Sex Determination And Disorders Of

Question 1

When is the sex of a fetus determined?

Answer 1

7th week of development

Question 2

What main genes influence the bipotential gonad?

Answer 2

WT1 and SF1

Question 3

What is the main cause of the determination between male and female?

Answer 3

Presence of an intact Y chromosome.

Question 4

Which gene drives male development? Briefly describe what it triggers.

Answer 4

SRY.
SRY then interacts with SOX9. It also upregulates FGF9.
These then work together to upregulate SF1.

Causes development of male reproductive system and regression of Müllerian ducts. Gonad undergoes testis development

Question 5

What role does SF1 play?

Answer 5

SF1 cause the differentiation of Leydig cells and Sertoli cells.

Question 6

What is the significance of Leydig cells?

Answer 6

They produce testosterone which then:

• causes Wolffian ducts to develop into male internal genitalia
• testosterone converts into dihyrotestosterone which causes formation of male external genitalia.

Question 7

What is the significance of Sertoli cells?

Answer 7

Produce anti-mullerian hormone (AMH) which causes degeneration of mullerian structures.

Question 8

What drives female development? What are the main genes involved?

Answer 8

Lack of the Y chromosome.
Ovaries develop in the presence of WNT4 and DAX1 (which inhibits SOX9).
WNT4 is particularly important as loss of this gene in a 46,XX results in partial testis development.

Question 9

What happens to the gonad in the absence of SRY?

Answer 9

The wolffian duct degenerates.

The Müllerian duct develops into internal female genitalia.

Question 10

What happens if the pathway from either the male or the female development is disrupted?

Answer 10

Results in a disorder of sexual development.

A patient whose karyotype doesn’t concord with their phenotypic sex.

Question 11

What are the three general categories of DSD?

Answer 11

• sex chromosome DSDs which includes Turners and Klinefelter
• disorder of gonadal development
• disorder of hormone synthesis and action

Question 12

A male patient presents with infertility, analysis shows a 46,XX karyotype, what might the cause be? Which is most common?

Answer 12

• Translocation of SRY to another chromosome
• inappropriate activation of the male cascade e.g SOX9 dup
• problems with the female cascade e.g. mutation of DAX1, WNT4 del
• remember possibility of mosaic Klinefelter (46,XX/47,XXY) and of mosaic structural Y abnormalities
• also could be a translocation which has disrupted a gene involved in either the male or female cascades.

90% of these cases are a result of translocation of Y material onto an autosome.

Question 13

A patient is 46,XX SRY positive…..

• when would this typically be detected?
• what is the clinical phenotype?

Answer 13

• Usually present in adolescent period due to atypical sexual development or due to infertility later on,
• Clinically they are similar to Klinefelter Syndrome but are shorter with unimpaired intelligence,
• they are infertile as the remaining genes on the Y chromosome aren’t there e.g. genes involved in sperm production.

Question 14

If a patient is female but has a 46,XY karyotype, what could be the cause?

Answer 14

• Mutation of SRY
• Mutation of other gene in male determining cascade e.g. deletion of SOX9
• Mutation of gene in the female determining cascade e.g. duplication of WNT4
• disorder involving the biochemical pathway of testosterone.

Question 15

What is 46,XY complete gonadal dysgenesis?

Answer 15

Patient has intact chromosome with SRY

• 15-20% have SRY mutation/del
• remaining likely to have mutations of other genes involved in male cascade.

Female external genitalia, streak gonads, infertility.
Patient has high risk of developing gonadoblastoma and removal is 1st decade of life is recommended.

Question 16

What conditions fall under the 46,XY DSD category?

Answer 16

Complete gonadal dysgenesis (previously Swyer)

• externally female with streak gonads - the gonad fails to develop into either the testis or an ovary
• mutation in SRY or other gene from male cascade

Partial gonadal dysgenesis
Biochemical pathway disorders such as androgen insensitivity syndrome.

Question 17

What is classical congenital adrenal hyperplasia? What is the relevance to cytogenetics?

Answer 17

• 21-hydroxylase deficiency
• 21-hydroxylase plays a role in producing cortisol (protects from stress) and aldosterone (regulates salt)
• when 21-hydroxylase is deficient, substances that it usually uses to make the above hormones build up and are converted to androgens
• excess of androgens = abnormality of genitalia in females
• ‘classic’ type can be divided into salt wasting or simple virilising types
• type depends on the mutation present e.g. mutations that result in non-functional enzyme = salt wasting type which is the most severe whereas mutations that allow low levels of functioning enzyme have the simple virilising type.
• FEMALE infants present with ambiguous genitalia and so it is important to do a direct FISH so that the genetic sex of the baby can be confirmed.

Question 18

What is androgen insensitivity syndrome? What might the phenotype be?

Answer 18

Phenotype - female presenting with infertility and amenorrhea.

• karyotype is 46,XY with normal SRY and therefore testosterone and AMH is produced
• however they have a deficiency which means they don’t respond to the testosterone
• this means that the external genitalia fail to masculinise
• however, they can respond to AMH and therefore the Müllerian ducts degenerate meaning no uterus or ovaries
• also able to respond to oestrogen and this makes them look phenotypically female e.g. breasts.

Question 19

What is Klinefelter Syndrome?

Answer 19

47,XXY - extra X chromosome

Question 20

What are the features of Klinefelter Syndrome?

Answer 20

Can be very mild and not diagnosed until puberty or adulthood! Some may never be diagnosed!

Main features:
- small testes with reduced amount of testosterone

This low amount of testosterone causes:
- delayed or incomplete puberty
- breast tissue development
- less facial and body hair.
They can also have a small penis and undescended testis. 

Tend to be taller than their peers.
They can have mild learning issues with speech and language problems.

Question 21

Why are Klinefelter patients infertile?

Answer 21

Due to low testosterone and low testicular volume - testis unable to provide environment for healthy sperm production .

Very low levels of spermatogenesis can be obtained via testicular biopsy and then ICSI can be used to achieve pregnancy.