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Sexual development in XXY boys compared with controls, aged 16-18 years (number of boys at each stage)
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Twelve boys with Klinefelter's syndrome (47,XXY) identified by sex chromatin screening at birth were examined at between ages 16 and 18 years, together with 12 controls matched for social class and birth order from the same newborn population. Physical examination, psychometric assessment, personality, and degree of psychosexual development were as...
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... although the recorded duration is slightly longer than the controls. The Edinburgh newborn cytogenetic survey reported here 5/14 (36%)[2] and Ratcliffe et al. in a study of adolescent KS boys in Edinburgh identified by a previous newborn chromatin survey found a prevalence of 4/11 (36.4%) at age 16 years[18]. Stewart et al. in the Toronto newborn cytogenetic survey follow-up study found 7/28 (25%) by age 18 years[5], and Robinson et al. ...
The aim was to define the true incidence of gynaecomastia in adolescent boys with Klinefelter syndrome (KS) and to observe testosterone treatment effects on its duration by examination of the prospectively collected data from a specialist referral clinic for boys with KS, with comparison being made with KS boys identified by a historical newborn chromosome screening programme, together with chromosomally normal controls. Fifty-nine boys over age 13 years were referred to a specialist KS clinic; 21 developed gynaecomastia. The comparator was 14 KS boys identified at birth and 94 chromosomally normal control boys. Testosterone was routinely started at the onset of puberty if gynaecomastia, a manifestation of clinical hypogonadism, was present. Oral or transdermal testosterone was administered in the morning, in a reverse physiological rhythm, and doses were increased according to standard pubertal regimens. The incidence of gynaecomastia was not increased in both the KS cohorts compared with controls. The incidence and age of onset of gynaecomastia was 35.6%, at 12.3 (1.8) years in the KS clinic group; 36.0%, at 13.7 (0.6) years in the newborn survey group; and 34.0%, at 13.6 (0.8) years in the controls. Full resolution of the gynaecomastia occurred in the 12/14 KS clinic boys on testosterone treatment who had completed puberty and as long as adherence was maintained.
Conclusion: The incidence of gynaecomastia in KS boys (overall 35.6%) is not increased over typically developing boys. Commencing testosterone when gynaecomastia develops with physiological dose escalation and full adherence can result in the resolution of the gynaecomastia. What is Known:
• Gynaecomastia is a common feature in Klinefelter syndrome men.
• Hypogonadism occurs from mid-puberty onwards with the absence of the usual rise in testosterone levels.
What is New:
• The incidence of pubertal gynaecomastia in Klinefelter syndrome is not different from typically developing boys.
• Early and prompt starting of testosterone gel treatment and increasing the dose physiologically may help to resolve the gynaecomastia without the need for surgery.
... After infancy, Leydig cells are in a quiescent stage until puberty. Therefore, symptoms of testosterone deficiency appear at the earliest during adolescence (Ratcliffe et al., 1982;Rey et al., 2011). Testis histology of adolescent patients has revealed Leydig cell hyperplasia and hypertrophy, with fibrosis and hyalinization of the interstitium and peritubular connective tissue (Gordon et al., 1972;Wikstrom et al., 2004;Aksglaede et al., 2006;Wikstr€ om et al., 2007). ...
... The presence of spermatozoa was related neither to androgen receptor CAGn length nor to TVs achieved during puberty. As shown earlier, TVs scarcely increased during puberty (Ratcliffe et al., 1982;Wikstr€ om et al., 2006). This impaired testicular growth is the consequence of continuous apoptotic germ cell loss that starts during foetal life or early 6 Andrology, 1-9 infancy, and a lacking elongation of most of the seminiferous tubules during adolescence (Coerdt et al. 1985;Aksglaede et al., 2006;Sciurano et al., 2009;Vialard et al. 2012). ...
... Testosterone levels are significantly lower in Klinefelter men, starting at puberty (Smyth and Bremner 1998). Furthermore, Klinefelter boys are less likely to show stereotypical masculine interests, and are less sexually interested in girls compared to their 46,XY counterparts (Ngun et al. 2014) which could be a consequence of lower testosterone levels at puberty Ratcliffe et al. 1982). This lower testosterone level could also be involved in the increased rate of gender disconformity observed among Klinefelter males. ...
