Transcript Xs and Os of Turner Syndrome

Xs & Os of Turner Syndrome
Karine Khatchadourian MD, MSc, FRCPC
Pediatric Endocrinologist CHEO
May 7, 2016
Objectives
Diagnosis of Turner Syndrome
To review the major health issues that are
associated with Turner’s Syndrome and the
general screening necessary for these
issues
To understand the main hormonal heath
issues that we screen for in Turner’s
Syndrome and to discuss how they are
managed
Turner Syndrome (TS)
Common condition present in 1 in 2000 to
1 in 2500 newborn girls
We talk about syndrome when doctors see
several clinical features that tend to occur
together
The diagnosis of TS requires the presence
of these features + absence of all or part of
second X chromosome in some or all cells
of the body
Features of Turner Syndrome
and Frequency
Very frequent (>50%)
Growth deficiency
Absent pubertal development
Infertility
Recurrent ear infections
Lymphedema of hands and feet (swelling)
Tendency towards obesity
High arched palate, small lower jaw, dental
crowding
Some learning disability
Features of Turner Syndrome
and Frequency
Frequent 25-50%
Short 4th finger in hand
Eyes: ptosis (droopy eyes) and strabismus
(eyes misaligned)
Feeding problems
Sensorineural hearing loss
Kidney malformation
Hypertension (high blood pressure)
Increased birth marks (naevi)
Features of Turner Syndrome
and Frequency
Less Frequent 10-25%
Scoliosis
Heart issues: stenosis (coarctation) of aorta,
bicuspid aortic valve
Thyroid: hypothyroidism and even less
frequent is hyperthyroidism
Increased liver enzymes
Diabetes Mellitus
Features of Turner Syndrome
and Frequency
Uncommon (<10%)
Patellar dislocation
Congenital hip dislocation
Celiac Disease
Inflammatory Bowel disease
Osteoporosis
Aortic dissection
Juvenile Rheumatoid Arthritis
Genetics
~ 50% 45X
Mosaicism
Structural abnormalities
of the X chromosome
Small percentage have
some Y chromosome
material
Screening at diagnosis of TS
Adapted from Care of Girls and Women with TS: A guideline of the Turner Syndrome Study Group: J Clin Endo Metab 2007
All patients
Cardiovascular evaluation by specialist
Renal ultrasound
Hearing evaluation by an audiologist
Evaluation for scoliosis/kyphosis
Evaluation for knowledge of TS; referral to support groups
Evaluation for growth and pubertal development
Ages 0–4 yr
Evaluation for hip dislocation
Eye exam by pediatric ophthalmologist (if age > 1)
Ages 4–10 yr
Thyroid function tests (T4, TSH) and celiac screen (TTG Ab)
Educational/ psychosocial evaluations
Orthodontic evaluation (if age > 7)
Age > 10
Thyroid function tests (T4, TSH) and celiac screen (TTG Ab)
Educational and psychosocial evaluations
Orthodontic evaluation
Evaluation of ovarian function/estrogen replacement
LFTs, FBG, lipids, CBC, Cr, BUN
BMD (if age >18 yr)
Ongoing Monitoring in TS
Adapted from Care of Girls and Women with TS: A guideline of the Turner Syndrome Study Group: J Clin Endo Metab 2007
All ages
Cardiological evaluation as indicated
Blood pressure annually
ENT and audiology every 1–5 yr
Girls <5 yr
Growth Rate Annually
School age
Liver and thyroid screening annually
Celiac screen every 2–5 yr
Educational and social progress annually
Dental and orthodontic as needed
Older girls and adults
Fasting lipids and blood sugar annually
Liver and thyroid screening annually
Celiac screen as indicated
Age-appropriate evaluation of pubertal development and
psychosexual adjustment
Growth
At least 95% of girls with Turner Syndrome
(TS) have short stature
The cause of short stature is likely related
to a complex interaction of various
hormonal and genetic effects
Growth can be affected in all stages of life
in an individual with TS
Growth
Intrauterine growth restriction (IUGR) has
been reported to occur in newborns with
TS
Studies have revealed that newborns with
TS are born in the low normal range for
length compared to newborns without TS
-an average length 2.8cm below the mean
Poor growth may be noticed in infancy
Growth
The poor growth that occurs in childhood in
girls with TS is felt to be composed of 2
main features
-delay in the onset of the childhood
component of growth
-decreased growth velocity throughout
childhood and adolescence
Absent pubertal growth spurt
Growth in girls with TS: missing
one copy of SHOX gene found
on X chromosome
http://www.medscape.org/viewarticle/445555
Short Stature: Combination 2
Main Factors
TS girls growth hormone levels are typically
normal
-There is however impaired response at the level of
the growth plates to their own growth hormone
Missing one copy of SHOX
TS Growth Curve
Untreated girls with TS
Average height 144 cm
(4 foot 9 inches)
Around 20 cm lower
(8 inches) shorter than
women without TS
←164 cm
←144 cm
Treatment with
Growth Hormone
Synthetic growth hormone (made in the lab) used
as treatment for over 25 years
Growth hormone given by injection 6-7 times a
week until growth completed
Growth expected with growth hormone: 2-4 inches
(5-10 cm) above expected final height without GH
treatment
Treatment with
Growth Hormone
Treatment monitored every 4-6 months by
pediatric endocrinologist
Adjustments based on weight, growth velocity and
value of IGF-1 (blood test indirectly looks at GH)
Treatment continued until:
Growth slows down to <2 cm per year
Bone age of 14 years (tells us growth plates have
closed)
Better
Response to Growth Hormone
1. Longer duration of treatment (started younger)
2. Taller parents leading to taller mean parental
height
3. Taller height at start of treatment
4. Compliance (taking the medication)
5. Higher dose of growth hormone
Growth Hormone Treatment
It is estimated that girls with TS can reach
an average adult height of 150cm with GH
therapy
A Canadian Study showed an average
height gain of 7.3cm over girls who were
not treated1
1 Canadian Growth Hormone Advisory Committee. Impact of Growth Hormone
Supplementation on Adult Height in Turner Syndrome: Results of the Canadian RCT.
