What is Turner syndrome?

Turner syndrome (TS) is a chromosomal condition that describes girls and women with common features that are caused by complete or partial absence of the second sex chromosome. The syndrome is named after Dr. Henry Turner, who was among the first to describe its features in the 1930's. TS occurs in approximately 1 of 2,000 female's born and in as many as 10% of all miscarriages.

How is Turner syndrome diagnosed?

Diagnosis is made through a test called a karyotype, which is usually performed on cells in the amniotic fluid before birth and on cells in the blood after birth. A trained specialist counts the chromosomes in the white blood cells and looks for abnormalities. Females normally have two X chromosomes (46,XX) and males have one X and one Y (46,XY). Turner syndrome individuals are missing all or part of one of their sex chromosomes. About half of girls with Turner syndrome have only one X chromosome (45,X). Another third have two X chromosomes, but part of one X is missing. Other individuals with Turner syndrome have a mosaic pattern: some of their cells are missing an X chromosome (45,X), while other cells have different chromosome composition (such as 46,XX)

Turner syndrome may be diagnosed throughout the life span, including adulthood, if signs are subtle. Signs that indicate a karyotype is needed can include:

• Fetal abnormalities such as cystic hygroma (fluid around the neck), or incidentally when a routine amniocentesis is performed (e.g., for advanced maternal age)

• Webbed neck (excess skin) or lymphedema (swelling of hands and feet) in newborns

• Specific heart problems in infants

• Slow growth and/or short stature

• Delayed puberty or amenorrhea (lack of menstrual cycles)

• Infertility or menstrual irregularities.
  

What are the primary characteristics of Turner syndrome?

Short stature
The most common feature of Turner syndrome is short stature. The average height of an adult TS woman who has not received human growth hormone treatment is 4’8”. Individuals tend to be a little shorter at birth, averaging 18.5” compared to an average of 20” for all girls. Growth failure continues after birth, and most girls with TS fall below the normal female growth curve for height during early childhood. TS girls who are not treated with hormone replacement usually do not have a pubertal growth spurt; many will continue to grow at a slow rate until they are in their twenties. Many girls who undergo growth hormone treatment have been able to achieve adult height within the lower range of normal.

Premature ovarian failure
Most (90%) TS individuals will experience early ovarian failure. In the general population, the ovaries produce eggs and hormones necessary for the development of secondary sexual characteristics. Estrogen replacement therapy is necessary for breast development, feminine body contours, menstruation and proper bone development. About a third of TS individuals will show some signs of breast development without estrogen treatment; however, many will not complete puberty, and those that do often have premature ovarian failure. Therefore, the majority of individuals will require estrogen from puberty until the normal age of menopause. Fertility without assisted reproduction therapy is rare (less than 1%).

Physical features
Many characteristic features are associated with Turner syndrome. Their presence and severity vary greatly from individual to individual.

• Narrow, high-arched palate (roof of the mouth)

• Retrognathia (receding lower jaw)

• Low-set ears

• Low hairline (the hair on the neck is closer to the shoulders)
  

• Webbed neck (excess or stretched skin)
  

• Slight droop to eyes

• Strabismus (lazy eye)

• Broad chest

• Cubitus valgus (arms that turn out slightly at the elbows)

• Scoliosis (curvature of the spine)

• Flat feet

• Small, narrow fingernails and toenails that turn up (usually if lymphodema was present at birth)
  

• Short fourth metacarpals (the ends of these bones form the knuckles)

• Edema (swelling) of hands and feet, especially at birth

• Intelligence - TS individuals are on average of normal overall intelligence with the same variance as the general population. They do, however, often have difficulty with spatial-temporal processing (imagining objects in relation to each other), nonverbal memory and attention. This may cause problems with math, sense of direction, manual dexterity and social skills. New and better ways to compensate for these problems, which currently fall under the general category of nonverbal learning disabilities, are being researched.

What are the associated risks with Turner syndrome?

