Sex Chromosome Structure And Abnormalities

Question 1

What is important about PAR1 and where is it?

Answer 1

Sits at the top of Xp
Pairs with the Y
Contains the SHOX gene
Does not undergo X inactivation

Question 2

What other key areas exist on the X?

Answer 2

• X inactivation center at Xq13
• Xp11.2-p22.1 implicated in ovarian failure
• Xq13-q26 is critical region for ovarian function and breakpoints within here have been associated with gonadal insufficiency(except Xq22)

Question 3

Briefly describe the structure of the Y chromosome.

Answer 3

Pseudoautosomal region on Yp - common to X and Y and pairs during meiosis
SRY sits proximal to PAR
Distal Yq - heterochromatic block which can be variable in size

Question 4

What are the main sex chromosome syndromes?

Answer 4

Turner
Klinefelter
XYY
Multiple X Syndromes

Question 5

What is the most common cause of Turner syndrome?

Answer 5

Monosomy X (55%)

Question 6

What are the other causes of Turner syndrome (other than straight forward 45,X)

Answer 6

~25% have an abnormal X such as i(X)(q10)

~15% are mosaic either for 45,X or for structural abnormalities

Question 7

What percentage of Turner syndrome pregnancies are lost before term?

Answer 7

95%

Question 8

What are some of the typical features that you would see in someone with Turner syndrome? (Particular thought to newborn v childhood v adolescent.)

Answer 8

Newborn: small for dates (maybe IUGR in pregnancy) and excess skin at nape of neck (cystic hygroma in pregnancy).

Childhood:

• Short stature
• wide spaced nipples (shield shaped chest)
• broad chest
• short neck and low hairline
• cubitus valgus (elbows bow outward)

Adolescence:

• short stature
• delayed puberty (no secondary sexual characteristics)

Question 9

What are the other classic features of Turner syndrome? What would you not typically expect to see?

Answer 9

20-30% have congenital heart malformations
33-60% have structural kidney anomalies (horseshoe kidney)
Streak ovaries
Infertile
No secondary sexual characteristics

They do not typically have any mental retardation.

Question 10

What is the origin Turner syndrome associated with?

Answer 10

Advanced paternal age.

Question 11

What is the liveborn frequency of Turner syndrome?

Answer 11

1 in 2000-5000

Question 12

Why do the ovaries degenerate in Turner syndrome?

Answer 12

Genes on the X chromosome are necessary for ovarian MAINTENANCE

Such genes communicate with genes on the autosome to maintain normal ovaries, if they are missing the ovaries will degenerate.

Question 13

How may mosaic Turner syndrome patients differ to non-mosaic?
What numerical cell lines might you see in a mosaic?

Answer 13

• may have milder phenotype
• may be taller
• may spontaneously enter puberty
• likely to have secondary amenorrhea and premature menopause due to low numbers of oocytes
• may be fertile
• may sometimes see 47,XXX cell along with 45,X and 46,XX (dependant on when the error occurred)

Question 14

What structural abnormalities might be seen in Turner syndrome? What affect might this have on the phenotype?

Answer 14

• i(X)(q10)
• r(X)
• del(Xq)

May show fewer Turner features. Some may retain fertility as the structurally abnormal X can partially synapse with the normal X and segregate in a 1:1 manor.

Question 15

What needs to be ascertained if the karyotype is 45,X/46,X,+mar?

Answer 15

Whether the marker contains any Y material.

If Y material present in a phenotypic female then there may be an elevated risk of gonadoblastoma.

Question 16

Why might you potentially see a more severe phenotype in a patient with 45,X/46,X,+mar?

Answer 16

If the marker is X derived and doesn’t contain XIST.
There won’t be any X inactivation so will end up with functional disomy, phenotype will depend on genetic content of marker.

Question 18

What are the treatment options for Turner syndrome?

Answer 18

Growth hormone treatment
Puberty treatment - hormones can be used to cause secondary sexual characteristics to develop and can be cycled to induce periods (Turner patients have a functioning womb, it’s just their ovaries that degenerate)
Fertility - oocyte donation, gamete or embryo transplant

Surgery to remove streak ovaries if Y material is detected.

Question 19

If a patient has a low level 45,X cell line with the majority 46,XX, should we be concerned? What could explain it?

Answer 19

If the patient doesn’t have any features of Turner Syndrome then no.
This could just be age related loss of X.

Question 20

What are the critical regions that are associated with premature ovarian failure?

Answer 20

Critical region 1: Xq21.1

Critical region 2: Xq23-q28

Question 21

What can occur if breakpoints disrupt either of the critical regions on the X?

Answer 21

Premature ovarian failure (POF).

This is the failure of the ovaries before 40 years of age.

Question 22

What causes Klinefelter Syndrome?

Answer 22

47,XXY

A male with an extra X chromosome.

Question 23

What is the main clinical indication in Klinefelter Syndrome? When do they usually present?

Answer 23

They usually present as adults with fertility issues.

Question 24

How common is Klinefelter Syndrome?

Answer 24

1 in 500-1000.

Question 25

What other clinical features might you see in a Klinefelter patient? Are these mild or severe?

Answer 25

• may be tall
• disproportionally long limbs
• may have gynaecomastia (there is a resulting increased risk of breast carcinoma)
• may be mild developmental delay
• IQ may be lower than unaffected siblings

Features tend to be mild, they are often just part of ‘normal’ population until they try to have children.

Question 26

Why are Klinefelter patients infertile?

Answer 26

Primarily due to low testosterone and this causes underdevelopment of the testes.

Question 27

What are the other sex chromosome abnormalities?

Answer 27

47,XYY
47,XXX
48,XXXY
48,XXXX
49,XXXXY
49,XXXXY

Question 28

What is the most common mechanism behind the polysomies such as XXXX, XXYY, XYYY, XXXY, XXXXX, XXXXY?

Answer 28

Successive non-disjunctions in one parent with the other parent contributing a single sex chromosome.

Question 29

Briefly describe the expected phenotype in a patient with 47,XXX?

Answer 29

Very mild phenotype:

• mild developmental delay,
• mild motor delay.

But varies wildly and is generally considered to be ‘normal variant’

Question 30

What phenotype do you see in the remaining sex chromosome polysomies? What is the main cause of this?

Answer 30

Mental retardation - extent worsening with increased number of X’s, severe 49,XXXXX and XXXXY.
Some can have ‘Downs like’ features.
Reduced fertility.

The extra Xs will all be inactivated - it is the small regions which aren’t inactivated which cause the phenotype.