Turner Syndrome

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Turner Syndrome - An Update
Paul Hofman 2007
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Karyotype versus Phenotype in Turner Syndrome
Karyotype chromosomal structure Phenotype
Physical characteristics how the person looks
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maternal
paternal
q
centromere
Most TS features occur when this area is missing
p
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X Inactivation
q
centromere
p
maternal
paternal
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45XO
Maternal
Paternal/
q
centromere
p
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Karyotype versus Phenotype in Turner Syndrome
There is some correlations but karyotypes are not
predictive of what any particular girl with TS
will have 45XO most common and severest phenotype
(highest incidence of cardiac, renal
abnormalities and other dysmorphic features)
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Karyotype versus Phenotype in Turner Syndrome
45XO/46XX Some cells have normal XX and some have
XO (often called a mosaic pattern as two distinct
cell lines). The frequency of each cell line can
vary from tissue to tissue- this can change the
phenotype. Generally the least severe phenotype.
Increased mean height and spontaneous puberty in
up to 40.
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maternal
paternal
Iso q
q
centromere
q
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Karyotype versus Phenotype in Turner Syndrome
46Xi(Xq) Increased risk of autoimmunity esp
thyroid and inflammatory bowel disease and
deafness. Structural problems uncommon.
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Ring Chromosome
(r)ing
centromere
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Karyotype versus Phenotype in Turner Syndrome
46Xr(X) Ring Chromosome often small and can be
a mosaic pattern (ie not in all
cells) Spontaneous periods in 33. Congenital
abns uncommon. Intellectual dysfunction in those
with a small ring chromosome.
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Karyotype versus Phenotype in Turner Syndrome
45X/46XY Have male karyotype in some cells
(46XY). Often taller and there is an increased
risk of gonadal tumour.
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Imprinting what is it and what does it mean for
Turner Syndrome?
We all possess two alleles for each gene product
one from our mother and one from our father. In
most genes the end result is the combination of
these two alleles (eg handedness). In some genes,
especially those related to growth one allele is
permanently turned off. This occurs at or soon
after fertilisation and is called imprinting.
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X Inactivation
Imprinting also occurs on the X chromosome. One
half of the X chromosomes are randomly
inactivated (ie roughly half maternal and half
paternal) However in 45XO there is only one
chromosome - this is usually maternal (70) but
can be paternal (30) in origin. Does inheriting
only one parents chromosome change the phenotype
seen in TS?
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Parent of Origin Effects
Personality/ learning One British
study Maternal X - poorer verbal skills -
poorer sociobehavioural skills Not substantiated
in several subsequent studies.
Nature 37705-08, 1997
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Parent of Origin Effects
Growth Several studies shown effects on
growth Maternal X - maternal and midparental
height - greater height gain with growth
hormone Paternal X - weakly associated with
parents height. - poorer final height.
JCEM 91 3002-10, 2006 Genetics and Molecular
Research 6(1)1-7, 2007
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Parent of Origin Effects
Hearing Loss one recent study Paternal X -
Strongly associated with an increased risk of
hearing impairment. Of 50 subjects, 23 (46 had
sensorineural hearing loss (SNHL)). 12 of 18 with
Xpat (67) had SNHL versus 11 of 32 Xmat
(34). JCEM 91 3002-10, 2006
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Parent of Origin Effects
Kidneys and eyes Maternal X - all renal
abnormalities occurred in this group Paternal X
- ocular problems more common
JCEM 92 846-852, 2007
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Parent of Origin Effects
Metabolism two recent studies Maternal X -
Increased total abdominal and visceral fat
accumulation. - more atherogenic lipid
profile.
JAMA March 22/29 (12) 295, 1373-74, 2006 JCEM
92 846-852, 2007
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Body Composition
Altered in adult TS (42.5 9.7 years)
showing Increased fat mass including increased
visceral fat. Reduced muscle mass. Reduced
exercise capacity.
n55
n54
European J of Endocrinology, 155 583-92. 2006
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Body Composition
Effect of growth hormone Increased lean and bone
mass Reduced fat mass Effects independent of
oestrogen and still apparent gt one year after
finishing growth hormone.
JCEM 91 4302-05, 2006
n39 11.9 yrs
n28 12.8 yrs
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Body Composition
Effect of oestrogen replacement IM or transdermal
oestrogen may result in reduced fat mass
accumulation. Spray on gel (17b oestradiol) used
in young lean adult TS women (n9, 23 years) for
1 year. Total lean mass increased by 1kg compared
to oral HRT group with no significant change in
fat mass between groups. The route of
administration may be more important than
previously considered watch this space.
Gynecological Endocrinology, 22(10) 590-94, 2006
