What is Turner Syndrome?

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Turner syndrome is a rare genetic condition whereby the X chromosome is either completely or partially missing. Typically, a female has two X chromosomes. One of the X chromosomes is received from the egg, and the other from the sperm. Turner syndrome can cause various developmental issues.  

TS occurs in approximately 1 in 2000 liveborn females.ⁱ Most patients are diagnosed during adolescence or adulthood,ⁱⁱ though sometimes the parent will know before delivery that their fetus has monosomy X.ⁱⁱⁱ

A commonly asked question regarding monosomy X and mosaic TS revolves around the survival rate of those with TS. Typically, TS is not considered life-threatening, though women with it may face a shorter life expectancy.^iv However, pregnancies are at higher risk for miscarriage when the fetus has monosomy X.  

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What are the symptoms of Turner syndrome?

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The most common symptoms associated with TS are growth failure and small stature (>95 percent), which may become more apparent as the female is growing. The child will have lapses in growth during expected growth spurts, such as during puberty. Other than growth issues, one of the symptoms of TS a woman may experience is failure of the ovaries to produce or respond to sex hormones (hypergonadotropic hypogonadism 90-95 percent). As a result, a woman with TS may deal with issues of infertility. Pre-diabetes (15-50 percent), diabetes (10 percent), and hyper- or hypothyroidism (15-30 percent) may occur as well.^v  

Other possible TS symptoms/medical problems include the following:^vi

• High blood pressure (50 percent)
• Learning disabilities and psychological problems (>50 percent)  
• Liver issues (50 percent)  
• Abnormally small jawbone (60 percent)  
• Webbed neck (40 percent)  
• Broad chest or shield chest (30 percent)  
• Hearing defects (30 percent)  
• Poor vision (20-30 percent)
• Swelling of the hands and feet (lymphedema) (25 percent)  
• Kidney malformations (>15 percent)  
• Celiac disease (allergy to gluten) (10 percent)
• Inflammatory bowel disease such as Crohn’s or ulcerative colitis (3 percent)

Skeletal abnormalities (>85 percent) and heart valve anomalies (bicuspid aortic valve 15-35 percent) may also arise.^vii Congenital heart defects abnormalities are common in TS, potentially leading to medical problems such as aortic dissection. This is a rare occurrence, but a 100x higher risk than in non-affected individuals; aortic dissection occurs when there is a tear in the lining of the aorta – the largest blood vessel in the body.^viii

Patients with 45, X TS (see below) often have more severe manifestations of the disease than Mosaic (46,XX/45,X) Turner patients.^ix

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What Causes Turner syndrome?

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At the highest level, TS is caused by the absence of one of the chromosomes that determines biologic sex (male or female).^x

Chromosomes are structures found inside the nucleus (core) of the cells of the body that contain the body’s genetic material (DNA). In TS, either the entire X chromosome is missing from the affected patient’s cells (the patient has only 45 chromosomes instead of the expected 46, indicated as 45, X), or the affected patient has a blend of affected and unaffected cells in their body (mosaic). While unaffected females have two X chromosomes (46,XX), those with TS, while still biologically female, have either one X chromosome (45,X) or are mosaic. A mosaic embryo is one in which some of the cells have both X chromosomes (46,XX) while some cells lack the X chromosome (45,X) (45,X/46,XX). In some cases, patients with TS can also have part of a Y (male) chromosome in some of their cells (45,X/46XY).^xi

When describing chromosomes, the convention is to list the number of chromosomes, followed by the chromosomal sex. As there are typically 46 chromosomes, a non-affected female patient would be 46,XX. Similarly, a non-affected male would be 46,XY.  

Individuals with TS are biologically female, even though the second X chromosome is missing or impartial. It is important to note that while TS is a genetic condition, it is caused by a sporadic (random) genetic event, i.e., is not inherited from parental chromosomes^xii and is not a condition that runs in families.

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How is Turner syndrome diagnosed?

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The timing of a TS diagnosis generally depends on the development trajectory and severity of any of the typical signs that indicate the potential presence of this condition. TS is commonly diagnosed in childhood in girls with abnormally short stature or during adolescence due to delayed puberty or the failure to start menstruation. At this point, a physician can provide early intervention. Girls with 45,X TS are typically diagnosed earlier as they have more severe symptoms. Some individuals are not diagnosed until they are adults.^xiii

If a female has signs or symptoms of TS, a blood sample is taken to confirm the diagnosis. This blood sample undergoes a genetic analysis called a karyotype, which looks at the size, shape, and number of chromosomes in multiple cells. Sometimes, if Mosaic TS is suspected, skin biopsies from different parts of the body are taken and tested for karyotype, due to the fact that in Mosaic Turner, different cells in the body can have different karyotypes.^xiv

