У человека синдром клайнфельтера проявляется при трисомии егэ

Klinefelter Syndrome

Classically, Klinefelter syndrome is characterized by very small, firm testes; azoospermia and infertility; varying degrees of androgen deficiency and eunuchoidism; and uniformly elevated gonadotropin concentrations.^20,221,222 It is the most common sex chromosome abnormality and the most common cause of primary hypogonadism, resulting in androgen deficiency and impaired sperm production. It occurs prenatally and neonatally in 1 of every 500 to 700 males, and the prevalence in adults is 1 in 2500.^1,2 Because the syndrome does not cause premature death in boys, the low adult prevalence indicates that Klinefelter syndrome is often overlooked and underdiagnosed in men. Given the almost uniform finding of extremely small testes and other phenotypic abnormalities, it is surprising that about 75% of men with Klinefelter syndrome are never diagnosed. This might be due to failure to recognize mild phenotypes or failure to perform a testicular exam. The risk of having a child with Klinefelter syndrome increases with both maternal and paternal age.

The chromosomal abnormality in Klinefelter syndrome is the presence of one or more extra X chromosomes due to maternal meiotic nondisjunction (mostly in meiosis I) in approximately 50% of the cases or paternal meiotic nondisjunction in the remaining cases.^20,221,222 The principal karyotype in 90% of men with Klinefelter syndrome is 47,XXY. Most of the remaining 10% have mosaic Klinefelter syndrome (47,XXY/46,XY), in which there is a 47,XXY karyotype in some tissues or cells and a normal 46,XY karyotype in other tissues or cells. Mosaicism occurs as a result of postfertilization mitotic nondisjunction. Men with mosaic Klinefelter syndrome usually demonstrate a variable and less severe phenotype that depends on the specific tissues in which an extra X chromosome is present. Some men with mosaicism have a normal karyotype in the testis with intact spermatogenesis and fertility. Rarely, men with Klinefelter syndrome have morethan one extra X chromosome (e.g., 48,XXXY, 49,XXXXY). Men with these variants manifest a more severe phenotype than is seen in classic Klinefelter syndrome.

Infants with Klinefelter syndrome may manifest micropenis, hypospadias, cryptorchidism, or developmental delay.^222,223 During childhood, boys with the syndrome commonly have small testes and reduced penile length relative to age-matched normal individuals and may manifest relatively tall stature, clinodactyly, hypertelorism, gynecomastia, elbow dysplasia, high-arched palate, hypotonia, language delay or learning and reading disabilities requiring therapy, and behavioral problems.^222,224 However, these manifestations may be mild and are often missed. Fewer than 10% of boys with Klinefelter syndrome (usually those with the most severe phenotype) are diagnosed before puberty. At puberty, the testes fail to increase in size and become firm due to a progressive loss of germ cells and seminiferous tubule hyalinization and fibrosis; Sertoli cell products, inhibin B, and AMH decline to very low or undetectable serum concentrations; circulating testosterone concentrations increase but to less than normal concentrations in some boys, resulting in varying degrees of eunuchoidism and gynecomastia; and FSH concentrations are disproportionately elevated relative to LH concentrations. Elevation of serum LH disproportionately to FSH is an indication of a disorder other than Klinefelter syndrome or any cause of primary hypogonadism that affects both Sertoli cell and Leydig cell dysfunction—for example, rare diseases such as disorders of testosterone biosynthesis or abnormalities of LH or its receptor should be considered.

Abstract

Klinefelter syndrome (KS) is a genetic condition resulting from an additional X chromosome in phenotypic males (47,XXY). KS affects ~ 1 in 600 males however historically only ~ 25% are accurately diagnosed in their lifetime. Testicular development and function in impaired, often resulting in hypergonadotropic hypogonadism and the classic physical phenotype of small testes, long extremities, gynecomastia, and azoospermia. Testosterone replacement is standard treatment, however there is practice variability on when to initiate this therapy. Other frequently associated manifestations include mild developmental delays, language-based learning disabilities and disorders of insulin resistance which add to the increased morbidity and mortality in this condition. There are multiple mechanisms proposed for how the additional X chromosome results in the physical phenotype of KS and the heterogeneity among affected individuals. Recent advances in KS include early diagnosis identified through noninvasive prenatal screening and successful retrieval of viable sperm through testicular sperm extraction.

