Turner syndrome in
childhood and adolescence
– a multifaceted state of health
Line Cleemann, MD. August 2009
1
PhD thesis
Department of Pediatrics
Hillerød Hospital
Copenhagen University May 2009
Public defense October 2009
2
Turner syndrome
• Great diversity
• ↑ morbidity
• Osteoporosis, diabetes, hypertension
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Turner syndrome
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Great diversity
↑ morbidity
Osteoporosis, diabetes, hypertension
↑ mortality
Cardiovascular disease, congenital
malformations of the heart
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Turner syndrome
• Well-established treatments:
• Growth hormone
• Female sex hormones (estrogen)
5
Turner syndrome
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Well-established treatments:
Growth hormone
Female sex hormones (estrogen)
↑ focus on associated diseases
→ increased well-being
6
Turner syndrome
• Health-issues need research
• Morbidity / mortality / quality of life
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Turner syndrome
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Health-issues need research
Morbidity / mortality / quality of life
Normal size of the uterus
Bone health
Aortic dilation
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Turner syndrome
• Absent pubertal development
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Turner syndrome
• Absent pubertal development
• Spontaneous puberty ~ 30%
• Spontaneous pregnancies ~ 2-5%
• Premature ovarian failure ~ 95%
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Turner syndrome
• Absent pubertal development
• Spontaneous puberty ~ 30%
• Spontaneous pregnancies ~ 2-5%
• Premature ovarian failure ~ 95%
• Female sex hormones (estrogen)
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Estrogen
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Puberty
Feminization
Uterus
Bone
Heart
Brain
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The Uterus
• Conventional treatment with estrogen
• Pubertal induction √
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The Uterus
• Conventional treatment with estrogen
• Pubertal induction √
• Normal size and shape of the uterus ÷
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The Uterus
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Conventional treatment with estrogen
Pubertal induction √
Normal size and shape of the uterus ÷
Optimal estrogen treatment ?
”Window” of opportunity
Estrogen dose/duration
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The Uterus
• Methods of examination
• Ultrasound transabdominal
• Observer-dependent
16
The Uterus
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Methods of examination
Ultrasound transabdominal
Observer-dependent
Magnetic resonance imaging (MRI)
Accurate measurements
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The Uterus
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Methods of examination
Ultrasound transabdominal
Observer-dependent
Magnetic resonance imaging (MRI)
Accurate measurements
Never used in TS
Uterus and ovaries
Future fertility treatment!
18
The Bones
• ↓ Bone mineral
density (BMD)
• ↑ Osteoporosis and
fractures
19
The Bones
• Method of examination
• DEXA-scan
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The Bones
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Method of examination
DEXA-scan
Underestimates the ”true” BMD
Body size
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The Bones
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Method of examination
DEXA-scan
Underestimates the ”true” BMD
Body size
Adjustment factors
Normal BMD in some studies
No consensus
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The Bones
• Clinical use difficult
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The Bones
• Clinical use difficult
• ↑ Fracture risk
• But normal / reduced BMD?
24
The Bones
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Clinical use difficult
↑ Fracture risk
But normal / reduced BMD?
Multiple factors
Bone size, geometry, architecture and quality
→ Bone strength
Partly independent of BMD
25
The Bones
• Bone-achitecture
• modeling ↔ remodeling
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The Bones
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Bone-achitecture
modeling ↔ remodeling
By-products in blood and urine
Biochemical bone markers
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The Bones
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Remodeling
Bone formation ↔ bone resorption
Coupled
Adulthood
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The Bones
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Remodeling
Bone formation ↔ bone resorption
Coupled
Adulthood
Modeling
Bone formation / bone resorption
Un-coupled
Childhood
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The Bones
• Postmenopausal women
• Combined use of bone markers and BMD in
fracture risk assesment
• The same in TS?
30
The Heart
Congenital heart
disease
Bicuspid aortic
valve 13-34%
Coarctation of the
aorta 4-14%
Dilation ? Perhaps
up to 50%
Dissection ?
Hypertension
30-50 %
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The Heart
• ↑ Aortic dissection
• Young and adult
women with TS
CH. Gravholt Cardiol Young, 2006; 16:1-7
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The Heart
• ↑ Aortic dissection
• Young and adult
women with TS
• 2-8 % of all deaths
in TS
• 10-25 % no obvious
cause
CH. Gravholt Cardiol Young, 2006; 16:1-7
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The Heart
• Individual risk prediction?
• No consensus guidelines
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The Heart
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Individual risk prediction?
No consensus guidelines
Continuous evaluation of aortic dimensions
Individuals presumed to be at risk
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The Heart
• Clinical use difficult
• Dilation → dissection ???
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The Heart
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Clinical use difficult
Dilation → dissection ???
Body size!
