Beyond Just XX or XY: The Complexities of Biological Sex

One of the reasons human biology is so interesting is because it’s so complex; rarely are there neat answers. 

We’re often taught that when it comes to biological sex, everything fits into two boxes: XY and XX. However, it turns out that, just like the rest of biology, things are a little more complicated than that. 

Some people not have chromosomes or sexual characteristics that neatly fit into those two boxes. These people have disorders of sex development (DSDs), also known as differences of sex development or intersex conditions. Due to the taboo nature of the subject and differing opinions of what qualifies as a DSD, it's hard to pin down exactly how many people have DSDs—estimations have ranged between 0.05% and 1.7% of the world’s population.

Before we start discussing the details, let’s define some terms that often come up in discussions of sex:

Sex determination refers to the chromosomes an individual has—typically XX or XY. 

Sex differentiation refers to the anatomical development of reproductive systems—for example, people with XX chromosomes tend to have cervixes, vaginas, uteruses, etc. 

Gender refers to the “norms, behaviors, and roles” typically associated with femininity and masculinity. Gender pertains more to culture than biology, so we won’t discuss it here. 

Those definitions limit humans to one of two options, but as we said before, biology tends to be complicated!

Today on the Visible Body Blog, we’re going to discuss sex chromosomes, genes, and DSDs. 

Processes of sex determination and differentiation 

Let’s start at the beginning: spermatogenesis and oogenesis. During the process of meiosis, specialized sex cells (spermatogonia or oogonia) duplicate themselves and divide to create gametes (sperm or eggs). 

GIF of meiosis I model from Visible Biology. 

Sperm and eggs each have one set of chromosomes—but sometimes those sets aren’t the typical 23 chromosomes. This is how people can inherit a combination of X and Y chromosomes other than  the usual XX or XY. We’ll touch on this more later!

During fertilization, the sperm and egg fuse to form a zygote, which divides into more cells to become an embryo. 

The egg carries an X chromosome, and the sperm can carry X or Y. The Y chromosome carries 55 genes compared to the X’s 900+, and one of the Y chromosome’s genes is the SRY gene. The SRY gene provides instructions for making the sex-determining region Y protein. This protein typically causes the fetus to develop testes. 

Remember how we said that the SRY gene is carried on the Y chromosome? Well, it’s possible for X and Y chromosomes to swap some DNA, causing the X chromosome to carry the SRY gene. 

At six weeks of development, the fetus’s genes dictate which gonads develop. More than 25 genes contribute to sex differentiation! 

Fetuses with XY chromosomes typically develop testes, and those testes produce hormones that spur the development of male sex organs, while fetuses with XX chromosomes typically develop female sex organs. However, that’s not always the case.

Typical reproductive system anatomy from Human Anatomy Atlas 2022 +. 

DSDs 

Let’s take a quick look at a few DSDs, including two of the most common disorders, trisomy X and Klinefelter syndrome.

It’s important to note that not all DSDs are a result of a karyotype (an individual's set of chromosomes) outside of XX and XY. Like we mentioned before, more than 25 genes contribute to sex differentiation: mutations of these genes can all alter sex differentiation, which means that there is a wide range of DSDs. 

Trisomy X

Trisomy X, also known as XXX syndrome, occurs when a person has three X chromosomes. Trisomy X is caused by nondisjunction, which happens when the X chromosomes fail to separate properly. Nondisjunction occurs during anaphase of mitosis or either stage of meiosis. Trisomy X is usually caused by nondisjunction during meiosis. 

Trisomy X occurs in 1 in 1,000 female births. It’s estimated that only 10% of people with trisomy X are diagnosed, since symptoms can be mild or not present at all. 

Physical characteristics associated with trisomy X include: 

• Above average height
• Epicanthal folds 
• Clinodactyly (a bent or curved finger)
• Wide-spaced eyes
• Decreased muscle tone (hypotonia)

People with trisomy X sometimes have medical problems like: 

• Seizures
• Autoimmune conditions
• Premature ovarian failure 

People with trisomy X have a higher rate of motor and speech delays as children, learning disabilities, anxiety, and depression. 

