NORD gratefully acknowledges Melissa L. Crenshaw, MD, FACMG, FAAP, Chief, Division of Genetics, Johns Hopkins All Children's Hospital, and Carolyn A. Bondy, MD, Chief, Section on Epigenetics & Development, National Institute of Child Health and Human Development, NIH Clinical Center, for assistance in the preparation of this report.
Turner syndrome is a rare chromosomal disorder that affects females. The disorder is characterized by partial or complete loss (monosomy) of one of the second sex chromosomes. Turner syndrome is highly variable and can differ dramatically from one person to another. Affected females can potentially develop a wide variety of symptoms, affecting many different organ systems. Common symptoms include short stature and premature ovarian failure, which can result in the failure to attain puberty. Most women with Turner syndrome are infertile. A variety of additional symptoms can occur including abnormalities of the eyes and ears, skeletal malformations, heart anomalies, and kidney abnormalities. Intelligence is usually normal, but affected individuals may experience certain learning disabilities. Turner syndrome may be diagnosed before birth or shortly after birth or during early childhood. However, in some cases, the disorder may not be diagnosed until well into adulthood, often as an incidental finding. Most cases do not run in families and appear to occur randomly for no apparent reason (sporadically).
Turner syndrome is named for Henry Turner who, in 1938, was one of the first doctors to report on the disorder in the medical literature. Turner syndrome is one of the most common chromosomal disorders and likely the most common genetic disorder of females.
The symptoms and severity of Turner syndrome can be quite variable from one person to another. Many features of the disorder are nonspecific and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Almost all females with Turner syndrome exhibit growth failure and attain a final height that is shorter than average (short stature). Children may initially display normal growth, usually for the first few years of life. However, in most cases, the growth rate eventually becomes slower than normal and affected children do not experience normal growth spurts (e.g., no growth spurt during puberty). If untreated, the final height in Turner syndrome is usually less than 5 feet.
Another common feature of Turner syndrome is the failure of the ovaries to develop properly (gonadal dysgenesis). Gonadal dysgenesis can cause the loss of ovarian function early during childhood (premature ovarian failure). Normally, the ovaries produce sex hormones (e.g. estrogen and progesterone) at puberty. These hormones are necessary for the onset of puberty and the proper development of secondary sexual characteristics. Most affected females will require hormone replacement therapy to develop breasts and normal female body contours, undergo proper bone growth, and to begin menstruation. In some cases, affected individuals may begin to undergo breast development and may begin menstruating without therapy (spontaneous pubertal development), but most will stop developing sexually and stop menstruating at some later point during their teen-age years.
Intelligence is usually normal in females with Turner syndrome. However, affected females may develop learning disabilities, especially difficulties with visual-spatial relationships. An example would be right-left disorientation. Affected individuals may have difficulties with directional sense, learning math, nonverbal memory and attention. Affected females may also experience difficulty in certain social situations.
Females with Turner syndrome may develop a variety of distinctive physical features including a short neck with a webbed appearance, a low hairline at the back of the head, low-set ears, and narrow fingernails and toenails that are turned upward. A broad chest with widely spaced nipples may occur, which is sometimes referred to as “shield chest.” Some individuals may have swollen, puffy hands and feet. These symptoms may occur due to lymphedema, a condition affecting the lymphatic system. The lymphatic system is a circulatory network of vessels, ducts and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. Lymphedema is characterized by swelling due to fluid accumulation (edema) in the affected parts of the body.
Additional physical findings may include a receding jaw (retrognathia), crossed eyes (strabismus), lazy eyes (amblyopia), drooping eyelids, and a narrow, high-arched roof of the mouth (palate). Some individuals may have skeletal malformations including short bones of the hands, specifically the fourth metacarpals, arms that are turned out at the elbows, and flat feet (pes planus). In approximately 10% of cases, abnormal sideways curvature of the spine (scoliosis) may also occur.
