Karyotype distribution
Klinefelter syndrome patients
47XXY
3863 (86.3%)
46XY/47XXY
383 (8.5%)
48XXXY
157 (3.5%)
49XXXXY
66 (1.5%)
48,XXY + trisomy of chromosome 18
5 (0.1%)
47,XXY/48,XXXY
2 (<0.01%)
Undetermined
1 (0 < 0.01%)
The principle genetic cause of KS is meiotic nondisjunction. Nondisjunction is a condition characterized by failure of homologous chromosomes or sister chromatids to properly separate during cell division, resulting in daughter cells with abnormal chromosome number or otherwise known as aneuploidy.
It is generally agreed that most autosomal trisomies result from maternal meiotic nondisjunction, with less than 10% originating from paternal errors [8]. Contrary to this, the condition is different in sex chromosomal aneuploidy such as KS, where a paternal origin for meiotic nondisjunction occurs in almost 50% of cases [8, 9]. When KS results from an extra maternal X-chromosome, it probably occurs due to nondisjunction during the first or second meiotic divisions, whereas when the additional X-chromosome comes from a paternal origin, nondisjunction of the first meiotic division is the only possibility, as a meiosis II error will result in either XX or YY gametes (Figs. 9.1 and 9.2) [8]. Mosaic forms of KS, on the other hand, arise either from nondisjunction in an early mitotic division of a normal 46XY zygote, or from loss of one of the extra X-chromosomes of a 47XXY conception, a process called trisomy rescue. Maternal age is a well-known risk factor for KS. Bojesen et al. detected a fourfold increase in the prevalence of KS cases when maternal age was greater than 40 years [6]. Paternal age, however, has been considered less influential [10]. A recent review by Fonseka et al. confirmed lack of evidence correlating paternal age with autosomal aneuploidy but depicted a minor effect on sex chromosomal trisomies [11]. Other studies did find an influence for advanced paternal age but only in fathers with paternally inherited KS offspring [12].
Fig. 9.1
47XXY of maternal origin
Fig. 9.2
47XXY of paternal origin
KS is portrayed through a wide phenotypic spectrum ranging from normal or near normal presentation to poor virilization, sterility, and learning or behavioral problems manifesting at an early age. It is unknown why certain men present on one end of the phenotypic spectrum while others present on the other. Genomic imprinting, a phenomenon where certain genes are expressed while others are silenced in a parent-of-origin-specific manner [9], may help explain this variability.
Another explanation depends on the degree of gene polymorphisms occurring secondary to X-chromosome inactivation. The androgen receptor (AR) gene located on the X-chromosome, and encoding the AR contains a highly polymorphic trinucleotide (CAG) repeat sequence. The length of this CAG repeat is inversely related to the functional response of the AR. In other words, the shorter the AR CAG repeat sequence the more marked the androgen effect is. Patients with KS appear to have an inactivation of the shortest AR CAG repeat in a process called skewed or nonrandom X-chromosome inactivation [13]. Patients having short AR CAG repeat lengths generally respond well to androgen therapy and are able to form more stable partnerships and achieve a higher level of education compared with long CAG repeats. On the contrary, patients with long CAG repeat lengths generally have an increased body height and arm span, decreased bone density, decreased testicular volume, and gynecomastia [13]. This nonrandom X-chromosome inactivation might also explain the diversity of the KS phenotype.
Endocrine Function and Spermatogenesis in Klinefelter Syndrome
There is evidence suggesting that infants with KS have an initial embryonal testicular development that is similar to 46XY infants. Germ cells originating in the yolk sac undergo migration to the urogenital ridge [14]. This is followed by the initiation of secretory function of mesenchymal (nacent Leydig) cells and Sertoli cells [14]. Hunt et al. demonstrated a normal number of migrating germ cells to the genital ridge followed by a reduction in their mitotic proliferation and expansion as the testis develops [15]. The latter was confirmed by Mikamo et al. who displayed a progressive diminution in the number of spermatogonia from 24 to 0.1% of control value, over the course of the first year of life [16]. Studies performed on the prepubertal KS boys reveal marked reduction in the number of spermatogonia with evidence of differentiation arrest at the spermatogonium or early primary spermatocyte stage [17]. Moreover, immature Sertoli cells also have reduced capability of transforming into adult mature cells [18].
