Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome

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Clinical Endocrinology (2006) 65, 9297 doi: 10.1111/j.1365-2265.2006.02554.xO R I G I N A L A R T I C L E 2006 The Authors92Journal compilation 2006 Blackwell Publishing LtdBlackwell Publishing LtdGenetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndromeAnne M. Wikstrm*, Jodie N. Painter, Taneli Raivio*, Kristiina Aittomki and Leo Dunkel*Hospital for Children and Adolescents, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland, Folkhlsan Institute of Genetics, University of Helsinki, Finland, Department of Clinical Genetics, Helsinki University Central Hospital, University of Helsinki, Finland and Department of Paediatrics, Kuopio University Hospital, University of Kuopio, Kuopio, Finland SummaryObjective To investigate how genetic features of the X chromosomeinfluence growth, pubertal development and testicular degenerationin adolescent boys with Klinefelter syndrome (KS). Previous studieshave suggested that genetic features of the X chromosome maycontribute to the wide phenotypic variation in KS.DesignA prospective clinical study.Patients Fourteen nonmosaic 47,XXY boys, aged 10139 years.Measurements The relationship of genetic features of the X chro-mosome, including parental origin of X chromosomes, the CAGrepeat length of the androgen receptor (AR) gene, and X inactivationwith progression of pubertal development, growth and testicularfunction in KS boys.Results Paternal (47,XmXpY, n = 3) as compared to maternal(47,XmXmY, n = 11) origin of the supernumerary X chromosomewas associated with a later onset of puberty. In 47,XmXpY patients,serum LH concentrations increased above 10 IU/l at 125 06 years(mean SD), Tanner stage P2 occurred at 125 07 years, and pubertalacceleration of growth was noted at 139 14 years and peak velocityat 145 08 years. All of these occurred 1319 years later than in47,XmXmY patients (P = 001009). In 47,XmXmY subjects, CAG repeatlength (range 1726) correlated with age at which serum LH levelfirst exceeded 10 IU/l (rs = 063, P = 006, n = 10) and testosterone10 nmol/l (288 ng/dl) (rs = 078, P = 002, n = 10).Conclusions Paternal origin of the supernumerary X chromosomeis associated with later onset of puberty and longer CAG repeats ofthe AR with later pubertal reactivation of the pituitarytesticular axisin KS boys. Identifying genetic factors that affect the phenotype maylead to a better understanding of the pathogenesis of KS.(Received 9 March 2006; returned for revision 7 April 2006; finally revised 10 April 2006; accepted 11 April 2006)IntroductionThe classical phenotype of Klinefelter syndrome (KS) with gynae-comastia, small firm testes, dysgenetic seminiferous tubules withaspermatogenesis, high levels of gonadotrophins and low normaltestosterone levels is well recognized.1 The possibility of behaviouraland neurological problems in KS is also acknowledged. There is,however, a wide variation in the KS phenotype, ranging from indi-viduals with severe hypogonadism and/or behavioural problems inchildhood to those with infertility as the only presenting symptom asadults. Only 40% of all individuals with KS are diagnosed; less than10% are diagnosed prenatally and another 10% during childhood.2Several genetic features of the X chromosome have been proposedto affect the phenotype, but to date this issue has not been thoroughlyinvestigated. The parental origin of the supernumerary X chromosomeresults in different doses of paternally and maternally derived genes.Furthermore, due to imprinting, the paternal and maternal allelescould be differentially expressed.3 As a dosage compensation mechanismin subjects with two X chromosomes, one of the X chromosomes israndomly inactivated.3,4 It has, however, been shown that over 15%of X chromosomal genes escape inactivation5 and, consequently, awidely accepted hypothesis is that these genes are responsible formany of the features of KS.6 As in normal females, skewed X chro-mosome inactivation, defined