A technical question about Swyer Syndrome and CAIS

[QuimReaper]

I have become interested in these syndromes as a result of their getting a lot of discussion on these boards, and although this question has nothing do with FWR, posters here seem exceptionally well-versed in DSDs, so I hope nobody minds me popping a couple of incidental questions here.

First: my understanding is that without hormone treatment, children with Swyer Syndrome never experience puberty due to lack of gonads. I'm just wondering, what actually happens in cases where Swyer Syndrome goes untreated (as must have happened historically and globally)? Or in general when someone doesn't experience puberty for some other medical reason? Do they stay in a pre-pubertal state for their whole lives, and is their life expectancy normal?

Secondly: my understanding is that people with CAIS produce testosterone, but do not at all respond to it; but that all bodies (XX or XY) produce some amount of oestrogen (I think in the pituitary gland?) and it is this that CAIS cases respond to, resulting in an apparently female appearance.

If I'm right about that, why is it that the same isn't true of Swyer Syndrome? And if I'm wrong about that, how is it that people with CAIS do experience female-typical puberty (breast growth etc., although obviously not menarche) and those with Swyer don't?

Thanks in advance to any clever MNers who can answer these!

Hmmmm….

Am I understanding this correctly - a human female with XY-SRY was found to have apparently normal ovaries? Apologies if I’ve misunderstood the paper.

Is this an odd presentation of Swyer’s or not? I’m guessing not because Swyer’s results in an individual with no ovaries, so this must be …. something else??

It mentions mutations of the CBX2 gene and states that this usually suppresses development of ovarian tissue in XY gonads. So presumably the mutation -although a disorder for XY individuals in general - might not be one for an XY-SRY female.

Females are expected to have ovaries, so can a mutation which allows the development of ovaries in a female (albeit one with an unexpected karyotype) really be considered a disorder??

If not, then what is the disorder part? Would that have to be the presence of a Y chromosome instead of an X?

Ovaries and Female Phenotype in a Girl with 46,XY Karyotype and Mutations in the CBX2 Gene

We effectively end up with two types of female - ones for whom missing ovaries is outside the normal for their body type (XX) and ones for whom missing ovaries is the default (XY-SRY).

No. There is one type of female - people with no SRY.

As I understand all humans have tissue that should develop into either testes or ovaries, including those with DSDs including Swyers. It doesn't develop properly that's all. It's still there - it isn't missing.

Except people with Y chromosomes are not expected to have ovaries, so how can lack of ovaries be abnormal for a female with XY chromosomes?

So in the interest of fair sporting. Would it be fair to say initial test XX cheek swap good to play.
XY cheek swap requires further tests find out if they have ovaries or under developed testes?

Except people with Y chromosomes are not expected to have ovaries, so how can lack of ovaries be abnormal for a female with XY chromosomes?

No. People with an SRY gene are the ones who aren't expected to develop ovaries from gonadal tissue.

People without an SRY are expected to develop ovaries.

You need to start from the SRY gene, not the chromosomes.

No! XX can have SRY - La chapelle syndrome.

Cheek swab to test for presence or absence of SRY.

@titchy

People without an SRY are expected to develop ovaries.
You need to start from the SRY gene, not the chromosomes.

Right, ok.

So the paper below is … what?

No SRY, so ovaries expected. Ovaries are present. All good so far.
XY chromosomes are also present, which is unusual but not something to dwell on because the -SRY+ovaries is normal for females and due to lack of SRY the individual is a female.

So…no DSD then…???

Doesn’t seem quite right! 😳
Ovaries and Female Phenotype in a Girl with 46,XY Karyotype and Mutations in the CBX2 Gene

Sorry, the more I think about this the more confusing it seems!

Starting from SRY (present is male, absent is female).
Females expected to have ovaries, males not expected to.

XY+SRY = male, no expectation of ovaries.
XX-SRY = female, expectation of ovaries
XY-SRY = female, expectation of ovaries

I don’t see how the last one can be true.

How easy is it for a lab to find the SRY gene, especially if it's in the wrong place

I'm almost starting to understand why the ioc dropped chromosome sex testing but the testosterone test just doesn't seem fair

A single x chromosome / with no sry gene makes you female. Women with Turner syndrome are undoubtedly female not male. So female is not XX it can be XO

And female bodied people can be genetically X(Y without SRy)

And male bodied people can be X(Xwith sry)

So the sry gene (which is almost always, but not always, attached to the Y chromosome is the blueprint which drives fetal development away from default female setting.

I'm not a scientist but I think that article is suggesting that the CBX2 gene has effectively acted to fix what would otherwise have led to a DSD. So she has been incredibly lucky - though note this is a child and we don't know whether she will go onto be fertile, though the indication is she will be.

