DOI: 10.1161/CIRCULATIONAHA.111.

088633

Moderate Aortic Enlargement and Bicuspid Aortic Valve are

Associated with Aortic Dissection in Turner Syndrome:

Report of the International Turner Syndrome Aortic Dissection Registry

Running title: Carlson et al.; Aortic dissection in Turner syndrome

Misty Carlson, MD1; Nathan Airhart, MD1; Leo Lopez, MD2; Michael Silb erba ch,, MD2
Silberbach,
ber bach
ba ch

1
Oregon
Or
reg
egon
on H
Health
ealt
eal h & Sc
lt S
Science OR;; 2Children’s Hospital
ience University, Portland, OR Hospita
taal at
at Montefiore, Bronx, NY

Addr
Ad
Address
dress for
fo Correspondence:
Corr
Co rres
espo
p nd
po nden
ence
ce::
Mich
c aeel Si
Michael S lb
ber
erba
b ch
ba
Silberbach,ch,, MD
Dept. of Pediatrics, CDRC-P
Oregon Health and Science University
3181 SW Sam Jackson Park Rd.
Portland, OR 97239
Tel: 503-494-318
Fax: 503-494-2824
E-mail: silberbm@ohsu.edu

Journal Subject Codes: [109] Clinical genetics; [35] CV surgery: aortic and vascular disease;
[41] Pediatric and congenital heart disease, including cardiovascular surgery; [79] Aneurysm,
AVM, hematoma

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 DOI: 10.1161/CIRCULATIONAHA.111.088633

Abstract:

Background - Girls and women with Turner syndrome are at risk for aortic dissection and

rupture. However the size of the aorta and the clinical characteristics among those with Turner

syndrome and dissection has received little attention.

Methods and Results - We obtained medical records from 20 individuals who voluntarily

participated in the International Turner Syndrome Aortic Dissection (ITSAD) Registry. Type-A

dissections occurred in 17/20 (85%) and type-B occurred in 3 cases where 1 occurred after

coarctation stent placement. Of those with spontaneous aortic dissections, 18/19 (95%) had an

associated cardiac malformation that included a bicuspid aortic valve. In one individual
ind
nddiv
ividuall there
idua
idua ther
theree
er

was no predisposing finding other than having Turner

u syndrome. Associated
Associated pregnancy was

documented
do
ocu
ume
ment
nted
nt ed iin 1/19
n 1/
/19 (13/19,
19, 668%)
1 (5%). More than half (13/1 medical
8%) came to medi
dica
call attention > 24 hours
ca

aafter
fteer the onsett of ssymptoms.
ym
mpt
p om
omss.
s. Fo those
Forr th
hos
osee with
with type-A
h ty
ype-A dissections
-A dis
isssect ons tthe
ctio mean
hee m ascending
ean as
scend
ndin
din aortic
ingg ao tic ssize
aort i e
iz

index
nde ((ASI-AAO)
d x (A SI-A
SI -AAO
-A AO) wa
AO wass 2.7
2.77 ± 0. cm/m2
0.66 cm
m/m ((n=9).
/m22 (n =9)..
=9).

Conclusions
C i s - Aortic
oncllusions ic ddissection
Aortiic
Aort io iin
is ctiion
issect nTTS occurs
S oc curs iin
occu yyoung
n yo ungg iindividuals
un ndi
nd
divid
ivid u ls aatt sm
idua smaller
all
al
ller aortic
le ao rtiic ddiameters
ort ia ters
iamet

than the general population or other forms of genetically triggered aortopathy. The absence of

aortic valve or other cardiac malformations appears to markedly reduce the risk of aortic

dissection However, aortic dissection can occur in TS without cardiac malformations or

hypertension. TS individuals > 18 years with an ASI-AAO above 2.5 cm/m2 should be

considered for an aortic operation to prevent aortic dissection.

Key words: aorta; aortic dissection; outcome; sudden death; Turner syndrome

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 DOI: 10.1161/CIRCULATIONAHA.111.088633

Introduction

Aortic dissection occurs in individuals with fibrillin 1 mutations (Marfan syndrome), collagen

mutations (Ehlers-Danlos syndrome), transforming growth factor ȕ receptor mutations (Loeys-

Dietz syndrome), and postulated primary disorders of aortic wall composition such as familial

thoracic aortic disease and dissection (FTAAD), bicuspid aortic valve (BAV) and Turner

syndrome (TS).1 Despite the fact that aortic dissection occurs rarely in TS (36/100,000 person

years) it is six times more common in the TS population compared to the general population.2 It

also occurs at a much younger age in the TS population compared to the general population. The

average age at dissection in the TS population is 30.71 years compared to 68 years3 in the general

female population. To better understand the natural history, risk factors, and ech
echocardiographic
hoc
ocar
a di
diog
ogra
ograph
raphiic

features of aortic dissection in women with TS, the International Turner Syndrome Aortic

