Turner syndrome was first described in the 1930s by Otto Ullrich ' followed by Henry Turner.2 Until the availability of routine cytogenetic analysis in the 1960s, diagnosis was based solely upon the presence of short stature, gonadal dysgenesis, distinct physical stigmata, and other organ abnormalities.
Turner syndrome affects one in every 2,000 to 5,000 live-born females, corresponding to approximately 1.5 million affected women worldwide.3 The karyotype performed on peripheral lymphocytes shows complete loss of one X chromosome in approximately 50% of patients with Turner syndrome (see Figure 1, page 191). In 60% of these cases, the paternal X is lost during meiosis.4 Other patients with Turner syndrome have different chromosomal abnormalities, including partial absence of one X chromosome, duplication of one arm of the X chromosome with loss of the other arm, or various mosaicisms.5 Karyotyping of a number of different tissues shows a higher percentage of mosaicism than is evident on analysis of white blood cells alone. Approximately 1% to 2% of all conceptuses have a 45X karyotype; of these, 99% abort spontaneously, especially during the first trimester.3 A smaller percentage of these conceptuses are lost in the second trimester; these fetuses often have massive lymphedema and cystic bygroma.6
unlike Trisomy 21 or Klinefelter syndrome, Turner syndrome is not associated with advanced materna! age. It can be detected during the triple maternal marker screening (with aFP, estradici, and HCG) in combination with measurement of maternal progesterone and inhibin A levels.7'8 Some of the most common prenatal fetal ultrasound findings suggesting Turner syndrome are nuchal thickening, cystic hygroma of the neck, aortic coarctation, renal abnormalities, growth retardation, and relatively short limbs. Because the positive predictive value of prenatal karyotype and ultrasound findings is not conclusive and mosaicism is more easily detected on postnatal blood karyotypes than on karyotypes of cells from amniocentesis, Turner syndrome diagnosis must be confirmed by postnatal karyotyping.6
There is great variability in the clinical presentation of patients with Turner syndrome, both among the various chromosomal abnormalities of Turner Syndrome and among individuals with the same karyotype. Because of this variation, the age at diagnosis may vary greatly. Some patients may be diagnosed at birth in light of physical features such as lymphedema of hands and feet. Others may be noticed because of short stature in the first decade of life. Still others present because of delayed puberty, infertility, or even premature ovarian failure.
Lymphedema most commonly presents in the neonate. It results from maldevelopment of the lymphatic system, which leads to swelling of the hands and feet. The appearance of aerai lymphedema is different from the more diffuse swelling of congestive heart disease. Lymphedema results from delayed opening of the lymphatic vessel lumens and can explain the pathophysiology of the webbed neck and the auricular malformation, both thought to result from fetal cystic hygroma that resolves prior to birth. It can also explain coarctation of the aorta.9 Toenails and fingernails may be narrow, hyperconvex, deep-set, or some combination, as a result of lymphedema of the distal extremities.
Lymphedema usually resolves within the first year of life. However, it may continue to be a problem later in life. Treatment with pubertal hormones or growth hormone (GH) may exacerbate lymphedema.
Facial features may include maxillary hypoplasia, high-arched palate, relatively small mandible with retrognathia, downslanting palpebrai fissures, ? epicanthal folds, and ptosis. In addition, prominent, low-set, posteriorly rotated auricles, low posterior hairline, short neck, and webbing of the neck (pterygium coli) may be indicative of the disorder. Reconstructive surgery of the ears and neck may be considered. However, the increased risk of keloid formation in patients with Turner syndrome should be discussed with the family.
The ratio of the internipple distance ^ to the chest width is similar to that in the normal population. However, due to the difference in body proportions, patients with Turner syndrome seem to have widely spaced nipples.9 Nipples may be inverted, hypoplastic, or both. Mild pectus excavatum may be present.
The most common skeletal feature is short stature, which is discussed in detail later in this article. Patients with Turner syndrome have disproportionately short legs. Therefore, they have a higher ratio of upper segment (the distance from the head to the superior border of the pubic bone) to lower segment (the distance from the superior border of the pubic bone to the floor).
