OVERVIEW: What every practitioner needs to know

Are you sure your patient has Turner syndrome? What are the typical findings for this disease?

Turner syndrome (TS) is caused by the absence of the short arm of one X chromosome in a female in every cell of the body. The most common karyotype in TS is 45,X, with an entire missing X chromosome, but mosaicism with a normal and 45,X cell line is also common, and variant karyotypes can also be present. The incidence is around 1 in 4000 live births. The most common phenotypic manifestations include the following:

— short stature

–lymphedema leading to a webbed neck

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–low anterior hairline

–shield chest

–cubitus valgus

–congenital heart defects

Findings in infancy can include short stature, webbed neck, lymphedema or cutis laxa from prenatal lymphedema, strabismus, congenital heart defects such as bicuspid valve or coarctation of the aorta, and renal abnormalities such as horsheshoe kidney or others.

Childhood manifestations include short stature with short, broad neck and low anterior hairline, increased number of nevi, shield chest, cubitus valgus, and Madelung deformity. Scoliosis is common.

Adrenarche and breast development occur in up to 30% of girls with TS, but few reach menarche due to premature ovarian failure. Up to 5% of girls may achieve spontaneous pregnancy. Ptosis and amblyopia are more common. Otitis media can be recurrent; conductive or sensorineural hearing loss may be present. Learning difficulties with visuospatial skills and executive function are more common, or social skills may be impeded. Additionally, aortic root dilation and aortic dissection can occur in this population.

Almost all women with Turner syndrome have infertility due to ovarian failure. Over 95% of fetuses with Turner syndrome result in spontaneous abortion. Turner syndrome is not typically associated with significant developmental delay or mental retardation, although minor learning and social difficulties can occur.

What other disease/condition shares some of these symptoms?

Noonan syndrome was once called “male Turner syndrome” because of similar phenotypic manifestations. However, Noonan syndrome is an autosomal dominant condition; thus, it can occur in either males or females. Similar features include short stature, short webbed neck, low posterior hairline, ptosis, widely spaced nipples, lymphedema, and scoliosis. Individuals with Noonan syndrome can have congenital heart defects, most commonly pulmonic stenosis. Around 25% of patients have developmental delay/mental retardation, unlike Turner syndrome. Bleeding diathesis occurs in around half of patients (not an associated feature of Turner syndrome), and infertility is not associated with Noonan syndrome. Six genes are known to be causative of Noonan syndrome. The distinction between the two conditions can be made by karyotype.

Congenital lymphedema and primary lymphedema can be caused by a variety of genetic and acquired factors.

What caused this disease to develop at this time?

  • Turner syndrome is caused by the absence of one copy of at least the short arm of the X chromosome. One copy of most of the X chromosome is inactivated in females to compensate for the dosage difference between males and females. However, around 20%-25% of that X remains active, and many of those genes are present on the short arm of X, with a complementary gene on the Y chromosome. Most of the features of Turner syndrome are due to haploinsufficiency of these genes, including the SHOX gene (causes short stature and skeletal abnormalities) and likely a gene controlling the development of lymphedema. Gonadal dysgenesis is most likely caused by several genes on both arms of the X chromosome, due to abnormal pairing during meiosis and other factors.

  • Around 50% of cases are due to full monosomy of chromosome X (45,X), 20%-30% of cases are mosaic with a normal and abnormal cell line (45,X/46,XX or other line), and the remaining 20%-30% are caused by a structural variant. One common variant is isochromosome Xq, with two copies of the long arm of the X chromosome and a missing copy of the short arm (Xp) (46,X iso(Xq)).

  • Around 2/3 of the missing X in 45,X patients is paternal in origin.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • A karyotype, or chromosome analysis, should be ordered if Turner syndrome is suspected. Full monosomy will be demonstrated by X (45,X). The presence of a mosaic line (45,X/46,XX) may indicate a milder phenotype, depending on what tissues contain the normal or 45,X cell line. A karyotype may not detect low level mosaicism, and at least 20 cells should be studied if mosaicism is being considered. Isochromosome Xq is usually phenotypically similar to 45,X, and the presence of a ring chromosome X can be variable, depending on the genetic material missing.

