If you are familiar with developmental biology, you will know there are additional karyotypes—chromosome combinations—beyond XX and XY, such as X, XXY, XYY, and XXXY. Some claim these karyotypes prove there are more than two sexes in humans. For example, in an article titled ‘The 6 Most Common Biological Sexes in Humans,’ Joshua Kennon writes, “Humans are not just born male and female. There are at least six biological sexes that can result in fairly normal lifespans.” Kennon then lists six karyotype variations in humans: XX, XY, X, XXY, XYY, and XXXY. There’s one problem, however: karyotypes are not sexes.
A karyotype is simply an individual’s collection of chromosomes, and chromosomes hold genetic information. In humans, errors during cell division in meiosis can result in atypical combinations of chromosomes. For example, a sperm cell may accidentally receive an extra X with its Y. Thus, if it fertilizes an egg with an X chromosome, the fetus would develop with 47:XXY. This is how atypical karyotypes such as 45:X (Turner syndrome); 47:XXY (Klinefelter syndrome); and 48:XXXY are produced. But are these unique karyotypes additional sexes?
In biology, sexes are defined by reproductive role—evolutionary mechanisms by which individuals reproduce. In species like ours that reproduce through two gametes of differing size (which includes most higher order species within the plant and animal kingdoms) there are only two sexes—male and female. The male sex is the phenotype that produces many small, motile gametes (sperm) and the female sex is the phenotype that produces few few large, sessile gametes (eggs).        Therefore, sex is one’s reproductive role, and karyotype is the collection of chromosomes which encode the development of one’s sex. Thus, karyotype is not sex.
Now that we know how sex is defined, let’s go back to the six karyotype variants. Each of these variations result in a male or a female, not additional sexes. Why? The answer is because sex determination in mammals is binary: the system results in just two sexes. The important distinction between these karyotypes is found in the presence or absence of the Y chromosome. More specifically, the Y chromosome carries the SRY gene, which encodes the sex-determining region Y protein that triggers male sex differentiation and subsequent development.  
Thus, if the fetus has a Y chromosome with an active and functioning SRY gene, the fetus develops a small gamete producing phenotype and is therefore a male. If the fetus lacks the active and functioning SRY gene, the fetus develops a large gamete producing phenotype and is therefore a female. Knowing this pattern, we can now return to the six karyotypes and easily predict the resulting sex.
A karyotype of 45:X results in a large gamete producing phenotype, and thus a female.
46:XX also results in a female.
47:XXY results in a small gamete producing phenotype, and thus a male.
46:XY results in a male.
47:XYY also results in a male.
And 48:XXXY…you guessed it…a male.
Those who claim karyotypes form new sexes are using a sleight-of-hand trick. One moment, they are discussing karyotype, the next, sex—without defining the difference. By conflating the two, they incorrectly argue that karyotype variation forms additional sexes, and yet none of these karyotype variants result in a third reproductive role. No matter the karyotype, only two roles are ever produced: male and female. In fact, while most karyotypes beyond XX and XY result in infertility, when individuals with these conditions are fertile, they produce either sperm or ova, not a third gamete type. Thus, they are not additional sexes.
As evolutionary biologist Colin Wright notes, “A person with Klinefelter syndrome (47:XXY) is not a new sex in the same way that a person with Down’s syndrome (who has 3 instead of 2 copies of chromosome 21) is not a new species.”
If you’d like to learn more about how karyotypes do not form additional sexes, refer to the sources below, or send a message to Zach (@zaelefty) on Twitter.
 Kennon, J. (2013). The 6 most common biological sexes in humans. Joshua Kennon.
 NIH. (2020). Karyotype. National Human Genome Research Institute.
 NIH. (2020). Klinefelter Syndrome. Genetics Home Reference, National Library of Medicine.
 Parker, GA., et al. (1972). The origin and evolution of gamete dimorphism and the male-female phenomenon. J. Theor. Biol., 36, 529-553.
 Kodric-Brown et al. (1987). Anisogamy, sexual selection, and the evolution and maintenance of sex. Evolutionary Ecology, 1, 95-105.
 Charlesworth, B. (1994). The nature and origin of mating types. Evolutionary Genetics in Current Biology, 4(8).
 Czaran, T., Hoekstra. R. (2004). Evolution of sexual asymmetry. BMC Evolutionary Biology, 4(34).
 Lehtonen, J., Kokko, H. (2011). Two roads to two sexes–unifying gamete competition and gamete limitation. Behavioral Ecology & Sociobiology, 65, 445-459.
 Parker, GA. (2014). The sexual cascade and the rise of pre-ejaculatory sexual selection, sex roles, and sexual conflict. CSH Persp Bio.
 Lehtonen, J., Parker, G. (2019). Evolution of the two sexes under internal fertilization and alternative evolutionary pathways. The American Naturalist, 193(5), 702-71.
 Lehtonen, J., Parker, G. (2014). Gamete competition, gamete limitation, and the evolution of two sexes. Molecular Human Reproduction, 20(12).
 Sekido, R., Lovell-Badge, R. (2009) Sex determination and SRY, Down to a wink and a nudge. Trends in Genetics, 25(1).
 Kashimada, K., Koopman, P. (2010). Sry, the master switch in mammalian sex determination. Development, 137.
 Gamble, T., Zarkower, D. (2012). Sex determination. Current Biology, 22(8).
 Gilbert, SF. (2000). Chromosomal sex determination in mammals. Developmental Biology, 6th edition. Sunderland (MA), Sinauer Associates.
 Kimball, J. (2020). Sex chromosomes. LibreText.org.
 Wright, C. (2020). Sex chromosome variants are not their own unique sexes. Colin Wright: Reality’s Last Stand, Substack.