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• W2055039739 abstract "Klinefelter syndrome is the most prevalent chromosome abnormality and genetic cause of azoospermia in males. The availability of assisted reproductive technology (ART) has allowed men with Klinefelter syndrome to father their own genetic offspring. When providing ART to men with Klinefelter syndrome, it is important to be able to counsel them properly on both the chance of finding sperm and the potential effects on their offspring. The aim of this review is twofold: [1] to describe the genetic etiology of Klinefelter syndrome and [2] to describe how spermatogenesis occurs in men with Klinefelter syndrome and the consequences this has for children born from men with Klinefelter syndrome. Klinefelter syndrome is the most prevalent chromosome abnormality and genetic cause of azoospermia in males. The availability of assisted reproductive technology (ART) has allowed men with Klinefelter syndrome to father their own genetic offspring. When providing ART to men with Klinefelter syndrome, it is important to be able to counsel them properly on both the chance of finding sperm and the potential effects on their offspring. The aim of this review is twofold: [1] to describe the genetic etiology of Klinefelter syndrome and [2] to describe how spermatogenesis occurs in men with Klinefelter syndrome and the consequences this has for children born from men with Klinefelter syndrome. DiscussYou can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/maiburgm-genetic-origin-klinefelter-syndrome-spermatogenesis/ You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/maiburgm-genetic-origin-klinefelter-syndrome-spermatogenesis/ The phenotype of what was later named “Klinefelter syndrome” was first described in 1942 by Harry Klinefelter (1Klinefelter H.F. Reifenstein E.C. Albright F. Syndrome characterised by gynecomastia, aspermatogenesis without a-leydigism, and increased excretion of follicle-stimulating hormone.J Clin Endocrinol. 1942; 2: 615-627Crossref Scopus (608) Google Scholar). He reported nine men with gynecomastia, small testes, and azoospermia. In 1959, it was first demonstrated that men with Klinefelter syndrome have an additional X chromosome, resulting in a 47,XXY karyotype (2Jacobs P.A. Strong J.A. A case of human intersexuality having a possible XXY sex-determining mechanism.Nature. 1959; 183: 302-303Crossref PubMed Scopus (576) Google Scholar). Nowadays, it is known that a 47,XXY karyotype is found in 80%–90% of men with Klinefelter syndrome, whereas the remaining cases show a mosaic karyotype (46,XY/47,XXY), additional X chromosomes (e.g., 48,XXXYor 48,XXYY), or structurally abnormal X chromosomes (e.g., 47,X,iXq,Y) (3Bojesen A. Juul S. Gravholt C.H. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study.J Clin Endocrinol Metab. 2003; 88: 622-626Crossref PubMed Scopus (622) Google Scholar, 4Lanfranco F. Kamischke A. Zitzmann M. Nieschlag E. Klinefelter's syndrome.Lancet. 2004; 364: 273-283Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar). Klinefelter syndrome is the most prevalent chromosomal disorder in humans, with an estimated frequency of 1:500 to 1:1,000 men (3Bojesen A. Juul S. Gravholt C.H. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study.J Clin Endocrinol Metab. 2003; 88: 622-626Crossref PubMed Scopus (622) Google Scholar). It is also the most frequent genetic cause of azoospermia (5Tuttelmann F. Werny F. Cooper T.G. Kliesch S. Simoni M. Nieschlag E. Clinical experience with azoospermia: aetiology and chances for spermatozoa detection upon biopsy.Int J Androl. 2011; 34: 291-298Crossref PubMed Scopus (77) Google Scholar, 6Vincent M.C. Daudin M. De M.P. Massat G. Mieusset R. Pontonnier F. et al.Cytogenetic investigations of infertile men with low sperm counts: a 25-year experience.J Androl. 2002; 23 (discussion 44–5): 18-22Crossref PubMed Scopus (84) Google Scholar). Most men with Klinefelter syndrome are diagnosed when they have failed to achieve a pregnancy and are diagnosed with azoospermia. However, a significant proportion of men with Klinefelter syndrome remain undiagnosed, probably because of the wide phenotypic variability and lack of knowledge of the syndrome among health professionals (3Bojesen A. Juul S. Gravholt C.H. