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​Cihat Şen, ​Nicola Volpe

Cecilia Villain, Daniel Rolnik, M. Mar Gil

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First trimester diagnosis of an unusual case of double aneuploidy with karyotype 48,XXY,+18 (Klinefelter-Edwards syndromes)

Hakan Gölbaşı, Merve Saka Güvenç, Ceren Gölbaşı, İbrahim Ömeroğlu, Atalay Ekin

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First trimester diagnosis of an unusual case of double aneuploidy with karyotype 48,XXY,+18 (Klinefelter-Edwards syndromes). Perinatal Journal 2022;30(1):75-80 DOI: 10.2399/prn.22.0301003

Author(s) Information

Hakan Gölbaşı1,
Merve Saka Güvenç2,
Ceren Gölbaşı3,
İbrahim Ömeroğlu1,
Atalay Ekin1

  1. Department of Perinatology, Tepecik Training & Research Hospital, University of Health Sciences, İzmir, Turkey
  2. Department of Medical Genetics, Tepecik Training & Research Hospital, University of Health Sciences, İzmir, Turkey
  3. Department of Obstetrics & Gynecology, School of Medicine, İzmir Tınaztepe University, İzmir, Turkey

Hakan Gölbaşı, Department of Perinatology, Tepecik Training & Research Hospital, University of Health Sciences, İzmir, Turkey, [email protected]

Publication History

Manuscript Received: November 18, 2021

Manuscript Accepted: January 27, 2022

Earlyview Date: January 27, 2022

Publication date: April 05, 2022

Conflicts of Interest

Funding: This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with Ethical Standards: The authors stated that the standards regarding research and publication ethics, the Personal Data Protection Law and the copyright regulations applicable to intellectual and artistic works are complied with and there is no conflict of interest.

Double aneuploidy cases involving autosomal and sex chromosomes are very rare. Therefore, it is difficult to determine the clinical features and prognosis of these cases. In this case, a fetus with 48,XYY,+18 karyotype is presented.
Cystic hygroma, cleft lip and palate, and clubbed foot were detected in the prenatal ultrasonographic evaluation of a 31-year-old pregnant woman at 13 weeks of gestation. Chorionic villus sampling revealed double aneuploidy including Klinefelter and Edwards syndromes. The molecular result was consistent with the occurrence of nondisjunction error involving chromosome 18 in maternal meiosis I (mat MI) but the finding of the extra X chromosome could not be fully explained. Post-abortion fetal pathology specimen confirmed prenatal diagnosis.
Double aneuploidy cases may rarely present with structural anomalies due to maternal meiosis error, without advanced maternal age, as in this case.

Klinefelter, Edwards, trisomy 18, 48XXY, double aneuploidy, structural anomaly, meiosis nondisjunction, case report.

