variant klinefelter syndrome 47,x,i(x)(q10),y and normal 46,xy karyotype in monozygotic adult twins

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ß 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:1906–1911 (2007) Clinical Report Variant Klinefelter Syndrome 47,X,i(X)(q10),Y and Normal 46,XY Karyotype in Monozygotic Adult Twins D. Stemkens, 1 F.J. Broekmans, 2 P.M.M. Kastrop, 2 R. Hochstenbach, 1 B.G. Smith, 1 and J.C. Giltay 1 * 1 Department of Biomedical Genetics, University Medical Center, Utrecht, The Netherlands 2 Department of Obstetrics, Gynecology and Neonatology, University Medical Center, Utrecht, The Netherlands Received 30 October 2006; Accepted 9 April 2007 Klinefelter syndrome (KS; 47, XXY) is characterized by increased body height, hypergonadotrophic hypogonadism, and infertility. We describe a patient with a variant KS (47,X,i(Xq),Y) who has a twin brother with a 46,XY karyotype. Molecular studies showed that the twins were monozygotic. The presence of an isochromosome Xq in one of two monozygotic twins allows precise investigation of its phenotypic effect. The patient was somewhat shorter (3.5 cm) and had a smaller volume of the testes (8 vs. 18 ml) as compared to his twin brother. Furthermore he had increased gonadotrophin levels and an extreme oligoasthe- noteratozoospermia (OAT). These data support the view that genes on Xp cause increased body height and genes on Xq cause infertility in KS. To our knowledge this is the first report on a heterokaryotypic monozygotic twin with a variant KS. ß 2007 Wiley-Liss, Inc. Key words: isochromosome Xq; Klinefelter syndrome; heterokaryotypic monozygosity; infertility; body height How to cite this article: Stemkens D, Broekmans FJ, Kastrop PMM, Hochstenbach R, Smith BG, Giltay JC. 2007. Variant Klinefelter syndrome 47,X,i(X)(q10),Y and normal 46,XY karyotype in monozygotic adult twins. Am J Med Genet Part A 143A:1906 – 1911. INTRODUCTION Klinefelter syndrome (KS) is the most common form of sex chromosomal aneuploidy. About 80% of cases are due to a supernumerary X-chromosome (47,XXY). The remaining 20% have 46,XY/47,XXY mosaicism, higher grade sex chromosomal aneu- ploidies (48,XXXY, 48,XXYY, 49,XXXXY) or structu- rally abnormal X-chromosomes such as 46,XX males with the SRY gene on one of the X-chromosomes [Nieschlag and Behre, 1997]. An example of a rare structural rearrangement is isochromosome Xq (47,X,i(Xq),Y), which is described in 17 patients with KS [Bleau et al., 1987; Arps et al., 1996]. Other rare variants are monozygotic (MZ) twins concordant for 47,XXY karyotype [Hatch and Moore, 1985; Schlegelberger et al., 1986; Fujii et al., 1999]. The most common features of KS are small testes, sparse body and facial hair, increased body height, gynecomastia, increased LH and FSH, low-normal level of testosterone, infertility, and lower intelli- gence level compared with their siblings [Bender et al., 1999; Aksglaede et al., 2006]. Patients with 46,XY/47,XXY mosaicism have fewer clinical symptoms with only some being subfertile. Patients with higher grade sex chromosomal aneuploidies have severe mental retardation and 46,XX males with the SRY gene have decreased body height compared to normal 46,XY males [Nieschlag and Behre, 1997]. Patients with isochromosome Xq have characteristic features of KS such as infertility and elevated plasma LH and FSH levels but they have normal to short body height and an intelligence level which may not be different from that of the general population [Arps et al., 1996]. Here we describe an unusual monozygotic twin, one of which has a 47,X,i(X)(q10),Y,9ph karyotype and the other has a normal 46,XY,9ph karyotype. This case provides an opportunity to study the effect of the isochromosome Xq on the phenotype in these monozygotic twin brothers with the same genetic background. CLINICAL REPORT A 30-year-old male (W.J.) visited the department for Reproductive Medicine of University Medical *Correspondence to: J.C. Giltay, Department of Biomedical Genetics, KC04.084.2, University Medical Center, P.O. Box 85090, 3508 AB Utrecht, The Netherlands. E-mail: [email protected] DOI 10.1002/ajmg.a.31856

