Thompson & Thompson Genetics in Medicine, 8th Edition

Case 47. Turner Syndrome (Female Monosomy X)



• Nondisjunction

• Prenatal selection

• Haploinsufficiency

Major Phenotypic Features

• Age at onset: Prenatal

• Short stature

• Ovarian dysgenesis

• Sexual immaturity

History and Physical Findings

L.W., a 14-year-old girl, was referred to the endocrinology clinic for evaluation of absent secondary sexual characteristics (menses and breast development). Although born small for gestational age, she had been in good health and had normal intellect. No other family members had similar problems. Her examination was normal except for short stature, Tanner stage I sexual development, and broad chest with widely spaced nipples. After briefly discussing causes of short stature and delayed or absent sexual development, her physician requested follicle-stimulating hormone (FSH) level, growth hormone (GH) level, bone age study, and chromosome analysis. These tests showed a normal GH level, an elevated FSH level, and an abnormal karyotype (45,X). The physician explained that L.W. had Turner syndrome. L.W. was treated with GH supplements to maximize her linear growth; 1 year later, she started estrogen and progesterone therapy to induce the development of secondary sexual characteristics.


Disease Etiology and Incidence

Turner syndrome (TS) is a panethnic disorder caused by complete or partial absence of a second X chromosome in females. It has an incidence of between 1 in 2000 and 1 in 5000 liveborn girls. Approximately 50% of TS cases are associated with a 45,X karyotype, 25% with a structural abnormality of the second X chromosome, and 25% with 45,X mosaicism (see Chapter 6).

Monosomy for the X chromosome can arise either by the failure to transmit a sex chromosome to one of the gametes or by loss of a sex chromosome from the zygote or early embryo. Failure to transmit a paternal sex chromosome to a gamete is the most common cause of a 45,X karyotype; 70% to 80% of patients with a 45,X karyotype are conceived from a sperm lacking a sex chromosome. Loss of a sex chromosome from a cell in the early embryo is the likely cause of 45,X mosaicism.


The mechanism by which X chromosome monosomy causes TS in girls is poorly understood. The X chromosome contains many loci that do not undergo complete X inactivation (see Chapter 6), several of which appear to be necessary for ovarian maintenance and female fertility. Although oocyte development requires only a single X chromosome, oocyte maintenance requires two X chromosomes. In the absence of a second X chromosome, therefore, oocytes in fetuses and neonates with TS degenerate, and their ovaries atrophy into streaks of fibrous tissue. The genetic bases for the other features of TS, such as the cystic hygroma, lymphedema, broad chest, cardiac anomalies, renal anomalies, and sensorineural hearing deficit, have not been defined but presumably reflect haploinsufficiency for one or more X-linked genes that do not normally undergo inactivation in the female.

Phenotype and Natural History

Although 45,X conceptuses account for between 1% and 2% of all pregnancies, less than 1% of 45,X conceptions result in a liveborn infant. In view of the mild phenotype observed in patients with TS, this high rate of miscarriage and its timing is remarkable and suggests that a second sex chromosome is generally required for intrauterine survival, particularly at the beginning of the second trimester.

All patients with TS have short stature, and more than 90% have ovarian dysgenesis. The ovarian dysgenesis is sufficiently severe that only 10% to 20% of patients have spontaneous pubertal development (breast budding and pubic hair growth), and only 2% to 5% have spontaneous menses. Many individuals also have physical anomalies, such as webbed neck, low nuchal hairline, broad chest, cardiac anomalies, renal anomalies, sensorineural hearing deficit, edema of the hands and feet, and dysplastic nails. Nearly 50% of patients have a bicuspid aortic valve and therefore an increased risk for aortic root dilatation and dissection; nearly 60% have renal anomalies and an increased risk for renal dysfunction.

Most patients have normal intellectual development. Those with intellectual impairment usually have an X chromosome structural abnormality. Socially, individuals with TS tend to be shy and withdrawn (see Chapter 6).

