1. Turner Syndrome -
An Update
Paul Hofman
2007

2. Karyotype versus Phenotype in
Turner Syndrome
Karyotype = chromosomal structure
Phenotype = Physical characteristics – ‘how the person looks’

3. q centromere p Most TS features occur when this area is missing
maternal
paternal q
centromere
Most TS features occur when this area is missing p

4. X Inactivation q
centromere p
maternal
paternal

5. 45XO
Paternal/
Maternal q
centromere p

6. 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)

7. 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%.

8. maternal
paternal
Iso q q
centromere q

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

10. Ring Chromosome
(r)ing
centromere

11. 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.

12. 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.

13. 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.

14. ‘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?

15. 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

16. 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: , 2006
Genetics and Molecular Research 6(1):1-7, 2007

17. 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: , 2006

18. Parent of Origin Effects
Kidneys and eyes
Maternal X
- all renal abnormalities occurred in this group
Paternal X
- ocular problems more common
JCEM 92: , 2007

19. 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, , 2006
JCEM 92: , 2007

20. 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:

21. 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: , 2006
n=28
12.8 yrs
n=39
11.9 yrs

22. 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 (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): , 2006

23. 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 years or years. Predicted height in both groups was cm. All received growth hormone.
Final height was 154 cm in the early pubertal induction group and cm in the late pubertal induction group
JCEM, 90:

24. 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:

25. 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: J Ped. Psychology31(9): , 2006

26. Cognition and Turner Syndrome
Therapeutic recommendations (by Harnadek and Rourke)
J Learning Disability, 27:

27. 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:

28. 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:

29. 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:

30. 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:

31. 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:

32. 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:

33. Self perception profile
Hormone Research, 66: 277:

34. Self-Esteem and social adjustment – influence of pubertal management and sexuality
French!
566 young adult TS women ( years)
Low self esteem associated with
- hearing impairment
- limited sexual experience
JCEM 91: , 2006

35. 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: , 2006

37. Turner Syndrome – Incidence, diagnostic delay and mortality
Danish Cytogenetic register – 781 TS between
Incidence: 50/100,000 (1:2000 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 91: , 2006

38. JCEM 91: , 2006

39. 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: , 2006

41. 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: , 2006

42. Thank You