The carrying angle formed between the humérus and ulna normally measures 12° m women. In most patients with Turner syndrome, this angle measures 15° to 30° due to developmental abnormalities of the trochlear head. This increased carrying angle is termed cubitus valgus.
Most patients with Turner syndrome also have the "knuckle sign" or < "metacarpal sign" - a shortened fourth metacarpal so that a straight line can be drawn between the third and fifth proximal inteiphalangeal joints without traversing the fourth proximal interphalangeal joint Shortening of the fourth metatarsals leads to a similar pattern in the feet.
Madelung deformity is an uncommon finding in patients with Turner syndrome. It consists of shortening and bowing of the radius with dorsal subluxation of the distal ulna, due to a reduced number of SHOX gene copies on the short arm of the X chromosome.
Scoliosis and kyphosis are more common in Turner syndrome than in the general population. Scoliosis may worsen with GH treatment.10,11 Examination of the back should be a routine part of the physical examination. Infants with Turner syndrome are also more likely to develop congenital hip dislocation.
There is increased risk of osteopenia and osteoporosis, especially after adolescence. The early initiation of estrogen and GH therapy may decrease the risk of osteoporosis. Because of their increased susceptibility to osteoporosis, adults with Turner syndrome are more likely to develop skeletal fractures than are other women. Therefore, assuring adequate exercise and intake of calcium and Vitamin D are important components of treatment of patients with Turner syndrome.
Patients with Turner syndrome are more likely to have benign pigmented nevi, which become more prominent with age. Hemangiomas are also more common and may enlarge within the first year of life; thereafter, they are likely to regress slowly. Commonly, patients with Turner syndrome have atopic or seborrheic dermatitis and rarely present with essential hyperhidrosis or alopecia arcata. The risk of keloid formation also is higher. This issue should be discussed with the family before any elective surgery.
Vision and Hearing Problems
Strabismus, occurring as early as the neonatal period, ptosis, ambylopia, and cataracts are more common in individuals with Turner syndrome. Because of the increased frequency of these problems, ophthalmologic examination should be a routine part of the care of patients with Turner syndrome.
The inner, middle, and outer ear may each be affected. Early in childhood, because of the structural abnormalities of the temporal bone and the acute angle of the Eustachian tube, patients with Turner syndrome are more prone to fluid collection in the middle ear. Middle-ear effusion may, in turn, lead to secondary bacterial infection and, occasionally, to cholestotoma. Many patients require myringotomy tubes. Short female children presenting with frequent otitis media should be evaluated for Turner syndrome.
Missing or Damaged Chromosome in the 23rd Pair Results in Turner Syndrome
With Turner syndrome, conductive hearing loss is more common in children and sensorineural hearing loss is more common in adults. However, sensorineural hearing loss may occur as early as age 6. There is a correlation between the karyotype and the hearing defects; patients with 45 XO are more likely to have hearing loss than are patients with other karyotypes.12 Examination of the ears for ear infections should be a part of routine check up, and hearing should be tested by audiologic methods between ages 6 and 12 months. Testing should be performed on infants younger than 4 months if newborn screening was not performed.3 Thereafter, annual audiologic study is desirable.
Otitis media should be treated aggressively at any age, and myringotomy tubes should be considered for treatment of chronic middle ear congestion. Speech delay may result from the hearing impairment, high-arched palate, or both.
Turner syndrome causes cardiovascular anomalies in approximately 75% of spontaneously-aborted fetuses and in more than 30% of patients.9 There is a strong correlation bet ween cystic hygroma, webbed-neck, and hypoplastic left heart; 45 X fetuses commonly have decreased blood flow through Ae left heart13 In an Italian study, the prevalence of congenital heart diseases (with the exception of ventricular septal defect) was higher in patients with Turner syndrome than in the general population.14 Among patients with Turner syndrome, the study found the highest incidence of congenital heart disease was in 45X patients.
Bicuspid aortic valve is the most common cardiac abnormality in patients with Turner syndrome, occurring in 30% to 50%. Other frequent cardiac anomalies may include aortic dilatation, dissection, and even rupture. These can occur at a relatively young age and can cause death in patients as young as: 4. Abnormalities including arterial hypertension, cardiac conduction defects, and mitral valve prolapse are also common.