Klinefelter syndrome (KS)

Klinefelter syndrome, also known as 47, XXY, is the most common DSD, occurring in 1 in 500 male births. 

Like trisomy X, nondisjunction typically causes KS. It can result from nondisjunction of the maternal or paternal chromosomes; maternal nondisjunction can occur during either stage of meiosis and paternal nondisjunction occurs during meiosis II. 

People with KS tend to have the following characteristics: 

• Taller than average
• Sparse body and facial hair
• Small phallus and testes
• A low-to-average testosterone level 
• Intention tremors 
• Overweight

KS is associated with an increased risk of diabetes, autoimmune diseases, and hypothyroidism, as well as an increased risk of learning disabilities and verbal and communication delays and difficulties. 

Experts say that up to two thirds of KS cases go undiagnosed, and diagnosis doesn’t usually occur until the person experiences fertility problems as an adult. The vast majority of people with KS are considered infertile, but thanks to assisted reproductive techniques, it’s possible for them to have children. 

Swyer syndrome

People with Swyer syndrome have XY chromosomes and functional female genitalia. However, they lack ovaries. 

The cause of Swyer syndrome is unknown, and several genes may be involved. 

Because they do not have ovaries to produce sex hormones, people with Swyer syndrome will not go through puberty unless they have horomone replacement therapy. Swyer syndrome usually goes undiagnosed until the teenage years, when puberty and menstruation do not occur. With hormone replacement therapy, puberty will develop normally. 

People with Swyer syndrome tend to be taller than average, have a small uterus, and an enlarged clitoris. They can become pregnant through an egg donation. Notably, about 30% of people with Swyer syndrome develop a tumor in the scar tissue that develops where the ovaries would be. 

Turner syndrome

Turner syndrome occurs when a person has a single X chromosome (monosomy X) or one whole X chromosome and one partial X chromosome. The exact cause of Turner syndrome is unknown. 

Turner syndrome karyotype. Note the single x chromosome. Photo from Wikipedia Commons. 

People with Turner syndrome may have

• A webbed neck
• Heart defects
• Early loss of ovarian function 
• Short stature
• Skeletal malformations
• A low hairline at the back of the neck
• Swollen hands and feet

Some symptoms are connected to the SHOX gene, which helps regulate other genes. Because the protein SHOX encodes contributes to the growth and maturation of the skeleton, missing one SHOX gene on the missing or incomplete X chromosome results in short stature. 

Many individuals with Turner syndrome need hormone replacement therapy to start puberty. Congenital heart defects are a concern for people with Turner syndrome, as they increase the risk of complications like high blood pressure and aortic dissection. 

Androgen insensitivity syndrome

People who have androgen insensitivity syndrome (AIS) have XY chromosomes and are resistant to androgens, the sex hormones that influence the development of male organs. 

People with complete AIS have female external genitalia and undescended testes. They do not have uteruses. They may have… 

• Partial closing of the outer vagina
• A short vagina
• No cervix 
• An enlarged clitoris 

People with partial AIS, where the body only partially resists androgens, can have typically female, typically male, or ambiguous genitalia. 

Mosaicism

The last condition we’ll talk about is mosaicism. Unlike the other syndromes we’ve covered, mosaicism isn’t a DSD, but it can be connected to a DSD.

Mosaicism is when a person has two or more genetically different sets of cells. It’s likely caused by an error in mitosis wherein a cell doesn’t split evenly into two cells, creating cells with different numbers of chromosomes. Experts actually think that mosaicism occurs at a small level in most people. 

Mosaicism is tied to several DSDs. For example, mosaic Klinefelter syndrome means that some of the cells have XXY chromosomes and some have XY chromosomes. Mosaic KS tends to have fewer symptoms than non-mosaic KS. 

Read more

DSDs have long been stigmatized and misunderstood—including by the medical community. If you’d like to learn more, check out these articles. 

• “Intersex: seeking the beauty in difference” via Mosaic
• “Sex redefined” via Nature
• “The Body, The Self” via Harvard Medicine
• “Ambiguous Genitalia And Disorders of Sexual Differentiation” via StatPearls
  
  

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