as > 80% preferential inactivation ofone of the X chromosomes, can also occur in KS.3,4 This leads topredominant expression of the genes on one of the X chromosomes,and as Iitsuka et al.3 suggested, in 47,XmXpY subjects skewed inacti-vation of the Xm could result in a situation where only paternallyderived genes are expressed. In the case of Xp inactivation the situationequals that of a normal male with perhaps a less severe phenotype.In the maternally derived cases the extra X chromosome is due tonondisjunction during the first (M-I) or second (M-II) meioticdivision, or in postzygotic mitotic divisions.3,6,7 In cases of errors in M-II or in mitosis, the 47,XXY subject has two identical X chromosomes.7Anne M. Wikstrm and Jodie N. Painter contributed equally to the study.Correspondence: Anne Wikstrm, HUCH, Hospital for Children and Adolescents, PO Box 281, 00029 Helsinki, Finland. Tel.: + 358 9 47175293; Fax: + 358 9471 75888; E-mail: anne.wikstrom@fimnet.fi Genetic factors in Klinefelter syndrome93 2006 The AuthorsJournal compilation 2006 Blackwell Publishing Ltd, Clinical Endocrinology, 65, 9297This isodisomy could, as in cases of skewed X inactivation, lead toexpression of recessive mutations of X-linked genes, and accordinglyto a more adverse phenotype.Androgen-related genes might play a particular role in modulatingthe differences in the KS phenotype. The androgen receptor (AR)gene is located on the X chromosome. The N-terminal domain ofexon 1 of the AR gene contains a highly polymorphic CAG repeat,the length of which is inversely associated with the activity of thereceptor.8 It is possible that a subtle modulation of AR function couldcontribute to the variability in KS phenotypes, especially becausemost of these patients have low normal or low androgen levels.The aim of our study was to investigate the impact of genetic featuresof the X chromosome on growth during childhood and adolescence,and on onset and progression of puberty in boys with KS. In an earlierstudy9 we noted wide differences in the testicular degeneration inadolescent boys with KS, hence we also wanted to evaluate howgenetic factors influence this process.Subjects and methodsSubjectsFourteen nonmosaic 47,XXY boys were followed-up prospectivelyfor 425 months (median 18). In addition, data from routine clinicalvisits prior to and after the systematic surveillance period were collectedfrom patient records. None of the subjects was or had previouslybeen on androgen therapy. At the start of the systematic prospectivefollow-up, their median age was 115 years (range 100139). Someof the clinical and hormonal data have already been published.9The boys visited the Hospital for Children and Adolescents, HelsinkiUniversity Central Hospital every fourth to sixth month. The visitsincluded physical examination with assessment of puberty accordingto Tanner.10 Body mass index (BMI) was calculated as weight (kg)divided by the height squared (m2). Width and length of the testeswere measured with a ruler to the nearest millimetre; testicular volume(ml) was calculated by the formula 052 length width2 and wasexpressed as the mean volume of the left and right testes (Tvol).11Serum hormone levels were determined by methods describedpreviously.9 Bone age was assessed annually according to the methodof Greulich and Pyle.12 Reported heights of the parents were recorded.The parents of each boy gave their informed consent for their sons andtheir own participation in this study, which was approved by the researchethics committee of the Hospital District of Helsinki and Uusimaa.Genetic studiesFor this study, blood samples were collected from all 14 boys and 27parents. Genomic DNA was extracted from whole ethylenediamine-tetraacetic acid (EDTA)-blood with the PUREGENE DNA isolationkit (Gentra Systems, Minneapolis, MN, USA). Parental origin of theX chromosomes was determined by genotyping each boy and bothparents (with the exception of one father) at 10 microsatellite loci:DXS6807, DXS989, DXS1068, DXS1003, DXS6800, DXS6797,DXS1001, DXS984, DXS1193 