  • All girls with Turner syndrome should have FISH testing for the presence of Y chromosomal material, which would increase the risk for gonadoblastoma. Girls with a 45,X/46,XY phenotype are also at high risk for gonadoblastoma with mixed gonadal dysgenesis (immature ovarian and testicular tissue). The gonadal tissue should be removed to prevent malignancy.

Would imaging studies be helpful? If so, which ones?

  • Prenatal ultrasound abnormalities suggestive of Turner syndrome include cystic hygroma, non-immune fetal hydrops, or associated heart defects including coarctation of the aorta .

  • Echocardiogram or cardiac MRI and EKG should be performed at diagnosis and regularly thereafter for the presence of cardiac anomalies associated with TS. Aortic dilation, leading to dissection, is more common in this population; therefore, serial echocardiograms in adolescence and adulthood should be performed.

  • Renal ultrasound should be performed at diagnosis to look for associated structural abnormalities present in 30%-40% of TS patients.

  • Formal audiology and ophthalmology exams should be initiated at diagnosis.

  • DEXA scan should be performed in late adolescence for possible osteoporosis.

Confirming the diagnosis


If you are able to confirm that the patient has Turner syndrome, what treatment should be initiated?

  • Once a diagnosis of Turner syndrome is established, growth hormone (GH) therapy, now considered standard of care in TS, should be initiated. Adult height is maximized when GH is begun as early as 9 months of age. Additionally, there is evidence that growth hormone reduces abdominal adipose development and improves glucose tolerance (thereby decreasing diabetes mellitus risk) in girls with TS. Non-aromatizable steroids such as oxandrolone have been used in conjunction with growth hormone in some patients.

  • Echocardiogram and/or cardiac MRI should be ordered to investigate possible structural abnormalities or aortic dilation. Follow-up imaging studies should occur every 5-10 years to evaluate aortic diameter, and evaluation for aortic dissection should occur in the presence of rapid onset chest pain.

  • TSH and T4 levels should be monitored every 1-2 years for hypothyroidism, present in 10%-30% of affected individuals.

  • Developmental evaluation should occur at diagnosis, as well as for possible cognitive or psychosocial delays. Treatment with physical, occupational, or speech therapy should be initiated as needed.

  • Hormone replacement therapy should be given to girls with TS who have failed to undergo spontaneous puberty in order to normalize development of secondary sexual characteristics, including breast development, increase in uterus size and shape, bone maturation, and other estrogen-requiring functions. The therapy should mimic normal growth and development of secondary sexual characteristics as closely as possible. Estradiol via transdermal patch or gel is the preferred method of administration, as it achieves natural levels of estrogen in the blood. There should be discussion of the risk of sexually transmitted diseases and the possibility (although unlikely) of pregnancy.

What are the adverse effects associated with each treatment option?

Growth hormone is associated with increased risk for scoliosis, diabetes, cardiovascular events, intracranial hypertension, slipped capital femoral epiphysis, pancreatitis, and new malignancies. Insulin resistance may be increased during therapy, but may improve once therapy is discontinued because of decreased body composition. Lymphedema may also occur by administration of growth hormone, possibly due to salt retention. Excess anabolic steroid use may cause virilization and maturation of the skeleton too rapidly.

What are the possible outcomes of Turner syndrome?

Up to 95% of conceptuses with Turner syndrome are spontaneously lost, and many pregnancies diagnosed via chorionic villus sampling or amniocentesis will result in miscarriage, especially those with pleural effusion or cystic hygroma. Those girls who are diagnosed prenatally who survive to term tend to be less severely affected than postnatally diagnosed children who are tested based on clinical features. In fetuses with mosaicism (45,X/46,XX; 45,X/46,XXiq; 45,X/46,XY), the degree of mosaicism in the tested sample is not necessarily correlated with severity of phenotype.

Whether TS is diagnosed prenatally or postnatally, a discussion of the wide range of severity outcomes is crucial. The most likely phenotypic features include short stature and premature ovarian failure. Some individuals have cardiac defects, such as coarctation of the aorta (~10%), bicuspid aortic valve (~15%), or others. Other health problems can include renal anomalies, hearing loss, or lymphedema. Most girls with TS have intellectual functioning in the normal range, although they may have specific learning difficulties such as in visuospatial skills. Congenital hip dislocation is more common in TS, and scoliosis occurs in childhood in around 10%. Hypothyroidism and hyperthyroidism are more common, as is celiac disease. There is a mildly increased risk for diabetes type 1. Mosaic Turner syndrome may be associated with a less severe phenotype but is difficult to ascertain based on testing only one tissue (i.e., blood).