Autosomal trisomy is a genetic disorder that occurs as a result of nondisjunction in the maternal meiotic phase. Trisomy 13, 18 and 21 are the most commonly diagnosed types of autosomal trisomy. Sex chromosome trisomies such as XXX (triple X syndrome), XXY (Klinefelter syndrome) and XYY (XYY syndrome) are caused by parental meiotic nondisjunction or postzygotic nondisjunction. These chromosomal aberrations are seen very rarely as double aneuploidy with an incidence of less than 1 in 30,000 births.[1] Clinical features and prognosis are not well known in such cases, due to the scarce availability of follow-up data and the limited number of cases reported in the literature. In this case report, a prenatally diagnosed fetus with 48,XYY,+18 karyotype is presented.
Case Report
A 31-year-old, gravida 2, abort 1 woman was referred to the Perinatology Outpatient Clinic of Tepecik Training and Research Hospital due to fetal cystic hygroma at 13 weeks gestation. Prenatal ultrasonographic examination revealed cystic hygroma, cleft lip and palate, and clubfoot (Fig. 1). QF-PCR examination of chorionic villus sampling material detected the chromosome 18 markers as 1:1:1 and 2:1. This result was compatible with Trisomy 18. QF-PCR result of the patient's sex chromosomes was also found to be consistent with XXY. Afterward, FISH analysis was performed on the chorionic villus sampling material, and probes related to chromosome 18 had 3 detected signals, probes related to chromosome X had 2 detected signals, and probes related to chromosome Y had 1 detected signal. These studies showed that the prenatal result is consistent with 48,XXY,+18 (Figs. 2 and 3). Chromosome analysis was performed from the mother and father's peripheral blood. Both of mother and father’s peripheral blood chromosomal analyses showed a normal karyotype. The molecular results, along with the 48,XXY,+18 karyotype, were compatible with the occurrence of nondisjunction error involving chromosome 18 in maternal meiosis I (mat MI) but the finding of the extra X chromosome could not be fully explained. Nondisjunction of XXY chromosome might be related to maternal meiosis 1 or maternal meiosis 2 (mat MI or MII) (Table 1). The parents opted for termination of pregnancy at 14 weeks of gestation. Images of the anatomic specimen were not available as termination was performed elsewhere. Post-abortion fetal pathology specimen evaluation confirmed prenatal diagnosis.
The present case was prenatally identified with two aneuploidies involving Klinefelter syndrome and trisomy 18 and ultrasound findings with cleft lip and palate, clubbed foot, and cystic hygroma. The occurrence of double aneuploidy in the same fetus is known to be an uncommon phenomenon. The first case with autosomal and sex chromosomal anomalies (48,XXY,+21) was presented by Ford et al. in 1959.[2] Since double aneuploidy cases usually result in abortion, there are few cases reported in the literature. Diego-Alvarez et al. reported the rate of double aneuploidy 2.18% among 321 karyotyped spontaneous abortions between 4 and 24 weeks of gestation.[3] However, the expected frequency of double aneuploidy among very early spontaneous abortions is thought to be higher than the observed one. Therefore, the occurrence of clinically undetected pregnancy losses might be the main reason of the scarcity of data on such rare aneuploidies. Furthermore, advances in ultrasonographic devices and screening for aneuploidy over the years provide improvements in the prenatal diagnosis of these cases.
The most frequently reported double aneuploidies in live births involve sex chromosomes combined with either trisomy, 13, 18, or 21.[4] Thus far, a total of 16 case reports in the literature described the combination of trisomy 18 and Klinefelter syndrome. The diagnosis was made postnatally in most of the cases. Only four (%25) of these fetuses were diagnosed during the prenatal period (Table 2). Van Ravenswaaij-Arts et al. performed amniocentesis at 31 weeks of gestation, due to polyhydramnios and fetal growth retardation, bilateral cleft lip on ultrasound. The sample analyzed revealed a 48,XXY,+18 karyotype that was initially misinterpreted as pseudomosaicism.[5] Komwilaisak et al. reported a 33-week fetus with ultrasound findings of large for the date, single umbilical artery with the absence of the left umbilical artery, polyhydramnios, and fetal growth restriction. Karyotyping from the cordocentesis led to the diagnosis of 48,XXY/+18, which was confirmed after delivery of the fetus.[6] Begam et al. presented a case of 34 weeks with several markers of chromosomal anomalies including choroid plexus cyst, severe asymmetrical intrauterine growth restriction, strawberry-shaped head, micrognathia, cerebellar hypoplasia, membranous ventricular septal defect, bilateral clubfeet, clinodactyly, and pectus excavatum. Amniocentesis and cytogenetic analysis of their case revealed double aneuploidy of both trisomy 18 and Klinefelter syndrome, 48,XXY+18.[7] Chen et al. delivered a fetus at 22 weeks of gestation with clenched hands, arthrogryposis of the left wrist, aplasia of the left thumb, micrognathia, low-set ears, hypertelorism, rocker-bottom feet, and a normal penis. Cytogenetic analysis of cultured amniocytes revealed a karyotype of 48,XXY,+18.[8]
Taken together, infants or fetuses with a karyotype of 48,XXY,+18 may present typical abnormalities of trisomy 18 and Klinefelter syndrome. The most common findings were growth restriction, heart defects, micrognathia,[8] suggesting the clinical picture is dominated by the symptoms associated with trisomy 18. Among all prenatally detected cases, the diagnoses were possible in the second or third trimester of pregnancy. In literature, however, this is the first reported case of 48,XXY,+18 syndrome detected in the first trimester of pregnancy by chorion villus sampling. Most of the mentioned findings in previous cases were not present in our case due to the diagnosis in the early weeks of gestation. But it should also be kept in mind that some associated structural anomalies of 48,XXY,+18 syndrome could be demonstrated before routine mid-trimester anomaly scan.
It has been found that the extra chromosomes in double aneuploidy are almost always of maternal origin. Similarly, extra chromosomes in our case were originated from meiosis 1 for chromosome 18 and meiosis 1 and 2 for chromosome X. The most proposed explanation for the cause of nondisjunction was advanced maternal age. It has been demonstrated that maternal age in double trisomy cases is significantly higher than that for single trisomy cases.[9] In contrast to the literature, we did not find maternal age as a contributing factor for the development of nondisjunction.
There was great variation in neonatal survival of fetuses with a double aneuploidy. Hou reported a case with the longest survival. In his report, a male fetus was delivered at 39 weeks of gestation with growth restriction and multiple structural anomalies including VSD, PDA, PS, facial dysmorphism, micrognathia, microcephaly, single umbilical artery, congenital diaphragmatic hernia, left renal hypoplasia, right hydronephrosis, clenched hands, clinodactyly, inguinal hernia, high-arched palate, and cryptorchidism. Cytogenetic analysis of that case revealed double aneuploidy of both trisomy 18 and Klinefelter syndrome, 48,XXY+18, and remained alive up to 21 months. All other antenatally reported cases were terminated or resulted in neonatal death.[8]
In conclusion, we presented a rare case of double aneuploidy (48,XXY,+18) with cystic hygroma, cleft lip and palate, and clubfoot diagnosed at early weeks of gestation. In this case, extra chromosomes were of maternal origin but not associated with advanced maternal age. Therefore, the possibility of this rare chromosomal abnormality should be considered in the differential diagnosis of structural malformations in the first trimester of pregnancy even in the absence of advanced maternal age.
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  2. Ford CE, Jones KW, Miller OJ, Mittwoch U, Penrose LS, Ridler M, et al. The chromosomes in a patient showing both mongolism and the Klinefelter syndrome. Lancet 1959;1(7075):709–10. [PubMed] [CrossRef