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study.J Clin Endocrinol Metab. 2003; 88: 622-626Crossref PubMed Scopus (622) Google Scholar, 7Giltay J.C. Maiburg M.C. Klinefelter syndrome: clinical and molecular aspects.Expert Rev Mol Diagn. 2010; 10: 765-776Crossref PubMed Scopus (27) Google Scholar). Since the introduction of intracytoplasmic sperm injection (ICSI) (8Palermo G. Joris H. Devroey P. Van Steirteghem A.C. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte.Lancet. 1992; 340: 17-18Abstract PubMed Scopus (2853) Google Scholar) and testicular sperm extraction (TESE) (9Silber S.J. Van Steirteghem A.C. Liu J. Nagy Z. Tournaye H. Devroey P. High fertilization and pregnancy rate after intracytoplasmic sperm injection with spermatozoa obtained from testicle biopsy.Hum Reprod. 1995; 10: 148-152Crossref PubMed Scopus (429) Google Scholar), a considerable number of men with Klinefelter syndrome have been able to father genetically own offspring. In light of this possibility for paternity, a review of the genetic etiology of the syndrome as well as its effects on spermatogenesis is useful in order to allow discussion of the potential risks of this treatment. This review has two main objectives. First, we describe the genetic etiology of Klinefelter syndrome. In this section we address normal meiosis and focus on paternal and maternal causes of nondisjunction. Second, we describe how spermatogenesis occurs in men with Klinefelter syndrome and discuss the possible consequences for offspring from men with Klinefelter syndrome. Before the first meiotic division, the amount of DNA is doubled (replication), resulting in 46 chromosomes, each consisting of two chromatids (2n,4c). The first meiotic division (reduction division) involves segregation of homologous chromosomes (2n,4c) and gives rise to haploid (23 chromosomes; 1n,2c) germ cells: two secondary spermatocytes (male meiosis) or one secondary oocyte and one polar body (female meiosis). In male meiosis, the second meiotic division (segregation of sister chromatids; 2c → c) gives rise to spermatids that subsequently mature into spermatozoa. In female meiosis, the second meiotic division is finished only after fertilization, giving rise to a mature (fertilized) oocyte and a second polar body. Thus, each male germ cell entering meiosis eventually gives rise to four spermatozoa, whereas one complete round of female meiosis eventually produces one mature oocyte (10Larsen W.J. Human embryology.3rd ed. Churchill Livingstone, Philadelphia, PA2001Google Scholar, 11Strachan T. Read A.P. Human molecular genetics.3rd ed. Garland Publishing, New York2004Google Scholar). During prophase of meiosis I, homologous chromosomes pair and form connections called chiasmata. In male meiosis, the (largely nonhomologous) X and Y chromosome pair at the tips of their short and long arms, the pseudoautosomal regions 1 and 2 (PAR1 and PAR2). Paired homologous chromosomes exchange random DNA segments at the chiasmata, a process called crossing over, which results in a recombination of these segments. Crossing over takes place during prophase of meiosis I and is nonrandomly distributed along the chromosomes, with at least one exchange per chromosome arm (except for the short arms of acrocentric chromosomes). Genomewide recombination rates in female meioses are approximately 1.6- to 1.7-fold greater than in male meioses (12Lynn A. Ashley T. Hassold T. Variation in human meiotic recombination.Annu Rev Genomics Hum Genet. 2004; 5: 317-349Crossref PubMed Scopus (131) Google Scholar). The PAR1 region (2.6 Mb) contains one obligatory crossover (13Rappold G.A. The pseudoautosomal regions of the human sex chromosomes.Hum Genet. 1993; 92: 315-324Crossref PubMed Scopus (194) Google Scholar). Pairing and crossing over at the smaller (320-kb) pseudoautosomal region (PAR2) at the tip of the long arms of the X and Y chromosomes is not essential for completing meiosis (14Flaquer A. Rappold G.A. Wienker T.F. Fischer C. The human pseudoautosomal regions: a review for genetic epidemiologists.Eur J Hum Genet. 2008; 16: 771-779Crossref PubMed Scopus (48) Google Scholar, 15Li L. Hamer D.H. Recombination and allelic association in the Xq/Yq homology region.Hum Mol Genet. 