Novel Insights from Clinical Practice Fetal Diagn Ther 2014;36:255–258 DOI: 10.1159/000355603
Received: April 14, 2013 Accepted after revision: September 10, 2013 Published online: December 20, 2013
Prenatal Diagnosis and Management of Monozygotic Twins Discordant for Turner Syndrome Chenyu Gou a, b Yu Gao a Baojiang Chen a Qun Fang a a
Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, and b Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
Established Facts • Monozygotic (MZ) twins discordant for Turner Syndrome are rare. • Clinical issues regarding prenatal diagnosis and management of heterokaryotypic MZ twins remain.
Novel Insights • The present cases add some new insights into the mechanism of the MZ twinning process and the discordance of Turner syndrome as well as optimizing the therapeutic schedule.
Key Words Monozygotic twins · Turner syndrome · Heterokaryotypia · Selective feticide
Abstract Discordance for Turner syndrome in monozygotic (MZ) twins, which is known as heterokaryotypia, is very rare in MZ pregnancies. The combined effect of idiochromosome loss due to an anaphase lag and the relocation of discordant blastomeres may trigger the twinning procedure and discordance of Turner syndrome. We present 2 cases of MZ
© 2013 S. Karger AG, Basel 1015–3837/13/0363–0255$38.00/0 E-Mail [email protected] www.karger.com/fdt
twins discordant for Turner syndrome that were diagnosed prenatally by ultrasound and cytogenetic studies (one fetus was 45,X and the other 46,XX). Both cases, which involved monochorionic (MC) diamniotic twins, underwent selective feticide and had favorable outcomes for the remaining twin. Ultrasound, amniocentesis of both sacs (dual amniocentesis) and zygosity determination are indispensable in diagnosing heterokaryotypia. Selective feticide is a treatment option in cases of heterokaryotypic MC diamniotic twins, and in our cases, it resulted in favorable outcomes for the remaining twin. © 2013 S. Karger AG, Basel
Qun Fang Fetal Medicine Center, Department of Obstetrics and Gynecology The First Affiliated Hospital of Sun Yat-Sen University 58 2nd Zhongshan Road, Guangzhou 510080 (PR China) E-Mail fang_qun @ 163.com
Introduction
In past decades, monozygotic (MZ) twins were considered identical in gender, genotype, phenotype, disease susceptibility and psychological character, while twins with discordant phenotypes were classified as dizygotic [1]. Heterokaryotypic MZ twins are rare, and only case reports exist in the literature [2, 3]. Prior to the availability of prenatal diagnosis, these cases were diagnosed postpartum. Over 99% of monochorionic (MC) twins are MZ, and they are at risk of complications such as twin-to-twin transfusion syndrome and unequal placental sharing which carries an increased risk for the demise of one or both twins, so MC twins gain more attention in clinical treatment than dichorionic (DC) MZ twins. Besides, with MC twins discordant for Turner syndrome, there is a risk of spontaneous demise of the affected twin. Studies have shown that the demise of one MC twin results in an increased risk of neurodevelopmental compromise in the remaining twin [4, 5]. As such, identifying and managing heterokaryotypia in MC MZ twins in the antenatal period is a significant clinical concern. We report on the prenatal diagnosis, management and outcome of two pairs of discordant MZ twins. In each pair, karyotyping confirmed that one female twin had Turner’s syndrome (45,X) and the co-twin was normal (46,XX).
