DIAGNOSIS AND MANAGEMENT OF YOUNG
WOMEN WITH TURNER SYNDROME (TS)
Carolyn Bondy, MD
National Institute of Child Health,
National Institutes of Health (NIH)
Center for Human Reproduction
April 9, 2013
I have no declarations and no
conflict of interest in regards to this
presentation
Objectives
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Criteria for diagnosis of Turner syndrome (TS)
Epidemiology and chromosomal origins
Diagnostic tests and screening evaluation
Potential for endogenous fertility
Outcomes of spontaneous and OD pregnancies
Medical management
Psychosocial concerns
X chromosome genomic imprinting and ischemic
heart disease
Monosomy X or TS: combined
clinical & genetic dx
• Absent or fragmented
2nd sex chromosome
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Patients have given
written authorization for
use of photos
Phenotypic female
Early ovarian failure
Short stature
Congenital heart defects
Hypothyroidism
Hearing loss
Osteoporosis
NICHD TS PROTOCOL 2001-2012
• 400 participants 7-67 yrs
• Recent focus on
cardiovascular evaluation
• ~100 participants in
longitudinal follow-up
studies focused on aortic
complications and
ischemic heart disease
STUDY PARTICIPANTS BY AGE GROUP
Epidemiology
• 1/200 conceptions
• 1/2500 live births
• <50% adults with TS are
diagnosed
• Sporadic
• Not clearly related to maternal
age
• All races & regions
• Only monosomy compatible
with life
Stochholm K et al. JCEM
2006;91:3897-3902
Chromosomal Origins
• Non-disjunction of sex chromosomes during meiosis
– 45X
• Non-disjunction during early embryonic mitoses
– Cell line mosaicism: 45X/46XX; 45X/47XXX; 45X/46XY
– Abundance of normal cell line typically attenuates phenotype
• Fragmentation of a sex chromosome during meiosis
– 46XiXq, 46XdelXp, 46XdelY
– Loss of the fragmented X or Y in some cells
during embryonic development
cell line mosaicism 45X/46XiXq, etc
The Lyon Hypothesis
• In cells with multiple Xchromosomes, all but one
are inactivated during
embryogenesis
• X-inactivation leads to
clumped chromatin, termed
Barr bodies, considered
inert (Lyonization)
• So is the 2nd X totally
superfluous?
Why a 45,X phenotype ?
• Pseudoautosomal genes
– Present on both X & Y
– Not inactivated
• SHOX – short stature
• ??Congenital heart disease
Pseudoautosomal
region 1 (PAR1)
Y
X
PAR2
Trimethylation of H3 at Lys4;
Khalil et al, 2007
• Genomic imprinting of Xlinked genes
• 46,XX females are 50:50
mosaic for XM & XP
– 45,X females are
monosomic for XM OR XP
– ??Ischemic heart disease
Presented age 27 - infertility
•OCP to regulate
menses age 15
•Cont. til age 25
•Father 6’, mother 5’5”
•Her predicted ht 5’6”
•High-arched palate
•Low posterior hairline
•Cubitus valgus
45,X[45]/46,XrX[5]
Clues from PMH, FH and PE
• Chronic otitis, shorter than sisters, less than
mid-parental height (F-5” + M)/2; history
Coarc repair, other CHD
• Mx nevi, high-arched palate, short 4th MCP or
MTP, short or web neck, low hair line, low set
ears
To confirm the diagnosis of TS
 20-30 cell peripheral blood karyotype is gold
standard
 3-5 ml blood in heparinized tube at room T˚
 Cytogenetics referral lab
 2-3 wk turnaround & costly
 New methods
 Whole genome snp chips
Affymetric Cytosnp
B allele
frequency
Log R ratio
Karyotype =
46,X, del (Xp11)
Illumina Hapmap Bead Chip
46,X,idic(X)(p11)
Troublesome karyotypes
ring
marker
