“A Sex Chromosome Anomaly in a Case of Gonadal Dysgenesis (Turner’s Syndrome)” (1959), by Charles Edmund Ford, K. W Jones, Paul E. Polani, J. C De Almeida, and J. H Briggs

In 1959, Charles Edmund Ford and colleagues published “A Sex Chromosome Anomaly in a Case of Gonadal Dysgenesis (Turner’s Syndrome),” hereafter “A Sex Chromosome Anomaly,” in The Lancet. Turner syndrome is a chromosomal disorder that affects one in 2,000 female births and results in developmental issues such as short stature, infertility, and congenital heart disease. Prior to “A Sex Chromosome Anomaly,” researchers did not know the cause of Turner syndrome, but Ford and colleagues found that the cause is a sex chromosome irregularity. In the article, the team explains that they examined the cells of a person with Turner syndrome and determined that she had just one X chromosome instead of the typical two. Thus, they concluded that the cause of Turner syndrome is a missing X chromosome and called for a new classification of the condition. “A Sex Chromosome Anomaly” was one of the first papers to identify the cause of Turner syndrome, and it provided scientists with a better understanding of individuals with a nontypical sex chromosome pattern.   

1. Background and Context
2. Article Roadmap
3. Detailed Content
4. Impact

Background and Context

At the time of publication, the authors of “A Sex Chromosome Anomaly” were researchers and doctors in England. Ford and Jones were a part of the Medical Research Council, a research program based in the United Kingdom that had been funding medical research since 1913. Specifically, they were members of the council’s Radiobiology Unit, which was a specialized group that focused on studying the biological effects of radiation on cell tissues and their molecular components. Polani, Almeida, and Briggs were affiliated with Guy’s Hospital in London, England. After publishing “A Sex Chromosome Anomaly,” both Polani and Briggs went on to coauthor other articles on human chromosomes. 

Prior to “A Sex Chromosome Anomaly,” researchers understood the physical symptoms of Turner syndrome but did not understand the cause of the disorder. In 1938, Henry H. Turner published a paper that described a new syndrome that he observed, and which future researchers called Turner syndrome. In his paper, Turner noted commonalities in seven of his female patients who had symptoms that researchers previously thought were unrelated. Most of the patients Turner observed had short stature, a lack of sexual and physical development, infertility, and a webbed neck, which is an extension of skin from the side of the neck to the shoulders. Turner’s observations documented the existence of Turner syndrome, but his research did not explain what caused it. “A Sex Chromosome Anomaly” is a case report in which the authors sought to determine whether Turner syndrome has a chromosomal cause, and they did so by studying the cells of one individual with Turner syndrome.

In “A Sex Chromosome Anomaly,” Ford and colleagues discuss chromosomes and the role they play in human sex determination. Each chromosome in a person’s cells is made up of a single, very long DNA molecule. The DNA is associated with proteins that fold and pack it into a more compact structure called chromatin. The DNA in chromosomes provides the information that shapes the many traits that make up the body and its functions. There are specific chromosomes, called sex chromosomes, which guide the development of biological sex in organisms. In humans, people with two X chromosomes typically develop as female, while people with one X and one Y chromosome typically develop as male. However, occasionally there can be chromosomal abnormalities, which may result in an atypical number of chromosomes, such as missing a chromosome or having an extra one. For people with chromosomal abnormalities in their sex chromosomes, researchers prior to Ford and colleagues were uncertain how to categorize their biological sex.

In the 1950s, researchers used a method called nuclear sexing to determine a person’s biological sex by analyzing their cells. With the nuclear sexing method, researchers apply a chemical dye to a cell and examine it for the presence of an inactive X chromosome, called a Barr body. Compared to an active X chromosome, a Barr body is a small and densely packed structure. When dye is applied, a Barr body stains dark blue, and cells with a Barr body are said to be chromatin positive. Biological females typically have two X chromosomes, and one of the X chromosomes is typically inactive, forming a Barr body. Researchers at the time thought that if a person had an inactive X chromosome, or was chromatin positive, they must be biologically female, and if a person did not have an inactive X chromosome, or was chromatin negative, it indicated that they were biologically male. However, when researchers looked at the cells of someone with Turner syndrome, they found that the individual was chromatin negative, indicating no inactive X chromosome, even though the individual seemed to be developing as a biological female. Thus, the nuclear sexing method indicated to Ford and colleagues that there was likely a chromosomal difference that caused Turner syndrome.

Article Roadmap

“A Congenital Sex Anomaly” consists of three sections. In the first section, an untitled introduction, the researchers cite the prior work of coauthor Polani to justify their hypothesis that a sex chromosome abnormality might cause Turner Syndrome, and they explain that to test their hypothesis, they directly analyzed one patient’s cells. Then, in “Case Report,” the authors describe their patient as a fourteen-year-old female with symptoms of Turner syndrome, and they discuss the patient's personal and family medical history. Ford and colleagues include a subsection of “Case Report” titled “Investigations,” in which they explain that by analyzing the patient’s cells, they found that the patient was missing an X chromosome but also did not have a Y chromosome. Finally, in “Discussion,” the authors caution that sex typing using chromatin negativity and positivity as a gauge may not always accurately predict a person’s sex, since, as their findings show, their patient was female yet was chromatin negative. They conclude that that errors of chromosome distribution during egg or sperm development likely cause the missing X chromosomes in individuals with Turner Syndrome.

