Paul Hofman2007

Karyotype versus Phenotype in Turner Syndrome

Karyotype = chromosomal structure

Phenotype = Physical characteristics – ‘how the person looks’

p

q

centromere

Most TS features occur when this area is missing

maternal paternal

p

q

centromere

X Inactivation

maternal paternal

p

q

centromere

45XOMaternalPaternal/

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%.

q

q

centromere

maternal paternal

Iso q

Karyotype versus Phenotype in Turner Syndrome

46Xi(Xq) Increased risk of autoimmunity esp thyroid and inflammatory bowel disease and deafness. Structural problems uncommon.

(r)ing

centromere

Ring Chromosome

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, 2006Genetics 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, 2006JCEM 92: 846-852, 2007

Body CompositionAltered in adult TS (42.5 ± 9.7 years) showing:

Increased fat mass including increased visceral fat.

Reduced muscle mass.

Reduced exercise capacity.

European J of Endocrinology, 155: 583-92. 2006

n=54n=55

Body CompositionEffect 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=2812.8 yrs

n=3911.9 yrs

Body CompositionEffect 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 growthOestrogen 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 growthThis 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 EffectsAndrogen

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

sexualityFrench!

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

sexualityLow 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