sent for selective feticide, and the procedure was approved by the hospital Ethics Committee. The feticide was performed on twin A by bipolar cord coagulation at 19 weeks of gestation. The blood flow dynamics of twin B, including activity of the umbilical artery and MCA-PSV, normalized soon after the feticide and remained normal at the follow-up ultrasound examinations. The normal female infant was born at 39 weeks of gestation by vaginal delivery and weighed 3,350 g with a length of 49 cm at birth. The baby was 2 years old with normal development at the time of this report. Case 2 A 38-year-old woman pregnant by in vitro fertilization, gravida 2, para 0, had an ultrasound examination at 11 weeks of gestation. The sonographic result revealed MC diamniotic twins with the image of only one single placenta and absence of a ‘twin peak’. An enlarged nuchal translucency (6.9 mm) was shown in one twin. The patient was referred to our hospital at 16 weeks of gestation. Ultrasound examination showed fetal growth restriction, hygroma colli, pleural effusion, edema of the entire body and a single umbilical artery in twin A. No structural malformation was identified in twin B. Dual amniocentesis was performed immediately, and a karyotype analysis of amniotic fluid cells showed that the abnormal fetus (twin A) was 45,X and the normal co-twin (twin B) was 46,XX. The zygosity analysis indicated MZ twins with 16 identical polymorphic microsatellite markers. The MCA-PSV of twin B was 19.3 cm/s (1.0 MoM). The couple gave written consent for selective feticide, and approval was obtained from the Ethics Committee. The feticide was performed on twin A by radiofrequency ablation at 18 weeks of gestation. The blood flow dynamics of twin B remained normal at the subsequent ultrasound examinations. A normal female infant with a birth weight of 2,900 g and a length of 48 cm was born at 39 weeks of gestation by vaginal delivery. At the time of this report, the baby was 10 months old, and no difference was found when she was compared with age-matched children.
Case Reports Case 1 A 28-year-old Chinese woman, gravida 3, para 1, had conceived naturally. She had two previous pregnancies with a malformed fetus, but fetal chromosomal analysis was not performed on either pregnancy. The sonographic examination at 13 weeks of gestation showed a twin pregnancy and thin dividing membrane (‘T’ sign) in the presence of a single placenta, which revealed MC diamniotic twins. Sonographic images also showed cervical cystic hygroma in one twin. The patient was referred to our hospital at 17 weeks of gestation. Ultrasound revealed hygroma colli (40 mm), ascites and polyhydramnios in twin A, but no detectable malformations in twin B. Amniotic fluid was sampled separately from each amniotic cavity at 18 weeks of gestation. Twin A was confirmed to have Turner syndrome (45,X) by karyotype analysis, and twin B was a normal 46,XX fetus. Zygosity analysis indicated that the twins shared 16 identical microsatellite markers, which predicted MZ probability up to 99.99%. Five days after admission, ultrasound examination showed edema of the entire body of twin A. A color Doppler flow image showed absent end diastolic velocity of the fetal umbilical artery in both fetuses, and the middle cerebral artery peak systolic velocity (MCA-PSV) of twin B increased to 32.7 cm/s [1.36 multiples of the median (MoM)], which indicated that twin B was moderately anemic and at risk of intrauterine fetal death (IUFD). After extensive counseling, the couple gave written con-
256
Fetal Diagn Ther 2014;36:255–258 DOI: 10.1159/000355603
Discussion
MZ twins with discordant genders, Turner syndrome and other chromosomal abnormalities in one MZ fetus have been described occasionally [1–3]. The prevalence of heterokaryotypic MZ twins and MZ twins discordant for Turner syndrome remains unknown. This is in part due to several reasons, as described below. Firstly, incorrect identification of the zygosity of discordant twins may occur if the placenta or chorionicity is only investigated macroscopically. DC twinning was formerly defined as dizygotic without further confirmation, especially in DC twins with discordant phenotypes. Approximately 14% of DC twins are actually MZ twins [6], so some discordant DC twins may actually be MZ twins. Secondly, karyotype analysis and zygosity determination were unavailable in some cases. Some patients pregnant with abnormal twins terminated pregnancies without prenatal karyotyping and zygosity analysis. IUFD in Gou /Gao /Chen /Fang
