Phenotypic and Fertility Variability in Klinefelter Syndrome: Evidence of Natural Fatherhood in Non-Mosaic 47,XXY Men and Rare 48,XXYY Cases

Phenotypic and Fertility Variability in Klinefelter Syndrome: Evidence of Natural Fatherhood in Non-Mosaic 47,XXY Men and Rare 48,XXYY Cases | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Phenotypic and Fertility Variability in Klinefelter Syndrome: Evidence of Natural Fatherhood in Non-Mosaic 47,XXY Men and Rare 48,XXYY Cases İlyas Yücel, Gülbahar Güzel Erdal, Ğarip Demir, Mahmut Balkan, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8144683/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Apr, 2026 Read the published version in Endocrine → Version 1 posted 9 You are reading this latest preprint version Abstract Purpose Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in males, characterised primarily by the 47,XXY karyotype. The syndrome exhibits significant clinical and genetic variability and can affect reproductive capacity. This study aims to investigate variability in phenotypic characteristics according to age group and karyotype, and to evaluate rare reproductive outcomes such as natural fatherhood, as well as specific conditions such as gender dysphoria. Methods A retrospective review was conducted on 40 KS patients (28 adult males, 2 adults with gender dysphoria [GD], and 10 pediatric patients) diagnosed between 2020 and 2025. Clinical features, hormone levels (FSH, LH, estradiol, testosterone), testicular volumes, karyotypes, and semen analyses (using the 2020 World Health Organization [WHO] criteria) were evaluated. Mosaicism was confirmed through FISH. Results Among 40 patients, 36 (90%) had non-mosaic 47,XXY, 2 (5%) were mosaic 46,XY/47,XXY, and 2 (5%) had 48,XXYY karyotypes. Pediatric patients had age-appropriate hormones and small testes without hypogonadism. Adults displayed hypergonadotropic hypogonadism, reduced testicular volume (mean 4.9 ± 0.2 mL), and varied semen profiles: azoospermia 60%, oligospermia 30%, normospermia 10%. Notably, two non-mosaic 47,XXY men achieved natural conception. GD adults showed similar endocrine profiles with hypogonadism. Conclusion Although rare, normospermia and natural fatherhood are possible in KS, highlighting the need for early diagnosis, individualized management, and fertility preservation strategies to optimize reproductive outcomes and quality of life. Klinefelter syndrome 47 XXY Spontaneous paternity Natural fatherhood Normospermia 48 XXYY variant Sex chromosome aneuploidy gender dysphoria Background KS is the most common sex chromosome aneuploidy in males, occurring in approximately 1 in 500–1,000 live male births [1–3]. It is defined by the presence of one or more extra X chromosomes and was first described by Dr. Harry Klinefelter in 1942 [3]. Most patients carry the classic 47,XXY karyotype, while about 10% exhibit mosaic forms (46,XY/47,XXY) or higher-order aneuploidies, such as 48,XXXY, 48,XXYY, or 49,XXXXY [4,5]. KS typically arises from errors in meiotic segregation during gametogenesis, with the extra X chromosome inherited from either maternal or paternal gametes [6,7]. Paternally derived aneuploidy occurs only during meiosis I, whereas maternal KS can result from errors in meiosis I or II, with meiosis II errors more common [8]. Advanced maternal age has been associated with increased KS incidence, whereas the effect of paternal age remains controversial [9]. Less common genetic types include other numerical aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY), mosaicism (46,XY/47,XXY), and structural abnormalities of sex chromosomes [10]. Patients with higher-order aneuploidies often present with more severe phenotypes, including congenital malformations, taller stature, and more pronounced cognitive or motor delays, whereas mosaic patients generally show milder phenotypes with larger testicular volumes and higher sperm counts [10,11]. The underlying pathology of KS involves increased susceptibility to meiotic errors during spermatogenesis, leading to aneuploid or polyploid gametes. Genetic contributors include polymorphisms in checkpoint genes regulating chromosomal synapsis and segregation. Physiologically, the additional X chromosome disrupts interstitial and Sertoli cell function, altering testicular endocrinology and metabolism and collectively impairing normal sperm development [12,13]. Spermatogenesis is usually severely impaired in KS, and azoospermia is detected in approximately 90% of patients. However, in some cases, limited preserved spermatogenic activity may be present, enabling biological fatherhood through assisted reproductive techniques such as testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) [12–14]. Epigenetic mechanisms play an important role in KS. Irregularities in DNA methylation and histone modifications can affect genes that are involved in sexual development, cognitive function and metabolism. These irregularities can lead to gonadal insufficiency, hormonal imbalance, and behavioural differences. Incomplete inactivation of the X chromosome contributes to the emergence of characteristic phenotypic features by preventing the silencing of certain genes. Increased copy number variations (CNVs) amplify the gene dosage effect, thereby enhancing phenotypic diversity. X-linked CNVs are more prevalent in KS patients [8,15–19].These genetic and epigenetic factors explain the biological basis of reproductive disorders and phenotypic heterogeneity in KS. Furthermore, molecular findings guide clinical approach, patient follow-up, and assisted reproductive technologies (ART) [17–21]. The clinical presentation of KS is highly variable. In newborns, micropenis, hypospadias or undescended testicles may be observed, while hypergonadotropic hypogonadism usually manifests during puberty. In adult males, gynecomastia, incomplete virilisation, progressive testicular failure and infertility are common. Laboratory tests usually show increased FSH and LH levels and decreased testicular volume; testicular degeneration may be associated with impaired germ cell maturation, Sertoli–Leydig cell dysfunction, X-inactive specific transcript (XIST) abnormalities, or PAR1 gene overexpression [22–25]. KS is also associated with multisystem comorbidities such as metabolic syndrome, type 2 diabetes, cardiovascular disease, osteoporosis, eye and dental problems, and certain types of cancer; depression and anxiety also increase morbidity [26,27]. This retrospective study includes 40 cases of KS confirmed by karyotype analysis. The aim of the study was to describe the clinical, hormonal, and reproductive characteristics of KS in different age groups in greater detail and to determine the most appropriate approaches to reproductive health and fertility preservation. Study Design and Participants This retrospective study examined patients diagnosed with KS at Dicle University Hospital between 2020 and 2025. Inclusion criteria included a confirmed KS diagnosis by karyotype analysis, complete clinical and hormonal data, and at least one semen analysis for adults. Patients were excluded if they had undergone prior testicular surgery, had a history of chemotherapy or radiotherapy, or had incomplete medical records. The study population consisted of 28 adult males, 2 GD adults, and 10 pediatric patients. GD individuals had not received gender-affirming hormonal therapy prior to evaluation. Pediatric patients were prepubertal at the time of assessment. Mosaic cases were evaluated using standard cytogenetic analysis, and suspected mosaicism was further confirmed by fluorescence in situ hybridization (FISH) on at least 100 interphase cells to ensure accurate detection of abnormal cell lines. All participants underwent an evaluation of their clinical features, hormonal profiles (serum FSH, LH, estradiol and total testosterone) and testicular characteristics. Semen analysis was performed only in adult patients and followed WHO 2020 criteria. