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Prenatal diagnosis of trisomy 20 mosaicism by maternal serum screening for Down syndrome
European Journal of Obstetrics & Gynecology and Reproductive Biology 86 (1999) 175–177
Original Article
Prenatal diagnosis of trisomy 20 mosaicism by maternal serum screening for Down syndrome Jen-Huang Chen, Te-Yao Hsu*, Chia-Yu Ou, Lih-Feng Chang, Shiuh-Young Chang, Yung-Kuei Soong Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung, Lin-Kou, Taiwan Received 30 November 1998; accepted 5 March 1999
Abstract We report two cases of prenatally diagnosed trisomy 20 mosaicism associated with positive Down syndrome screening at 16 weeks’ gestation. Both infants exhibited normal growth and mental development.These cases suggest that the multiple-marker screening test may play an important role in prenatal detection and diagnosis of chromosomal anomalies in addition to Down syndrome. 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Trisomy 20 mosaicism; Maternal serum screening; Prenatal diagnosis; Down syndrome
1. Introduction Prenatal diagnosis of trisomy 20 mosaicism through amniocentesis has been reported in many studies. Most affected fetuses show normal phenotypes; few have one or more birth defects, especially renal and cardiac anomalies. Trisomy 20 cells are found more frequently in extraembryonic tissues than in the fetus itself [1,2]. Multiple-marker screening for Down syndrome is now established in many countries. While positive results on maternal serum screening tests have been associated with several chromosomal abnormalities in addition to trisomy 21 [3–7], trisomy 20 mosaicism is seldom reported. Two cases of trisomy 20 mosaicism prenatally diagnosed through amniocentesis was found to be related with positive multiple-marker screening in our study. Both fetuses presented normal phenotypes at birth and good prognosis was noted at regular pediatric follow-up. Chromosomal studies revealed normal karyotypes in one fetus, but trisomy 20 cells were found in skin and placental *Corresponding author. Tel.: 1886-7-7317123; fax: 1886-7-7322915.
tissues of another. The results of our study indicated the need for detailed prenatal ultrasound examination and special counselling when trisomy 20 mosaicism is detected prenatally.
2. Case report
2.1. Case 1 A 25-year-old woman, gravida (G) 2, para (P)1, underwent amniocentesis at 18 weeks’ gestation due to a history of trisomy 21 in her first child. Previous chromosomal studies of this couple showed normal karyotypes in both and they were not consanguineous. Maternal serum screening for Down syndrome had been performed at 16 weeks’ gestation by ultrasound dating. It showed a risk of one in 49 pregnancies (Table 1). Cultured amniotic fluid cells were harvested on the 8th day and cytogenetic analysis revealed trisomy 20 mosaicism (Table 2). Detailed ultrasonography showed no obvious abnormality. After counselling, the pregnancy was continued to term. A male
0301-2115 / 99 / $ – see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0301-2115( 99 )00063-9
J. Chen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 86 (1999) 175 – 177
176
Table 1 Summary of maternal serum screening test results a
Case 1 Case 2
Maternal age (years)
MSAFP (MoM)
Free b-hCG (MoM)
Down syndrome risk b
25 40
0.67 2.12
3.82 2.03
1 in 49 pregnancies 1 in 170 pregnancies
a MSAFP, maternal serum alpha-fetal protein; b-hCG, beta human chorionic gonadotropin; MoM, multiple of the medium. b The risk was calculated from maternal age, MSAFP and free b-hCG levels.
infant with a grossly normal appearance and a body weight of 3950 g was delivered via cesarean section at 39 weeks’ gestation. The cytogenetic analysis of fetal cord blood, skin, and placental tissues revealed normal karyotypes (Table 2). Subsequent assessment of the child at regular pediatric follow-up for 1 year showed normal growth and mental development.