Turner syndrome is reported to approach 99% in singletons [7]; some cases of a ‘vanished’ twin or IUFD of one twin may be the result of a nonviable chromosomal abnormality. The prevalence and developmental mechanism of MZ twins discordant for Turner syndrome remain unknown. Postzygotic nondisjunction is one theory of heterokaryotypic formation in MZ twins. Although postzygotic nondisjunction is a reasonable explanation for 45,X/47,XXX, 45,X/47,XXY mosaic or trisomy in discordant MZ twins, the pathogenesis may be more complicated if a pure 45,X or 45,X/46,XX or 45,X/46,XY twin is identified with a normal co-twin. Based on these two cases, the combined effect of idiochromosome loss due to anaphase lag and the ‘recognition and repulsion’ [8] of discordant blastomeres may be an important mechanism of the MZ twinning process and the discordance of Turner syndrome. Anaphase lag results when one or more chromatids are left in the cytoplasm during mitosis anaphase due to loss of spindle fibers. The chromatids left in the cytoplasm eventually degrade. As a result, the daughter cells become hypodiploid (monosomy). Abnormal chromosomes are more likely to be lost in mitosis. Abnormalities of chromosomes X, Y, 13, 18 and 21 are most commonly detected by fluorescence in situ hybridization. Uematsu et al. [7] reported that the majority of Turner syndrome patients are maternal X dominant in 45,X cells, which results from mitotic loss of abnormal paternal idiochromosomes. Idiochromosome loss in a few cells after fertilization in early embryology may trigger Turner syndrome discordant twinning. In our cases, some 46,XX cells might have lost idiochromosomes and mutated into 45,X cells, resulting in the formation of two recognizably discordant cell clones. Different cell clones relocate by cell recognition and repulsion and form heterokaryotypic embryos. The report of Zech et al. [9] on one heterokaryotypic MZ twin pair which originated from a 47,XXY zygote supports this theory. Twin A was female with karyotype 46,XX, while twin B was male with hypospadias and mosaic karyotype 46,XY/46,XX. The DNA analysis revealed that the twins inherited an identical maternal-origin chromosome X, and the second chromosome X of twin A and chromosome Y were derived from the father. Zech et al. [9] deduced that one colony of blastomeres lost the paternal chromosome X while the other colony lost chromosome Y, and the discordance triggered the twinning process. There are additional hypotheses about the mechanisms of heterokaryotypia in MZ twins, such as postzygotic nondisjunction, an apoptotic process within the in-
ner cell mass, erroneous mitosis after twinning and trisomic rescue [10]; however, direct evidence is required. Important clinical issues remain, such as the identification of heterokaryotypic MZ twin pregnancies. High risk factors, including parental chromosomal abnormality, advanced maternal age, difficult reproductive history and in vitro fertilization conception, should be carefully monitored in cases of confirmed MC twin pregnancy. Abnormal ultrasound findings such as enlarged nuchal translucency, cystic hygroma, fetal hydrops or discordant genders in MC twins should prompt consideration of chromosomal abnormalities such as Turner syndrome. The second issue concerns the diagnostic methods of heterokaryotypia in MZ twins. Amniocentesis of both sacs, also named ‘dual amniocentesis’, should be performed, and zygosity should be determined by DNA studies when discordant MZ twins are suspected [11]. Chorionic villus sampling may be inappropriate because approximately 75% of MZ twins share the same placenta or a fused placenta, and the karyotypes of placentas are not identical to the karyotypes of the fetuses [1]. It may not be feasible to karyotype fetal blood because blood most likely exchanges between MC twins through placental vascular anastomoses. Massively parallel sequencing of cell-free fetal DNA (cffDNA) in maternal plasma is evolving rapidly. cffDNA from MZ twins discordant for Turner syndrome is similar to a 45,X/46,XX or 45,X/46,XY mosaic singleton, because the 45,X cell line may be covered by cffDNA originating from 46,XX or 46,XY cells [12]. cffDNA testing may be a possible screening method for heterokaryotypic MZ twins, once its effectiveness for identifying mosaicism is improved [13]. Zygosity should be determined by DNA studies rather than by chorionicity. The third clinical issue concerns the prognosis of heterokaryotypic MZ twins diagnosed prenatally. The three treatment strategies are termination of the pregnancy, expectant management and selective feticide. Termination of the entire pregnancy (with loss of the normal fetus) is a straightforward strategy accompanied by ethical concerns and potential negative psychological effects on the prospective parents. Expectant management could be the choice of parents who accept the heterokaryotypic twins. Chromosomal abnormality in heterokaryotypic MZ twins is an indication for selective fetal reduction, associated with a 17% fetal loss rate after cord coagulation including iatrogenic preterm prelabor rupture of membranes, IUFD, miscarriage and prenatal death [14, 15]. Zygosity is important in the mechanism of heterokaryotypic twins, while chorionicity is critical for fetal outcome in twin
