Genetics and Immunology · Reproductive Genetics
Abstract
Klinefelter Syndrome (KS) is characterized by an extreme heterogeneity in its clinical and genetic presentation. The relationship between clinical phenotype and genetic background has been partially disclosed; nevertheless, physicians are aware that several aspects concerning this issue are far to be fully understood. By improving our knowledge on the role of some genetic aspects as well as on the KS, patients' interindividual differences in terms of health status will result in a better management of this chromosomal disease. The aim of this review is to provide an update on both genetic and clinical phenotype and their interrelationships.
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By this author
Semen Analysis · Sperm Function Testing
Preimplantation genetic testing for male factor infertility: lights and shadows
Mazzilli R et al., 2026 · Journal of endocrinological investigation
Male factor could contribute, alone or in combination with female factor, to the inability to conceive in a couple in more than half of cases. The effect of male factor infertility (MFI) on embryological assisted reproductive technology (ART) outcomes remains an ongoing discussion. to evaluate the impact of MFI on embryo aneuploidy rates, to better understand the role and possible indication for Preimplantation genetic testing for aneuploidies (PGT-A), considering the role of sperm characteristics, paternal age, sperm DNA fragmentation and sperm aneuploidies. this narrative review included all available articles, published up to January 2026. Available evidence, often based on heterogeneous and old-fashioned methodologies, suggests that MFI may impair embryonic development, particularly in terms of fertilization rate and blastulation rate, more than embryo euploidy; however, a comprehensive evaluation of MFI should be integrated into clinical practice in the context of couple infertility, to also optimize the efficiency and outcomes of ART. Promising results emerged from sperm DNA fragmentation as a tool to predict embryo euploidy, but further investigations involving larger sample sizes and improved standardization are required.
Neoplastic Risk in Patients With Klinefelter Syndrome
Graziani A et al., 2026 · Andrology · Free to read
Besides gonadal involvement (hypogonadism, male factor infertility, and testicular hypotrophy), patients with Klinefelter syndrome (KS) may suffer from several extra-gonadic complications, including neoplastic events. The aim of this review is to summarize all major clinical evidence dealing with the association between KS and neoplastic diseases and provide practical suggestions for the management of patients with KS regarding neoplastic risk. This narrative review was conducted through a comprehensive search of the PubMed database, using combinations of the following keywords: "Klinefelter syndrome," "cancer," "neoplasm," "breast cancer," "germ cell tumor," "lymphoma," and "testosterone replacement therapy". KS is associated with a higher risk of breast cancer and mediastinal germ cell tumors and an apparent higher risk of hematological malignancies, in particular non-Hodgkin lymphoma and leukemia. Evidence on testicular cancer is limited, with no clear increase in risk attributable to KS, while prostate cancer has a lower risk and lower mortality rate. Given the complexity of the syndrome and the limited available evidence, regular clinical follow-up with targeted investigations when clinically indicated may facilitate early diagnosis and management of associated comorbidities.
Bone Mineral Density · Measurement
Impact of reference gender on bone mineral density and fracture risk assessment in transgender adults
Scala A et al., 2026 · Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · Free full text on PubMed Central
In transgender adults, reference-gender choice alters Z-scores and fracture-risk estimates. Z-scores differ by 0.4-0.6 SD, with male references identifying more individuals with low BMD for age, especially in those assigned male at birth. Dual-reference reporting is advisable until further evidence becomes available. Transgender individuals, especially those assigned male at birth (AMAB), exhibit lower bone mineral density (BMD) compared with the cisgender population. Interpretation of densitometric data is challenging, as the choice of reference gender can significantly influence Z-scores and fracture risk scores. This study aims to evaluate the impact of the gender reference database (male or female) on the assessment of BMD and fracture risk in transgender adults prior to gender-affirming hormone therapy (GAHT). We conducted a cross-sectional analysis of 249 transgender individuals (153 assigned female at birth - AFAB and 96 AMAB) aged 18-43 years, recruited in the Hospitals of Padua and Brescia (Italy). Z-scores were calculated using both male and female reference databases and FRAX scores were computed using both gender inputs. Associations with anthropometric, biochemical, and hormonal parameters were explored. Z-scores differed systematically depending on the reference gender, with mean ΔZ ranging 0.4-0.6 SD across skeletal sites. Switching reference databases frequently led to reclassification of BMD status. AMAB individuals showed a higher prevalence of low BMD for age, particularly when assessed against male references (27.1%), whereas AFAB participants generally maintained normal BMD. However, FRAX scores remained low. BMI and 25-OH vitamin D levels were independent predictors of BMD and Z-scores in AMAB individuals. The choice of reference gender significantly influences densitometric interpretation in young transgender adults. Until further evidence becomes available, calculating Z-scores using both male and female reference databases is advisable. Early preventive interventions remain essential to preserve bone health.
