Case report

Double trisomy (48,XXY,+21) in monozygotictwins: case report and review of the literature

Dimitrios Iliopoulos a,*, George Poultsides b, Vasiliki Peristeri c,Georgia Kouri a, Alexandros Andreou c, Nikolaos Voyiatzis a

a Laboratory of Cytogenetics, 2nd Department of Pediatrics, A.H.E.P.A. Hospital, School of Medicine,Aristotelian University of Thessaloniki, Thessaloniki, Greeceb School of Medicine, University of Athens, Athens, Greece

c Department of Neonatology, Hippocratic Hospital, Thessaloniki, Greece

Received 7 May 2003; accepted 21 August 2003

Abstract

The occurrence of double aneuploidy in the same individual is a relatively rare phenomenon. Wedescribe twin newborns with typical clinical features of Down’s syndrome, of which one revealed48,XXY,+21 GTG-band karyotype. The second newborn died 2 days after its birth, and was clinicallydiagnosed having Down syndrome. Due to the same clinical features of the twins, the commonplacenta and amniotic sac, we speculate that they were monozygotics and as a result the secondnewborn should also be a Klinefelter. The purpose of this report is to present a rare case of possiblecoincidence of double aneuploidy in newborn twins. A review of the literature showed that doubletrisomy (48,XXY,+21) in a twin newborn infant has never occurred.© 2003 Elsevier SAS. All rights reserved.

Keywords: Double aneuploidy; Down syndrome; Klinefelter syndrome; Meiotic non-disjunction

1. Introduction

Down syndrome is the most common chromosomal abnormality in humans with anincidence of one in 770 livebirths [13]. Although it is the most intensively studied humanchromosomal abnormality, little is known about its cause and only advanced maternal ageis confirmed as a risk factor. On the other hand, Klinefelter syndrome affects approximately

* Corresponding author.E-mail address: dimitrios.iliopoulos@jefferson.edu (D. Iliopoulos).

Annales de Génétique 47 (2004) 95–98

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© 2003 Elsevier SAS. All rights reserved.doi:10.1016/j.anngen.2003.08.025

one in 1000 newborn males, and is due to an extra X chromosome in two third of cases [11].Variant and mosaic karyotypes predominate for the rest of the cases. Phenotypic expressionof the syndrome varies with the number of X chromosomes and the degree of endocrino-logic dysfunction [8]. In 1959, the first case of double aneuploidy (48,XXY,+21) in thesame individual was reported. Since then, a number of cases have been described. We reportthe first case of monozygotic twins sharing a 48,XXY,+21 GTG band karyotype and aDown syndrome phenotype.

2. Case report

The infants were delivered by cesarean section, secondary to placenta previa, at28 weeks of gestation. They were monozygotic, sharing a common placenta and amnioticsac. The father was 42-year-old and unrelated to the mother, who was 43-years-old.Otherwise the couple also had a healthy 3.5-years-old son. The first infant developed mildrespiratory distress syndrome and died at 41 days of life due to respiratory infection. Birthweight was 1375 g, length 38 cm and head circumference 25 cm. The second infant expiredon the second day of life secondary to severe respiratory distress syndrome complicated bypneumothorax. Birth weight was 1240 g, length 38 cm and head circumference 26 cm.

Both infants had the clinical features of Down syndrome, which included a flat facialprofile, upslanted palpebral fissures, a flat nasal bridge with epicanthial folds, micrognathiaand microcephaly, low-set ears with downfolding ear lobes, brachydactyly with singlepalmar creases, and a short sternum (Fig. 1). Physical exam further revealed poor muscletone, joint hyperflexibility and a weak cry.

Chromosomal analysis was performed from peripheral blood samples using standardprocedures in the second day of their life. Sixty GTG-banded metaphases from PHA-stimulated peripheral blood lymphocytes demonstrated a karyotype of 48,XXY,+21(Fig. 2). The karyotypes from both parents were normal with no evidence of mosaicism.

Fig. 1. View of the face and body of the first infant (35-days-old) with karyotype 48,XXY,+21, reveals signs ofDown syndrome.

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3. Discussion

In 1959, Ford et al. [4] described the first case of double aneuploidy 48,XXY,+21. Otherdouble aneuploidies that are found frequently are 48,XXX,+21; 46,X,+21; 48,XXY,+18and 48,XYY,+18 [1,12]. Previous studies suggest that double (autosomal andX-chromosomal) aneuploidy might be more frequent than predicted by multiplying thefrequencies of the individual aneuploidies. This possibly increased frequency might beexplained by an individual tendency to non-disjunction [10].

We report a case of a twin newborn that revealed Down and Klinefelter syndromessimultaneously. The mother of the twins was 43-years-old and this is highly related to theextra 21 chromosome that both infants have. Maternal age is the only known risk factor forDown syndrome [3,5]. A previous study suggests that birth prevalence rates of Downsyndrome plotted by maternal age form a J-shaped curve, with women from 20 through24 years of age having the lowest prevalence rate (1/1400 births). For women 35-years-old,the rate is approximately 1/350 births and for women 45-years-old and older the rate risesto 1/25 births [6]. As much as 95% of Down syndrome is caused by trisomy 21, whichtypically results from non-disjunction during meiosis. Non-disjunction can occur duringmeiosis I (MI) when the chromosome pairs fail to separate or during meiosis II (MII) whenchromatids fail to separate. Lorda-Sanchez et al. [9] presented a 48,XXY,+21 patient withthe extra chromosome 21 derived from the mother and the meiotic error most probablyoccurring in MII. Overall, the mother contributes the extra chromosome in 85% and thefather in 15% of cases. At least 1% of the patients have mosaicism with normal and trisomy21 cell lines. In addition, in 4% of cases the child received the extra copy of chromosome21 from a parent who is a carrier of a balanced translocation-involving chromosome 21 orhas a de novo translocation [2].

Karyotype analysis of the first infant demonstrated that along with Down syndrome ithad an extra X chromosome. Klinefelter syndrome is one of the most common causes ofhypogonadism. Overall the birth incidence of 47,XXY is one in 1000 males with an

Fig. 2. GTG-banded karyotype of the patient. The patient’s karyotype reveals the presence of an additional 21 andX-chromosome (48,XXY,+21).

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increased risk at increased maternal age. The extra chromosome is of maternal origin in56% and parental in 44%. It usually arises by non-disjunction at either the first (36%) orsecond (10%) maternal meiotic division and rarely as a mitotic error after fertilization.About 15% are mosaic 46,XY/47,XXY [2]. In the aforementioned study by Lorda-Sanchezet al. [9] using DNA polymorphisms, it was shown that in a 48,XXY,+21 patient the extrachromosome X was the result of paternal first meiotic non-disjunction of X and Y. Otherstudies showed that almost 50% of the 47,XXY Klinefelter syndrome patients followpaternal first meiotic failure [7].

In this report we presented a rare case of possible coincidence of double aneuploidy innewborn twins and as we indicated previously, any similar case published, is not found. Theonly factor that seems responsible for this aneuploidy is the advanced maternal age. Agenetic control of meiosis in animals is verified by many different examples of meioticmutations that predispose to non-disjunction but has not been fully established in humans.It will be interesting in the future to define the different factors predisposing to non-disjunction in humans.

References

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