Monozygotic Twins Discordant for Turner Syndrome
Fetal Diagn Ther 2014;36:255–258 DOI: 10.1159/000355603
257
pregnancies. It is a thorny problem in MC heterokaryotypic twin management. If the abnormal fetus of the discordant MC twins dies spontaneously or is dying, as in the two presented cases, the co-twin may be thrust into acute hypovolemic ischemia by transplacental exsanguination, which may result in brain damage or double fetal death [16]. Bipolar cord coagulation and radiofrequency ablation are considered effective methods for fetal reduction. The two cases presented showed favorable outcomes of the normal fetuses after selective feticide. Ultrasound monitoring should be emphasized for assisting in optimizing the therapeutic schedule. The ultrasound indices should include amniotic fluid volume, growth rate and blood flow dynamics, such as Doppler velocimetry of the umbilical artery and MCA of both fetuses. MCA-PSV is the gold standard for noninvasive screening of fetal anemia. MCA-PSV >1.29 and >1.5 MoM reveal moderate and severe fetal anemia, respectively. Trieu et al. [17] reported that if MCA-PSV of the donor in twin-to-twin transfusion syndrome was above 1.5 MoM after laser treatment, the donor might be at a higher risk for IUFD within a week. Thus, MCA-PSV is vital to seize the moment for clinical intervention [17]. More information may be provided if the cardiac functions of both twins can be evaluated. In expectant man-
agement, the interval of ultrasound monitoring should be no more than 2 weeks. The first postfeticide ultrasound screening should be performed within 24 h to evaluate the condition of the surviving twin. The biweekly follow-up ultrasound is an indispensable part of postfeticide monitoring. The combination of idiochromosome loss and cell recognition and repulsion may be a cause of discordant Turner syndrome in MZ twins. Dual amniocentesis and zygote determination should be performed to diagnose heterokaryotypic MZ twins. Selective reduction seems to be a valuable treatment option for MC heterokaryotypic twins in cases in which the normal fetus is severely affected by the abnormal co-twin. Ultrasound is indispensable in diagnosing and monitoring heterokaryotypic MZ twins.
Acknowledgements This work was supported by the National Nature Science Foundation of China (Grant No. 8127075), the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20110171120065) and the Science and Technology Planning Project of Guangzhou, China (2012J4300085).
References 1 Nieuwint A, Van Zalen-Sprock R, Hummel P, et al: ‘Identical’ twins with discordant karyotypes. Prenat Diagn 1999;19:72–76. 2 Gilbert B, Yardin C, Briault S, et al: Prenatal diagnosis of female monozygotic twins discordant for Turner syndrome: implications for prenatal genetic counselling. Prenat Diagn 2002;22:697–702. 3 Kaplowitz PB, Bodurtha J, Brown J, et al: Monozygotic twins discordant for UllrichTurner syndrome. Am J Med Genet 1991;41: 78–82. 4 Ong SS, Zamora J, Khan KS, et al: Prognosis for the co-twin following single-twin death: a systematic review. BJOG 2006;113:992–998. 5 Fernandez-Miranda ML, Cruceyra BM, Rodriuez-Gonzalez R, et al: Twin pregnancy with intrauterine death of one fetus: maternal and neonatal outcome of surviving fetus (in Spanish). Ginecol Obstet Mex 2012; 80: 254– 262. 6 Carroll SG, Tyfield L, Reeve L, et al: Is zygosity or chorionicity the main determinant of fetal outcome in twin pregnancies? Am J Obstet Gynecol 2005;193:757–761.
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7 Uematsu A, Yorifuji T, Muroi J, et al: Parental origin of normal X chromosomes in Turner syndrome patients with various karyotypes: implications for the mechanism leading to generation of a 45,X karyotype. Am J Med Genet 2002;111:134–139. 8 Machin GA: Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. Am J Med Genet 1996;61:216–228. 9 Zech NH, Wisser J, Natalucci G, et al: Monochorionic-diamniotic twins discordant in gender from a naturally conceived pregnancy through postzygotic sex chromosome loss in a 47,XXY zygote. Prenat Diagn 2008;28:759– 763. 10 Bourthoumieu S, Yardin C, Terro F, et al: Monozygotic twins concordant for blood karyotype, but phenotypically discordant: a case of ‘mosaic chimerism’. Am J Med Genet A 2005;135:190–194. 11 Vink J, Wapner R, D’Alton ME: Prenatal diagnosis in twin gestations. Semin Perinatol 2012;36:169–174. 12 Rehder H, Schoner K, Kluge B, et al: Klinefelter twins presenting with discordant aneuploidies, acardia, forked umbilical cord and with different gonadal sex despite monozygosity. Prenat Diagn 2012;32:173–179.
