Which of the following is the most likely characteristic among persons with Klinefelter syndrome?

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.

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.

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.

Prevalence

Klinefelter syndrome is the most common sex chromosome disorder in males, with a prevalence ranging from 85 to 250 per 100,000 live-born males (Gravholt et al., 2018). Maternal age has a significant impact on the prevalence of Klinefelter syndrome (Bojesen et al., 2003) due to an increased risk of maternal nondisjunction with age. Also, reduced semen quality and associated paternal nondisjunction may impact on the prevalence (Morris et al., 2008). It is possible that we will see an increase in Klinefelter syndrome in the future due to increased maternal age and reduced semen quality in the Western world (Morris et al., 2008), which seems to occur on a multifactorial background, where both lifestyle and possibly endocrine disrupting chemicals may play a role.

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's Syndrome (XXY)

With an additional X chromosome, Klinefelter's syndrome boys develop a tall stature, but, failing to mature sexually, they appear eunuchoid after puberty (Fig. 13‐20). As young men, their unusual height and lack of secondary sexual characteristics may draw medical attention. In fact, physicians most often diagnose Klinefelter's syndrome only after puberty. Physicians sometimes first diagnose the disorder when an infertility evaluation shows that the man has testicular dysgenesis and lacks sperm.

Klinefelter's syndrome individuals have a below average IQ, typically between 80 and 90. However, only about 25% have any degree of mental retardation, and it is usually mild. Klinefelter's syndrome boys tend to have dyslexia and other learning disabilities. According to some reports, they have a passive personality and decreased libido.

Behavioral phenotype

There has been considerable interest in the behavioral phenotype of Klinefelter syndrome in recent years. One reason is the possibility that the condition is associated with an increased risk of schizophrenia or affective disorder with psychotic features, especially auditory hallucinations (van Rijn et al., 2006; Savic, 2012; Cederlöf et al., 2014). This contrasts with Turner syndrome, where no such increased risk of major psychiatric morbidity is found.

Klinefelter men sometimes find social interactions relatively difficult. They may appear introverted, anxious, impulsive, quiet, unassertive, and socially withdrawn (Geschwind et al., 2000). Socially inappropriate and antisocial behavior was once thought to be more common than expected in those with the syndrome, but this is influenced to some degree by an ascertainment bias. It is important to bear in mind that most cases in the general population are never identified (Bojesen et al., 2003, 2006). Although the syndrome is apparently overrepresented among males in prison, imprisonment is associated with checks for chromosomal anomalies, hence ascertainment is enhanced. Nevertheless, there is recent evidence that the risk of convictions for sexual abuse, burglary, and arson could be increased in this population of men, even when ascertainment bias is considered (Stochholm et al., 2012).

3.2 Neuroanatomic findings

Tables 6.1 and 6.2 also summarize neuroanatomic findings. As can be seen, with the exception of Turner and Klinefelter syndromes, little is known about the neuroanatomy of SCAs. For females with Turner syndrome, the most consistent findings are reduced parietal lobar volumes (see Raznahan et al., 2010 for a review). This finding is consistent with the relatively greater visuospatial processing difficulties (Bender, Linden, & Robinson, 1991) reported for females with 45, X and contrasts with the findings for SCAs with supernumerary X chromosomes in which language abilities tend to be more impacted. For females with trisomy X, the limited research available documents reduced total brain volume (Warwick et al., 1999). Finally, for females with tetra- and pentasomy X, brain imaging studies of groups of individuals have not been conducted to the best of our knowledge.

Structural MRI studies of males with additional X chromosomes suggest decreases in both gray and white matter (for a review, see Lenroot, Lee, & Giedd, 2009). For males with 47, XXY, reductions in gray matter are most pronounced in the temporal and frontal lobes (DeLisi et al., 2005; Giedd et al., 2007), two regions thought to be important for language abilities, a prominent aspect of the phenotype (Bender et al., 1991). Further, the Giedd et al. (2007) study reported preserved parietal white matter volumes in XXY, a finding that is consistent with the relatively stronger visuospatial processing abilities reported for males with XXY (Bender et al., 1991). Other studies have identified increased white matter hyperintensities (Warwick et al., 1999) and decreased fractional anisotropy, an indirect measure of white matter connectivity, in males with 47, Xxy (DeLisi et al., 2005). Consistent with these findings, one case study of three males with 49, XXXXY suggested decreased total brain volume and thinner corpus callosum volumes (Hoffman, Vossough, Ficicioglu, & Visootsak, 2008). More research is needed with larger samples to characterize brain development in this rare group (and the other rarer forms of SCA).

Less is known about males with additional Y chromosomes. Structural MRI scans of males with 48, Xxyy reveal nonspecific white matter abnormalities (Tartaglia et al., 2008). The limited research on males with 47, Xyy has suggested that there are no significant brain volume differences (Warwick et al., 1999). However, additional research is needed to more clearly delineate the 48, Xxyy and 47, Xyy neuroanatomic phenotypes.