Male Factor Treatment · Surgical Management
Predictive parameters of semen outcome improvement after varicocele treatment by scleroembolization: a retrospective study
De Toni L et al., 2026 · Journal of endocrinological investigation · Free full text on PubMed Central
Varicocele is a recognized male factor of infertility. Surgical/microsurgical correction represents a therapeutical option to improve fertility outcomes but predictive parameters for the identification who can actually benefit from varicocele correction are under investigated. Here we aimed to identify baseline predictors of semen outcome improvement after varicocele treatment by scleroembolization approach. 85 patients receiving varicocele treatment by anterograde scleroembolization (ASE, N = 42) or retrograde scleroembolization (RSE, N = 43) were retrospectively recruited. Basal and 6-months follow-up evaluation of semen, hormonal and ultrasound parameters (US) were performed to address the respective effect of varicocele treatment. In addition, basal parameters were assessed as clinical outcome predictors. Varicocele grade reduction was observed in more than 90% of patients (P < 0.001). Compared to basal, significant increase of sperm concentration (10.0 ± 9.2 × 106cells/mL vs. 23.4 ± 26.9 × 106cells/mL; P < 0.001), total sperm count (TSC 39.0 ± 54.5 × 106cells vs. 70.3 ± 90.6 × 106cells, P < 0.001) and total motile sperm count (TMS, 9.8 ± 12.8 × 106cells vs. 36.7 ± 58.1 × 106cells, P < 0.001), was observed, with no differences between RSE or ASE. All US parameters were also improved (all P < 0.001). Logistic regression analysis of basal semen and ultrasound parameters showed that basal sperm motility and left testis-mean transit time (L-MTT) were associated with TSC and TMS doubling at follow-up. However, Receiver Operating Characteristic curve analysis showed that only basal L-MTT basal sperm was consistently associated with TSC and TMS doubling at follow-up (respectively: AUC = 0.834, CI: 0.747-0.921 and AUC = 0.805, CI: 0.708-0.901; both P < 0.001). Baseline sperm count and US parameters represent useful clinical descriptors to address those subjects eligible for varicocele correction.
Related research
Reproductive Genetics · Chromosomal Abnormalities
First baseline data of the Klinefelter ItaliaN Group (KING) cohort: clinical features of adult with Klinefelter syndrome in Italy
Pasquali D et al., 2022 · Journal of endocrinological investigation · Free full text on PubMed Central
Klinefelter syndrome (KS) is frustratingly under-diagnosed. KS have a broad spectrum of clinical features, making it difficult to identify. We describe KS clinical presentation in a large Italian cohort. This is the first observational cohort study within a national network, the Klinefelter ItaliaN Group (KING). Primary outcomes were to describe the basic clinical features and the actual phenotype of KS in Italy. Secondary outcomes were to determine age at diagnosis and geographical distribution. We performed a basic phenotyping and evaluation of the hormonal values of 609 adult KS patients. Mean age at diagnosis was 37.4 ± 13.4 years. The overall mean testicular size was 3 ml, and 2.5 ml in both testes in untreated KS group. BMI was 26.6 ± 5.8 kg/m2, and 25.5% of KS had metabolic syndrome (MetS). LH and FSH were increased, and mean total testosterone were 350 ± 9.1 ng/dl. A descriptive analysis showed that 329 KS patients were evaluated in Northern Italy, 76 in Central and 204 in Southern Italy. Analysis of variance demonstrated significant statistical differences (p < 0001) between the age at diagnosis of the three geographical groups. Compared with the expected number among male patients matched for age in Italy, only 16% of KS patients received a diagnosis. These data are the results of the only national database available that collects the clinical and hormonal data of the KS patients, currently referred at the KING centers. In Italy the typical KS patient is overweight, with small testes, and elevated LH and FSH. Only 25.5% of them are diagnosed with MetS. Early detection and timely treatment are mandatory.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
The Klinefelter Puberty
Milardi D et al., 2020 · Klinefelter's Syndrome
Klinefelter syndrome (KS) is a common genetic disorder characterized by an additional X chromosome in males. A deficient androgen production and a varied observed response of end-organs to testosterone can lead to delayed progression of puberty with reduction in muscle development and facial/body hair, osteoporosis, and gynecomastia. Medical management during puberty focuses on the preservation of fertility and testosterone replacement treatment (TRT) to reduce the current or future consequences of testicular fibrosis. However, more research is needed to establish the need and conditions for TRT in adolescence, as well as the opportunity and timing for sperm recovery in adolescents and young boys with KS. Furthermore, screening for associated diseases such as metabolic syndrome, osteoporosis, and malignancies should be guaranteed during this lifetime. Preventive care should be provided by diagnosis, ideally through a multidisciplinary approach.