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Page 1: Variant Klinefelter syndrome 47,X,i(X)(q10),Y and normal 46,XY karyotype in monozygotic adult twins

� 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:1906–1911 (2007)

Clinical Report

Variant Klinefelter Syndrome 47,X,i(X)(q10),Y andNormal 46,XY Karyotype in Monozygotic Adult Twins

D. Stemkens,1 F.J. Broekmans,2 P.M.M. Kastrop,2 R. Hochstenbach,1 B.G. Smith,1 and J.C. Giltay1*1Department of Biomedical Genetics, University Medical Center, Utrecht, The Netherlands

2Department of Obstetrics, Gynecology and Neonatology, University Medical Center, Utrecht, The Netherlands

Received 30 October 2006; Accepted 9 April 2007

Klinefelter syndrome (KS; 47, XXY) is characterized byincreased body height, hypergonadotrophic hypogonadism,and infertility. We describe a patient with a variant KS(47,X,i(Xq),Y) who has a twin brother with a 46,XYkaryotype. Molecular studies showed that the twins weremonozygotic. The presence of an isochromosome Xq in oneof two monozygotic twins allows precise investigation of itsphenotypic effect. The patient was somewhat shorter(3.5 cm) and had a smaller volume of the testes (8 vs. 18ml) as compared to his twin brother. Furthermore he had

increased gonadotrophin levels and an extreme oligoasthe-noteratozoospermia (OAT). These data support the view thatgenes on Xp cause increased body height and genes on Xqcause infertility in KS. To our knowledge this is the firstreport on a heterokaryotypic monozygotic twin with avariant KS. � 2007 Wiley-Liss, Inc.

Key words: isochromosome Xq; Klinefelter syndrome;heterokaryotypic monozygosity; infertility; body height

How to cite this article: Stemkens D, Broekmans FJ, Kastrop PMM, Hochstenbach R, Smith BG,Giltay JC. 2007. Variant Klinefelter syndrome 47,X,i(X)(q10),Y and normal 46,XY karyotype in

monozygotic adult twins. Am J Med Genet Part A 143A:1906–1911.

INTRODUCTION

Klinefelter syndrome (KS) is the most commonform of sex chromosomal aneuploidy. About 80% ofcases are due to a supernumerary X-chromosome(47,XXY). The remaining 20% have 46,XY/47,XXYmosaicism, higher grade sex chromosomal aneu-ploidies (48,XXXY, 48,XXYY, 49,XXXXY) or structu-rally abnormal X-chromosomes such as 46,XX maleswith the SRY gene on one of the X-chromosomes[Nieschlag and Behre, 1997]. An example of a rarestructural rearrangement is isochromosome Xq(47,X,i(Xq),Y), which is described in 17 patients withKS [Bleau et al., 1987; Arps et al., 1996]. Other rarevariants are monozygotic (MZ) twins concordantfor 47,XXY karyotype [Hatch and Moore, 1985;Schlegelberger et al., 1986; Fujii et al., 1999]. Themost common features of KS are small testes,sparse body and facial hair, increased body height,gynecomastia, increased LH and FSH, low-normallevel of testosterone, infertility, and lower intelli-gence level compared with their siblings [Benderet al., 1999; Aksglaede et al., 2006]. Patientswith 46,XY/47,XXY mosaicism have fewer clinicalsymptoms with only some being subfertile. Patientswith higher grade sex chromosomal aneuploidies

have severe mental retardation and 46,XX males withthe SRY gene have decreased body height comparedto normal 46,XY males [Nieschlag and Behre, 1997].Patients with isochromosome Xq have characteristicfeatures of KS such as infertility and elevatedplasma LH and FSH levels but they have normal toshort body height and an intelligence level whichmay not be different from that of the generalpopulation [Arps et al., 1996]. Here we describe anunusual monozygotic twin, one of which has a47,X,i(X)(q10),Y,9ph karyotype and the other has anormal 46,XY,9ph karyotype. This case provides anopportunity to study the effect of the isochromosomeXq on the phenotype in these monozygotic twinbrothers with the same genetic background.