Several medical problems occur more frequently in individuals with Turner syndrome than in the general population. It is important that TS individuals are screened regularly to see if any of these problems exist. Most of these conditions can be managed successfully with good medical care.

Heart
Some form of cardiac abnormality occurs in approximately one-third of TS patients. Problems are primarily left-sided and may include:

• coarctation (narrowing) of the aorta and bicuspid aortic valve (a valve with two leaflets instead of the usual three).
• TS individuals are also at higher risk for hypertensionor high blood pressure.
  
• TS patients should receive an echocardiogram or MRI to evaluate the heart at the time of diagnosis regardless of age and have their heart re-evaluated periodically for aortic root enlargement.
• All individuals with TS should be aware of the symptoms of dissection of the aorta, an uncommon but life-threatening complication. These include sudden, severe, sharp, stabbing, tearing, or ripping chest pain, intense anxiety, rapid pulse, profuse sweating, nausea and vomiting, dizziness, fainting or shortness of breath.

Kidney
Thirty percent of TS individuals will have kidney abnormalities. Many of the abnormalities do not cause any medical problems; however, some may result in urinary tract infections and an increased risk of hypertension. It is recommended that TS individuals receive a renal ultrasound examination at the time of diagnosis.

Thyroid
Hypothyroidism (low level of thyroid hormone) caused by autoimmune thyroiditis (inflammation of thyroid gland) occurs frequently in individuals with TS. It can be diagnosed with a blood test and is easily treated with thyroid hormone.

Ears
Otitis media (ear infection) is extremely common in TS girls particularly in infancy and early childhood. Aggressive treatment of infections is appropriate. The majority (50-90%) of TS women will also develop early sensorineural (nerve) hearing loss and may require hearing aids earlier than the general population.

How can Turner Syndrome be treated?

The treatment of TS individuals should be individualized; physicians, family and patients should decide on treatment options together.

Growth Hormone Therapy
Human growth hormone (hGH) is an FDA-approved drug used to increase the growth rate and achieve greater final height in TS patients. Therapy should be considered when a TS individual experiences growth failure and/or drops below the 5th percentile of the normal female growth curve. The expected increase in height depends upon many factors, including how early GH is started, what dose is given, the duration of treatment, if anabolic steroids (such as oxandrolone) are also given, and how late estrogen therapy is begun. Gains in height between 5 and 16 cm (2 and 6 inches) have recently been reported; however, not every individual responds to growth hormone. Treatment is discontinued when growth is very slow(less than 2 cm or 1 inch per year) or if the patient has reached a satisfactory height.

Estrogen Therapy
This therapy is necessary in most TS individuals because of ovarian failure. Therapy is typically started at 12-14 years of age but should be individualized to optimize both growth and pubertal development. Estrogen is given in small doses to initiate puberty and breast development. The dose is then increased and progesterone is added in order to initiate a monthly menstrual cycle. TS individuals can experience normal sexual function on estrogen therapy. Because of the role estrogen plays in maintaining healthy bone mass, it is generally recommended that the therapy continue until the age of normal menopause (approximately 50 years of age).

Becoming a Family
Many options are available to TS women who wish to have children. The most common fertility solution for TS women is adoption. At this time, assisted reproduction technology options for TS women who wish to become pregnant is discouraged from specific medial specialists due to the increased rate of mortality related to cardiac issues. The reproductive technology options include in-vitro fertilization with egg donation by a related or anonymous donor or donor embryo transfer. It is critical that a TS patient undergo a thorough physical evaluation (particularly cardiac and renal) before attempting pregnancy and include a high risk prenatal physician from the onset of pregnancy.

It's important to note that many women consider their "family" as an extension of relatives, nieces, nephews, and neighbors. Some women with TS, as other women in the United States are happy without having children.  With the help of medical specialists and a good social support system, a woman with Turner syndrome has many choices that will enable her to live a happy, healthy life.