and DXS1073. The length of the CAGnrepeat in exon 1 of the AR gene and the degree of X chromosomeinactivation were determined essentially as outlined in Suzuki et al.13The CAG alleles were sized initially by genotyping, and the lengthsof the repeats subsequently confirmed by sequencing all homozygoussamples. The degree of skewing of X inactivation was estimated forall heterozygous samples according to the equations outlined inIitsuka et al.3 using the peak area values for each allele. All genotypingand sequence reactions were electrophoresed in an ABI 3700(Applied Biosystems, Foster City, CA, USA) and analysed with Gen-eMapper v37 (Applied Biosystems) and Sequencher v45 (GeneCodes Corporation, Ann Arbor, MI, USA), respectively.Calculations and statistical analysesMidparental target height (SD) for each KS boy was calculated bysubtracting 171 from the arithmetic mean of the parents heights anddividing this difference by 10. For predicting adult height for the KSsubjects, the method of Bayley and Pinneau was used.14 For convertingheight in centimetres to SD scores, age-specific growth norms fornormal Finnish boys were used. The X-weighted biallelic mean CAGrepeat length was calculated by a method described previously:15 eachallele in a genetic pair was multiplied by its percentage of expression(100% % inactivity) and added together.Descriptive data are reported as median and range or as mean SD.MannWhitney U-tests were used to compare differences between boyswith paternal (Xp) and maternal (Xm) origin of the supernumeraryX chromosome. Spearmans rank correlations were calculated forassociations between continuous parameters and X-weighted biallelicmean CAG repeat length. Significance was set at P < 005.ResultsWe investigated the impact of all genetic features of the X chromosomelisted in Table 1 on the phenotypes in Table 2. For biochemical markersof onset of puberty, LH and testosterone levels clearly exceedingprepubertal levels were used.Parental origin of the supernumerary X chromosomeThe origin of the X chromosomes was unambiguously assigned for allcases (Table 1). Although the sample from the father was not availablefor patient 13, the supernumerary X chromosome was assigned asmaternal because all marker alleles of the proband were maternal.The extra X chromosome was paternal in three (21%) and maternalin 11 (79%) cases.Parental origin of the supernumerary X chromosome did notinfluence the growth during childhood (ages 29 years). Relativeheights in this period were 063 103 SD and 019 054 SD forthe 47,XmXmY and 47,XmXpY boys, respectively (P = ns). Predictedadult heights were 147 105 SD and 134 079 SD (P = ns) forsubjects with 47,XmXmY and 47,XmXpY, respectively. Furthermore,there was no difference in body composition between these twogroups during puberty (BMI after age 10 years: 47,XmXmY, 196 26and 47,XmXpY, 175 08; P = ns).The onset and progression of puberty was delayed in the 47,XmXpYboys compared to the 47,XmXmY boys as indicated by clinical markersand serum hormone measurements (Fig. 1). Tanner stage P2 was notedat age 125 07 years in the 47,XmXmY boys, and at 139 14 years 94A. M. Wikstrm et al. 2006 The AuthorsJournal compilation 2006 Blackwell Publishing Ltd, Clinical Endocrinology, 65, 9297in the 47,XmXpY boys (P = 009) (Fig. 1a); the same trend was seenfor the increase in testicular size (P = ns) (Fig. 1b). There was a laterincrease in serum LH concentration in boys with a 47,XmXpYkaryotype; LH rose above 10 IU/l at age 125 06 years and at138 10 years in the 47,XmXmY and 47,XmXpY boys, respectively(P = 004) (Fig. 1c). A similar trend was seen for testosterone (P = ns)(Fig. 1d). As signs of a slower progression of puberty, the pubertalacceleration (take-off) in height velocity (47,XmXmY 119 05 years;47,XmXpY 138 08 years; P = 001) and peak velocity (47,XmXmY132 06 years; 47,XmXpY 145 08 years; P = 002) in height growthoccurred later in the 47,XmXpY subjects (Figs 1e and 1f). The 47,XmXpYboys were also older when they reached