Congenital heart defects may be associated with Turner syndrome, especially in individuals with lymphedema. Such defects may include bicuspid aortic valve, in which the aortic valve has two flaps (leaflets) instead of three. The aorta is the main artery of the heart. The aortic valve regulates blood flow from the heart into the aorta. The flaps open and close to allow the passage of blood. Since there are only two flaps instead of three, the aortic valve does not function properly. A bicuspid aortic valve may or may not cause clinically apparent symptoms. Approximately 5-10% of individuals may have a congenital heart defect known as coarctation of the aorta, a condition characterized by narrowing of the aorta, which causes the heart to pump harder in order to force blood through constricted area. The condition can be mild and go undiagnosed until adulthood or be more serious, which can be associated with a variety of symptoms including pale skin, irritability, heavy sweating and difficulty breathing. If untreated, severe cases can result in insufficient blood flow to the organs of the body or eventually progress to congestive heart failure.
The heart defects associated with some cases of Turner syndrome can increase the risk of severe, life-threatening complications including high blood pressure of the arteries of the lungs (pulmonary hypertension) or aortic dissection, a condition in which there is a tear in the inner wall of the aorta. Blood rushes into the middle layer of the aorta causing the middle and inner layers to separate (dissect). Aortic dissection can potentially cause the outer wall of the aorta to rupture.
Kidney (renal) abnormalities may occur in some cases including horseshoe kidneys or absence (agenesis) of a kidney. Kidney abnormalities increase the risk of urinary tract infections and high blood pressure (hypertension). Liver abnormalities may include a fatty liver. Some affected individuals may have thyroid disease, which can cause decreased activity of the thyroid (hypothyroidism). Thyroid disease usually occurs because the immune system mistakenly attacks thyroid tissue, a condition known as Hashimoto’s syndrome (autoimmune thyroiditis). Symptoms can vary from one person to another, but can include fatigue, sluggishness, muscle aches, constipation, a hoarse voice and pale, dry skin.
Some individuals with Turner syndrome may have multiple tiny colored spots (pigmented nevi) on the skin.
Affected females may also be prone to infections of the middle ear (otitis media), especially during infancy and early childhood. Chronic otitis media may be associated with hearing loss due to blockage of sound waves (conductive hearing loss). This hearing loss usually resolves as a child ages and ear infections become less frequent. Hearing abnormalities in young children may affect or delay speech development. In adults, hearing loss due to an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss) may occur and may worsen with age.
Certain individuals with Turner syndrome appear to be at greater risk than the general population for developing certain disorders including diabetes, Celiac disease and osteoporosis. Osteoporosis is characterized by a general loss of bone density that can lead to an increased risk of fractures. Gastrointestinal problems including feeding difficulties and gastroesophageal reflux (GERD) may also occur.
Turner syndrome is caused by partial or complete loss (monosomy) of the second sex chromosome. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual and they come in pairs. We receive one copy from each parent. Chromosomes are numbered from 1 through 22; the 23rd pair normally consists of one X and one Y chromosome for males and two X chromosomes for females. Thus, females with a normal chromosome make-up (karyotype) have 46 chromosomes, including two X chromosomes (46, XX karyotype). Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered.
In females with Turner syndrome, all or a portion of one of the second sex chromosome is missing. The reason that this occurs is unknown and is believed to result from a random event. In some cases, the chromosomal abnormality appears to arise spontaneously (de novo) due to an error in the division of a parent’s reproductive cells, either in the father’s sperm or the mother’s egg. This results in the genetic error being contained in all cells of the body.
In many cases, only a certain percentage of an individual’s cell may be affected. This is referred to as mosaicism. Specifically, some cells have the normal 46 chromosomes (one cell line) while other cells do not have the normal 46 chromosomes (second cell line). This second cell line may contain various abnormalities such as partial or complete loss of the X chromosome. In these cases, the loss of genetic material from the X chromosome usually occurs because of spontaneous errors very early during fetal development. Theoretically, individuals with Turner syndrome mosaicism may have fewer developmental problems than other cases because fewer cells are affected. However, this is difficult to predict. Further research is necessary to completely understand the complicated factors involved in the development of the various symptoms associated with Turner syndrome.