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University XXX (06.02.2020./No: 125). Informed consent was obtained from all individual participants included in the study. Hormonal Assessment Serum levels of follicle-stimulating hormone (FSH), luteinising hormone (LH), estradiol, and total testosterone were measured for all participants. Analyses were carried out using the Siemens ADVIA Centaur XP analyser and Immulite 2000 XPi kits, following standard laboratory procedures recommended by the manufacturer. Testis Volume Measurement Testis volumes were measured by an experienced urologist using ultrasonography (USG). Volume calculations were based on measurements of the length, width, and thickness of the testis. Karyotype Analysis Cytogenetic karyotyping was performed on peripheral blood lymphocyte cultures. At least 20 metaphase cells were examined for each patient to attempt to detect a 47,XXY karyotype. In cases with suspected mosaicism, extended cytogenetic analysis was performed to characterise the abnormal cells in more detail. Sperm Analysis Sperm samples were collected after 2–3 days of sexual abstinence. Analysis parameters were evaluated according to the 2020 WHO criteria; ejaculate volume, sperm concentration, motility, morphology, and viability were measured[28]. All analyses were performed at the Dicle University Andrology Laboratory in accordance with standard protocols. Sperm concentration, motility, and morphology were assessed using the Hamilton Thorne Computer-Assisted Sperm Analysis (CASA) system, while sperm viability was assessed using the Eosin–Nigrosin staining method. Statistical Analysis Data were analysed using SPSS version 22.0. Continuous variables were presented as mean ± standard deviation (SD) or median with interquartile range (IQR) according to their distribution. Relationships between hormonal parameters and testicular volume were evaluated using Pearson or Spearman correlation analyses, as appropriate. Results with p < 0.05 were considered significant. Results The patient population studied consisted of 28 adult males, 2 GD adults, and 10 pediatric patients.Pediatric patients had prepubertal hormone levels (mean FSH 1.8 ± 0.4, LH 0.9 ± 0.25 mIU/mL, testosterone 1.2 ± 0.3 nmol/L) and small testicular volumes (mean 1.2 ± 0.3 mL) with no signs of hypogonadism, reduced libido, or gynecomastia (Tables 1 – 2 ). Table 1 Hormonal profiles in pediatric, adult, and GD patients with KS Group Parameter n Mean (SE) Median (IQR) Range Normal Range Child Age (years) 10 8.5 (0.8) 8.0 (7.0–9.0) 6.0–10.0 - Child FSH (mIU/mL) 10 1.8 (0.4) 1.6 (1.2–2.0) 0.5–3.5 0.5-4.0 Child LH (mIU/mL) 10 0.9 (0.25) 0.8 (0.6–1.2) 0.1–2.5 0.1–3.0 Child Estradiol (pg/mL) 10 10.5 (2.0) 9.0 (8.0–12.0) 5.0–20.0 5–20 Child Testosterone (nmol/L) 10 1.2 (0.3) 1.0 (0.8–1.4) 0.3–2.5 0.1–3.0 Adult Age (years) 30 30.28 (1.62) 30.0 (26.0–34.0) 11.0–47.0 - Adult FSH (mIU/mL) 30 26.84 (3.36) 25.55 (19.68–33.25) 0.25–63.94 1.5–12.4 Adult LH (mIU/mL) 30 16.47 (1.77) 16.88 (12.9–19.76) 0.07–35.53 1.7–8.6 Adult Estradiol (pg/mL) 30 30.69 (5.34) 26.33 (25.38–33.82) 24.43–41.31 10–40 Adult Testosterone (nmol/L) 30 9.85 (0.45) 9.7 (8.9–10.8) 5.2–11.9 12–35 Adult Trans Age (years) 2 29.5 (0.5) 29.5 (29.0–30.0) 29–30 - Adult Trans FSH (mIU/mL) 2 10.0 (1.0) 10.0 (9.5–10.5) 9–11 1.5–12.4 Adult Trans LH (mIU/mL) 2 8.0 (0.8) 8.0 (7.5–8.5) 7–9 1.7–8.6 Adult Trans Estradiol (pg/mL) 2 35.0 (2.0) 35.0 (34–36) 33–37 10–40 Adult Trans Testosterone (nmol/L) 2 5.0 (0.5) 5.0 (4.5–5.5) 4–6 12–35 Table 2 Clinical features in pediatric, adult, and GD patients with KS Group Parameter n Mean (SE) Median (IQR) Range Normal Range Child (n = 10) Height 10 136 ± 4 136 (133–139) 128–142 128–138 Child Total Testicular Volume (mL) 10 1.2 (0.3) 1.1 (0.9–1.4) 0.5–2.0 0.5–3 Child Hypogonadism (%) 10 0 (–) 0 (0–0) 0 < 1.0 nmol/L testosterone (prepubertal) Child Decreased Libido (%) 10 0 (–) 0 (0–0) 0 – Child Gynecomastia (%) 10 0 (–) 0 (0–0) 0 – Child Height (m) 10 1.28 (0.15) 1.30 (1.20–1.35) 1.10–1.45 – Child Biacromial Diameter (cm) 10 30 (1.2) 30 (29–31) 28–32 – Adult (n = 28) Total Testicular Volume (mL) 28 4.9 (0.2) 4.8 (4.0–5.5) 3.0–7.0 24–60 Adult Hypogonadism (%) 28 50 (–) 48 (42–55) 35–65 < 12 nmol/L testosterone Adult Decreased Libido (%) 28 52 (–) 50 (45–55) 35–65 – Adult Gynecomastia (%) 28 32 (–) 30 (25–35) 20–45 – Adult Height (m) 28 1.83 (0.05) 1.82 (1.78–1.86) 1.72–1.92 – Adult Biacromial Diameter (cm) 28 42 (1.5) 42 (41–44) 39–46 – Trans (n = 2) Total Testicular Volume (mL) 2 4.0 (0.3) 4.0 (3.7–4.3) 3.5–4.5 24–60 Trans Hypogonadism (%) 2 100 (–) 100 (100–100) 100 < 12 nmol/L testosterone Trans Decreased Libido (%) 2 100 (–) 100 (100–100) 100 – Trans Gynecomastia (%) 2 50 (–) 50 (50–50) 50 – Trans Height (m) 2 1.80 (0.03) 1.80 (1.78–1.82) 1.77–1.82 – Trans Biacromial Diameter (cm) 2 41 (0.5) 41 (40.5–41.5) 40–42 – Adult patients exhibited hypergonadotropic hypogonadism with elevated gonadotropins (FSH 26.8 ± 3.36, LH 16.47 ± 1.77 mIU/mL) and decreased testosterone (9.85 ± 0.45 nmol/L), and moderately increased estradiol (30.7 ± 5.34 pg/mL). Mean testicular volume was 4.9 ± 0.2 mL. Clinically, 50% reported low libido, 32% had gynecomastia, and 47% showed biochemical hypogonadism. Mean height was 1.83 ± 0.05 m, and biacromial diameter was 42 ± 1.5 cm (Tables 1 – 2 ). GD adults had similar endocrine profiles, testicular volumes averaging 4.0 ± 0.3 mL, and exhibited hypogonadism and decreased libido; 50% had gynecomastia. Semen analyses of adult patients showed 60% azoospermia, 30% oligospermia, and 10% normospermia (Table 3 ). Two adults (5%) achieved spontaneous fatherhood (both 47,XXY). Karyotypes included 36 47,XXY, 2 mosaic 46,XY/47,XXY, and 2 48,XXYY. Both GD patients were 47,XXY and azoospermic. Table 3 The distribution of karyotypes and semen analysis in KS patients. Parameter Number of Patients Percentage (%) Karyotype Distribution Azoospermia 18 60% 16: 47,XXY, 2: 48,XXYY Oligospermia 9 30% 1:46XY/47,XXY 8:47,XXY Normospermia 3 10% All 46XY/47,XXY Spontaneous Fatherhood 2 5% Both 47,XXY Trans Individuals 2 6.7% 1:46XY/47,XXY 1:47/XXY Overall, adult patients with KS exhibited progressive gonadal dysfunction and impaired spermatogenesis, although a small subset of patients with preserved spermatogenesis were able to achieve spontaneous fatherhood. In contrast, pediatric patients generally maintained normal hormonal function. These findings underscore the variability in phenotypic expression and fertility potential in KS and highlight the importance of early diagnosis and individualized management strategies. Discussion KS is the most common sex chromosome abnormality in males. It is characterised by the presence of one or more additional X chromosomes, typically resulting in a 47,XXY karyotype. This study included a total of 40 KS patients, of whom 10 were children and 30 were adults. Notable findings in the adult group included two individuals with a non-mosaic 47,XXY karyotype who could father children spontaneously, two individuals diagnosed with GD and two rare cases with a 48,XXYY karyotype. These results emphasise the significant phenotypic and genotypic diversity associated with KS. The literature reports that approximately 80–90% of cases have a non-mosaic 47,XXY karyotype, 7–15% have a mosaic 46,XY/47,XXY karyotype and the phenotype varies depending on the ratio of cell lines in mosaic individuals[3,29]. In our cohort, 79.4% of cases were non-mosaic 47,XXY, 14.7% were mosaic and 5.9% had a 48,XXYY karyotype. The incidence of congenital and systemic anomalies in 48,XXYY cases is significantly higher than in classic 47,XXY cases. The literature reports that pathologies such as inguinal hernias, cardiac defects, renal malformations, skeletal anomalies and thromboembolic complications occur in around 56% of individuals with 48,XXYY syndrome, whereas in classic 47,XXY cases, this figure is around 18%[1,2]. Systemic pathologies were also observed in the 48,XXYY cases within our cohort, with one patient presenting deep vein thrombosis (DVT) and the other exhibiting renal pathology. Additionally, individuals with 48,XXYY syndrome tend to be taller and show notable delays in motor and cognitive development [30,31]. Therefore, identification of KS cases with a 48,XXYY karyotype necessitates a multidisciplinary approach addressing both systemic complications and cognitive function. In our cohort, the average age of children in the pediatric KS group who were referred to our clinic with a preliminary diagnosis of microorchidism and/or micropenis was 8.5 years. They were observed to be in the prepubertal period. Their mean height was measured as 136 ± 4 cm, which was close to the upper limit of the 128–138 cm range reported by Aksglæde et al. for children aged 8–10 years[32]. This finding is consistent with the accelerated growth pattern described in KS from early childhood onwards. While children with KS typically enter puberty at a normal age with timely activation of the hypothalamic GnRH, they commonly present with reduced testicular volume. When we calculated the standard deviation score (SDS) for testicular volume according to age, the mean testicular volume in our pediatric cases was approximately − 1.0 SDS. This finding is consistent with the − 0.9 ± 1.4 SDS reported by Zeger et al. in a study including 55 children and adolescents with KS [33], suggesting that structural changes associated with KS may be present at an early stage. Therefore, KS should be considered in prepubertal children presenting with tall stature, particularly if micropenis, microorchidism, or reduced testicular volume are observed on physical examination. Study conducted by Shanlee et al., involving a cohort of 86 children aged between 4 to 11 years diagnosed with KS, a minor subgroup exhibiting elevated age-dependent FSH and LH levels during the prepubertal phase was discerned (10% for FSH and 7% for LH), which indicates a