III), and vascular (EDS type IV) types are by
far the most common.
A variety of cardiovascular complications have been associ-
dium-sized arteries, varicose veins, easy bruising, dilation
and/or rupture of the aortic sinus and rupture of the aor-
ta.1,3,5–12Pepin et al.13recently reported the prevalence of car-
diovascular complications in a large cohort of patients with
vascular EDS; these primarily involve rupture or dissection of
medium-sized arteries and the descending aorta. The preva-
lence of cardiovascular complications in the classical and hy-
permobile forms are unknown. We began to perform baseline
echocardiographic evaluations on all EDS patients seen in our
clinics after having identified a few cases of EDS with aortic
root dilation, some of whom had complications.12The data
indicate that the prevalence of aortic root dilation in these two
gitudinal follow-up of a large cohort of EDS patients will be
necessary to determine whether or to what extent these pa-
tients are at risk for serious complications such as aortic rup-
ture, valvular insufficiency, or dissection.
MATERIALS AND METHODS
All patients were seen in an outpatient setting between 1994
and 1999, either at Cincinnati Children’s Hospital Medical
Center (CHMC) or at the Clinical Center at the National In-
stitute of Human Genome Research (NIHGR). The study was
approved by the institutional review boards of both institu-
tions, and informed consent was given for the study. At the
time that this study was initiated in 1994, the subject popula-
tion was limited to those who had the diagnosis of Ehlers-
Danlos syndrome types I, II, or III. The diagnosis of EDS was
made by a clinical geneticist (R.J.W., C.A.F.) on the basis of
clinical criteria and the exclusion of other confounding diag-
noses. During the course of the study, a new classification for
the Ehlers-Danlos syndromes was proposed and adopted.4
From 1994 through 1997, the diagnosis of EDS subtypes was
I, II, and III, using the 1988 Berlin classification.2The new
I and II were combined as classical EDS. EDS type III was in
essence renamed as the hypermobile type. Patients entered
criteria published with the new classification4(Table 1). The
hyperextensibility of skin, and thin atrophic scars. The dermis
is fragile and is easily bruised. Family history had to have been
consistent with new dominant mutation or autosomal domi-
nant transmission in a pedigree. The diagnosis of the hyper-
ity of joints and soft, velvety skin. Individuals with this type
have normal scarring, but may have stretchy skin. Nearly all
Cincinnati, Ohio; and3National Human Genome Research Institute, NIH, Bethesda,
dation, Cincinnati OH 45229-3039.
Received: November 16, 2001.
Accepted: February 26, 2002.
a r t i c l e
May/June 2002 ? Vol. 4 ? No. 3
Genetics IN Medicine
patients with the hypermobile form had a positive family his-
tory consistent with autosomal dominant inheritance.
have overlapping clinical features with other forms of EDS or
other heritable connective tissue disorders that can occasion-
ally make the specific diagnosis more difficult. For some study
subjects, the diagnosis of the classical or hypermobile forms of
oratory testing, including electrophoretic analysis of type III
collagen chains to exclude the vascular form,14the kyphosco-
liosis form15,16or the arthrochalasia forms of EDS.4Some in-
dividuals with the hypermobile form who had associated pec-
tus excavatum, scoliosis, or severe myopia were evaluated for
Marfan syndrome and were included only if they had dermal
features of hypermobile EDS and if the Marfan syndrome was
clinically excluded.17There is no diagnostic test for the hyper-
mobile forms of EDS, as its molecular basis is not known.
