“Congenital Heart Disease in Patients with Turner’s Syndrome” (1998), by Laura Mazzanti, Emanuele Cacciari, and the Italian Study Group for Turner Syndrome

In 1998, researchers Laura Mazzanti and Emanuele Cacciari published “Congenital Heart Disease in Patients with Turner’s Syndrome,” hereafter “Congenital Heart Disease,” in The Journal of Pediatrics. Turner syndrome is a genetic disorder caused by a missing X chromosome and affects one in 1,500 to 2,500 female births. Turner syndrome can result in various developmental issues, such as stunted physical and sexual growth, infertility, and congenital heart disease, or developmental malformations of the heart. At the time of publication, other researchers had established a link between congenital heart defects and Turner syndrome. However, there was little research on the relationship between what specific chromosomal pattern a person had and the types of congenital heart defects that a person presented with. “Congenital Heart Disease” established links between certain types of chromosomal patterns with various congenital heart defects, which the authors argue should allow for improved medical intervention and a better quality of life for people with Turner syndrome.

1. Author Backgrounds
2. Background and Context
3. Article Roadmap
4. Article Content
5. Study Impact

Author Backgrounds

Mazzanti and Cacciari conducted their research for “Congenital Heart Disease” at the First Pediatric Clinic at the University of Bologna in Bologna, Italy. Mazzanti got her degree in medicine and surgery at the University of Bologna Medical School in 1974 and began specializing in pediatrics in 1977. Cacciari was a professor as well as Mazzanti’s research guide for a period of time. Both Mazzanti and Cacciari published papers on the prevalence of different Turner syndrome symptoms prior to “Congenital Heart Disease” and afterward. Mazzanti published many papers on other genetic conditions, such as Noonan syndrome and Wolf-Hirschhorn syndrome, both of which result in delayed or altered growth. Cacciari also published many papers on hormonal treatments for Turner syndrome. Cacciari worked as a professor at the University of Bologna since 2006. He died in 2011. Starting in 2006, Mazzanti worked as an associate professor in pediatrics at the University of Bologna and retired in 2018. At the time of publishing “Congenital Heart Disease,” Mazzanti was also a coordinator for the Italian Study Group for Turner Syndrome, which collected information for research on patients with Turner syndrome from multiple medical centers across Italy.

Background and Context

The biological cause of Turner syndrome was unknown until 1959 when Charles Edmund Ford and colleagues published an article explaining the chromosomal cause of Turner syndrome. Chromosomes consist of tightly wound genetic material called DNA, which contains the information that codes for the traits that make up one’s body and its functions. There are chromosomes called sex chromosomes in the cells of an organism that influence the development of biological sex characteristics. In humans, people who develop as biological females typically have two X chromosomes, while people who develop as biological males typically have one X chromosome and one Y chromosome. Ford and colleagues analyzed the cells of a female patient with Turner syndrome and found that the patient was missing an X chromosome in their cells.

After Ford and colleagues’ discovery that a missing X chromosome can cause Turner syndrome, other researchers found more chromosomal patterns that can also cause the syndrome. Another chromosomal pattern that results in Turner syndrome is chromosome mosaicism, which is where different cells have different numbers of X chromosomes. Some cells might have only one X chromosome, while other cells might have two. Another chromosomal pattern is structural abnormalities on the X chromosome, which is when the X chromosome is structurally different from a typical X chromosome, which still results in symptoms associated with Turner syndrome. Before “Congenital Heart Disease,” few researchers had looked for trends in which chromosomal patterns were more likely to cause symptoms of Turner syndrome. In “Congenital Heart Disease,” the scientists use data on patients with Turner syndrome to analyze whether there is a connection between certain types of congenital heart disease and the type of chromosomal pattern they have.

Article Roadmap

“Congenital Heart Disease” consists of four sections. The first section is an untitled introduction in which the researchers explain their motivations for writing the paper, specifically the lack of research evaluating a link between congenital heart disease and the chromosomal pattern of people with Turner syndrome. The second section, titled “Methods,” explains how they grouped their subjects into three groups based on whether they had a missing X chromosome in all their cells, X-mosaicism, or a structural abnormality on an X chromosome. The researchers further divided the groups into subgroups based on how severe their physical symptoms of Turner syndrome were. In the third section, titled “Results,” the researchers state that those with Turner syndrome had a higher risk and prevalence of congenital heart disease when compared to the general population and were more commonly associated with a missing X chromosome in all cells. Finally, in the last section, titled “Discussion,” the researchers conclude that there is a higher prevalence of congenital heart disease in individuals with Turner syndrome who are missing an X chromosome.

