Vol. 16: Summer, 1998

Management of Common Genetic Disorders

Turner Syndrome

Introduction
Turner syndrome is a condition in females characterized by short stature, gonadal dysgenesis, and a variety of other major and minor anomalies due to the lack of a normal second sex chromosome. It is the most common female sex chromosome abnormality, occurring in approximately 1/2500 female live births. The remaining X chromosome is maternally inherited in two-thirds of girls with a 45,X karyotype. However, Turner syndrome is not associated with advanced maternal age.
Several cytogenetic abnormalities occur in Turner syndrome including 45,X, mosaicism with other cell lines, structural abnormalities of the second X chromosome, and/or cryptic Y mosaicism. Mosaicism for a normal cell line can be demonstrated in approximately 70% of Turner syndrome individuals. Low level mosaicism may be necessary for fetal survival since 1-2% of all conceptuses are 45,X but 99% of these abort spontaneously. Fifteen percent of spontaneous abortions have a 45,X karyotype.
Girls with a 45,X karyotype should have a sufficient number of cells analyzed to evaluate for low level mosaicism, and the use of fluorescent in situ hybridization using Y chromosome probes should be considered in the presence of a marker chromosome, ambiguous genitalia at birth, or virilization at puberty. There is a 15-25% risk of gonadoblastoma or dysgerminoma if Y chromosome material is present and, therefore, prophylactic gonadectomy is recommended by 6 years in these girls.
Clinical Features
The "classic" features of Turner syndrome include short stature, edema of the hands and feet, webbed neck or cystic hygroma, low posterior hair line, shield chest with wide spaced nipples, cubitus valgus, coarctation of the aorta, bicuspid aortic valve, horseshoe kidney, and lack of spontaneous secondary sexual development. However, these clinical features vary with patient age and are not present in all individuals with Turner syndrome. Only 15% of girls with Turner syndrome are diagnosed in the neonatal period. Over half of girls with Turner syndrome are not diagnosed until 12 to 14 years of age when they fail to develop secondary sexual characteristics.
Cardiovascular abnormalities are the primary cause of increased mortality in Turner syndrome. Consultation by a pediatric cardiologist is indicated at the time of diagnosis, and an initial echocardiogram should be obtained to evaluate the cardiac anatomy, especially for left-sided anomalies such as bicuspid aortic valve (50%) and coarctation of the aorta (20%). Prophylactic antibiotics for dental or surgical procedures, which may cause bacteremia, are recommended for all individuals with abnormal echocardiograms. Coarctation of the aorta requires surgical intervention, and individuals with bicuspid aortic valve are at increased risk to develop progressive aortic dilatation and/or dissection. Therefore, Turner syndrome patients with abnormal echocardiograms require ongoing cardiology management.
The frequency of echocardiogram and consultation by a cardiologist in those patients whose initial evaluation was normal is not agreed upon. Some authors advocate annual echocardiograms, however, most pediatric cardiologists recommend consultation and echocardiography every five years in asymptomatic individuals to screen for aortic root dilatation or aneurysm.
Hypertension is a common feature of Turner syndrome due to cardiac and renal anomalies as well as idiopathic hypertension. Therefore, blood pressure and peripheral pulses should be assessed at each physical examination. Hypertension should be treated aggressively.
Renal anomalies are very common in Turner syndrome and a renal ultrasound should be obtained at the time of diagnosis. If a renal anomaly is detected, urinary tract infections may be more common and, therefore, should be strongly considered, and aggressively treated, in the febrile infant or young child.