Further study to identify Y-materialFISH, PCR or array
Concern about Y chromosome material
 ~12% risk for gonadoblastoma
 large primordial germ cells, immature
granulosa or Sertoli cells , stromal cells
 Unknown risk for conversion to
malignancy, e.g., dysgerminoma
 Anecdotal evidence
 Standard of care at present –
laparascopic bilateral gonadectomy
 Psychological counseling
 Consider preservation of ovarian
follicles
Fertility Preservation in Girls with Turner Syndrome
Borgström Birgit, Hovatta Outi -Karolinska Institutet, JCEM 2009
• 15/56 biopsied girls
had ovarian follicles
• Recommend
laparascopic
harvesting/freezing
of juvenile ovarian
tissue for later
fertility
Ovarian Failure in TS
 Fetal ovaries develop normally but experience accelerated follicular atresia
 Biphasic FSH levels – difficulty in predicting spontaneous puberty (Conte et al.,
1975)
 Spontaneous menarche in ~16% (Pasquino et al., 1997)
 More common in 45,X/46,XX
 2 amenorrhea or irregular cycles in ~half of these girls within 2 yrs
 Spontaneous pregnancy in 1-2%
NICHD, NIH, DHHS
Illustrative Case
• Swedish woman with menarche and full pubertal
development age 13, irregular menses
• Premature menopause diagnosis ~age 32
• At least two unsuccessful IVF w/donated oocytes
• Spontaneous pregnancy age 36 w/ NSVD
• 2nd spontaneous pregnancy age 38
– Htn, chest pain, aortic dissection 7th month
– Emergency C-section and aortic repair
• Endocrine clinic- 45,X/46,X,delY—DX TS
• Prophylactic gonadectomy age 40
Journal of Assisted Reproduction and
Genetics 21;229-230,
Comments…
• Consider the diagnosis of TS
– Hypergonadotropic hypogonadism
• Do not assume infertility if Y chromosome
material is detected
– Oocyte preservation
• Serious cardio complications in natural as
well as ART pregnancies
Illustrative case(2)
• DG- classic presentation of TS dx’d at birth
• Participated in pediatric GH Rx protocol in 1990’s.
– Started on estradiol at age 12 per protocol; dose escalated
to full pubertal development by age 15, lost to f/u
• Spontaneous full term pregnancy age 18
– Evaluated in our TS protocol at age 20
• Height 4’7”, single kidney, BAV, FSH 40, no visible ovaries
• Prescribed OCP for HRT
– Returned for protocol f/u age 25 - 3 mo pregnant
• Delivered 2nd healthy son at full term and reportedly resumed OCP
– PBC karyotype 200/200 cells 45,X; skin bx 45,X
Comments (2)
• Patients, parents and care-givers of girls with
full blown TS dx’d in infancy may assume
pregnancy is not possible or that the girl will
not sexually active
• Importance of patient/parent sex education in
this special situation
X chromosome genes and fertility
Gene dose
Short
BAV
Stature
POF
Autoimmunity
(>25 yo)
45,X
1 Xp, 1 Xq
100%
32%
95%
32%
46,X,delXp
1 Xp, 2 Xq
100%
27%
90%
20%
46,X,i(Xq)
1 Xp, 3 Xq
100%
22%
95%
38%
46,X,del(Xq)
2 Xp, 1 Xq
10%
0
100%
5%
46,XX
2 Xp, 2 Xq
1%
<0.5%
1%
5%
SS, BAV and autoimmunity clearly related to haploinsufficiency for Xp
genes
POF seems equally prevalent in Xp deletions with normal or even extra
Xq complement, and in Xq deletions with normal Xp complement
NIH study, Hadnott et al
• Of 276 women with Turner syndrome >25 yr:
– 88% had no children
– 9% adopted children
– 3% spontaneous or assisted pregnancy (1)
• Participants had a total of 13 pregnancies and 14 live
births
• One child had cerebral palsy; the others were
chromosomally and developmentally normal.