Klinefelter Syndrome and Its Variants

Klinefelter syndrome and its variants are the most common forms of sex chromosome aneuploidy, with a reported incidence of 1 in 500 to 1 in 1000 live male births.¹⁸⁰ This incidence may be increasing.¹⁸¹ The classic form of Klinefelter syndrome is associated with a 47,XXY karyotype and is caused by meiotic nondisjunction of the sex chromosomes during gametogenesis (Fig. 24.18).¹⁸ This abnormality occurs during spermatogenesis in approximately 50% of patients and during oogenesis or postzygotic division in approximately 50%.¹⁸⁰ Mosaic forms of Klinefelter syndrome (46,XY/47,XXY) likely represent mitotic nondisjunction within the developing zygote and are thought to occur in approximately 10% of individuals with Klinefelter syndrome. Other chromosomal variants of Klinefelter syndrome (e.g., 48,XXXY) can be seen.

The clinical features of Klinefelter syndrome and its variants are summarized inTable 24.4.¹⁸⁰ In the most obvious situations, a young man may be diagnosed because of small testes, gynecomastia, poor androgenization at puberty, eunuchoid proportions,or infertility. Other features, such as learning difficulties, speech and language delay, behavioral issues, and altered motor development, may occur, and early educational support focusing on any specific areas of difficulty is important.^182,183 It is likely that the clinical detection of Klinefelter syndrome based on postnatal karyotyping is biased toward detection of those individuals with a more severe phenotype, and it is estimated that as few as 25% of men with Klinefelter syndrome may be diagnosed throughout their life span. However, this pattern may change as diagnosis of Klinefelter syndrome on prenatal genetic testing becomes increasingly common.

The development of testes and a male phenotype in individuals with Klinefelter syndrome provides important evidence for the key role of the presence of the Y chromosome (rather than X chromosome number) in testis determination and subsequent prenatal androgen production. However, testicular function may not be completely intact; micropenis and hypospadias may be presenting features in some cases, and some studies report mildly elevated FSH concentrations during the postnatal “minipuberty” together with testosterone levels in the lower half of the normal range.¹⁸⁴

A more predictable elevation in gonadotropin concentrations (e.g., FSH, LH) occurs in the periadolescent period in patients with Klinefelter syndrome, after activation of the HPG axis.^185,186 By midadolescence, plasma concentrations of FSH are increased in 90% of patients with Klinefelter syndrome, and plasma concentrations of LH are increased in 80%. Other serum markers of testicular function (e.g., peripubertal inhibin B, midpubertal INSL3) are often below the normal ranges.^173,186 Although puberty usually starts at a normal age with an appropriate rise in testosterone in classic Klinefelter syndrome, serum testosterone levels off around midpuberty with an increase of gonadotropins. In the majority of young adults, serum testosterone is in the lower half of the reference range.^185,187 Testes usually remain small and firm; the median length and volume are 2.5 cm and 3 mL, but most are smaller than 3.5 cm (range 1–7 mL).¹⁸⁵ Testes typically appear inappropriately small for the degree of androgenization. The serum estradiol concentration is often elevated, which contributes to the gynecomastia observed during the adolescent period.

Clinical Presentation

Klinefelter’s syndrome is present in about 1 in 1000 living males. Azoospermia, gynecomastia, and the presence of small atrophic testes in otherwise normal males are the clinical hallmarks of the disease. The characteristic features of patients affected with Klinefelter’s syndrome usually first become apparent during adolescence. In a classical scenario, the diagnosis is suggested by the presence of small testes (less than 3 cm in length), commonly but not always accompanied by bilateral gynecomastia, in adolescent boys seeking medical advice because of a delayed onset of puberty. These features can be associated with a variable degree of eunuchoidism, that is, altered body proportions and tall stature. However, in particular instances, the diagnosis of Klinefelter’s syndrome can also be made as early as during the neonatal period or as late as during adult life.