bone age 12 years (47,XmXmY119 08 years, 47,XmXpY 135 06 years; P = 003) (Fig. 1g). As thepubertal increase in reproductive hormones is strongly associated withacceleration of the testicular degeneration process in KS subjects,9the 47,XmXpY boys had a later appearance of testicular degeneration.X chromosome isodisomy/heterodisomyJudged by the microsatellite loci, five of the 11 boys with a maternallyderived extra X chromosome displayed uniparental X chromosomeisodisomy (M-II, Table 1). X chromosome isodisomy/heterodisomydid not influence the phenotypes listed in Table 2.X chromosome inactivationX inactivation status could be determined for 6/14 subjects (43%),the remainder being homozygous for the AR gene CAG repeat(Table 1). Patients 4 and 8 showed skewed X inactivation, the ratiosbeing 18 : 82 and 17 : 83 (Table 1). No significant differences in thephenotypic features listed in Table 2 were observed between subjectswith or without skewed X inactivation.CAG repeat lengthThe lengths of the AR gene CAG repeat varied within the normal range,from 17 to 26 (Table 1). No association was seen between the origin ofthe supernumerary X chromosome and the length of the CAG repeats(Table 1). Thus, to investigate the influence of the CAG repeat lengthson the phenotype, the 47,XmXpY boys were excluded from these analyses,because of the major impact of the origin of the extra X chromosomedescribed above. We calculated Spearmans rank correlations for CAGrepeat lengths with the phenotypic features listed in Table 2. CAGrepeat lengths did not influence the growth parameters in Table 2.The CAG repeat length correlated with the hormonal markers foronset of puberty; boys with longer CAG repeats had later increases inserum LH and testosterone levels [CAG length vs. LH 10 IU/l; rs =063, P = 006, n = 10, and CAG length vs. testosterone 10 nmol/lTable 1. Genetic data for 14 nonmosaic 47,XXY boysPatientOrigin of extra X chromosomeNumber of CAG repeatsInactivity ratio short : long allelePreferentially active alleleArithmetic mean of CAG repeatsX-weighted biallelic mean of CAG repeats1 M-I 17 : 17 172 M-I 19 : 22 69 : 31 long 205 2113 M-II 26 : 26 264 M-I 19 : 26 18 : 82* short 225 2025 M-II 22 : 22 226 M-II 22 : 22 227 M-I 22 : 24 69 : 31 long 23 2348 P 20 : 21 17 : 83* short (P) 205 2029 M-II 26 : 26 2610 P 20 : 22 32 : 68 short (P) 21 20611 M-II 20 : 20 2012 P 24 : 24 2413 M-I 22 : 22 2214 M-I 20 : 21 50 : 50 205 205M-I, first maternal meiosis; M-II, second maternal meiosis; P, paternal.*Skewed X chromosome inactivation.Table 2. Investigated phenotypes in 14 boys with Klinefelter syndrome (KS)GrowthMean height (SD) between ages 2 and 9 years, related to target heightPredicted adult height (SD), related to target heightBody composition during puberty (mean BMI after age 10 years)Onset of pubertyClinical markers: Age at Tanner stage P2Age at testicular volume 2.0 mlHormonal markers: Age at S-LH 10 mlAge at S-testosterone 10 nmol/mlProgression of pubertyAge at acceleration of velocity (take-off) in height growthAge at peak velocity in height growthChronological age at bone age (BA) 120 yearsTesticular degenerationAge at S-FSH 100 IU/lAge at S-LH 100 IU/lAge at S-inhibin B 32 pg/mlGenetic factors in Klinefelter syndrome 95 2006 The AuthorsJournal compilation 2006 Blackwell Publishing Ltd, Clinical Endocrinology, 65, 9297(288 ng/dl); rs = 078, P = 002, n = 10] (Fig. 2a and 2b). No evidentassociation was seen between CAG repeat length and the clinicalmarkers for onset of puberty.Progression of puberty as indicated by age at take-off (rs = 070, P =005, n = 9) and peak velocity in height growth (rs = 058, P = 010, n = 9)was also slower in boys with a longer CAG repeat length (Fig. 2c and 2d).Furthermore, in these boys the testicular degeneration occurredlater, as indicated by a slower increase in serum FSH and LH levels tohypergonadotrophic levels over 100 IU/l (FSH; rs = 065, P = 005,n = 10, and LH; rs = 094, P = 004, n = 6) (Fig. 2e and 2f), and aslower decrease in serum inhibin B levels below 32 pg/ml (rs = 064,P = 006, n = 10) (Fig. 2g).DiscussionThe underlying basis for the wide variation in the severity of the KSphenotype is unknown, but previous studies have suggested thatFig. 