Dissection
Diss
Di ssec
ss eccti
tion
on
n (ITSAD)
(IT
ITSA
AD)
D) Registry was established inn 2005.
2 05. This review
20 ew of
of the
the registry data describes

the
he ssigns, symptoms
igns, sym
mpt
ptom
omss and
om echocardiographic
and ec
echo
hoccard
ho card
diogr features
ographicc fe
eatu
ure preceding
ress pr
reced
eced ng aaortic
din rtic ddissection
orrtic issse
sect on in 220
ctio
ctio women
0 wo
wome
meen

with
wiith TS.
TS.
S

Methods

Study Population

A voluntary registry was established to capture cases of aortic dissection in women with TS.

Subjects were recruited through the Turner Syndrome Society of the United States (TSSUS,

http://www.Turneryndrome.org/) and by word of mouth from 2005-2010. Survivors themselves,

or individuals aware of a TS dissection were either mailed a questionnaire or completed it

directly on the TSSUS website. The questionnaire was used to screen subjects so that all those

enrolled in the registry had both Turner syndrome and an aortic dissection. Enrollees were asked

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 DOI: 10.1161/CIRCULATIONAHA.111.088633

to sign medical release forms which were then sent to the primary care provider, primary

cardiologist, and any medical center or medical care provider who administered care during the

dissection event. No subjects had a genetic abnormality other than Turner syndrome. Written

consent was obtained from all subjects or their parents or guardians and a written assent was

obtained from children able to read the form.

Questionnaire

Each subject with TS or her parent completed a standardized questionnaire regarding karyotype,

45,X or non-45,X (non-45,X incudes a variety of other TS chromosomal arrangements), history

of heart disease, prior cardiac surgery, hypertension, growth hormone (GH) therapy, other

medications, thyroid disorders, renal or urologic defects, hearing defects, and oth
other
th medical
her medic
ed ical
ic al

problems.

Data
Da ta collection
col
olle
lect
lectio
ction

All
A ll available
a ailable medical
av dicaal records
medi
me reco
re rdss were
cord
co rd were reviewed
vieewedd with
rev h particular
with parti culaar attention
tiicula attenttion paid
tten paid to Turner
Tur
urnner
ner

genotype/phenotype,
gennoty
ge noty
type
pe/p
pe /phe
/p heno
he nottyp
type, hheart
pe, hear
ear disease
a t di
ise asee ((from
seas
as from
fr om eechocardiographic,
choc
ocar
oc arrdiioggraaph magnetic
phiic, ma
magn e icc rresonance
gnnet e onnan
es cee iimaging,
ance maginng,
mag ng, oorr

evaluation),
autopsy eval
lua
uati
tion
tionn), hhistory
isto
ist ry ooff hy
hypertension,
hype
pert
per en
nsiion blood
on,, bl
bloo pressures,
oood pr
pres
ssu
sure
res,
re s aage,
s, symptoms,
g , sy
ge symp
mpto
mptoms
to outcome,
m , ou
ms outc
tcom
tc ome, surgicall
om

and/or autopsy findings, tissue histology, dates of recent echocardiographic studies, and aortic

root and ascending aortic size. In particular we looked for evidence of serial measurements of

the ascending aortic diameter in order to compute the aortic size index (ASI). ASI4 was

computed by dividing the size of the aortic root or ascending aorta by the body surface area

(BSA).5 All available echocardiogram reports were reviewed. The data from each report

included the date of the echocardiogram, the patient’s height, weight and/or BSA, the diagnosis

and characterization of congenital heart disease if present, and the size of the aortic root and

ascending aorta if available. For the purposes of this study “sinus of Valsalva” diameter was

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 DOI: 10.1161/CIRCULATIONAHA.111.088633

considered to be synonymous with the aortic root diameter. Also, the ascending aorta was

assumed to represent the region above the sino-tubular junction and proximal to the innominate

as recently described6 Study protocols were approved by the Institutional Review Board at

Oregon Health & Science University.

Statistical Analysis

Descriptive analysis (mean and standard deviation for continuous variables, frequency and

relative frequency for categorical variables) was performed on each parameter of interest to

study the distribution of the data. General linear mixed model regression with repeated measures

was used to examine changes over time of the aortic size index at the level of the ascending

aorta.

