The Rate of Sex Chromosome Aneuploidies in Prenatal Diagnosis and Subsequent Decisions in Western Turkey

Abstract

Aims: Sex chromosome abnormalities (SCAs) are the most common genetic disorder with a frequency of 1/400 or 1/500 live births. In this study we aimed to evaluate the initial indications, frequencies, and pregnancy termination rates of pregnancies with SCAs referred to Ege University Medical Faculty, Department of Medical Genetics. Prenatal diagnosis was performed in 7505 cases in the period of January 1998 through December 2009. Results: In this study, their initial indications and fetal karyotype results were evaluated retrospectively. A total of 60 pregnancies (0.80%) with SCA were evaluated. Turner syndrome was the most commonly diagnosed SCA in prenatal diagnosis (60%). The most common referral reason for pregnancies with Turner syndrome was cystic hygroma on ultrasonography. Of 14 pregnancies having a prenatal diagnosis with SCA (Turner syndrome: 7, Klinefelter syndrome: 5, Mosaic Turner syndrome: 2), 12 with SCA (85.7%) were terminated. The ratio of SCA in the prenatally diagnosed cases was similar to those reported in the literature. Although the ratio of terminated pregnancies with Turner syndrome was similar to those reported from European countries, all the pregnancies with Klinefelter syndrome have chosen termination, which showed a regional difference in Turkey. Conclusion: It is important to consider the decisions of the families during the genetic counseling sessions of the couples having SCAs.

Introduction

Prenatal diagnosis is performed on 8% of all pregnancies in our country (Savaci et al., 2008). Advanced maternal age, increased risk in prenatal biochemical screening tests, abnormal ultrasonography findings, known chromosome abnormalities in one of the parents, and having a child with chromosomal abnormality are the most common indications for prenatal diagnosis (Kim et al., 1989). Numerical abnormalities (aneuploidies) of 13, 18, 21, and sex chromosomes account for approximately 90% of chromosomal abnormalities detected in the prenatal period (Preis et al., 2004; Summers et al., 2007). Sex chromosome abnormalities (SCAs) are the most common genetic disorder with a frequency of 1/400 or 1/500 live births. Phenotypic findings in SCAs are relatively milder than autosomal chromosome disorders. Among all live births, or at the fetal stage, the most common SCAs are trisomies (XXX, XXY, and XYY). Clinical findings are limited to infertility or developmental abnormalities in the four most commonly identified syndromes, which are Klinefelter syndrome, Turner syndrome, Trisomy X, and XYY (Liao and Li, 2008; Shaw et al., 2008). Because there are generally mild developmental disorders in patients with SCAs, diagnosing those syndromes makes it harder for parents to decide on termination. The aim of this study was to evaluate the incidence of SCAs in the prenatal diagnosis procedures together with their referral reasons and to report the pregnancy outcomes of women who have been contacted.

Materials and Methods

A total of 7505 fetal karyotype results of the cases that were referred to the Ege University Medical Faculty, Department of Medical Genetics, between January 1998 and December 2009 for prenatally diagnosis because of high risk of chromosomal abnormality were evaluated retrospectively. Among all samples, 6300 were amniocentesis, 650 abortus, 500 chorionic villus sampling (CVS), and 55 cordocentesis. Referral indications and results of the cytogenetic analysis were evaluated.

Before evaluation, it was known that all cases were provided genetic counseling before prenatal diagnosis. Families were comprehensively informed about the probable risks of chromosomal abnormalities as well as the complications of invasive procedures. An informed consent form was obtained from all families who decided to have the invasive test and chromosome analysis. CVS was performed between 10 and 12 weeks, amniocentesis between 16 and 20 weeks, and cordocentesis after 21th week. The outcomes of each pregnancy with SCA were determined by telephone interview conducted by genetic counselors. All families were informed about their prenatal results by genetic counseling.

Results

Among the files of 7505 cases, which had undergone prenatal diagnosis, SCAs were detected in 60 cases (1/125; 0.80%). Of the cases diagnosed with SCA, 36 (60%) were Turner syndrome, 10 (16.6%) were Klinefelter syndrome, 7 (11.6%) were mosaic Turner syndrome, 2 (3.3%) were mosaic Klinefelter syndrome, 2 (3.3%) were 47,XYY, 1 (1.6%) was Trisomy X, 1 (1.6%) was mosaic Trisomy X, and 1 was inv(Y) (1.6%; Table 1). In the group of spontaneous abortion, 22 cases revealed chromosomal anomaly, all of which were diagnosed with Turner syndrome. In 6 of 10 cases (60%) diagnosed with Klinefelter syndrome, the initial indication was advanced maternal age. In two cases (100%) diagnosed with Trisomy X and mosaic Trisomy X, the initial indication was advanced maternal age (Table 2).

