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TURNER SYNDROME

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DESCRIPTION

Turner syndrome, also known as Ullrich-Turner syndrome and monosomy X, was first described by Henry Turner in 1938 (Turner, 1938). However, it was not until 1959 that the chromosomal basis for the condition was first reported (Ford et al., 1959). Turner syndrome is a sex chromosomal abnormality typically involving the presence of one X chromosome and the complete absence of a second sex chromosome. This condition has a karyotype of 45,X.

Turner syndrome may additionally occur if a second sex chromosome, usually the X chromosome, is present but has a structural abnormality. These structural abnormalities include isochromosome (one arm of a chromosome is lost and the other arm is duplicated) with karyotype 46,X,i(Xq), deletion (loss of part of a chromosome) with karyotype 46,X,del(X), and ring chromosome (a single chromosome suffers two breaks and the broken ends are joined together, forming a ring) with karyotype 46,X,r(X). Turner syndrome may also occur with mosaicism, where some of the cells in the body have a Turner syndrome chromosome complement and other cells in the body have a different chromosome complement, either normal (karyotype 45,X/46,XX) or abnormal (e.g., karyotype 45,X/47,XXX). Although Turner syndrome is generally considered to affect only females, a Y chromosome may also be present (karyotype 45,X/46,XY). However, the 45,X/46,XY karyotype can result in a variety of different phenotypes besides Turner syndrome, including normal male (Chang et al., 1990; Wheeler et al., 1988).

Table 1. Karyotypes commonly associated with Turner syndrome

Karyotype Description
45,X monosomy X
45,X/46,XX monosomy X mosaic with normal female sex chromosome complement
46,X,i(Xq) isochromosome X
46,X,del(X) deletion chromosome X
46,X,r(X) ring chromosome X
45,X/47,XXX monosomy X mosaic with triple X chromosome complement
45,X/46,XY monosomy X mosaic with normal male sex chromosome complement

Karyotypes may occur as listed or as part of mosaicism.

Approximately 50-70% of Turner syndrome cases are due to 45,X (Huang et al., 2002; Savendahl and Davenport, 2000; Ruiz et al., 1999; Jacobs et al., 1997; Gravolt et al., 1996; Gotzsche et al., 1994; Hook and Warburton, 1983). The karyotype 45,X/46,XX accounts for roughly 15% of Turner syndrome cases, and the other karyotypes contribute to Turner syndrome cases to a lesser degree (Gravolt et al., 1996; Hook and Warburton, 1983) (Table 2).

Table 2. Proportion of Turner syndrome cases represented by various karyotypes in several studies

Karyotype* Gravolt et al., 1996

(n=304)

Hook and Warburton, 1983

(n=1043)

45,X 56% 58%
45,X/46,XX 17% 15%
46,X,i(Xq) 11% 15%
46,X,del(X) 8% 6%
46,X,r(X) 5% 2%
45,X/47,XXX 3% 5%

*Except for 45,X and 45,X/46,XX, the karyotypes include mosaicism of the karyotypes. Karyotypes including the Y chromosome are excluded.

The distribution of Turner syndrome karyotypes varies with pregnancy outcome and the time when the diagnosis is made (Gravolt et al., 1996; Hook and Warburton, 1983). The karyotype 45,X comprises a higher proportion of fetal deaths than live births (Hook and Warburton, 1983), indicating that 45,X is less likely to survive to term than other Turner syndrome karyotypes (see Prevalence and pregnancy outcome). A higher proportion of prenatally diagnosed Turner syndrome cases than postnatally diagnosed cases or live births are comprised of the karyotype 45,X/46,XX (Gravolt et al., 1996; Hook and Warburton, 1983). The difference may reflect incomplete ascertainment of 45,X/46,XX cases after delivery because of Turner syndrome cases with the mosaic karyotype may have a milder phenotype than for the 45,X karyotype and thus may not be as completely diagnosed postnatally (Gotzsche et al., 1994; Moore et al., 1990; Hook and Warburton, 1983; Hall et al., 1982).