GENETIC OVERVIEW OF TURNER SYNDROME

Turner Syndrome (TS) is a chromosome abnormality affecting about 1 in every 2,000 female births and up to10% of miscarriages. TS is characterized clinically by short stature, ovarian failure, and a variety of other features such as extra neck skin, heart abnormalities, mild hearing loss, and others.

Genetically, TS is due to the absence of all or part of one sex chromosome, usually one X. This abnormality, also called monosomy X, is denoted medically as the 45,X (older literature used XO) karyotype, as opposed to the usual 46,XX female karyotype. Many, perhaps most, girls and women with TS are actually mosaic, meaning that they have cells with more than one karyotype. Often there is a mix of 46,XX and 45,X cells, and in this case the resulting clinical abnormalities tend to be milder than in 45,X TS. Mosaicism, especially 45,X/46,XX, is frequently detected by prenatal diagnosis (amnicentesis). Occasionally there is mosaicism for cells containing Y chromosome material - but not enough to cause male sexual features. Girls with TS and Y chromosome mosaicism are at increased risk of developing a tumor of the gonads and should have their non-functioning ovaries removed.

Molecularly, most TS features result from having one rather than two copies of certain X chromosome genes. To date, one gene called SHOX has been clearly implicated in TS. Loss of one copy of SHOX is the main cause of short stature in TS. Identification of TS genes may lead to better treatments for short stature and other symptoms.

This article was provided by Dr. Andrew Zinn.

GROWTH IN TURNER SYNDROME

Growth in Turner syndrome (TS) is decreased, and on average the girl with TS will grow to be 8 inches (20 cm) shorter than she would have been. This is because at least one of the genes that influences growth, the SHOX gene, located on the very ends of the short arms of the X chromosomes, is usually missing and accounts for much of this growth deficit. The growth decrease can be present at birth, with the infant being just bit smaller than average, and proceeds to become more obvious by two to three years and gradually more obvious thereafter. At the time of puberty, whether the girl has some of her own estrogen or takes it as replacement, the growth spurt is much less than average. Each of these phases adds up to the ~ 8 inch difference.

The growth of girls with TS not treated for their short stature has been studied sufficiently that TS-specific growth curves have been created and are available. Some bones grow even more slowly than others. The lower jaw bone may be quite small and contribute to orthodontic issues. The bones in the hands and wrist may be particularly affected, and some girls have small knuckles (due to short metacarpal bones). A few have bowing of the forearm and deformity of the wrist (Madelung deformity). There may also be changes in the knees which give a knocked-knee appearance, and in rare patients the hip(s) can be dislocated at birth or the top of the hip bone can slip off the long-bone during later years of growth (slipped capital femoral epiphysis). Finally the bones of the spine may grow in a curved fashion resulting in spinal curvature called scoliosis.

While girls with Turner syndrome do not lack pituitary growth hormone (GH), it has been shown in clinical studies that giving growth hormone can overcome some of the height deficit. The average height gain is about 4 inches (10 cm) or half of the deficit, with early institution of GH associated with greater growth and taller final height. GH is given by injection, and usually started in the preschool or early school years (unless diagnosis is delayed) since catch-up growth takes time. Once started, treatment usually continues so that growth can continue faster than if not treated, and isn’t stopped until final height is reached (growing end of bones fuse, called “fused epiphyses”) or the girl and her family are satisfied with height reached. The majority of TS girls will also need estrogen therapy, and its timing is somewhat related to how much growth deficit is remaining at the time feminization is desirable. Estrogen contributes much less to a growth spurt in girls with TS than it does in girls without TS. On the other hand, it is the hormone that is responsible for the bones fusing. Thus, pediatric endocrinologists, who generally supervise growth hormone treatment, balance the need for feminization with the inches that can still be achieved before the bones fuse. The earlier growth hormone is started, and the taller the girl is, the earlier in adolescence that estrogen can be started without a negative effect on final height.

This article was contributed by Dr. Barbara Lippe