Fetal Diagn Ther 2014;36:255–258 DOI: 10.1159/000355603
13 Jiang F, Ren J, Chen F, et al: Noninvasive Fetal Trisomy (NIFTY) test: an advanced noninvasive prenatal diagnosis methodology for fetal autosomal and sex chromosomal aneuploidies. BMC Med Genomics 2012;5:57. 14 Lewi L, Gratacos E, Ortibus E, et al: Pregnancy and infant outcome of 80 consecutive cord coagulations in complicated monochorionic multiple pregnancies. Am J Obstet Gynecol 2006;194:782–789. 15 Beck V, Lewi P, Gucciardo L, et al: Preterm prelabor rupture of membranes and fetal survival after minimally invasive fetal surgery: a systematic review of the literature. Fetal Diagn Ther 2012;31:1–9. 16 Evans MI, Lau TK: Making decisions when no good choices exist: delivery of the survivor after intrauterine death of the co-twin in monochorionic twin pregnancies. Fetal Diagn Ther 2010;28:191–195. 17 Trieu NT, Weingertner AS, Guerra F, et al: Evaluation of the measurement of the middle cerebral artery peak systolic velocity before and after placental laser coagulation in twinto-twin transfusion syndrome. Prenat Diagn 2012;32:127–130.
Gou /Gao /Chen /Fang
Copyright: S. Karger AG, Basel 2014. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Received: April 14, 2013 Accepted after revision: September 10, 2013 Published online: December 20, 2013
Prenatal Diagnosis and Management of Monozygotic Twins Discordant for Turner Syndrome Chenyu Gou a, b Yu Gao a Baojiang Chen a Qun Fang a a
Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, and b Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China
Established Facts • Monozygotic (MZ) twins discordant for Turner Syndrome are rare. • Clinical issues regarding prenatal diagnosis and management of heterokaryotypic MZ twins remain.
Novel Insights • The present cases add some new insights into the mechanism of the MZ twinning process and the discordance of Turner syndrome as well as optimizing the therapeutic schedule.
Key Words Monozygotic twins · Turner syndrome · Heterokaryotypia · Selective feticide
Abstract Discordance for Turner syndrome in monozygotic (MZ) twins, which is known as heterokaryotypia, is very rare in MZ pregnancies. The combined effect of idiochromosome loss due to an anaphase lag and the relocation of discordant blastomeres may trigger the twinning procedure and discordance of Turner syndrome. We present 2 cases of MZ
© 2013 S. Karger AG, Basel 1015–3837/13/0363–0255$38.00/0 E-Mail [email protected] www.karger.com/fdt
twins discordant for Turner syndrome that were diagnosed prenatally by ultrasound and cytogenetic studies (one fetus was 45,X and the other 46,XX). Both cases, which involved monochorionic (MC) diamniotic twins, underwent selective feticide and had favorable outcomes for the remaining twin. Ultrasound, amniocentesis of both sacs (dual amniocentesis) and zygosity determination are indispensable in diagnosing heterokaryotypia. Selective feticide is a treatment option in cases of heterokaryotypic MC diamniotic twins, and in our cases, it resulted in favorable outcomes for the remaining twin. © 2013 S. Karger AG, Basel
Qun Fang Fetal Medicine Center, Department of Obstetrics and Gynecology The First Affiliated Hospital of Sun Yat-Sen University 58 2nd Zhongshan Road, Guangzhou 510080 (PR China) E-Mail fang_qun @ 163.com
Introduction
In past decades, monozygotic (MZ) twins were considered identical in gender, genotype, phenotype, disease susceptibility and psychological character, while twins with discordant phenotypes were classified as dizygotic [1]. Heterokaryotypic MZ twins are rare, and only case reports exist in the literature [2, 3]. Prior to the availability of prenatal diagnosis, these cases were diagnosed postpartum. Over 99% of monochorionic (MC) twins are MZ, and they are at risk of complications such as twin-to-twin transfusion syndrome and unequal placental sharing which carries an increased risk for the demise of one or both twins, so MC twins gain more attention in clinical treatment than dichorionic (DC) MZ twins. Besides, with MC twins discordant for Turner syndrome, there is a risk of spontaneous demise of the affected twin. Studies have shown that the demise of one MC twin results in an increased risk of neurodevelopmental compromise in the remaining twin [4, 5]. As such, identifying and managing heterokaryotypia in MC MZ twins in the antenatal period is a significant clinical concern. We report on the prenatal diagnosis, management and outcome of two pairs of discordant MZ twins. In each pair, karyotyping confirmed that one female twin had Turner’s syndrome (45,X) and the co-twin was normal (46,XX).
