Klinefelter's syndrome is the most common chromosomal aneuploidy [15]. Though, it is usually underdiagnosed, only 25% of the patients are diagnosed, and most of them are diagnosed in adulthood owing to the effects of production of hyper- gonadotropic hypogonadism [16]. The clinical data of the studied Klinefelter syndrome patients is summarized in Table 1. In the current study we diagnosed these patients in childhood (8–16 years). 57.1% of the patients were the offsprings of consanguineous marriage, Vallabhajosyula et al., [17] reported consanguinity in 22.2% of their patients. Developmental delay occurred in 48.6% of the patients although Tartaglia et al., [18] noticed developmental delay in 35% of his KF patients. This may be owing to his larger cohort and differences in age. Facial dysmorphism including epicanthal folds, hypertelorism, depressed nasal bridge was identified in 28.6%, our study is in agreement with previous investigators [19, 20]. Furthermore, it is worth noticing that gynecomastia, undescended testis and tall stature are hallmarks of KF syndrome, and their recognition could improve the rate of early diagnosis. Gynecomastia was present in 28.6% of our patients. Similarly, Chang et al., [21] claimed that gynecomastia was found in 28% of their patients. Undescended testis was detected in 60% of the studied patients. Bojesen et al., [22] reported cryptorchidism in 37% of KF patients [22]. Moreover, tall stature was observed in 69.6% of the studied patients. Our findings are in agreement with former studies elucidating that the presence of three copies of the SHOX gene, a possible effect of X chromosome dosage explains excess height in KS [16, 21]. Moreover, congenital heart disease (CHD) was revealed in 54.3%. Claus et al., [16] noted CHD in the form of mitral valve prolapse in 50%. Additionally, intellectual disability was assessed in 57.1% of the patients. Similarly, Simonetti et al., [23] recorded intellectual disability present in KF relies on an imbalance in X-chromosome gene expression. On the other hand, it was reported that the majority of subjects with 47, XXY karyotype have a normal intellectual level [24].
In our study, the karyotype (47, XXY) confirmed the clinical diagnosis of KF in all patients (Fig. 1). This is consistent with previous investigators [16, 19, 23].
The biochemical findings of the patients are summarized in Table 2 and 3.
Our findings revealed a statistically significant variance between cases and controls in terms of Heat Shock Protein- 70 (HSP). Previous studies concluded that high level of HSP may enhance the pathogenesis of male infertility [7]. Increased serum HSP70 suggests oxidative stress, systemic inflammation, and maintenance of immune homeostasis which is likely due to the supernumerary X chromosome that contributes to several pathologies in KF syndrome [25, 26]. Furthermore, we recorded higher levels of the inflammatory cytokines TNF- α in the KF syndrome in relation to the controls. This is consistent with Lefevre et al., [27] who claimed that the excess number of X chromosomes influences inflammatory cytokine production. This emphasizes the view that chronic low-grade inflammation is involved in the pathogenesis of Klinefelter syndrome. The high level of heat Shock Protein − 70 in the patients with Klinefelter syndrome correlated with the low level of testosterone in our patients. Recent studies indicated that heat Shock Protein − 70 plays a role in testicular damage [28]. Thus, testosterone treatment has been the keystone in the care for patients with KS.
Moreover, the high level of TNF-α in the patients with Klinefelter syndrome correlated with the low level of testosterone, this is consistent with the previous research that stated that testosterone attenuates the peripheral inflammatory process by inhibiting the expression and function of the inflammatory cytokines TNF-α [29].
Interestingly, our results showed significant differences in HSP70 in KF with intellectual disability and those with normal mentality (Table 4). Rising evidence verified that accumulation of damaged protein aggregates and dysfunction of intracellular degradative system are orchestrating the neurodegenerative processes [30, 31]. We suggest that the accumulation of the HSP70 in KF which plays a role in neuronal development could contribute to the intellectual disability.
The inflammatory cytokines TNF-α was observed in higher levels in the patients with Klinefelter syndrome with intellectual disability than those without intellectual disability (Table 4). TNF-α is associated in the pathogenesis of neurodegenerative disorders and cognitive dysfunction [32]. Cytokine dysregulation may highlight the clinical outcome and raised pro-inflammatory biomarkers appear to be an important feature in KF syndrome.