Because of the high frequency of cardiovascular problems in patients with Turner syndrome, cardiologisls should be a part of the multidisciplinary team caring for them. Each newly diagnosed patient should have a cardiology referral. If the diagnosis is made during the prenatal period and the prenatal ultrasound was normal, the newborn still needs a cardiac evaluation.
Echocardiography is useful in excluding coarctation. Before echocardiography, blood pressure should be checked in upper and lower extremities and in both right and left anas. If a blood pressure difference of greater than 10 tnmHg is detected, prompt referral to a pediatrie cardiologi st should be made. In others, blood pressure should be monitored at least yearly thereafter because of the increased frequency of hypertension. Patients with most structural cardiac defects will require antibiotic prophylaxis for surgical procedures and dental work.
If the cardiac evaluation is normal, periodic echocardiography should be performed by a pediatrie cardiologist to monitor for aortic dilatation. If dilatation is detected, periodic MRI is needed to monitor the degree of dilatation. Because more females with Turner syndrome are becoming pregnant with the use of assisted reproduction techniques, evaluation for aortic dilatation is particularly crucial. The force of labor may induce aortic rupture in some patients with aortic dilatation.
Congenital renal abnormalities are approximately nine times more common in patients with Turner syndrome than in the general population.'5 In a study by Lippe et al.,16 one-third of patients with Turner syndrome showed renal dysmorphism on ultrasound. Renal abnormalities include double collecting system, horseshoe kidney, rotational abnormalities, ectopic/pelvic kidney, absent kidoey, ureteropelvic obstruction, or aberrant blood supply.
Renal ultrasound is recommended at the time of diagnosis. If significant abnormalities are present, patients should have appropriate nephrology/urology follow-up exam. Urinary tract infections and renal obstruction should be diagnosed promptly and treated vigorously.17 Patients with Turner syndrome, with and without structural abnormalities, are at increased risk for chronic urinary tract infections.
Even in the absence of cardiac and renal abnormalities, hypertension is common in patients with Turner syndrome.18 Therefore, blood pressure measurement should be a routine part of the physical examination. If hypertension is confirmed, patients should be treated aggressively, especially in light of the susceptibility of these patients to aortic dilatation.
Patients with Turner syndrome also are more likely to develop inflammatory bowel disease (IBD). Among Turner syndrome patients, women with the isochrome Xq karyotype are at the highest risk to develop IBD. This might be explained by the fact that a gene on the long arm of the X chromosome may be associated with immune dysfunction. Approximately 52% of patients with Turner syndrome who have IBD have isochrome Xq.17 Delayed puberty and short stature may be presenting symptoms of both IBD and Turner syndrome. Therefore, well-controlled IBD patients with short stature or delayed puberty should be tested for Turner syndrome.
The incidence of celiac disease is also increased in patients with Turner syndrome. In an Italian study, the prevalence of celiac disease among patients with Turner syndrome was approximately 6.4%. Among these patients, approximately 60% presented with a subclinical picture, leading to delay in the diagnosis of celiac disease. The incidence of other autoimmune diseases was also increased. l9 Routine screening for celiac disease is recommended.
Gastrointestinal hemorrhage, especially of the colon, primarily is due to developmental vascular abnormalities and is more common in patients with Turner syndrome.9 Therefore, in patients presenting with iron-deficiency anemia, disorders of the gastrointestinal tract, including IBD, and vascular causes of gastrointestinal hemorrhage must be considered.
In a recent study by Salerno et al.,20 liver function tests were normal in patients with Turner syndrome younger than 7. Initiation of hormone therapies particularly resulted in a consistent increase in serum liver enzymes, espedaily with estrogen and oxandrolone treatments.20 Estrogen and oxandrolone are associated with liver dysfunction in many patients with Turner syndrome, but a minority had liver dysfunction before initiation of hormone treatments. Therefore, liver function tests should be monitored and use of transdermal estrogen should be considered in those patients presenting with elevated liver function tests.
Intelligence is normal in patients with Turner syndrome. However, they may be at risk for developing behavioral and social difficulties. Their attention span may be short, and spatial perception and visual motor integration may be impaired. Younger girls may experience hyperactivity and behave immaturely; older girls may develop depression and poor peer relations.