Results
Resu
Re sult
su ltss
lt

Aortic
A orrtic
rt dissect
dissections
tio
ionns occ
occurred
cccurrre
redd in 220
0 in
ind
individuals
dividdualls bbetween
etwe
ween 11988
we 988 and
988 and 20
2010
010 w
with
ith th
thee me
median
ediian
a ye
year
ear of
ear

2004
20
004 ((Table
T blle 11).
Ta ). Seventeen
Seveent
ntee
eenn of
o the
the 20
20 registry
regi
regi
gist
strry subjects
st sub
ubjjec
jectss had
haad a Stanford
Stan
St an
nfo
ord type-A
typpe-
e-AA aortic
aort
ao rttic ddissection
issseect
ctioon7
io

and three patients

pati
tien
ents
ents developed
dev
e el
elop
oped
ed a type-B
typ
ype-
e-B
B dissection
diss
di ssec
ss ecti
ection
ti on (cases
(ca
case
s s 11,
se 11, 14,
14, 20).
20)
0).. In
In on
onee su
subj
bjec
bj ectt (c
ec
subject (cas
a e #14) a
(case

type-B dissection occurred in the cardiac catheterization laboratory during stent placement for

coarctation of the aorta. Her datum was not included in further comparisons. Thus among the

entire cohort of those with spontaneous aortic dissections only 2/19 (11%) had type-B aortic

dissection.

The average age at the time of dissection was 31.5 years ± 9.1 (range 18 – 48 years).

Eighteen of the 19 subjects had congenital heart disease documented by echocardiography,

surgery, or autopsy. One subject had no history of hypertension and had no evidence of

congenital heart disease (CHD) found during autopsy. All of the 18 subjects with CHD had a

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 DOI: 10.1161/CIRCULATIONAHA.111.088633

BAV. Five subjects had an aortic arch obstruction (3 with repaired coarctation including 1 who

was stented at the time of dissection, and a fourth with previously operated interrupted aortic

arch). The fifth subject had an unrepaired coarctation that was not discovered until autopsy (case

#9). Eighteen of the 19 subjects had documentation of at least one blood pressure measurement.

One third of these subjects (6/18, 33%) met criteria for hypertension based on blood pressure

recordings that were documented in the medical records. Nine of the 19 (47%) subjects were

being treated with antihypertensive medications at the time of the dissection. 10/19 (53%) had

taken growth hormone for short stature.

Symptoms and survival in patients with spontaneous dissection (Table 1)

All but one subject, (1/19, 5%) had symptoms prior to death or operation. One subject
j ct (1/19,
subje
ubje (1/
1/19
19,,
19

5%) died 1 hour after the onset of chest pain. Five additional subjects (5/19, 26%) reported

symptoms
ymp
mpto mss between
toms
to e weeen 1- 24 hours prior to presentation,
bet ti n, but 13 subjects
presentaation c s (13/19,
subjeect (1 3/19, 68%) had symptoms
13/

ffor
or > 24 hourss prior
r or to
pri to presentation.
pres
pr esen
es en
nta
tati on.. The
tion
on The most
ost common
moost co
omm on symptoms
mmoon sym ms were
ympptom
ptom werre chest
we cheestt pain
ainn as
pai a reported
rep
por
ortted

by 116/19
6/19
6/ 1 ssubjects,
19 jects, nneck/
ubjject
ub ecck// bback
ackk pa
ac pain
ain ((6/19),
6/19
6/ ), sshortness
19),
19 t esss off bbreath/dyspnea
hortn
hor reaath/
re h/dy
h/ dysp
dy sppne (5/19),
neaa (5
5/1
/19)
9),, na
9) nnausea/vomiting
usea/v
use /v
vom
mit
itiingg

(5/19), weakness/dizziness
5/19), weak
kne
ness
s /d
ss n sss ((4/19),
dizzziine ) ffeeling
4 199),
4/ e liing ooff do
ee doomm ((2/19),
om 2 199), aand
2/ nd aabdominal
b om
bd omin
inal
inal ppain
ainn (1
ai (1/19).
(1/1
/19)
/1 9).. The initia
9) initial
a

presentation was sudden death for 9 subjects (7/9 presented in cardiac arrest). Seven of the 19

(37%) survived after developing a dissection. The duration of symptoms did not correlate with

likelihood of survival (30% > 24 hours versus 50 % < 24 hours, Fisher’s exact test p=0.99).

However, when younger age is taken into account it appears that death tends to be more likely in

those with a longer duration of symptoms. The small sample size does not allow significance but

the trend appears to be that the younger TS subjects ignore symptoms longer and are more likely

to die. For example, among the TS subjects who were younger than the median age of 31 years,

9 had symptoms > 24 hours prior to presentation and 7 died (78%).