Article Content

In the untitled introduction section, Mazzanti and Cacciari state that their reason for evaluating data on congenital heart defects and their connections to chromosomal patterns in people with Turner syndrome is the lack of research on the subject at the time of publication in 1998. The scientists used data from the Italian Study Group for Turner Syndrome, or ISGTS. The researchers specifically point to a lack of evidence on the varying chromosomal patterns that cause Turner syndrome and how they result in different congenital heart defects, especially using echocardiographic data. Physicians and medical researchers use echocardiographic data to find out how well the heart is functioning. An echocardiogram uses ultrasound imaging and records thr heart rhythm and is crucial for the diagnosis and medical intervention of heart disorders. The researchers restate that their goal with their paper was to gather information on the types of heart defects that the patients have, what chromosome pattern they have, if there is a connection, and how it compares to the general population.  

In the “Methods” section, the researchers explain the demographics of their subjects, how they grouped their subjects based on what chromosomal pattern they presented, and what degree of severity they presented for physical symptoms of Turner syndrome. The researchers explain that they gathered 594 individuals with Turner syndrome from the Italian Study Group for Turner Syndrome who came from across Italy. The individuals’ ages ranged from one month to twenty-four years. The researchers categorized the individuals into three groups according to the chromosomal patterns they had. The three groups consisted of one group with a missing X chromosome in all cells, the second with X-mosaicism, and the final group with structural abnormalities present on the X chromosome. The researchers report that they grouped 483 of the subjects into subgroups called minor, moderate, and severe according to the severity of their physical symptoms. The researchers also made sure to record the frequency of heart disease in each subgroup.

Also in the “Methods” section, the researchers describe what heart examinations they conducted on the patients and explain that they explored other aspects of the patients’ lives to rule out any outside forces contributing to their heart disease. The heart examinations consisted of chest X-rays, an electrocardiogram, which measures the electrical signals that keep the heart beating, and an echocardiogram, which forms medical images of the heart to determine its ability to function. To rule out any other causes of heart problems, researchers looked at a patient’s case history, which consisted of each of their birth conditions, growth, heart defects, symptoms, and whether they had any previous heart operations. The researchers also had physical examinations done on the subjects.

In the “Results” section, Mazzanti and Cacciari observed five congenital heart defects that were a result of malformations in the chambers and valves of the heart. The heart is divided into four separate chambers and has a left and right side. The top chambers are called the left and right atria, and the bottom chambers are called the left and right ventricles. There are valves, or openings, that assist in moving blood in and out of the specific chambers. The right side of the heart collects deoxygenated blood and sends it to the lungs through a tube-like structure called the pulmonary artery. The lungs then oxygenate the blood and use veins called pulmonary veins to send it to the left side of the heart. The left side of the heart then pumps the oxygenated blood through the aortic valve, which separates the left ventricle and the aorta. The aorta is another tube-like structure that sends oxygenated blood to the rest of the body.

Continuing in the “Results” section, the researchers describe how the risk and prevalence of congenital heart disease in general, as well as with certain specific defects, were much higher in their study participants compared to the general population. The researchers state that out of the 594 individuals they studied, 136 had some form of congenital heart disease, or 22.9 percent. The researchers note that the general population had a prevalence of congenital heart disease of two percent, showing that the people with Turner syndrome in their study had a higher risk of congenital heart disease. The most common heart malformation that Mazzanti and Cacciari observed in patients with Turner syndrome was a malformation of the bicuspid aortic valve, with seventy-four patients out of the 136 patients having it, or 54.4 percent. The bicuspid aortic valve is a malformation in which the aortic valve has two cusps instead of the typical three cusps. Two cusps in the aortic valve can result in problems in the structure of the valve over time, and an enlargement of the aorta, which can cause problems in the heart delivering blood to the rest of the body. The prevalence of ventricular septal defect, which is a hole in the wall that separates the two bottom chambers of the heart, was less frequent in the individuals with Turner syndrome in the study. The researchers also found that thirty patients had multiple heart defects. Those who had an aortic valvular disease, which is when the aortic valve has issues causing a narrowed aorta and a backward flow of blood, had multiple heart malformations associated with it.      