Klinefelter’s syndrome can be diagnosed during the first year of life in children evaluated for microphallus, hypospadias, or cryptorchidism. Later during childhood but before adolescence, the diagnosis may be suspected on the basis of a subnormal testicular size. Indeed, in normal men, more than 80% of the total testicular volume is accounted for by the seminiferous tubules, the anatomical structures where spermatogenesis takes place. In Klinefelter’s syndrome, an abnormal fibrosis of these tubules begins before puberty. When this pathological process is severe enough, atrophy of the testes may already become evident during mid-childhood. At the other end of the spectrum of clinical presentations, a number of patients can achieve significant virilization and go undiagnosed until adulthood. These patients can be discovered incidentally during the workup of a malignancy but are usually diagnosed on the occasion of their evaluation for infertility.

Serum levels of the male hormone testosterone are normally low in prepubertal boys and begin to rise during early puberty. In boys affected with Klinefelter’s syndrome, a decreased capacity of the testes to secrete testosterone becomes evident in many cases as puberty continues. Therefore, testosterone levels tend to be either low-normal or frankly decreased in adult patients. This occurs despite an elevation above normal values of the circulating levels of luteinizing hormone (LH), the hormone that normally stimulates testosterone production by the testes. Because of the lack of testosterone, affected patients rarely become normally virilized. On the other hand, the levels of the female hormone estradiol, which is also normally secreted by the human testes, are usually elevated in Klinefelter’s patients. These anomalies result in an imbalance between the two sex hormones, with increased estradiol levels and diminished testosterone values producing a hormonal milieu favorable to the development of bilateral gynecomastia. This is observed in more than 90% of Klinefelter’s patients.

Klinefelter Syndrome and Variants

In 1942, Klinefelter, Reifenstein, and Albright described a syndrome characterized by eunuchoidism, gynecomastia, azoospermia, increased gonadotropin levels, and small, firm testes. By 1959, these patients were noted to have a 47,XXY karyotype (Jacobs and Strong, 1959).

Klinefelter syndrome represents the most common major abnormality of sexual development. By definition, males with at least one Y chromosome and at least two X chromosomes have Klinefelter syndrome. The classic 47,XXY complement arises as a result of nondisjunction during meiosis; it occurs in 1 of 600 liveborn males (Morris et al, 2008). But the phenotype is also associated with 48,XXYY and 49,XXXYY, and an exaggerated form of the phenotype is associated with 48,XXXY and 49,XXXXY. The mosaic form 46,XY/47,XXY is associated with milder phenotypic features of classic 47,XXY Klinefelter syndrome. Perhaps as a result of phenotypic variability, Klinefelter syndrome is believed to be underdiagnosed, with a 25% diagnostic rate in one Danish study (Bojesen et al, 2003).

In 47,XXY adults, seminiferous tubules degenerate and are replaced with hyaline. As a result, testes are firm and small, less than 3.5 cm in length. Histologically, Leydig cells appear to predominate. They are seen in large clumps in certain areas of the testes, sometimes resembling Leydig cell tumors. However, the absolute volume of Leydig cells is not increased and is probably lower than normal. Serum levels of testosterone are low-normal and those of gonadotropins are elevated. Plasma estradiol levels tend to be high, with gynecomastia the result of an increased ratio of estradiol to testosterone. The vast majority of patients are azoospermic, and the presence of sperm suggests 46,XY/47,XXY mosaicism. There does appear to be a depletion of germ cells with the onset of puberty (Wikström et al., 2004). Fertility, with the benefit of testicular sperm extraction and intracytoplasmic sperm injection (ICSI), has been reported in patients with Klinefelter syndrome. A recent meta-analysis examining ICSI outcomes reported a 43% live birth rate per ICSI cycle (Corona et al., 2017). Some infertility experts advocate coupling intracytoplasmic sperm injection with preimplantation diagnosis given the lower rate of normal embryos from Klinefelter syndrome patients (54%) versus controls (77%) (Staessen et al, 2003). However, there have been over 200 normal live births reported using ICSI without preimplantation genetic analysis, which brings into question the utility of this testing in predicting outcomes (Ni et al., 2016).

The decreased androgen production may impair normal secondary sexual development. Muscle development may be poor, and the fat distribution is more typical of females than of males. Normal amounts of pubic and axillary hair may be present, but facial hair is sparse. Patients tend to be taller than average, mainly because of the disproportionate length of their legs, which is present even in childhood. Otherwise, few if any distinguishing features are present in the prepubertal child.