This raises an argument on how spermatogenesis in KS patients occurs. Two hypotheses have been brought forward. The first one is based on the notion that some 47XXY spermatogonia are capable of completing meiosis, which would explain the increase in sex chromosomal aneuploidy rate present [17, 19]. The second hypothesis suggests that KS patients may have patches of 46XY spermatogonial stem cells and the higher aneuploid sperm results from meiotic errors caused by a compromised testicular environment [20]. Certainly, testicular histopathologic evaluation of adult KS patients demonstrates patchy areas of extensive fibrosis and hyalinization of seminiferous tubules [21] interspersed with areas containing larger more differentiated cellular structure [22]. Intuitively, however, one would argue against the latter hypothesis, especially because the majority of KS patients are nonmosaic.
Contrary to sperm production, endocrine function in KS patients appears to follow a normal pattern until puberty. Several studies have indicated that prepubertal KS boys have normal serum levels of testosterone, follicular stimulating hormone (FSH), luteinizing hormone (LH), and inhibin B until the onset of puberty [23–25]. After an initial rise in serum testosterone, the level plateaus remains consequently at a low–normal range throughout puberty [24, 25]. Such level appears to be sufficient for KS boys to progress through puberty and develop satisfactory secondary sexual characteristics [23, 26].
Serum estradiol levels are generally high among KS prepubertal and pubertal boys, irrespective of the presence or absence of gynecomastia, with a tendency to have higher estradiol/testosterone ratio throughout puberty [23, 27]. Patients with KS exhibit an initial increase in inhibin B similar to normal boys before the clinical onset of puberty, but the levels soon drop thereafter in association with a simultaneous increase in serum testosterone [18, 24]. From mid-puberty onward, a gradual increase in FSH and LH concentrations is seen in KS patients, with FSH levels increasing somewhat earlier and more markedly than do LH levels [23, 24, 27].
Clinical Manifestations
Case Scenario 1
A 14-year-old boy presents with a delay in puberty. He has a history of learning difficulty since 8 years of age characterized by troubles with spelling and composition. Although he required additional help at school, his IQ was normal and he was able to progress academically along with his peers. An impulsive behavior was noted during his psychological evaluation, however without sufficient findings to support a diagnosis of attention deficit disorder. His physical examination reveals tall stature (99 percentile for age), gynecomastia, and small testes. A chromosomal study reveals a 47,XXY karyotype.
Case Scenario 2
A young adult man presents with primary infertility of 2 years duration. He has no significant past medical history apart from a slight delay in puberty. He reports normal sexual activity with good libido, normal erection and ejaculation. His physical examination reveals no gynecomastia, normal penile size, and bilateral testicular atrophy. A chromosomal study reveals a 47,XXY karyotype.
The two case scenarios signify the variability of the clinical presentation of patients with KS according to their age and degree of phenotypic affection. Before puberty, it is usually difficult to recognize boys with KS for the principle reasons that were described in the previous section. Discrete physical anomalies such as a mild decrease of testicular volume and increase in lower limb length may be seldom noticed. After puberty, small firm testes and varying symptoms of androgen deficiency characterize the syndrome. These symptoms can be classified into the following:
Consequences of Hypogonadism: a delay in the development of normal secondary sexual characteristics is typically present. Reduced facial and body hair has been reported by about 20% of KS patients [28]. While most patients achieve normal penis size, approximately 70% of patients complain of falling libido and potency from the age of 25 years [29].
Gynecomastia: KS patients have a 50% higher incidence of gynecomastia [30], attributed to testosterone deficiency and/or reduction in testosterone/estradiol ratio [31].
Anthropometry and Body Composition: an accelerated growth is usually seen among KS patients from childhood resulting in a taller stature than their normal counterparts [30]. Although KS patients generally have a normal body mass index (BMI), they typically have an increase in body fat and a decrease in lean muscle mass resulting in an unfavorable muscle/fat ratio [32]. Our understanding of the androgenic effect on body fat mass is centered on investigations on hypogonadal aging men. Androgens have a negative effect on adipose tissue development as they inhibit the differentiation of pluripotent cells into fat cells [33]. Nonetheless, the increase in body fat in KS patients is witnessed even before puberty, suggesting a possible genetic influence on this observation [34].