1995; 4: 2013-2016Crossref PubMed Scopus (27) Google Scholar). The purpose of crossing over is twofold: [1] to generate diversity within a population and [2] to ensure accurate segregation of chromosomes during meiosis I (16Handel M.A. Schimenti J.C. Genetics of mammalian meiosis: regulation, dynamics and impact on fertility.Nat Rev Genet. 2010; 11: 124-136Crossref PubMed Scopus (338) Google Scholar). The latter will be discussed below. Nondisjunction is the failure of chromosomes to separate (disjoin) at anaphase during meiosis I (paired homologs), meiosis II (sister chromatids), or mitosis (sister chromatids) (11Strachan T. Read A.P. Human molecular genetics.3rd ed. Garland Publishing, New York2004Google Scholar), giving rise to daughter cells with an aberrant number of chromosomes. The proper formation and resolution of chiasmata is necessary to keep the homologs in the right position during meiosis for their accurate separation into their daughter cells. “Classical” nondisjunction in meiosis I can result from failure to resolve chiasmata (“true nondisjunction”), premature resolution of chiasmata or failure to establish chiasmata (“achiasmate nondisjunction”). Another mechanism, premature separation of sister chromatids, can result in one complete chromosome and a single chromatid segregating together in meiosis I (17Hassold T. Hunt P. To err (meiotically) is human: the genesis of human aneuploidy.Nat Rev Genet. 2001; 2: 280-291Crossref PubMed Scopus (1715) Google Scholar). Nondisjunction has long been regarded as the main mechanism leading to aneuploidy. Interestingly, however, using array comparative genomic hybridization (array-CGH) on first polar bodies, it has recently been shown that chromatid errors (premature separation; 3:2 ratio of sample vs. control DNA) were 11.5 times more common than whole chromosome errors (nondisjunction; 2:1 ratio) (18Gabriel A.S. Thornhill A.R. Ottolini C.S. Gordon A. Brown A.P. Taylor J. et al.Array comparative genomic hybridisation on first polar bodies suggests that non-disjunction is not the predominant mechanism leading to aneuploidy in humans.J Med Genet. 2011; 48: 433-437Crossref PubMed Scopus (57) Google Scholar). Handyside et al. (19Handyside A.H. Montag M. Magli M.C. Repping S. Harper J. Schmutzler A. et al.Multiple meiotic errors caused by predivision of chromatids in women of advanced maternal age undergoing in vitro fertilisation.Eur J Hum Genet. 2012; 20: 742-747Crossref PubMed Scopus (107) Google Scholar), who studied both polar bodies and the corresponding zygote by array-CGH, also conclude that almost all meiosis I errors are caused by premature division of sister chromatids. Finally, anaphase lagging is the failure of a chromosome or chromatid to be incorporated into a daughter cell following cell division (11Strachan T. Read A.P. Human molecular genetics.3rd ed. Garland Publishing, New York2004Google Scholar). Chromosomes or chromatids not entering a daughter cell are lost, resulting in aneuploidy (monosomy) for that chromosome. It has always been assumed that most human trisomies originate from nondisjunction at maternal meiosis I (20Thomas N.S. Hassold T.J. Aberrant recombination and the origin of Klinefelter syndrome.Hum Reprod Update. 2003; 9: 309-317Crossref PubMed Scopus (115) Google Scholar). Indeed, paternal meiotic errors account for only 10% of autosomal trisomies. However, this is very different for sex chromosomal aneuploidies, including Klinefelter syndrome that results from a nondisjunction event in the father in nearly half of the cases (20Thomas N.S. Hassold T.J. Aberrant recombination and the origin of Klinefelter syndrome.Hum Reprod Update. 2003; 9: 309-317Crossref PubMed Scopus (115) Google Scholar, 21Stemkens D. Roza T. Verrij L. Swaab H. van Werkhoven M.K. Alizadeh B.Z. et al.Is there an influence of X-chromosomal imprinting on the phenotype in Klinefelter syndrome? A clinical and molecular genetic study of 61 cases.Clin Genet. 