Klinefelter Syndrome Variants

Patients with Klinefelter syndrome and more than two X chromosomes have greater physical and learning disabilities associated with a number of malformations. These include microcephaly, proximal radioulnar synostosis, undescended testes, congenital heart disease, cleft palate, and short incurved fifth digit. The facies is characteristic with prognathism, epicanthus, hypertelorism, myopia, strabismus, and mid-face hypoplasia. The maximum number of sex chromatin bodies per nucleus is always one fewer than the total number of X chromosomes, indicating that X-inactivation ensures that only one X chromosome is functionally active. However, abnormal dosage of X/Y homologous loci, which normally escape X-inactivation, is thought to be responsible for the level of clinical disability associated with additional X chromosomes. Male differentiation occurs irrespective of the number of X chromosomes and this attests to the dominant male-determining effect of the SRY gene on the Y chromosome. The XXY condition has been observed in a number of other species including mouse, cat, horse, and sheep; in each case, male differentiation is apparent.

Other variants of Klinefelter syndrome are known. SRY + XX males, in whom the SRY locus has been transferred to the X chromosome by accidental recombination within the differential segments of the X and Y chromosomes, show little disability other than infertility. Those with sex chromosome mosaicism, that is, XY/XXY or XX/XXY, also tend to show less disability than XXY patients. XY/XXY patients are occasionally fertile and XX/XXY patients may rarely be found to be true hermaphrodites.

Pearls & Considerations

VII.E Klinefelter Syndrome

Klinefelter syndrome (KS) is a sex chromosome disorder and occurs due to the presence of an extra X chromosome in males (XXY). It is estimated that 1 in 700 to 1 in 900 live male births are affected by KS. Early research linked KS with psychiatric disorders, criminal behavior, and mental retardation. These studies had methodological concerns that impacted validity; however, many still hold to these early findings. In truth, males with KS are at risk for developmental, learning, language, and behavioral problems along with psychiatric disorders, but they are not inherently criminal.

Physical manifestations of KS result in impairment of normal genital and sexual development. Although persons with KS enter puberty at the typical age, inadequate testosterone levels prevent normal pubertal progress. Hypogonadism is present with a slowed development of or lack of secondary sexual characteristics. In addition, KS leads to smaller than normal testes that often contribute to infertility. Cognitive abilities range from mild mental retardation to above-average intelligence. In general, persons with KS have deficits in verbal abilities, whereas nonverbal abilities are typically in the average range. Behaviorally, individuals with KS may be reserved, withdrawn, and immature, and they are at risk for having poor peer relationships. Self-esteem problems also have been described. In contrast, they also have been described as being easygoing, underactive, compliant, and, consequently, well liked by teachers.

44.4.4 Fertility

KS patients are usually considered infertile, but with the development of the testicular sperm extraction (TESE) and intracytoplasmatic sperm injection (ICSI) methodologies, it is now possible to extract viable sperm from the testes by surgical biopsy and inject it directly into an extracted ovum. Worldwide more than 60 children have been born after successful ICSI treatment in KS couples (164,176). There have been concerns about an increased risk of chromosome aberrations in the offspring because an increased number of both autosomal and sex-chromosome aneuploidy has been found in spermatozoas extracted or ejaculated from KS men (177). As a consequence, professional genetic counseling and options of prenatal diagnosis or even preimplantation genetic diagnosis should always be offered to couples seeking infertility treatment where the male is suffering from KS.

Implications of Non-reproductive Impairments

KS is a key risk factor for early-onset osteoporosis (Bojesen et al., 2011). The etiology is likely multifactorial but testosterone is thought to play a key role. It has been well defined that testosterone in men and estrogen in women play a vital role to bone health. Thus, in KS, testosterone deficiency can lead to decreased bone formation and resorption. Other possible mechanisms for osteoporosis in KS are abnormalities in CAG length, low levels of insulin-like factor 3 and X-chromosome inactivation (Ferlin et al., 2011; Wikstrom et al., 2006). Men with KS have also been shown to be susceptible to metabolic dysfunction including type 2 diabetes, decreased muscle, increased adiposity, decreased insulin sensitivity, decreased muscle strength and oxygen consumption capacity (Gravholt et al., 2011).

