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

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.