Etiology

The Turner syndrome karyotype 45,X occurs as a result of nondisjunction at either stage of meiosis (meiosis I or meiosis II), resulting in the absence of one sex chromosome after fertilization. The nondisjunction may involve either the maternal or paternal gamete. Since only one sex chromosome is present in 45,X, the parental source of the nondisjunction must be inferred by identifying which parent contributed the X chromosome that is present. The nondisjunction will have occurred in the parent whose sex chromosome is absent. Moreover, since 45,X results from the absence of a chromosome, the exact meiotic division (I or II) where the nondisjunction occurred cannot be determined (Jacobs and Hassold, 1995).

In 75-85% of the cases of 45,X, the X chromosome is of maternal origin, indicating that it was the paternal sex chromosome that was lost (Monroy et al., 2002; Uematsu et al., 2002; Jacobs et al., 1997; Larsen et al., 1995; Connor and Loughlin, 1989; Hassold et al., 1990; Hassold et al., 1988; Sanger et al., 1977). The nondisjunction is most frequently of paternal origin in all pregnancy outcomes, suggesting that parental origin does not influence survival of the conceptus (Jacobs and Hassold, 1995) (Table 3).

Table 3. Parental origin of the X chromosome present in 45,X by pregnancy outcome
Pregnancy outcome Maternal Paternal
Total live births 105 (80%) 27 (20%)
Elective terminations 5 (71%) 2 (29%)
Fetal deaths 49 (83%) 10 (17%)
Total 159 (80%) 39 (20%)

Derived from Jacobs and Hassold, 1995

Maternal and paternal age have not been found to affect parental origin of the X chromosome (Lorda-Sanchez et al., 1992; Hassold et al., 1992).

The abnormal X chromosome in 46,X,i(Xq) is of maternal and paternal origin with roughly equal frequency, while the majority of 46,X,del(X) and 46,X,r(X) and almost all Y chromosome abnormalities in Turner syndrome are of paternal origin (Uematsu et al., 2002; Jacobs et al., 1997). The different parental origin distributions for the various types of Turner syndrome karyotypes suggest that difference mechanisms operate in causing 45,X and other Turner syndrome karyotypes (Monroy et al., 2002; Connor and Loughlin, 1989). It has been suggested that the high proportion of paternal errors resulting in Turner syndrome may result from the absence of pairing along most of the X and Y chromosomes during meiosis I in the father, which may make the sex chromosomes susceptible to both nondisjunction and structural errors (Jacobs et al., 1997).

Phenotype

The phenotype of Turner syndrome is believed to result from haplo-insufficiency of genes expressed in both sex chromosomes. The clinical features of Turner syndrome are frequently obvious during infancy and childhood. Nevertheless, the Turner syndrome phenotype is widely variable. Patients with karyotypes other than 45,X often have milder symptoms (e.g., fewer cardiovascular anomalies) and diagnosed at a later age than patients with 45,X; however, phenotype cannot be predicted from karyotype (Savendahl and Davenport, 2000; Gotzsche et al., 1994; Moore et al., 1990; Hall et al., 1982).

The clinical features of Turner syndrome has been reported in detail in the literature (Ranke and Saenger, 2001; Savendahl and Davenport, 2000; Linden et al., 1996; Saenger, 1996; Ranke and Grauer, 1994; Lippe, 1991; Buyse, 1990). The more commonly reported features of Turner syndrome include short stature, lymphedema (edema of the hands and feet), webbing of the neck, low posterior hairline, low set ears, nail dysplasia (narrow, hyperconvex, deeply set nails), broad chest, widely spaced nipples (often hypoplastic or inverted), anomalous often prominent ears, and micrognathia. Less commonly reported features include ptosis of the eyelids, hypertelorism, vertebral and other skeletal anomalies, and single transverse palmar crease.

Major structural birth defects frequently reported among patients with Turner syndrome consist of left-sided cardiac or aortic anomalies, particularly coarctation of the aorta, dilatation of the aorta, bicuspid aortic valve, and aortic stenosis but also hypoplastic left heart syndrome and partial anomalous pulmonary venous return (Barr and Oman-Ganes, 2002; Goldmuntz, 2001; Gotzsche et al, 1994; Moore et al., 1990; Natowicz and Kelley, 1987). Turner syndrome patients also often have urinary system abnormalities such as horseshoe kidney, duplication of the renal collecting system, malrotation of kidney, absent kidney, and ureteropelvic or ureterovesical obstruction (Barr and Oman-Ganes, 2002; Hall and Gilchrist, 1990; Lippe et al., 1988; Hall et al., 1982).