2006; 70: 43-48Crossref PubMed Scopus (51) Google Scholar). In cases of Klinefelter syndrome with an additional maternal X, nondisjunction in either the first or second meiotic division is most likely to have occurred. In paternal cases, the additional X chromosome can only be the result of nondisjunction in the first meiotic division, because a meiosis II error will result in either XX or YY gametes (and therefore XXX or XYY zygotes) (20Thomas N.S. Hassold T.J. Aberrant recombination and the origin of Klinefelter syndrome.Hum Reprod Update. 2003; 9: 309-317Crossref PubMed Scopus (115) Google Scholar). As mentioned previously, premature separation of sister chromatids in meiosis I might be a more common cause of aneuploidy than originally thought (18Gabriel A.S. Thornhill A.R. Ottolini C.S. Gordon A. Brown A.P. Taylor J. et al.Array comparative genomic hybridisation on first polar bodies suggests that non-disjunction is not the predominant mechanism leading to aneuploidy in humans.J Med Genet. 2011; 48: 433-437Crossref PubMed Scopus (57) Google Scholar). This mechanism could also underlie the origin of nonmosaic XXY cases of either paternal or maternal origin. Aberrant meiotic recombination has been shown to play an important role in the etiology of nondisjunction in Klinefelter syndrome (20Thomas N.S. Hassold T.J. Aberrant recombination and the origin of Klinefelter syndrome.Hum Reprod Update. 2003; 9: 309-317Crossref PubMed Scopus (115) Google Scholar, 22Lorda-Sanchez I. Binkert F. Maechler M. Robinson W.P. Schinzel A.A. Reduced recombination and paternal age effect in Klinefelter syndrome.Hum Genet. 1992; 89: 524-530Crossref PubMed Scopus (95) Google Scholar). The vast majority of Klinefelter cases of paternal origin result from a “nullitransitional” meiosis I nondisjunction, that is, a meiotic division with complete absence of recombination of the PAR regions, but “transitional” (with occurrence of crossing over) paternally derived cases also occur. Maternal cases with either absent or normal recombination have also been described (20Thomas N.S. Hassold T.J. Aberrant recombination and the origin of Klinefelter syndrome.Hum Reprod Update. 2003; 9: 309-317Crossref PubMed Scopus (115) Google Scholar, 23Tempest H.G. Meiotic recombination errors, the origin of sperm aneuploidy and clinical recommendations.Syst Biol Reprod Med. 2011; 57: 93-101Crossref PubMed Scopus (42) Google Scholar). In addition to studies using DNA markers in Klinefelter men (or fetuses) and their parents to assess recombination, direct analysis of 24,XY disomic sperm of a normal 46,XY male showed a significantly lower recombination frequency compared with 23,X or 23,Y sperm (24Shi Q. Spriggs E. Field L.L. Ko E. Barclay L. Martin R.H. Single sperm typing demonstrates that reduced recombination is associated with the production of aneuploid 24,XY human sperm.Am J Med Genet. 2001; 99: 34-38Crossref PubMed Scopus (76) Google Scholar). Not only the number of crossing overs but also the localization of chiasmata seems to be important for meiosis to occur accurately. Crossing overs occurring too near or too far from the centromere have been described in autosomal trisomies: for example, trisomy 21 and trisomy 16. However, the position of recombination was normal in cases with Klinefelter syndrome as reviewed by Lamb et al. (25Lamb N.E. Sherman S.L. Hassold T.J. Effect of meiotic recombination on the production of aneuploid gametes in humans.Cytogenet Genome Res. 2005; 111: 250-255Crossref PubMed Scopus (121) Google Scholar). Maternal age is a well-known risk factor for meiotic nondisjunction, especially in Down syndrome. Bojesen et al. found a 4-fold increase in the prevalence of Klinefelter cases with maternal age greater than 40 years compared with those with maternal age below 24 years (3Bojesen A. Juul S. Gravholt C.H. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study.J Clin Endocrinol Metab. 2003; 88: 622-626Crossref PubMed Scopus (622) Google Scholar). A maternal age effect was also shown in Klinefelter cases with a normal recombination pattern and in cases with postzygotic mitotic nondisjunction (resulting from a mitotic error early in the developing zygote) (20Thomas N.S. Hassold T.J. Aberrant recombination and the origin of Klinefelter syndrome.Hum Reprod Update. 2003; 9: 309-317Crossref PubMed Scopus (115) Google Scholar). The latter could be explained by the fact that in humans the first three mitotic divisions are solely controlled by maternal protein and RNA (26Braude P. Bolton V. Moore S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development.Nature. 