Turner Syndrome affects approximately 1 in 2,000 to 1 in 2,500 live female births. However, the actual incidence rate at conception is much higher, as it’s estimated only 1-2% of fetuses with Turner Syndrome will result in live birth. Around 10-15% of confirmed pregnancies that end in miscarriage occur with fetuses that are 45,X. Unlike other chromosomal abnormalities, there does not appear to be a strong correlation between maternal or paternal age and prevalence of Turner Syndrome.

Turner Syndrome is caused by the loss of a second sex chromosome, leading to improper amounts of expression of genes on the X chromosome. In biological females with two sex chromosomes (XX), one of the X chromosomes is inactivated by a process called dosage compensation. This ensures that all cells across the body have the proper amount of expression from genes across the X chromosome. However, around ~15% of genes on the X chromosome “escape” X inactivation, and it is critical that these genes are able to produce a higher dose of expression for human development. In Turner Syndrome, there is no second chromosome to provide higher expression of these “escaped” genes, and the absence of this leads to the symptoms observed. 

The loss of an X chromosome is not inherited, and occurs randomly. The most common cause of X chromosome loss, and therefore Turner Syndrome, is called nondisjunction. Nondisjunction is an error that occurs during meiosis, or the cell division process that gives rise to germ cells such as egg and sperm. Generally, all germ cells have one copy of each chromosome. However, in nondisjunction, the precursor cell that gives rise to the egg or sperm does not divide properly, and the resulting germ cells have either two copies of a particular chromosome, or no copies at all. In children born genetically female, one X chromosome is inherited from the mother’s egg and one from the father’s sperm. In an egg or sperm that ultimately gives rise to individuals with Turner Syndrome, the X chromosome has been lost, and upon fertilization this results in a 45,X individual. Around 60-80% of 45,X women inherit their one X chromosome maternally (from their mother). This means the majority of the time, it is the fertilizing sperm that has lost the X chromosome.

Turner Syndrome can also be caused by cell division errors that occur after fertilization. This causes mosaicism. In mosaicism, there is a cell division error in the developing embryo during mitosis, resulting in a subset of cells that no longer have an X chromosome. Because only a subset of cells are affected, often individuals with mosaicism have a more mild form of the disease.

The number of X chromosomes in the other cells of patients with mosaicism depends on the nature of the cell division error. Some individuals will have cells with two X chromosomes. Other individuals will have different chromosomal abnormalities in their remaining cells. Some have 47,XXX cells, meaning there is an extra X chromosome. Around 10-12% of individuals can have remaining cells which have Y chromosomes, making these cells 46,XY. The presence of a Y chromosome in a subset of cells is of clinical concern, because while individuals with Turner Syndrome develop biologically as female, the presence of the Y chromosome can often lead to gonadoblastoma, or germ cell tumors. Which type of mosaicism is present will affect clinical manifestation and symptom severity, leading to wide variation.

Turner Syndrome can also result from structural abnormalities of the X chromosome. In this case, the individual has one complete X chromosome, and one X chromosome which has been altered. It may have just a portion deleted, or it can be an isochromosome, where there are either two short arms (p) or two long arms (q) instead of the typical chromosome with one p and one q arm. It is also possible for a chromosomal break to occur and result in the X chromosome reforming in a ring. In all of these cases, the pieces of the X chromosome which are missing contain genetic information, and which pieces are missing will affect clinical manifestations of the disease. 

While we do not know the precise consequence of losing a copy of each individual gene on the X chromosome, one gene which is known to drive symptoms of Turner Syndrome is the loss of the SHOX gene. The SHOX gene encodes a protein called a transcription factor which is important for regulating the growth and development of bones in the body. Loss of the SHOX gene leads to short stature, a symptom observed in Turner Syndrome.

Turner Syndrome is a multi-systemic disorder, meaning that depending on the loss of genetic information many systems in the body can be affected. The three most common symptoms are short stature, a webbed neck, and gonadal dysgenesis, or underdeveloped ovaries or testes. However, Turner Syndrome can impact the cardiovascular, renal, and auditory systems as well. 

• Growth and development symptoms

  • The defining skeletal feature of Turner Syndrome is short stature, evident by age 5. Individuals with Turner Syndrome are on average approximately 8 inches shorter than the general population.

  • Around 30% of individuals are born with a webbed neck, which is the result of fluid build-up behind the neck during fetal development. This fluid build-up is common due to underdevelopment of the lymphatic system. 

  • Many individuals with Turner Syndrome also have osteoporosis, or a significant reduction in bone density that increases the risk of fracture.

• Reproductive symptoms

  • Turner Syndrome frequently causes premature loss of ovarian function. While the ovaries develop normally during fetal development, the absence of a second X chromosome leads to the rapid decay of oocytes (eggs), and breakdown of ovarian tissue can begin shortly after birth. 

  • Without the estrogen produced by healthy ovaries, the uterus often remains underdeveloped.

  • Nearly 90% of girls do not undergo puberty, and will not start their menstrual cycle without hormone therapy. 

  • Most individuals with Turner Syndrome experience infertility, with only 2-5% able to conceive naturally. Individuals that can conceive often have significant mosaicism (see explanation in Causes). 