Short stature is virtually universal in Turner syndrome, regardless of the karyotype. Girls with Turner syndrome may have some mild intrauterine growth retardation, but more typically have a normal growth rate until 2 years of age. A progressive deceleration in growth occurs from 2 to 11 years of age, and there is very slow growth during adolescence with an absence of a pubertal growth spurt. The average height in untreated adult women with Turner syndrome is 143 cm (4'8"). Individuals with Turner syndrome develop progressive growth hormone deficiency and do not develop the normal pubertal increase in growth hormone and insulin-like growth factor. Girls with Turner syndrome should be treated with growth hormone when their height falls below the 5th percentile on the normal growth curve, usually between 2 to 5 years of age. Anabolic steroids may be added at 9 to 12 years. Therapy is continued until the bone age is greater than 15 years and the growth rate falls to less than 2 cm. per year. On this regimen, the final adult height is often greater than 150 cm (4'11").
After growth hormone therapy is completed, estrogen therapy is initiated to induce puberty, usually between 12 to 15 years of age. Estrogen therapy is continued throughout life to prevent osteoporosis and premature atherosclerotic heart disease. Progestin therapy is added 12 months after starting estrogen therapy to promote a normal menstrual cycle.
Other endocrine issues for individuals with Turner syndrome include hypothyroidism, carbohydrate intolerance, osteoporosis, and infertility. Hypothyroidism, usually due to autoimmune thyroiditis, occurs in up to half of adult women with Turner syndrome. Annual thyroid screening with appropriate intervention is recommended.
Although the majority of adult women with Turner syndrome have an abnormal glucose tolerance test, due to mild insulin resistance, the incidence of diabetes mellitus is not increased. Therefore, routine glucose tolerance testing is not necessary. Obesity, which is present in about 40% of women with Turner syndrome, may increase insulin resistance and appropriate diet and exercise should be encouraged.
Premature osteoporosis is very common in Turner syndrome. Estrogen therapy may help to ameliorate the problem; however, adequate calcium intake and regular weight-bearing exercises are also recommended. Bone densitometry is recommended every 3 to 5 years, beginning at age 20.
Other Medical Considerations
The vast majority of women with Turner syndrome are infertile, although 2 to 5% have spontaneous menses due to residual ovarian function. Over 50 natural pregnancies have been reported in women with Turner syndrome. There appears to be an increased incidence of congenital anomalies, including chromosome abnormalities, spina bifida, and congenital heart defects. Turner syndrome patients with spontaneous pubertal development should be referred for genetic and reproductive counseling.
For the remainder of women with Turner syndrome, in vitro fertilization with donor eggs is an option. Some centers have achieved pregnancy rates of 50 to 60% with this technique in Turner syndrome women. A thorough medical evaluation is strongly recommended prior to conception to rule out any contraindications such as cardiac or renal dysfunction.
Other issues that require monitoring by the primary care physician include an increased incidence of hearing loss and scoliosis. Otitis media and associated conductive hearing loss are common due to eustachian tube abnormalities. In addition, there is a high incidence of progressive sensorineural hearing loss. Therefore, annual hearing evaluations are recommended. Scoliosis occurs in about 10% of Turner syndrome girls, usually during adolescence. Careful monitoring and early intervention are recommended.
Conclusion
Intelligence is usually normal in individuals with Turner syndrome. However, many individuals with Turner have difficulty with visual-spatial relationships and there is an increased incidence of attention deficit disorder which may interfere with school performance. Therefore, it is recommended that a developmental evaluation be performed prior to starting school. Most women with Turner syndrome can expect to lead healthy and productive lives.
References:
Health Supervision for Children With Turner Syndrome. Committee on Genetics. Pediatrics 96 (6): 1166-1173, 1995
Saenger P. Turner's syndrome. N Engl J Med 335(23):1749-1754, 1996
Saenger P. Clinical review 48: The current status of diagnosis and therapeutic intervention in Turner's syndrome. J Clin Endocrinol Metab 77(2):297-301, 1993

Contributed by Peggy Pearson, MD (AZ)

The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131

Table of Contents:
Management of Common Genetic Disorders

Introduction
Achondropasia
Down Syndrome / Trisomy 21
Fragile X Syndrome
Marfan Syndrome
Neurofibromatosis
Turner Syndrome
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