Complete echocardiograms were performed by experienced
Society of Echocardiography18and were measured using the
nal long-axis views (Fig. 1) at four levels: (1) annulus (defined
and (4) proximal ascending aorta were obtained following the
lar to the long axis of the aorta, using the leading edge technique
Echocardiogram of the aorta from a young patient with a dilated aortic sinus in
The Ehlers-Danlos syndromes
classification (1997) Berlin classification (1988)Clinical featuresInheritancea
Classical typeI Gravis
Soft, hyperextensible skin; easy
bruising; thin, atrophic scars;
hypermobile joints; varicose veins;
prematurity of affected newborns
AD Mutations in pro?1(V) or pro?2(V)
chains of type V collagen (COL5A1,
COL5A2) in some families
Hypermobility type III Soft skin; large and small joint
Vascular type IV Arterial-ecchymoticThin, translucent skin with visible
veins; easy bruising; absence of skin
and joint extensibility; arterial,
bowel, and uterine rupture
ADMutations in COL3A1; abnormal type III
collagen synthesis, secretion, or
Kyphoscoliosis type VI Soft skin; muscle hypotonia; scoliosis:
joint laxity; hyperextensible skin
AR Lysyl hydroxylase deficiency, mutations in
Arthrochalasia type VIIA, VIIB Arthrochalasia
Congenital hip dislocation; severe
joint hypermobility; soft skin with
or without abnormal scarring
ADDeletion of exons from type I collagen
genes that encode the amino-terminal
propeptide cleavage site of COL1A1
(type A) or COL1A2 (type B)
Dermatosporaxis type VIIC Severe skin fragility; sagging,
Recessive mutations in type
I collagen N-peptidase
aAD, autosomal dominant; AR, autosomal recessive.
bIncludes rare forms (types V, VIII, and X) from the 1988 Berlin classification that have only been described in a few families.
Aortic root dilation in EDS
May/June 2002 ? Vol. 4 ? No. 3
and indexed for body surface area (Fig. 2) according to age.18
(1994–1995) did not have all four measurements, and measure-
All patients with the classical and the hypermobile forms of
EDS who received diagnostic evaluations at Cincinnati Chil-
dren’s Hospital (CHMC) or at the Clinical Center at the Na-
tional Institute for Human Genome Research (NIHGR) from
1994 to 1999 also received baseline echocardiograms. Patients
who had an abnormal measurement underwent repeat echo-
cardiograms at 6- or 12-month intervals, depending on the
for the purpose of this study, only the echo measurements at
the time of diagnosis were included in the analysis.
Seventy-one EDS patients qualified for the study based on a
2). The age at first echocardiogram ranged from 1 to 60 years.
15 years to 40 years, including the 95% limits for patients over 40 years of age.18Values within circles are from patients over 40 years of age.
Aortic sinus and supra-aortic ridge measurements indexed for body surface area and age. Top: Data for patients aged 1 month to 15 years. Bottom: Data from patients aged from
Wenstrup et al.
Genetics IN Medicine
The study population was 61% female; nearly all of the excess
in female cases was contributed by the older NIHGR popula-
tion. The average age at entry into the study was 23.4 years.
Forty-two of 71 patients had classical EDS (types I/II), and the
remaining patients had the hypermobile form (type III).
determined by previously described methods18(Table 3). In
some of the group over 40 years of age, only sinus measure-
ments were available. Neither the age-adjusted height nor the
age-adjusted body surface area deviated significantly from
population norms (data not shown). The age at diagnosis of
ARD ranged from 7 to 60 years. The prevalence of ARD was
EDS (33% and 17% respectively), but the results did not
achieve statistical significance.
Four EDS patients were excluded because they were ascer-
tained on the basis of aortic abnormalities. One of these was
previously reported (Patient 5).12Two of these had originally
basis of joint laxity and aortic disease; one of these two had
replacement with a Teflon graft. If these patients were not ex-
cluded, the prevalence of ARD in this population would be
32% (23 of 75) instead of 28% (20 of 71).
Four had dilation at the supra-aortic ridge without dilation at
the aortic sinus. None had dilation at the level of the aortic
tal to the supra-aortic ridge. The high prevalence of ARD, at
least in the aortic sinus measurements of younger patients,
than due to a subset of easily distinguishable outliers (Fig. 3,
top). The general upward shift was not noticeable in measure-
ments of the supra-aortic ridge, where far fewer abnormal
measurements were made (Fig. 3, bottom).