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 DOI: 10.1161/CIRCULATIONAHA.111.088633

Pregnancy

Three registry subjects had a history of pregnancy prior to their aortic dissection (case # 6, 11,

20). In one instance (case #19) a successful pregnancy and delivery occurred 2 years after the

aortic dissection. Of the 3 who were pregnant prior to dissection, one underwent assisted

reproductive therapy (case # 11) in the others (case # 6 and 20) the pregnancies occurred

spontaneously in individuals with mosaic karyotypes. Two of these subjects had spontaneous

type-B dissections (case #11 & 20). Interestingly, these were the only cases of spontaneous

dissection that were type-B in the entire cohort. Case #6 had an unobstructed BAV and had a

type-A dissection. Her ascending aorta was found to be 3.3 cm/m2 that was the largest echo

diameter of the ascending aorta reported in this study. The echo study was performed
perfo
fo
orm d 90
med 90 days
days

prior to her dissection. Case #11 had a type-B dissection in her third trimester. She also had a

BAV,
AV, mild
BA ildd dilation
mil tiion of her ascending aorta, and a large
dilati
di larrge aneurysm
la m of the
of th
he left
le subclavian artery

documented
documented by
docu by CT and
n echocardiography
and ech
chooca
ocardi
ardiiog
ogra hy 8 years
raph
ph yearss prior
or to
prio to tthe
hee ppregnancy.
reggnan
gnanccy. She
cy. Sh underwent
he un
unde
d rw
de rweent assisted
ent as
assi
s sted

reproductive
epr
prod
oduc
od u ti
uc ve ttherapy
tive py ((ART)
herrap
he rapy ART)
AR with
T) w ithh im
it implantation
impl
mplan
anta
an tati
ta tionn ooff tw
ti two embryos.
wo em
mbr
bryo
yoos. Symptoms
s Syymp
mpto m ooccurred
toms
ms ccur
cc urrre at 336
redd at weeks
6 week
w eek
e s

gestation and maternal

d ma
m teern al ddeath
rnal eaath ffollowed
oll
llow e an
owed
ow an emergent
emer
eme ge
er nt cesarean
gent ces
esar
area
ar eann section
ea seccti
se n in
t on in which
whic
wh ichh 2 he
ic healthy
heal
alth
al t y infants
th

were delivered. Post-mortem examination confirmed that the origin of the dissection was at the

takeoff of the aneurysmal left subclavian artery. In case #20 there was a history of a spontaneous

pregnancy 17 years prior to the event. A CT scan identified a left aortic arch and indicated that

the origin of the dissection was at the origin of an anomalous right subclavian artery.

Echocardiography

Fifteen of the 19 registry subjects who had spontaneous dissections had imaging reports with

aortic dimensions available for review. Of those with preceding echocardiograms 7 of the 15

subjects had serial measurements: 5 had serial measurements of the ascending aorta (mean=2.2

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 DOI: 10.1161/CIRCULATIONAHA.111.088633

measurements, range 1 to 5; mean total follow-up time 733 days). 2 had serial measurements of

the aortic root

Among the 9 individuals with type-A aortic dissection and available echocardiographic

data the range of ascending aortic diameter was 2.3 to 5.1 cm (mean = 4.1 ± 0.9 cm). The

minimum ASI-AAO was 1.5 cm/m2 and maximal diameter was 3.3 cm/m2. The average ASI-

AAO was 2.7 ± 0.6 cm/m2 (Figures 1 and 2). In this group the aortic root size index was 2.3 ±

0.4 cm/m2. Four subjects had echocardiograms performed within 2 months of their dissection

(mean = 50 days). In those individuals, the mean ASI-AAO was 3.1 cm/m2.

In the 2 individuals with spontaneous type-B aortic dissections the ASI-aortic root was 2

and 2.1 cm/m2 (cases # 11 and 20) and in case #20 the ASI-AAO was 1.9 cm/m
cm/m2 (not
nott available
m2 (n ava
vail
ilab
ilablle

for case #11).

Growth
Gr
Grow
owth
owth rate
rat
atee

Figure
F igu
gure demonstrates
u 2 dem
mon
onst
s rate
ratess th available
thee av
vai
aila ble eechocardiographic
labble chocaard
rdiogrrap measurements
raphicc measure
reme ntss off tthe
ment ASI-AAO
he A SII-A AO aamong
-AAO mo
ong
g9

individuals
ndi
divi
vidu
vi d al
du who
alss wh
w had
o ha type-A
ad a ty
ype A ddissection
p -A iss
ssec
ecti
ec tion ASI
on A SI ggrowth
r wt
ro rrates
wthh rate
atees we r calculated
were
re calc
calcul
lc ed uusing
u ateed
ul ng llinear
sing
si mixed
ineaar mixe
in mixeed

model regression.
regresssi
sion The
o . T
on mean
hee m ASI-AAO
eann AS
ea SI-
I AA
AAO growth
O gr
grow
owth
ow rrate
th ra t w
te was
as 00.085cm/m2/year
.085
.0 85cm
85 cm/m
cm m2/
2/ye ar ((95%CI
year
ye 95
5%C
%CII -0
-0.11 to

0.82). This result suggests that a significant increase in the aortic growth velocity cannot be

established in this small group since the 95% CI of the growth rate contains a zero value.