• One pre-eclampsia
• One (mother of twins) has dilation of asc. aorta
Fertility and Sterility
Volume 95, 2011, 2251–2256
Oocyte donation in TS
• Karnis et al 2003 estimated ~2% maternal
mortality (F&S)
– Aortic rupture or dissection
• Chevalier et al 2011 < 35% of women prescreened for CVS disease
– Poor fetal and maternal outcomes; 2/93 patients
died due to aortic rupture (JCEM)
• Hagman et al 2013 reviewed 122 deliveries- no
fatalities and generally good fetal outcomes
Aortic diameters in a TS pregnancy
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AA
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STJ
Week Pregnancy
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C-section
30 yo married social worker had IVF,
referred to cardiologist at 12 wks
Initial echo showed probable BAV
and ? aortic dilation
Followed monthly until 24 wks when
↑ in AA diameter noted; betablocker initiated
Elective C-section at 37 wks
Follow-up echos return to baseline?
Fatal aortic dissection 2 yrs later
ASRM pages
Increased maternal cardiovascular mortality associated
with pregnancy in women with Turner syndrome
•Practice Committee of the American Society for Reproductive Medicine
•Received 22 November 2011. Accepted 29 November 2011. Available online 21 December 2011.
 TS a relative contra-indication to pregnancy
 Comprehensive cardiological and maternal-fetal medicine
eval. before considering pregnancy by oocyte donation.
 Cardiac MRI revealing any significant abnormality and/or
ASI >2 cm/m2 (ascending aortic diameter/BSA) represents
an absolute contraindication for attempting pregnancy in a
woman with Turner syndrome.
 Women with normal cardiac MRI and evaluation who
decide to attempt pregnancy after thorough counseling are
still at much higher risk for associated morbidity and
mortality and require careful observation and frequent
formal reevaluation throughout gestation and postpartum.
Medical Management
Prevalence
Screen
TX
F/U
Short stature
99%
Predicted ht
NA
NA
Ovarian fail.
95%
Hx, PE, FSH
Estrogen/prog
Annual
Heart
50%
Cardiol./CMR
Thyroid
40-50%
TSH, abs
Thyroxine
Annual
Hearing loss
30-50%
Audiometry
Amplification
Q3 yr or prn
HTN
30-40%
BP, 24h
monitor
Standard
Annual
Renal anom
30%
Ultrasound
Correct obstr.
PRN
Osteoporosis
25%
DXA/size*
HRT, standard
Adm, q3-5 yr
Metabolic
25-30%
Lipids, CRP, HA1c
Standard
Annual
Liver
30%
LFTs , US
Celiac
5%
tTG, EMA
Abn-per cardiol
WNL- q3-5 yr
Annual LFTs
Gluten free
Prn
• Gradual induction of sexual maturation
beginning by age 12
• Full dose by age 18 through ~ age 40
– OC, 2 mg estradiol, 100 mg transdermal estradiol
– Best choice for cycling is unknown
– Adherence is paramount
• Beginning age 35-40
– lower dose, plan to taper and dc by age 50
HRT and Bone Health in TS
Age 30, 45X
HRT age 12-18,
off 18-30yrs
Age 30, 45X
HRT since age 12
SCREENING FOR CHD IN TS
Normal and Coarcted Aortas
Aortic Valve: Bicuspid or tricuspid?
TAV
BAV
Dilation of Ascending
Aorta
A
Cardiac magnetic resonance
angiography (CMRA) showing a dilated
ascending aorta (solid arrow) and
normal descending aorta (open arrow).
This patient has a distinctive squaring
off and elongation of the transverse
aortic arch with a prominent kink at the
transition to descending aorta
(arrowhead) termed ETA.
Although the actual diameter of the
ascending aorta in this woman was
only 3.7 cm, which is considered at the
upper limit of normal for women of her
age, it is almost 3-fold larger than the
descending aorta (normal
ascending/descending ratio is < 1.5).