Detailed Content

In the untitled introduction section, Ford and colleagues explain that physicians understood the physical symptoms of Turner syndrome and used them to identify patients with the disorder but did not yet understand its biological causes. The team explains that gonadal dysgenesis is a disorder in which a female fails to develop secondary sex characteristics, or characteristics that are not directly involved in the process of reproduction but are associated with a particular biological sex, such as enlarged breasts and pubic hair. The researchers describe Turner syndrome as a more severe expression of gonadal dysgenesis. However, as of 2024, recognize that Turner syndrome is just one type of gonadal dysgenesis, and that gonadal dysgenesis can affect both male and female gonads. The authors explain that among individuals with Turner syndrome, the female gonads, or ovaries, are either underdeveloped or completely absent resulting in infertility. However, they state that they do not know what causes those symptoms.

Continuing in the untitled introduction section, Ford and colleagues explain that their hypothesis that Turner syndrome is the result of a chromosome abnormality is based on the work of coauthor Polani, who explored the inheritance patterns of X-linked traits in individuals with Turner syndrome. X-linked traits are traits that pass from parent to offspring through the X chromosome. For males to present a specific X-linked trait, they must have a gene for that trait on their one X chromosome, and for females to have a specific X-linked trait, they must have a gene for it on both of their X chromosomes. Due to the fact that males only need a single copy of the gene to show an X-linked trait, more males have X-linked traits than females. Since color blindness is an X-linked trait, Polani analyzed people with Turner syndrome to determine how many of them were color blind. When they compared a group of people with Turner syndrome to a group of people developing as biologically female without Turner syndrome, they found that a much larger proportion of people with Turner syndrome had the color blindness trait. In their article, Polani and colleagues explain that people with Turner syndrome likely had a missing sex chromosome, designated as XO, or had an XY chromosome pattern. Thus, to determine the actual chromosome pattern in people with Turner syndrome, Ford and colleagues examined the sex chromosomes themselves.

To find the chromosomal pattern in people with Turner syndrome, Ford and colleagues decided to look at the cells, and then the chromosomes, of a patient with Turner syndrome. They state that previous researchers analyzed the chromosomes of human cells by analyzing either bone marrow cells, which are cells present in the spongy interior of a bone, or cells from tissue cultures. The research team explains that in their article, they chose to analyze the number of chromosomes present in the bone marrow cells of one patient with Turner syndrome.

In “Case Report,” the researchers describe the symptoms of the patient they studied and explain that they analyzed the family history and personal history of the patient. The researchers state that the patient was fourteen years old, had a short stature, and lacked secondary sex characteristics. The researchers also state that the patient was backward at school, which, as of 2024, is an outdated term that likely meant the patient had a learning disability. The researchers found that none of the patient’s relatives had Turner syndrome. Furthermore, the researchers state that the mother of the patient had a healthy pregnancy and normal delivery, and the patient had typical development in their early years.

In the subsection of “Case Report” titled “Investigations,” the researchers explain that they also conducted a general health checkup. Specifically, they describe that they conducted X-rays of the heart, chest, internal organs, and bones, and those results were normal and healthy for her age.

In the next part of “Investigation,” the researchers explain that they analyzed the patient’s marrow cells and found that the cells did not contain an inactive X chromosome. To visibly see the sex chromosome pattern in the patient’s cells, the authors explain that they first extracted marrow cells from the patient. Then, they allowed the marrow cells to incubate for one hour before treating them with colchicine, a chemical that pauses the process of cell division. They paused the process of cell division at a step when the chromosomes are compacted and can be clearly distinguished. Then, the researchers stained the cells with a dye to make the chromosomes visible. Finally, the researchers placed the cells under a microscope so that they could closely examine them. They found that the patient had a chromatin-negative staining pattern, meaning they did not have an inactive X chromosome.

The researchers explain that they counted the total number of chromosomes in a sample of the patient’s cells and found that those cells contained only one X chromosome but also did not contain a Y chromosome. Upon examining 102 of the patient’s cells, the team states that nearly all the cells had forty-five chromosomes rather than the typical forty-six chromosomes. They explain that they then observed fourteen of those cells more closely to study factors such as the location of the centromeres, which are small structures that hold each half of a chromosome together. Centromere location on chromosomes can vary and differs between males and females. In females, it is common to see four small chromosomes with centromeres located on one end, whereas for males, it is common to see five small chromosomes with centromeres located on one end because one of those chromosomes is the Y chromosome. The researchers recorded that in all fourteen cells of the patient, there were four chromosomes present with the centromeres located toward one end of the chromosome, indicating that there was no Y chromosome. Furthermore, there are typically sixteen medium-length chromosomes with centromeres positioned in the middle of the cell in females, and two of those chromosomes are the X chromosomes. Thus, for males, it is standard to see only fifteen medium-length chromosomes with centromeres positioned in the middle because they have only one X chromosome. In all fourteen of the patient’s cells, the researchers found only fifteen medium-length chromosomes with the centromere located in the middle, indicating that an X chromosome was missing. The researchers explain that they could then conclude that since the patient did not have a Y chromosome but also did not have two X chromosomes, their sex chromosome pattern must be XO.

