What is Turner syndrome?

Typically, a female has two X chromosomes. One of those X chromosomes is received from the mother’s egg, and the other from the father’s sperm. Turner syndrome (TS) is a rare genetic condition where one of the X chromosomes is either completely or partially missing. It can cause various physical and sexual development issues.

TS occurs in approximately 1 in 2,000 liveborn females.ⁱ Most patients are diagnosed during adolescence or adulthood,ⁱⁱ though sometimes their parents will know before delivery that the fetus has monosomy X.ⁱⁱⁱ

A commonly asked question regarding monosomy X and mosaic Turner syndrome revolves around the survival rate. TS is not considered life-threatening, though females with this chromosomal abnormality may face a shorter life expectancy.^iv However, it is important to note that a pregnancy has a higher risk for miscarriage when the fetus has monosomy X.

What are the symptoms of Turner syndrome?

The most common symptoms associated with Turner syndrome are growth failure and small stature (affecting more than 95 percent of individuals with TS), 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 a female may experience is failure of the ovaries to produce or respond to sex hormones (known as hypergonadotropic hypogonadism, which affects 90 to 95 percent of TS individuals). As a result, a female with TS may deal with issues of infertility. Pre-diabetes (15 to 50 percent), diabetes (10 percent), and hyper- or hypothyroidism (15 to 30 percent) may occur as well.^v

Here are some other possible Turner syndrome symptoms and medical concerns:^vi

Skeletal abnormalities (greater than 85 percent) and heart valve anomalies (bicuspid aortic valve, 15 to 35 percent) may also arise.^vii

Congenital heart defects are also common in TS, potentially leading to medical problems such as aortic dissection (when there is a tear in the lining of the aorta, the largest blood vessel in the body). Though the occurrence is rare, it is still 100x higher than in individuals without TS.^viii

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

What causes Turner syndrome?

At the highest level, Turner syndrome 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).  When describing chromosomes, the convention is to list the number of chromosomes, followed by the chromosomal sex. Since there are typically 46 chromosomes, a non-affected female patient would be 46,XX and a non-affected male would be 46,XY.

In TS, there are three things that can happen:^xi

• ‍45,X: In this case, the entire X chromosome is missing from the affected patient’s cells, meaning the patient has only 45 chromosomes instead of the expected 46.
• ‍45,X/46,XX: This case is called mosaic TS, and the affected patient has a blend of affected and unaffected cells in their body.  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). It is written as 45,X/46,XX.
• ‍45,X/46,XY: In some cases, patients with TS can also have part of a Y (male) chromosome in some of their cells (45,X/46XY).^xii

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 random genetic event, meaning it is not inherited from parental chromosomes^xiii and is not a condition that runs in families.

How is Turner syndrome diagnosed?

The timing to diagnose Turner syndrome generally depends on the development trajectory and severity of the symptoms. TS is commonly diagnosed in early childhood in females with abnormally short stature or during adolescence due to delayed puberty or the failure to start menstruation. At this point, a physician can diagnose Turner syndrome and provide early intervention. Females with 45,X TS are typically diagnosed earlier as they have more severe symptoms. Some individuals are not diagnosed until they are adults.^xiv

If a female has signs or symptoms of TS, a blood sample will be 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 Turner syndrome is suspected, skin biopsies from different parts of the body are taken and tested for karyotype because different cells in the body can have different karyotypes in mosaic Turner syndrome.^xv

It is also possible to screen for TS before a child is born. If an intended parent 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 translucency value (measurement of thickness of translucent space behind the neck of the fetus), or other physical features can indicate increased risk of TS.^xvi If PGT-A, NIPT, or ultrasound indicate TS, the diagnosis can be confirmed prenatally using chorionic villus sampling (CVS) or amniocentesis.^xvii

Once a formal diagnosis has been issued for a patient with TS, a physician will want to conduct further testing to determine any issues associated with the condition and to develop a management plan. Here are some of the tests that may be conducted:^xviii

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

Are individuals with Turner syndrome able to get pregnant?

Turner syndrome can have multiple effects on fertility and pregnancy.

Ovarian failure

Statistics indicate that more than 90 percent of females with Turner syndrome have 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 medically treated.^xix

However, approximately 5 to 20 percent of individuals with TS externally appear to develop normally during puberty without medical assistance, and have spontaneous menstrual cycles, although subsequent ovarian failure and early menopause often ensues.^xx,xxi,xxii

Given that females with TS and 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.^xxiii

Intervention before puberty

When TS cases are diagnosed early, doctors can provide intervention before puberty. Specifically, growth hormone therapy is often used to stimulate growth.

Estrogen therapy is also 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.^xxiv In other words, because ovarian failure will continue, many of these females with TS will still be infertile.

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.^xxv Females with TS using 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.^xxvi

Pregnancy risks

Individuals with TS that are considering pregnancy should consult with their physician as the risk of complications is higher. When females with TS use their own eggs or donor eggs, they are more likely to experience hypertension and other cardiovascular complications during pregnancy; therefore, cardiovascular screening is recommended.^xxvii,xxviii In addition, the female may be at higher risk of having a miscarriage, preterm labor, complications from thyroid dysfunction, diabetes, and potential congenital risks.^xxix,xxx

Spontaneous pregnancy

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

Potential future fertility options

One option for females with TS in the future may be cryopreservation of prepubertal ovarian tissue prior to the inevitable occurrence of ovarian failure after puberty.^xxxiii Then, there might be an option for eggs to be extracted from young females with TS prior to puberty, before the ovaries degenerate. However, this process 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.^xxxiv,xxxv

Conclusion

Turner syndrome is a medical condition that can have serious implications. However, the earlier it is diagnosed, the earlier an appropriate treatment plan can be developed and implemented. Females who are concerned about their fertility and pregnancy options should speak to a physician if they suspect they have TS or have already been diagnosed.