CLINICAL REPORT

A 30-year-old male (W.J.) visited the departmentfor Reproductive Medicine of University Medical

*Correspondence to: J.C. Giltay, Department of Biomedical Genetics,KC04.084.2, University Medical Center, P.O. Box 85090, 3508 AB Utrecht,The Netherlands. E-mail: [email protected]

DOI 10.1002/ajmg.a.31856

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Center Utrecht with his 25-year-old femalepartner because of primary infertility of 1 year’sduration. Routine investigations in the womanrevealed no abnormalities. The male partnerreported a history of body building exercises duringa total period of 3 years. Anabolic steroids had beenadministered until 5 years ago. Neither sexuallytransmitted disease, nor signs of maldescensus ofthe testes were reported. Alcohol consumptionwas 5 U per week and no regular medication wasused.

Physical examination revealed a healthy lookingmale with a normal male appearance, bodyheight 174.5 cm (�0.8 SD for age), sitting height89 cm (�0.4 SD for height), leg length 85.5 cm(þ0.97 SD for sitting height), arm span 178 cm(þ0.03 SD for height) and BMI 30 kg/m2 [Gerver andde Bruin, 1996]. There was a normal male pattern ofbody hair and he had no gynecomastia. Examinationof the abdomen showed no abnormalities. Examina-tion of the external genitalia revealed both testes tobe normally positioned, but on palpation had a weakconsistency and a volume of 8 ml (normal range 12–30 ml [Nieschlag and Behre, 1997]). There were noabnormalities of the epididymis and the vas deferens.Also no signs of a varicocele were found. Semenanalyses repeatedly showed an extreme oligoasthe-noteratozoospermia (OAT) with a total motile spermcount of 0.001 and0.02� 106. Increased levels of FSH(41.9 U/L, normal range 3–16 U/L) and LH (22.4 U/L,normal range 2–15 U/L) were found. Testosterone(15 nMol/L, normal range 10–35 nMol/L) andprolactin (0.27 U/L, normal range <0.5 U/L)were within the normal range. Magnetic resonanceimaging of the sella tursica revealed no abnormalitiesof the pituitary especially no signs of pituitaryadenomas.

Chromosomal analysis revealed a 47,X,i(X)(q10),Y,9ph karyotype. Fluorescent in situ hybridi-zation (FISH) showed two signals with a centromereX probe and one signal with a centromere Y probe in198 out of 200 cells. The remaining two cells showedone signal of each probe. This result is compatiblewith a non-mozaic 47,X,i(X)(q10),Y,9ph karyotype.To further characterize the breakpoint of theisochromosome X [Wolff et al., 1996] we performedadditional FISH experiments with two probeslocated on the proximal short arm of the X-chromosome, Xp11.1. The most proximal probehybridized to the isochromosome X whereas themore distal did not, indicating that the iso X in factwas a dicentric chromosome with a breakpoint in Xpbetween the probes used (data not shown). DNAanalyses revealed no deletions in the AZF-a, b, and cloci on chromosome Yq11. Because of the extremeOAT in the patient, ICSI treatment was offered afterdiscussing the potential risk for a chromosomeabnormality in his offspring. In order to estimate thisrisk, FISH on semen was attempted to determine

the aneuploidy of the spermatozoa. Due to thelow number of sperm that were left after theFISH procedure this attempt was unsuccessful.Two ICSI treatment cycles were done leading toa one embryo and two embryo replacement,respectively. However, no pregnancy was estab-lished and the couple decided not to proceed withthe treatment.

The patient had three healthy brothers, onesupposed dizygotic twin brother and two youngerbrothers. The patient was working as a carpenter, histwin brother was soldier in the army. All had similar,relatively low levels of education and occupation asthe patient. There were no reports of particular(verbal) learning disabilities. All brothers werereported to be a few centimeters taller than thepatient. The patient’s family history was negative forinfertility and one of his younger brothers had adizygotic twin, the other two brothers had nochildwish.