No normative data
Method of examination
37
The Heart
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Method of examination
Echocardiography (ECHO)
Magnetic resonance imaging (MRI)
Never before in girls and young women with
TS
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Study Design
• Cross-sectional study
• Longitudinal study - ongoing
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Participants
• 41 girls and young women with TS
• Mean age 16.7 years (11.2-24.9)
• Recruited from all regions of Denmark
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Participants
• 2 groups of controls:
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Participants
• 2 groups of controls:
• 50 healthy, age-matched girls and young
women
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Participants
• 2 groups of controls:
• 50 healthy, age-matched girls and young
women
• 107 healthy girls and young women matched
for pubertal development stage
• Historic controls
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Methods
• All TS
• Physical examination
• Blood and urine tests
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Methods
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All TS
Physical examination
Blood and urine tests
DEXA-scan of the bones
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Methods
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All TS
Physical examination
Blood and urine tests
DEXA-scan of the bones
Ultrasound of the uterus and ovaries
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Methods
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All TS
Physical examination
Blood and urine tests
DEXA-scan of the bones
Ultrasound of the uterus and ovaries
MRI of the uterus and ovaries
MRI of the aorta
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Methods
• Controls:
• Blood and urine
samples
• DEXA-scan of the
bones
• MRI of the uterus
and ovaries
• MRI of the aorta
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Methods
• Controls:
• Blood and urine
samples
• DEXA-scan of the
bones
• MRI of the uterus
and ovaries
• MRI of the aorta
• Controls (historic):
• Pubertal stage
• Ultrasound of the
uterus and ovaries
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Results….
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Anthrometrics
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TS compared to controls:
↓ Height
↔ Weight
↑ Body mass index
↓ Body surface area
↑ Body fatt
↓ Muscle mass
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Puberty and Hormones
n/N (%)
Spontaneous puberty
21/41 (51)
Induced puberty
16/41 (39)
Prepubertal stage
4/41 (10)
Patients with spontaneous puberty
Spontaneous menarche
Yes
9/21(43)
No
12/21(57)
Current use of HRT†
HRT
Yes
30/41 (73)
No
11/41 (27)
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Puberty and Hormones
n/N (%)
Spontaneous puberty
21/41 (51)
Induced puberty
16/41 (39)
Prepubertal stage
4/41 (10)
Patients with spontaneous puberty
Spontaneous menarche
Yes
9/21(43)
No
12/21(57)
Current use of HRT†
HRT
Yes
30/41 (73)
No
11/41 (27)
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Puberty and Hormones
n/N (%)
Spontaneous puberty
21/41 (51)
Induced puberty
16/41 (39)
Prepubertal stage
4/41 (10)
Patients with spontaneous puberty
Spontaneous menarche
Yes
9/21(43)
No
12/21(57)
Current use of HRT†
HRT
Yes
30/41 (73)
No
11/41 (27)
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Puberty and Hormones
• Age at initiation of estrogen therapy
• 13.6±1.7 years (10.5-17.4 years)
• Recommendation ~ 12 years
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Puberty and Hormones
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Age at initiation of estrogen therapy
13.6±1.7 years (10.5-17.4 years)
Recommendation ~ 12 years
Duration of treatment
4.0±2.2 years
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The Uterus
• Mean uterine volume by MRI
• ↓ in TS compared to controls
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The Uterus
• Mean uterine volume by MRI
• ↓ in TS compared to controls
• Mean uterine volume by US
• ↔ in TS and controls
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Ultrasound
120
Controls
Turner syndrome
100
80
Uterine volume (ml)
P=0.007
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P=0.03
40
20
0
B1
B2
B3
B4
B5
Tanner stage (breast)
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US or MRI?
• MRI measured a slightly larger uterine size
than US
• More precise
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US or MRI?
• Detection of ovaries
• Ultrasound 27% (n=11)
• MRI 44% (n=17)
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US or MRI?
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Detection of ovaries
Ultrasound 27% (n=11)
MRI 44% (n=17)
Detection of follicles (eggs)
Ultrasound 24% (n=10)
MRI 33% (n=13)
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The Bones
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TS compared to controls:
↓ Bone mineral density (BMD)
Shaft of the lower arm
The hip
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The Bones
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TS compared to controls:
↓ Bone mineral density (BMD)
Shaft of the lower arm
The hip
↔ BMD
The spine
The distale part of the lower arm
Correcting for body size
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The Bones
0.7
Turner syndrome;
R=0.59, P<0.0005
Controls;
R=0.56, P<0.0005
0.6
aBMDarm
g/cm2
0.5
0.4
0.3
10
12
14
16
18
Age (years)
20
22
24
26
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The Bones
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Bone markers
TS compared with controls
↔ bone formation markers
↑ bone resorption markers in TS
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The Bones
2
Turner syndrome;
R= -0.875, P<0.0005
Controls;
R= -0.725, P<0.0005
1
0
ln-CTX
µg/L
-1
-2
-3
10
12
14
16
18
20
22
24
26
Age (years)
67
The Aorta
Pos4 Pos5
Pos3
Pos2
Pos1
Pos6
Pos7
Pos8
Pos9
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The Aorta
• Definition dilation/dissection
• Results from the control group
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The Aorta
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Definition dilation/dissection
Results from the control group
Dilation =
Diameter > mean diameter +2SD
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The Aorta
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Definition dilation/dissection
Results from the control group
Dilation =
Diameter > mean diameter +2SD
Dissection=
Diameter > mean diameter x 1.5
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The Aorta
• Mean aortic diameters in all positions
• Absolute and adjusted for body surface area
• ↓ or ↔ in TS compared to controls
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The Aorta
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Mean aortic diameters in all positions
Absolute and adjusted for body surface area
↓ or ↔ in TS compared to controls
In 4 patients with TS
• Aortic dilation in 1-4 positions
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The Aorta
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Mean aortic diameters in all positions
Absolute and adjusted for body surface area
↓ or ↔ in TS compared to controls
In 4 patients with TS
Aortic dilation in 1-4 positions
In 1 patient with TS
Aortic dissection in 1 position
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The Aorta
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Controls
Regression Controls
Turner Syndrome
Regression TS
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26
24
Aortic diameter
at pos2 (mm)
22
20
18
16
14
0.8
1.0
1.2
1.4
1.6
1.8
2.0
BSA (m2)
75
The Aorta
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Controls
Regression Controls
Turner Syndrome
Regression TS
24
22
20
Aortic diameter
at pos7 (mm)
18
16
14
12
10
0.8
1.0
1.2
1.4
BSA (m2)
1.6
1.8
2.0
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The Aorta
• Correlation between body surface area and
aortic dimensions in all positions
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The Aorta
• Correlation between body surface area and
aortic dimensions in all positions
• Congenital heart disease:
• Co-arctation of the aorta (former)
• Bicuspid aortic valve
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In conclusion.....