Klinefelter Syndrome

Classically, Klinefelter syndrome is characterized by very small, firm testes; azoospermia and infertility; varying degrees of androgen deficiency and eunuchoidism; and uniformly elevated gonadotropin concentrations.^20,221,222 It is the most common sex chromosome abnormality and the most common cause of primary hypogonadism, resulting in androgen deficiency and impaired sperm production. It occurs prenatally and neonatally in 1 of every 500 to 700 males, and the prevalence in adults is 1 in 2500.^1,2 Because the syndrome does not cause premature death in boys, the low adult prevalence indicates that Klinefelter syndrome is often overlooked and underdiagnosed in men. Given the almost uniform finding of extremely small testes and other phenotypic abnormalities, it is surprising that about 75% of men with Klinefelter syndrome are never diagnosed. This might be due to failure to recognize mild phenotypes or failure to perform a testicular exam. The risk of having a child with Klinefelter syndrome increases with both maternal and paternal age.

The chromosomal abnormality in Klinefelter syndrome is the presence of one or more extra X chromosomes due to maternal meiotic nondisjunction (mostly in meiosis I) in approximately 50% of the cases or paternal meiotic nondisjunction in the remaining cases.^20,221,222 The principal karyotype in 90% of men with Klinefelter syndrome is 47,XXY. Most of the remaining 10% have mosaic Klinefelter syndrome (47,XXY/46,XY), in which there is a 47,XXY karyotype in some tissues or cells and a normal 46,XY karyotype in other tissues or cells. Mosaicism occurs as a result of postfertilization mitotic nondisjunction. Men with mosaic Klinefelter syndrome usually demonstrate a variable and less severe phenotype that depends on the specific tissues in which an extra X chromosome is present. Some men with mosaicism have a normal karyotype in the testis with intact spermatogenesis and fertility. Rarely, men with Klinefelter syndrome have morethan one extra X chromosome (e.g., 48,XXXY, 49,XXXXY). Men with these variants manifest a more severe phenotype than is seen in classic Klinefelter syndrome.

Infants with Klinefelter syndrome may manifest micropenis, hypospadias, cryptorchidism, or developmental delay.^222,223 During childhood, boys with the syndrome commonly have small testes and reduced penile length relative to age-matched normal individuals and may manifest relatively tall stature, clinodactyly, hypertelorism, gynecomastia, elbow dysplasia, high-arched palate, hypotonia, language delay or learning and reading disabilities requiring therapy, and behavioral problems.^222,224 However, these manifestations may be mild and are often missed. Fewer than 10% of boys with Klinefelter syndrome (usually those with the most severe phenotype) are diagnosed before puberty. At puberty, the testes fail to increase in size and become firm due to a progressive loss of germ cells and seminiferous tubule hyalinization and fibrosis; Sertoli cell products, inhibin B, and AMH decline to very low or undetectable serum concentrations; circulating testosterone concentrations increase but to less than normal concentrations in some boys, resulting in varying degrees of eunuchoidism and gynecomastia; and FSH concentrations are disproportionately elevated relative to LH concentrations. Elevation of serum LH disproportionately to FSH is an indication of a disorder other than Klinefelter syndrome or any cause of primary hypogonadism that affects both Sertoli cell and Leydig cell dysfunction—for example, rare diseases such as disorders of testosterone biosynthesis or abnormalities of LH or its receptor should be considered.

Abstract

Klinefelter syndrome (KS) is a genetic condition resulting from an additional X chromosome in phenotypic males (47,XXY). KS affects ~ 1 in 600 males however historically only ~ 25% are accurately diagnosed in their lifetime. Testicular development and function in impaired, often resulting in hypergonadotropic hypogonadism and the classic physical phenotype of small testes, long extremities, gynecomastia, and azoospermia. Testosterone replacement is standard treatment, however there is practice variability on when to initiate this therapy. Other frequently associated manifestations include mild developmental delays, language-based learning disabilities and disorders of insulin resistance which add to the increased morbidity and mortality in this condition. There are multiple mechanisms proposed for how the additional X chromosome results in the physical phenotype of KS and the heterogeneity among affected individuals. Recent advances in KS include early diagnosis identified through noninvasive prenatal screening and successful retrieval of viable sperm through testicular sperm extraction.