sent for selective feticide, and the procedure was approved by the hospital Ethics Committee. The feticide was performed on twin A by bipolar cord coagulation at 19 weeks of gestation. The blood flow dynamics of twin B, including activity of the umbilical artery and MCA-PSV, normalized soon after the feticide and remained normal at the follow-up ultrasound examinations. The normal female infant was born at 39 weeks of gestation by vaginal delivery and weighed 3,350 g with a length of 49 cm at birth. The baby was 2 years old with normal development at the time of this report. Case 2 A 38-year-old woman pregnant by in vitro fertilization, gravida 2, para 0, had an ultrasound examination at 11 weeks of gestation. The sonographic result revealed MC diamniotic twins with the image of only one single placenta and absence of a ‘twin peak’. An enlarged nuchal translucency (6.9 mm) was shown in one twin. The patient was referred to our hospital at 16 weeks of gestation. Ultrasound examination showed fetal growth restriction, hygroma colli, pleural effusion, edema of the entire body and a single umbilical artery in twin A. No structural malformation was identified in twin B. Dual amniocentesis was performed immediately, and a karyotype analysis of amniotic fluid cells showed that the abnormal fetus (twin A) was 45,X and the normal co-twin (twin B) was 46,XX. The zygosity analysis indicated MZ twins with 16 identical polymorphic microsatellite markers. The MCA-PSV of twin B was 19.3 cm/s (1.0 MoM). The couple gave written consent for selective feticide, and approval was obtained from the Ethics Committee. The feticide was performed on twin A by radiofrequency ablation at 18 weeks of gestation. The blood flow dynamics of twin B remained normal at the subsequent ultrasound examinations. A normal female infant with a birth weight of 2,900 g and a length of 48 cm was born at 39 weeks of gestation by vaginal delivery. At the time of this report, the baby was 10 months old, and no difference was found when she was compared with age-matched children.