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The Uterus
• A smaller uterus in TS
• → conventional treatment with estrogen
insufficient for uterine growth
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The Uterus
• A smaller uterus in TS
• → conventional treatment with estrogen
insufficient for uterine growth
• More ovaries and follicles were detected by
MRI than US
• → future treatments of infertility
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The Uterus
• A smaller uterus in TS
• → conventional treatment with estrogen
insufficient for uterine growth
• More ovaries and follicles were detected by
MRI than US
• → future treatments of infertility
• Ovarian biopsies
• Cryopreservation
• Later re-implantation
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The Bones
• Bone mass accrual in TS
• Sufficient at the spine and the hip
• Insufficient at the shaft of the lower arm
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The Bones
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Bone mass accrual in TS
Sufficient at the spine and the hip
Insufficient at the shaft of the lower arm
Not responsive to estrogen treatment
Genetics
Prepubertal estrogen
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The Bones
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Bone mass accrual in TS
Sufficient at the spine and the hip
Insufficient at the shaft of the lower arm
Not responsive to estrogen treatment
Genetics
Prepubertal estrogen
↔ Bone formation in TS and controls
↑ Bone resorption in TS
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The Bones
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Bone mass accrual in TS
Sufficient at the spine and the hip
Insufficient at the shaft of the lower arm
Not responsive to estrogen treatment
Genetics
Prepubertal estrogen
↔ Bone formation in TS and controls
↑ Bone resorption in TS
→ Imbalance in bone modeling
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The Aorta
• The first study
• Evaluate aortic dimensions in girls and young
women with TS by MRI
• Compared to age-matched controls
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The Aorta
• The aorta was not enlarged in TS
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The Aorta
• The aorta was not enlarged in TS
• Body surface area predicted aortic size
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The Aorta
• The aorta was not enlarged in TS
• Body surface area predicted aortic size
• More accurate identification of the pediatric
patients with TS at risk of future dissection
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Future Perspectives
• Infertility
• One of the most significant problems
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Future Perspectives
• Infertility
• One of the most significant problems
• Optimizing the growth of the uterus
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Future Perspectives
• The vast majority of adult bone mass
• Childhood and adolescence
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Future Perspectives
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The vast majority of adult bone mass
Childhood and adolescence
Prevent childhood fractures
Delay the development of osteoporosis
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Future Perspectives
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The vast majority of adult bone mass
Childhood and adolescence
Prevent childhood fractures
Delay the development of osteoporosis
Estrogen treatment obvious
Consensus and guidelines needed
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Future Perspectives
• Explanatory factors
• Aortic dilation / dissection
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Future Perspectives
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Explanatory factors
Aortic dilation / dissection
Updated guidelines
Threshold for aortic diameter
Medical or surgical therapy
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Collaborators
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Hillerød Hospital:
Dep. of Pediatrics
Dep. of Gynecolgy and Obstetrics
Dep. of Clinical Physiology
Dep. of Imaging and Radiology
Dep. of Clinical Biochemistry
The Hospital Administration
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Extern partners
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Aarhus University:
Medical dep. M (Endocrinology and Diabetes)
Medical Research Laboratories
Dep. of Clinical Biochemistry
Rigshospitalet, Copenhagen:
Dep. of Growth and Reproduction
Statens Serum Institut
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Thanks to….
• All the girls and young women with TS and
their families
• The Danish Turner Syndrome Society
• My supervisors:
• Professor Sven O. Skouby
• Kirsten Holm, MD, PhD
• Claus H. Gravholt, MD, DMSc
• And many, many more……
100
Thank you for your
attention!
101
Questions?
102