Klinefelter Syndrome and Its Variants

Klinefelter syndrome and its variants are the most common forms of sex chromosome aneuploidy, with a reported incidence of 1 in 500 to 1 in 1000 live male births.¹⁸⁰ This incidence may be increasing.¹⁸¹ The classic form of Klinefelter syndrome is associated with a 47,XXY karyotype and is caused by meiotic nondisjunction of the sex chromosomes during gametogenesis (Fig. 24.18).¹⁸ This abnormality occurs during spermatogenesis in approximately 50% of patients and during oogenesis or postzygotic division in approximately 50%.¹⁸⁰ Mosaic forms of Klinefelter syndrome (46,XY/47,XXY) likely represent mitotic nondisjunction within the developing zygote and are thought to occur in approximately 10% of individuals with Klinefelter syndrome. Other chromosomal variants of Klinefelter syndrome (e.g., 48,XXXY) can be seen.

The clinical features of Klinefelter syndrome and its variants are summarized inTable 24.4.¹⁸⁰ In the most obvious situations, a young man may be diagnosed because of small testes, gynecomastia, poor androgenization at puberty, eunuchoid proportions,or infertility. Other features, such as learning difficulties, speech and language delay, behavioral issues, and altered motor development, may occur, and early educational support focusing on any specific areas of difficulty is important.^182,183 It is likely that the clinical detection of Klinefelter syndrome based on postnatal karyotyping is biased toward detection of those individuals with a more severe phenotype, and it is estimated that as few as 25% of men with Klinefelter syndrome may be diagnosed throughout their life span. However, this pattern may change as diagnosis of Klinefelter syndrome on prenatal genetic testing becomes increasingly common.

The development of testes and a male phenotype in individuals with Klinefelter syndrome provides important evidence for the key role of the presence of the Y chromosome (rather than X chromosome number) in testis determination and subsequent prenatal androgen production. However, testicular function may not be completely intact; micropenis and hypospadias may be presenting features in some cases, and some studies report mildly elevated FSH concentrations during the postnatal “minipuberty” together with testosterone levels in the lower half of the normal range.¹⁸⁴

A more predictable elevation in gonadotropin concentrations (e.g., FSH, LH) occurs in the periadolescent period in patients with Klinefelter syndrome, after activation of the HPG axis.^185,186 By midadolescence, plasma concentrations of FSH are increased in 90% of patients with Klinefelter syndrome, and plasma concentrations of LH are increased in 80%. Other serum markers of testicular function (e.g., peripubertal inhibin B, midpubertal INSL3) are often below the normal ranges.^173,186 Although puberty usually starts at a normal age with an appropriate rise in testosterone in classic Klinefelter syndrome, serum testosterone levels off around midpuberty with an increase of gonadotropins. In the majority of young adults, serum testosterone is in the lower half of the reference range.^185,187 Testes usually remain small and firm; the median length and volume are 2.5 cm and 3 mL, but most are smaller than 3.5 cm (range 1–7 mL).¹⁸⁵ Testes typically appear inappropriately small for the degree of androgenization. The serum estradiol concentration is often elevated, which contributes to the gynecomastia observed during the adolescent period.

Clinical Presentation

Klinefelter’s syndrome is present in about 1 in 1000 living males. Azoospermia, gynecomastia, and the presence of small atrophic testes in otherwise normal males are the clinical hallmarks of the disease. The characteristic features of patients affected with Klinefelter’s syndrome usually first become apparent during adolescence. In a classical scenario, the diagnosis is suggested by the presence of small testes (less than 3 cm in length), commonly but not always accompanied by bilateral gynecomastia, in adolescent boys seeking medical advice because of a delayed onset of puberty. These features can be associated with a variable degree of eunuchoidism, that is, altered body proportions and tall stature. However, in particular instances, the diagnosis of Klinefelter’s syndrome can also be made as early as during the neonatal period or as late as during adult life.

