madman
Super Moderator
Summary
Klinefelter syndrome (KS) is an uncommon chromosomal disorder in males that has a variable clinical appearance. Classic KS involves an extra X chromosome, (47, XXY), although other variations may exist, including a milder mosaic form as well as multiple extra sex chromosomes with more dramatic phenotypes. KS is underdiagnosed, especially prepubertally, owing to a paucity of concrete clinical signs; however, diagnostic rates increase during and after puberty, as the consequences of hypergonadotropic hypogonadism begin to manifest. Testicular failure causing decreased circulating testosterone (T) and germ cell depletion, a hallmark feature in KS commonly begins shortly after the onset of puberty and leads to the most commonly recognized KS traits: small testes, azoospermia, gynecomastia, decreased facial and pubic hair.
While many KS men maintain adequate T levels leading up to young adulthood, some may have lower T levels at an earlier age leading to varied levels of androgenization and clinical KS features. At certain critical time points, absent or decreased T may alter the development of normal male reproductive organs, external genitalia, development of secondary sexual characteristics and spermatogenesis. Testicular failure in utero may lead to ambiguous genitalia, cryptorchidism and/or hypospadias, all of which depend on fetal T production. In the neonatal period and childhood decreased T levels during the mini-puberty of infancy may negatively impact germ cell differentiation and male neuropsychological development. Finally, decreased T during pubertal and young adulthood can lead to decreased virilization during puberty, eunuchoid skeleton and decreased spermatogenesis. Depending on the timing of the testicular failure, a reproductive window of sperm production may exist to achieve paternity for KS men. The presence or absence of clinical characteristics reflecting decreased androgenization provides an insight into the relative testicular function during this developmental time points for those with KS and contributes to variability within the syndrome.
Introduction
Klinefelter syndrome (KS), the most common chromosomal aberration in males occurs in roughly 1 in 600 births and may be underestimated due to variability in clinical features. Previous studies approximate a KS the diagnosis rate of only 25%, with only 10% of patients diagnosed before puberty [1]. Males born with at least two X chromosomes and at least one Y chromosome meets the diagnostic criteria, and the classical syndrome including tall stature, small testes, hypergonadotropic hypogonadism and azoospermia, are based on the most common 47, XXY karyotype; however, phenotypic variation still exists within the classical genotype. Multiple genetic aberrations of varying clinical severity have also been described, including a mosaic (46, XY/ 47, XXY) form with milder features. Furthermore, the rarer, non-classic KS karyotypes with multiple aneuploidies (48, XXXY; 49, XXXYY, 48, XXYY) are associated with dramatic phenotypes that make childhood diagnosis more attainable [2]. The combination of variability and minimal early syndromic signs makes childhood diagnosis difficult. Early diagnosis may be essential, as it may allow clinicians to appropriately manage the decreased androgen production and worsening spermatogenesis that occurs over time for those with KS [3].
Physiologic circulating testosterone (T) levels play a crucial role at critical developmental stages and throughout the male lifespan. Early in the neonatal period, T is elevated and critical for male sexual differentiation, notably contributing to testicular descent into the scrotum and, after being converted to dihydrotestosterone (DHT), normal penile development and urethra [4,5]. After the “mini-puberty of infancy” between 3 and 6 months of age, T levels remain low throughout childhood until the onset of puberty, when T influences the development of secondary sexual characteristics [6]. Into adulthood, normal T levels are involved in the health maintenance of multiple organ systems, and intratesticular T fosters spermatogenesis and male fertility.
Despite the variable clinical presentation, the often profound hypergonadotropic hypogonadism contributes to the commonly observed KS features in adulthood: infertility, small testes, gynecomastia, and decreased facial and pubic hair [7]. Although hypogonadism, in general, is recognized as a disease of older men, it is important to recognize that a relative T deficiency worsening throughout life, as in those with KS can have a profound impact starting as early as the neonatal period [8]. A lower frequency of childhood manifestations may exist, contributing to difficulty in early KS diagnosis, due to the observed decrease of testicular function that may begin in mid-puberty, with germ cell depletion and hyalinization of seminiferous tubules [3]. Clinician recognition of diagnoses that may result from lower T levels, such as cryptorchidism, or an attenuated increase at critical developmental time points, such as puberty may help identify young boys who are at-risk for KS. In this review, we investigate what is known about conditions associated with decreased androgenization and the relative frequencies in which they exist from the neonatal period until young adulthood in order to describe the developmental clinical spectrum of KS.
Fetal and neonatal period
Ambiguous genitalia
Cryptorchidism
Hypospadias
Mini-puberty of infancy
Childhood
Adolescence and young adult
Puberty
Skeletal features
Spermatogenesis
Conclusion
KS is a complex genetic disorder with variable traits outlined in Table 1. The clinical spectrum in KS revolves around the timing of and relative T concentrations throughout the fetal, childhood, and pubertal years. The presence or absence of clinical characteristics reflecting decreased androgenization provides an insight into the relative testicular function during developmental time points for those with KS and contributes to variability within the syndrome. Although the frequency of identifiable KS features is lower during childhood, clinicians should consider the diagnosis when there is a presence of or combination of any of these traits. Early diagnosis in KS and directed therapy may successfully mitigate many of the consequences of hypogonadism during critical developmental steps as well as improve the chance of paternity if fertility evaluation can occur before or during the reproductive window of favorable SRR. Furthermore, earlier diagnosis can not only help define the true prevalence of this disorder but also help elicit scientifically-derived treatments to improve the quality of life for men with KS.