potential subclinical dysfunction of Sertoli and germ cell activities[34]. No significant increase in FSH and LH concentrations was observed among any of the ten pediatric subjects in the present investigation. This absence of elevation is plausibly attributable to the limited sample size of pediatric participants in our analysis. Aksglæde et al. reported an average testicular volume of 3 ml in adult KS patients [32]. This value is lower than the average of 4.9 ml in our cohort, suggesting that testicular volume can vary from person to person. In our study, FSH and LH levels were normal in two of the thirty adult cases (6.6%), while they were significantly elevated in the remaining cases (93.4%). Total testosterone levels in adult patients were within the low-normal range. In their review study, Butler et al. found that the rate of gynaecomastia in individuals with KS was 35.6% [35]. Aksglæde et al. found this rate to be 43.8% in patients over ten years of age [32]. Nieschlag found that 70% of patients over 25 years of age experienced loss of libido[36]. In our study, hypergonadotropic hypogonadism was detected in 50% of patients, decreased libido in 52%, and gynaecomastia in 32%. These findings are commonly observed in adult cases of KS and result from testicular fibrosis, seminiferous tubule hyalinization, and a marked loss of spermatogenesis [32,37]. Decreased libido and gynaecomastia are attributed to testosterone deficiency and hormonal imbalance caused by this testicular damage. Infertility is a frequent clinical outcome in adult KS, with azoospermia occurring in nearly 90% of affected individuals[3]. Various studies have reported KS prevalence as 10–15% in azoospermic men, 3–4% in the infertile general population, and 2–5% in severe oligospermic men[38,39]. In our study, azoospermia was present in 18 (60%) of 30 infertile adult men, oligospermia in 9 (30%), and normospermia in 3 (10%). The oligospermia rate is generally reported in the literature as 5–10% [39,40]. Normospermia is rarely reported in the literature and is mostly associated with mosaic KS cases. Prior to our research, the medical literature contained just a single report of a pregnancy achieved by a non-mosaic KS male, which required PGT-A due to oligozoospermia; no cases of unassisted natural fatherhood had been described[41]. This is the first study to observe normospermia and spontaneous fatherhood in non-mosaic KS cases. Natural fatherhood in individuals with KS is considered exceptionally uncommon, according to current literature. [41–43]. The three cases of KS in our cohort are examples of natural pregnancies that are rare from both a genetic and clinical perspective[44,45]. In our first case, a 22-year-old man fathered a child naturally. However, eight years later, his partner experienced recurrent miscarriages, and his semen analysis revealed a significant reduction in sperm concentration and motility (Table 4 ). In our second case, the patient became a father spontaneously at the age of 18; however, infertility developed six years later and semen analysis revealed low sperm parameters (Table 4 ). In our third case, despite normal semen parameters, IVF failure was observed (Table 4 ). These cases may be associated with increased chromosomal abnormalities in spermatozoa in men with KS, particularly autosomal disomies[18,46,47]. Normal XY germ cells are rarely present in the testis and have a limited functional lifespan due to an impaired testicular microenvironment [48,49]; which increases the risk of post-fertilisation embryo loss[50,51]. Furthermore, although normospermia and natural conception may be possible at a young age, loss of spermatogenesis foci with advancing age may result in TESE failure and an increased risk of infertility. Therefore, the early detection of sperm in men with KS, alongside experimental approaches such as SSC banking and in vitro spermatogenesis, is crucial for preserving the chance of biological fatherhood in the future[11,52,53]. These cases highlight the complexity of the genotype–phenotype relationship in men with KS. Table 4 Hormonal profiles and semen parameters of normospermic non-mosaic KS patients Case Age (years) LH (mIU/mL) FSH (mIU/mL) Total Testosterone (nmol/L) Sperm Concentration (million/mL) Total Sperm Count (million) Total Motility (%) Immotile (%) 1 22 5.0 5.06 5.4 17.3 (first) / 5 (2 years later) 76 / 6 51 / <10 – / ~90 2 18 4.76 4.01 4.56 15 30 20 – 3 25 6.0 4.8 8.1 16 35 30 – KS in individuals with gender dysphoria (GD) is an area of growing research interest. Several studies have reported that the prevalence of KS in GD individuals ranges from 1.2% to 2.86% [44–47,54,55]. In our cohort, GD was detected in two out of 30 adult KS cases (6.6%). This finding suggests that the frequency of GD may be higher in individuals with KS. However, larger studies are needed to draw definitive conclusions on this matter. In conclusion, while infertility, hormonal and testicular structural changes are prominent in the literature on KS, our study presents noteworthy findings such as the first 47,XXY cases to achieve spontaneous pregnancy, GD individuals diagnosed with GD, and rare cases with a 48,XXYY karyotype These cases highlight the importance of personalised fertility management, as well as testicular and hormonal assessments, and experimental approaches in KS during the early stages. Conclusion In our cohort of 30 adult cases of KS, three exhibited normospermic characteristics, which are rare in KS. Two of these cases were able to father children naturally. Furthermore, gonadal dysgenesis (GD) was detected in 6.6% of cases. These findings indicate that, although rare, normospermia and the possibility of fathering children naturally exist in individuals with KS; however, larger studies are needed to draw definitive conclusions. The finding of GD suggests that gonadal dysfunction may be increased in individuals with KS, and larger studies are also needed in this regard. Small testicular volume in the prepubertal period, especially in tall children, should be considered a warning sign for KS. Infertility is one of the most common clinical problems in males with KS, and phenotypic diversity is associated with karyotype, X chromosome inactivation, parental origin of the X chromosome, and androgen receptor polymorphisms. Therefore, it is recommended that cases of KS be managed with early diagnosis, individualised long-term follow-up, and a multidisciplinary approach (endocrinology, urology, genetics, psychiatry). Sperm deficiency can be partially managed with early fertility preservation strategies and assisted reproductive technologies; genetic counselling is recommended to ensure quality of life and healthy reproductive potential. Declarations Acknowledgement: The authors did not receive support from any organization for the submitted work. Gülbahar Güzel Erdal, İlyas Yücel, Ğarip Demir: Writing – review & editing, Writing – original draft, Methodology collected the clinical data. Edip Ünal: Writing – review & editing. Mahmut Balkan, Selahattin Tekeş, Diclehan Oral: Writing – review & editing, Methodology, collected the clinical data. Mahir Binici, Mert İpekçi, Kadriye Merve Baykale: collected the clinical data, All authors approved the final draft of the manuscript. References F. Lanfranco, A. Kamischke, M. Zitzmann, and E. Nieschlag, Lancet 364 , 273 (2004). K. A. Groth, A. Skakkebæk, C. Høst, C. H. Gravholt, and A. Bojesen, J Clin Endocrinol Metab 98 , 20 (2012). M. Bonomi, V. Rochira, D. Pasquali, G. Balercia, E. A. Jannini, A. Ferlin, and K. I. G. (KING), J Endocrinol Invest 40 , 123 (2016). A. M. Wikström and L. Dunkel, Best Pract Res Clin Endocrinol Metab 25 , 239 (2011). L. Abramsky and J. 