3.2.1 Klinefelter Syndrome

Klinefelter Syndrome (KS) represents the most common sex chromosome aneuploidy in humans, accounting for the main genetic cause of nonobstructive azoospermia (NOA). About 80–90% of KS patients carry the 47, XXY karyotype, while nearly 10% display various grades of mosaicism with the 46, XY/47, XXY karyotype or rarely present higher-grade sex chromosomal aneuploidy, such as 48, XXXY, 49, XXXXY, or structurally abnormal X chromosomes. Although the incidence of the syndrome is relatively high (1:660 in live births and 1:300 in spontaneous abortions), about two-thirds of KS patients are still misdiagnosed or remain undiagnosed [6]. The remaining 32% of KS patients are diagnosed in the following age groups: (i) in the fetus, during prenatal genetic diagnosis (10%); (ii) in childhood mainly for cognitive problems (3%); (iii) in adolescent age due to delayed puberty and gynecomastia (2%); and (iv) in adulthood due to infertility or sexual dysfunction (17%).

Heterogeneous clinical phenotypes of the disease, which may range from different grades of undervirilization, eunuchoid habitus, tall stature, long extremities, gynecomastia, hypergonadotropic hypogonadism, and azoospermia (90%), are likely related to the genotype. The overdosage of the SHOX (short stature homeobox) gene, located in the pseudo-autosomal region 1 (PAR1) on the short arm of Y and X chromosomes together with the delay of testosterone-induced closure of epiphyses have been proposed as possible explanations for the tall stature. In the majority of mosaic KS cases, few spermatozoa can be found in the ejaculate. A constant finding in KS patients is the small firm testis, due to testicular hyalinization and fibrosis, leading to testicular failure. Elevated LH and FSH levels are universal, whereas decline in the testosterone levels shows high interindividual variability. For most of the subjects, serum-testosterone concentrations after the age of 15 years remain in the low-normal adult range, and there is no absolute decline as they age. Testicular sperm extraction by conventional way (cTESE) and especially microsurgical TESE (micro-TESE) combined with intracytoplasmic sperm injection (ICSI) represent an opportunity for KS patients to father their own biological children. The average sperm retrieval rate (SRR) is about 40% [7] ranging from 28 to 62.5% [8], and it has been suggested that the success rates progressively decrease after the age of 30 [9]. Many different parameters have been studied with the aim to establish predictive factors for successful sperm retrieval, but available data have failed to identify clinically useful prognostic markers. Since apoptosis of spermatogonia and histological changes have been detected at onset of puberty, the question about the timing of testis biopsy has been the object of long debate. Preserving the fertility potential of young KS patients has been proposed in three different age groups: (i) pre-pubertal; (ii) peri-pubertal; and (iii) young adulthood. Some authors suggested that early pre-pubertal testicular sampling – before the complete germ cell loss occurs – might offer a greater chance of retrieving gametogenic cells. Although spermatogonia can be found in about 50% of a small number of adolescent KS boys by (m)TESE, testicular tissue freezing techniques as well as in vitro maturation strategies require further investigation. Data by Rohayem and colleagues in 2015 [9] suggest that the most promising predictive factors of finding spermatozoa in late adolescence and young adulthood are the patients’ age (between 15 and 25 years at biopsy) and the near compensated Leydig cell function. The cut-off values for hormones have been found to be a combination of total serum testosterone above 7.5 nmol/l with an LH below 17.5 U/l; however, these findings need further validation. Still, overall data in the literature do not support the necessity of adolescent TESE, since various studies have not found higher retrieval rates of spermatozoa in post-pubertal boys versus young adult KS patients [9]. Regarding the data of 1,248 adult KS patients in the meta-analysis performed by Corona and colleagues [7], the SRR was on average 40% and the live birth rate was about 16% of subjects who underwent TESE approach. Sperm retrieval was independent of a number of clinical and biological parameters such as age, testis volume, hormonal status, and bilateral approach [7,9].

Another controversial topic is related to androgen replacement therapy, which was supposed to have a negative influence on the future fertility of KS patients. Recently published reports did not confirm the deleterious effect of testosterone supplementation [7,9]. Some authors found that using hormonal stimulation by aromatase inhibitors improved the chances of successful SRR.

In KS patients with successful sperm retrieval, the genetic constitution of spermatozoa has been questioned. Recent evidence suggests that non-mosaic KS patients who produce sperm have mosaicism confined to the testis, and only 46, XY spermatocytes can achieve meiosis. However, in the analysis of sperm from KS patients assessed by using cell fluorescence in situ hybridization (FISH), higher aneuploidy rates of sex chromosomes and autosomes (especially chromosomes 13, 18 and 21) have been revealed. It is highly likely that the elevated aneuploidy rate in spermatozoa from KS patients results from abnormal meiosis in 46, XY spermatocytes, rather than from 47, XXY spermatocyte cells, since the presence of a supernumerary X chromosome prevents meiosis. For the above reasons, Preimplantation Genetic Testing (PGT) is recommended, although with few exceptions, the nearly 200 babies born worldwide from KS fathers with ICSI without PGT were normal. According to a study on a large cohort undergoing prenatal genetic diagnosis, KS accounts for 0.17% (188 out of 106,000) of all cases, which was similar to the incidence detected at birth by various studies [10].

KS is not confined to infertility but includes a series of comorbidities leading to increased mortality and morbidity, such as metabolic syndrome, autoimmune diseases (i.e. systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, etc.), venous thromboembolism, bone fractures due to osteoporosis, behavioral and socio-economic problems, etc. (Figure 3.1). They also present susceptibility to specific neoplasias, like breast cancer or extragonadal germ cell tumors and hematological malignancies [6]. The possible development of comorbidities implies that these patients need follow up (possibly by a multidisciplinary team) throughout their lifetime in order to actuate preventive strategies (life style change, diet, regular physical exercise, etc.) and therapies (i.e. testosterone replacement therapy, etc.).

Figure 3.1 Phenotypic characteristics and co-morbidities in KS.

3.2.2 Down Syndrome

Trisomy 21 occurs with an estimated frequency of 1:150 conceptions, 1:600 live births in the general population, and it correlates with advanced maternal age. The presence of an extra chromosome 21 has a detrimental direct and indirect effect on the reproductive capacity of the affected male subjects. The detailed pathophysiology of infertility in men with Down syndrome has not yet been elucidated. According to investigations addressing the causes of infertility, hormonal deficits, morphological alterations of the gonads, abnormal spermatogenesis, and psychological and social factors related to the mental retardations may play roles in this process. To date, three cases of parenting by fathers with Down syndrome have been described in the literature [11].

3.3.1 Detectable with Karyotyping

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