It is also possible to screen for TS before a child is born. If an individual is undergoing IVF treatment, preimplantation genetic testing for aneuploidy (PGT-A) can screen for an increased risk in an embryo before it is transferred. After 10 weeks' gestation, a non-invasive prenatal test (NIPT, which examines fetal DNA in the maternal blood) can indicate if there is a missing X chromosome. Similarly, in a prenatal screening ultrasound, an increased nuchal translucency value (measurement of thickness of translucent space behind the neck of fetus), or other anatomic features can indicate increased risk of TS.^xv If PGT-A, NIPT, or ultrasound indicate TS, the diagnosis can be confirmed prenatally using chorionic villus sampling (CVS) or amniocentesis.^xvi

For individuals born with TS, once a formal diagnosis has been issued, a physician will want to conduct further testing to determine any issues associated with the condition and to develop a management plan. Testing for TS can include any of the following:^xvii

• Renal ultrasounds
• Heart ultrasounds (echocardiograms)
• Blood pressure measurement
• Thyroid function testing
• Hearing testing
• Vision testing
• Orthopedic evaluation

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Are individuals with Turner syndrome able to get pregnant?

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When discussing human development and TS, it is important to note the effect of the chromosomal abnormality on fertility. Although it is rare, especially in non-mosaic TS, some people do achieve spontaneous pregnancy despite the condition.^xviii

In pregnancies using their own eggs or those using donor eggs, women with TS are more likely to experience hypertension and other cardiovascular complications during pregnancy; therefore, cardiovascular screening is recommended.^xix,xx In addition, the woman may be at higher risk of having a miscarriage, preterm labor, complications from thyroid dysfunction, diabetes, and potential congenital risks.^xxi,xxii  

Statistics indicate that more than 90 percent of women with TS have gonadal failure (primary ovarian failure, meaning the ovaries do not function normally). In most patients, puberty is delayed and followed by progressive ovarian failure (slow loss of ovarian tissue leading to complete lack of function), which cannot be treated with medical care.^xxiii

However, approximately 5-20 percent of those with TS do externally appear to develop normally during puberty without medical assistance, and have spontaneous menstrual cycles, although subsequent ovarian failure and early menopause often ensues.^{xxiv,xxv,xxvi}  

Nonetheless, it may be possible for these patients to achieve pregnancy spontaneously.^xxvii In a study examining 480 French women with TS, 52 spontaneous pregnancies were observed in 27 patients within the cohort.^xxviii The rates of miscarriage and caesarian section were higher in these pregnancies compared to the general population.

Given that those with natural menstrual cycles are likely to lose fertility at a young age, they are often encouraged to consider egg cryopreservation (freezing) if they wish to conceive genetically related children later in life.^xxix

When TS cases are diagnosed early, doctors can provide intervention before puberty. Specifically, prior to puberty, growth hormone is often given to stimulate growth. Estrogen therapy is typically started at the time of normal puberty to stimulate normal growth and development of secondary sex characteristics (breast development, pubic hair, etc.), while progesterone may be added to establish normal menstrual cycles. However, these hormonal interventions do not prevent primary ovarian failure; they simply replace the hormones that the ovaries are not producing.^xxx In other words, because ovarian failure will continue, many of these women will still be infertile.  

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Unfortunately, over 90 percent of people with TS do not have functional ovaries despite adequate pubertal estrogen treatment. In this group, oocyte or embryo donation should be considered for those hoping to achieve a viable pregnancy.^xxxi Women with TS utilizing donor eggs or embryos to achieve a pregnancy need supplemental hormones during pregnancy as their bodies do not produce the normal amounts of estrogen, progesterone, and other pregnancy hormones.^xxxii Individuals with TS that are considering pregnancy should consult with their physician as the risk of complications is higher, as described above.

One option for women with TS in the future may be cryopreservation of prepubertal ovarian tissue prior to the inevitable occurrence of ovarian failure after puberty.^xxxiii This means that down the road, there may be an option for eggs to be extracted from girls with TS prior to puberty, before the ovaries degenerate. However, this is investigational at this time as the non-mature eggs would need to be matured in a lab prior to being able to be used for a pregnancy.^xxxiv,xxxv

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Conclusion

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While TS is a disease that can have serious implications, the earlier it is diagnosed, the earlier an appropriate treatment plan can be developed and implemented. Women who are concerned about their fertility and commensurate pregnancy options should speak to a physician if they suspect they have TS, or if they have been diagnosed at an earlier point in their lives.