The spectrum of neuropsychological phenotypes

47XXY has been traditionally associated with a particular neuropsychological phenotype, including deficits in specific domains of cognition, mainly regarding verbal processing abilities and adaptation problems, as well as attention deficits and social skill impairments. As a consequence, XXY individuals are prone to suffering from learning difficulties, and their achievements regarding academic performance and professional status are reported to be inferior to those of their peers of comparable socio-economic status. However, it should be underscored that much of the related literature has been based on earlier studies when only XXY patients presenting more severe phenotypes could be identified. In order to avoid such bias, subsequent studies were carried out on cohorts of newborns screened for 46 XY and followed up prospectively until young adulthood. These and subsequent studies included a broader spectrum of XXY cases and demonstrated that the majority of XXY individuals fall within the average range concerning their intellectual abilities, behaviour, attention, social skills and adaptive functioning. Nevertheless, even these studies have methodological flaws as boys identified in this way usually have undergone pro-active tutoring intervention that has probably modified their final outcome.

Neuroimaging studies have shown characteristic structural and functioning differences between XXY individuals and age/educational level-matched controls. These differences concern mainly the grey matter of the frontal lobe, which is crucially involved in executive functioning as well as the amygdala and the hippocampus, regions associated with social responsiveness. A more recent voxel-based morphometric study demonstrated a decrease in the total brain volume in XXY, which concerned both the grey and white matter; however, correlation with data from neuropsychological test scores did not reveal significant associations between these differences and cognitive impairment.

The cognitive phenotype

The overall cognitive ability of XXY patients falls in the average to low average range. In particular, the distribution of the estimated Full-Scale IQ (FSIQ) shows a significant overlap with controls but with a small leftward shift of the curve with a mean FSIQ of around 90. Mild impairment of cognitive development is found in 4.2% of cases, and it is mainly driven by deficits in the verbal conceptual domain (Verbal IQ, VIQ) rather than the nonverbal or spatial domain (Performance IQ, PIQ). The VIQ deficit consists of delayed expressive as well as receptive language skills, starting at an early developmental stage and may result in academic difficulties which surpass the area of literacy and may expand in math calculation and problem-solving. Academic difficulties may also persist in adulthood, however, over time, an increase is observed in VIQ relative to PIQ.

Behavioural features and social responsiveness

XXY has been steadily associated with socio-emotional impairment, as 32% of patients have been reported to present anxiety, and 24% have depressive disorders. Nevertheless, the behavioural and emotional functioning of XXY individuals generally falls in the average range regarding both internalising and externalising behaviours. Particularly regarding internalising behaviours such as anxiety, depression and withdrawal, a recent study of XXY children reports that at least 25% of individuals obtain scores in the at-risk or clinically significant ranges for each domain, with this figure surpassing 50% regarding the withdrawal domain. Concerning externalising behaviours, over 25% of XXY children obtained scores in the mild-to-moderate or severe range in most domains of social responsiveness.

These scores indicate that XXY individuals may present an increased risk for internalising distress and for social difficulties and raise the question if a significant proportion of XXY patients meet the criteria for an autism spectrum disorder (ASD). According to recent studies, the prevalence of ASD among XXY ranges from 5 to 48% depending on the population studied and the tools used for assessment and XXY individuals show difficulties in cognitive flexibility, reduced emphatic understanding and decreased visual fixation to the eye region

Despite their average cognitive functioning, it has been demonstrated that the occupational achievements of XXY individuals still fall behind compared to their peers, suggesting that normal cognition is not adequate to compete in a complex social and working environment. The term “executive function” (EF) has been introduced to describe the ability to coordinate a variety of higher-order processes in order to achieve goal-directed problem-solving. Successful EF often requires the control of behavioural and emotional responses as well as the ability to hold attention while completing a specific task. Attention deficits have been demonstrated among XXY, and increased rates of Attention-Deficit/ Hyperactivity Disorder (ADHD) have been reported in cohorts of XXY children. In a recent study of 57 XXY children and adolescents, 36% met the criteria for a diagnosis of ADHD based on parent reports, with the vast majority presenting predominantly inattentive symptoms without significant hyperactivity or impulsivity, suggesting that attention deficits may probably emerge as a consequence of verbal processing difficulties. Moreover, such problems are usually detected in childhood and abate as XXY individuals progress to adulthood with subsequent improvement of VIQ.

Insights into the Pathogenesis of XXY

The aneuploidy in xxy is the result of non-disjunction (e.g. the failure of homologous X chromosomes to separate at anaphase that can take place both in meiosis I and meiosis II of maternal oogenesis or during meiosis I of paternal spermatogenesis (non-disjunction of paternal meiosis II results in either 47 XXX or 47 XYY karyotypes. The possibility that the supernumerary X chromosome in XXY is either of paternal or maternal origin seems to be almost equal. Less frequently (~3%), non-disjunction occurs during mitosis of the early post-zygotic divisions. Advanced maternal age is the only evidence-based risk factor for XXY. In particular, maternal age >40 was associated with a 4-fold increase in the risk of conceiving an XXY fetus as compared to maternal age. The evidence relating advanced paternal age to sex chromosome aneuploidies is less robust.