1988; 332: 459-461Crossref PubMed Scopus (1112) Google Scholar); with increasing maternal age, the chance of mitotic errors in the first cell divisions increases and therefore perhaps also the chance of Klinefelter syndrome of postzygotic origin. In a recent review of both epidemiologic studies and direct fluorescence in situ hybridization (FISH) studies, Fonseka et al. conclude that there is very little or no evidence for a correlation between paternal age and autosomal aneuploidy and some—albeit debatable—evidence for a relation with sex chromosomal trisomies and paternal age (27Fonseka K.G. Griffin D.K. Is there a paternal age effect for aneuploidy?.Cytogenet Genome Res. 2011; 133: 280-291Crossref PubMed Scopus (34) Google Scholar). So far, aberrant recombination and increased maternal age are the only known factors associated with increased occurrence of nondisjunction. Theoretically, deletions within the PAR1 region could also hamper pairing of the X and Y chromosome and therefore impede recombination, increasing the risk of nondisjunction. This led to the hypothesis that interstitial Y chromosome deletions could be more common in paternally derived Klinefelter cases. However, a study of PAR1 deletions in Klinefelter men of paternal origin with demonstrated failure of recombination did not show an association between the presence of deletions and absence of recombination (28Thomas N.S. Collins A.R. Hassold T.J. Jacobs P.A. A reinvestigation of non-disjunction resulting in 47, XXY males of paternal origin.Eur J Hum Genet. 2000; 8: 805-808Crossref PubMed Scopus (48) Google Scholar). Whether PAR2 deletions are more common in (paternally derived) Klinefelter men is unknown, but not expected given the fact that pairing at the PAR2 region is not required to complete meiosis (14Flaquer A. Rappold G.A. Wienker T.F. Fischer C. The human pseudoautosomal regions: a review for genetic epidemiologists.Eur J Hum Genet. 2008; 16: 771-779Crossref PubMed Scopus (48) Google Scholar, 15Li L. Hamer D.H. Recombination and allelic association in the Xq/Yq homology region.Hum Mol Genet. 1995; 4: 2013-2016Crossref PubMed Scopus (27) Google Scholar). The presence of other deletions on the long arm of the Y chromosome, such as deletions of AZF (azoospermia factor) regions in men with Klinefelter syndrome, has also been the subject of discussion. Although initial studies suggested an increased prevalence of AZF deletions (29Mitra A. Dada R. Kumar R. Gupta N.P. Kucheria K. Gupta S.K. Y chromosome microdeletions in azoospermic patients with Klinefelter's syndrome.Asian J Androl. 2006; 8: 81-88Crossref PubMed Scopus (55) Google Scholar), larger, more recent studies have not detected complete deletions of AZFa, AZFb, or AZFc in men with Klinefelter syndrome, and a prevalence of partial deletions (gr/gr and b2/b3 deletions) similar to karyotypically normal infertile men (30Rajpert-De Meyts E. Ottesen A.M. Garn I.D. Aksglaede L. Juul A. Deletions of the Y chromosome are associated with sex chromosome aneuploidy but not with Klinefelter syndrome.Acta Paediatr. 2011; 100: 900-902Crossref PubMed Scopus (18) Google Scholar, 31Simoni M. Tuttelmann F. Gromoll J. Nieschlag E. Clinical consequences of microdeletions of the Y chromosome: the extended Munster experience.Reprod Biomed Online. 2008; 16: 289-303Abstract Full Text PDF PubMed Scopus (122) Google Scholar). Ten percent to 20% of men with Klinefelter syndrome show a mosaic (mainly 46,XY/47,XXY) karyotype (4Lanfranco F. Kamischke A. Zitzmann M. Nieschlag E. Klinefelter's syndrome.Lancet. 2004; 364: 273-283Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar). Mosaic karyotypes arise from either nondisjunction in an early mitotic division of the developing (46,XY) zygote, or from loss of one of the X chromosomes of a 47,XXY conception (“trisomy rescue”) due to anaphase lagging. Klinefelter syndrome shows a wide phenotypic spectrum, ranging from mild or aspecific (undetected) cases, to sterility, to learning or behavioral problems and/or physical features becoming manifest at an early age. Genomic imprinting, that is, the differential expression of genes depending on parental origin, has been proposed as an explanation for the clinical variability of several features like motor impairment, language problems and growth parameters (21Stemkens D. Roza T. Verrij L. Swaab H. van Werkhoven M.K. Alizadeh B.Z. et al.Is there an influence of X-chromosomal imprinting on the phenotype in Klinefelter syndrome? A clinical and molecular genetic study of 61 cases.Clin Genet. 