2.2. Case 2 A 40-year-old woman, G6P4, was referred for amniocentesis at 161 weeks’ gestation by ultrasound dating because of advanced maternal age. Maternal serum screening for Down syndrome performed at the same time showed a risk of one in 170 pregnancies (Table 1). Cytogenetic analysis of amniotic fluid cells harvested after 8 days of culture revealed mosaic trisomy 20 (Table 2). The family history was unremarkable and the couple was not consanguineous. No obvious abnormality other than intrauterine growth retardation (IUGR) was found in the fetus during detailed ultrasound examination. After counselling, the parents decided to continue this pregnancy. A female infant with normal appearance and a body weight of 2270 g was delivered at 40 weeks’ gestation (below the 5th percentile, as our data). Subsequent chromosomal studies revealed a karyotype of ‘47,XX, 120’ in skin and placental tissues and a normal karyotype in cord blood. The girl has exhibited normal growth and mental development during the first 2 years of pediatric follow-up.
3. Discussion Trisomy 20 mosaicism, with a reported incidence of nearly one in 7000 pregnancies [8–11], is a common
autosomal mosaicism found in amniotic cell cultures. It accounts for approximately 16% of cases of prenatally diagnosed chromosomal mosaicisms [1]. Hsu et al. reported that in most (90%) cases of prenatally diagnosed trisomy 20 mosaicism, children are born with grossly normal phenotypes and exhibit normal development; only about 10% have one or more serious birth defects [1]. Moreover, because the abnormalities found in affected fetuses are inconsistent and non-specific, no caused relationship between trisomy 20 mosaicism and a specific malformation syndrome can be established [1]. As of now, trisomy 20 mosaicism remains a problem for prenatal genetic counselling. There seems to be a relationship between the high percentage (.50%) of trisomy 20 cells among the amniotic fluid cultures and the risk of severe anomalies [1,12], and such a claim was used as a basis for genetic counselling. Subsequent reports, however, suggested it is inadvisable to use the percentage of trisomy 20 cells detected in the amniotic fluid to estimated the risk figure [2]. In our cases, the percentage of trisomy 20 cells among the amniotic fluid culture were 20% (8 / 40) in case 1 and 57.5% (23 / 40) in case 2. No abnormal somatic and psycho-motor development was found in case 1. But in case 2, IUGR was noted and trisomy 20 cells were found in skin and placental tissues. We speculate that the etiology of IUGR may correlate with this type of chromosomal mosaicism found in the placental tissue. While there may be insufficient evidence to verify the association of the presence of trisomy 20 cells in amniotic fluid with the frequency of severe anomalies, it can suggest that more effort and caution should be made for such cases with high percentage of trisomy 20 cells among the amniotic fluid cultures in prenatal evaluation and genetic counselling. Multiple-marker screening for Down syndrome, generally performed in the early second trimester, is now widely utilized in many parts of the world. The detection rate of this screening test has been reported to be greater than 60% [13]. In addition to trisomy 21, positive screening results seem to be associated with many other chromosomal abnormalities, such as Turner syndrome, Klinefelter syndrome, marker chromosome, and 18q deletion [3–7]. However, the detection of trisomy 20 mosaicism by this screening test is rarely reported: to the best of our knowledge, there has been only one previously reported case [5]. Given the incidence of trisomy 20 mosaicism (one in 7000 pregnancies), the widely used multiple-
Table 2 Summary of the cytogenetic studies Tissue Amniotic fluid cells Cord blood cells Skin fibroblasts Placental tissue
Case 1 (n, %) 46,XY
47,XY 120
Case 2 (n, %) 46,XX
47,XX 120
32 50 50 50
8 (20%) – – –
17 (42.5%) 50 (100%) – –
23 (57.5%) – 50 (100%) 50 (100%)
(80%) (100%) (100%) (100%)
J. Chen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 86 (1999) 175 – 177
marker screening throughout the world, and the rarity of detection of trisomy 20 mosaicism with this screening method, we believe that multiple-marker screening is not very sensitive for this type of chromosomal anomaly. Since many chromosomal anomalies could cause the abnormalities of fetuses and placentas, the production and secretion of screening markers (human chorionic gonadotropin, alpha-fetoprotein and unconjugated estriol) would be influenced to a level which may lead to the positive screening result [6,7,14,15]. Because trisomy 20 mosaicism is rarely associated with fetal anomalies and the aneuploid cells are seldom found in fetal and placental tissues, this chromosomal abnormality would not be expected to have a great impact on the levels of screening markers. This would account for the weak sensitivity of multiple-marker screening for trisomy 20 mosaicism. However, this is only our speculation and is based on limited data. Further studies with large numbers of cases are needed for evaluating the association of multiplemarker screening and trisomy 20 mosaicism.