2005 J Clin Endocrinol Metab 90: 3360
Growth Hormone Side Effects
Generally very safe
Side effects rare:
1.Fluid retention (swelling hands/legs)
2.Elevated fluid pressure in brain: benign intracranial
hypertension
3. Displacement of growth plate of femur: Slipped
capital femoral epiphyses (SCFE)
4. May lead to higher blood sugars
5. Curvature of spine (scoliosis)
Key Points
Short stature key feature in TS
Treatment with growth hormone has
shown to improve final height in girls
with TS
Let’s talk about Puberty!
Period of time during which sexual
development occurs
Usually starts between ages 8 -13 in girls
Tanner staging: the physical changes of
puberty on a scale of 1 to 5
Tanner Staging
Carel JC and Leger J, N Eng J Med 2008
Normal Puberty
(ages on average)
Breast: 10 ½ - 11 yrs
Pubic Hair: 11 ½ yrs
Peak Growth Spurt:
12 yrs
Menarche (first period):
12 ½ yrs
Bone growth stops
within 2 years after
menarche
Rosen DS. Pediatric in Review 2004
Babic B and Kives S, Turner Syndrome: Across the Lifespan
Androgens from Adrenals
(Adrenarche) is normal in girls with TS
Androgens: pubic hair, body odour
Babic B and Kives S, Turner Syndrome: Across the Lifespan
Girls with Turner syndrome
Genes on X chromosome important for ovarian
development and function
Egg loss accelerated leading to ovarian failure
Most girls don’t enter spontaneous puberty
(up to 30% will)
16% have first period spontaneously although will
end prematurely in most
Goal and Benefits of Estrogen
in Girls with TS
Growth/Initiate puberty
Improved self-esteem and quality of life
May improve verbal and not verbal memory
Improve risk for cardiovascular disease
Bone strength/ osteoporosis
Estrogen Side Effects in
Girls with TS
Replace the estrogen that ovaries should normally
be producing
Side effects uncommon
Nausea
Fluid retention
Irregular bleeding
Mood swings
Estrogen Treatment in
Girls with TS
Follow patient to see if spontaneous puberty up to
age 11-12
Doctor will order tests:
FSH: Follicular Stimulating Hormone
LH: Luteinizing hormone
Estradiol
Bone Age
FSH
LH 
Babic B and Kives S, Turner Syndrome: Across the Lifespan
Timing of Treatment
Depends on height
Depends on age of diagnosis
Depends on timing of growth hormone initiation
Depends on bone age
(usually start at bone age 11)
Treatment
If no spontaneous puberty, estrogen started age
12-13 yrs
If spontaneous puberty, follow progression, might
need estrogen eventually
Visit to endocrinologist every 6 months
Dose gradually increased every 6 months over 2-3
years
Treatment
Estrogen for growth:
breast, uterine
Estrogen for long-term
Addition of progesterone
After 2 yrs on estrogen or if there are signs of
breakthrough bleeding
Addition of Progesterone
Progesterone added
first 10-12 days of each month
to mimick
normal menstrual cycle
Treatment
After 2 years on estrogen treatment alone:
1. Estrogen 1 tablet daily (or patch) + Progesterone
1 tablet daily first 10-12 days of each month
Or
2. Estrogen + Progesterone combined in Oral
Contraceptive Pill (1 tablet daily) or Patch
Forms of Estrogen
Tablet
Estrace
Transdermal Patch
Estraderm, Estradot
Patch to be cut (1/6-1/8 initially)
Changed once or twice weekly
Forms of Estrogen
Both oral tablet and Patch similar results for:
Breast growth
Linear growth
Lipid profile
One study found increase in bone mineral density
and uterine growth with transdermal patch
Cost similar
Question of preference and compliance
Oral Progesterone
(added once we see breakthrough bleeding)
Provera
(medroxyprogesterone acetate)
Combination
estrogen + progesterone
Oral contraceptive pill
- Different brand names
(Alesse, Marvelon)
Transdermal patch
-Ortho Evra
Other treatments not standard
of care
Androgen (testosterone treatment)
Estrogen started earlier (infancy and
childhood)
Key Points