So genetically 'disordered' definitely with the Y instead of second X, but maybe not disorder of the DSD type.

XY-SRY = female, expectation of ovaries

I don’t see how the last one can be true.

Why not?

Easy! And only needs to be done once in the athletes lifetime. So cheap compared to the myriad of dope testing athletes undertake.

I came across the paper linked because I was furiously googling to see if XY individuals can have ovaries.

That was the only thing I found that seemed to indicate they can, and even that hints it’s unusual.

Why do I think it unlikely?

Well, sex is determined at conception. Usual arrangement is XX female and develops ovaries, XY male and does not.

Tonight I have learned that this isn’t quite accurate, that +SRY is male, -SRY is female. However, SRY is usually located on Y chromosome, anywhere else is not commonplace. So chance of XY-SRY having development that generates ovaries is vanishingly small as quite out of the ordinary for females. Most XY-SRY would be a condition such as Swyer’s where defined ovaries are absent.

From the paper I’m guessing that for ovaries to occur in XY-SRY there would need to be a significant mutation such as the one mentioned on the CBX2 gene.

It seems unreasonable therefore to expect an XY-SRY to have ovaries.

Have I got that wrong?

So if XY-SRY doesn't have ovaries does that mean they have testes?

Reading the IBA wording they've copped out people with DSD aren't allowed to compete on safety grounds. So maybe the IOC need to take the same view.

“So the sry gene (which is almost always, but not always, attached to the Y chromosome is the blueprint which drives fetal development away from default female setting.”

I thought we moved away from female as the default setting. I thought the embryo has potential for both, and develops according to the hormone mix sloshing about (technical term! 😁)

Will go back to those handy diagrams and check…

It seems unreasonable therefore to expect an XY-SRY to have ovaries.

Well yes, but that's because that's what the disorder is.

It doesn't mean they are male because you wouldn't expect to find ovaries. Any more than the trisomies aren't an extra chromosome because you'd expect an extra chromosome in someone with Downs or Edwards.

I think it’s about to get even more confusing! 😆

I ended up reading all sorts of things yesterday (most of which I didn’t understand) but one article caught my eye:

Researchers identify female sex determining gene in mice

This states:
They found that one form of the WT1 protein (-KTS) was essential to gonad formation, as in its absence, neither Sertoli cells nor granulosa cells could form in both XY and XX mice.
The higher amounts of -KTS reduced the expression of Sry in XY gonads and increased genes involved in ovarian development. The production of SRY never reached the level needed to trigger testes development.
This meant that an XY mouse developed female gonads in the presence of too much -KTS, showing that the -KTS form of WT1 is an early trigger for female gonad development, regardless of XX or XY chromosomes.

So it seems as though trying to determine sex by the presence of a functioning SRY gene* isn’t enough, it has to be a dominant SRY gene. It may be that in science terms dominant is the same as functioning, but then again not.

The article describes the Wt1 gene as a gene which is an early determining factor of ovary development in mice. Females have ovaries (this seems to be the takeaway from this thread - XY females with no functioning SRY lack ovaraies and this lack is the DSD of those females - apologies if I have misunderstood), so presumably it would be incorrect to describe the differences between male and female being just a lack of the gene that determines maleness, yes?

I’m also left wondering if this -KTS/WT1 is present in XX individuals. It seems its mutated in XY individuals that possess ovaries, so is it unmutated in XX individuals with ovaries?

If, as mentioned above, it is essential to gonad formation, as in its absence, neither Sertoli cells nor granulosa cells could form does this mean that it is possible for individuals to both lack the SRY gene and Wt1 as well?

In which case, if functional SRY=male and Wt1=female, what would an individual without either be classed as?

It seems odd to consider that a female is someone lacking the male switch (SRY) if there’s evidence that there’s also a female switch. That makes female the default by the back door, and as @KeirSpoutsTwaddle said, isn’t that considered to be incorrect now?? On the other hand, if Wt1 is the ‘female switch’ then could it not equally be argued that a male is someone lacking the female switch to keep the male switch suppressed.

*From what I can work out on one of the other threads (table half way down page 2), an individual classed as female can have XY chromosomes with or without the SRY gene. The paper I found last night suggested that a mutation in another gene effectively overrides the SRY one, so producing apparently normal ovaries. I’m taking from this that the mere presence of SRY is not enough to be classed as male, so the sports testing shouldn’t rely solely on this either.

On a simple logic level I see this, but when we’re told that female=noSRY, then I don’t.

If mere absence of a functioning SRY gene makes an individual female, then no matter what the genetic makeup the absence is correct - as the lack of SRY is not a disorder of males.