B
3.7 cm
Value of CMR in TS
• Diagnose occult but clinically significant
– Coarctation - dissection
– Anomalous pulmonary veins
• Detects abnormal aortic valve in 15% of cases not visualized
on cardiac echo
• Visualize entire aortic arch revealing ascending dilatation
relative to descending
NICHD, NIH
Ho et al, Circulation, 2004; Matura et al, Circulation 2007; Sachdev et al,
JACC 2008
Shortcomings of Cardiac Echo
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28 yo Latina
Routine GH and ERT
Hashimoto’s thyroiditis
Cardiac echo age 18 –
mild coarc
• Cardiac echo at 25
“stable”
• BP 125/85; Ht 4’10”
• neck webbing; 3/6
diastolic murmur
R
BAV w/ AR; Asc ao aneurysm 4 cm
Descending ao aneurysm 6.1 cm
Illustrative Case 3
• 62 yo woman referred for osteoporosis
– PMH -Coarc repair age 12, always short, no puberty,
Cochlear implants, no medications
– Recent back pain prompted plain Xrays (aortic
calcifications) and DXA (diffuse osteoporosis)
– PE- Many signs of TS, appearing considerably older than
62. Disparity in right and left arm BP (R>L). Bilat carotid
bruits. Tanner 1 breast and T2 pubic hair.
• What test(s) would you order?
CT Angiography
L. subclavian a.
Coarc repair
True lumen
Aortic
dissection
False
lumen
R. Kidney
Proximal stenosis of left subclavian artery
Atherosclerotic plaque with ulceration and dissection of the
abdominal aorta, occlusion of l. renal a.
Calcified coronary plaques
Final comments
• It is never too late to diagnose TS
• There is an excess of atherosclerosis as well as
congenital heart disease
QOL Issues in TS
• Carel et al in JCEM 2005-2006
– disappointment with GH treatment for SS. Self-esteem
and social adjustment in young women with TS more
influenced by pubertal management and sexuality
• NIH
– major concerns related to TS (Sutton et al 2005)
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Infertility
Short stature
Sexual development and function
Health
Importance of “Truth Telling”
• During interview sessions addressing concerns about living with TS, 30/97
participants spontaneously mentioned that all or part of their TS
diagnosis had been withheld from them
• Fifteen girls and women from whom a secret had been kept knew every
aspect of their diagnosis except the infertility component
– “The doctor finished his exam and I got dressed and went in. And he just kind of
stopped, put his pen down and went, ‘you know you’re not having kids ever, don't
you?' So that was the hardest time.” (Diagnosed at 17, learned of infertility at 19.)
– “I did get upset with my mother [when I found out]…. She… didn't explain. She said,
‘Well, what’s the big deal?' I said, ‘I think it would have helped me to understand myself
a little bit better. To tell—to fill in the gaps to tell you more of the story.’” (Diagnosed at
17, learned infertile at 28)
– “There I am at this sterile place. And I found out that since the age of 9 to 16, everyone
knew something I had no knowledge of about me that was pretty darn important. I was
told [I was infertile] in such a horrendous way. And all I knew was that the people that I
trusted forever were willing to betray me.” (Diagnosed at 9, learned infertile at 16).
Sutton et al, Peds 2006
Shyness, Social Anxiety, and Impaired Self-Esteem in
Young Women with Ovarian Failure
Shyness
• NIH Study
– Women with
46,XX with normal
ovarian function
(NC)
– Women with
46,XX premature
ovarian failure
(POF)
– Women with TS
NICHD, NIH
Social Anxiety
40
25
20
30
15
10
20
5
10
0
NC
TS
POF
NC
Self-Esteem
TS
POF
Depression (CES-D)
40
15
35
10
30
5
25
0
NC
TS
POF
NC
TS
POF
Schmidt et al.,
JAMA 2006
Psychosocial Outcomes in TS
• Adults w/ TS 25 yr and older in NIH Study*
– N=261
– Average age 38 yr; average height 147 cm
– 65% had a baccalaureate degree (vs. 25% US women)
– 6% had advanced degree (vs. 3% US women)
– 80% employed (vs. 55% US women)
• Similar findings in recent Danish registry study- suggesting
ascertainment bias not crucial (Stochholm et al EJE, 2012)
*Gould et al, J Women’s Health 2013
X Chromosome Imprinting
• Genomic imprinting of X-linked genes
– Men monosomic for XM
– Because or random X-inactivation, women are
~50:50% mosaic XM & XP
– Genes imprinted or silenced on XM will be
expressed in ~50% of female but in no male
cells
– Genes imprinted on XP will be expressed in
~50% of female but suppressed in male cells
46,XMY
46,XMX
P
• To test hypothesis that X imprinting
causes gender differences in body
composition and IHD risk, we compare
groups of women monosomic for XM vs.