Most girls with TS have ovarian failure
Need help with treatment to enter/progress
through spontaneous puberty
Estrogen treatment usually initiated age
12-13 and then progesterone added later
on
Autoimmune Disease
Increased Risk for autoimmune
disease
Hypothyroidism most common
-5-40% of girls/women with TS
Celiac Disease
-4-6% of girls/women with TS
Cardiovascular Screening
Adapted from Care of Girls and Women with TS: A guideline of the Turner Syndrome Study Group: J
Clin Endo Metab 2007
Screening: all pts at time of Dx
evaluation by a cardiologist with expertise in CHD
comprehensive exam including blood pressure in all extremities
all require clear imaging of the heart, aortic valve, aortic arch, pulmonary veins
echo for infants and young girls
MRI and echo for older girls and adults
ECG
Monitoring: follow-up depends on clinical situation
For pts with apparently normal CVS and age-appropriate BP
reevaluation with imaging at timely occasions: transition, before attempting
pregnancy; appearance of HTN. Girls who have only had an echo should have an MRI
when old enough
otherwise imaging q5-10 yrs
For pts with pathology: as per cardio
Cardiovascular risk factors
Increased risk of obesity
Hypertension 50%
Impaired glucose tolerance in 10-34%
Type 2 diabetes 4x more common / also
earlier than the general population
Increased cholesterol levels
Screening at diagnosis of TS
Adapted from Care of Girls and Women with TS: A guideline of the Turner Syndrome Study Group: J Clin Endo Metab 2007
All patients
Cardiovascular evaluation by specialist
Renal ultrasound
Hearing evaluation by an audiologist
Evaluation for scoliosis/kyphosis
Evaluation for knowledge of TS; referral to support groups
Evaluation for growth and pubertal development
Ages 0–4 yr
Evaluation for hip dislocation
Eye exam by pediatric ophthalmologist (if age > 1)
Ages 4–10 yr
Thyroid function tests (T4, TSH) and celiac screen (TTG Ab)
Educational/ psychosocial evaluations
Orthodontic evaluation (if age > 7)
Age > 10
Thyroid function tests (T4, TSH) and celiac screen (TTG Ab)
Educational and psychosocial evaluations
Orthodontic evaluation
Evaluation of ovarian function/estrogen replacement
LFTs, FBG, lipids, CBC, Cr, BUN
BMD (if age >18 yr)
Ears & Eyes
Ear
-Middle Ear Infections common
-conductive hearing loss
-sensorineural hearing loss
-speech
Eyes
-Amblyopia/ Strabismus
-farsightedness
-Red-green color deficiency
Bones
Increased risk of decreased BMD
Risk Factors:
-estrogen non-compliance
-vitamin D deficiency
-smoking / alcohol
-celiac disease
Ensure good Calcium and Vitamin D
intake
Weight bearing exercise
Other
Skeletal System
-Increased risk of congenital hip dislocation
-Scoliosis and kyphosis
Learning
-Impairment of nonverbal skill
math, direction sense
-Increased rate of ADD (24%)
-Excel at verbal skills, many adults University level
education
Other
Urinary tract
-Congenital malformations 3040%
Liver disease
-elevated liver enzymes
-usually not associated with true
disease
Transition
At time of completion
of growth and puberty
Gradual shifting from
parent to adolescent
Transition of focus
from growth to puberty
and sexual
development
Healthy eating and
active living
Adult care plan with
new health care
provider
Bondy et al. Care of Girls and Women with Turner Syndrome: A guideline of the Turner Syndrome Study Group. J Clin Endo Metab:
92 (1) :10-25
Conclusions
Girls and women with TS face different
health challenges at different ages and
stages
A health check-list (or screening program)
facilitates the medical care of girls and
women with TS
By maintaining a regular follow-up with
your health care team and a healthy
lifestyle you can ensure ongoing optimal
health!
THANK YOU FOR YOUR
ATTENTION!
Special thanks to Dr Ahmet for help with slides