1 Parental origin of the extra X chromosome: influence on markers for onset and progression of puberty in boys with KS. M, maternal; P, paternal. Means for the groups are also shown.Fig. 2 X-weighted biallelic mean of AR gene CAG repeat length: influence on markers for onset and progression of puberty (ad) and testicular degeneration (eg). Linear regression lines are shown.96 A. M. Wikstrm et al. 2006 The AuthorsJournal compilation 2006 Blackwell Publishing Ltd, Clinical Endocrinology, 65, 9297genetic features of the X chromosome might play a role. The resultsof the present study suggest such genetic effects on the onset and pro-gression of puberty, and the development of testicular degeneration.The parental origin of the extra X chromosome could influence theKS phenotype through altered dosage of paternally and maternallyderived genes, and imprinting. In our study the three subjects witha paternal additional X chromosome showed later onset and slowerprogression of puberty. Jacobs et al.16 suggested that parental origin ofthe extra X chromosome has no evident effect on the phenotypes ofKS males. This view was based on the finding of a similar proportionof maternally and paternally derived cases among subjects diagnosedprenatally and as newborns, or in adulthood because of signs ofhypogonadism.16 In this study, however, the phenotypes were notstudied.16 Zinn et al.17 found that the parental origin of the super-numerary X chromosome had no impact on anthropometric andphysical findings, which is in accordance with our results. They alsomeasured FSH, LH, testosterone and oestradiol concentrations intheir subjects aged 0139 years, and found no differences in testicularfunction between the maternally and paternally derived cases.17 Thestudy by Zinn et al.17 was, however, cross-sectional, while our study waslongitudinal, and in our series the phenotypic differences becameapparent during follow-up.A predominant hypothesis is that the altered dosage of some X-linked genes may affect the KS phenotype.18 In KS the supernumeraryX chromosome is probably inactivated in the same manner as innormal females. Approximately 15% of X-linked genes escape inacti-vation, 20% show a variable inactivation pattern, and around 65%are always inactivated.5 Depending on whether the maternally orpaternally derived X chromosome is preferentially inactivated, thedosage of maternally and paternally derived genes varies. Therefore, ithas been suggested that X chromosome inactivation patterns, especiallyskewed X inactivation, influence KS phenotypes.3 To date, no studyhas thoroughly evaluated the impact of skewed X inactivation. Thestudy by Zinn et al. had two subjects with skewed X inactivation, andno association with phenotypic features was seen.17 This aspect was notevaluated in the study by Zitzmann et al.,19 who had five individualswith skewed X inactivation in their cohort of 77 adult KS males.Similarly, no differences were seen between the two boys with skewedX inactivation and the other 12 boys in our study. Conclusionsshould, however, be drawn with caution because of the small numberof patients in these studies.In 47,XmXmY subjects the X chromosomes can be either identical(isodisomy) or different (heterodisomy). Isodisomy could lead todouble dosage of some harmful genes, which escape X inactivation.However, our study and the earlier study by Zinn et al.17 did not findan impact on the KS phenotype.Androgen-related genes located on the X chromosome might playa particular role in the differences in the KS phenotype. Two recentstudies have shown that KS infants have a physiological increase inserum testosterone during the first months of life, but that the levelsare lower than in controls.20,21 During puberty, the serum testosteronelevels remain within the low normal range,9,22,23 but in adulthood,over half of the