2006; 70: 43-48Crossref PubMed Scopus (51) Google Scholar). The variable CAG repeat length of the androgen receptor (AR) gene, which is inversely associated with androgen action, has also been studied to demonstrate a possible genotype-phenotype correlation in men with Klinefelter syndrome (32Bojesen A. Hertz J.M. Gravholt C.H. Genotype and phenotype in Klinefelter syndrome—impact of androgen receptor polymorphism and skewed X inactivation.Int J Androl. 2011; 34: e642-e648Crossref PubMed Scopus (50) Google Scholar, 33Zitzmann M. Depenbusch M. Gromoll J. Nieschlag E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients.J Clin Endocrinol Metab. 2004; 89: 6208-6217Crossref PubMed Scopus (183) Google Scholar). A longer AR CAG repeat has been associated with smaller testes (33Zitzmann M. Depenbusch M. Gromoll J. Nieschlag E. X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients.J Clin Endocrinol Metab. 2004; 89: 6208-6217Crossref PubMed Scopus (183) Google Scholar), later onset, and slower progression of puberty and slower testicular degeneration (34Wikstrom A.M. Painter J.N. Raivio T. Aittomaki K. Dunkel L. Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome.Clin Endocrinol (Oxf). 2006; 65: 92-97Crossref PubMed Scopus (51) Google Scholar) in Klinefelter syndrome. Whether genetic imprinting and/or variations in the AR gene CAG repeat length play a role in the fertility phenotype of Klinefelter syndrome, for example, the variable presence of spermatozoa in testicular tissue, is currently unknown. The X chromosome contains over a thousand genes, 10% of which are specifically expressed in the testis (35Ross M.T. Grafham D.V. Coffey A.J. Scherer S. McLay K. Muzny D. et al.The DNA sequence of the human X chromosome.Nature. 2005; 434: 325-337Crossref PubMed Scopus (798) Google Scholar). Mutation analysis of known (X-linked) fertility genes in infertile, karyotypically normal, patients has been largely unsuccessful (36Nuti F. Krausz C. Gene polymorphisms/mutations relevant to abnormal spermatogenesis.Reprod Biomed Online. 2008; 16: 504-513Abstract Full Text PDF PubMed Scopus (125) Google Scholar), probably because the mutation rate in any of these genes is very small and/or because polymorphisms in these genes only have a small effect size and might only lead to fertility problems if associated with other genetic and/or environmental factors. However, a gene dosage effect rather than (inactivating) point mutations can be expected in Klinefelter syndrome. Even though X-inactivation occurs in Klinefelter men as in (46,XX) women (37Tuttelmann F. Gromoll J. Novel genetic aspects of Klinefelter's syndrome.Mol Hum Reprod. 2010; 16: 386-395Crossref PubMed Scopus (107) Google Scholar), about 15% of X-chromosomal genes, as well as genes in the pseudoautosomal regions, consistently escape X-inactivation. An additional 10% is randomly inactivated (38Carrel L. Willard H.F. X-inactivation profile reveals extensive variability in X-linked gene expression in females.Nature. 2005; 434: 400-404Crossref PubMed Scopus (1429) Google Scholar). As a consequence, X-chromosomal genes escaping inactivation have a higher expression level in men with Klinefelter syndrome compared with karyotypically normal men. The overdosage of gene products may compromise testicular function or influence the meiotic process itself and therefore play a role in the etiology of infertility in Klinefelter males. One of the hallmark features of Klinefelter syndrome is azoospermia. From the first description of the syndrome in 1942, patients have therefore been regarded as infertile. However, sperm has been found in the ejaculate in 7.7%–8.4% of (apparently) nonmosaic Klinefelter patients (4Lanfranco F. Kamischke A. Zitzmann M. Nieschlag E. Klinefelter's syndrome.Lancet. 