In addition to the complications resulting from their congenital anomalies, women with TS have an increased incidence of osteoporotic fractures, thyroiditis, diabetes mellitus type 1 and type 2, inflammatory bowel disease, and cardiovascular disease. The causes of the diabetes mellitus, thyroid disorders, and inflammatory bowel disease are unclear. Estrogen deficiency is probably largely responsible for the osteoporosis and the increased incidence of atherosclerosis, ischemic heart disease, and stroke, although diabetes mellitus probably accentuates the cardiovascular effects of estrogen deficiency.


When stature in an individual with TS falls below the 5th percentile, she is usually treated with GH supplements until her bone age reaches 15 years (Fig. C-47). On average, this treatment results in a gain of 10 cm in predicted height; the improvement in final height is less, however, the later GH therapy is started. Concurrent estrogen therapy decreases the effectiveness of GH.


FIGURE C-47 Growth curves for normal (shaded dotted lines) and approximately 350 Turner syndrome girls (solid lines). None of the subjects received hormone treatment. See Sources & Acknowledgments.

Estrogen therapy is usually initiated at approximately 14 to 15 years of age to promote development of secondary sexual characteristics and reduce the risk for osteoporosis. Progesterone therapy is added to the regimen to induce menses either at the time of the first vaginal breakthrough bleeding or in the second year of estrogen therapy. Both are associated with an increased risk for thrombosis, and case reports indicate that there may be an increased risk in patients with TS above the general population of hormone therapy users.

In addition, medical management usually includes serial echocardiography to evaluate aortic root dilatation and valvar heart disease, renal ultrasonography to find congenital renal anomalies, and a glucose tolerance test to detect diabetes.

Patients who have complete ovarian dysgenesis do not ovulate spontaneously or conceive children. If they have adequate cardiovascular and renal function, women with TS can have children by in vitro fertilization and ovum donation. They do, however, have a significantly increased risk for aortic dissection and rupture with pregnancy.

Inheritance Risk

TS is not associated with advanced maternal or paternal age. Although there have been a few familial recurrences, TS is usually sporadic, and the empirical recurrence risk for future pregnancies is not increased above that of the general population. If TS is suspected on the basis of fetal ultrasound findings, such as a cystic hygroma, the diagnosis should be confirmed by karyotyping of chorionic villi or amniocytes.

Only a few pregnancies have been reported among spontaneously menstruating patients with TS. Among the resulting offspring, one in three has had congenital anomalies, such as congenital heart disease, Down syndrome, and spina bifida. The apparently increased risk for congenital anomalies may be due to ascertainment bias in reporting, because pregnancy is unusual in TS. If the increased risk is a real finding, the cause is unknown.

Questions for Small Group Discussion

1. Some observations have suggested that patients with Turner syndrome who inherit a paternal X chromosome are more outgoing and have better social adaptation than those who inherit a maternal X chromosome. What molecular mechanisms could explain this?

2. X-chromosome monosomy is the only viable human monosomy (other than the Y in males). Discuss possible reasons.

3. Discuss possible reasons for the high rate of birth defects among the children of women with Turner syndrome.

4. Maternal meiotic nondisjunction gives rise more frequently to Down syndrome and paternal meiotic nondisjunction to Turner syndrome. Discuss possible reasons.

5. Discuss the psychosocial support and counseling that are appropriate and necessary for patients with Turner syndrome.


Gonzalez L, Witchel SF. The patient with Turner syndrome: puberty and medical management concerns. Fertil Steril. 2012;98:780–786.

Hong DS, Reiss AL. Cognitive and neurological aspects of sex chromosome aneuploidies. Lancet Neurol. 2014;13:306–318.

Hook EB, Warburton D. Turner syndrome revisited: review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss. Hum Genet. 2014;133:417–424.

Legro RS. Turner syndrome: new insights into an old disorder. Fertil Steril. 2012;98:773–774.