Case Reports Case 1 A 28-year-old Chinese woman, gravida 3, para 1, had conceived naturally. She had two previous pregnancies with a malformed fetus, but fetal chromosomal analysis was not performed on either pregnancy. The sonographic examination at 13 weeks of gestation showed a twin pregnancy and thin dividing membrane (‘T’ sign) in the presence of a single placenta, which revealed MC diamniotic twins. Sonographic images also showed cervical cystic hygroma in one twin. The patient was referred to our hospital at 17 weeks of gestation. Ultrasound revealed hygroma colli (40 mm), ascites and polyhydramnios in twin A, but no detectable malformations in twin B. Amniotic fluid was sampled separately from each amniotic cavity at 18 weeks of gestation. Twin A was confirmed to have Turner syndrome (45,X) by karyotype analysis, and twin B was a normal 46,XX fetus. Zygosity analysis indicated that the twins shared 16 identical microsatellite markers, which predicted MZ probability up to 99.99%. Five days after admission, ultrasound examination showed edema of the entire body of twin A. A color Doppler flow image showed absent end diastolic velocity of the fetal umbilical artery in both fetuses, and the middle cerebral artery peak systolic velocity (MCA-PSV) of twin B increased to 32.7 cm/s [1.36 multiples of the median (MoM)], which indicated that twin B was moderately anemic and at risk of intrauterine fetal death (IUFD). After extensive counseling, the couple gave written con-
256
Fetal Diagn Ther 2014;36:255–258 DOI: 10.1159/000355603
Discussion
MZ twins with discordant genders, Turner syndrome and other chromosomal abnormalities in one MZ fetus have been described occasionally [1–3]. The prevalence of heterokaryotypic MZ twins and MZ twins discordant for Turner syndrome remains unknown. This is in part due to several reasons, as described below. Firstly, incorrect identification of the zygosity of discordant twins may occur if the placenta or chorionicity is only investigated macroscopically. DC twinning was formerly defined as dizygotic without further confirmation, especially in DC twins with discordant phenotypes. Approximately 14% of DC twins are actually MZ twins [6], so some discordant DC twins may actually be MZ twins. Secondly, karyotype analysis and zygosity determination were unavailable in some cases. Some patients pregnant with abnormal twins terminated pregnancies without prenatal karyotyping and zygosity analysis. IUFD in Gou /Gao /Chen /Fang
Turner syndrome is reported to approach 99% in singletons [7]; some cases of a ‘vanished’ twin or IUFD of one twin may be the result of a nonviable chromosomal abnormality. The prevalence and developmental mechanism of MZ twins discordant for Turner syndrome remain unknown. Postzygotic nondisjunction is one theory of heterokaryotypic formation in MZ twins. Although postzygotic nondisjunction is a reasonable explanation for 45,X/47,XXX, 45,X/47,XXY mosaic or trisomy in discordant MZ twins, the pathogenesis may be more complicated if a pure 45,X or 45,X/46,XX or 45,X/46,XY twin is identified with a normal co-twin. Based on these two cases, the combined effect of idiochromosome loss due to anaphase lag and the ‘recognition and repulsion’ [8] of discordant blastomeres may be an important mechanism of the MZ twinning process and the discordance of Turner syndrome. Anaphase lag results when one or more chromatids are left in the cytoplasm during mitosis anaphase due to loss of spindle fibers. The chromatids left in the cytoplasm eventually degrade. As a result, the daughter cells become hypodiploid (monosomy). Abnormal chromosomes are more likely to be lost in mitosis. Abnormalities of chromosomes X, Y, 13, 18 and 21 are most commonly detected by fluorescence in situ hybridization. Uematsu et al. [7] reported that the majority of Turner syndrome patients are maternal X dominant in 45,X cells, which results from mitotic loss of abnormal paternal idiochromosomes. Idiochromosome loss in a few cells after fertilization in early embryology may trigger Turner syndrome discordant twinning. In our cases, some 46,XX cells might have lost idiochromosomes and mutated into 45,X cells, resulting in the formation of two recognizably discordant cell clones. Different cell clones relocate by cell recognition and repulsion and form heterokaryotypic embryos. The report of Zech et al. [9] on one heterokaryotypic MZ twin pair which originated from a 47,XXY zygote supports this theory. Twin A was female with karyotype 46,XX, while twin B was male with hypospadias and mosaic karyotype 46,XY/46,XX. The DNA analysis revealed that the twins inherited an identical maternal-origin chromosome X, and the second chromosome X of twin A and chromosome Y were derived from the father. Zech et al. [9] deduced that one colony of blastomeres lost the paternal chromosome X while the other colony lost chromosome Y, and the discordance triggered the twinning process. There are additional hypotheses about the mechanisms of heterokaryotypia in MZ twins, such as postzygotic nondisjunction, an apoptotic process within the in-