Discussion

The results of this study indicate that individuals with Turner syndrome and BAV experience

aortic dissection at a young age and at considerably smaller aortic diameters than those who

develop aortic dissection in the general population. Previous studies have suggested risk is better

predicted by relative aortic size rather than absolute aortic size, therefore, correcting the aortic

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 DOI: 10.1161/CIRCULATIONAHA.111.088633

diameter for the calculated BSA (the aortic size index, ASI) has been proposed.4 This correction

is critical in the TS population because a hallmark of the syndrome is short stature. In the

ITSAD registry, the mean ASI-AAO of subjects with available measurements was 2.7 ± 0.6

cm/m2. Matura et al 8 found the 95 percentile of the ASI-AAO in 166 TS women without

dissection to be 1.96 cm/m2 (mean 1.89 ± 0.34 cm/m2). Consistent with our findings, in that

study the ASI-AAO diameters were greater than 2.5 cm/m2 in the 3 TS individuals who had

dissection. The data from the ITSAD registry supports the conclusion of Matura et al that an

aortic size index of > 2.5 cm/m2 should prompt clinicians to consider an aortic operation to

prevent aortic dissection.

In contrast, Davies et al 4 stratified risk in 805 non-Turner syndrome subj

subjects
bjeects
t w
ts who
ho hhad
ad
ad

either genetically triggered aortopathy or aortopathy syndromes. Davies et al demonstrated that

those
hosse with
with an
an AS
SI-A O of 2.75cm/m2 or less had
ASI-AAO
I-AA ad a ~ 4%/ year dissection
diiss
s eccti
tioon
on risk. In absolute

terms,
erm
ms, the mean
meaan ascending
assceend
n in
ng aortic
ao
ort
rtic
ic measurement
meas
easur
surem
ment inn women
wom
men
en with
witth TS
TS who
who had
had aaortic
orticc di
orti diss
dissection
sseecti
ecti
tion
onn inn

the
he present
pres
pr e en
es entt study
stud
st udyy was
was 4.1
4.1 cm,
cm which
m, wh
whic well
ichh iss w
ic below
elll be
el elo
l w the 5.55 cm tthreshold
the 5. hrressho d pproposed
h ld ropo
ropose
po s d to
se o pproceed
roceed
roc
ceed
dwwith
ih
it

prophylacticc aortic
aor
orti
ticc surgery
s rg
su rger
e y inn the
th
he general
geene
n ra
rall population
popu
popula
pul ti
lat on aand
nd ssignificantly
igni
ignifi
nifica
fic nt
ca ntly
ly llower
ower
ow e tthan
er hann th
ha the
he 5.0 cm

threshold recommended for those with Marfan syndrome or BAV.9

Aortic growth rate as a risk factor

In patients with connective tissue disorders associated with an increased incidence of aortic

dissection such as Marfan or Loeys-Dietz syndrome, the rate of ascending aortic dilatation is

predictive of dissection.10 Based on these findings, patients with Loeys-Dietz and Marfan

syndromes who have a diameter of 4.5-5 cm at the aortic root or rate of increase greater than

0.5cm/yr are referred for surgical intervention to prevent further progression and dissection.11

Lanzarini et al.12 failed to identify progressive aortic dilation on serial echocardiographic

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 DOI: 10.1161/CIRCULATIONAHA.111.088633

measurements of the aortas of 78 Turner patients over a median of 3 years of follow-up.

However that study did not have a dissection cohort for comparison. Among the small group of

five ITSAD registry subjects with available serial echocardiographic measurements we could not

identify a change in there ascending aorta diameters. While an increasing growth velocity of the

aortic diameter is always concerning, these data suggest that aortic dissection can occur in the

setting of normal aortic growth rate.

Other risk factors

Patients with TS have an increased prevalence of BAV, hypertension and aortic coarctation,

which are established risk factors for aortic aneurysm and dissection. Indeed, 95% (18 /19) of

our subjects that experienced spontaneous aortic dissection in the ITSAD registry
registrry also
allsoo had
had a

BAV. BAV is associated with a 9-fold increased risk of aortic dissection in otherwise

genetically
gene
ge neti
ne ticcall
ti call orm
mal -appearing individuals.13 Wh
normal-appearing
llyy no al-a While
hil
ile TS alone is an
n ind
independent
dep
pendent
en risk factor for

aortic
ao
orttic
i enlargement
enlargeme
meentt a cconcomitant
onnco
omi
mita
tant
ta nt B
BAV
AV hhas
as aan
n inc
incremental
creemen
enta
en tall ef
effect
ffe
fecct oon
n ao
aortic
orttic ddimensions
im
men
nsi
s ons
ons att

multiple
mu
ult
l ip l levels
iple
le levelss and
vel and thus
thuus
th us pprobably
blyy contributes
robbabl
babl cont
contrributes to the
bute
te he risk
the rissk for
for dissection.
diss
di s ecti
ss ecti o .14 It is
tion
on is important
i po
imporrtan
rt nt to
t

ecognize, however,
recognize, how
ow
wev
e er
er,, that
th
hat
a approximately
app
ppro
r xi
xima
mate
ma t ly
te y 30%
30% of all
alll those
tho
h see with
witth TS hhave
avee BA
av V 15 14
BAV.
V.