Gender Dysphoria is characterized by a marked incongruence between the cerebral sex and biological sex. To investigate the possible influence of karyotype on the etiology of Gender Dysphoria we carried out the cytogenetic analysis of karyotypes in 444 male-to-females (MtFs) and 273 female-to-males (FtMs) that attended the Gender Identity Units of Barcelona and Málaga (Spain) between 2000 and 2016. The karyotypes from 23 subjects (18 MtFs and 5 FtMs) were also analysed by Affymetrix CytoScan™ high-density (HD) arrays. Our data showed a higher incidence of cytogenetic alterations in Gender Dysphoria (2.65%) than in the general population (0.53%) (p < 0.0001). When G-banding was performed, 11 MtFs (2.48%) and 8 FtMs (2.93%) showed a cytogenetic alteration. Specifically, Klinefelter syndrome frequency was significantly higher (1.13%) (p < 0.0001), however Turner syndrome was not represented in our sample (p < 0.61). At molecular level, HD microarray analysis revealed a 17q21.31 microduplication which encompasses the gene KANSL1 (MIM612452) in 5 out of 18 MtFs and 2 out of 5 FtMs that corresponds to a copy-number variation region in chromosome 17q21.31. In conclusion, we confirm a significantly high frequency of aneuploidy, specifically Klinefelter syndrome and we identified in 7 out of 23 GD individuals the same microduplication of 572 Kb which encompasses the KANSL1 gene.
... After infancy, Leydig cells are in a quiescent stage until puberty. Therefore, symptoms of testosterone deficiency appear at the earliest during adolescence (Ratcliffe et al., 1982;Rey et al., 2011). Testis histology of adolescent patients has revealed Leydig cell hyperplasia and hypertrophy, with fibrosis and hyalinization of the interstitium and peritubular connective tissue (Gordon et al., 1972;Wikstrom et al., 2004;Aksglaede et al., 2006;Wikstr€ om et al., 2007). ...
... The presence of spermatozoa was related neither to androgen receptor CAGn length nor to TVs achieved during puberty. As shown earlier, TVs scarcely increased during puberty (Ratcliffe et al., 1982;Wikstr€ om et al., 2006). This impaired testicular growth is the consequence of continuous apoptotic germ cell loss that starts during foetal life or early 6 Andrology, 1-9 infancy, and a lacking elongation of most of the seminiferous tubules during adolescence (Coerdt et al. 1985;Aksglaede et al., 2006;Sciurano et al., 2009;Vialard et al. 2012). ...
Patients with Klinefelter's syndrome experience progressive testicular degeneration resulting in impaired endocrine function and azoospermia. What proportion of adolescents develop testosterone deficiency during puberty and how many have spermatozoa in their semen is unclear to date. We aimed to investigate testicular function during puberty and young adulthood in patients with Klinefelter's syndrome and to assess testosterone effects in target tissues. The clinical data of 281 patients with non-mosaic Klinefelter's syndrome aged 10-25 years without previous testosterone replacement were reviewed. In late pubertal adolescents, semen analyses were evaluated, and testicular volumes, hormone and haemoglobin (Hb) levels, the number of CAG repeats and final height data were compared to those of 233 age-matched controls with pubertal gynaecomastia. Spontaneous pubertal virilisation to Tanner stages IV-V occurred. Serum T levels ≥10 nmol/L were reached in 62% of patients with Klinefelter's syndrome and in 85% of controls at ages 15-25 (TKFS : 12.2 ± 5.4 vs. TC : 16.6 ± 7.2 nmol/L). LHKFS levels were elevated >10 U/L in 84%, and normal in all controls (LHKFS : 18.6 ± 12.2 vs. LHC : 3.5 ± 1.6 U/L). In nine of 130 (7%) adolescents with Klinefelter's syndrome, spermatozoa (oligozoospermia) were found in semen; all had T levels >7 nmol/L and eight of nine had LH levels ≤18 U/L, while their hormone levels, number of CAG repeats and testicular volumes were not different from those of adolescents with azoospermia. Controls had normal sperm concentrations in 73% (46/63). Semen volumesKFS were normal in 55% vs. 78% in controls; HbKFS was normal in 89% (HbC : 97%). Mean final heightKFS was 185 ± 8 cm vs. 181 ± 7 cm in controls. Hypergonadotropic hypogonadism develops during early puberty in adolescents with Klinefelter's syndrome and remains compensated in over 60% during ages 15-25, with sufficient testosterone secretion for spontaneous accomplishment of pubertal development. Spermatozoa in semen are rare and associated with T levels >7 nmol/L. Parameters reflecting androgen deficiency in target tissues may help to optimise timing of testosterone substitution, which should preferably not be initiated before fertility status has been clarified.