Short stature is one of the most common phenotypic features of Turner syndrome. The growth pattern in patients with Turner syndrome can be summarized as intrauterine growth retardation on average causing a reduction of 2.8 cm in length and an average birth weight of 2.18 kg, followed by a period of growth decline from -0.7 to -1.2 SD at birth to -2 SD by age 3. Significant deceleration occurs after age 3, accompanied by failure to undergo the puberta growth spurt, leading to continued but slow growth for many years if untreated.9,21 In general, patients are expected to grow to a final height approximately 20 cm less than the mid-parental height. Once the diagnosis is made, growth should be assessed using a Turner-syndrome-specific growth chart, available on the Web site for the Turner Syndrome Society of the United States.22
A study of girls with Turner syndrome aged 2 to 8 showed no statistical difference in GH levels, peak amplitudes, or peak frequencies compared with those in age-matched controls. However, in girls with Turner syndrome aged 9 to 20, there is a significant decrease in mean 24-hour GH levels, peak amplitudes, and peak frequencies compared with age-matched normal girls. All patients with Turner syndrome had decreased serum IGF-I concentrations and delayed bone ages.23
Growth hormone treatment without the need for GH stimulation tests was approved in the United States in 19% for treatment of short stature in patients with Turner syndrome. Many of these patients have normal responses to GH-provocative tests. Growth hormone treatment increases pre-treatment growth velocity by 50% to 150% within the first year after treatment is started. Because GH secretion is normal (at least before age 9), the GH dose used is pharmacological. The standard GH dose for patients with Turner syndrome is 0.375 mg per kilogram of weight per week, divided into small doses and given subcutaneously 6 to 7 days per week. While undergoing GH treatment, patients should be seen by a pediatrie endocrinologist every 3 months. If GH is started, IGF- 1 and IGFBP3 levels should be monitored regularly, and the GH dose should be adjusted to normalize these parameters.
Treatment can be started as young as age 2. The advantage of starting GH treatment early is that the most robust growth occurs in infants and toddlers. On the other hand, the stress of injection is greater in young patients.
Those started on GH earlier will experience a greater increase in height. If, at the time of initiation of therapy, height is significantly below 5% and the child is aged 9 to 12, anabolic steroids such as oxandrotone can be used in combination with GH to hasten the growth spurt. If bone age advances excessively, oxandrolone therapy should be discontinued.24 Virilization, including facial hair and clitorimegaly, are side effects of anabolic steroids and should be monitored. Family and patient input are important in deciding when GH treatment should be discontinued.
After growth is complete, a leglengthening procedure is an option, but experience is limited in patients with Turner syndrome.
In patients with Turner syndrome, the ovaries undergo the same differentiation as in the 46XX population until 14 to 18 weeks of gestation. The normal oocyte loss between the prenatal period and menopause accelerates in patients with Turner syndrome to occur within the prenatal period and the first few months to years of postnatal life. With the initiation of raeiosis, the ovaries of patients with Turner syndrome undergo rapid loss of oocytes, progressive stromaï fibrosis, and streak formation.25 Ultrasound findings of the ovaries are consistent with streak gonads, or the ovaries are too small to be visualized. The paramesonephric or Mullerian ducts develop normally, giving rise to normal Fallopian tubes, uterus, and vagina. In adults with untreated Turner syndrome, however, the uterus remains prepubertal.17
Normally, in both sexes, during the first weeks and months of life, gonadotropin and sex steroid levels are higher than later in childhood and decline within the first year of life. In patients with Turner syndrome, the levels of gonadotropifls may be abnormally elevated for the first 2 to 4 years of life, in association with the abnormaliy low estradici levels. Later in childhood, follicle stimulating hormone (FSH) levels decline to normal values.6 Most authors, recommend checking the gonadotropin levels at the usual time of puberty to ascertain the timing of puberty in patients with Turner syndrome. Those with constitutional delay may have prepubertal gonadotropin levels until later in adolescence.
The timing for initiation of replacement therapy is important. Failure to undergo spontaneous puberty is one of the causes for short stature in Turner syndrome. On the other hand, treatment with estrogen may hasten the closow of the growth plates and lead to a shorter aduit height.