When patient W.J. was informed on his karyotypicabnormality,wediscussed thepossible consequencefor his twin brother (J.J.) of having the sameabnormality and thus being infertile. They couldbe monozygotic twin brothers, despite the fact thatthey had always been told to be dizygotic. Wetherefore invited his twin brother J.J. for karyotyping.Like the patient, twin brother J.J. reported a history ofbody building exercises including biannual admin-istration of anabolic steroids which he, in contrast tohis brother, had continued until a few months beforethe first time of presentation. He had a strikingphysical resemblance to the patient W.J. His bodyheight was 178 cm (�0.4 SD for age), sitting height90 cm (�0.8 SD for height), leg length 88 cm (þ1.0 SDfor sitting height), arm span 183 cm (þ0.3 SD forheight), and BMI 26.7 kg/m2 [Gerver and deBruin, 1996]. His testes volume was 18 ml and hehad a normal male pattern of body hair and nogynecomastia.

Chromosome analysis revealed a normal 46,XY,9ph karyotype. Initially, we interpreted this as aconfirmation of the dizygosity of the twins. But giventhe physical resemblance, we wanted to obtainmore information about the zygosity and carriedout additional investigations. DNA marker analysisrevealed that the twins were monozygotic with aprobability of more than 99%. This surprisingobservation was a strong indication that the auto-somal chromosomes of the twin brothers wereidentical, and that the extra isochromosome Xqin the infertile patient was the only differencebetween him and his twin brother. We theninitiated further experiments to obtain some moreinsight into the mechanism underlying this chromo-somal aberration and the origin of the extraisochromosome Xq. Unfortunately, the patient didnot want to involve his parents in any additionalinvestigation.

HETEROKARYOTYPIC MONOZYGOTIC TWINS 1907

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We also invited J.J. for semen analysiswhich showed a mild oligoteratozoospermia with asperm density of 16.0� 106 sperm/ml and atotal motile sperm count of 13.22� 106. Because hissemen parameters were somewhat decreased, wewanted to repeat the semen analysis and investigatehis hormonal status. However, prior to the secondtime of presentation he had been using anabolicsteroids during 1.5 months. Accordingly, bothsemen parameters and hormone levels wereseverely depressed. The second semen analysisshowed an extreme oligoteratozoospermia with asperm density of 0.2� 106 sperm/ml and atotal motile sperm count of 0.14� 106. Endocrinol-ogy revealed an FSH of <1.0 U/L (normal range 3–16 U/L), LH <1.0 U/L (normal range 2–15 U/L), testosterone 0.46 nMol/L (normal range 10–35 nMol/L), and prolactin 0.27 U/L (normal range<0.5 U/L).

MATERIALS AND METHODS

Metaphase spreads from lymphocytes wereprepared and trypsin-Giemsa banded accord-ing to standard techniques. DNA isolation formperipheral blood leukocytes and AZF a, b, c,analyses were performed as described [Kremeret al., 1997].

To determine zygosity, DNA markers were ana-lyzed with the AmpFISTER Profiler Plus PCRAmplification kit (P/N4303326) from Applied Bio-systems (Foster City, CA) according to the manufac-turer’s instructions. This kit contains the followingnine highly polymorphic autosomal markers and anX and Y marker: D3S1358, vWA, FGA, D8S1179,D21S11, D18S51, D5S818, D13S317, D7S820, andAmelogenin.

For further analysis of the identity of the X-chromosomes in the two brothers and the isochro-mosome Xq in one of them (W.J.), we used thefollowing markers distributed along the X-chromo-some: DXS1003 on the p arm and DXS6789 andDXS6797 on the q arm.

FISH experiments were carried out to determinewhether the breakpoint in the isochromosomeX was either in the short arm of the X or in thecentromere. The following probes were used,both located in Xp11.1, from proximal todistal: RP13-971O21 and RP11-12L02 [Ishkanianet al., 2004]. The FISH experiments were per-formed according to standard procedures [Giltayet al., 1998].