... A different explanation for the significant higher gender dysphoric symptoms observed in KS individuals can be related to the decreased masculine behavior and gender nonconformity previously reported in this population [52][53][54]. In particular, it has been observed that KS boys feel more negatively about their male gender role and are judged less masculine by the peer group [54], which can be-according to some authors [53,55]-a consequence of lower testosterone levels at midpuberty [56]. ...
Introduction:
An increased risk of autistic traits in Klinefelter syndrome (KS) has been reported. In addition, some studies have shown an increased incidence of gender dysphoria (GD) and paraphilia in autism spectrum disorder.
Aim:
The aim of this study was to evaluate the presence of (i) paraphilic fantasies and behaviors; and (ii) GD symptomatology in KS.
Methods and main outcomes measures:
A sample of 46 KS individuals and 43 healthy male controls (HC) were evaluated. Subjects were studied by means of several psychometric tests, such as Autism Spectrum Quotient (AQ) and Reading the Mind in the Eyes Revised (RME) to measure autistic traits, Gender Identity/GD questionnaire (GIDYQ-AA), and Sexual Addiction Screening Test (SAST). In addition, body uneasiness psychopathological symptoms were assessed using Symptom Checklist 90 Revised (SCL-90-R). The presence and frequency of any paraphilic fantasy and behavior was assessed by means of a clinical interview based on Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria. Finally, all individuals included were assessed by Wechsler Adult Intelligence Scale-Revised to evaluate intelligence quotient (IQ). Data from a subsample of a previous published series of male to female GD individuals, with the battery of psychological measures useful to provide a psychopathological explanation of GD in KS population available, was also considered.
Results:
When compared with HC, KS reported significantly lower total, verbal and performance IQ scores and higher SCL-90 obsession-compulsive symptoms (all P < 0.001). In line with previously reported findings, KS showed higher autistic traits according with both RME and AQ tests (P < 0.001). With respect to sexuality, KS showed a significant higher frequency of voyeuristic fantasies during masturbation (52.2% vs. 25.6%) and higher SAST scores (P = 0.012). A mediation role of obsessive symptoms on the relationship between Klinefelter and SAST was confirmed (unstandardized estimate b = 2.75, standard error = 0.43 P < 0.001). Finally, KS individuals showed significantly higher gender dysphoric symptoms than HC (P = 0.004), which were mediated by the presence of autistic traits (Sobel's test; P < 0.05).
Conclusions:
KS is associated with hypersexuality, paraphilic behaviors, and GD, which were mediated by obsessive-compulsive and autistic traits. Alessandra D. Fisher, Giovanni Castellini, Helen Casale, Egidia Fanni, Elisa Bandini, Beatrice Campone, Naika Ferruccio, Elisa Maseroli, Valentina Boddi, Davide Dèttore, Alessandro Pizzocaro, Giancarlo Balercia, Alessandro Oppo, Valdo Ricca, and Mario Maggi. Hypersexuality, paraphilic behaviors, and gender dysphoria in individuals with Klinefelter's syndrome. J Sex Med **;**:**-**.