In adolescent and adult patients who have not received estrogen replacement, brain imaging studies may show pituitary enlargement or microadenoma. Physicians should be aware of this, especially during the evaluation of delayed puberty, because pituitary enlargement may be part of the picture of 1\imer syndrome, rather than evidence of a strictly pituitary cause for pubertal delay.
Even though up to 30% of patients with Turner syndrome will experience some pubertal development, in most of these, puberty will be arrested.26 A recent Italian study demonstrated that 16.1% of patients with Turner syndrome had spontaneous puberty. It occurred in approximately 14% of X-monosomic patients and in 32% of patients with mosaici sm including cell lines with more than one X.-7
It is optimal to start hormone replacement at an appropriate age so that the patient does not experience psychological problems among peers. Ideally, it is recommended that estrogen therapy should be started by age 15 but not before age 12? It should be individualized to optimize growth and development and to meet the specific needs of the patient.
At the initiation of therapy, bone age should be obtained, in addition to FSH, Juteinizing hormone, and estradiol levels. Puberty induction hi patients with Turner syndrome should mimic natural puberty. Different hormone regimens are available. However, these, too, should be individualized. In patients with liver disease, transdermal estrogen should be considered, because it eliminates the first pass through the liver. Conjugated equine estrogene and micronized estradiol are other options. The conjugated estrogene have a long track record; however, these may cause a higher incidence of hypertension and thromboembolic disease than does transdermal estrogen, and the dose is not as easy to regulate with blood levels as is micronized estradiol.28
Conjugated estrogene can be started at a low dose of approximately one-sixth to one-fourth of an adult dose (0.150 to 0.300 mg). The low dose should be continued with increments as required to mimic normal pubertal growth. On a low dose, most girls will experience Tanner 3 breast development within 1 year. Once a dose of 0.625 mg is reached, breakthrough bleeding occurs, or Tanner stage 4 breast development is reached, progesterone should be started.
Starting the cyclic therapy on a calendar month is recommended for convenience. Estrogen may be given throughout the month, and 5 mg daily of medroxyprogesterone can be given on days 1 through 12 of each month. Initiation of progesterone prevents uterine hyperplasia and thereby reduces the risk of estrogen-induced neoplasia. Relatively low starting doses of medroxyprogesterone are recommended to prevent side effects on carbohydrate and lipid metabolism. If menstrual bleeding is not induced by 5 mg of medroxyprogesterone, then either the medroxyprogesterone dose is too low or the estrogen dose is too low. Ultrasound of the uterus may be helpful in distinguishing between these possibilities, because a thickened endometrial stripe suggests adequate estrogen and implies inadequate progesterone.
If instead of conjugated estrogens, micronized estrogens are used, estradici levels can be followed to ascertain adequate levels. Micronized estradici may be started at a dose of 0.25 mg daily. The dose can be gradually increased to 1 mg daily; at this estradiol dose (or at a lower dose if vaginal spotting has occurred or if breasts reach Tanner stage 4), medroxyprogesterone should be added as with the use of conjugated estrogens.
In those patients who want additional growth in height as well as pubertal changes, low-dose estradici in intramuscular form can be used. Estrogen in low doses of 1 to 1.5 mg intramuscularly each month stimulates linear growth. The rationale for use of intramuscular estrogen is that this route avoids the first pass effects on the liver induced by oral administration. One of the first-pass effects of oral estrogens is to decrease hepatic production of IGF-I. Reduction in IGF-I, in turn, decreases growth. In a study by Rosenfield et al.,29 teenagers with Turner syndrome treated with intramuscular estrogen grew, on average, 2.6 cm more than a group treated with oral estrogen.29
Height, weight, Tanner staging, and blood pressure should be monitored every 3 to 6 months after initiation of therapy with sex steroids. A bone age film also should be obtained every 6 months.30 Gynecologic examination is recommended if the patient becomes sexually active or if irregular bleeding occurs. After cyclic therapy is started, breast self-examination is recommended every month.
