Chromosomal causes of infertility/disorders of sexual differentiation

Question 1

Features of Turner syndrome? (8)

Answer 1

Failure to enter puberty/develop 2ndry sexual characteristics
Infertility
Short stature
Coarctation of the aorta
Structural renal abnormalities
Webbed neck
Peripheral oedema
Lower IQ than siblings

Question 2

How does mosaic Turners differ?

Answer 2

May show fewer symptoms

Question 3

How can Turner’s females have children?

Answer 3

IVF with donor eggs

Question 4

Turners recurrence risk?

Answer 4

If 45, X then recurrence risk is low; but if structurally abnnormal (i.e. 46,XX but one is normal and other is abnormal) then need to request maternal blood sample to karyotype and estimate recurrence risk

Question 5

Where do the majority of Turners syndrome come from?

Answer 5

Non-disjunction in the father

Question 6

Testing performed for Turner’s syndrome?

Answer 6

Karyotype analysis on blood sample in lithium heparin (for infertility)
Can also test prenatally

Question 7

Turnaround time for Turner’s sample?

Answer 7

Postnatal karyotype analysis- 28 days (different if prenatal)

Question 8

In partial X-chromosome deletions, what does the effect on fertility depend on?

Answer 8

The position of the breakpoints- the more proximal, the more severe the effect

Question 9

When do Xq deletions result in ovarian failure?

Answer 9

If they involve the critical region for ovarian failure (Xq13-q26)

Question 10

X deletion phenotypes:

a) Xp22.22
b) Xp11
c) Xp21

Answer 10

a) SHOX gene, leads to short stature if disrupted
b) primary amenorrhoea
c) secondary amenorrhoea

Question 11

Symptoms of Klinefelter syndrome?

Answer 11

Small testes- involute after puberty
Gynaecomastia
Infertility
Low testosterone levels

Question 12

How can patients with Klinefelters have children?

Answer 12

ICSI may be possible if there are some sperm

Question 13

Incidence of XXY?

Answer 13

1 in 500-1000 newborn males

Question 14

How is Klinefelter’s usually diagnosed?

Answer 14

Fertility problems, incidental finding, occasionally mild development delay in childhood

Question 15

Recurrence risk for XXY?

Answer 15

Very low- almost all cases due to non-disjunction

Question 16

Testing performed for XXY and turnaround time?

Answer 16

Karyotype, blood sample in lithium heparin, 28 days

Question 17

Y chromosome microddeletion phenotypes?

Answer 17

AZFa = no sperm, no treatment
AZFb = no sperm, no treatment
AZFc = some sperm may be available, consider TESE and ICSI
AZFbc no sperm, no treatment
AZFabc = this is most likely due to an abnormal karyotype

Question 18

How would a male with an isodicentric Y chromosome present?

Answer 18

Phenotypically male (because SRY present) but lack of spermatogenesis due to lack of AZF region in long arm

Question 19

Specimen recieved/test performed for Y chromosome microdeletions?

Answer 19

Blood sample in EDTA

ARMS

Question 20

Why do the majority of individuals with balanced X-autosome translocations have no phenotype?

Answer 20

Get selection for inactivation for the normal X chromosome- may get symptoms if X-inactivation is skewed

Question 21

Phenotype of men with X-autosome translocations?

Answer 21

Infertile

Question 22

What happens if critical region on the X chromosome for POF is involved in an X-autosome translocation?

Answer 22

May be a risk of gonadal dysgenesis and primary amenorrhoea

Question 23

In X-autosome translocation, if the breakpoint disrupts a disease gene then what may happen?

Answer 23

The woman may manifest an X-linked disorder

Question 24

How do individuals with reciprocal autosomal translocations present?

Answer 24

Infertility/miscarriage/incidental/family contact tracing

Question 25

In a Robertsonian translocation what are the breakpoints?

Answer 25

q10;q10

Question 26

Why do individuals with Robertsonian translocations not display symptoms?

Answer 26

Short arm of acrocentric chromosomes is non-coding, hence loss of this does not have a phenotypic effect

Question 27

If a Robertsonian translocation involves a) chr 13 b) chr 21 there is an increased risk of what?

Answer 27

a) Patau syndrome

b) Down syndrome

Question 28

What may a male carrier of a Robertsonian translocation experience?

Answer 28

Fertility problems due to reduced sperm production

Question 29

What are the possible outcomes for the offspring of an individual with a Robertsonian translocation?

Answer 29

May be normal, or have missing/extra chromosomal material and hence show a phenotype