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Oestrogen route and growth
Oestrogen route of administration may affect
puberty growth spurt. A small study examined
giving IM oestradiol to 7 TS at either 12-12.9
years or 14-14.9 years. Predicted height in both
groups was 150.8 cm. All received growth
hormone. Final height was 154 cm in the early
pubertal induction group and 152.9 cm in the late
pubertal induction group
JCEM, 906424-30. 2005
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Oestrogen route and growth
This equates to a pubertal height gain of 17.3
cm in the early oestrogen group 15.0 cm in the
late pubertal group 11.4 cm after oral oestrogen
therapy at 12 years age. Oral oestrogens have
major effects on the liver which maty reduce
pubertal growth. Transdermal oestrogen now
available here Watch this space!
JCEM, 906424-30. 2005
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Cognition and Turner Syndrome
Non verbal disability Characterised by -
deficits in maths and science - Impaired
performance in visuo-motor tasks that have
a spatial component. - impaired adaptation to
novel situations - impaired social competence -
increased anxiety and depression - Increased
ADHD (18 fold increase in TS)
Hormone Research, 65 47-56. 2006. J Ped.
Psychology31(9) 945-55, 2006
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Cognition and Turner Syndrome
Therapeutic recommendations (by Harnadek and
Rourke)
J Learning Disability, 27144-54. 1994.
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Cognition and Turner Syndrome
a) Sex Steroid Effects on the Brain b) Lack
of an X chromosome/ genes involved in
neurocognitive development and behaviour c)
Imprinting (? real) d) Environmental
interactions
Hormone Research, 65 47-56. 2006
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Sex Steroid Effects
Oestrogen Improves adult womens verbal memory,
articulatory speed and fine motor
abilities. Oestrogen supplementation to young TS
girls has improved verbal memory. Doesnt
improve spatial deficits.
Hormone Research, 65 47-56. 2006
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Sex Steroid Effects
Androgen TS women are also androgen
deficient. Higher testosterone levels in men and
women associated with better spatial ability,
mathematics and problem solving. Women tx with
androgens after ovariectomy have improved
memory, complex information processing and
logical reasoning. Oxandrolone tx of TS girls
improved working memory after 2 years of tx
Hormone Research, 65 47-56. 2006
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Haploinsufficiency (one chromosome)
Most of the genes involved in neurocognitive and
behaviour involve areas of the X chromosome that
dont get inactivated and there are usually two
copies of the gene available. Therefore in TS
there is a reduction in the gene dose and
possible developmental consequences as a
result.
Hormone Research, 65 47-56. 2006
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Environment
Shyness, social anxiety and impaired self esteem
reduced equally in adults with TS (n100, age
34.7 years) and women with premature ovarian
failure (n100, 30.9 years) and healthy controls
(n35, 35.8 years).
Hormone Research, 65 47-56. 2006
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Self reported psychosocial function and body
image perception
30 TS women (age 22.1 years) matched to 44 non TS
women (20.5 years). No difference on most scores
including all behavioural and emotional problems.
They perceived themselves as socially less
competent. BMI was related to the appraisal
score.
Hormone Research, 66 277 277-84. 2006
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Self perception profile
Hormone Research, 66 277 277-84. 2006
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Self-Esteem and social adjustment influence of
pubertal management and sexuality
French! 566 young adult TS women (18.3-31.2
years) Low self esteem associated with - hearing
impairment - limited sexual experience
JCEM 912972-79, 2006
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Self-Esteem and Social Adjustment influence of
pubertal management and sexuality
Low social adjustment associated with lower socio
economic class and an absence of sexual
experience Age at pubertal development associated
with age at first sexual experience. Delayed
pubertal induction had a long lasting effect on
sex life.
JCEM 912972-79, 2006
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Turner Syndrome Incidence, diagnostic delay and
mortality

• Danish Cytogenetic register 781 TS between
  1970-2001.
• Incidence 50/100,000 (12000 female births)
• There was a delay in diagnosis with the mean age
  being 15.1 years! Although this is historical
  many patients still seem to be missed until their
  20s.
• There is a decreasing age at diagnosis over the
  30 years study period.

JCEM 913897-02, 2006
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JCEM 913897-02, 2006
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Turner Syndrome mortality
Overall mortality was increased compared to the
general population (standardised mortality rate
(SMR) 2.86 almost 3 times the risk of
dying) There was a karyotype risk with XO
SMR4.08 isoXq SMR 3.86 other karyotypes
SMR 2.1
JCEM 913897-02, 2006
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Turner Syndrome mortality
Commonest causes of death Congenital
abnormalities (probably mainly cardiac) Coronary
artery disease Metabolic/ endocrine (eg
inadequate HRT) DIABETES MELLITUS was a
contributing cause of death in 22 of cases.
JCEM 913897-02, 2006
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Thank You