Table 1.

Sex Chromosome Abnormalities in Prenatal Diagnosis

Diagnosis	No. of cases	%
Turner syndrome	36	60
Klinefelter syndrome	10	16.6
Mosaic Turner syndrome	7	11.6
Mosaic Klinefelter syndrome	2	3.3
47,XYY	2	3.3
Trisomy X	1	1.6
Mosaic trisomy X	1	1.6
inv(Y)	1	1.6
Total	60	100

Table 2.

Distribution of Sex Chromosome Abnormalities According to the Indications for Prenatal Diagnosis

Indication	Turner syndrome n (%)	Klinefelter syndrome n (%)	Mosaic Turner syndrome n (%)	Mosaic Klinefelter syndrome n (%)	47,XYY n (%)	Trisomy X n (%)	Mosaic Trisomy X n (%)	Inv(Y) n (%)
AMA	2 (5.5)	6 (60)	2 (28.5)	1 (50)	—	1 (100)	1 (100)	—
HRRPBST	1 (2.7)	2 (20)	3 (42.8)	1 (50)	1 (50)	—	—	1 (100)
AFU	3 (8.3)	2 (20)	1 (14.2)	—	1 (50)	—	—	—
Cystic hygroma	8 (22.2)	—	1 (14.2)	—	—	—	—	—
Spontaneous abortion	22 (61.1)	—	—	—	—	—	—	—
Total	36 (100)	10 (100)	7 (100)	2 (100)	2 (100)	1 (100)	1 (100)	1 (100)

AMA, advanced maternal age; HRRPBST, high-risk result in prenatal biochemical screening tests; AFU, abnormal finding in USG; USG, ultrasonography.

Fourteen families where prenatal diagnosis revealed SCA (Turner syndrome: seven; Klinefelter syndrome: five; mosaic Turner syndrome: two) were contacted by telephone to learn the pregnancy outcomes and two cases (14.3%) with prenatally diagnosed Turner syndrome and mosaic Turner syndrome had decided to continue their pregnancy.

Discussion

Prenatal karyotype analysis can be performed only using invasive methods. SCAs are the most commonly diagnosed chromosomal abnormalities in the prenatal period and live birth (Shaw et al., 2008). In our study, 60 of 7505 cases with prenatal diagnosis performed had SCA (0.80%) and this result is correlated with the literature (Berková et al., 2009). Turner syndrome was the most common SCA in the prenatal period (60%). The most common indication for Turner syndrome among all prenatal diagnostic tests except spontaneous abortions was cystic hygroma (22.2%). It was reported that the karyotype results of 38.8% of the cases diagnosed with cystic hygroma were compatible with Turner syndrome (Alpman et al., 2009). On the other hand, the most common SCA in live births were 47,XXX, 47,XXY, and 47,XYY. The most common chromosome aneuploidy is Turner syndrome in the prenatal period, and most of them result in miscarriages. The second most common SCA in this study was Klinefelter syndrome (16.6%). In the present study, the indication for prenatal diagnosis in 9 of 16 cases (56.2%) having trisomies was advanced maternal age, which is correlated with the increase in the incidence of trisomies in advanced maternal age.

As severe dysmorphic findings or mental retardation is not observed in 47,XXX and 47,XYY syndromes, they are often diagnosed in couples during prenatal diagnosis incidentally or when they apply to health services because of infertility (Liao and Li, 2008; Shaw et al., 2008). Therefore, it is difficult for the families with a fetus having a prenatally diagnosed SCA to make a decision on whether to terminate the pregnancy or not (Brun et al., 2004; Liao and Li, 2008). In our study, 2 of 14 families (14.3%) having a prenatal diagnosis with SCA had decided to continue their pregnancy. The reason for the first family was religious beliefs, and for the second, it was absence of mental retardation in Turner syndrome. Unfortunately, either we could not contact with the remaining families or they refused to join the study.