Klinefelter syndrome (KS) is an uncommon chromosomal disorder in males that has a variable clinical appearance. Classic KS involves an extra X chromosome, (47, XXY), although other variations may exist, including a milder mosaic form as well as multiple extra sex chromosomes with more dramatic phenotypes. KS is underdiagnosed, especially prepubertally, owing to a paucity of concrete clinical signs; however, diagnostic rates increase during and after puberty, as the consequences of hypergonadotropic hypogonadism begin to manifest. Testicular failure causing decreased circulating testosterone (T) and germ cell depletion, a hallmark feature in KS commonly begins shortly after the onset of puberty and leads to the most commonly recognized KS traits: small testes, azoospermia, gynecomastia, decreased facial and pubic hair.
While many KS men maintain adequate T levels leading up to young adulthood, some may have lower T levels at an earlier age leading to varied levels of androgenization and clinical KS features. At certain critical time points, absent or decreased T may alter the development of normal male reproductive organs, external genitalia, development of secondary sexual characteristics and spermatogenesis. Testicular failure in utero may lead to ambiguous genitalia, cryptorchidism and/or hypospadias, all of which depend on fetal T production. In the neonatal period and childhood decreased T levels during the mini-puberty of infancy may negatively impact germ cell differentiation and male neuropsychological development. Finally, decreased T during pubertal and young adulthood can lead to decreased virilization during puberty, eunuchoid skeleton and decreased spermatogenesis. Depending on the timing of the testicular failure, a reproductive window of sperm production may exist to achieve paternity for KS men. The presence or absence of clinical characteristics reflecting decreased androgenization provides an insight into the relative testicular function during this developmental time points for those with KS and contributes to variability within the syndrome.
Introduction
Klinefelter syndrome (KS), the most common chromosomal aberration in males occurs in roughly 1 in 600 births and may be underestimated due to variability in clinical features. Previous studies approximate a KS the diagnosis rate of only 25%, with only 10% of patients diagnosed before puberty [1]. Males born with at least two X chromosomes and at least one Y chromosome meets the diagnostic criteria, and the classical syndrome including tall stature, small testes, hypergonadotropic hypogonadism and azoospermia, are based on the most common 47, XXY karyotype; however, phenotypic variation still exists within the classical genotype. Multiple genetic aberrations of varying clinical severity have also been described, including a mosaic (46, XY/ 47, XXY) form with milder features. Furthermore, the rarer, non-classic KS karyotypes with multiple aneuploidies (48, XXXY; 49, XXXYY, 48, XXYY) are associated with dramatic phenotypes that make childhood diagnosis more attainable [2]. The combination of variability and minimal early syndromic signs makes childhood diagnosis difficult. Early diagnosis may be essential, as it may allow clinicians to appropriately manage the decreased androgen production and worsening spermatogenesis that occurs over time for those with KS [3].
Physiologic circulating testosterone (T) levels play a crucial role at critical developmental stages and throughout the male lifespan. Early in the neonatal period, T is elevated and critical for male sexual differentiation, notably contributing to testicular descent into the scrotum and, after being converted to dihydrotestosterone (DHT), normal penile development and urethra [4,5]. After the “mini-puberty of infancy” between 3 and 6 months of age, T levels remain low throughout childhood until the onset of puberty, when T influences the development of secondary sexual characteristics [6]. Into adulthood, normal T levels are involved in the health maintenance of multiple organ systems, and intratesticular T fosters spermatogenesis and male fertility.
Despite the variable clinical presentation, the often profound hypergonadotropic hypogonadism contributes to the commonly observed KS features in adulthood: infertility, small testes, gynecomastia, and decreased facial and pubic hair [7]. Although hypogonadism, in general, is recognized as a disease of older men, it is important to recognize that a relative T deficiency worsening throughout life, as in those with KS can have a profound impact starting as early as the neonatal period [8]. A lower frequency of childhood manifestations may exist, contributing to difficulty in early KS diagnosis, due to the observed decrease of testicular function that may begin in mid-puberty, with germ cell depletion and hyalinization of seminiferous tubules [3]. Clinician recognition of diagnoses that may result from lower T levels, such as cryptorchidism, or an attenuated increase at critical developmental time points, such as puberty may help identify young boys who are at-risk for KS. In this review, we investigate what is known about conditions associated with decreased androgenization and the relative frequencies in which they exist from the neonatal period until young adulthood in order to describe the developmental clinical spectrum of KS.
Fetal and neonatal period
Ambiguous genitalia
Cryptorchidism
Hypospadias
Mini-puberty of infancy
Childhood
Adolescence and young adult
Puberty
Skeletal features
Spermatogenesis
Conclusion
KS is a complex genetic disorder with variable traits outlined in Table 1. The clinical spectrum in KS revolves around the timing of and relative T concentrations throughout the fetal, childhood, and pubertal years. The presence or absence of clinical characteristics reflecting decreased androgenization provides an insight into the relative testicular function during developmental time points for those with KS and contributes to variability within the syndrome. Although the frequency of identifiable KS features is lower during childhood, clinicians should consider the diagnosis when there is a presence of or combination of any of these traits. Early diagnosis in KS and directed therapy may successfully mitigate many of the consequences of hypogonadism during critical developmental steps as well as improve the chance of paternity if fertility evaluation can occur before or during the reproductive window of favorable SRR. Furthermore, earlier diagnosis can not only help define the true prevalence of this disorder but also help elicit scientifically-derived treatments to improve the quality of life for men with KS.