XP
XM
NICHD, NIH
XP
Body Composition & IHD Risk Factors
• We compared
– BMI
– Total body fat (by DXA)
– Visceral and sc abdominal fat
by CT
– Lipids
• In age-matched women
monosomic for XM vs. XP
• Both groups had ovarian failure
and very low levels endogenous
sex steroids
NICHD, NIH
XM
XP
Visceral Fat and IHD Risk Factors Selectively
Increased in XM Women
XP
XP
XM
P
BMI
26 (6)
27 (6)
0.15
BF%
36 (8)
37 (8)
0.55
VAT
14 (8)
25 (19)
<0.001
TGs
101 (42)
132 (60)
0.02
LDL-Ch
103 (41)
137 (44)
0.005
NICHD, NIH
XM
Van et al., JAMA, 2005
Incidence of coronary disease related to
parental origin of the single X
• Further study to determine actual incidence of
coronary atherosclerosis
– >age 34 - CT Ca++ score
– “pure” 45X
– Parental DNA for POO genotyping
X Chromosome Origin and
Atherosclerosis
Parental Origin Of X-chromosome
P
Paternal X (n=15)
Maternal X (n=35)
Age; years (SD)
42.6 (7.7)
45.6 (7.0)
0.155
BMI; kg/m2 (SD)
28.4 (7.9)
28.6 (6.6)
0.81
Estrogen Index % (SD)
74.5 (34.3)
75.4 (31.1)
0.89
Family CAD history n (%)
2 (13.3%)
5 (14.3%)
0.93
Obesity n (%)
6 (40%)
15 (42.9%)
0.85
Dyslipidemia n (%)
7 (47%)
21 (60%)
0.39
Hypertension
4 (27%)
19 (54%)
0.068
Diabetes n (%)
3 (20%)
7 (20%)
>0.99
Tobacco use n (%)
1 (6.7%)
3 (8.6%)
0.82
Prevalence n (%)
0
14
0.0021*
Calcium score; AU (SD)
0
91.7 (312.4)
0.0052$
CORONARY ATHEROSCLEROSIS
Coronary atherosclerosis
%
Coronary atherosclerosis determined by CT Ca++
46,XMY
45,XM
46,XX
45,XP
60
50
40
30
20
10
0
45-54
Age group (years)
Comparing healthy population data from Framingham
XM Linked to Abdominal Adiposity and
IHD Risk
• Normal 46,XMY men and 45,XM
women
– Greater visceral adiposity,
atherogenic lipids &
Inflammation compared to 46,
XM XP women
– This is not due to sex steroids
45,X
M
46,XMY
• 46,XX protection may be due to
imprinting of unknown X-linked
genes resulting in:
– Selective expression high risk
genes from XM
– Selective expression of
protective genes from XP
PM
46,XMXX
NICHD, NIH
XP
Gratitude
• NICHD
–
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Vladimir Bakalov
Harley Gould
Liat Gutin
Clara Cheng
Jian Zhou
Helen Hougen
Rachel Poliquin
Kateri McCarthy
• NHLBI
– Douglas R Rosing
– Andrew Arai
– Vandana Sachdev
• NIH CC Radiology
– Vincent Ho
– Ahmed Gharib
• Girls and women with
TS and their familes