• Cardiovascular symptoms

  • Cardiovascular symptoms are the most common cause of morbidity and early mortality in individuals with Turner Syndrome. Approximately ⅓ to ½ of individuals are born with a heart defect. 

  • Around 10-12% have coarctation of the aorta, or a narrowing of the aorta, which is the largest artery that leaves the heart. This often requires surgical intervention in infancy. 

  • Around 30% are born with a bicuspid aortic valve, or a condition where the valve that regulates blood flow from the heart to the aorta has two leaflets instead of three, which can lead to valve leakage or narrowing over time. 

  • Individuals with Turner Syndrome are at a higher risk of hypertension, or high blood pressure (50% of children and 60% of adults), and as a result, an increased risk of aortic dissection. 

• Renal Symptoms

  • Around 30% of individuals with Turner Syndrome have renal symptoms, the most common being “horseshoe kidney”, a condition where the two kidneys are fused at the base. While often benign, this can lead to increased risk of urinary tract infections and increased blood pressure. 

• Auditory and Vision Symptoms

  • Recurrent ear infections occur in almost all children with Turner Syndrome due to the shortened eustachian (middle ear) tubes. 

  • Wandering or crossed-eyes affect around one out of three of individuals with Turner Syndrome. Other common vision issues include nearsightedness, droopy eyes, and color blindness.

• Psychosocial Symptoms

  • While Turner Syndrome is not associated with intellectual disability, many young girls with Turner Syndrome experience social challenges and anxiety, particularly during the teenage years.

Turner Syndrome is diagnosed through genetic testing. Karyotyping, or the visual analysis of an individual’s chromosomes, is the most straightforward method since it clearly shows the absence of a complete second X chromosome. Depending when the individual is diagnosed, genetic material may be obtained in different ways: 

• Prenatal diagnosis - In many cases, an individual with Turner Syndrome may be identified before they are born, usually either by Amniocentesis or Chorionic Villus Sampling (CVS).

  • Amniocentesis is performed between the 14th and 20th week of pregnancy, and tests the genetic material of fetal cells found in amniotic fluid.

  • CVS takes tissue from the placenta for genetic analysis between the 10th and 13th week of pregnancy.

• Postnatal diagnosis - In other cases, genetic testing is done after an individual is born when symptoms, such as short stature, cause suspicion of Turner Syndrome. Diagnosis is usually done by karyotyping or Chromosomal Microarray Analysis (CMA).

  • CMA is similar to karyotyping, but higher resolution, with an ability to detect microdeletions or microduplications of small regions of the chromosomes. It isn’t necessary to use this level of resolution to identify Turner Syndrome, but it may be used during the diagnostic process so the clinician can identify any other possible chromosomal abnormalities.

• Adult diagnosis - Occasionally, Turner Syndrome will be diagnosed in an adult incidentally, usually when they are receiving genetic testing for another purpose, such as family planning, or evaluating the cause of infertility or repeated miscarriage.

Because Turner Syndrome affects so many systems, treatment is multidisciplinary and focuses on managing each symptom as they emerge throughout lifespan. Treatment is tailored to each individual’s symptoms, but the most common treatments are below.

• Growth Promoting Therapy

  • The use of recombinant human growth hormone is near universal in pediatric treatment. It is typically started between 4 and 6 years of age. It works by stimulating the production of a molecule called IGF-1, which helps promote bone growth. 

  • When started at a young age, treatment with growth hormone can allow individuals to grow taller, with a goal of adding another 2-3 inches of height.

• Hormone Replacement Therapy

  • Estrogen treatment to maintain estrogen levels is vital for both physical and psychological health. Estrogen treatment is usually initiated between 11 and 12 years of age with transdermal skin patches. The dose is gradually increased over two to four years to mimic the progression of puberty. 

  • Sometimes progesterone treatment is added to help maintain ovarian health and regular menstrual cycles. 

• Cardiovascular Care

  • Management of cardiovascular health is lifelong, and focuses on lowering blood pressure and monitoring health of the aorta.

  • Hypertension must be treated aggressively, often starting in childhood with the use of beta-blockers or ACE inhibitors.

  • Regular echocardiograms are recommended to monitor the integrity and dimensions of the aorta.

  • Prophylactic aortic surgery may be recommended in patients at high risk of aortic dissection.

• Gonadectomy 

  • In individuals with the presence of a Y chromosome in their mosaicism, ovaries often develop abnormally and are removed due to the high likelihood of tumor formation.

• Psychological Support

  • Therapy and mental health resources can be helpful for teenagers and adults as they age and navigate their diagnoses. 

The prognosis of individuals with Turner Syndrome has improved greatly over the last few decades due to better management of cardiovascular care and improved hormone treatments. Life expectancy is still reduced compared to the general population, by an estimation of 10 - 12.5 years. This reduction is primarily driven by cardiovascular symptoms. Individuals with Turner Syndrome who experience cardiovascular symptoms are at much higher risk for aortic dissection than the general population, and these events can be fatal. The risk is highest during young adulthood and pregnancy. However, with early diagnosis, ongoing vigilance and intervention, many women live a normal lifespan. 

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