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

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  • 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:19061911 (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:19061911.


    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.


    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:

    DOI 10.1002/ajmg.a.31856

  • Center Utrecht with his 25-year-old femalepartner because of primary infertility of 1 yearsduration. 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(0.97 SD for sitting height), arm span 178 cm(0.03 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 1230 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 316 U/L) and LH (22.4 U/L,normal range 215 U/L) were found. Testosterone(15 nMol/L, normal range 1035 nMol/L) andprolactin (0.27 U/L, normal range

  • 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
  • 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 patients 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).


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

  • 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