... A different explanation for the significant higher gender dysphoric symptoms observed in KS individuals can be related to the decreased masculine behavior and gender nonconformity previously reported in this population [52][53][54]. In particular, it has been observed that KS boys feel more negatively about their male gender role and are judged less masculine by the peer group [54], which can be-according to some authors [53,55]-a consequence of lower testosterone levels at midpuberty [56]. ...
... Measured cord-blood testosterone in two 47, XXY infants and one with mosaicism (46, XX/47, XXY) revealed significantly lower levels than in three control infants, 41 and the peak of testosterone during the period between 30 and 80 days after the birth when testosterone and gonadotropin surges occur in male infants, called mini-puberty, is lower in KS men than in a control population, indicating an early damage of Leydig cell function. 42 A low risk of death from prostate cancer in KS subjects has been described, which could be linked to lower testosterone levels. 12 The influence of hypogonadism and testosterone replacement therapy on the incidence of testicular cancer is not clear. ...
Klinefelter syndrome (KS) is a hypergonadotropic hypogonadism characterized by a 47, XXY karyotype. The risk of testicular cancer in KS is of interest in relation to theories about testicular cancer etiology generally; nevertheless it seems to be low. We evaluated the need for imaging and serum tumor markers for testicular cancer screening in KS. Participants were 40 consecutive KS patients, enrolled from December 2009 to January 2013. Lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and beta-human chorionic gonadotrophin subunit (β-HCG) serum levels assays and testicular ultrasound (US) with color Doppler, were carried out at study entry, after 6 months and every year for 3 years. Abdominal magnetic resonance (MR) was performed in KS when testicular US showed micro-calcifications, testicular nodules and cysts. Nearly 62% of the KS had regular testicular echotexture, 37.5% showed an irregular echotexture and 17.5% had micro-calcifications and cysts. Eighty seven percent of KS had a regular vascular pattern, 12.5% varicocele, 12.5% nodules <1 cm, but none had nodules >1 cm. MR ruled out the diagnosis of cancer in all KS with testicular micro calcifications, nodules and cysts. No significant variations in LDH, AFP, and β-HCG levels and in US pattern have been detected during follow-up. We compared serum tumor markers and US pattern between KS with and without cryptorchidism and no statistical differences were found. We did not find testicular cancer in KS, and testicular US, tumor markers and MR were, in selected cases, useful tools for correctly discriminating benign from malignant lesions.
... Thirdly, there is an increased rate of homosexual behavior and gender non-conformity among KS males Schiavi, Theilgaard, Owen, & White, 1988;Theilgaard, 1984). For instance, KS boys have more problems relating to other boys, are less likely to show stereotypically masculine interests, and are less sexually interested in girls compared to their 46,XY counterparts-which could be a consequence of lower T levels at puberty Ratcliffe, Bancroft, Axworthy, & McLaren, 1982). Similarly, KS men feel more negatively about conventional gender roles during childhood, judged as less masculine by others, and have poorer self-esteem in adulthood compared to control males (Schiavi et al., 1988). ...
Klinefelter Syndrome (KS) is the most common sex chromosome aneuploidy in men and is characterized by the presence of an additional X chromosome (XXY). In some Klinefelter males, certain traits may be feminized or shifted from the male-typical pattern towards a more female-typical one. Among them might be partner choice, one of the most sexually dimorphic traits in the animal kingdom. We investigated the extent of feminization in XXY male mice (XXYM) in partner preference and gene expression in the bed nucleus of the stria terminalis/preoptic area and the striatum in mice from the Sex Chromosome Trisomy model. We tested for partner preference using a three-chambered apparatus in which the test mouse was free to choose between stimulus animals of either sex. We found that partner preference in XXYM was feminized. These differences were likely due to interactions of the additional X chromosome with the Y. We also discovered genes that differed in expression in XXYM versus XYM. Some of these genes are feminized in their expression pattern. Lastly, we also identified genes that differed only between XXYM versus XYM and not XXM versus XYM. Genes that are both feminized and unique to XXYM versus XYM represent strong candidates for dissecting the molecular pathways responsible for phenotypes present in KS/XXYM but not XXM. In sum, our results demonstrated that investigating behavioral and molecular feminization in XXY males can provide crucial information about the pathophysiology of KS and may aid our understanding of sex differences in brain and behavior.