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Visootsak, B. Rosner, E. Dykens, N. Tartaglia, and J. M. Graham Jr, Am J Med Genet A 143A , 1198 (2007). N. Tartaglia, N. Ayari, S. Howell, C. D’Epagnier, and P. Zeitler, Acta Paediatr 100 , 851 (2011). L. Aksglaede, N. E. Skakkebaek, K. Almstrup, and A. Juul, Acta Paediatr 100 , 793 (2011). M. P. D. Zeger, A. R. Zinn, N. Lahlou, P. Ramos, K. Kowal, C. Samango-Sprouse, and J. L. Ross, J Pediatr 152 , 716 (2007). S. M. Davis, A. D. Rogol, and J. L. Ross, Endocrinol Metab Clin North Am 44 , 843 (2015). G. Butler, U. Srirangalingam, J. Faithfull, P. Sangster, S. Senniappan, and R. Mitchell, Arch Dis Child 108 , 166 (2022). E. Nieschlag, Dtsch Arztebl Int 110 , 347 (2013). L. Aksglaede, K. Link, A. Giwercman, N. Jørgensen, N. E. Skakkebaek, and A. Juul, Am J Med Genet C Semin Med Genet 163C , 55 (2013). J. Gonçalves, K. L. Grove, and C. F. Deschepper, Regul Pept 57 , 55 (1995). G. Forti, G. Corona, L. Vignozzi, C. Krausz, and M. Maggi, Sex Dev 4 , 249 (2010). S. Brilli and G. Forti, Expert Rev Endocrinol Metab 9 , 239 (2014). Z. Laron, Z. Dickerman, R. Zamir, and A. Galatzer, Arch Androl 8 , 149 (1982). D. Z. Li, J Endocrinol Invest 34 , 570 (2011). M. Zakeri, F. Taheri, M. A. Zaimy, M. Rezanezhadi, and A. L. Abdullah, (n.d.). M. K. Auer, J. Fuss, G. K. Stalla, and A. P. Athanasoulia, Fertil Steril 100 , 1103 (2013). K. Khatchadourian, S. Amed, and D. L. Metzger, J Pediatr 164 , 906 (2013). R. Fernández, A. Guillamón, E. Gómez-Gil, I. Esteva, M. C. Almaraz, J. Cortés-Cortés, B. Lamas, E. Lema, and E. Pásaro, Genes Genomics 40 , 465 (2018). G. W. Davies and J. Parkinson, Australas Psychiatry 26 , 313 (2017). A. Komsky-Elbaz, A. Raziel, I. Ben-Ami, O. Bern, B. Maslansky, Y. S. Gidoni, R. Ron-El, and D. Strassburger, J Assist Reprod Genet 32 , 1113 (2015). D. Van Saen, H. Tournaye, and E. Goossens, Fertil Steril 97 , 319 (2011). M. Bonduelle, E. Van Assche, H. Joris, K. Keymolen, P. Devroey, A. Van Steirteghem, and I. Liebaers, Human Reproduction 17 , 2600 (2002). I. Plotton, A. Brosse, B. Cuzin, and H. Lejeune, Ann Endocrinol (Paris) 75 , 118 (2014). H. Sadri-Ardekani, M. A. Akhondi, F. van der Veen, S. Repping, and A. M. M. van Pelt, JAMA 305 , 2416 (2011). S. S. Pendergraft, H. Sadri-Ardekani, A. Atala, and C. E. Bishop, Biol Reprod 96 , 720 (2017). A. Inoubli, G. De Cuypere, R. Rubens, G. Heylens, E. Elaut, E. Van Caenegem, B. Menten, and G. T’Sjoen, J Sex Med 8 , 475 (2010). M. J. Ferreira, J. L. Castedo, J. P. Pedro, C. D. Salazar, C. F. Costa, and D. M. Carvalho, J Endocr Soc 4 , SUN (2020). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 01 Apr, 2026 Read the published version in Endocrine → Version 1 posted Editorial decision: Revision requested 30 Nov, 2025 Reviews received at journal 30 Nov, 2025 Reviews received at journal 25 Nov, 2025 Reviewers agreed at journal 23 Nov, 2025 Reviewers agreed at journal 23 Nov, 2025 Reviewers invited by journal 23 Nov, 2025 Editor assigned by journal 21 Nov, 2025 Submission checks completed at journal 21 Nov, 2025 First submitted to journal 18 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8144683","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":546890863,"identity":"543fbc4f-1848-4514-a281-8dc91e4cb028","order_by":0,"name":"İlyas Yücel","email":"","orcid":"","institution":"Institute of Medical Sciences, Department of Medical Biology and Genetic, Dicle University","correspondingAuthor":false,"prefix":"","firstName":"İlyas","middleName":"","lastName":"Yücel","suffix":""},{"id":546890864,"identity":"9c82bfda-526f-45f8-a277-3ac9c7dc396d","order_by":1,"name":"Gülbahar Güzel Erdal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYFAC5jYGxgYo+0EFA4MBYS2MSFoSzpCsJbGNCC3yEYltD37usMuXj0h/+CBx3mF5c/bmAww/Krbh1GJ4I7HdsPdMsuXGGwnJBonbDhvu7DmWwNhz5jZuLTMS2yR425gNDGckHJMAamHccCPHgJmxDb8Wyb9t9UAtie0/EucctieoRV4isU2at+2wgbxEMhtDYsPhRIJaDHgethvLth03MOB5xiyRcCw9ecOZYwkH8flFvj352MO3bdUG8u3pDz98qLG23XC8+eCDHxV4bDmAymgGkwewKYXb0oDKqMOneBSMglEwCkYoAACMy2CxDzLUzQAAAABJRU5ErkJggg==","orcid":"","institution":"Institute of Medical Sciences, Department of Medical Biology and Genetic, Dicle University","correspondingAuthor":true,"prefix":"","firstName":"Gülbahar","middleName":"Güzel","lastName":"Erdal","suffix":""},{"id":546890865,"identity":"0f986268-eced-43e5-a9a3-87720f0c42b7","order_by":2,"name":"Ğarip Demir","email":"","orcid":"","institution":"Department of Molecular Biology and Genetics, Gebze Technical 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Sciences, Department of Medical Biology and Genetic, Dicle University","correspondingAuthor":false,"prefix":"","firstName":"Kadriye","middleName":"Merve","lastName":"Baykale","suffix":""}],"badges":[],"createdAt":"2025-11-18 11:23:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8144683/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8144683/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12020-026-04591-x","type":"published","date":"2026-04-01T15:59:51+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":96253283,"identity":"3a1c2f92-69f7-4f34-9f5d-882ec8757944","added_by":"auto","created_at":"2025-11-19 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07:39:54","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":84577,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8144683/v1/64114a279a23db48180719b2.html"},{"id":106344325,"identity":"47ce3319-1e2f-410b-91f9-0f08a83cc159","added_by":"auto","created_at":"2026-04-07 16:13:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":825665,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8144683/v1/94f06d87-8abe-4fd6-b75b-fca2881f4501.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Phenotypic and Fertility Variability in Klinefelter Syndrome: Evidence of Natural Fatherhood in Non-Mosaic 47,XXY Men and Rare 48,XXYY Cases","fulltext":[{"header":"Background","content":"\u003cp\u003eKS is the most common sex chromosome aneuploidy in males, occurring in approximately 1 in 500\u0026ndash;1,000 live male births [1\u0026ndash;3]. It is defined by the presence of one or more extra X chromosomes and was first described by Dr. Harry Klinefelter in 1942 [3]. Most patients carry the classic 47,XXY karyotype, while about 10% exhibit mosaic forms (46,XY/47,XXY) or higher-order aneuploidies, such as 48,XXXY, 48,XXYY, or 49,XXXXY [4,5]. KS typically arises from errors in meiotic segregation during gametogenesis, with the extra X chromosome inherited from either maternal or paternal gametes [6,7]. Paternally derived aneuploidy occurs only during meiosis I, whereas maternal KS can result from errors in meiosis I or II, with meiosis II errors more common [8]. Advanced maternal age has been associated with increased KS incidence, whereas the effect of paternal age remains controversial [9].\u003c/p\u003e\u003cp\u003eLess common genetic types include other numerical aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY), mosaicism (46,XY/47,XXY), and structural abnormalities of sex chromosomes [10]. Patients with higher-order aneuploidies often present with more severe phenotypes, including congenital malformations, taller stature, and more pronounced cognitive or motor delays, whereas mosaic patients generally show milder phenotypes with larger testicular volumes and higher sperm counts [10,11].\u003c/p\u003e\u003cp\u003eThe underlying pathology of KS involves increased susceptibility to meiotic errors during spermatogenesis, leading to aneuploid or polyploid gametes. Genetic contributors include polymorphisms in checkpoint genes regulating chromosomal synapsis and segregation. Physiologically, the additional X chromosome disrupts interstitial and Sertoli cell function, altering testicular endocrinology and metabolism and collectively impairing normal sperm development [12,13]. Spermatogenesis is usually severely impaired in KS, and azoospermia is detected in approximately 90% of patients. However, in some cases, limited preserved spermatogenic activity may be present, enabling biological fatherhood through assisted reproductive techniques such as testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) [12\u0026ndash;14].\u003c/p\u003e\u003cp\u003eEpigenetic mechanisms play an important role in KS. Irregularities in DNA methylation and histone modifications can affect genes that are involved in sexual development, cognitive function and metabolism. These irregularities can lead to gonadal insufficiency, hormonal imbalance, and behavioural differences. Incomplete inactivation of the X chromosome contributes to the emergence of characteristic phenotypic features by preventing the silencing of certain genes. Increased copy number variations (CNVs) amplify the gene dosage effect, thereby enhancing phenotypic diversity. X-linked CNVs are more prevalent in KS patients [8,15\u0026ndash;19].These genetic and epigenetic factors explain the biological basis of reproductive disorders and phenotypic heterogeneity in KS. Furthermore, molecular findings guide clinical approach, patient follow-up, and assisted reproductive technologies (ART) [17\u0026ndash;21]. The clinical presentation of KS is highly variable. In newborns, micropenis, hypospadias or undescended testicles may be observed, while hypergonadotropic hypogonadism usually manifests during puberty. In adult males, gynecomastia, incomplete virilisation, progressive testicular failure and infertility are common. Laboratory tests usually show increased FSH and LH levels and decreased testicular volume; testicular degeneration may be associated with impaired germ cell maturation, Sertoli\u0026ndash;Leydig cell dysfunction, X-inactive specific transcript (XIST) abnormalities, or PAR1 gene overexpression [22\u0026ndash;25]. KS is also associated with multisystem comorbidities such as metabolic syndrome, type 2 diabetes, cardiovascular disease, osteoporosis, eye and dental problems, and certain types of cancer; depression and anxiety also increase morbidity [26,27].\u003c/p\u003e\u003cp\u003eThis retrospective study includes 40 cases of KS confirmed by karyotype analysis. The aim of the study was to describe the clinical, hormonal, and reproductive characteristics of KS in different age groups in greater detail and to determine the most appropriate approaches to reproductive health and fertility preservation.