Hormonal Agents · Androgens and DHEA
The Klinefelter syndrome: current management and research challenges
Nieschlag E et al., 2016 · Andrology
Following the 1st International Workshop on the Klinefelter Syndrome in 2010 (Juul et al., 2011), the 2nd IWKS took place in Münster, Germany from March 10 to 12, 2016 and was organized by the Centre of Reproductive Medicine and Andrology of the University of Münster. During the program, talks were presented by leading researchers in the field followed by lively discussions among the 120 participants. The talks comprehensively covered basic and clinical aspects of the syndrome. The basic aspects included the mechanisms of X chromosome inactivation (Joost Gribnau, Christine Disteche), sex chromosome evolution in the primate lineage (Gabriel Marais), epigenetics (Joana Viana), gene expression studies (Liborio Stuppia), and animal models (Art Arnold, Armin Raznahan, Joachim Wistuba). Among the clinical aspects, current views on early/prenatal diagnosis (Frank Tüttelmann) and transitional care (Niels E. Skakkebæk, Alan Rogol) were reviewed. A large part of the workshop was devoted to comorbidities – with focus on cardiovascular and metabolic problems (Michael Zitzmann, Anders Bojesen) as well as osteoporosis (Alberto Ferlin). Neuropsychological, behavioral, and socioeconomic aspects were discussed (Hanna Swaab, Anne Skakkebæk, Nicole Tartaglia). Divergent experiences and opinions on fertility preservation and optimal time for TESE were presented (Sabine Kliesch, Hervé Lejeune). Following new findings on testicular steroidogenesis (Manuela Simoni), testosterone replacement in infants and young children (Carole Samango-Sprouse) and age-specific recommendations for management of patients with Klinefelter Syndrome (KS) met with great interest (Anders Juul). Differences and similarities between KS and Turner syndrome provided further insights into disorders of sex chromosome aneuploidies (Claus H. Gravholt). Finally, results of the 'dsd-LIFE study' on quality of life, satisfaction with care and needs of adolescents and men with KS (Birgit Köhler) and the European COST Initiative on DSD including KS (Olaf Hiort) were presented (for details of the program see www.klinefelter2016.de). The purpose of the concluding round table was to discuss – based on the presentations and interactions of this workshop – the shortcomings of current care of patients with KS and to indicate future directions for patient management and research. As an introduction, tribute was paid to Harry F. Klinefelter (1912–1990), who first described this syndrome in 1942 (Klinefelter et al., 1942). Of the 120 workshop participants, only Alan Rogol and Eberhard Nieschlag had met Harry Klinefelter in person, the former as one of his medical teachers at John Hopkins in Baltimore and the latter at an International Klinefelter Symposium in Murnau in the Bavarian Alps in 1983 (Bandmann et al., 1984). The discussion was opened by arguments for and against neonatal screening for KS as this question had come up repeatedly during the workshop. Alan Rogol gave the reasons for screening all male newborns for 47,XXY (and perhaps all children for sex chromosome aneuploidy): primarily in anticipation of services required in childhood, such as early treatment of deficits encountered in speech, behavior/regulation of emotion, physical findings, delayed childhood milestones. Furthermore, for information of parents, doctors, and health care practitioners as well as school and pre-school personnel (as much as parents wish, for there is a risk of stigmatization). An overarching service/education that pediatricians have to offer is anticipatory guidance, and newborn screening would allow pediatricians to provide this guidance to families concerned with KS. However, based on his experience in Denmark, Claus H. Gravholt felt that it was premature to screen large populations for KS, as we do not yet have evidence that the different treatment options that we can provide are efficient and reduce morbidity, mortality, and improve outcome. There is no proof yet that early diagnosis and treatment [truncated]
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Spermatogenesis in Klinefelter syndrome
Selice R et al., 2010 · Journal of endocrinological investigation
Klinefelter syndrome (KS) (47,XXY) is the most common sex chromosomal disorder, and it is a frequent form of male hypogonadism and infertility. Although the majority of these patients are azoospermic, they might have severe oligozoospermia or residual single-residual foci with spermatogenesis in the testis. We report our experience on sperm retrieval in the ejaculate and testis, and evaluate the frequency of chromosome abnormalities in sperm of KS. Eighty-four 47,XXY KS were evaluated with seminal analysis, body hair distribution, reproductive hormones, ultrasonographic scanning of the testis and prostate, bilateral testicular sperm extraction (TESE), sperm or testicular cells sex chromosomes aneuploidies. Out of 84 patients, 7 (7/84; 8.3%) had sperm in the ejaculate. Out of the 77 azoospermic patients, 24 underwent TESE and 9 (9/24; 37.5%) had successful sperm recovery. The comparison of reproductive hormones, age and testicular volume did not show significant differences between patients with and without successful sperm recovery in semen or TESE . Patients without successful sperm recovery in semen analysis or TESE had signs of hypoandrogenism more evident than patients with successful sperm recovery. Patients with KS produced a higher number of sperm aneuploidy with respect to normozoospermic fertile controls and non-genetic severely oligozoospermic men. Men with KS are not always sterile. In some of these patients sperm can be found in semen or in the testis, but the proportion of sperm aneuploidy is high. Signs of hypoandrogenism seem to be associated with low sperm recovery rate.
Genetics and Immunology › Reproductive Genetics › Chromosomal Abnormalities
PMID 27644703 27644703 DOI 10.1007/s40618-016-0541-6 10.1007/s40618-016-0541-6 Bonomi et al. 2017, Bonomi 2017