The common occurrence of BAV in this group of TS individuals suggests that those

without BAV have a markedly reduced risk for dissection. Importantly, one subject in our study

(1/19, 5%) who suffered aortic dissection had a completely normal aortic valve, no other

structural cardiac disease at autopsy, and no clinical evidence for hypertension. Our previous

review of the case literature describing 87 Turner individuals with aortic dissection failed to find

structural heart disease or hypertension in approximately 10% of cases.16 Aortic enlargement

and dissection in otherwise completely healthy Turner individuals adds further evidence to the

theory that there is a fundamental large-vessel arteriopathy associated with the Turner

10
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 DOI: 10.1161/CIRCULATIONAHA.111.088633

phenotype.17 14 In this regard, there has been concern that individuals with Turner syndrome are

at greater risk from balloon angioplasty procedures. There was a single case in the ITSAD

registry of type-B dissection that occurred during placement of a stent for coarctation (case # 14).

However, a recent review of outcomes in a large multi-institutional study found no deaths among

29 coarctation angioplasty/stenting procedures in Turner syndrome.18

One subject in the ITSAD registry suffered from an aortic dissection during pregnancy

and 2 others had pregnancies prior to dissection. Approximately 0.5 % of TS individuals

become pregnant spontaneously.19 In the ITSAD registry 1 of the 19 cases of the spontaneous

aortic dissection (~ 5 %) occurred during pregnancy. Furthermore the significance of a remote

unclear. Two cases of pregnancy-associated aortic dissecti

history of pregnancy is unclear. dissection
ion
on w
were
ere re
rece
recently
cent
ce ntly
y

eported20 and a review of the previous literature review describes 7 additional cases.1 In those 7
reported

ca
asees, the
cases, the
he pregnancies
pre
regn
gnan
anci
an c es were the result of assistedd reproductive
ci reproductive therapy
ther
errapyy (ART).
(ART). In six of the cases

the
he dissection
dissection occurred
occuurre
redd du
duri
during
ring
ri ng pregnancy,
preegn
gnan
an
ncy, an
and
nd inn oone
ne ccase
asse iitt ooccurred
ccur
cc urre
redd 1 year
yearr after
aft
fter
err ART.
ART
RT.

Maternal
Ma
ate
tern
rnal
rn al death
dea
eath
th occurred
occcur
urre
redd in 86%
86% of those
thoosee w
who
ho ddissected.
ho isse
issect
c ed.
ed Th
The ne
nnew
w ca
case
see ddescribed
e crrib
es bed
e iin
n th
thi
this
is sstudy
tuddy
tu

(#11)
#11) brings the
the total
tot
otal
a number
al num
u be
berr off reported
rep
epor
o teed di
diss
dissections
ssec
ss ecti
ec tiion
ns du
during
uri
ring
ng aassisted
ssis
ss isted Turner
is Tur
urne
nerr pregnancies
ne prreg
egna
nanc
na ncie
nc i s to 10.

Assessment of the incremental dissection risk caused by pregnancy is problematic since the total

number of Turner pregnancies is not well known. Aortic dissection is estimated to occur in at

least 2% of Turner pregnancies.20, 21 Given the vanishingly small risk of aortic dissection in non-

Turner pregnancy22 the relative risk for dissection for those with Turner syndrome who become

pregnant is considerable. In addition, there is recent evidence that fewer than 40% of Turner

pregnancies are associated with a completely normal fetal-maternal outcome.20 Therefore we

agree with the recent guideline published by the American Society of Reproductive Medicine

that pregnancy is an absolute contraindication for those with TS and a documented cardiac

11
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 DOI: 10.1161/CIRCULATIONAHA.111.088633

anomaly and that those with no cardiovascular disease are at high risk and require “careful

observation and frequent formal monitoring throughout gestation and postpartum.” 23

Strengths/Limitations

This registry represents the largest single group of TS patients that have had a dissection with

accurate medical records to confirm the diagnosis and identify the clinical features associated

with aortic dissection. Medical records were obtained on all of the subjects in the registry to

confirm the presence and type of congenital heart disease, the presence of hypertension, and

other important medical history that may be associated with TS and aortic dissection. The study

is limited in its voluntary nature and inherent selection bias. Thus it is possible that dissections

occurring during the study period were missed.Aortic measurements in the disse
dissection
seecttio
i n

population were obtained from echocardiogram reports and were not directly measured by us.