References [1] Hsu LYF, Kaffe S, Perlis TE. Trisomy 20 mosaicism in prenatal diagnosis – a review and update. Prenat Diagn 1987;7:581–96. [2] Hsu LYF, Kaffe S, Perlis TE. A revisit of trisomy 20 mosaicism in prenatal diagnosis – an overview of 103 cases. Prenat Diagn 1991;11:7–15. [3] Wenstrom KD, Williamson RA, Grant SS. Detection of fetal Turner syndrome with multiple-marker screening. Am J Obstet Gynecol 1994;170:570–3. [4] Barnes-Kedar I, Amiel A, Maor O, Fejgin M. Elevated human chorionic gonadotropin levels in pregnancies with sex chromosome abnormalities. Am J Med Genet 1993;45:356–7.
177
[5] Benn PA, Horne D, Briganti S, Greenstein RM. Prenatal diagnosis of diverse chromosome abnormalities in a population of patients identified by triple-marker testing as screen positive for Down syndrome. Am J Obstet Gynecol 1995;173:496–501. [6] Chen CP, Chern SR, Liu FF, Jan SW, Lee CC, Chang YC, Yue CT. Prenatal diagnosis of a deletion of 18q in a fetus associated with multiple-marker screen positive result. Prenat Diagn 1997;6:571–6. [7] Saller DN, Canick JA, Schwartz S, Blitzer MG. Multiple-marker screening in pregnancies with hydropic and nonhydropic Turner syndrome. Am J Obstet Gynecol 1992;167:1021–4. [8] Tolmie JL, Ferguson-Smith ME, Gilmore D, Ferguson-Smith MA. Normal development in two six-year-old boys born after prenatal diagnosis of trisomy 20 mosaicism. Prenat Diagn 1987;7:597–601. [9] Bui TH, Iselius L, Lindsten J. The European collaborative study on prenatal diagnosis: mosaicism, pseudomosaicism and single abnormal cells in amniotic fluid cell cultures. Prenat Diagn 1984;4(Spec ISS):145–62. [10] Hsu LYF, Perlis TE. United states survey on chromosome mosaicism and pseudomosaicism in prenatal diagnosis. Prenat Diagn 1984;4(Spec ISS):97–130. [11] Worton RG, Stern RA. Canadian collaborative study of mosaicism in amniotic fluid cell cultures. Prenat Diagn 1984;4(Spec ISS):131– 44. [12] Djalali M, Steinbach P, Schwinger E, Schwanitz G, Tettenborn U, Wolf M. On the significance of true trisomy 20 mosaicism in amniotic fluid culture. Hum Genet 1985;69:321–6. [13] Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston P, Chard T, Haddow JE, Knight GJ, Palomaki GE, Canick JA. Maternal serum screening for Down’s syndrome in early pregnancy. Br Med J 1988;298:883–7. [14] Jauniaux E, Nicolaides KH, Nagy AM, Brizot M, Meuris S. Total amount of circulating human chorionic gonaotropin alpha and beta subunits in the first trimester trisomies 21 and 18. J Endocrinol 1996;148:27–31. [15] Newby D, Aitken DA, Crossley JA, Howatson AG, Macri JN, Connor JM. Biochemical markers of trisomy 21 and the pathophysiology of Down’s syndrome pregnancies. Prenat Diagn 1997;10:941–51.