In some cases, rarer chromosome abnormalities (other than complete or partial monosomy) can cause Turner syndrome. Such abnormalities include ring chromosome or isochromosome X. Ring chromosomes occur when the ends of a chromosome break off and the long and short arms join together to form a ring. Isochromosomes occur when one arm of a chromosome is missing and is replaced by an identical version of the other arm.
In rare cases, some cells have one copy of the X chromosome, while other cells have one copy of the X chromosome and some Y chromosome material. The amount of Y chromosome material is not enough to cause the development of any male features, but is associated with an increased risk of developing a form of cancer known as gonadoblastoma.
Most symptoms of Turner syndrome occur due to the loss of specific genetic material from one of the X chromosomes. So far, one gene has been conclusively shown to play a role in the development of Turner syndrome. The SHOX gene encodes a protein that helps to regulate other genes in the body. The protein product of the SHOX gene plays a role in the growth and maturation of the skeleton. Researchers believe that the loss of one SHOX gene on the altered X chromosome is the main cause of short stature in females with Turner syndrome.
We are learning more about how the genes on the X chromosome are related to Turner syndrome. The SHOX gene is known to be a major contributor to the development of short stature and other skeletal findings. The UTX gene may be implicated in potential immune issues underlying the repeated episodes of otitis media, which are common. Most recently, the TIMP3 and TIMP1 genes have been identified to be involved in the development of bicuspid aortic valve and aortic abnormalities found in Turner syndrome.
Researchers believe that additional, as-yet-unidentified genes on the X chromosome play a role in the development of other symptoms of Turner syndrome. For example, these genes may encode proteins that are involved in the proper development of the lymphatic and cardiovascular systems. More research is necessary to identify all of the genes that play a role in the development of the clinical features of Turner syndrome.
Turner syndrome affects approximately 1 female in 2,000-2,500 live female births. It is estimated that more than 70,000 women and girls in the United States have Turner syndrome. There are no known racial or ethnic factors that influence frequency of the disorder. In some cases, the disorder is diagnosed before birth or shortly after birth. However, mild cases can remain undiagnosed until later in life and even during adulthood.
a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Turner syndrome should be suspected in girls with growth deficiency or short stature of unknown cause.
A diagnosis of Turner syndrome is often confirmed by chromosomal analysis, which is usually achieved by determining the karyotype. Karyotyping is a laboratory test that evaluates the number and structure of chromosomes. Karyotyping can be done on almost any type of tissue. In most cases, a blood sample is used to ascertain a person’s karyotype.
Turner syndrome is being increasingly diagnosed before birth (prenatally). Screening for Turner syndrome and other chromosome abnormalities can be performed by noninvasive testing on a maternal blood sample. Definitive testing can be done by CVS or amniocentesis. CVS is performed at 10-12 weeks of pregnancy and involves the removal of tissue samples from a portion of the placenta, while amniocentesis is performed at 16-18 weeks gestation and involves taking a small sample of the fluid around the fetus.
In certain cases, certain physical findings associated with Turner syndrome may be seen on a fetal ultrasound. For example, the accumulation of lymph fluid near the neck of a developing fetus can sometimes be seen on a routine fetal ultrasound. If prenatal testing shows a Turner syndrome karyotype but normal ultrasound findings, it can be difficult to predict the extent to which the baby will develop signs of Turner syndrome after birth.
Clinical Testing and Work-Up
Specific imaging techniques such as magnetic resonance imaging (MRI) may be performed to assess affected individuals for the presence of symptoms potentially associated with Turner syndrome such as liver, kidney or heart abnormalities. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Many individuals with a diagnosis of Turner syndrome undergo a complete cardiac workup to assess the structure and function of the heart. This will include an echocardiogram.
