I spoke with an individual a few days ago who had Klinefelter Syndrome (KS). For those who aren’t familiar, KS is one of the most common intersex conditions in which a “genetic male” inherits at least one extra copy of the X chromosome. Rare variants involve additional X copies, which tend to result in more severe symptomology; meanwhile, mosaicism, in which only some cells of the body carry an extra X, can also occur resulting in milder, sometimes even undetected, symptoms. According to Orphanet, approximately 6-9 cases are diagnosed for every 10,000 births. That means that for every 1,000 boys born, 1 or 2 will have KS.
Symptoms in KS are represented well by the following illustration:
As you can see, males with KS often have a feminized appearance, although there’s a range in severity which can be likened to a spectrum. Similar to the Castrati who were once castrated in order to preserve their singing voices before the 19th century, those with KS tend to be tall. They also often experience gynaecomastia, or breast development, and most have small testes and are infertile.
Interestingly, there are some scientists who have postulated that the boy pharaoh, Tutankhamun, had an intersex condition similar to KS, noting pronounced female-like hip formation and small shoulder width. Though it was originally believed that his father, Akhenaten, exhibited similar effeminate characteristics based on statues, it is now known that Akhenaten’s skeleton showed no signs of feminization [1].
A statue of Akhenaten.
Of relevance to readers here, those with KS may also have a higher risk for autism [2]. One study by Ross et al. (2012) estimated that approximately 12% of boys with KS met autism cutoff according to the Social Communication Questionnaire. Other neurodevelopmental issues, such as developmental delay and learning disabilities, are also very common.
There are many rare genetic conditions that share significant association with autism. Probably several hundred at least. Yet why is KS in particular so interesting? One reason is that, given the hormonal involvement, it may be a good condition in which to study the Female Protective Effect in autism, which I wrote of last spring.
To go back to the conversation I had with the individual with KS a few days ago: as I mentioned, some individuals become more feminized than others with the condition. This particular individual had low testosterone, almost around the levels of a woman with polycystic ovarian syndrome, and higher estrogen levels, close to normal for a woman. Though this individual was born with male genitalia and experienced a significantly delayed pubescence (age 18), she nevertheless has gone through pubertal changes more akin to that of a female. Accordingly, she has adopted the role of a female as well.
One of the most interesting things she told me however was that, prior to puberty she had been diagnosed with autism, which included a significant language delay. According to her account, once she hit puberty, her symptoms dramatically improved and she no longer met criteria for the diagnosis. At present she still has a diagnosis of ADHD and mild learning disability, but no longer carries the autism label.
While this is only a single anecdotal case, nevertheless it sparked my curiosity. Did this individual, due to the high levels of estrogen her body began producing at pubescence, experience a modestly reversible female protective effect of her autistic traits? Is there something about estrogen and the accompanying female hormonal cocktail that protects the plastic brain from certain symptoms of autism, even reversing them at particular stages of development?
If this is something that occurs in a subset of these patients (perhaps the minority with breast development?) perhaps we can study neurodevelopment in pre- and post-pubescent KS males. Perhaps we could even develop animal models to mimic the effects so that we can delve deeper into the biology in order to better understand the gender bias.
I’d just like to reiterate that this was only a single anecdotal case, and this hypothesis could ultimately be unfounded. But it’s certainly some fascinating food for thought and worthy of further study.
Science Over a Cuppa 
Obviously, XX females are different. However, would such a hypothesis also suggest that XX females might show variation in autism symptoms with changes in estrogen levels?
Hard to say, Erica. This is really early speculation on my part, reflective of some of the recent genetics work in autism combined with neuroanatomical studies on white and gray matter differences between men and women which I’ve been reading of late. It could be possible, although the background on which estrogen acts would undoubtedly be important. These Klinefelter boys are certainly more “male” prior to pubescence, but in reference to the anecdote I provided of the KS transgender, there’s some distinctive feminization that occurs in these individuals that could feasibly affect neurodevelopment, and further study would be needed to determine whether that’s indeed the case. In the general autism population, if such effects could be witnessed, I’m sure it will vary by causative factors (genetics, environment) and different people will have different “ceilings” in terms of plasticity. However, the fact that high-functioning autistic females tend to score better in the socio-communication domain as compared to their male counterparts (something which harkens back to socio-communicative differences between the sexes in general), it does cause me to wonder whether estrogen alone or a combination of pubescent endocrine influences might not drive some of those differences, leading to differences in socio-communicative capacity between the sexes in both the general population and in autism. I would say that, even if differences are subtle, it would be impossible for hormonal changes not to have an effect on cognition, perhaps even symptom severity. If I recall from my psych days, performance in language tasks vary in women according to whether they’re in menstruation or midluteal phase. On the other hand, stress simply from being a teenager could be a confounding factor.
Klinefelter Syndome is not inherited and mosaic Klinefelter Syndrome is also not inherited. KS and XYY stndrome is always caused by a reproductive error, sperm or egg mutations. Increasing levels of exposure to benzene in the workplace increases the fequency of XY sperm. Benzene is a common industrial chemical and ubiquitous environmental pollutant, and exposure to benzene is practically unavoidable for the general population.
http://ehp.niehs.nih.gov/0901531/
http://ghr.nlm.nih.gov/condition/klinefelter-syndrome
Hey, Robert. I had read somewhere that it was theoretically possible for mosaic KS to be inherited from father to son, however there are no documented cases. Then again, the occurrence estimates are probably low, especially for those with mosaic forms due to subtle symptomology, so even though it could be extremely rare it’s not definite that mosaic KS hasn’t ever been inherited. But, as mentioned, that’s just strictly theoretical.
I know several XXY on testosterone replacement therapy who still have autism or autistic traits even after decades of therapy when one could assume traits should have vanished. Testosterone improves attention/concentration, tiredness/energy and mood as well as general well-being but it does not change the effects of the second X chromosome who mostly affect social behavior.
That’s interesting. Do these individuals share effeminate characteristics similar to the XXY individual I described? E.g., near-female levels of hormones, etc.
in some cases, estradiol values are enhanced and in most cases FSH/LH are elevated but I’m not sure if this was ever examined. It would be especially interesting to know whether prenatale sex hormone levels show similarities. Some, but not all XXY lack mini-puberty and need temporary testosterone treatment before puberty. With respect to autism, I find these articles about XXY fairly interesting:
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010887
and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164392/
Thanks for the info, Forscher.
You’re welcome. If you’re interested in more information, I collected much here:
http://factsaboutklinefelter.com/literatur/
(I’m not a studied medic but a studied atmospheric physicist)
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Given 99.9% of XXY’s are sterile it seems highly unlikely Tutankhamun, having ‘fathered’ two daughters was indeed XXY or some other variant?
hey there, I see this is 8 years old but I’m mosaic xxy, straight. Was always so difficult to find any information about this but little by little Google is digging up a little more. Is the person who wrote this piece still around and interested in this subject, I might like to talk to you lol. hi I’m Steve.
Hi, Steve! I’m still around, although admittedly this isn’t my area of expertise. But how can I be of help?