Prenatal Diagnosis of Turner Syndrome - Wiley Online Library

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Prenatal Diagnosis of Turner Syndrome Report on 69 Cases Csaba Papp, MD, Artur Beke, MD, Gabor Mezei, MD, Zsanett Szigeti, MD, Zoltán Bán, MD, Zoltan Papp, MD

Objective. This study was conducted to evaluate the diagnostic value of different sonographic signs of fetuses with Turner syndrome in the first and second trimesters of pregnancy. Methods. Between 1990 and 2004, Turner syndrome was found in 69 of 22,150 fetal karyotypings. Congenital anomalies detected by sonography were analyzed. Results. Of the 514 (2.3%; 514/22,150) chromosome aberrations that were diagnosed, 69 Turner syndrome cases were found (13.4%; 69/514). Twenty-four fetuses had a 45,X karyotype (34.8%), and 45 fetuses were mosaic (65.2%). Forty-seven fetuses (68.1%; 47/69) showed symptoms on sonography. A substantial proportion of fetuses with Turner syndrome showed early-onset signs that could be detected in the first trimester (29.8%;14/69). The most common findings with sonography were hygroma colli (26.1%; 18/69), fetal hydrops (11.6%; 8/69), cardiac defects (13%; 9/69), and increased nuchal translucency (13%; 9/69). Among heart defects, coarctation of the aorta was the most common (44.4% of all cardial defects). Soft markers were also detected with relatively high frequency (23.2%; 16/69). Conclusions. The diagnosis of severe Turner syndrome is possible in early pregnancy. A search for soft markers during secondtrimester sonography and extensive use of echocardiography may increase the detection rate of Turner syndrome. Key words: early pregnancy; echocardiography; prenatal sonography; Turner syndrome.

Abbreviations AC, amniocentesis; BGN, biglycan; CH, cystic hygroma; CHD, congenital heart defect; CPC, choroid plexus cyst; CS, chondroitin sulfate; CVS, chorionic villus sampling; NT, nuchal translucency

Received January 19, 2006, from the First Department of Obstetrics and Gynecology, Semmelweis University, Faculty of Medicine, Budapest, Hungary. Revision requested February 27, 2006. Revised manuscript accepted for publication March 5, 2006. Address correspondence to Csaba Papp, MD, First Department of Obstetrics and Gynecology, Semmelweis University, Faculty of Medicine, H1088 Budapest, Baross ut 27, Hungary. E-mail: [email protected]

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urner syndrome (or Ullrich-Turner syndrome) is the most common sex chromosome abnormality in female fetuses and is caused by a complete or partial X monosomy in some or all cells. Turner syndrome affects 1 in 2500 female live births,1 although only approximately 1% of fetuses with 45,X survive to term,2 and as many as 15% of spontaneous miscarriages have a 45,X karyotype.3 In approximately 50% of the cases, the affected individuals have a 45,X karyotype, whereas the others display various abnormalities of one of their sex chromosomes or may be mosaic.4 Turner syndrome is characterized by short stature, broad chest, nuchal skin folds or web neck anomaly (pterygium colli), and gonadal dysgenesis. Although some studies suggest that Turner syndrome can be identified by a multiple biochemical marker screening,5 the most useful tool in the prenatal diagnosis of Turner syndrome is sonography. Typical findings of Turner syndrome are nuchal cystic hygroma (CH), nonimmune hydrops, and renal and cardiac defects6; however, neither sonography nor maternal

© 2006 by the American Institute of Ultrasound in Medicine • J Ultrasound Med 2006; 25:711–717 • 0278-4297/06/$3.50


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serum screening should be considered diagnostic of Turner syndrome, and karyotype confirmation (either by amniocentesis [AC] or by chorionic villus sampling [CVS]) should be obligatory.7 The objective of this study was to evaluate the diagnostic value of different sonographic signs detectable in the first and second trimesters of fetuses with Turner syndrome in a relatively long series from a single institution.