Rett Syndrome in Males

Descriptions of males with RTT have been few. A small number of males (less than 15) with more than one X chromosome (47,XXY–Klinefelter syndrome) or with two populations of cells (so-called somatic mosaicism) has been described with typical clinical features of RTT and mutations in MECP2. In addition, males with a rapidly progressively encephalopathy (less than 20) or with developmental delays with or without progressive motor impairment have also been identified both at the clinical and molecular level. More recently, males with duplications (triplication has been noted in at least one instance) of varying length at Xq28 have been noted. These number more than 150 and are likely to increase as genome-wide screening techniques are increasingly employed. These males have a widely varying phenotype but all demonstrate delayed development, absent speech, and a shuffling gait. A significant proportion also has recurrent sinusitis and upper respiratory infections thought to be due to another gene in the duplicated region.

Language in sex chromosome aneuploidies

Sex chromosome syndromes represent an obvious test-case for whether parts of language function are tied to genetic sex. A number of different sex chromosome aneuploidies exists. Here, only the trisomies are discussed: 47, XXY (Klinefelter syndrome), 47, XYY (XYY syndrome) and 47, XXX (Triple X syndrome).

Klinefelter syndrome (KS), 47, XXY, is the most frequent sex chromosome syndrome (1 per 660 live born males) (Gravholt et al., 2018). People with KS are phenotypically male, but have an extra X chromosome. They typically have small testes, hypergonadotropic hypogonadism, and testosterone deficiency along with a number of more or less outspoken neural, cognitive, and psychological traits (see Gravholt et al., 2018 for an extensive review). Given that people with KS have an extra X-chromosome and lack testosterone, one could expect their linguistic profile to lean towards the stereotypical female profile. This, however, does not turn out to be the case. KS people score significantly below education matched controls on a range of cognitive tests with verbal skills displaying the largest effects (Skakkebæk et al., 2015). KS males exhibit deficits in different language domains, including verbal fluency (Boone et al., 2001) and general expressive skills (Rovet et al., 1996). Reading, writing, and literacy are also heavily affected in KS persons (Rovet et al., 1996). A study found that speech and language therapy was needed for 47% of boys with KS, compared to 18% among their male siblings (Bishop et al., 2009). Approximately 50% of both children and adults with KS show some level of dyslexia (Bender et al., 1986). Different genetic functions (Vawter et al., 2007; Bishop and Scerif, 2011) have been suggested to explain the language problems, but none have been replicable so far.

The XYY (47, XYY) syndrome affects one in 1000 phenotypical males (Ross et al., 2009). Contrary to KS, people with XYY syndrome usually have normal testosterone levels (Bardsley et al., 2013). Persons with XYY syndrome display similar linguistic effects to those seen in KS, although they can be more severe (Ross et al., 2009). More than 70% of 47 XYY boys were found to receive speech and language therapy, compared to 18% among their nonaffected male siblings (Bishop et al., 2009). Verbal impairments include difficulty in naming, receptive vocabulary, and oral fluency (Hong and Reiss, 2014). Reading and spelling have also been found to be affected to a similar or worse degree than what is seen in KS (Ross et al., 2009).

Trisomy X (TX), 47, XXX, is the most common female chromosomal abnormality, occurring in approximately 1 in 1000 female births (Tartaglia et al., 2010). TX females also display language problems in the form of speech delays in conjunction with other cognitive deficits and learning disabilities (Tartaglia et al., 2010). 40% of 47, XXX girls received speech and language therapy, compared to 4% among their female siblings (Bishop et al., 2009).

Viewing these effects together, one finds that the different sex chromosome trisomies share a tendency to give rise to problems with language and communication (Bishop and Scerif, 2011). Supporting this, the sex chromosome trisomies have been found to be overrepresented in random samples of children with language and reading disorders (Simpson et al., 2013). The finding that a large proportion (40%–70%) of trisomy persons have a history of speech and language therapy (Bishop et al., 2009) suggests that a link exists between language development and the burden of an extra sex chromosome, and the fact that 47, XYY boys have the highest rates suggests that adding a Y chromosome may be more detrimental than adding an extra X chromosome. Another study found that the addition of a Y chromosome had a greater impact on pragmatic language, while the addition of an X chromosome had a disproportionately greater impact on structural language (Lee et al., 2012). Further studies are needed to replicate these findings.

All groups also have higher prevalence of autism spectrum disorder symptoms, although TX women may again be less affected (Bishop et al., 2009; Bruining et al., 2009; Tartaglia et al., 2010; Skakkebæk et al., 2014).

Further, it is worth noting that in Turner syndrome, 45, X0, where a woman/girl only has one X-chromosome, language and literacy is usually found to be in the normal range (Murphy, 2009), despite other cognitive deficits. With respect to speech/language deficits, it thus seems that duplication of a sex chromosome is more detrimental than haploinsufficiency.

Language lateralization in sex chromosome trisomies has also been investigated using functional imaging. One study found that KS men were less lateralized than a control group (van Rijn et al., 2008), but this finding has not been replicated (Wallentin et al., 2016), and a recent study failed to find atypical lateralization for any of the sex chromosome trisomies (Wilson and Bishop, 2018b). We thus find a somewhat specific language deficit related to sex chromosome functioning, but without any concrete neural correlate for it. Given the small number of studied cases as well as the large within-group variability, research is still needed to fully understand the significance of these observations.