KS males have serum testosterone levels belownormal.7,24 The length of the CAG stretch in exon 1 of the AR geneis inversely related to the activity of the receptor, and may modulate itsresponse to androgens.8 Zitzmann et al.19 found a positive correlationbetween CAG repeat length and body height and presence ofgynecomastia, while there was an inverse association with bonedensity, social status and testicular volume, and even to responseto androgen substitution. In the study by Zinn et al., the only inves-tigated parameter that was associated with CAG repeat length waspenile length; the correlation was inverse.17In our study, the KS boys with a longer CAG repeat showed a lateronset and slower progression of puberty and a slower testiculardegeneration process. These findings are in agreement with diminishedAR response to androgens when the AR gene has a longer CAGrepeat. We have previously reported that the testicular degenerationprocess accelerates at the onset of puberty.9 After an increase inserum testosterone to levels above 25 nmol/ l (721 ng/dl), there is arapid decline in the serum levels of the Sertoli cell-specific markersinhibin B and anti-Mllerian hormone. This suggests that androgensmay play a role in initiating this degeneration process. The presentfinding of lower AR activity with a slower testicular degenerationprocess supports this hypothesis.In our cohort only one boy was diagnosed by an amniocentesiswhile the other 13 boys initially presented between the ages of 5 and105 years with speech, learning and/or behavioural problems. Thus,our patient series may contain ascertainment bias and the phenotypicfeatures may be different in totally unselected cohorts of patientsdiagnosed prenatally or in patients diagnosed in adulthood becauseof infertility. Earlier studies have shown that the supernumeraryX chromosome is paternal in 5060% and maternal in 4050% ofKS cases,3 while in our study the percentages were 21% and 79%,respectively. Further studies including a larger number of subjectsare therefore needed to confirm our preliminary results.In conclusion, genetic features of the X chromosome appear toplay a part in modulating KS phenotypes. In the present study wehave shown that parental origin of the supernumerary X chromosomeand the length of the CAG repeat of the AR gene influence pubertaldevelopment. Furthermore, androgens may play a role in the patho-genesis of the testicular degeneration in KS, the mechanisms ofwhich is unknown. Identifying genetic factors that contribute to thesubstantial variation in the KS phenotype will lead to a better under-standing of the pathogenesis of KS, and may through more targetedtherapeutic measures offer better prognosis and improvement inquality of life for the patients.AcknowledgementsThis work was supported by grants from the Medical Society ofFinland (Finska Lkaresllskapet), the Finnish Medical Foundationand the Hospital District of Helsinki and Uusimaa.References1 Klinefelter, H.F., Reifenstein, E.C. & Albright, F. (1942) Syndromecharacterized by gynecomastia, aspermatogenesis without a-Leydigism,and increased excretion of follicle-stimulating hormone. Journal ofClinical Endocrinology, 2, 615627.2 Bojesen, A., Juul, S. & Gravholt, C.H. (2003) Prenatal and postnatalprevalence of Klinefelter syndrome: a national registry study. Journalof Clinical Endocrinology and Metabolism, 88, 622626.Genetic factors in Klinefelter syndrome 97 2006 The AuthorsJournal compilation 2006 Blackwell Publishing Ltd, Clinical Endocrinology, 65, 92973 Iitsuka, Y., Bock, A., Nguyen, D.D., Samango-Sprouse, C.A.,Simpson, J.L. & Bischoff, F.Z. (2001) Evidence of skewed X-chromosome inactivation in 47,XXY and 48,XXYY Klinefelterpatients. American Journal of Medical Genetics, 98, 2531.4 Willard, H.F. (2001) The sex chromosomes and X chromosomeinactivation. In: C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle eds. TheMetabolic and Molecular Bases of Inherited Disease, 8th edn. McGraw-Hill, New York, 11911211.5 Carrel, L. & Willard, H.F. (2005) X-inactivation profile revealsextensive variability in X-linked gene expression in females. Nature,434, 400404.6 Simpson, J.L., de la Cruz, F., Swerdloff, R.S., Samango-Sprouse, C.,Skakkebaek, N.E., Graham, J.M. Jr, Hassold, T., Aylstock, M.,Meyer-Bahlburg, H.F., Willard, H.F., Hall, J.G., Salameh, W., Boone, K.,Staessen, C., Geschwind, D., Giedd, J., Dobs, A.S., Rogol, A., Brinton, B.