Paul Hofman

2007
Karyotype versus Phenotype in
Turner Syndrome

Karyotype = chromosomal structure

Phenotype = Physical characteristics –
‘how the person looks’
maternal paternal

centromere

p Most TS features
occur when this
area is missing
X Inactivation
q

centromere

maternal paternal
45XO
Paternal/ Maternal
q

centromere

p
 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)
 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%.
maternal paternal

Iso q
q

centromere

q
 Karyotype versus Phenotype in
Turner Syndrome
46Xi(Xq) Increased risk of autoimmunity esp
thyroid and inflammatory bowel disease and
deafness. Structural problems uncommon.
 Ring Chromosome

(r)ing

centromere
 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.
 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.
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.
 ‘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?
 Parent of Origin Effects
Personality/ learning – One British study
Maternal X
- poorer verbal skills
- poorer sociobehavioural skills
Not substantiated in several subsequent studies.

Nature; 37:705-08, 1997

 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
 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
 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

 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
 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.
n=55
n=54 European J of Endocrinology,
155: 583-92. 2006
 Body Composition
Effect of growth hormone
Increased lean and bone mass
Reduced fat mass
Effects independent of oestrogen and still apparent
> one year after finishing growth hormone.

JCEM 91: 4302-05, 2006

n=28 n=39
12.8 yrs 11.9 yrs
 Body Composition
Effect of oestrogen replacement
IM or transdermal oestrogen may result in reduced
fat mass accumulation.
Spray on gel (17 oestradiol) used in young lean
adult TS women (n=9, 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
 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, 90:6424-30. 2005

 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, 90:6424-30. 2005
 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
 Cognition and Turner Syndrome

Therapeutic recommendations (by Harnadek and

Rourke)

J Learning Disability, 27:144-54. 1994.

 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

 Sex Steroid Effects

Oestrogen
Improves adult women’s verbal memory,
articulatory speed and fine motor abilities.
Oestrogen supplementation to young TS girls
has improved verbal memory. Doesn’t improve
spatial deficits.

Hormone Research, 65: 47-56. 2006

 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
Haploinsufficiency (one chromosome)

Most of the genes involved in neurocognitive and

behaviour involve areas of the X chromosome that
don’t 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

 Environment

Shyness, social anxiety and impaired self esteem

reduced equally in adults with TS (n=100, age 34.7
years) and women with premature ovarian failure
(n=100, 30.9 years) and healthy controls (n=35,
35.8 years).

Hormone Research, 65: 47-56. 2006

 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

 Self perception profile

Hormone Research, 66: 277: 277-84. 2006

 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 91:2972-79, 2006

 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 91:2972-79, 2006

 Turner Syndrome – Incidence,
diagnostic delay and mortality
Danish Cytogenetic register – 781 TS between
1970-2001.
Incidence: 50/100,000 (1:2000 female births)
a) 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.
b) There is a decreasing age at diagnosis over the
30 years study period.
JCEM 91:3897-02, 2006
JCEM 91:3897-02, 2006
 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 SMR=4.08
isoXq SMR= 3.86
other karyotypes SMR = 2.1

JCEM 91:3897-02, 2006

 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 91:3897-02, 2006
Thank You