The researchers then acknowledge that, at the time of writing in 1959, recognizing the X and Y chromosomes individually was still a challenging process. Thus, to confirm their conclusion about the patient’s chromosome pattern, they paired up the forty-five chromosomes present by size and shape and found that one chromosome was indeed missing its pair. The researchers concluded that it must be the one X chromosome without its pair. The researchers provide two figures to support that conclusion. One figure displays all the chromosomes present in one cell during cell division, and the other figure shows the same chromosomes lined up in pairs, except for the one chromosome, assumed to be the X chromosome, which was missing its pair. The researchers reasoned that a human is unlikely to develop to maturity without one of its autosomal, or non-sex chromosomes, but could potentially survive if it was missing a sex chromosome. Therefore, the missing chromosome must be an X chromosome.

In “Discussion,” the researchers argue that their observations have implications for more than just the understanding of Turner syndrome. The authors state that the patient they observed was anatomically and psychologically female, and yet by the nuclear sexing method she would be classified as male. The researchers reiterate that the patient is not biologically male because there is no Y chromosome present, but at the same time, the patient’s cells lacked an X chromosome, which contradicted the scientific understanding of the 1950s that all people either had two X chromosomes or one X and one Y chromosome. Ford and colleagues thus conclude that it is not possibly to determine definitively on the basis of nuclear sexing whether someone is male or female, and that therefore one should avoid using the terms male and female with respect to the results of nuclear sexing and should instead use the less presumptuous terms chromatin negative or chromatin positive.

The researchers also use the “Discussion” section to explain that errors in chromosome distribution during egg formation may have resulted in their patient’s missing X chromosomes. During the typical process of meiosis that produces egg cells, chromosome pairs separate and move to opposite poles of the egg progenitor cell before the cell splits in two. However, sometimes the two chromosomes fail to separate, a phenomenon called nondisjunction, resulting in eggs with an atypical number of chromosomes.

The researchers support their hypothesis about nondisjunction as a cause of the missing X chromosome by referring to the 1925 work of geneticists Thomas Hunt Morgan, Calvin Bridges, and Alfred Sturtevant from New York City, New York, who found evidence of nondisjunction in fruit flies. They state that in a female fruit fly, if the two X chromosomes in a cell fail to separate, it results in one egg cell with no X chromosomes and another egg cell with two attached X chromosomes. If a male fruit fly fertilizes the egg with no X chromosomes, the resulting zygote will have either YO or XO sex chromosomes. Thus, the researchers conclude that nondisjunction during egg cell development could explain the missing X chromosome in Turner syndrome in humans.

However, the researchers note that there is evidence that nondisjunction can also occur during sperm cell development, and studies of color-blindness in people with Turner syndrome support the idea that Turner syndrome can result from nondisjunction during sperm development. If an individual with Turner syndrome is color blind and got their X chromosome from the father’s sperm, then you would expect the father to also be color blind, but that is most often not the case. That finding suggests that the person got their X chromosome from the mother’s egg, which implies that the sperm contained neither X nor Y chromosome, and thus was a product of nondisjunction.

Impact

According to Google Scholar, as of 2024, “A Sex Chromosome Anomaly” has been cited over 1,500 times, and since its publication, researchers have continued to investigate the variation of sex chromosome distribution in the cells of individuals with Turner syndrome. For example, in 2002, Ayumi Uematsu and colleagues, who were a group of researchers working in various hospitals in Japan, published an article about the possible cause of the missing X chromosome in those with Turner syndrome. According to Uematsu and colleagues, the missing X chromosome is most likely due to a mistake in sperm cell production rather than egg production. The article thus supports Ford and colleagues’ idea that nondisjunction during sperm cell development may explain at least some cases of Turner syndrome. In 2022, Fan and colleagues, a group of researchers working in various hospitals and health departments in China, published an article that explores how the biological process of methylation in X chromosomes, or the biological addition of methyl groups to DNA molecules, influences the expression of genes in people with Turner syndrome.

“A Sex Chromosome Anomaly” brought a greater scientific understanding of how sex inheritance happens and how errors in the process can result in genetic disorders like Turner syndrome. It also further confirmed that humans can live with some chromosomal abnormalities, despite the health concerns they pose. Additionally, the authors of “A Sex Chromosome Anomaly” pushed for a more nuanced understanding of the results of nuclear sexing. As of 2024, researchers are still conducting studies on the complexities of Turner syndrome, but “A Sex Chromosome Anomaly” was one of the first to document a chromosomal cause of the condition.