Original Article
Prenatal diagnosis of trisomy 20 mosaicism by maternal serum screening for Down syndrome Jen-Huang Chen, Te-Yao Hsu*, Chia-Yu Ou, Lih-Feng Chang, Shiuh-Young Chang, Yung-Kuei Soong Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, 123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung, Lin-Kou, Taiwan Received 30 November 1998; accepted 5 March 1999
Abstract We report two cases of prenatally diagnosed trisomy 20 mosaicism associated with positive Down syndrome screening at 16 weeks’ gestation. Both infants exhibited normal growth and mental development.These cases suggest that the multiple-marker screening test may play an important role in prenatal detection and diagnosis of chromosomal anomalies in addition to Down syndrome. 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Trisomy 20 mosaicism; Maternal serum screening; Prenatal diagnosis; Down syndrome
1. Introduction Prenatal diagnosis of trisomy 20 mosaicism through amniocentesis has been reported in many studies. Most affected fetuses show normal phenotypes; few have one or more birth defects, especially renal and cardiac anomalies. Trisomy 20 cells are found more frequently in extraembryonic tissues than in the fetus itself [1,2]. Multiple-marker screening for Down syndrome is now established in many countries. While positive results on maternal serum screening tests have been associated with several chromosomal abnormalities in addition to trisomy 21 [3–7], trisomy 20 mosaicism is seldom reported. Two cases of trisomy 20 mosaicism prenatally diagnosed through amniocentesis was found to be related with positive multiple-marker screening in our study. Both fetuses presented normal phenotypes at birth and good prognosis was noted at regular pediatric follow-up. Chromosomal studies revealed normal karyotypes in one fetus, but trisomy 20 cells were found in skin and placental *Corresponding author. Tel.: 1886-7-7317123; fax: 1886-7-7322915.
tissues of another. The results of our study indicated the need for detailed prenatal ultrasound examination and special counselling when trisomy 20 mosaicism is detected prenatally.
2. Case report
2.1. Case 1 A 25-year-old woman, gravida (G) 2, para (P)1, underwent amniocentesis at 18 weeks’ gestation due to a history of trisomy 21 in her first child. Previous chromosomal studies of this couple showed normal karyotypes in both and they were not consanguineous. Maternal serum screening for Down syndrome had been performed at 16 weeks’ gestation by ultrasound dating. It showed a risk of one in 49 pregnancies (Table 1). Cultured amniotic fluid cells were harvested on the 8th day and cytogenetic analysis revealed trisomy 20 mosaicism (Table 2). Detailed ultrasonography showed no obvious abnormality. After counselling, the pregnancy was continued to term. A male
0301-2115 / 99 / $ – see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0301-2115( 99 )00063-9
J. Chen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 86 (1999) 175 – 177
176
Table 1 Summary of maternal serum screening test results a
Case 1 Case 2
Maternal age (years)
MSAFP (MoM)
Free b-hCG (MoM)
Down syndrome risk b
25 40
0.67 2.12
3.82 2.03
1 in 49 pregnancies 1 in 170 pregnancies
a MSAFP, maternal serum alpha-fetal protein; b-hCG, beta human chorionic gonadotropin; MoM, multiple of the medium. b The risk was calculated from maternal age, MSAFP and free b-hCG levels.
infant with a grossly normal appearance and a body weight of 3950 g was delivered via cesarean section at 39 weeks’ gestation. The cytogenetic analysis of fetal cord blood, skin, and placental tissues revealed normal karyotypes (Table 2). Subsequent assessment of the child at regular pediatric follow-up for 1 year showed normal growth and mental development.