Genetic counseling is very important while making the decision of termination for families with SCAs detected in their fetuses. The management of pregnancy in case of SCAs may be related in part to genetic counseling strategy. It is a widely accepted rule that prenatal genetic counseling should be nondirective. Termination decision of the pregnancy with SCAs may depend on many factors such as the training of counselor, the presence or absence of mosaicism, type of SCA, year of diagnosis, and social and economic background of the country. Studies have shown that the rate of pregnancy termination after genetic counseling sessions given by the obstetricians is higher than those given by the geneticists or perinatologists (Kim et al., 2002; Clementi et al., 2006). Termination rates of fetuses with prenatally detected SCAs in various countries are summarized in Table 3 (Gravholt et al., 1996; Meschede et al., 1998; Christian et al., 2000; Sagi et al., 2001; Kim et al., 2002; Bojesen et al., 2003; Forrester and Merz, 2003; Brun et al., 2004; Mezei et al., 2004; Clementi et al., 2006; Liao and Li, 2008; Shaw et al., 2008; Balkan et al., 2010). Because of high population and relatively less health insurance coverage than Western countries, pregnancy termination rates are much higher in China than in any other country (Liao and Li, 2008). In our center, although all genetic counseling sessions are given by the medical geneticists, a relatively high rate of pregnancy termination was found. Balkan et al. (2010) from the southeast part of Turkey has reported a similar study evaluating the pregnancy outcomes of aneuploidies detected in the prenatal diagnosis. In that study, the rate of pregnancy termination in SCAs was 60%, which was less than the present study (85.7%). The difference in termination rates of the pregnancies with SCA in the same country is considered relatively small as both studies were based on a very small number of pregnancies. On the other hand, the major factor that may have affected the pregnancy outcomes between those two studies could be the regional differences. The Human Development Index (HDI) provides information about the differences between the different regions in a country (United Nations Development Programme. History of the Human Development Report, 1998). Southeast Anatolia, along with Middle East and Northeast Anatolia, has been reported as having the lowest index values in Turkey. Difference between the HDI values in two regions combined with some other confounding factors such as counselor expertise, specialization of genetic counselor, and standardization problems during the genetic counseling sessions in different centers may have caused the difference between the pregnancy termination rates. In Turkey, equalization of HDI all over the country and, as it has been stated by Balkan et al. (2010), legislation to reduce the differences in approaches between different regions and health centers regarding parental decision-making to terminate or continue a pregnancy are desperately needed. The limitation of our study is the low number of families contacted to learn the pregnancy outcomes. Therefore, further studies with larger series from different regions may be suggested to determine the termination rates in pregnancies with SCAs in Turkey.

Table 3.

Pregnancy Termination Rates After Prenatal Diagnosis of Sex Chromosome Aneuploidy

Authors	Country	45,X n (%)	47,XXY n (%)	47,XXX n (%)	47,XYY n (%)	Mosaic 45,X n (%)	Overall termination rate in sex chromosome abnormality n (%)
Liao and Li	China	18/18 (100)	16/16 (100)	5/5 (100)	1/2 (50)	—	40/41 (97.5)
Shaw et al.	Taiwan	4/4 (100)	4/12 (33.3)	5/13 (38.4)	2/7 (29)	—	15/36 (41.6)
Sagi et al.	Israel	5/5 (100)	17/20 (85)	4/6 (67)	6/8 (75)	—	32/39 (82)
Brun et al.	France	38/41 (93)	10/31 (32)	4/16 (25)	2/10 (20)	—	54/98 (55.1)
Gravholt et al.	Denmark	56/62 (90)	—	—	—	—	56/62 (90)
Christian et al.	Canada	6/7 (86)	21/24 (87)	17/26 (65)	3/15 (20)	7/11 (63.6)	54/83 (65)
Balkan et al.	Turkey	4/5 (80)	0/3 (0)	2/2 (100)	—	—	6/10 (60)
Mezei et al.	Budapest	13/18 (72)	13/18 (72)	2/7 (29)	2/5 (40)	4/18 (22)	34/66 (51.5)
Forrester and Merz	Hawaii	25/74 (33.8)	11/28 (39.2)	2/12 (16.6)	2/7 (28.5)	5/17 (29)	45/138 (32.6)
Bojesen et al.	Denmark	—	114/163 (70)	—	—	—	114/163 (70)
Meschede et al.	Germany	—	4/23 (17)	2/12 (17)	1/10 (19)	—	7/45 (15.5)
Kim et al.	Korea	—	3/6 (50)	2/4 (50)	0/1 (0)	2/4 (50)	7/15 (46.6)
Our study	Turkey	6/7 (85.7)	5/5 (100)	—	—	1/2 (50)	12/14 (85.7)
Average		175/241 (72.6)	218/349 (62.4)	45/103 (43.7)	19/65 (29.2)	19/52 (36.5)	476/810 (58.7)

In conclusion, the rate of SCAs combined with the pregnancy outcomes in West Turkey is similar to those reported from European countries. Further studies evaluating the effect of genetic counselors on pregnancy outcomes of those cases with SCAs need to be established.

Footnotes

Disclosure Statement

The authors declare that no conflicts of interest exist.

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