It is often assumed that women have XX chromosomes and men have XY, but biology is more complex. Some women have XY chromosomes — a natural variation in sex development. They grow up identifying and living as women, and most only discover well into puberty that they are different. Danish researchers have, for the first time, mapped how many women have XY chromosomes. The proportion was higher than expected.
You cannot see it if you do not know what you are looking for. One in about 15,000 people with XY chromosomes is born and grows up as a girl. And neither these girls nor their parents know it. These girls do not discover anything different until puberty.
“Girls born with XY chromosomes have a variation in sex development caused by mutations in genes that influence sexual development, so male characteristics are not expressed. They live their lives as girls and then women, and a few can even give birth. Our research, which is the first nationwide survey in the world, shows that this group is up to 50% larger than previously assumed. How these girls discover the facts and talk openly about their situation also varies greatly,” explains Claus Højbjerg Gravholt, who led the study and is Clinical Professor in the Department of Clinical Medicine of Aarhus University.
Together with colleagues, he is investigating why sex chromosome variations occur and how people with XY chromosomes can be women. Two types of genetic mutations mostly make the difference; these were previously called Morris syndrome and Swyer syndrome, these are now described as types of 46,XY differences of sex development (DSD).
“Androgen insensitivity syndrome is one example of 46,XY DSD. People with this variation produce typical or high levels of testosterone and other androgens, but the testosterone does not affect the foetal cells that usually develop into male sexual organs because of a mutation in the androgen receptor gene. People with this variation have XY chromosomes but are women in their social identity and physical appearance. They do not have internal female reproductive organs, and they develop internal gonads located in the abdominal cavity.”
An unseen variation
Typically, most of the girls with androgen insensitivity syndrome discover by puberty that they differ from other girls. They do not menstruate, and most will never be able to give birth. Apart from the discovery that more women have XY chromosomes than previously assumed, the researchers were also surprised about the variation in when these girls and women discover that something is different. The girls with androgen insensitivity syndrome were diagnosed at an average age of 7–8 years old but some 34-year-old women with the syndrome had not yet been diagnosed.
“This is surprising, although most of these women may know that they cannot give birth and that their bodies develop in some ways differently from other women. They just do not know why. Even more surprising, however, is the fact that the average age of girls being diagnosed with gonadal dysgenesis, previously known as Swyer syndrome, is 17 years.”
The reason for this high age at diagnosis is presumably that these women actually develop sexual organs that are similar in form and function to those of most women. Women with gonadal dysgenesis have a mutation in the SRY gene of the Y chromosome that encodes for a protein known as the testicular determining factor that normally results in the testicles developing in the early weeks of foetal development.
In the absence of the protein, the testicles do not form, and sexual organs typically associated with women’s anatomy develop instead, though they may differ in certain aspects from those of most cisgender women.
“The women do not develop secondary female characteristics such as breasts, but they have a womb, so with appropriate hormone treatment and fertilized egg implantation they can actually become pregnant and give birth. A key medical consideration is that their ovaries are not developed.”
Healthcare providers may discuss options to reduce cancer risk, which may or may not include surgical removal of the ovaries, tailored to each individual’s circumstances and with informed patient consent.
Denmark is unique
Claus Højbjerg Gravholt’s group focuses on the hhealth conditions sometimes associated with variations in sex chromosomes. These are mostly important for the people with these variations but are also important in a wider context for understanding many disease processes at the genetic, molecular, clinical and epidemiological levels.
“The idea is that this research can help us to understand major disease groups such as type 2 diabetes and heart disease that are more frequent among people with sex chromosome variations. Since these people have a higher prevalence of the resulting diseases, detecting the patterns is also easier. Ultimately, we hope that this knowledge will benefit these women and other people with diabetes or heart disease.”
The Danish researchers mainly focus on helping and treating the women and men with sex chromosome variations. People with these variations may experience physical health needs related to reproductive function, hormone levels, or other associated conditions, and they can also face psychological or social challenges, especially if they encounter stigma or lack of information.
“Learning later in life about having a variation in sex development can be emotionally challenging, particularly if open and accurate information has not been available earlier. Some find it a relief, others need time to adjust, and support can help people process the news in ways that affirm their identity,” concludes Claus Højbjerg Gravholt.
“Incidence, prevalence, diagnostic delay, and clinical presentation of female 46,XY disorders of sex development” was published in September 2016 in the Journal of Clinical Endocrinology and Metabolism. In 2013–2015, the Novo Nordisk Foundation awarded a grant for research on sex chromosome syndromes to the Claus Højbjerg Gravholt group at the Department of Clinical Medicine of Aarhus University.