Echocardiographic evaluation of patients who had either
at two clinical genetics centers demonstrated an unexpectedly
ences in ARD rates by sex. The overall prevalence of ARD was
Subjects (n) 42 29 71
Age, mean (range) 14.4 (1–49) 29.6 (6–60) 20.6
Female/male22/20 21/8 43/28
EDS subtype: classical/hypermobility 20/2222/742/29
Percentage of EDS patients with ARD
ARD total9/42 (21%) 11/29 (34%)28%
Age at initial ARD diagnosis,
14.4 yr (7–21) 33.0 yr (9–60) 23.4 yr
Female/male 22%/20%28%/50% 27%/28%
20%/22% 45%/0% 33%/17%
(bottom) above and below the mean value (0). The sinus measurements appear broadly
shifted upward in the EDS populations, whereas it is not as evident in the supra-aortic
Aortic root dilation in EDS
May/June 2002 ? Vol. 4 ? No. 3
substantially higher in classical EDS (33%) than in hypermo-
bile EDS (17%), but the two forms had an identical frequency
(CHMC). Relatively few patients with the hypermobile form
were studied at NIHGR; none had ARD. A future study with a
ingly, ARD was found more frequently than mitral valve pro-
lapse, which has previously been identified as a cardiac com-
plication of EDS.1,3
In the absence of complete ascertainment of all known pa-
tients with EDS within a defined geographical region, preva-
lence data using consecutive patients seen in two clinical cen-
ters in two geographic regions may be the best alternative. At
the very least, the prevalence estimates included in this report
should reflect the expected frequency of ARD among EDS pa-
Cincinnati) was a combined genetics–cardiology clinic spe-
an important potential source of ascertainment bias might be
patients who were identified on the basis of prior or suspected
cardiovascular disease, which would be expected to enrich the
calculated ARD prevalence both including or excluding those
individuals. The prevalence rates of 32% and 27%, which are
the result of including or excluding patients identified on the
basis of their aortic abnormalities, respectively, may represent
patients with the classical or hypermobile forms (types I, II,
and III). These data represent the first prevalence rates for this
complication in the Ehlers-Danlos syndrome. In contrast, the
major aortic complications of the vascular form of EDS (type
IV)—dissection and rupture—are likely not preceded by ves-
proximal aorta.14Our experience indicates that the onset of
sectional data elicited by the study design do not provide in-
sion of patients with predetermined aortic disease limited our
ability to determine the percentage of patients with EDS that
have serious complications of ARD such as valvular insuffi-
ciency, aortic rupture or dissection, or preemptive replace-
ment with an aortic graft.
Our study size is particularly limited in the older age group.
It appears that significant ARD is present in the young but less
so in young or older adults. A possible explanation for this is
normalize as it stiffens with age. Measurement error in
younger children has a higher impact: 1- or 2-mm measure-
ment discrepancies in a small structure may result in a larger
error; however, careful measurement technique over time
should cancel or minimize that error in the same patient. A
longitudinal study with a larger patient base will help clarify
these remaining issues.
Overall, the frequency of ARD is substantially lower in EDS
ments by two-dimensional echocardiogram. Some of this dif-
ference may be related to the fact that aortic enlargement rep-
resents a major diagnostic criterion for the Marfan syndrome
but not EDS.
Information about rates of progression and complication
ers19found that 80% had increased aortic root diameter. After
follow-up of 5 years, one fourth of these had an increase in
centage of Marfan patients with ARD who progress to aortic
valvular insufficiency, rupture, dissection, or preemptive re-
pair is not precisely known. Hence, for patients with EDS,
cross-sectional data indicates that further longitudinal studies
are necessary to determine onset of ARD, the likelihood of
progression of ARD relative to increases in body size and age-
dependent-norms, and whether these patients are at risk for
the above complications.
It is possible that EDS patients with ARD have a specific
molecular defect that renders them susceptible to aortic dis-
and COL5A2).21–27Routine laboratory diagnosis of this form
of EDS is still not practical, and segregation analysis of some
families with classical EDS have excluded COL5A1 and
COL5A2 in some.24,28The genetic basis of the hypermobile
form of EDS (type III) is unknown. It may be that the current
clinical classification of EDS will be modified with the advent
of a molecular nosology and improvement in laboratory diag-
nosis and that risk for ARD may eventually be limited to indi-
viduals with specific gene defects.
In conclusion, our data indicate that aortic dimensions, at
least at the aortic sinus (Figs. 2 and 3), are shifted broadly
a general effect on connective tissue biomechanics than with a
model that is based on a subset of outliers having a common
progression of ARD in patients who have EDS diagnosed by
current clinical criteria.
This project was funded by a grant from the Children’s
1.Beighton P. The Ehlers-Danlos syndromes. In: Beighton P, editor. McKusick’s her-
itable disorders of connective tissue. St. Louis: Mosby, 1992:189–251.
Wenstrup et al.
Genetics IN Medicine