Finally,
Fi
inaall
llyy,
y, oonly
nly
nly 4 off tthe
he 10 individuals for whom A
ASI-AAO
S -AAO was kno
SI known
noown
w pprior
rioor to dissection had
ri

echocardiograms
ec
cho
ocardiogram
amss within
with
with
thin
in
n 2 months
mon
onth
thss of
of the
the event.
eveent
ent. We cannot
caann
annot
not exclude
excl
clud
ude th
ud the
he poss
ppossibility
osssib
ibil
ilit
itty th
that
att

progressive
prog
pr ogre
og ress
re ivee aortic
s iv
ss aortiic
aort ic enlargement
enl
nlaarggeme n occurred
gemeent occ urreed for
ccuurre for the
he other
th other 6 individuals
inddivi
in diviidu
d al aafter
a s af teer th
thee mostt rrecent
most ecen
en
nt

echocardiogram.
echocardiogr
gram
am.. H
am However,
owev
ow e err, th
ev thiss iiss th
the fi
firs
first
rsst an
andd on
only
nly sstudy
tu
udy tto
o pr
prov
provide
o id
ov de an
anyy se
seri
serial
rial
a
al

echocardiographic data in TS individuals with aortic dissection. We await accrual of subjects to

the ITSAD registry that may help to validate these preliminary observations.

Conclusion

Aortic dissection is a rare but often catastrophic malady in individuals with TS. It occurs in

younger individuals and at significantly smaller aortic diameters than the general population.

The profile of those who dissect include age > 18 years, presence of BAV, and typical symptoms

> 24 hours prior to presentation in more than half of the individuals. The absence of BAV

12
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 DOI: 10.1161/CIRCULATIONAHA.111.088633

appears to markedly reduce the risk of aortic dissection but does not eliminate it. The fact that

death occurs in many younger TS women who have symptoms for more than 24 hours before

they seek medical attention emphasizes the need to increase awareness of the critical significance

of chest pain in young TS women.

The ideal timing for interventions to protect Turner individuals at risk is unknown. In

other aortopathy syndromes that are better studied, such as those with Marfan syndrome, surgical

intervention is postponed unless a significant change in the aortic growth velocity is documented,

or until the absolute aortic diameter is greater than 4.5 cm, a diameter that is larger than most of

the patients in the ITSAD registry. Our results suggest that in Turner syndrome a stable growth

velocity may not be a reassuring finding. We agree with Matura et al.8 that in Turner
Turne
ner individuals
ne in
ndi
divi
vidduals
vi du

> than 18 years of age ASI-AAO > 2.5 cm/m2 may be an indication for preventive operative

intervention.
nteerv
rven
enti
ention
tion.
on

Acknowledgments:
A ckkn
knowledg dgme
ment ntts: The authors
The auuth would
thoorss wo oul thank
uldd likee too th
hannk Dr Thuan
Dr.. Th
T uan N Nguyen,
guyen en,, P
en PhD
hD fofforr ad
additional
ddiitioonall
biostatistical
bi
ios
osta
taati
tist iccal aanalysis
stic naaly
ysi and
siss an
nd he helpful
herr he
help
lpfu
lp ccomments
full comm
fu omm
mmen nts aand Krista
ndd K riist Gaeta
staa Ga
Gaet
etta fo ttechnical
forr tec
echni
chniica assistance.
call asssi
sisstan
an
ncee.

Funding Sour
Sources:
urrce
c s: This
Thiss stu
study
tu
udy w wasa ffunded
as u de
un d d by tthe
he TTurner
urne
ur nerr Sy
Synd
Syndrome
ndro
ndrome
ro me SSociety
ocie
oc iety
ie ty ooff th
the
he UnUnit
United
i ed States
(TSSUS),
TSS
SSUS
US)) GGenentech
enen
en ente ch Center
tech Cen
ente
terr fo Clinical
forr Cl
Clin
inic
ical Research
al R esea
es earrch ((San Francisco,CA),
Sann Fr
Sa Fran
anci
cisc CA)) tthe
scoo CA he EEli Lilly
li L illy
il Company
ly C ompa
om pany
ny
(Indianapolis, IN) Oregon Clinical and Translational Research Institute (OCTRI), grant number
UL1 RR024140 from the National Center for Research Resources (NCRR), a component of the
National Institutes of Health (NIH), and NIH Roadmap for Medical Research (N.A. and T.N.)

Conflict of Interest Disclosures: None.