& Paulsen, C.A. (2003) Klinefelter syndrome: expanding the pheno-type and identifying new research directions. Genetics in Medicine,5, 460468.7 Lanfranco, F., Kamischke, A., Zitzmann, M. & Nieschlag, E. (2004)Klinefelters syndrome. Lancet, 364, 273283.8 Zitzmann, M. & Nieschlag, E. (2003) The CAG repeat polymorphismwithin the androgen receptor gene and maleness. International Journalof Andrology, 26, 7683.9 Wikstrom, A.M., Raivio, T., Hadziselimovic, F., Wikstrom, S., Tuuri, T.& Dunkel, L. (2004) Klinefelter syndrome in adolescence: onset ofpuberty is associated with accelerated germ cell depletion. Journal ofClinical Endocrinology and Metabolism, 89, 22632270.10 Tanner, J.M. (1962) Growth at Adolescence, 2nd edn. Blackwell,Oxford, UK.11 Hansen, P. & With, T.K. (1952) Clinical measurements of testes. ActaMedica Scandinavica, 206, 457465.12 Greulich, W.W. & Pyle, S.L. (1959) Atlas of Skeletal Development ofthe Hand and Wrist, 2nd edn. Stanford University Press, Stanford,CA.13 Suzuki, Y., Sasagawa, I., Tateno, T., Ashida, J., Nakada, T., Muroya, K.& Ogata, T. (2001) Mutation screening and CAG repeat lengthanalysis of the androgen receptor gene in Klinefelters syndromepatients with and without spermatogenesis. Human Reproduction,16, 16531656.14 Bayley, N. & Pinneau, S.R. (1952) Tables for predicting adult heightfrom skeletal age: revised for use with the GreulichPyle hand standards.Journal of Pediatrics, 40, 423441.15 Hickey, T., Chandy, A. & Norman, R.J. (2002) The androgen receptorCAG repeat polymorphism and X-chromosome inactivation inAustralian Caucasian women with infertility related to polycysticovary syndrome. Journal of Clinical Endocrinology and Metabolism,87, 161165.16 Jacobs, P.A., Bacino, C., Hassold, T., Morton, N.E., Keston, M. &Lee, M. (1988) A cytogenetic study of 47,XXY males of known originand their parents. Annals of Human Genetics, 52, 319325.17 Zinn, A.R., Ramos, P., Elder, F.F., Kowal, K., Samango-Sprouse, C.& Ross, J.L. (2005) Androgen receptor CAGn repeat length influencesphenotype of 47,XXY (Klinefelter) syndrome. Journal of ClinicalEndocrinology and Metabolism, 90, 50415046.18 Aksglaede, L., Wikstrom, A.M., Rajpert-De Meyts, E., Dunkel, L.,Skakkebaek, N.E. & Juul, A. (2006) Natural history of seminiferoustubule degeneration in Klinefelter syndrome. Human ReproductionUpdate, 12, 3948.19 Zitzmann, M., Depenbusch, M., Gromoll, J. & Nieschlag, E. (2004)X-chromosome inactivation patterns and androgen receptorfunctionality influence phenotype and social characteristics as wellas pharmacogenetics of testosterone therapy in Klinefelter patients.Journal of Clinical Endocrinology and Metabolism, 89, 62086217.20 Lahlou, N., Fennoy, I., Carel, J.C. & Roger, M. (2004) Inhibin B andanti-Mullerian hormone, but not testosterone levels, are normal ininfants with nonmosaic Klinefelter syndrome. Journal of ClinicalEndocrinology and Metabolism, 89, 18641868.21 Ross, J.L., Samango-Sprouse, C., Lahlou, N., Kowal, K., Elder, F.F. &Zinn, A. (2005) Early androgen deficiency in infants and young boyswith 47,XXY Klinefelter syndrome. Hormone Research, 64, 3945.22 Salbenblatt, J.A., Bender, B.G., Puck, M.H., Robinson, A., Faiman, C.& Winter, J.S. (1985) Pituitarygonadal function in Klinefeltersyndrome before and during puberty. Pediatric Research, 19, 8286.23 Topper, E., Dickerman, Z., Prager-Lewin, R., Kaufman, H., Maimon, Z.& Laron, Z. (1982) Puberty in 24 patients with Klinefelter syndrome.European Journal of Pediatrics, 139, 812.24 Smyth, C.M. & Bremner, W.J. (1998) Klinefelter syndrome. Archivesof Internal Medicine, 158, 13091314.

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