Growth hormone therapy should be administered and managed by a pediatric endocrinologist, if possible. It is given to help girls with TS reach an increased height for age and adult height, and is recommended to begin as soon as growth failure is documented (decreased height percentiles on the normal growth curve). Starting at an earlier age has been shown to increase final height without increased side effects. In girls over 9 years of age, adding a non-aromatizable anabolic steroid has been recommended but must be monitored closely for possible virilization or premature skeletal maturation.

Once it has been established that puberty will not occur spontaneously (as early as 12 years of age), estrogen therapy is recommended for the development of secondary sexual maturation. The family should be counseled that replacement is usually required until the age of normal menopause.

What causes this disease and how frequent is it?

  • Turner syndrome occurs in 1 in every 2500 live born females. It is much more common in conceptuses, but most spontaneously abort.

  • The features of TS occur due to the absence of one copy of the short arm (p arm) of an X chromosome in the presence of a normal X chromosome. The most common karyotype in girls with TS is 45,X, but other karyotypes, such as isochromosome Xq or a ring X chromosome, can also cause short stature and other features of Turner syndrome. The chance for having a child with Turner syndrome does not increase with maternal age like trisomic conditions such as Down syndrome. There is no known predisposing factor or environmental factor causing TS.

How do these pathogens/genes/exposures cause the disease?

  • In a typical 46,XX female, almost all of one copy of the X chromosome is inactivated in each cell. However, up to 25% of genes on the inactive X continue to be expressed, and many of these genes have similar genes on the Y chromosome. Most of these genes are located on the tip of Xp, thus having one missing copy of these genes (called the pseudoautosomal genes) in TS, which causes haploinsufficiency and the typical features seen in TS.

  • Deletion of one copy of the SHOX gene is causative of the short stature and other skeletal abnormalities.

  • There is likely a pseudoautosomal gene controlling lymphatic development, and haploinsufficiency of this gene leads to cystic hygroma and lymphedema.

  • Finally, oocyte formation and failure occurs due to haploinsufficiency of genes on both arms of the X chromosome that play a role in germ cell development as well as abnormal chromosome pairing during meiosis.

Other clinical manifestations that might help with diagnosis and management


What complications might you expect from the disease or treatment of the disease?


Are additional laboratory studies available; even some that are not widely available?


How can Turner syndrome be prevented?

There is no means of preventing Turner syndrome.

What is the evidence?

Resources for diagnosis and management of Turner syndrome:

Saenger, R, Wikland, KA, Conway, GS. “Recommendations for the diagnosis and management of Turner syndrome”. J Clin Endocrinol Metab. vol. 86. 2001. pp. 3061-9. (Review paper written by an international multidisciplinary workshop during the Fifth International Symposium on Turner Syndrome to update previous recommendations from 1994. Comprehensive approach to management of symptoms and treatment strategies for both children and adults with Turner syndrome.)

Bondy, C. “Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group”. J Clin Endocrinol Metab. vol. 92. 2007. pp. 10-25. (Review paper written by the Turner Syndrome Study Group, who studied peer-reviewed literature and expert opinion to make recommendations.)

Davenport, ML. “Approach to the patient with Turner syndrome”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 1487-95. (Review of the clinical features and healthcare checklist for patients with Turner syndrome using a patient example for explaining approach.)

Wooten, N, Bakalov, VK, Hill, S, Bondy, CA. “Reduced abdominal adiposity and improved glucose tolerance in growth hormone-treated girls with Turner syndrome”. J Clin Endocrinol Metab. vol. 93. 2008. pp. 2109-14. (Studied 76 girls with TS treated with GH vs. 26 girls with TS not treated with GH. Found a significantly lower abdominal adiposity rate and glucose tolerance in the treated group. All patients studied were in the pediatric population.)

Ongoing controversies regarding etiology, diagnosis, treatment