Females with Turner syndrome are at increased risk of otitis media, cardiovascular disease, hypertension, diabetes mellitus, thyroid disorders, collagen vascular disease, and obesity (Linden et al., 1996; Buyse, 1990).

Although most Turner syndrome patients are of unambiguous female sex (Ranke and Saenger, 2001), they usually suffer from ovarian failure (fibrous streak ovaries), infertility, and gonadal dysgenesis (Tarani et al., 1998; Linden et al., 1996). They rarely have spontaneous pregnancy and delivery of normal infants (Tarani et al., 1998).

Girls and women with Turner syndrome generally have average intelligence (Ranke and Saenger, 2001; Linden et al., 1996). They have been reported to have hyperactivity, delayed emotional maturity, poor relations with peers, timidity, and negative body image (McCauley et al., 1995; McCauley et al., 1987). Turner syndrome patients may have impairments in nonverbal, visual-spacial information processing, arithmetic, the coordination of motor and visual-perceptual skills (Romans et al., 1998; Bender et al., 1991; Downey et al., 1989)

Prenatal diagnosis

Turner syndrome may be prenatally diagnosed through cytogenetic analysis of cells obtained through such procedures as amniocentesis and chorionic villus sampling.

Maternal serum levels of alpha-fetoprotein (AFP) and total human chorionic gonadotropin (hCG) in the first trimester has not been found to be abnormal in the presence of fetuses with Turner syndrome (Spencer et al., 2000a). However, fetuses with Turner syndrome have been associated with increased nuchal translucency, lower maternal serum pregnancy-assisted plasma protein-A (PAPP-A) levels, and normal maternal serum free beta-hCG levels in the first trimester (Spencer et al., 2000b; Sebire et al., 1998; Pandya et al., 1995).

Maternal serum levels of AFP, hCG, estriol, and inhibin A in the second trimester have been reported to be abnormal in the presence of fetuses with Turner syndrome (Table 4). Which maternal serum markers are elevated or reduced depends on whether the fetus has non-immune hydrops (Ruiz et al., 1999; Lambert-Messerlian et al., 1998; Laundon et al., 1996; Saller et al., 1992). Second-trimester maternal serum levels of progesterone have been reported to be elevated in the presence of Turner syndrome fetuses with hydrops and slightly low in the presence of fetuses without hydrops ( Lambert-Messerlian et al., 1999). However, Turner syndrome is not systematically screened for using maternal serum markers, and one investigation found that the proportion of Turner syndrome cases in a population at increased risk of Down syndrome as a result of maternal serum screening was not greater than expected for the general population (Ryall et al., 2001).

Table 4. Pattern of multiple of median (MoM) levels for various second-trimester maternal serum screening markers in the presence of Turner syndrome fetuses
Reference   AFP hCG uE3 inhibin A
Overall hydrops slightly reduced elevated reduced elevated
  non-hydrops slightly reduced reduced reduced reduced
Ruiz et al., 1999 total 0.82 2.63 0.48  
  hydrops 0.83 5.90 0.32  
  non-hydrops 0.69 0.90 0.62  
Lambert-Messerlian et al., 1998 hydrops       3.91
  non-hydrops       0.64
Saller et al., 1992 hydrops 0.81 3.84 0.48  
  non-hydrops 0.71 0.52 0.45  

AFP - alpha-fetoprotein

hCG - human chorionic gonadotropin

uE3 - estriol

Prenatal ultrasound can detect nuchal cystic hygroma, non-immune hydrops, pleural effusions, ascites, left-sided cardiovascular anomalies such as coarctation of the aorta, renal anomalies, and growth retardation, conditions which are associated with Turner syndrome (Barr and Oman-Ganes, 2002; De Vigan et al., 2001; Ranke and Saenger, 2001; Ruiz et al., 1999; Lambert-Messerlian et al., 1998; Wenstrom et al., 1994; Stoll et al., 1993; Saller et al., 1992).

In spite of the fact that Turner syndrome may be prenatally diagnosed subsequent to an abnormal second-trimester maternal serum screen or ultrasound, most prenatally diagnosed cases are identified incidentally, such as through amniocentesis performed for advanced maternal age (Saenger, 1996). Prenatal diagnosis rates vary between studies, being reported as 12% in Denmark during 1970-1980 (Nielsen and Videbech, 1984), 32% in Denmark during 1970-1993 (Gravholt et al., 1996).