Bone Mineralization: Hypogonadism is a known cause of secondary osteoporosis in both men and women [35]. Many studies conducted on KS patients revealed a significant reduction of bone mineral density [36, 37], and a higher incidence of osteoporotic fractures of the hip, spine, or forearm [7, 38]. Such fractures were responsible for higher hospital admissions, employing significant morbidity and mortality on KS patients [7].
Diabetes and Metabolic Syndrome: An association between diabetes mellitus and KS has been established for reasons that remain poorly understood. The reported incidence has been between 15 and 50% [39] and is mainly attributed to genetic factors, endocrine imbalance, or autoimmune mechanisms. In a study of 70 KS patients who were compared to an age-matched control group, Bojesen et al. revealed a significant incidence of metabolic syndrome and insulin resistance [40]. Plasma low-density lipoprotein (LDL) cholesterol was increased while high-density lipoprotein (HDL) cholesterol was decreased compared with the control group [40].
Hypogonadism is an established risk factor for metabolic syndrome and diabetes mellitus. However, this relationship appears to be secondary to adiposity rather than testosterone itself. Testosterone replacement was successful in improving insulin sensitivity only in obese and not in lean hypogonadal men [41]. It is not known whether this is the governing rule in KS patients or if there may be other genetic influences that are responsible. Jiang-Feng et al. detected a higher prevalence of diabetes mellitus among KS patients compared with a group of idiopathic hypogonadotropic hypogonadism patients [42]. Their report also revealed that testosterone deficiency was not the only impelling factor for this finding, suggesting a potential genetic influence especially because the incidence of diabetes mellitus was significantly higher among mosaic (46XY/47XXY) compared to nonmosiac 47XXY patients in the study population (p = 0.008).
Cardiovascular Disease: Mitral valve prolapse has been found to commonly affect KS patients, placing them at a greater mortality risk [43]. Clotting defects with subsequent embolic events were also identified. One study reported an increased activity of plasminogen activator inhibitor-1 responsible for dysfunctional fibrinolysis [44]. In another recent study, an increased platelet activity has been detected [45]. High levels of C-reactive protein, LDL cholesterol, and triglycerides and low levels of HDL cholesterol were proposed as factors placing patients with KS at risk for ischemic heart disease. Adiponectin, an adipocyte-specific secretory protein having anti-atherogenic, anti-inflammatory, and anti-diabetic properties [46], has been found to be inversely proportional to testosterone level; a fact that helps explain the cardiovascular adverse effects of testosterone replacement [47]. Remarkably, patients with KS were found to have higher levels of adiponectin irrespective of their testosterone level [32]. This suggests that despite the previously mentioned risk factors, KS patients are in fact safeguarded against ischemic heart disease. Epidemiological data on mortality in patients with KS have found an increased mortality from diabetes, but the mortality from ischemic heart disease was significantly decreased [7].
Cancer: A 50-fold increased risk of breast cancer has been detected in KS patients [48]. Mediastinal germ-cell tumors have also been reported in more than 40 patients [49], most of them developing before the age of 30 years. Moreover, hematologic malignancies, such as leukemia and lymphoma (non-Hodgkin), have also been linked with KS [50]. Conversely, a recent study revealed a significantly decreased risk of death from prostate cancer [51], which expectedly is secondary to hypogonadism.
Cognitive Disturbances: Deficits in very specific domains of cognition such as language and executive functions are commonly associated with the syndrome. Activities, such as concept formation, problem solving, task switching, speed of response, and planning, which seem similar to those observed in cytogenetically normal dyslexic children, are particularly affected [52].
Psychiatric Disturbances: Studies from the late 1960s that were performed on prison inmates and psychiatric hospitals revealed an increased incidence of psychiatric illness among individuals with KS [53]. Ratcliffe et al. tracked patients with KS for a long duration and reported an increased frequency of referrals for psychiatric treatment [26]. A four- to fivefold increased incidence of KS has been detected in a survey searching for sex chromosome aberrations among patients with schizophrenia. The proposed reason for this association is possibly an overexpression of X-linked genes that escaped the X-chromosome inactivation seen in patients with KS [54].