\u003c/p\u003e\n\u003ch3\u003eStudy Design and Participants\u003c/h3\u003e\n\u003cp\u003eThis retrospective study examined patients diagnosed with KS at Dicle University Hospital between 2020 and 2025. Inclusion criteria included a confirmed KS diagnosis by karyotype analysis, complete clinical and hormonal data, and at least one semen analysis for adults. Patients were excluded if they had undergone prior testicular surgery, had a history of chemotherapy or radiotherapy, or had incomplete medical records.\u003c/p\u003e\u003cp\u003eThe study population consisted of 28 adult males, 2 GD adults, and 10 pediatric patients. GD individuals had not received gender-affirming hormonal therapy prior to evaluation. Pediatric patients were prepubertal at the time of assessment. Mosaic cases were evaluated using standard cytogenetic analysis, and suspected mosaicism was further confirmed by fluorescence in situ hybridization (FISH) on at least 100 interphase cells to ensure accurate detection of abnormal cell lines.\u003c/p\u003e\u003cp\u003eAll participants underwent an evaluation of their clinical features, hormonal profiles (serum FSH, LH, estradiol and total testosterone) and testicular characteristics. Semen analysis was performed only in adult patients and followed WHO 2020 criteria. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University XXX (06.02.2020./No: 125). Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eHormonal Assessment\u003c/h2\u003e\u003cp\u003eSerum levels of follicle-stimulating hormone (FSH), luteinising hormone (LH), estradiol, and total testosterone were measured for all participants. Analyses were carried out using the Siemens ADVIA Centaur XP analyser and Immulite 2000 XPi kits, following standard laboratory procedures recommended by the manufacturer.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTestis Volume Measurement\u003c/h3\u003e\n\u003cp\u003eTestis volumes were measured by an experienced urologist using ultrasonography (USG). Volume calculations were based on measurements of the length, width, and thickness of the testis.\u003c/p\u003e\n\u003ch3\u003eKaryotype Analysis\u003c/h3\u003e\n\u003cp\u003eCytogenetic karyotyping was performed on peripheral blood lymphocyte cultures. At least 20 metaphase cells were examined for each patient to attempt to detect a 47,XXY karyotype. In cases with suspected mosaicism, extended cytogenetic analysis was performed to characterise the abnormal cells in more detail.\u003c/p\u003e\n\u003ch3\u003eSperm Analysis\u003c/h3\u003e\n\u003cp\u003eSperm samples were collected after 2\u0026ndash;3 days of sexual abstinence. Analysis parameters were evaluated according to the 2020 WHO criteria; ejaculate volume, sperm concentration, motility, morphology, and viability were measured[28]. All analyses were performed at the Dicle University Andrology Laboratory in accordance with standard protocols. Sperm concentration, motility, and morphology were assessed using the Hamilton Thorne Computer-Assisted Sperm Analysis (CASA) system, while sperm viability was assessed using the Eosin\u0026ndash;Nigrosin staining method.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eData were analysed using SPSS version 22.0. Continuous variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median with interquartile range (IQR) according to their distribution. Relationships between hormonal parameters and testicular volume were evaluated using Pearson or Spearman correlation analyses, as appropriate. Results with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe patient population studied consisted of 28 adult males, 2 GD adults, and 10 pediatric patients.Pediatric patients had prepubertal hormone levels (mean FSH 1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4, LH 0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25 mIU/mL, testosterone 1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 nmol/L) and small testicular volumes (mean 1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 mL) with no signs of hypogonadism, reduced libido, or gynecomastia (Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eHormonal profiles in pediatric, adult, and GD patients with KS\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMean (SE)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMedian (IQR)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eRange\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNormal Range\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8.5 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.0 (7.0\u0026ndash;9.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6.0\u0026ndash;10.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFSH (mIU/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.8 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.6 (1.2\u0026ndash;2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.5\u0026ndash;3.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.5-4.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLH (mIU/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.9 (0.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.8 (0.6\u0026ndash;1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.1\u0026ndash;2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.1\u0026ndash;3.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEstradiol (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10.5 (2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e9.0 (8.0\u0026ndash;12.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.0\u0026ndash;20.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5\u0026ndash;20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTestosterone (nmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.2 (0.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.0 (0.8\u0026ndash;1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.3\u0026ndash;2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.1\u0026ndash;3.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e30.28 (1.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30.0 (26.0\u0026ndash;34.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11.0\u0026ndash;47.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFSH (mIU/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e26.84 (3.36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e25.55 (19.68\u0026ndash;33.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.25\u0026ndash;63.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.5\u0026ndash;12.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLH (mIU/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e16.47 (1.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e16.88 (12.9\u0026ndash;19.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.07\u0026ndash;35.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.7\u0026ndash;8.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEstradiol (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e30.69 (5.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e26.33 (25.38\u0026ndash;33.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e24.43\u0026ndash;41.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e10\u0026ndash;40\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTestosterone (nmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e9.85 (0.45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e9.7 (8.9\u0026ndash;10.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.2\u0026ndash;11.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12\u0026ndash;35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult Trans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e29.5 (0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e29.5 (29.0\u0026ndash;30.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e29\u0026ndash;30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult Trans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFSH (mIU/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10.0 (1.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e10.0 (9.5\u0026ndash;10.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e9\u0026ndash;11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.5\u0026ndash;12.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult Trans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLH (mIU/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8.0 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.0 (7.5\u0026ndash;8.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7\u0026ndash;9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.7\u0026ndash;8.