Materials and Methods The genetic counseling database of the First Department of Obstetrics and Gynecology, Semmelweis University Faculty of Medicine, was reviewed during this study. Cytogenetic records of fetuses were collected between 1990 and 2004, and fetuses with karyotypically documented Turner syndrome were analyzed. During the study period, 22,150 fetal chromosome analyses were performed, and 514 (2.3%) chromosome abnormalities were found. Among them, 69 fetuses with Turner syndrome (13.4%; 69/514) were identified prenatally. Singleton fetuses, who had prenatal sonography between 10 and 22 weeks’ gestation in our institution, constituted the study population. Mothers were referred to our genetic counseling unit for various reasons: advanced maternal age, family history of genetic problems in previous pregnancies, “suspect” sonographic findings from other institutions, and abnormal triple test results. In this respect, our study population was not truly representative of the population with Turner syndrome as a whole. Cytogenetic evaluation of the fetuses was performed by either AC (79.7%; 55/69) or CVS (20.3%; 14/69), followed by amniotic cell culture (with AC) or the direct analysis method (with CVS). G- or R-banding was used, and karyotypes were described according to the International System for Human Cytogenetic Nomenclature.8 A minimum of 20 metaphases from at least 5 cultures were analyzed. Mosaicism was considered if we detected the same chromosomal defect in more than 2 cells in 2 different cultures. All sonographic examinations were performed by 3 sonographers and were further evaluated by 2 obstetricians with great experience in maternal-fetal medicine. Two ultrasound machines were used for the examinations: a Philips Medical Systems (Bothell, WA) Ultramark 9 HDI 3000 and a GE Healthcare (Milwaukee, WI) Voluson 730. The course of the examinations fol712

lowed the guidelines of the Hungarian Society of Ultrasound in Obstetrics and Gynecology and routinely targeted all structures of the fetus: head (brain and face), neck, thoracic cavity (4-chamber-view of the heart and cardiac outflow tracts), abdominal cavity, extremities (hands and feet), spine, long bones, and genitalia. All abnormalities of each organ were recorded. If a patient had more than 1 sonographic examination, only the results of the first examination were included in the analysis. To rule out any bias, the sonographic examinations were done before the results of the cytogenetic evaluations of the fetuses were revealed. We considered the following quantitative sonographic signs to be “abnormal”: nuchal translucency (NT) thickness greater than 6 mm (second trimester); NT thickness greater than 3 mm (first trimester); short femur or humerus less than 10th percentile; pyelectasis greater than 4 mm; and ventriculomegaly greater than 10 mm. The sensitivity of the sonographic examination and of the different markers in detecting Turner syndrome was determined by standard statistical methods with the Sigmastat 3.0 statistical package (SPSS Inc, Chicago, IL).

Results From our database, 69 fetuses with Turner syndrome were evaluated during the study period. Between 1990 and 2004, we performed 22,150 fetal karyotypings and found 514 (2.3%) chromosome abnormalities. Among them, 69 fetuses with Turner syndrome were identified prenatally (13.4%; 69/514). Fetal karyotypes were diagnosed by AC (79.7%; 55/69) or CVS (20.3%; 14/69) after detailed sonographic examinations. Table 1 shows the demographic data of the study population. Of the fetuses with Turner syndrome, the average maternal age was 28.1 years (range, 17–45 years). Interestingly, the average maternal age of the fetuses with a mosaic was 31.8 years (range, 17–45 years), whereas among the mothers of fetuses with 45,X, it was only 24.4 years (range, 17–44 years). The median gestational age at the time of the sonographic examination was 17.5 weeks (range, 10–22 weeks). The 45,X karyotype was found in 24 cases (34.8%; 24/69); the other 45 cases (65.2%; 45/69) were mosaics (Table 2). Forty-seven fetuses (68.1%; 47/69) showed symptoms on sonography (Table 3), whereas in J Ultrasound Med 2006; 25:711–717


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22 cases (31.9%; 22/69), no abnormalities were found. A substantial proportion of fetuses with Turner syndrome showed early-onset signs that could be detected in the first trimester (20.3%; 14/69). Of the 24 cases of the 45,X karyotype, 22 fetuses with Turner syndrome (91.7%; 22/24) had congenital abnormalities on sonography, and 2 cases were missed (8.3%; 2/24). (In both cases, genetic AC was performed because of advanced maternal age. The parents decided to terminate the pregnancies after learning the fetal karyotype. Autopsy results revealed fetal heart defects in both fetuses [1 with ventricular septal defects and 1 with tetralogy of Fallot].) Twenty of the mosaic Turner syndrome cases (44.4%; 20/45) were not detected by sonography, whereas 25 fetuses (55.6%; 25/45) showed anomalies. Among the congenital anomalies detected by sonography on fetuses with Turner syndrome, CH was the most frequently seen (26.1%; 18/69). Most CH cases were diagnosed in the second trimester (72%; 13/18). Hydrops was seen in 8 (11.6%) of the 69 cases, and ventriculomegaly (>10 mm) was detected in 3 cases (4.3%). Congenital heart defects (CHDs) were diagnosed by sonography in 9 (13%) of the 69 cases. Four aortic coarctations (44.4% of the cardial defects; 4/9), 2 ventricular septal defects (23.2%; 2/9), 2 tetralogy of Fallot (23.2%; 2/9), and 1 dilated right ventricle were among the heart defects of fetuses with Turner syndrome. We introduced fetal echocardiography in our institution in 1994. All of the cardiac defects were diagnosed after that year. In our series, 8 fetuses (11.6%; 8/69) had renal abnormalities (6 with pyelectasis and 2 with renal cysts). There were no detectable signs by sonography in 22 fetuses with Turner syndrome. Among these, 20 cases (90.9%; 20/22) were mosaic, and 2 (9.1%; 2/22) had the 45,X karyotype. Increased NT (>3 mm) was detected in 9 fetuses with Turner syndrome (13%; 9/69), all in the first trimester. Together with 5 cases of CH that also were diagnosed before the 13th week, 14 fetuses with Turner syndrome (20.3%; 14/69) were detected during the first trimester in our series. A short femur or humerus and choroid plexus cyst (CPCs) were detected with a relatively high frequency (10.1% [7/69] and 8.7% [6/69], respectively). Echogenic bowel and echogenic intracardial focus were seen on sonography in 2 (2.9%) fetuses and 1 (1.4%) fetus, respectively. J Ultrasound Med 2006; 25:711–717