So a female can correctly be XX or XY (or a number of other things but I’m trying not to confuse myself even more! 😂) and that is correct for that female.

If XY is a correct expression of female, and XY are unlikely to have ovaries, then how can lack of ovaries in XY be considered a DSD of XY females?? That’s the default state of XY females, surely? When a DSD is a deviation from what is normally expected, I can’t see how an XY individual developing along the expected path for XY individuals is considered a deviation from the norm for XY females.

I can see it being an unexpected path for XY if XY is considered male…

I’m reading Wt1 as wtf which really isn’t helping.

This has been a really interesting conversation, and I understand much better now why ‘some people’ talk about genetic sex, hormonal sex and gender expression sex (if I remember correctly).

I thought that was bollocks on the basis they meant a 50yr old chap could take oestrogen and quickly acquire all the implications and practicalities of being a woman.

I think they were using it like that, but now understand where they got the concept.

It’s really clear though, that as we already knew, DSDs have nothing whatsoever to do with trans and gender identity.
It’s only relevance to sport is the implications for competitive fairness and safety.

There no need for any of this to become public speculation and discussion of people behave appropriately.

You're making a circular argument. You're saying a feature of the disorder is 'A' therefore an individual with 'A' isn't disordered because that's normal for someone with 'A'.

Someone with no SRY is female. The disorder is because in normal development they'd have 2 X chromosomes.

XY without an SRY is not normal development.

@titchy

XY without an SRY is not normal development.

This is exactly what I’m saying!

XY without SRY is not normal - it’s a disorder of an XY individual, not of an XX one.

Someone with no SRY is female.

Apparently not.
It appears that an individual can be classed as female with the following:

• 46 XY SRY+
• 47 XXY SRY+
• 45/46 XY SRY+
• 46 XY SRY+?

All have SRY, but female.

And it’s is also possible for 46 XX SRY- to be classed as male, a variation of De La Chappelle Syndrome. No SRY, but male.

Obviously there have to be other factors at play to stop the SRY doing its job in those females that possess it, but clearly SRY on its own isn’t enough to be classed as male.

So why do we default to now saying that +SRY= male, when we know that isn’t the case, yet we consider it wrong to say XX=male although that seems no less accurate?

It does feel a bit arbitrary from my, very lightly informed, position.

I assume it isn’t and that there is a damn good reason for it that I haven’t yet grasped.

I guess it would be helpful to somehow "map" the stages that determine female and male development (or none). I've tried to do that below based on my basic understanding of the issue. If anyone wants to build on it, or correct me, please do!

Step 1
So I guess it starts with the SRY gene (normally located on the Y chromosome, but could be present on the X chromosome).

+SRY = tells the gonadal tissue to develop into testes - Male pathway
-SRY (plus other factors??) = gonadal tissue develops into ovaries - Female pathway

Step 2
Then whether there are any other factors which stop the SRY gene from functioning correctly (that 'block' it, or I guess receptors in the body aren't functioning correctly).

SRY gene not blocked/ receptors functional - Male pathway
SRY gene blocked/receptors not functional - Female pathway

Step 3
Then you've got whether the testes actually function correctly

Testes produce testosterone - Male pathway
Testes don't produce testosterone - I don't think this leads to a complete female pathway as T is converted to oestrogen, so T needs to be produced? I guess this would lead to an androgynous presentation with XY genes and feminised gonads?

Step 4
Then you've got whether the testosterone is converted into DHT (the "more potent" version of T)

DHT produced - Male pathway
DHT not produced - Assuming presence of T, this is a Male pathway with feminised appearance (until puberty - as with the 5-ARD)

Step 5
Then you've got whether the testosterone receptors are working:

T/DHT received as normal - Male pathway
T/DHT somehow not received. - Female pathway, although PAIS I guess there might be some male pathway.

I'm sure there are other steps that go wrong but these seem like the ones covered in the discussions above. Also sure that this isn't necessarily a linear process!

From what I gather as well, there are a couple of key developmental steps - In utero development, a few weeks postnatal development, then puberty - which have a subtle role too. For XX with no DSD (i.e. women!), an exposure to T in utero can be a strong indicator of 'male characteristics' including a longer ring finger in comparison to the index finger, higher likelihood of attraction to females, and a higher likelihood of "masculine" behavioural traits. This is not considered a DSD.

Male homosexuality and "feminine" behavioural traits does not seem to be caused by lower T during any of these stages.

@WitchyWitcherson

Thank you, that’s helpful.

But where does an XX male with or without SRY fit in?? Apparently both are De La Chappelle and both male, but only one is SRY+.

My assumption is the other (SRY-) means no SRY at all, or does it mean suppressed SRY?