DEMOGRAPHIC AND REPRODUCTIVE FACTORS

Prevalence and pregnancy outcome

Since Turner syndrome is a chromosomal abnormality, and not all live births have cytogenetic analysis, the exact live birth prevalence of Turner syndrome is not known. The prevalence has been reported to be 2.6-8.2/10,000 female births or 0.9-4.0/10,000 births (Table 5). It is estimated that there are 50,000-75,000 women and girls with Turner syndrome in the United States (Saenger, 1996).

Table 5. Prevalence per 10,000 births of Turner syndrome
Reference Location Time period Rate
De Vigan et al., 2001 Europe 1996-1998 1.9
Stoll et al., 1993 France 1980-1987 1.0
Nielsen and Wohlert, 1991 Denmark 1969-1988 2.6, 5.3*
Hansteen et al., 1982 Norway 1978-1979 0.0
Hamerton et al., 1975 Canada 1970-1972 1.4, 3.0*
Jacobs et al., 1974 Scotland 1967-1972 0.9, 2.6*
Friedrich and Nielsen, 1973 Denmark 1969-1971 4.0, 8.2*

*rate per female births only

Turner syndrome is more common prenatally. It has been estimated that as many as 99% of conceptuses with 45,X result in fetal death within the first and second trimesters (Hook and Warburton, 1983; Hook, 1978) and that the probability of a 45,X conceptus surviving to term is 0.3% (Jacobs and Hassold, 1987).

The karyotype 45,X may occur in as many as 1.3% of all pregnancies, approximately 5-9% of early fetal deaths or spontaneous abortions, and 0.25% of late fetal deaths or stillbirths (Ford et al., 1996; Kalousek et al., 1993; Ohno et al., 1991; Jacobs and Hassold, 1987). One investigation observed that 9% of fetal deaths at 10-15 weeks' gestation and 13% of fetal deaths at 13 weeks' gestation were due to 45,X (Hook and Warburton, 1983).

Another investigation reported the Turner syndrome rate to be 17.6/10,000 females tested by amniocentesis and 39.2/10,000 females tested by CVS (Gravholt et al., 1996). Several studies have reported that 69-75% of prenatally diagnosed 45,X cases will not survive to term (Hook et al., 1989; Hook and Warburton, 1983). This is in contrast to a more recent study that reported only 25% of prenatally diagnosed cases (8% of cases identified through amniocentesis and 60% of cases identified through chorionic villus sampling) did not survive to term (Gravolt et al., 1996).

Conceptuses with 45,X are less likely than conceptuses with other Turner syndrome karyotypes to survive to term (Gravolt et al., 1996; Hook and Warburton, 1983; Hook, 1983). Investigations have reported that 69-75% of 45,X cases that were prenatally diagnosed and not electively terminated did not survive to term while 11-14% of 45,X/46,XX cases did not survive to term (Hook et al., 1989; Hook and Warburton, 1983). Another study found that among cases that were not electively terminated, 45,X cases consisted of 27% live births, 60% earlier fetal deaths, and 13% later fetal deaths while 45,X/46,XX cases consisted of 92% live births, 4% earlier fetal deaths, 4% later fetal deaths (Hook et al., 1989).

Some researchers have suggested that mosaicism of some degree must be present for survival in utero and that true 45,X does not exist (Hassold et al., 1992; Held et al., 1992; Hook and Warburton, 1983).

As a result of prenatal diagnosis, a portion of Turner syndrome cases are electively terminated (Chaabouni et al., 2001; De Vigan et al., 2001; Horger et al., 2001; Sagi et al, 2001; Christian et al, 2000; Perrotin et al, 2000; Mansfield et al, 1999; Gravholt et al., 1996; Verp et al, 1988; Holmes-Seidle et al, 1987; Nielsen and Videbec, 1984). Elective termination rates have been reported to vary by study and by karyotype (Table 6). Termination rates for 45,X are higher than for 45,X/46,XX and lower than for 45,X/47,XXX (Christian et al, 2000). One study reported the proportion of prenatally diagnosed cases of Turner syndrome to decrease in Denmark during 1970-1993 (Gravolt et al., 1996). Differences in termination rates between studies may reflect differences in time periods of the studies or differences in access to and/or use of prenatal diagnosis and elective termination.