2.2. Case 2 A 40-year-old woman, G6P4, was referred for amniocentesis at 161 weeks’ gestation by ultrasound dating because of advanced maternal age. Maternal serum screening for Down syndrome performed at the same time showed a risk of one in 170 pregnancies (Table 1). Cytogenetic analysis of amniotic fluid cells harvested after 8 days of culture revealed mosaic trisomy 20 (Table 2). The family history was unremarkable and the couple was not consanguineous. No obvious abnormality other than intrauterine growth retardation (IUGR) was found in the fetus during detailed ultrasound examination. After counselling, the parents decided to continue this pregnancy. A female infant with normal appearance and a body weight of 2270 g was delivered at 40 weeks’ gestation (below the 5th percentile, as our data). Subsequent chromosomal studies revealed a karyotype of ‘47,XX, 120’ in skin and placental tissues and a normal karyotype in cord blood. The girl has exhibited normal growth and mental development during the first 2 years of pediatric follow-up.
3. Discussion Trisomy 20 mosaicism, with a reported incidence of nearly one in 7000 pregnancies [8–11], is a common
autosomal mosaicism found in amniotic cell cultures. It accounts for approximately 16% of cases of prenatally diagnosed chromosomal mosaicisms [1]. Hsu et al. reported that in most (90%) cases of prenatally diagnosed trisomy 20 mosaicism, children are born with grossly normal phenotypes and exhibit normal development; only about 10% have one or more serious birth defects [1]. Moreover, because the abnormalities found in affected fetuses are inconsistent and non-specific, no caused relationship between trisomy 20 mosaicism and a specific malformation syndrome can be established [1]. As of now, trisomy 20 mosaicism remains a problem for prenatal genetic counselling. There seems to be a relationship between the high percentage (.50%) of trisomy 20 cells among the amniotic fluid cultures and the risk of severe anomalies [1,12], and such a claim was used as a basis for genetic counselling. Subsequent reports, however, suggested it is inadvisable to use the percentage of trisomy 20 cells detected in the amniotic fluid to estimated the risk figure [2]. In our cases, the percentage of trisomy 20 cells among the amniotic fluid culture were 20% (8 / 40) in case 1 and 57.5% (23 / 40) in case 2. No abnormal somatic and psycho-motor development was found in case 1. But in case 2, IUGR was noted and trisomy 20 cells were found in skin and placental tissues. We speculate that the etiology of IUGR may correlate with this type of chromosomal mosaicism found in the placental tissue. While there may be insufficient evidence to verify the association of the presence of trisomy 20 cells in amniotic fluid with the frequency of severe anomalies, it can suggest that more effort and caution should be made for such cases with high percentage of trisomy 20 cells among the amniotic fluid cultures in prenatal evaluation and genetic counselling. Multiple-marker screening for Down syndrome, generally performed in the early second trimester, is now widely utilized in many parts of the world. The detection rate of this screening test has been reported to be greater than 60% [13]. In addition to trisomy 21, positive screening results seem to be associated with many other chromosomal abnormalities, such as Turner syndrome, Klinefelter syndrome, marker chromosome, and 18q deletion [3–7]. However, the detection of trisomy 20 mosaicism by this screening test is rarely reported: to the best of our knowledge, there has been only one previously reported case [5]. Given the incidence of trisomy 20 mosaicism (one in 7000 pregnancies), the widely used multiple-
Table 2 Summary of the cytogenetic studies Tissue Amniotic fluid cells Cord blood cells Skin fibroblasts Placental tissue
Case 1 (n, %) 46,XY
47,XY 120
Case 2 (n, %) 46,XX
47,XX 120
32 50 50 50
8 (20%) – – –
17 (42.5%) 50 (100%) – –
23 (57.5%) – 50 (100%) 50 (100%)
(80%) (100%) (100%) (100%)
J. Chen et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 86 (1999) 175 – 177
marker screening throughout the world, and the rarity of detection of trisomy 20 mosaicism with this screening method, we believe that multiple-marker screening is not very sensitive for this type of chromosomal anomaly. Since many chromosomal anomalies could cause the abnormalities of fetuses and placentas, the production and secretion of screening markers (human chorionic gonadotropin, alpha-fetoprotein and unconjugated estriol) would be influenced to a level which may lead to the positive screening result [6,7,14,15]. Because trisomy 20 mosaicism is rarely associated with fetal anomalies and the aneuploid cells are seldom found in fetal and placental tissues, this chromosomal abnormality would not be expected to have a great impact on the levels of screening markers. This would account for the weak sensitivity of multiple-marker screening for trisomy 20 mosaicism. However, this is only our speculation and is based on limited data. Further studies with large numbers of cases are needed for evaluating the association of multiplemarker screening and trisomy 20 mosaicism.