Table 1. Demographic Characteristics of the Study Population Characteristic

Value

Mean maternal age, y (range) Mean maternal age of mosaics Mean maternal age of 45,X karyotypes Mean gestational age at sonography, wk (range) Indication for referral, % Advanced maternal age Abnormal serum screening Previous affected child Suspected fetal anatomy Other

28.1 (17–45) 31.8 (18–45) 24.4 (17–44) 17.5 (10–22) 34.8 26.1 18.8 7.2 13.0

Discussion From the database of our prenatal diagnostic unit, we selected a population of 69 Turner syndrome cases from the 514 chromosomal abnormalities that we diagnosed between 1990 and 2004. The frequency of this syndrome was 13.4% (69/514), which is similar to the findings of Nicolaides et al9 and Hume et al,10 who reported a 12.6% and 12.2% incidence, respectively, of Turner syndrome among chromosomal abnormalities. Congenital

Table 2. Karyotypes of Fetuses With Turner Syndrome Karyotype

45,X 45,X/46,XX 45,X/46,X,del(X)(q21) 45,X/46,X,del(X)(q23)

No. of Cases (%)

24 43 1 1

(34.8) (62.2) (1.5) (1.5)

Table 3. Fetal Congenital Anomalies in Turner Syndrome Cases Anomaly

Hygroma colli Edema/hydrops fetalis NT (>3 mm) Ventriculomegaly (>10 mm) Cardial defects Coarctation of aorta Ventricular septal defects Tetralogy of Fallot Dilated right ventricle Renal abnormalities Short femur (3 mm; 5 cases, CH). Of the 9 cases of increased NT, the nuchal thickness was 4.5 mm or greater in 8 cases (89%). This concurs with the recent data of Kagan et al,16 who found that the distribution of NT is different for each type of chromosomal defect, and, in fetuses with Turner syndrome, the nuchal thickness was 4.5 mm or greater in 90% of the cases. The difference in the appearance of NT in each chromosomal defect may reflect the heterogeneity of causes leading to the abnormal accumulation of subcutaneous fluid in the nuchal region of the fetus. Possible mechanisms of this early-onset fluid collection of fetuses with Turner syndrome include abnormalities of the great arteries of the heart, abnormal development of the lymphatic system, and abnormal composition of the extracellular matrix of different tissues.17–19 All of these

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mechanisms could be explained by the cytogenetic characteristics of Turner syndrome, as discussed below. It is known that proteoglycans are important components of connective tissues. These molecules are able to bind large amounts of water, thus swelling and resisting compression. Another important feature of many of the glycoproteins is their ability to interact with cells, other matrix proteins, and growth factors. These adhesive glycoproteins have the ability to influence cell behavior by affecting the attachment and migration of cells.20 von Kaisenberg et al21 reported that in the nuchal skin of fetuses with Turner syndrome, proteoglycan expression is substantially different from normal in the first trimester of pregnancy. The expression of chondroitin sulfates (CS-6 and CS-4) are increased, whereas biglycan (BGN) is underexpressed. Altered CS proteoglycan levels, and thus an abnormal consistency of extracellular matrix, can influence the cell migration of neural crest cells (which form the aortic arch) and cells that form blood and lymphatic vessels.22,23 This might be an explanation for lymphatic vessel hypoplasia and for a narrow aortic arch (with a consequential increase of impedance to flow in the aorta and overperfusion of the head and neck) in fetuses with Turner syndrome, resulting in large edemas in the nuchal region as early as the first trimester. The small proteoglycan BGN is encoded by the X chromosome; the BGN gene has been mapped to chromosome Xq27-q28.24 Because in Turner syndrome there is only 1 regulator gene acting on the BGN gene site, BGN messenger RNA and protein expression is reduced by 50% compared with the normal female or normal male (there is 1 regulator gene on the Y chromosome as well) karyotype.25 Biglycan is expressed in a range of tissues and cell types, including connective tissue, human skin, the cell surface of differentiating keratinocytes, and growing bone,26 and it is even located in the aorta. The clinical consequences of the underexpression of BGN in fetuses with Turner syndrome are as follows: decreased long bone growth, which causes the small stature of individuals with Turner syndrome; and low expression in the aorta, which causes extreme narrowing of the aortic isthmus with coarctation of the aorta at birth, a common finding in fetuses with Turner syndrome. As a