Diagnosis
The diagnosis of KS requires some degree of clinical suspicion in addition to a high level of awareness about its prevalence in men with delayed puberty, sexual dysfunction, low testosterone, and infertility. The condition can be suspected during the initial male fertility evaluation when signs and symptoms of hypogonadism are evident. Physical inspection usually reveals decreased facial and body hair together with gynecomastia and female fat distribution. Small testes having firm consistency are typically discovered on genital examination. A digital rectal examination may reveal atrophy of the prostate, which was documented in about 30% of cases in one study [55].
Azoospermia on semen analysis is the norm, though not the rule as about 8.3% of patients are able to produce sperm during ejaculation [56]. Endocrine evaluation demonstrates low serum testosterone in about 80% of adult patients with KS [31], secondary to some degree of Leydig cell dysfunction. Serum concentrations of sex hormone-binding globulin (SHBG) are high, resulting in further reduction of free testosterone. Estradiol, on the other hand, is commonly higher in KS patients than in normal men, disrupting the testosterone/estradiol ratio. Concentrations of LH and FSH are elevated, highlighting a hypergonadotropic hypogonadism picture. FSH is most consistent representing coherent damage of seminiferous tubules [57], which in its turn is associated with a decrease in inhibin B level [24].
Early diagnosis and treatment of KS boys should have favorable effects on their physical, academic, and social development and health [58]. Unfortunately, only 10% of men affected by KS are diagnosed in at a young age—the time when treatment may be most effective. Screening for KS in target populations such as children with learning disabilities or developmental problems has been proposed as a method that could offer early detection and treatment [58].
Buccal epithelial testing for Barr bodies, which correspond to the inactive supernumerary X-chromosome, is no longer used [59]. The diagnosis is currently confirmed cytogenetically through chromosome analysis of lymphocytes [59]. Sometimes a normal male karyotype may be reported requiring the use of skin fibroblasts or testicular biopsy samples to confirm chromosome mosaicism. Y chromosome microdeletion analysis is also indicated in KS patients as few reports have suggested an increased risk for such deletions in this population [60].
Because of the decreased level of testosterone and significantly increased risk of osteopenia and osteoporosis in men with low testosterone, bone density testing should be routinely performed in patients with KS. If osteopenia or osteoporosis is diagnosed, then additional laboratory tests including calcium, phosphorus, parathyroid hormone (PTH) calcium, and vitamin D3 should be measured.
The patients should be made aware of the increased risk of breast cancer and should be taught to perform regular self-breast examinations and seek advice if they detect a change in consistency of the breast tissue or in case there was discharge from the nipples.
Management
A multidisciplinary approach to patient management is vital to confront all features of the disease. Although achieving fertility is a principle goal, the clinician should not undervalue other consequences that may have an impact on patients’ quality of life and overall health. A number of factors must be considered such as the age at which the diagnosis was made, the presenting complaint, and whether fertility is pursued.
Managing Hypogonadism
In Adolescents and Adults
The marked hypogonadism experienced by KS boys preventing their progress through puberty needs to be addressed at some point with testosterone replacement therapy (TRT). This is aimed at promoting the development of secondary sexual characters and stimulating linear bone growth and muscle bulk. Evidence present today makes it unknown whether TRT carries a significant impact on fertility in men with KS. In the case series by Schiff et al. [61], five patients received TRT for a duration ranging from 2 to 14 years and in only one patient sperm could be retrieved through testicular sperm extraction (TESE). Furthermore, Ramasamy et al. documented a worse sperm retrieval rate (SRR) among patients with prior exposure to TRT [62]. Current best practice statements recommend initiating therapy in early to mid-puberty, or at the onset of hypogonadism [63–65], to ensure normal completion of puberty and prevent unfavorable effects of long-term androgen deficiency. Other physicians may choose to initiate therapy at an even earlier age aiming to correct decreased penile length, which may be relatively smaller in KS boys, though not to the extent of micropenis [66]. There are no specific TRTs or protocols intended for patients with KS. Age-appropriate formulations and/or doses may be determined according to clinical practice guidelines on the treatment of hypogonadal men [67].