Klinefelter’s syndrome can be diagnosed during the first year of life in children evaluated for microphallus, hypospadias, or cryptorchidism. Later during childhood but before adolescence, the diagnosis may be suspected on the basis of a subnormal testicular size. Indeed, in normal men, more than 80% of the total testicular volume is accounted for by the seminiferous tubules, the anatomical structures where spermatogenesis takes place. In Klinefelter’s syndrome, an abnormal fibrosis of these tubules begins before puberty. When this pathological process is severe enough, atrophy of the testes may already become evident during mid-childhood. At the other end of the spectrum of clinical presentations, a number of patients can achieve significant virilization and go undiagnosed until adulthood. These patients can be discovered incidentally during the workup of a malignancy but are usually diagnosed on the occasion of their evaluation for infertility.

Serum levels of the male hormone testosterone are normally low in prepubertal boys and begin to rise during early puberty. In boys affected with Klinefelter’s syndrome, a decreased capacity of the testes to secrete testosterone becomes evident in many cases as puberty continues. Therefore, testosterone levels tend to be either low-normal or frankly decreased in adult patients. This occurs despite an elevation above normal values of the circulating levels of luteinizing hormone (LH), the hormone that normally stimulates testosterone production by the testes. Because of the lack of testosterone, affected patients rarely become normally virilized. On the other hand, the levels of the female hormone estradiol, which is also normally secreted by the human testes, are usually elevated in Klinefelter’s patients. These anomalies result in an imbalance between the two sex hormones, with increased estradiol levels and diminished testosterone values producing a hormonal milieu favorable to the development of bilateral gynecomastia. This is observed in more than 90% of Klinefelter’s patients.

Klinefelter Syndrome and Variants

In 1942, Klinefelter, Reifenstein, and Albright described a syndrome characterized by eunuchoidism, gynecomastia, azoospermia, increased gonadotropin levels, and small, firm testes. By 1959, these patients were noted to have a 47,XXY karyotype (Jacobs and Strong, 1959).

Klinefelter syndrome represents the most common major abnormality of sexual development. By definition, males with at least one Y chromosome and at least two X chromosomes have Klinefelter syndrome. The classic 47,XXY complement arises as a result of nondisjunction during meiosis; it occurs in 1 of 600 liveborn males (Morris et al, 2008). But the phenotype is also associated with 48,XXYY and 49,XXXYY, and an exaggerated form of the phenotype is associated with 48,XXXY and 49,XXXXY. The mosaic form 46,XY/47,XXY is associated with milder phenotypic features of classic 47,XXY Klinefelter syndrome. Perhaps as a result of phenotypic variability, Klinefelter syndrome is believed to be underdiagnosed, with a 25% diagnostic rate in one Danish study (Bojesen et al, 2003).

In 47,XXY adults, seminiferous tubules degenerate and are replaced with hyaline. As a result, testes are firm and small, less than 3.5 cm in length. Histologically, Leydig cells appear to predominate. They are seen in large clumps in certain areas of the testes, sometimes resembling Leydig cell tumors. However, the absolute volume of Leydig cells is not increased and is probably lower than normal. Serum levels of testosterone are low-normal and those of gonadotropins are elevated. Plasma estradiol levels tend to be high, with gynecomastia the result of an increased ratio of estradiol to testosterone. The vast majority of patients are azoospermic, and the presence of sperm suggests 46,XY/47,XXY mosaicism. There does appear to be a depletion of germ cells with the onset of puberty (Wikström et al., 2004). Fertility, with the benefit of testicular sperm extraction and intracytoplasmic sperm injection (ICSI), has been reported in patients with Klinefelter syndrome. A recent meta-analysis examining ICSI outcomes reported a 43% live birth rate per ICSI cycle (Corona et al., 2017). Some infertility experts advocate coupling intracytoplasmic sperm injection with preimplantation diagnosis given the lower rate of normal embryos from Klinefelter syndrome patients (54%) versus controls (77%) (Staessen et al, 2003). However, there have been over 200 normal live births reported using ICSI without preimplantation genetic analysis, which brings into question the utility of this testing in predicting outcomes (Ni et al., 2016).

The decreased androgen production may impair normal secondary sexual development. Muscle development may be poor, and the fat distribution is more typical of females than of males. Normal amounts of pubic and axillary hair may be present, but facial hair is sparse. Patients tend to be taller than average, mainly because of the disproportionate length of their legs, which is present even in childhood. Otherwise, few if any distinguishing features are present in the prepubertal child.