Also in the “Results” section, the researchers state that the relative risk and prevalence of heart disease was higher in individuals missing an X chromosome in all cells and those who displayed more severe physical symptoms of Turner syndrome, than in participants with other chromosomal patterns. Patients with X structural abnormalities had a lower risk of congenital heart disease when compared with the other chromosomal patterns. The researchers also found that those with certain severe characteristics of Turner syndrome also had a higher prevalence and risk of congenital heart disease. Some of those included webbed neck and lymphedema, which is an accumulation of fluid in the lymphatic system that causes swelling in different body parts. Additionally, Mazzanti and Cacciari found that the individuals with severe Turner syndrome characteristics also were more likely to have a missing X chromosome in all their cells. Individuals missing an X chromosome in all cells were more likely to experience a severely webbed neck, as well as coarctation of the aorta, which is when the aorta is narrower than typical. The researchers noted that individuals with partial anomalous pulmonary venous drainage were associated only with the webbed neck symptom. Partial anomalous pulmonary venous drainage is when the pulmonary veins connect at the wrong locations and result in the mixing of different blood going to different parts of the body.

In the “Discussion” section, the researchers conclude that the missing X chromosome is what causes congenital heart disease and speculate on the connections between left-sided congenital heart defects and a missing X chromosome. The researchers clarify that their results were consistent with previous research on Turner syndrome and congenital heart defects where researchers used different technology from the authors of “Congenital Heart Disease.” The researchers reiterate that those with a missing X chromosome in all cells seemed to have congenital heart disease in the vessels that make up the left side of the heart. To explain their findings, Mazzanti and Cacciari cite researchers who hypothesize that lymphatic obstructions, which are blockages or accumulations of fluid in the lymphatic system, can alter the blood flow on the left side of the heart. The lymphatic system is made up of vessels that travel throughout the body and support the function of the immune system. The researchers note that the hypothesis supports their data, as lymphedema is one severe symptom of Turner syndrome. The researchers also note that left-sided heart defects are more common in males in the general population, who typically also only have one X chromosome. The researchers explain that the correlations found lead them to the hypothesis that left-sided heart defects are a result of the absent X chromosome. Finally, the researchers stress the importance of people with Turner syndrome having regular cardiac screenings, especially those who have a missing X chromosome in all their cells or present severe physical symptoms.

Study Impact

According to Google Scholar, 314 sources have cited “Congenital Heart Disease” as of 2024, including sources that further confirm the prevalence of congenital heart disease in those with Turner syndrome. Mazzanti and Cacciari conducted studies with another group of researchers in 1999, a year after “Congenital Heart Disease.” Mazzanti and colleagues published a long-term article that used different methods from “Congenital Heart Disease” to confirm a high prevalence of congenital heart disease in people with Turner syndrome. Then, in 2006, Mazzanti and colleagues published the results of a longer-term study in which they also tracked the chromosomal patterns of people with Turner syndrome and what congenital heart disease they had. The researchers found that in their observations, certain forms of congenital heart disease in people with Turner syndrome, such as aortic valvular disease, require long-term follow-up with a medical professional. Mazzanti and colleagues emphasize the importance of examinations of the heart and follow-ups at various ages to provide better medical intervention for people with Turner syndrome.

Furthermore, “Congenital Heart Disease” inspired more research on the X chromosome and its possible linkage to the formation of the left side of the heart, and more speculation on how a missing X chromosome can cause those congenital heart diseases. In 2023, Claus H. Gravholt and colleagues, researchers from Denmark and the Netherlands, reported that there is still not a strong understanding of the X chromosome and how exactly it affects the development of the left side of the heart. However, the researchers explain that by compiling data from previous research, many results show that a missing X chromosome relates to an increased chance of developing congenital heart disease. The researchers suspect there must be genes on the X chromosome that cause flaws in the development of the left side of the heart, again due to their compiled data showing most congenital heart defects on the left side in people with Turner syndrome. Gravholt and colleagues also report the same idea Mazzanti and Cacciari mentioned in their paper that there is a connection between congenital heart disease and an accumulation in the lymphatic system, further exploring the cause-effect relationship between the two.

“Congenital Heart Disease” provided data that a missing X chromosome was a likely contributor to congenital heart disease in people with Turner syndrome. Mazzanti and Cacciari’s work on “Congenital Heart Disease” also demonstrated the importance of cardiac screening in patients with Turner syndrome, allowing for better medical intervention and understanding of Turner syndrome.