  3. Diego-Alvarez D, Ramos-Corrales C, Garcia-Hoyos M, Bustamante-Aragones A, Cantalapiedra D, Diaz-Recasens J, et al. Double trisomy in spontaneous miscarriages: cytogenetic and molecular approach. Hum Reprod 2006;21:958–66. [PubMed] [CrossRef

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  5. van Ravenswaaij-Arts CM, Tuerlings JH, Van Heyst AF, Nijhuis JG, Niehof J, Smeets DF. Misinterpretation of trisomy 18 as a pseudomosaicism at third-trimester amniocentesis of a child with a mosaic 46,XY/47,XY, +3/48,XXY, +18 karyotype. Prenat Diagn 1997;17:375–9. [PubMed] [CrossRef

  6. Komwilaisak R, Ratanasiri T, Komwilaisak P, Luengwattanawanit S. Three-dimensional ultrasonographic findings of the rare chromosomal abnormality 48, XXY/+18: a case report. J Med Assoc Thai 2004;87:198–203. [PubMed

  7. Begam M, Bekdache GN, Murthy SK, Mirghani HM. Double aneuploidy of trisomy 18 and Klinefelter syndrome: prenatal diagnosis and perinatal outcome. J Perinat Med 2010;38:565–6. [PubMed] [CrossRef

  8. Chen CP, Chern SR, Chen CY, Wu PC, Chen LF, Pan CW, et al. Double aneuploidy with Edwards-Klinefelter syndromes (48,XXY,+18) of maternal origin: prenatal diagnosis and molecular cytogenetic characterization in a fetus with arthrogryposis of the left wrist and aplasia of the left thumb. Taiwan J Obstet Gynecol 2011;50:479–84. [PubMed] [CrossRef

  9. Li QY, Tsukishiro S, Nakagawa C, Tanemura M, Sugiura-Ogasawara M, Suzumori K, et al. Parental origin and cell stage of non-disjunction of double trisomy in spontaneous abortion. Congenit Anom (Kyoto) 2005;45:21–5. [PubMed] [CrossRef
Fig. 1.
Prenatal ultrasound findings at 14 weeks of gestation. (a) Cystic hygroma, (b) clubbed foot, (c) cleft lip and palate.
Fig. 2.
Positive quantitative fluorescent polymerase chain reaction results with extra short tandem repeat markers in 48,XXY,+18: Trisomy 18 is identified by a trisomic diallelic pattern for D18S978, D18S535, GATA178F11, and D18S976 (≥1.8) and a trisomic triallelic pattern for D18S386 (1:1:1). XXY is identified by a trisomic diallelic pattern for Amelogenin, T3:3X,XY2,ZFYX,T1:7X and XY3.
Fig. 3.
Interphase FISH analysis of direct chorionic villus sampling preparation demonstrating centromere-specific probe signals for chromosomes 18, X and Y. All 20 interphase cells analyzes contained two signals for X, one signal for Y and three signal for 18. These results are consistent with Klinefelter syndrome with Edwards syndrome.
Table 1.
Molecular analysis of 18 and X chromosomes with polymorphic markers. mat MI, maternal meiosis I nondisjunction error; mat MII, maternal meiosis II nondisjunction error.
Table 2.
Clinical findings of cases diagnosed with prenatal Edwards and Klinefelter (48,XXY,+18).