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult Trans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEstradiol (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e35.0 (2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e35.0 (34\u0026ndash;36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e33\u0026ndash;37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e10\u0026ndash;40\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult Trans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTestosterone (nmol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.0 (0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.0 (4.5\u0026ndash;5.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4\u0026ndash;6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12\u0026ndash;35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical features in pediatric, adult, and GD patients with KS\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMean (SE)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMedian (IQR)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eRange\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNormal Range\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHeight\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e136\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e136 (133\u0026ndash;139)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e128\u0026ndash;142\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e128\u0026ndash;138\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal Testicular Volume (mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.2 (0.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.1 (0.9\u0026ndash;1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.5\u0026ndash;2.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.5\u0026ndash;3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHypogonadism (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (\u0026ndash;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0\u0026ndash;0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;1.0 nmol/L testosterone (prepubertal)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDecreased Libido (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (\u0026ndash;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0\u0026ndash;0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGynecomastia (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (\u0026ndash;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0\u0026ndash;0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHeight (m)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.28 (0.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.30 (1.20\u0026ndash;1.35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.10\u0026ndash;1.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChild\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBiacromial Diameter (cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30 (1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e30 (29\u0026ndash;31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e28\u0026ndash;32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult (n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal Testicular Volume (mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.9 (0.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.8 (4.0\u0026ndash;5.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.0\u0026ndash;7.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e24\u0026ndash;60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHypogonadism (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50 (\u0026ndash;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e48 (42\u0026ndash;55)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e35\u0026ndash;65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;12 nmol/L testosterone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDecreased Libido (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e52 (\u0026ndash;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e50 (45\u0026ndash;55)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e35\u0026ndash;65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGynecomastia (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32 (\u0026ndash;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e30 (25\u0026ndash;35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20\u0026ndash;45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHeight (m)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.83 (0.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.82 (1.78\u0026ndash;1.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.72\u0026ndash;1.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBiacromial Diameter (cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42 (1.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e42 (41\u0026ndash;44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e39\u0026ndash;46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTrans (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal Testicular Volume (mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.0 (0.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.0 (3.7\u0026ndash;4.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.5\u0026ndash;4.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e24\u0026ndash;60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTrans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHypogonadism (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100 (\u0026ndash;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e100 (100\u0026ndash;100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;12 nmol/L testosterone\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTrans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDecreased Libido (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100 (\u0026ndash;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e100 (100\u0026ndash;100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTrans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGynecomastia (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50 (\u0026ndash;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e50 (50\u0026ndash;50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTrans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHeight (m)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.80 (0.03)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.80 (1.78\u0026ndash;1.82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.77\u0026ndash;1.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTrans\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBiacromial Diameter (cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41 (0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e41 (40.5\u0026ndash;41.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e40\u0026ndash;42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAdult patients exhibited hypergonadotropic hypogonadism with elevated gonadotropins (FSH 26.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.36, LH 16.47\u0026thinsp;\u0026plusmn;\u0026thinsp;1.77 mIU/mL) and decreased testosterone (9.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45 nmol/L), and moderately increased estradiol (30.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.34 pg/mL). Mean testicular volume was 4.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2 mL. Clinically, 50% reported low libido, 32% had gynecomastia, and 47% showed biochemical hypogonadism. Mean height was 1.83\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05 m, and biacromial diameter was 42\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 cm (Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGD adults had similar endocrine profiles, testicular volumes averaging 4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3 mL, and exhibited hypogonadism and decreased libido; 50% had gynecomastia.\u003c/p\u003e\u003cp\u003eSemen analyses of adult patients showed 60% azoospermia, 30% oligospermia, and 10% normospermia (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Two adults (5%) achieved spontaneous fatherhood (both 47,XXY). Karyotypes included 36 47,XXY, 2 mosaic 46,XY/47,XXY, and 2 48,XXYY. Both GD patients were 47,XXY and azoospermic.