ner cell mass, erroneous mitosis after twinning and trisomic rescue [10]; however, direct evidence is required. Important clinical issues remain, such as the identification of heterokaryotypic MZ twin pregnancies. High risk factors, including parental chromosomal abnormality, advanced maternal age, difficult reproductive history and in vitro fertilization conception, should be carefully monitored in cases of confirmed MC twin pregnancy. Abnormal ultrasound findings such as enlarged nuchal translucency, cystic hygroma, fetal hydrops or discordant genders in MC twins should prompt consideration of chromosomal abnormalities such as Turner syndrome. The second issue concerns the diagnostic methods of heterokaryotypia in MZ twins. Amniocentesis of both sacs, also named ‘dual amniocentesis’, should be performed, and zygosity should be determined by DNA studies when discordant MZ twins are suspected [11]. Chorionic villus sampling may be inappropriate because approximately 75% of MZ twins share the same placenta or a fused placenta, and the karyotypes of placentas are not identical to the karyotypes of the fetuses [1]. It may not be feasible to karyotype fetal blood because blood most likely exchanges between MC twins through placental vascular anastomoses. Massively parallel sequencing of cell-free fetal DNA (cffDNA) in maternal plasma is evolving rapidly. cffDNA from MZ twins discordant for Turner syndrome is similar to a 45,X/46,XX or 45,X/46,XY mosaic singleton, because the 45,X cell line may be covered by cffDNA originating from 46,XX or 46,XY cells [12]. cffDNA testing may be a possible screening method for heterokaryotypic MZ twins, once its effectiveness for identifying mosaicism is improved [13]. Zygosity should be determined by DNA studies rather than by chorionicity. The third clinical issue concerns the prognosis of heterokaryotypic MZ twins diagnosed prenatally. The three treatment strategies are termination of the pregnancy, expectant management and selective feticide. Termination of the entire pregnancy (with loss of the normal fetus) is a straightforward strategy accompanied by ethical concerns and potential negative psychological effects on the prospective parents. Expectant management could be the choice of parents who accept the heterokaryotypic twins. Chromosomal abnormality in heterokaryotypic MZ twins is an indication for selective fetal reduction, associated with a 17% fetal loss rate after cord coagulation including iatrogenic preterm prelabor rupture of membranes, IUFD, miscarriage and prenatal death [14, 15]. Zygosity is important in the mechanism of heterokaryotypic twins, while chorionicity is critical for fetal outcome in twin
Monozygotic Twins Discordant for Turner Syndrome
Fetal Diagn Ther 2014;36:255–258 DOI: 10.1159/000355603
257
pregnancies. It is a thorny problem in MC heterokaryotypic twin management. If the abnormal fetus of the discordant MC twins dies spontaneously or is dying, as in the two presented cases, the co-twin may be thrust into acute hypovolemic ischemia by transplacental exsanguination, which may result in brain damage or double fetal death [16]. Bipolar cord coagulation and radiofrequency ablation are considered effective methods for fetal reduction. The two cases presented showed favorable outcomes of the normal fetuses after selective feticide. Ultrasound monitoring should be emphasized for assisting in optimizing the therapeutic schedule. The ultrasound indices should include amniotic fluid volume, growth rate and blood flow dynamics, such as Doppler velocimetry of the umbilical artery and MCA of both fetuses. MCA-PSV is the gold standard for noninvasive screening of fetal anemia. MCA-PSV >1.29 and >1.5 MoM reveal moderate and severe fetal anemia, respectively. Trieu et al. [17] reported that if MCA-PSV of the donor in twin-to-twin transfusion syndrome was above 1.5 MoM after laser treatment, the donor might be at a higher risk for IUFD within a week. Thus, MCA-PSV is vital to seize the moment for clinical intervention [17]. More information may be provided if the cardiac functions of both twins can be evaluated. In expectant man-
agement, the interval of ultrasound monitoring should be no more than 2 weeks. The first postfeticide ultrasound screening should be performed within 24 h to evaluate the condition of the surviving twin. The biweekly follow-up ultrasound is an indispensable part of postfeticide monitoring. The combination of idiochromosome loss and cell recognition and repulsion may be a cause of discordant Turner syndrome in MZ twins. Dual amniocentesis and zygote determination should be performed to diagnose heterokaryotypic MZ twins. Selective reduction seems to be a valuable treatment option for MC heterokaryotypic twins in cases in which the normal fetus is severely affected by the abnormal co-twin. Ultrasound is indispensable in diagnosing and monitoring heterokaryotypic MZ twins.
Acknowledgements This work was supported by the National Nature Science Foundation of China (Grant No. 8127075), the Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20110171120065) and the Science and Technology Planning Project of Guangzhou, China (2012J4300085).
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