Klinefelter Syndrome Variants

Patients with Klinefelter syndrome and more than two X chromosomes have greater physical and learning disabilities associated with a number of malformations. These include microcephaly, proximal radioulnar synostosis, undescended testes, congenital heart disease, cleft palate, and short incurved fifth digit. The facies is characteristic with prognathism, epicanthus, hypertelorism, myopia, strabismus, and mid-face hypoplasia. The maximum number of sex chromatin bodies per nucleus is always one fewer than the total number of X chromosomes, indicating that X-inactivation ensures that only one X chromosome is functionally active. However, abnormal dosage of X/Y homologous loci, which normally escape X-inactivation, is thought to be responsible for the level of clinical disability associated with additional X chromosomes. Male differentiation occurs irrespective of the number of X chromosomes and this attests to the dominant male-determining effect of the SRY gene on the Y chromosome. The XXY condition has been observed in a number of other species including mouse, cat, horse, and sheep; in each case, male differentiation is apparent.

Other variants of Klinefelter syndrome are known. SRY + XX males, in whom the SRY locus has been transferred to the X chromosome by accidental recombination within the differential segments of the X and Y chromosomes, show little disability other than infertility. Those with sex chromosome mosaicism, that is, XY/XXY or XX/XXY, also tend to show less disability than XXY patients. XY/XXY patients are occasionally fertile and XX/XXY patients may rarely be found to be true hermaphrodites.

Pearls & Considerations

VII.E Klinefelter Syndrome

Klinefelter syndrome (KS) is a sex chromosome disorder and occurs due to the presence of an extra X chromosome in males (XXY). It is estimated that 1 in 700 to 1 in 900 live male births are affected by KS. Early research linked KS with psychiatric disorders, criminal behavior, and mental retardation. These studies had methodological concerns that impacted validity; however, many still hold to these early findings. In truth, males with KS are at risk for developmental, learning, language, and behavioral problems along with psychiatric disorders, but they are not inherently criminal.

Physical manifestations of KS result in impairment of normal genital and sexual development. Although persons with KS enter puberty at the typical age, inadequate testosterone levels prevent normal pubertal progress. Hypogonadism is present with a slowed development of or lack of secondary sexual characteristics. In addition, KS leads to smaller than normal testes that often contribute to infertility. Cognitive abilities range from mild mental retardation to above-average intelligence. In general, persons with KS have deficits in verbal abilities, whereas nonverbal abilities are typically in the average range. Behaviorally, individuals with KS may be reserved, withdrawn, and immature, and they are at risk for having poor peer relationships. Self-esteem problems also have been described. In contrast, they also have been described as being easygoing, underactive, compliant, and, consequently, well liked by teachers.

44.4.4 Fertility

KS patients are usually considered infertile, but with the development of the testicular sperm extraction (TESE) and intracytoplasmatic sperm injection (ICSI) methodologies, it is now possible to extract viable sperm from the testes by surgical biopsy and inject it directly into an extracted ovum. Worldwide more than 60 children have been born after successful ICSI treatment in KS couples (164,176). There have been concerns about an increased risk of chromosome aberrations in the offspring because an increased number of both autosomal and sex-chromosome aneuploidy has been found in spermatozoas extracted or ejaculated from KS men (177). As a consequence, professional genetic counseling and options of prenatal diagnosis or even preimplantation genetic diagnosis should always be offered to couples seeking infertility treatment where the male is suffering from KS.

Implications of Non-reproductive Impairments

KS is a key risk factor for early-onset osteoporosis (Bojesen et al., 2011). The etiology is likely multifactorial but testosterone is thought to play a key role. It has been well defined that testosterone in men and estrogen in women play a vital role to bone health. Thus, in KS, testosterone deficiency can lead to decreased bone formation and resorption. Other possible mechanisms for osteoporosis in KS are abnormalities in CAG length, low levels of insulin-like factor 3 and X-chromosome inactivation (Ferlin et al., 2011; Wikstrom et al., 2006). Men with KS have also been shown to be susceptible to metabolic dysfunction including type 2 diabetes, decreased muscle, increased adiposity, decreased insulin sensitivity, decreased muscle strength and oxygen consumption capacity (Gravholt et al., 2011).