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe distribution of karyotypes and semen analysis in KS patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of Patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePercentage (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eKaryotype Distribution\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAzoospermia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e60%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16: 47,XXY, 2: 48,XXYY\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOligospermia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1:46XY/47,XXY 8:47,XXY\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNormospermia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll 46XY/47,XXY\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpontaneous Fatherhood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBoth 47,XXY\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTrans Individuals\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.7%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1:46XY/47,XXY 1:47/XXY\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eOverall, adult patients with KS exhibited progressive gonadal dysfunction and impaired spermatogenesis, although a small subset of patients with preserved spermatogenesis were able to achieve spontaneous fatherhood. In contrast, pediatric patients generally maintained normal hormonal function. These findings underscore the variability in phenotypic expression and fertility potential in KS and highlight the importance of early diagnosis and individualized management strategies.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eKS is the most common sex chromosome abnormality in males. It is characterised by the presence of one or more additional X chromosomes, typically resulting in a 47,XXY karyotype. This study included a total of 40 KS patients, of whom 10 were children and 30 were adults. Notable findings in the adult group included two individuals with a non-mosaic 47,XXY karyotype who could father children spontaneously, two individuals diagnosed with GD and two rare cases with a 48,XXYY karyotype. These results emphasise the significant phenotypic and genotypic diversity associated with KS.\u003c/p\u003e\u003cp\u003eThe literature reports that approximately 80\u0026ndash;90% of cases have a non-mosaic 47,XXY karyotype, 7\u0026ndash;15% have a mosaic 46,XY/47,XXY karyotype and the phenotype varies depending on the ratio of cell lines in mosaic individuals[3,29]. In our cohort, 79.4% of cases were non-mosaic 47,XXY, 14.7% were mosaic and 5.9% had a 48,XXYY karyotype. The incidence of congenital and systemic anomalies in 48,XXYY cases is significantly higher than in classic 47,XXY cases. The literature reports that pathologies such as inguinal hernias, cardiac defects, renal malformations, skeletal anomalies and thromboembolic complications occur in around 56% of individuals with 48,XXYY syndrome, whereas in classic 47,XXY cases, this figure is around 18%[1,2]. Systemic pathologies were also observed in the 48,XXYY cases within our cohort, with one patient presenting deep vein thrombosis (DVT) and the other exhibiting renal pathology. Additionally, individuals with 48,XXYY syndrome tend to be taller and show notable delays in motor and cognitive development [30,31]. Therefore, identification of KS cases with a 48,XXYY karyotype necessitates a multidisciplinary approach addressing both systemic complications and cognitive function.\u003c/p\u003e\u003cp\u003eIn our cohort, the average age of children in the pediatric KS group who were referred to our clinic with a preliminary diagnosis of microorchidism and/or micropenis was 8.5 years. They were observed to be in the prepubertal period. Their mean height was measured as 136\u0026thinsp;\u0026plusmn;\u0026thinsp;4 cm, which was close to the upper limit of the 128\u0026ndash;138 cm range reported by Aksgl\u0026aelig;de et al. for children aged 8\u0026ndash;10 years[32]. This finding is consistent with the accelerated growth pattern described in KS from early childhood onwards. While children with KS typically enter puberty at a normal age with timely activation of the hypothalamic GnRH, they commonly present with reduced testicular volume. When we calculated the standard deviation score (SDS) for testicular volume according to age, the mean testicular volume in our pediatric cases was approximately \u0026minus;\u0026thinsp;1.0 SDS. This finding is consistent with the \u0026minus;\u0026thinsp;0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4 SDS reported by Zeger et al. in a study including 55 children and adolescents with KS [33], suggesting that structural changes associated with KS may be present at an early stage. Therefore, KS should be considered in prepubertal children presenting with tall stature, particularly if micropenis, microorchidism, or reduced testicular volume are observed on physical examination.\u003c/p\u003e\u003cp\u003eStudy conducted by Shanlee et al., involving a cohort of 86 children aged between 4 to 11 years diagnosed with KS, a minor subgroup exhibiting elevated age-dependent FSH and LH levels during the prepubertal phase was discerned (10% for FSH and 7% for LH), which indicates a potential subclinical dysfunction of Sertoli and germ cell activities[34]. No significant increase in FSH and LH concentrations was observed among any of the ten pediatric subjects in the present investigation. This absence of elevation is plausibly attributable to the limited sample size of pediatric participants in our analysis.\u003c/p\u003e\u003cp\u003eAksgl\u0026aelig;de et al. reported an average testicular volume of 3 ml in adult KS patients [32]. This value is lower than the average of 4.9 ml in our cohort, suggesting that testicular volume can vary from person to person. In our study, FSH and LH levels were normal in two of the thirty adult cases (6.6%), while they were significantly elevated in the remaining cases (93.4%). Total testosterone levels in adult patients were within the low-normal range. In their review study, Butler et al. found that the rate of gynaecomastia in individuals with KS was 35.6% [35]. Aksgl\u0026aelig;de et al. found this rate to be 43.8% in patients over ten years of age [32]. Nieschlag found that 70% of patients over 25 years of age experienced loss of libido[36]. In our study, hypergonadotropic hypogonadism was detected in 50% of patients, decreased libido in 52%, and gynaecomastia in 32%. These findings are commonly observed in adult cases of KS and result from testicular fibrosis, seminiferous tubule hyalinization, and a marked loss of spermatogenesis [32,37]. Decreased libido and gynaecomastia are attributed to testosterone deficiency and hormonal imbalance caused by this testicular damage. Infertility is a frequent clinical outcome in adult KS, with azoospermia occurring in nearly 90% of affected individuals[3]. Various studies have reported KS prevalence as 10\u0026ndash;15% in azoospermic men, 3\u0026ndash;4% in the infertile general population, and 2\u0026ndash;5% in severe oligospermic men[38,39].\u003c/p\u003e\u003cp\u003eIn our study, azoospermia was present in 18 (60%) of 30 infertile adult men, oligospermia in 9 (30%), and normospermia in 3 (10%). The oligospermia rate is generally reported in the literature as 5\u0026ndash;10% [39,40]. Normospermia is rarely reported in the literature and is mostly associated with mosaic KS cases. Prior to our research, the medical literature contained just a single report of a pregnancy achieved by a non-mosaic KS male, which required PGT-A due to oligozoospermia; no cases of unassisted natural fatherhood had been described[41]. This is the first study to observe normospermia and spontaneous fatherhood in non-mosaic KS cases.\u003c/p\u003e\u003cp\u003eNatural fatherhood in individuals with KS is considered exceptionally uncommon, according to current literature. [41\u0026ndash;43]. The three cases of KS in our cohort are examples of natural pregnancies that are rare from both a genetic and clinical perspective[44,45]. In our first case, a 22-year-old man fathered a child naturally. However, eight years later, his partner experienced recurrent miscarriages, and his semen analysis revealed a significant reduction in sperm concentration and motility (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). In our second case, the patient became a father spontaneously at the age of 18; however, infertility developed six years later and semen analysis revealed low sperm parameters (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). In our third case, despite normal semen parameters, IVF failure was observed (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). These cases may be associated with increased chromosomal abnormalities in spermatozoa in men with KS, particularly autosomal disomies[18,46,47]. Normal XY germ cells are rarely present in the testis and have a limited functional lifespan due to an impaired testicular microenvironment [48,49]; which increases the risk of post-fertilisation embryo loss[50,51]. Furthermore, although normospermia and natural conception may be possible at a young age, loss of spermatogenesis foci with advancing age may result in TESE failure and an increased risk of infertility. Therefore, the early detection of sperm in men with KS, alongside experimental approaches such as SSC banking and in vitro spermatogenesis, is crucial for preserving the chance of biological fatherhood in the future[11,52,53]. These cases highlight the complexity of the genotype\u0026ndash;phenotype relationship in men with KS.