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 DOI: 10.1161/CIRCULATIONAHA.111.088633

Table 1. Dissection registry subjects

Cardiac diagnosis Hypertension Most recent Ao measurement Location of Symptom

Patient # Age at dissection,y (comment) (Y/N) (cm) ASI dissection duration Outcome
11 18 BAV N Aortic Root: 2.6 2 Type A > 24 hr Death
Asc Ao: 3.2* 2.5*
2 18 BAV, coarctation Y Type A > 24 hr Death

3 21 BAV N Aortic Root: 4,3 2.5 Type A > 24 hr Alive

4 23 BAV, h/o IAA N Aortic Root: 3,2 2.3 Type A > 24 hr Death
Asc Ao: 4.1* 2.9*
5 24 BAV, coarctation N Asc Aorta: 3.6* 3* Type
Typ
ypee A > 24 hr Death
6 27 BAV N Aortic Root: 4.5 3 Type
Typ
pe A > 24 hr Alive
Asc Aorta: 5.0* 3.3*
7 28 BAV N Typee A
Typ < 24
2 hr Alive
8 28 BAV Y Aortic Root: 2.7 1.7 Type A > 24 hr Death
Asc Aorta: 4.2* 2.7*
BAV, unrepaired
9 28
8 coarctation N Aortic
Aort
o ic Root: 3.6 2.5
2.5 Type A < 24 hr Death
Asc
As
A sc Aorta: 4.5*
4.5* 3.2*
3.2.
100 299 BAV Y Aortic
Aortic Root: 2.2
Ao 1.7 Type A > 24 hr Death
11**
1*
** 299 BAV N Aortic
Aortic Root:
Ao Rooot: 3.3
3.3
3 2.1 Typee B
Typ < 24 hr Death
12
2 30 BAV
BA
AV Y Aortic
Aortic Root:
Ao R ott: 3.8
Ro 3.8
8 2
2.5 Type
Typ
ype A > 24
2 hr
h Death
Asc
Asc Aorta:
As Aorta
rta:: 2.3*
rta 2.3* 1.5*
1.5*
1.5
1331 34 BAV N Aortic
Aortic Root:
Ao Rooot:
ot 3.5
3.5 22.2
.2 Typee A
T
Typ < 24
2 hr
hr Death
Asc
A Ao:A : 5.1*
Ao 5.1* 3.2*
3..22*
ccoarctation
coa rctati
rct
cta onn
14 35 (disse
(di
(dissection
ssecti
sse ct on during
dur
uring stent)
stent
st en )
ent Y Aorti
Ao
Aortic
rticc Root
rti R
Root:
oo : 1.8
oot 1.8 11
1.1 Typee B
Typ < 24 hr Alive

15 37 BAV, VSD Y Aortic Root: 3.4 2.2 Type A > 24 hr Death

16 40
0 None
No e
Non N Type
Typ
ypee A < 24 hr Death
17 41 BAV N Typee A
Typ > 24 hr Alive
18 44 BAV N Asc Ao: 4.8 * 2.9* Type A > 24 hr Alive
19 48 BAV/severe AS Unknown Type A < 24 hr Alive
20** 48 BAV,abberrant RSA Y Aortic Root: 3.1 2 Type B >24 hr Alive
Asc Ao: 3.0* 1.9*
mean,SD,med,1stquart,3rdquart 30.5,8.7,28,23.5,38.5 Root=2.3,0.4,2.3,1.9,2.5 Root=3.4,0.7,3.5,2.7,3.9
(for type A dissections only) *Asc Ao=4.1,0.9,4.2,3.4,4.9 *Asc Ao=2.7,0.6,2.9,2.2,3.2
All hemodynamically significant heart defects repaired unless stated otherwise
**Not previously reported, reference is given for known prior reports others may or may not have been reported
AS=aortic stenosis, BAV = bicuspid aortic valve, IAA=interrupted aortic arch, VSD=ventricular septal defect,RSA=right subclavian artery

16
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Figure Legends:

Figure 1. Aortic root and ascending aorta size index in subjects with ascending aorta dissections.

Box plot shows median, minimum, maximum, first and third quartile. To provide a frame of

reference for absolute aortic measurements the ASI-AAO was computed based on the previously

reported average BSA of non-dissection TS women (1.54 m2).8 Dashed line “A” indicates a

diameter of 5.5 cm (ASI-AAO = 3.6), “B” indicates a diameter of 5 cm (ASI-AAO = 3.2), “C”

indicates a diameter of 3.9 cm (ASI-AAO = 2.5 ), and “D” indicates a diameter of 2.9 cm (ASI-

AAO = 1.89) which is the reported value for non-dissection TS women. 8

Figure 2. Ascending aorta size index measuredd by transthoracic echocardiography among 9

individuals
ndiivi
vidu
dual
du alss prior
al prriorr to their ascending aortic dissection.
dissect
ctio
cti n. Lines are serial
io ser
erria
i l measurements
mea
easurements in 5 subjects.
subjects

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Moderate Aortic Enlargement and Bicuspid Aortic Valve are Associated with Aortic Dissection
in Turner Syndrome: Report of the International Turner Syndrome Aortic Dissection Registry
Misty Carlson, Nathan Airhart, Leo Lopez and Michael Silberbach

Circulation. published online October 2, 2012;

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