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consequence of the narrow aortic arch, increased impedance to flow in the aorta may occur, and the overperfusion of the neck may lead to edemas in the nuchal region of the fetus.21 Interestingly, the fetal karyotype was 45,X in all of our early-onset cases with nuchal edema, supporting the theory that underregulation of the BGN gene and underexpression of BGN play pivotal roles in the pathomechanisms of the symptoms of severe Turner syndrome. Congenital heart defects were diagnosed in 13% (9/69) of fetuses with Turner syndrome. The incidence of CHDs in our series was somewhat lower than what other studies have reported, which is between 20%27 and 40%.11 Nevertheless, Baena et al14 reported a 10.4% incidence of CHD among fetuses with Turner syndrome, according to the data of 19 European registries. One possible explanation of our relatively low incidence of CHD can be that we did not have fetal echocardiography among our prenatal diagnostic options from the beginning of the study period. Echocardiography became part of our prenatal diagnostic services in 1994. As a consequence, some cases of CHD remained undetected during the first years of our study (between 1990 and 1994). Another possible reason for this low incidence of CHD in our study might be that 14 cases were diagnosed in the first trimester, and at that gestational age, the fetal heart cannot be visualized properly with sonography. Among CHDs, coarctation of the aorta was the most common (44.5%; 4/9). In all of the cases with coarctation, hygroma colli was also detected by sonography. This finding concurs with that of Clark,28 who reported an 8-fold higher incidence of coarctation of the aorta with a web neck (25%) versus a normal neck (3%). Because of the common association of hygroma colli and outflow tract heart defects, we do a careful search for CHD once we detect nuchal CH with a prenatal sonographic examination. We detected a somewhat higher than expected frequency of renal anomalies in our series (11.6%; 8/69). Fetal pyelectasis (>4 mm) was diagnosed in 6 cases, and 2 renal cysts were also detected. Although renal anomalies are recognized symptoms of Turner syndrome,11 they are sometimes difficult to diagnose. As a consequence, underestimation of the frequency may occur. In the study by Baena et al,14 some of the renal anomalies (18.2%) remained undetected


with sonography. We also detected 3 cases of fetal ventriculomegaly (4.3%; 4/69). This was an unexpected result, although not unprecedented.14 A short femur or humerus and CPC were detected with relatively high frequency (10.1% [7/69] and 8.7% [6/69], respectively). Echogenic bowel and echogenic intracardial focus were seen on sonography in 2 (2.9%) fetuses and in 1 (1.4%) fetus, respectively. The incidence of these markers in euploid fetuses is as follows: short femur, 5.2%29; CPC, 2%30; echogenic intracardial focus, 4.4%29; and echogenic bowel, 0.5%.31 These 4 symptoms belong to the group of “soft markers” or “minor anomalies” and are usually investigated in relation to autosomal aneuploidies, mainly trisomy 21. Interestingly, these markers were detected in our series rather frequently in fetuses with Turner syndrome (23.2%; 16/69). None of the findings were isolated; however, their importance is not negligible, and detection of them should prompt sonographers to consider the possibility of chromosomal defects and to look for other features of such defects. When considering the possible importance of a short femur and humerus in fetuses with Turner syndrome, one should keep in mind that one of the characteristics of this syndrome is short stature (other signs are broad chest, nuchal skin folds or web neck anomaly [pterygium colli], and gonadal dysgenesis). The wide range of somatic features of Turner syndrome indicates that a number of different X-located genes are responsible for the complete phenotype. A major part of short stature in Turner syndrome could be explained by the haploinsufficiency of a critical chromosomal region (distal of Xp22.2) in which the short stature homeobox (SHOX) gene resides and which escapes inactivation.32 During human embryogenesis, the SHOX gene is expressed predominantly in the limbs.33 The ubiquitin-specific peptidase 9 X chromosome (USP9X) gene is one of the candidate genes for the “Turner syndrome gonadal dysgenesis” gene, whereas the diaphanous homolog 2 (DIAPH2) gene (located at Xq22) is required for normal ovarian function.34 We conclude that severe forms of Turner syndrome can be diagnosed in early pregnancy with sonography. A search for soft markers on the second-trimester sonographic examination and extensive use of echocardiography increase the detection rate of Turner syndrome.

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