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Klinefelter Syndrome, Autism, & the Female Protective Effect?

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.

#raredisorder #Tutankhamun #autismspectrum #autismspectrumdisorder #progesterone #Nefertiti #femaleprotectiveeffect #developmentaldelay #castrati #genderbias #castrato #XXY #gynaecomastia #KlinefelterSyndrome #raregeneticdisorder #ASD #learningdisability #autism #testosterone #KingTut #estrogen #Akhenaten


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