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eHormonal profiles and semen parameters of normospermic non-mosaic KS patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLH (mIU/mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFSH (mIU/mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTotal Testosterone (nmol/L)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSperm Concentration (million/mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTotal Sperm Count (million)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTotal Motility (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eImmotile (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e17.3 (first) / 5 (2 years later)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e76 / 6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e51 / \u0026lt;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026ndash; / ~90\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e8.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026ndash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eKS in individuals with gender dysphoria (GD) is an area of growing research interest. Several studies have reported that the prevalence of KS in GD individuals ranges from 1.2% to 2.86% [44\u0026ndash;47,54,55]. In our cohort, GD was detected in two out of 30 adult KS cases (6.6%). This finding suggests that the frequency of GD may be higher in individuals with KS. However, larger studies are needed to draw definitive conclusions on this matter.\u003c/p\u003e\u003cp\u003eIn conclusion, while infertility, hormonal and testicular structural changes are prominent in the literature on KS, our study presents noteworthy findings such as the first 47,XXY cases to achieve spontaneous pregnancy, GD individuals diagnosed with GD, and rare cases with a 48,XXYY karyotype These cases highlight the importance of personalised fertility management, as well as testicular and hormonal assessments, and experimental approaches in KS during the early stages.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn our cohort of 30 adult cases of KS, three exhibited normospermic characteristics, which are rare in KS. Two of these cases were able to father children naturally. Furthermore, gonadal dysgenesis (GD) was detected in 6.6% of cases. These findings indicate that, although rare, normospermia and the possibility of fathering children naturally exist in individuals with KS; however, larger studies are needed to draw definitive conclusions. The finding of GD suggests that gonadal dysfunction may be increased in individuals with KS, and larger studies are also needed in this regard. Small testicular volume in the prepubertal period, especially in tall children, should be considered a warning sign for KS. Infertility is one of the most common clinical problems in males with KS, and phenotypic diversity is associated with karyotype, X chromosome inactivation, parental origin of the X chromosome, and androgen receptor polymorphisms. Therefore, it is recommended that cases of KS be managed with early diagnosis, individualised long-term follow-up, and a multidisciplinary approach (endocrinology, urology, genetics, psychiatry). Sperm deficiency can be partially managed with early fertility preservation strategies and assisted reproductive technologies; genetic counselling is recommended to ensure quality of life and healthy reproductive potential.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u003c/strong\u003e The authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003eG\u0026uuml;lbahar G\u0026uuml;zel Erdal, İlyas Y\u0026uuml;cel, Ğarip Demir: Writing \u0026ndash; review \u0026amp; editing, Writing \u0026ndash; original draft, Methodology collected the clinical data. Edip \u0026Uuml;nal: Writing \u0026ndash; review \u0026amp; editing. Mahmut Balkan, Selahattin Tekeş, Diclehan Oral: Writing \u0026ndash; review \u0026amp; editing, Methodology, collected the clinical data. Mahir Binici, Mert İpek\u0026ccedil;i, Kadriye Merve Baykale: collected the clinical data, All authors approved the final draft of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eF. Lanfranco, A. Kamischke, M. Zitzmann, and E. Nieschlag, Lancet \u003cstrong\u003e364\u003c/strong\u003e, 273 (2004).\u003c/li\u003e\n\u003cli\u003eK. A. Groth, A. Skakkeb\u0026aelig;k, C. H\u0026oslash;st, C. H. Gravholt, and A. Bojesen, J Clin Endocrinol Metab \u003cstrong\u003e98\u003c/strong\u003e, 20 (2012).\u003c/li\u003e\n\u003cli\u003eM. Bonomi, V. Rochira, D. Pasquali, G. Balercia, E. A. Jannini, A. Ferlin, and K. I. G. (KING), J Endocrinol Invest \u003cstrong\u003e40\u003c/strong\u003e, 123 (2016).\u003c/li\u003e\n\u003cli\u003eA. M. Wikstr\u0026ouml;m and L. Dunkel, Best Pract Res Clin Endocrinol Metab \u003cstrong\u003e25\u003c/strong\u003e, 239 (2011).\u003c/li\u003e\n\u003cli\u003eL. Abramsky and J. 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Carvalho, J Endocr Soc \u003cstrong\u003e4\u003c/strong\u003e, SUN (2020).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Klinefelter syndrome, 47,XXY, Spontaneous paternity, Natural fatherhood, Normospermia, 48,XXYY variant, Sex chromosome aneuploidy, gender dysphoria","lastPublishedDoi":"10.21203/rs.3.rs-8144683/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8144683/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eKlinefelter syndrome (KS) is the most common sex chromosome aneuploidy in males, characterised primarily by the 47,XXY karyotype. The syndrome exhibits significant clinical and genetic variability and can affect reproductive capacity. This study aims to investigate variability in phenotypic characteristics according to age group and karyotype, and to evaluate rare reproductive outcomes such as natural fatherhood, as well as specific conditions such as gender dysphoria.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA retrospective review was conducted on 40 KS patients (28 adult males, 2 adults with gender dysphoria [GD], and 10 pediatric patients) diagnosed between 2020 and 2025. Clinical features, hormone levels (FSH, LH, estradiol, testosterone), testicular volumes, karyotypes, and semen analyses (using the 2020 World Health Organization [WHO] criteria) were evaluated. Mosaicism was confirmed through FISH.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAmong 40 patients, 36 (90%) had non-mosaic 47,XXY, 2 (5%) were mosaic 46,XY/47,XXY, and 2 (5%) had 48,XXYY karyotypes. Pediatric patients had age-appropriate hormones and small testes without hypogonadism. Adults displayed hypergonadotropic hypogonadism, reduced testicular volume (mean 4.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2 mL), and varied semen profiles: azoospermia 60%, oligospermia 30%, normospermia 10%. Notably, two non-mosaic 47,XXY men achieved natural conception. GD adults showed similar endocrine profiles with hypogonadism.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eAlthough rare, normospermia and natural fatherhood are possible in KS, highlighting the need for early diagnosis, individualized management, and fertility preservation strategies to optimize reproductive outcomes and quality of life.\u003c/p\u003e","manuscriptTitle":"Phenotypic and Fertility Variability in Klinefelter Syndrome: Evidence of Natural Fatherhood in Non-Mosaic 47,XXY Men and Rare 48,XXYY Cases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-19 06:33:18","doi":"10.21203/rs.3.rs-8144683/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-30T18:09:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-30T18:05:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-25T11:22:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"18386535571396919620720937677628507882","date":"2025-11-23T16:09:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"237674247736536615375693396701172330616","date":"2025-11-23T10:15:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-23T10:05:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-21T06:09:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-21T06:09:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Endocrine","date":"2025-11-18T11:11:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"76b4bfc5-526d-4882-8ca0-af3354528166","owner":[],"postedDate":"November 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T16:09:22+00:00","versionOfRecord":{"articleIdentity":"rs-8144683","link":"https://doi.org/10.1007/s12020-026-04591-x","journal":{"identity":"endocrine","isVorOnly":false,"title":"Endocrine"},"publishedOn":"2026-04-01 15:59:51","publishedOnDateReadable":"April 1st, 2026"},"versionCreatedAt":"2025-11-19 06:33:18","video":"","vorDoi":"10.1007/s12020-026-04591-x","vorDoiUrl":"https://doi.org/10.1007/s12020-026-04591-x","workflowStages":[]},"version":"v1","identity":"rs-8144683","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8144683","identity":"rs-8144683","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}