Sex Chromosome Structure And Abnormalities Flashcards
What is important about PAR1 and where is it?
Sits at the top of Xp
Pairs with the Y
Contains the SHOX gene
Does not undergo X inactivation
What other key areas exist on the X?
- 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)
Briefly describe the structure of the Y chromosome.
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
What are the main sex chromosome syndromes?
Turner
Klinefelter
XYY
Multiple X Syndromes
What is the most common cause of Turner syndrome?
Monosomy X (55%)
What are the other causes of Turner syndrome (other than straight forward 45,X)
~25% have an abnormal X such as i(X)(q10)
~15% are mosaic either for 45,X or for structural abnormalities
What percentage of Turner syndrome pregnancies are lost before term?
95%
What are some of the typical features that you would see in someone with Turner syndrome? (Particular thought to newborn v childhood v adolescent.)
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)
What are the other classic features of Turner syndrome? What would you not typically expect to see?
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.
What is the origin Turner syndrome associated with?
Advanced paternal age.
What is the liveborn frequency of Turner syndrome?
1 in 2000-5000
Why do the ovaries degenerate in Turner syndrome?
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.
How may mosaic Turner syndrome patients differ to non-mosaic?
What numerical cell lines might you see in a mosaic?
- 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)
What structural abnormalities might be seen in Turner syndrome? What affect might this have on the phenotype?
- 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.
What needs to be ascertained if the karyotype is 45,X/46,X,+mar?
Whether the marker contains any Y material.
If Y material present in a phenotypic female then there may be an elevated risk of gonadoblastoma.
Why might you potentially see a more severe phenotype in a patient with 45,X/46,X,+mar?
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.
What are the treatment options for Turner syndrome?
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.
If a patient has a low level 45,X cell line with the majority 46,XX, should we be concerned? What could explain it?
If the patient doesn’t have any features of Turner Syndrome then no.
This could just be age related loss of X.
What are the critical regions that are associated with premature ovarian failure?
Critical region 1: Xq21.1
Critical region 2: Xq23-q28
What can occur if breakpoints disrupt either of the critical regions on the X?
Premature ovarian failure (POF).
This is the failure of the ovaries before 40 years of age.
What causes Klinefelter Syndrome?
47,XXY
A male with an extra X chromosome.
What is the main clinical indication in Klinefelter Syndrome? When do they usually present?
They usually present as adults with fertility issues.
How common is Klinefelter Syndrome?
1 in 500-1000.
What other clinical features might you see in a Klinefelter patient? Are these mild or severe?
- 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.
Why are Klinefelter patients infertile?
Primarily due to low testosterone and this causes underdevelopment of the testes.
What are the other sex chromosome abnormalities?
47,XYY 47,XXX 48,XXXY 48,XXXX 49,XXXXY 49,XXXXY
What is the most common mechanism behind the polysomies such as XXXX, XXYY, XYYY, XXXY, XXXXX, XXXXY?
Successive non-disjunctions in one parent with the other parent contributing a single sex chromosome.
Briefly describe the expected phenotype in a patient with 47,XXX?
Very mild phenotype:
- mild developmental delay,
- mild motor delay.
But varies wildly and is generally considered to be ‘normal variant’
What phenotype do you see in the remaining sex chromosome polysomies? What is the main cause of this?
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.
