Confined placental mosaicism of double trisomies 9 and 21: discrepancy between non-invasive prenatal testing, chorionic villus sampling and postnatal confirmation
Journal
Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology
Journal Volume
48
Journal Issue
2
Pages
251-253
Date Issued
2016
Author(s)
MING CHEN
Abstract
Confined placental mosaicism (CPM) is a prenatal condition of tissue-specific mosaicism in which a cytogenetic abnormality is confined to the placenta and is absent in the fetus1. Most CPM pregnancies are associated with good postnatal outcome but an impaired placenta may provide insufficient support for the pregnancy, leading to fetal complications such as intrauterine growth restriction (IUGR) or even intrauterine fetal demise (IUFD)2. Here we report an unusual case of a fetus with severe IUGR and oligohydramnios that was later diagnosed to have CPM of double trisomies 9 and 21, demonstrating the discrepancies between non-invasive prenatal testing (NIPT), chorionic villus sampling (CVS) and postnatal confirmation. A 40-year-old pregnant woman, gravida 2 para 1, was referred to our clinic at 32 weeks' gestation because of oligohydramnios and severe IUGR. Prior to this visit, she had received regular prenatal care in mainland China and the pregnancy had been uneventful until the third trimester. The patient opted for NIPT (NIFTY-Extended test; BGI, Shenzhen, China) instead of CVS and amniocentesis due to her advanced age. The risks of fetal trisomies 13, 18 and 21 were low but trisomy 9 was suspected. A detailed ultrasound examination found nearly no amniotic fluid and severe IUGR; estimated fetal weight was 699 g, corresponding to 24 + 2 weeks' gestation. As oligohydramnios made it difficult to identify fetal anatomy by ultrasound, magnetic resonance imaging (MRI) was performed subsequently. No significant anomaly was noted except oligohydramnios (Figure 1). Repeated NIPT with the genome-wide normalized score test3, performed by our laboratory, also indicated a high risk for trisomy 9 (P < 0.0001). Interphase fluorescence in-situ hybridization (FISH) on chromosomes 9, 13, 18 and 21 (Aquarius® Satellite CEP9 (D9Z1) probe set (Cytocell, Cambridge, UK) and AneuVysion® LSI 13/ CEP 18/ LSI 21 probe set (Abbott, IL, USA)) was then conducted on samples obtained from CVS, performed after genetic counseling was offered. Of 20 cells analyzed, trisomy 9 was detected in 100% (20/20) and trisomy 21 was detected in 35% (7/20) (ISCN nomenclature: nuc ish(RB1x2,D21S259/D21S341/D21S342x3)[7/20],(D9Z1x3),(D18Z1x2)[20]) (Figure 2a). Karyotyping of 50 fibroblasts from the cultured villi revealed full trisomy 9 but no trisomy 21 (i.e. 47,XX,+9) (Figure 2b). The parents elected to terminate the pregnancy at 32 + 4 weeks' gestation. An 800-g female fetus was aborted with grossly normal appearance except for a bulbous nose (Figure 2c). The family declined autopsy. Postnatal karyotyping of the umbilical cord blood (120 cells) and placenta (100 cells) gave results of 46,XX (Figure 2d) and 47,XX,+9, respectively. Analysis of the informative short tandem repeat (STR) markers of the fetus (cord blood) and both parents (blood) revealed no uniparental disomy (UPD) for chromosome 21 or 9. Because fetal tissue could not be analyzed, the discrepancy between the aneuploidy results from NIPT, CVS and placental karyotyping and the normal karyotype identified in the cord blood should be interpreted carefully. We considered that the most likely explanation in this case was CPM for trisomy 9 and mosaic trisomy 21, though fetal mosaicism of trisomy 9 or double trisomy cell lines cannot be excluded completely. The NIPT result of trisomy 9 was considered to originate from CPM since cell-free fetal DNA in the maternal blood is mostly of placental origin4. CPM of trisomy 9 is relatively rare but cases with maternal UPD of chromosome 9 related to CPM of trisomy 9 have been reported and characterized with features of facial dysmorphism, skeletal abnormalities, poor growth and neurodevelopmental impairment5, 6. Our study thus provides an unusual case in which CPM for trisomies 9 and 21 was associated with severe IUGR and oligohydramnios. These findings highlight the fact that caution should be taken when encountering trisomy from CVS, and detailed ultrasound, amniocentesis/cordocentesis and STR marker analysis should be performed to distinguish between true trisomy, mosaic trisomy, UPD due to fetoplacental chromosomal discrepancies or a CPM condition associated with adverse perinatal and obstetric outcomes. Our case also demonstrated an important example of a false-negative NIPT result for mosaic trisomy 21. This is unsurprising given the low level of mosaicism (35%). The fetal fraction of the cell-free DNA in this case was estimated as 13% by our in-house NIPT, and thus, theoretically, the fetal fraction of the trisomy-21 cells in the maternal plasma would be 4.6% (i.e. 13% × 35%), which is close to the lowest limit (4–5%) of the fetal fraction of cell-free DNA feasible for NIPT3. Similarly, the actual fraction of the fetal DNA in the maternal plasma may not reflect the percentage of the trisomy-21 cell line observed when karyotyping the villus samples, which can also lead to a negative NIPT result. In conclusion, as evidenced by the case presented here, clinicians should interpret aneuploidy results with great caution when a variety of prenatal diagnostic modalities are utilized and in which NIPT is included. H.-H. Cheng†#, G.-C. Ma‡§¶#, C.-C. Tsai†#, W.-J. Wu‡**, K.-C. Lan†, T.-Y. Hsu†, C.-W. Yang‡ and M. Chen*‡**††‡‡§§ †Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; ‡Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital; and Department of Genomic Science and Technology, Changhua Christian Hospital Healthcare System, Changhua, Taiwan; §Institute of Biochemistry, Microbiology and Immunology, Chung-Shan Medical University, Taichung, Taiwan; ¶Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan; **Department of Obstetrics and Gynecology, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan; ††Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan; ‡‡Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; §§Department of Life Science, Tunghai University, Taichung, Taiwan *Correspondence. (e-mail: mingchenmd@gmail.com; mchen_cch@yahoo.com)
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Type
journal article