Table 6. Termination rates (%) of prenatally diagnosed Turner syndrome cases
Reference Turner syndrome 45,X 45,X/46,XX 45,X/46,X,i(Xq) 45,X/47,XXX
Chaabouni et al., 2001 80        
Horger et al., 2001 67        
Sagi et al, 2001   100      
Christian et al, 2000   86 64 100 100
Perrotin et al, 2000   88      
Mansfield et al, 1999 (review) 72

(44-100)

       
Gravholt et al., 1996 71        
Verp et al, 1988 100        
Verp et al, 1988 (review) 74        
Holmes-Siedle et al, 1987   100      
Holmes-Siedle et al, 1987 (review)   100      
Nielsen and Videbec, 1984 71        

 



Mortality/survival

In the absence of serious problems such as cardiovascular and renal defects or hypertension, or if the problems are successfully treated, the life span of an individual with Turner syndrome is expected to be normal (Buyse, 1990).

The annual report for the birth defects registry in Hawaii reported the first-year mortality rate for Turner syndrome to be 5.3% (Merz and Forrester, 2000). One investigation reported that the infant mortality rate associated with all sex chromosome abnormalities increased during 1985-1997 (Lee et al., 2001).

Secular trends

One study reported the Turner syndrome rate increased in Denmark during 1970-1993 (Gravholt et al., 1996). Increasing Turner syndrome rates may reflect increased use of prenatal diagnosis, which might identify cases that would previously have been missed.

Sex

By definition, Turner syndrome occurs exclusively among females.

Maternal age

Various studies have reported either decreased risk of Turner syndrome with increasing maternal age (Ferguson-Smith and Yates, 1984; Carothers, et al., 1980; Warburton et al., 1980; Kajii and Ohama, 1979) or no association with maternal age (Ranke and Saenger, 2001; Gravholt et al., 1996; Lorda-Sanchez et al., 1992; Mathur et al., 1991; Hassold and Chiu, 1985). A couple investigations reported the mean gestational age of spontaneous abortions with 45,X to be reduced when compared to spontaneous abortions without chromosomal abnormalities (Ford et al., 1996; Ohno et al., 1991).

One study identified increased risk of Turner syndrome with increased maternal age (Bernasconi et al., 1994).

Race/ethnicity

The annual report for the birth defects registry in Hawaii has listed the Turner syndrome rates per 10,000 live births for the seven most common racial/ethnic groups (Merz and Forrester, 2000). The rates were highest for Japanese (6.7), black (5.6), and Chinese (5.0), intermediate for white (4.0) and Filipino (3.7), and lowest for Hawaiian (2.1), and Samoan (1.4).

Seasonality

Although one study reported two annual peaks for Turner syndrome rates (Jongbloet, 1971), other investigations have observed no significant seasonal variation in Turner syndrome rates (Videbach and Nielsen, 1984; Carothers, et al., 1980; Nielsen et al., 1973).

Geography

The annual report for the birth defects registry in Hawaii has reported the Turner syndrome rate per 10,000 live births to be higher in metropolitan Honolulu (4.9) than in the rest of Hawaii (3.9).

Diabetes

Although one investigation reported a higher rate of sex chromosomal abnormalities with maternal gestational diabetes, the rate of Turner syndrome was not increased (Moore et al., 2002).

Assisted Reproductive Technology (ART)

Turner syndrome have been reported among infants conceived by intracytoplasmic sperm injection (ICSI) (Aboulghar et al., 2001).

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Please Note: The primary purpose of this report is to provide background necessary for conducting cluster investigations. It summarizes literature about risk factors associated with this defect. The strengths and limitations of each reference were not critically examined prior to inclusion in this report. Consumers and professionals using this information are advised to consult the references given for more in-depth information. 

This report is for information purposes only and is not intended to diagnose, cure, mitigate, treat, or prevent disease or other conditions and is not intended to provide a determination or assessment of the state of health. Individuals affected by this condition should consult their physician and when appropriate, seek genetic counseling.

For more information:

Birth Defects Epidemiology and Surveillance
Texas Department of State Health Services
1100 W. 49th Street, Austin, Texas 78756
512-776-7232 Fax 512-776-7330

Document E58-10957F                    Revised August 2002

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Last updated February 10, 2012