The human androgen receptor gene (AR gene)was used to determine the methylation status ofthe X-chromosome [Allen et al., 1992] as describedbefore [Stemkens et al., 2006]. The methylation-sensitive CfoI enzyme was used to digest the active,unmethylated X-chromosome.

RESULTS AND DISCUSSION

Monozygotic Twinning

The mechanism underlying monozygotic twinningis poorly understood. However, it is well known thatmonozygotic twins are not always identical. Thetwin brothers presented here, one of which has avariant 47,X,i(X)(q10),Y,9ph karyotype and theother has a normal 46,XY,9ph karyotype, is anexample of heterokaryotypic monozygosity. Suchcases have been described for Turner syndrome[Rohrer et al., 2004], some of which also havediscordant phenotypic sex (45,X vs. 46,XY) [Perlmanet al., 1990], and Down syndrome [O’Donnell et al.,2004] but not for KS. Indeed, literature providesgrowing evidence that not all monozygotic twinsare genetically concordant on molecular andcytogenetic level [Hall, 1996b; Gringras and Chen,2001; Hall, 2003] and that these genetic forms ofdiscordance may even play a role in the mechanismcausing monozygotic twinning [Hall, 1996a; Machin,1996]. Genetic changes in cells as compared to theoriginal cells might induce the original cellsto recognize the new cells as different, causingrepulsion and separation of the new cell masses andthus cause monozygotic twinning [Hall, 1996a].Chromosomal mosaicism in the early embryo maynot be an uncommon feature. At the cleavage stage, ahigh rate of mosaicism was shown by preimplanta-tion genetic diagnosis. If the number of aneuploidcells at the morula stage reaches some thresholdlevel, the embryo may be eliminated in the majorityof cases [Munne, 2002]. Apparently only in a minorityof cases, mosaicism results in a division of cellmassesand thus monozygotic twinning.

Mechanisms Underlying HeterokaryotypicMonozygosity in This Twin

Most isochromosomes Xq, like the one in thepatient presented here, are dicentric and are derivedfrom breakage and reunion of sister-chromatids orhomologous X-chromosomes in proximal Xp [Wolffet al., 1996]. In the present case at least twomechanisms causing the formation of the heterokar-yotypic monozygotic twin are conceivable. In thefirst place, the isochromosome Xq could pre-zygotically be derived from the father or motherafter which the twin was conceived as a single47,X,i(X)(q10),Y zygote [James et al., 1997]. Atthe first post zygotic mitotic division, one cell lostthe isochromosome Xq, probably because of cen-tromeric instability of the isochromosome Xq. Thisresulted in two different cells, one with isochromo-some Xq (47,X,i(X)(q10),Y karyotype) and onewithout isochromosome Xq (46,XY karyotype).

Alternatively, the twin could be conceived as47,XXY in which the supernumerary X was derived

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from the father or mother. The isochromosome Xqcould have been arisen during one of the first postzygotic mitotic divisions by misdivision of one ofthe X-chromosomes into an isochromosome Xq,resulting in one cell with a 47,X,i(X)(q10),Y karyo-type and the other cell a 46,XY karyotype. In bothmodels, the heterokaryotypic cell masses were thenseparated into monozygotic twins.

Analysis of X Markers and Interpretation

X-chromosomal marker analysis revealed that bothtwins had a single allele of the Xp markers. Of all Xqmarkers, patient W.J. had two alleles whereas twinJ.J. had only one allele (Fig. 1). Furthermore, thecommon allele from the AR (Fig. 2a, allele 4)disappeared after digestion with CfoI (Fig. 2b)suggesting that this allele was the active one on thenormal X-chromosome. The supposed AR alleles onthe isochromosome Xq (allele 3) did not disappearafter digestion suggesting that the isochromosomeXq was methylated and inactive, as expected (Fig. 2).Theoretically, one would expect a double peakheight of allele 3. However, this technique does notallow precise quantitative analysis.