Few reports have looked into hormone replacement therapies that can minimize the deleterious effect of exogenous testosterone or even enhance sperm production. Mehta et al. used topical testosterone in combination with an aromatase inhibitor in ten patients for a period of 1–5 years before microsurgical testicular sperm extraction (microTESE) and were able to retrieve sperm from seven patients [68]. Other available options include the co-administration of intramuscular injections of human chorionic gonadotropin or clomiphene citrate. Such regimens were not evaluated in KS patients specifically, however, some evidence can be withdrawn from their use in hypogonadal men. In a retrospective analysis of 26 men treated with testosterone replacement therapy along with human chorionic gonadotropin (HCG), there were no differences in semen parameters after one year of treatment [69]. Remarkably, spontaneous pregnancy occurred in 35% of patients. Lower doses of HCG were also investigated and were successful in maintaining adequate intratesticular testosterone levels [70]. One disadvantage for continued HCG use is that FSH replacement should be considered after a period of time to maintain spermatogenesis. Clomiphene citrate also has been acknowledged as a reasonable alternative to exogenous testosterone in hypogonadal men. Despite a lower efficacy than injectable testosterone, clomiphene citrate is capable of achieving similar symptom relief [71]. Enclomiphene citrate, a newer estrogen receptor modulator, successfully normalized endogenous testosterone production and restored sperm counts through reestablishing the function of the hypothalamic-pituitary-testicular axis [72]. Concerns regarding safety of long-term use of clomiphene-like products emerged. Moskovic et al. looked into this issue through a follow-up of 46 patients receiving clomiphene citrate for a period of more than 12 months. No adverse events were detected in the whole group, concluding that it is an effective long-term therapy in appropriate patients [73]. Further studies of larger sample size and longer duration of follow-up are still required to estimate, with great certainty, treatment safety.
Fertility Management
Peripubertal KS Boys
Based on the knowledge, there is a constant decline in testicular function beginning at puberty. Some researchers have proposed the notion to seek fertility preservation at an earlier age even before staring TRT. Indeed, Mehta et al. reported the presence of sperm in the ejaculates of 70% of adolescents with KS aged 12–20 years [74]. Studies on testicular samples are understandably scarce in this age group. In a case report by Damani et al., sperm was successfully retrieved from the testicular tissue of a 15-year-old [75]. In another observational retrospective study, Aksglaede et al. [76] determined an age limit of 10 years after which there would be loss of germ cells from testicular tissue. After examining testicular tissue samples from 14 KS boys aged 10–14 years, Wikstrom et al. [18] were able to find germ cells in only half of them, suggesting the presence of testicular dysfunction in the peripubertal period. Moreover, all samples containing germ cells were from boys younger than 12 years of age with prepubertal-sized testicular volumes, normal serum inhibin B, and FSH concentrations. As such, researchers have looked into markers that can be examined in order to successfully time sperm retrieval. Serum inhibin B levels being normal in the prepubertal and early pubertal periods [24] make it an ideal marker to reflect the integrity and number of Sertoli cells. Unfortunately, this was not the case as seen in a study of Wikstrom et al. [17], where normal inhibin B levels were inconsistent with the presence of spermatogonia. Anti-Müllerian hormone is another marker that failed to denote spermatogenetic activity, although it is known to rise during prepuberty and early puberty in boys with KS and decline afterward [76]. Finally, insulin-like factor 3 (INSL3), a marker of Leydig cell function found to be normal before puberty in KS boys and known to decrease thereafter [77], does not correlate with testicular spermatogenic function.
Cryopreservation in Adolescents
Ethical concerns and challenges arise when obtaining sperm via masturbation from adolescent patients. Anejaculation or idiosyncratic masturbation that is common in this age group would further aggravate the challenge. The clinician should be able to approach this sensitive issue in an age-appropriate way and actively involve parents in a productive manner. Cryopreservation of sperm is currently offered to adolescents after a thorough discussion with them and their parents. Current recommendations are to bank sperm for all males at or above Tanner stage III [78], especially if viable sperm are found on semen analysis.
If masturbation cannot be accomplished, some have advocated the use of stimulatory techniques. Vibratory stimulation or, alternatively, electroejaculation under anesthesia can be attempted. Data on the use of these procedures are mainly drawn from studies performed on fertility preservation in cancer patients. In a study of patient and parent attitudes toward sperm preservation in boys undergoing chemotherapy, 70% were in favor of using masturbation or electrostimulation as a means of obtaining sperm for cryopreservation [79]. Invasive procedures to retrieve mature sperm from adolescents are currently not justified because of their negative endocrine effects and the high retrieval rates seen in adulthood.
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