... We did not observe spermaturia despite the fact that all subjects with KS were older than 12 years at the first urine collection and they all performed at least one urine collection, over a 5-day consecutive morning sampling period. Also, Ratcliffe et al. (1982) could not find spermatozoa in the morning urine in a group of 12 pubertal boys with KS, but in their study only one urine collection was done and all their patients were older than 16 years. In early puberty, spermaturia in first-voided morning samples may result from predominantly spontaneous and continuous nocturnal sperm flow to the urinary tract, while in late adolescence intermittent masturbatory ejaculations are thought to be responsible for the finding of more variable spermaturia. ...
Although germ cells in boys with Klinefelter syndrome (KS) are reduced in number as early as infancy, a severe germ cell loss occurs during mid-puberty. Therefore, we wanted to detect spermatogenesis at an early stage and investigate the strategy of preserving spermatozoa and/or testicular spermatogonial stem cells in adolescents with KS when signs of deteriorating spermatogenesis are observed.
Tanner staging, testicular size, serum inhibin B and spermaturia were assessed every 4 months before the attempt to procure gametogenic cells in seven non-mosaic 47,XXY adolescents, aged between 10 and 16 years.
Despite an increasing testis volume in the youngest and a Tanner staging of more than three in the oldest patients, no spermaturia was observed. In two patients serum inhibin B increased gradually, while in all others a rather rapid but variable decline was observed at different ages. No spermatozoa were observed after electroejaculation. No spermatocytes or spermatids were found at microscopic examination of single biopsies, while spermatogonia were identified in four subjects, three of whom had measurable serum inhibin B. Massive fibrosis and hyalinization were observed in all biopsies.
No spermatogenesis was documented in non-mosaic 47,XXY adolescents either by spermaturia, electroejaculation or testicular biopsy. Neither clinical nor hormonal parameters were of value in determining the timing for optimal spermatogonial stem cell retrieval. More data are needed to elucidate the potential role of testicular tissue cryopreservation in adolescents with KS. Therefore, at present, the cryopreservation of testes tissue for clinical reasons should not be recommended.
... For example, testosterone deficiencies have been reported in infants with KS, and some boys with KS maintain low levels of testosterone throughout childhood (Topper et al., 1982, Ross et al., 2005. In addition, some individuals with KS do not experience pubertal testicular enlargement, whereas others experience varying degrees of enlargement (Ratcliffe et al., 1982). This variability complicates definition of specific pubertal milestones in KS. ...
Klinefelter syndrome (KS) is a genetic disorder characterized by a supernumerary X chromosome. As such, KS offers a naturally occurring human model for the study of both X-chromosome gene expression and androgen on brain development. Previous neuroimaging studies have revealed neuroanatomical variations associated with KS, but have differed widely with respect to subject inclusion criteria, including mosaicism, pubertal status, and history of testosterone replacement therapy (TRT), all factors likely to influence neurodevelopment. We conducted a voxel-based morphometry study of regional gray and white matter (GM and WM, respectively) volumes in 31 KS males (mean age, 9.69 ± 1.70 years) and 36 typically developing (TD) male controls (10.99 ± 1.72 years). None of the participants with KS had received TRT, and all were prepubertal and had nonmosaic 47,XXY karyotypes. After controlling for age, males with KS showed trends (0.05 < p < 0.10) for significantly reduced total gray matter volume (TGMV) and total white matter volume (TWMV), relative to TD males. After controlling for TGMV and age, the KS group had significantly increased sensorimotor and parietal-occipital GM and significantly reduced amygdalar, hippocampal, insular, temporal, and inferior frontal GM relative to TD controls. After controlling for TWMV and age, the KS group had significantly increased left parietal WM as well as significantly reduced frontal and temporal WM. These findings are indicative of a characteristic prepubertal neuroanatomical phenotype that may be associated with cognitive-behavioral features of KS. This work offers new insight into the relationships among X-chromosome gene expression, neuroanatomy, and cognitive-behavioral functions impaired in KS, including language and attention.