Effect of Isochromosome Xq on Phenotype

Although the twins had a striking physical resem-blance, there were some phenotypic differences.Patient W.J. had lower body length (3.5 cm) andshorter extremities, with a difference of 2.5 cm in leglength and 5.0 cm in armspan and he had a smallervolume of the testes (8 vs. 18 ml) than his twin J.J.(Table I). Furthermore, patient W.J. had high LH andFSH levels (22.4 and 53.6 U/L), a normal testosteronelevel (15 nMol/L) and an extreme OAT (total motilesperm count of 0.001 and 0.02� 106). His twin J.J.had near normal sperm parameters at the first

analysis (sperm density 16.0� 106 sperm/ml, totalmotile sperm count 13.22� 106), which was a coupleof months after his last administration of anabolicsteroids. It is likely that these phenotypic differencescan be ascribed to the presence of the isochromo-some Xq, because the patient and his brother appearto be genetically identical apart from this isochromo-some Xq. The decreased sperm and hormonal valuesin brother J.J. at the second time of presentation (seeClinical Report section) can be ascribed to theadministration of anabolic steroids [Torres-Callejaet al., 2001].

The patient’s features are similar to those describedin literature [Bleau et al., 1987; Arps et al., 1996]. Inthese 17 published cases infertility, elevated plasmaLH and FSH levels, low or normal testosterone levels,sometimes gynecomastia, normal to short bodyheight, and average intelligence are reported.

The difference between patients with 47,XXY and47,X,i(Xq),Y karyotype, including our patient, is lack

FIG. 1. X-chromosomal markers. Patient W.J. with isochromosome Xq(47,X,i(Xq),Y) has two alleles of all Xq markers.

FIG. 2. X-inactivation androgen receptor. The active, unmethylated X-chromosome (a) is digested by CfoI enzyme (allele 4). In the subsequent PCR (b) only theinactive X-chromosome contributes to the production of a marker signal (allele 3).

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of increased body height and an intelligence levelcomparable to that of the general population by thelatter [Arps et al., 1996].

Isochromosome Xq is a structural rearrangementfrequently observed in Turner syndrome. The severeshort stature in these patients can at least in part beascribed to SHOX haploinsufficiency and quantita-tive alteration of the non-inactivated region. TheSHOX gene, short stature homeobox-containinggene, lies on the pseudoautosomal region at thetip of the short arm of the X and Y chromosome [Raoet al., 1997]. Furthermore, other X specific growthgenes escaping inactivation might be present onXp [Ogata and Matsuo, 1993; Rao et al., 1997]. Theobservation of increased body height in a variant KSpatient with an extra isodicentric Xq (pter->q22::q22->pter), with three copies of Xp and theproximal part of Xq, is in agreement with thepresence of growth genes on Xp [Zelante et al.,1991]. So the increased body height in patients with47,XXY, as compared to those with a 47,X,i(Xq),Ykaryotype, may be ascribed to the presence ofgrowth genes on the supernumerary Xp.

Hypergonadotrophic hypogonadism and inferti-lity are described both in KS patients with 47,XXYand those with an isochromosome Xq. Studies onpatients with structurally abnormal X-chromosomesshowed that additional material of Xq causesazoospermia in males [Patil et al., 1981; Kleczkowskaet al., 1988; Mark et al., 1999]. This observation is inagreement with the extreme OAT in our patient andthe near normal sperm parameters in his twinbrother. It should be noted however that we cannotdiscriminate whether the impaired fertility in ourpatient is related to the additional Xq material per seor to an impairment of meiosis due to the aneuploidkaryotype involving an abnormal X-chromosome.

To our knowledge, this is the first report of amonozygotic twin discordant for a variant KS. Ourobservation supports the view that increased bodyheight in KS can be ascribed to an extra copy of Xp,whereas infertility is caused by the presence of anextra copy of Xq.

ACKNOWLEDGMENTS

We thank Rolph Pfundt for providing us the FISHprobes on Xp11.1 and Pieter Jaap Krijtenburg forperforming the FISH experiments with these probes.

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TABLE I. Phenotypic Differences Between Patient W.J. and his Twin Brother J.J.

Body height (cm) Sitting height (cm) Leg length (cm) Arm span (cm) Testis volume (ml)

Patient W.J. 174.5 89.0 85.5 178.0 8Brother J.J. 178.0 90.0 88.0 183.0 18

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American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a