References [1] Hsu LYF, Kaffe S, Perlis TE. Trisomy 20 mosaicism in prenatal diagnosis – a review and update. Prenat Diagn 1987;7:581–96. [2] Hsu LYF, Kaffe S, Perlis TE. A revisit of trisomy 20 mosaicism in prenatal diagnosis – an overview of 103 cases. Prenat Diagn 1991;11:7–15. [3] Wenstrom KD, Williamson RA, Grant SS. Detection of fetal Turner syndrome with multiple-marker screening. Am J Obstet Gynecol 1994;170:570–3. [4] Barnes-Kedar I, Amiel A, Maor O, Fejgin M. Elevated human chorionic gonadotropin levels in pregnancies with sex chromosome abnormalities. Am J Med Genet 1993;45:356–7.
177
[5] Benn PA, Horne D, Briganti S, Greenstein RM. Prenatal diagnosis of diverse chromosome abnormalities in a population of patients identified by triple-marker testing as screen positive for Down syndrome. Am J Obstet Gynecol 1995;173:496–501. [6] Chen CP, Chern SR, Liu FF, Jan SW, Lee CC, Chang YC, Yue CT. Prenatal diagnosis of a deletion of 18q in a fetus associated with multiple-marker screen positive result. Prenat Diagn 1997;6:571–6. [7] Saller DN, Canick JA, Schwartz S, Blitzer MG. Multiple-marker screening in pregnancies with hydropic and nonhydropic Turner syndrome. Am J Obstet Gynecol 1992;167:1021–4. [8] Tolmie JL, Ferguson-Smith ME, Gilmore D, Ferguson-Smith MA. Normal development in two six-year-old boys born after prenatal diagnosis of trisomy 20 mosaicism. Prenat Diagn 1987;7:597–601. [9] Bui TH, Iselius L, Lindsten J. The European collaborative study on prenatal diagnosis: mosaicism, pseudomosaicism and single abnormal cells in amniotic fluid cell cultures. Prenat Diagn 1984;4(Spec ISS):145–62. [10] Hsu LYF, Perlis TE. United states survey on chromosome mosaicism and pseudomosaicism in prenatal diagnosis. Prenat Diagn 1984;4(Spec ISS):97–130. [11] Worton RG, Stern RA. Canadian collaborative study of mosaicism in amniotic fluid cell cultures. Prenat Diagn 1984;4(Spec ISS):131– 44. [12] Djalali M, Steinbach P, Schwinger E, Schwanitz G, Tettenborn U, Wolf M. On the significance of true trisomy 20 mosaicism in amniotic fluid culture. Hum Genet 1985;69:321–6. [13] Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston P, Chard T, Haddow JE, Knight GJ, Palomaki GE, Canick JA. Maternal serum screening for Down’s syndrome in early pregnancy. Br Med J 1988;298:883–7. [14] Jauniaux E, Nicolaides KH, Nagy AM, Brizot M, Meuris S. Total amount of circulating human chorionic gonaotropin alpha and beta subunits in the first trimester trisomies 21 and 18. J Endocrinol 1996;148:27–31. [15] Newby D, Aitken DA, Crossley JA, Howatson AG, Macri JN, Connor JM. Biochemical markers of trisomy 21 and the pathophysiology of Down’s syndrome pregnancies. Prenat Diagn 1997;10:941–51.