2004; 364: 273-283Abstract Full Text Full Text PDF PubMed Scopus (693) Google Scholar, 39Kitamura M. Matsumiya K. Koga M. Nishimura K. Miura H. Tsuji T. et al.Ejaculated spermatozoa in patients with non-mosaic Klinefelter's syndrome.Int J Urol. 2000; 7 (discussion 93–4): 88-92PubMed Google Scholar). Even a few spontaneous pregnancies in couples with a man with Klinefelter syndrome have been reported in the literature (40Kaplan H. Aspillaga M. Shelley T.F. Gardner L.I. Possible fertility in Klinefelter's syndrome.Lancet. 1963; 1: 506Abstract PubMed Scopus (27) Google Scholar, 41Laron Z. Dickerman Z. Zamir R. Galatzer A. Paternity in Klinefelter's syndrome—a case report.Arch Androl. 1982; 8: 149-151Crossref PubMed Scopus (84) Google Scholar, 42Terzoli G. Lalatta F. Lobbiani A. Simoni G. Colucci G. Fertility in a 47,XXY patient: assessment of biological paternity by deoxyribonucleic acid fingerprinting.Fertil Steril. 1992; 58: 821-822PubMed Scopus (92) Google Scholar, 43Warburg E. A fertile patient with Klinefelter's syndrome.Acta Endocrinol (Copenh). 1963; 43: 12-26PubMed Google Scholar). Moreover, with currently available assisted reproduction techniques such as TESE, sperm can be recovered from the testes of Klinefelter patients in about half of the cases (44Selice R. Di Mambro A. Garolla A. Ficarra V. Iafrate M. Ferlin A. et al.Spermatogenesis in Klinefelter syndrome.J Endocrinol Invest. 2010; 33: 789-793PubMed Google Scholar, 45Fullerton G. Hamilton M. Maheshwari A. Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009?.Hum Reprod. 2010; 25: 588-597Crossref PubMed Scopus (114) Google Scholar). The rate of sperm retrieval might be higher using the more recent surgical technique of microdissection TESE (55% compared with 42% as reviewed by Fullerton et al.) (45Fullerton G. Hamilton M. Maheshwari A. Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009?.Hum Reprod. 2010; 25: 588-597Crossref PubMed Scopus (114) Google Scholar). Using this sperm for ICSI offers a considerable number of Klinefelter men the opportunity to father their own genetic children. Together with these successes, concerns about the risk of (sex chromosomal) aneuploidy in these children have been raised. However, even though the aneuploidy rate of sperm from Klinefelter men appears to be increased compared with fertile controls (46Giltay J.C. van Golde R.J. Kastrop P.M. Analysis of spermatozoa from seven ICSI males with constitutional sex chromosomal abnormalities by fluorescent in situ hybridization.J Assist Reprod Genet. 2000; 17: 151-155Crossref PubMed Scopus (24) Google Scholar), the risks for the offspring appear to be small, with 1 XXY pregnancy in more than 100 children born after TESE-ICSI in males with nonmosaic Klinefelter syndrome reported in the literature (7Giltay J.C. Maiburg M.C. Klinefelter syndrome: clinical and molecular aspects.Expert Rev Mol Diagn. 2010; 10: 765-776Crossref PubMed Scopus (27) Google Scholar). How can this low (sex chromosomal) aneuploidy rate in children born from Klinefelter fathers be explained? This question has brought renewed attention to the discussion of how spermatogenesis (in particular meiosis) in men with Klinefelter syndrome occurs. Two hypotheses on how spermatogenesis occurs in Klinefelter men have been brought forward. According to some investigators, 47,XXY spermatogonia have the potential to complete meiosis, explaining both the increase in sex chromosomal aneuploidy rate as well as the presence of normal (haploid) spermatozoa (Fig. 1A) (47Foresta C. Galeazzi C. Bettella A. Marin P. Rossato M. Garolla A. et al.Analysis of meiosis in intratesticular germ cells from subjects affected by classic Klinefelter's syndrome.J Clin Endocrinol Metab. 1999; 84: 3807-3810Crossref PubMed Google Scholar, 48Yamamoto Y. Sofikitis N. Mio Y" @default.
• W2055039739 created "2016-06-24" @default.
• W2055039739 creator A5002367526 @default.
• W2055039739 creator A5062562983 @default.
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• W2055039739 date "2012-08-01" @default.
• W2055039739 modified "2023-10-16" @default.
• W2055039739 title "The genetic origin of Klinefelter syndrome and its effect on spermatogenesis" @default.
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