Additional evaluation should be done on thyroid and liver function, bone age, and growth. Hypertension screening should also be performed. Infants diagnosed at birth should receive a full ear, nose and throat examination including an auditory exam. Children, especially those who experience repeated otitis media, as well as adults, require periodic hearing evaluation. Affected individuals should also undergo thyroid function tests because of the potential for thyroid disease.
The treatment of Turner syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric specialists, surgeons, cardiologists, endocrinologists, speech pathologists, otolaryngologists, ophthalmologists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling is recommended for affected individuals and their families.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
There is no cure for Turner syndrome, but therapies have been developed that can improve physical development. With proper medical care, females with Turner syndrome should be able to lead full, productive lives. The primary therapies for affected individuals are growth hormone therapy and estrogen therapy.
Individuals with Turner syndrome may benefit from growth hormone (GH) therapy, which can help to normalize height. The Food and Drug Administration (FDA) has approved the use of recombinant GH for the treatment of children with Turner syndrome. Recombinant GH is artificially created in a lab. The best age for beginning GH therapy and the optimum duration of therapy in females with Turner syndrome is unknown. Generally, the earlier GH therapy is started, the more beneficial it tends to be for affected individuals. However, there are many individual factors that ultimately determine the effectiveness of GH therapy. Decisions regarding GH therapy in individuals with Turner syndrome are best made after consultation with a pediatric endocrinologist.
Most females with Turner syndrome require sex hormone replacement therapy in order to undergo normal development associated with puberty and to begin their menstrual periods. Estrogen and progesterone replacement therapy will generally promote puberty and the development of secondary sexual characteristics. Hormone replacement therapy is usually begun around 12-14 years of age. This is when most average girls will enter puberty. The timing of initiating puberty also takes into account growth progress on growth hormone replacement. Replacement therapy must be continued in order to maintain these characteristics and most women will require estrogen and progesterone therapy until menopause.
Most individuals with Turner syndrome remain unable to conceive children. In vitro fertilization (IVF) with a donor egg and an implanted pregnancy is sometimes possible. In most cases, these pregnancies carry risks and require close consultation with a patient’s healthcare team.
Females with Turner syndrome and Y chromosome material (Y chromosome mosaicism) are at an increased risk of developing a tumor of the gonads. In such cases, it is recommended that the non-functioning gonadal tissue be removed.
Additional treatment is symptomatic and supportive. For example, thyroid hormone replacement therapy may be used to treat individuals with thyroid disease. Correction of hearing loss with hearing aids is another important intervention, which can help with learning and social interaction.
Early intervention is important in ensuring that children with Turner syndrome reach their potential. Special services that may be beneficial to affected children may include special psychosocial support, speech therapy, and other such services.
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Contact for additional information about Turner syndrome:
Melissa L. Crenshaw, MD, FACMG, FAAP
Chief, Division of Genetics
Johns Hopkins All Children’s Hospital
601 5th St. S
St. Petersburg, FL 33701
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Silberbach M, Roos-Hesselink JW, Andersen NH, et al. Cardiovascular Health in Turner Syndrome: A Scientific Statement From the American Heart Association. Circ Genom Precis Med. 2018 Oct;11(10):e000048. https://www.ahajournals.org/doi/10.1161/HCG.0000000000000048
Gravholt CH, Anderson NH, Conway GS et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017; 177(3): G1-G70. http://ncbi.nlm.nih.gov/pubmed/28705803
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Danieal MS, Postellon, DC. Turner syndrome. Emedicine Journal, July 20, 2018. Available at: http://emedicine.medscape.com/article/949681-overview
Accessed January 7, 2019.
Mayo Clinic for Medical Education and Research. Turner Syndrome. November 18, 2017. Available at: http://www.mayoclinic.com/health/turner-syndrome/DS01017 Accessed January 7, 2019.
National Institute of Child Health and Human Development. Turner Syndrome, December 1, 2016. Available at: http://turners.nichd.nih.gov/ Accessed January 7, 2019.
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