ORIGINAL ARTICLE

Double aneuploidy in a Turkish child: Down–Klinefelter syndrome

Ali Karaman1 and Esref Kabalar2

Departments of 1Genetics and 2Pathology, State Hospital, Erzurum, Turkey

ABSTRACT The occurrence of double aneuploidy in theone person is a relatively rare phenomenon. A 5-year-old child,the second-born of non-consanguineous parents, possessed anextra X chromosome in addition to trisomy 21. The proband’sparents and his brother showed normal karyotype. The pheno-typic characteristics of the child have been discussed in lightof the published reports on double aneuploidies of XXY andtrisomy 21.

Key Words: double aneuploidy, Down syndrome, Klinefeltersyndrome

INTRODUCTION

The occurrence of double aneuploidy, the existence of two chromo-somal abnormalities in the same person, is a relatively rare phe-nomenon. Double aneuploidy leading to trisomy and/or monosomyof two different chromosomes arises because of two meiotic non-disjunctional events. Both of these aneuploidies could have thesame or different parental origin (Lorda-Sanchez et al. 1991).Several cases of double aneuploidy of XXY and trisomy 21 havebeen published since the first report by Ford et al. (1959). Thisabnormality has been recently described in a pair of monozygotictwins (Iliopoulos et al. 2004). Both sibs of the proband showing48,XXY,+21 were found to exhibit trisomy 21 in yet another study(Al Awadi et al. 1998). Recently, Bianca et al. reported a case ofdouble aneuploidy mosaicism with Down–Klinefelter’s syndrome(2005). In another study, Zaki et al. observed two cases of Down–Turner and Down–Klinefelter syndromes (2005). The clinical fea-tures of a 5-year-old boy who exhibited karyotype 48,XXY,+21have been presented here.

CASE HISTORY

A 5-year-old male was referred for chromosomal analysis becauseof dysmorphic features suggestive of Down syndrome. He was thesecond child of an unrelated couple. The mother was 25 years oldand the father was 30 years old at the time of the child’s birth. Thecouple also has a healthy 8-year-old son. The child had an openfontanelle, microcephaly, flat occipital, slanting palpebral fissures,hypotelorism, low-set and malformed ears, an open mouth, hypo-tonia, short broad hands, and clinodactyly (Fig. 1, Table 1). He didnot have any abnormalities of internal organs. The child was bornfollowing a normal gestation and delivery.

CYTOGENETICS

Chromosomal analysis was carried out in the proband, parents andnormal sib. For routine cytogenetic analysis, 0.3 mL of peripheral

blood was incubated in complete lymphocyte culture medium(20% fetal calf serum in Roswell Park Memorial Institute-1640with 2.5% phytohemagglutinin and 2% l-glutamine and 1% pen-strept in anincubator at 37°C for 72 h [all the reagents were fromBiological Industries, Beit Haemek, Israel]). Metaphases were har-vested by adding colcemid for 60 min, followed by hypotonicpotassium chloride (0.075 m) (Merck, Darmstadt, Germany) treat-ment for 10 min and fixation, using standard 3:1 methanol-aceticfixative (Merck). Chromosome preparations were stained withGTG-banding. Chromosomal analysis of the proband revealed48,XXY,+21 (Figs 2,3) with no evidence of mosaicism. The paren-tal and normal sib’s karyotypes were found to be normal.

DISCUSSION

We report here a case of a 5-year-old boy with features typical ofDown syndrome and the karyotype 48,XXY,+21. Studies on theincidence of an XXY chromosome pattern among people withDown syndrome have revealed that this double aneuploidy mightbe more frequent than predicted by multiplying the frequenciesof the individual aneuploidy (Mikkelsen et al. 1976). Althoughthe causes of aneuploidy are not well-understood, it is known thatthe most common chromosomal mechanism is meiotic non-disjunction. This refers to the failure of a pair of chromosomes todisjoin properly during one of the two meiotic divisions, usuallyduring meiosis I. The consequences of non-disjunction duringmeiosis I and meiosis II are different. If the error occurs duringmeiosis I, the gamete with 24 chromosomes contains both thepaternal and maternal members of the pair. If it occurs duringmeiosis II, the gamete with the extra chromosome contains bothcopies of either the paternal or the maternal chromosome (Nuss-baum et al. 2001).