Normal pregnancy can occur in approximately 3% of patients with Turner syndrome. A large portion of the remainder of patients may choose to use assisted reproduction technologies to achieve pregnancy. Cyclic sex steroid therapy prepares the uterus for a possible in vitro fertilization procedure, employing oocyte donation. In those patients undergoing spontaneous puberty but early ovarian failure, oocyte cryopreservation is an option for future intra-cytoplasmic sperm injections. Pregnancy may be associated with increased risk of aortic dissection in patients with Turner syndrome, particularly if patients go through labor. For this reason, pregnant patients should be managed in conjunction with cardiologists who are knowledgeable about the cardiovascular problems occurring in Turner syndrome.
Recent data indicate a Y chromosome is present in some tissues in 12.2% of patients with Turner syndrome. Frequently, the Y chromosome is not detectable in peripheral lymphocytes but may be detectable on chromosomal analysis of skin biopsies. The presence of Y chromosomes in some tissues is important because one of the tissues that may contain the Y chromosome is the gonad. The presence of Y chromosomes in dysgenic gonads is associated with increased risk of gonadoblastoma. The frequency of gonadoblastoma in patients with Turner syndrome and mosaicisms including a Y chromosome is 7% to 10%. 3I These data indicate that as many as 1 % of patients with Turner syndrome have gonadoblastoma. Cytogenetic and molecular techniques with polymerase chain reaction, coamplification polymerase chain reaction, and fluorescence in situ hybridization analysis can detect the Y-chromosome. Patients with Turner syndrome may benefit from discussion of these issues with geneticists to decide whether to perform tests for Y chromosome mosaicism. Currently, it is recommended that patients carrying the Y chromosome should undergo gonadectomy. In the future, additional studies may indicate which portion or portions of the Y chromosome may predispose to gonadoblastoma. Specific studies to establish the presence of these portions of the Y chromosome may be used to decide upon gonadectomy.
Obesity, Hyperlipidemia, and Carbohydrate Intolerance
The life expectancy of patients with Turner syndrome is reduced, on average, by approximately 13 years compared with other women. Women with Turner syndrome may be at increased risk to develop coronary artery disease because of their higher frequency of obesity and hypertension.17 Obesity may be a problem for some young girls with Turner syndrome. Prompt nutritional counseling may help control obesity. For adults with Turner syndrome, the goal for body mass index should be below 25 and waist/nip ratio below 0.8.26
A recent Danish study shows both type 1 and type 2 diabetes mellitus are more common in Turner syndrome with relative risks of 4.38 and 1 1.56, respectively.15 Patients with Turner syndrome who are significantly overweight, who have strong family histories of type 2 diabetes mellitus, or who have acanthosis nigricans should undergo regular monitoring of fasting and post-prandial serum glucose.3
Patients with Turner syndrome, along with other amenorrheic adolescents, have higher cholesterol values. This can be attributed to the hypoestrogenic state. Another contributing factor may be insulin resistance. Hyperinsulinism appears to stimulate lipid synthesis in arterial walls.32 GH treatment reduces total and low-density lipoproteine and increases high-density Upoproteins in patients with ltoer syndrome.33 As mentioned previously, estrogen replacement therapy, especially the progestin component, may have adverse effects on the carbohydrate and lipid metabolism.
A 10-year study from Taiwan showed increased incidence of autoimmune thyroid disease in children with Turner syndrome and recommended regular follow up of the thyroid antibodies and of thyroid function tests.34 Both Hashimoto and Graves' disease are more common in patients with Turner syndrome than in the general population.9 Therefore, thyroid function tests should be performed annually or promptly if signs or symptoms of thyroid dysfunction develop. Other autoimmune diseases, including juvenile rheumatoid arthritis, myasthenia gravis, and IgA deficiency, are also more common in patients with Turner syndrome.
Turner syndrome is a systemic disease requiring a multi-system management approach. This includes attention to the endocrine system, cardiovascular system, renal system, gastrointestinal system, ears, eyes, skeletal system, and skin, as well as to the psychology of the patient and the family. The primary care physician is central to the care of these patients. In addition to anticipating, diagnosing, and treating the various problems that may arise in patients with Turner syndrome, the primary care physician must coordinate the fairly large healthcare team needed for optimal care.
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34. dung P, Tsai WY, Hou JW, Hsiao PH, Lee JS. Autoimmune thyioiditis in children with Turner syndrome. J Formes Med Assoc. 2000;99(ll):823-826.