The cause of non-disjunction is uncertain. The most favoredexplanation is that of an aging effect on the primary oocyte whichcan remain in a state of suspended inactivity for up to 50 years.There is a well-documented association between advancing mater-nal age and increased incidence of Down syndrome. It is not knownhow or why advancing maternal age predisposes to non-disjunction.Research has shown that the absence of recombination in prophaseof meiosis I predisposes to subsequent non-disjunction. An alterna-tive explanation for the association of advancing maternal age withan increased risk of autosomal trisomy is that survival of trisomicembryos could be the result of an age-related reduction in ‘immu-nological’ competence (Robert et al. 1998). Most XXY cases couldarise from an error in paternal meiosis I and the remaining inmaternal meiosis I or II. On the other hand, trisomy 21 can originatein either of the divisions in both parents.

The present case and most of the published cases of 48,XXY,+21have shown features typical of Down syndrome alone. This canbe expected as features characteristic of Klinefelter syndrome arenot apparent until the postpubertal stage (Rajangam et al. 1996).

Correspondence: Ali Karaman, MD, Department of Genetics, State Hospi-tal, Erzurum Numune Hastanesi, 25240 Erzurum, Turkey. Email:alikaramandr@hotmail.com

Received 19 February 2007; revised and accepted 1 November 2007.

doi:10.1111/j.1741-4520.2007.00174.x Congenital Anomalies 2008; 48, 45–47 45

© 2007 The AuthorsJournal compilation © 2007 Japanese Teratology Society

Double aneuploidy involving both autosomal and sex chromosome-sis seldom described. Here we report the case of a child with adefinitive diagnosis of Down–klinefelter’s syndrome and we reviewthe relevant literature for this rare disorder.

REFERENCESAl Awadi SA, Naguib KK, Bastaki L et al. (1998) Down syndrome in

Kuwait: recurrent familial trisomy 21 in siblings. Downs Syndr Res Pract5: 131–137.

Bianca S, Indaco L, Ingegnosi C et al. (2005) Double aneuploidy mosaicismwith Down–Klinefelter’s syndrome. Eur J Med Gene 48: 75–76.

Ford CE, Jones KW, Miller OJ et al. (1959) The chromosomes in a patientshowing both mongolism and the Klinefelter syndrome. Lancet 1: 709–710.

Fig. 1 Child with Down–Klinefelter syndrome.

Fig. 2 Karyotype of the child with 48,XXY,+21. The long arrows indicatechromosomes X, the short arrows indicate chromosomes 21, andthe shortest arrow indicates chromosome Y.

Fig. 3 Complete karyotype of the child with Down–Klinefelter syndromeby GTG-banding.

Table 1 Phenotype and karyotype of the child with Down–Klinefelter syndrome

Phenotype Karyotype

Open fontanelle 48,XXY,+21

Microcephaly

Flat occipital

Slanting palpebral fissures

Hypotelorism

Low set and malformed ears

Open mouth

Short broad hand

Clinodactyly

Hypotonia

46 A. Karaman and E. Kabalar

© 2007 The AuthorsJournal compilation © 2007 Japanese Teratology Society

Iliopoulos D, Poultsides G, Peristeri V et al. (2004) A Double trisomy(48,XXY,+21) in monozygotic twins: case report and review of the lit-erature. Ann Genet 47: 95–98.

Lorda-Sanchez I, Petersen MB, Binkert F et al. (1991) A 48,XXY,+21Down syndrome patient with additional paternal X and maternal 21. HumGenet 87: 54–56.

Mikkelsen M, Fisher G, Stene J et al. (1976) Incidence study of Downsyndrome in Copenhagen, 1960–71: with chromosome investigation. AnnHum Genet 40: 177–182.

Nussbaum RL, Mclnnes RR, Willard HF (2001) Principles of clinical cyto-genetics. In: McInnes RR (eds). Thompson and Thompson Genetics

in Medicine, 6th edn. W.B. Saunders Company, Philadelphia, pp.140, 144.

Rajangam S, Verghese M, Tilak P, Thomas IM (1996) A 48,XXY,+21 –Down / Klinefelter Syndrome. J Clin Genet Tribal Res 2: 126–129.

Robert F, Mueller Ian D, Young (1998) Chromosomes. Emery’s Elements ofMedical Genetics, Tenth Edition. pp. 43, 45.

Zaki MS, Kamel AA, El-Ruby M (2005) Double aneuploidy in threeEgyptian patients: Down-Turner and Down–Klinefelter syndromes.Genetcouns 16: 393–402.

Child with Down–Klinefelter syndrome 47

© 2007 The AuthorsJournal compilation © 2007 Japanese Teratology Society