Several theories try to explain the impact of a supernumerary X chromosome on the phenotypic features of XXY. In normal females, the transcription of one of the two X chromosomes is randomly inactivated in order to compensate for the minimal gene content of the Y chromosome of the male cells. This inactivated X chromosome can be microscopically visualised in female cells as the Barr body (sex chromatin) and has been shown to be regulated by X inactive specific transcript (XIST) gene. XIST lies on the X chromosome and expresses a long noncoding RNA that literally coats the X chromosome selected for inactivation. In a similar way, in the somatic cells of XXY subjects, the supernumerary X chromosome is inactivated, and until recently, the detection of a Barr body has been used for the diagnosis of XXY. This inactivation of redundant genetic material is probably the reason that XXY is not characterised by severe phenotypic abnormalities compared to other aneuploidies.

Nevertheless, it was later demonstrated that only approximately 65% of genes on the X chromosome of normal females are inactivated, whereas the remaining 35% may escape this transcription inactivation either globally (20%) or randomly in a cell-type specific manner (15%). Ultimately, the tissues of females are mosaics of cells with a different X inactivation pattern. Such a mosaicism does not exist in XY subjects, whereas it is present in XXY

The existence of X inactivation has been recently supported among XXY patients in a population-wide study from Denmark, which related the most frequent comorbidities of XXY with corresponding gene deregulations and found that the most abundant deferentially expressed and up-regulated gene in XXY was XIST. The increased prevalence in XXY of several conditions, which are usually more common in women than in men (gynoid proportions, breast cancer, and autoimmune diseases), may be explained by such genetic peculiarities.

The androgen receptor (AR) gene is among these genes that undergo inactivation and is implicated in the variability of the phenotype observed among XXY patients. Of particular importance is the length of a stretch containing polyglutamine coding (CAG)n repeats. The shorter this stretch is, the higher is the activity of the receptor. Selective inactivation of the shorter of the two alleles would be associated with a more severe phenotype and diminished response to TRT.

In a recent study of anthropometric characteristics in KS, the length of the (CAG)n region correlated positively to arm length, arm span and leg length[20]. Moreover, there are terminal regions on the X and Y chromosomes that exhibit identical haplotypes, recombine during meiosis and therefore are inherited in an autosomal way. For this reason, they are referred to as pseudo autosomal regions (PAR1 and PAR2). Most of the genes on PAR escape X inactivation, resulting in two active copies in normal males but in three active copies among XXY. Such a gene is the Shortstature HomeobOX on chromosome X (SHOX), which is located on PAR1 and, via an increased gene-dose effect, is probably responsible for the tall stature and long legs observed in XXY. Nevertheless, it has to be stressed that the majority of genes that have been demonstrated to be deregulated in KS lie outside the X chromosome. This fact implies that the presence of a supernumerary chromosome may affect the expression of several genes throughout the genome. Accordingly, differential methylation of multiple loci relative to both male and female controls has been shown in XXY. The majority of these genes are related to energy balance and regulation of immunity.

Presence of Supernumerary X vs. Hypogonadism

As evident from the preceding description, phenotypic heterogeneity is a significant feature of XXY, while its manifestations can be attributed either to the aneuploidy and the impact of increased gene dosage by the supernumerary X or the presence of hypogonadism per se. Distinguishing the relative impact of each component on the phenotypic expression of XXY is a difficult task that is complicated by the fact that ageing modifies many aspects of the syndrome as symptoms and comorbidities accumulate.

Since in XXY, hypogonadism usually emerges in early adulthood, it is justified to consider signs and symptoms that are already present before puberty and prior to the onset of the hormonal derangement as sequels of aneuploidy rather than hypogonadism. Accordingly, the particular habitus with disproportionately long legs accompanied by abdominal obesity is observable since infancy, suggesting a genetic base.

In contrast, there are studies that have demonstrated an increased second to fourth finger ratio among XXY patients, similar to that observed in females, suggesting a relative androgen deficiency in the intrauterine milieu that may have an impact on XXY already from fetal life. The same conclusion may be drawn by the higher prevalence of anomalies of the development of the genital organs such as cryptorchidism and hypospadias.

The fact that verbal and attention deficits become evident in early childhood also suggests a genetic origin. Moreover, most of the cognitive traits observed in XXY are also seen in 47, XXX trisomy, which is not typically associated with hypogonadism, as well as in high-grade X chromosome aneuploidies, with a severity that depends on the number of supernumerary X chromosomes present in the karyotype. This concept is supported by evidence from neuroanatomical studies revealing differences in temporal and frontal lobe volume between KS prepubertal children and controls. Comparisons between XXY, Turner syndrome and controls suggest that this effect depends on the presence of an additional sex chromosome in a linear dose-dependent fashion. Such differences have also been identified at the genomic level by comparing microarray expression profiles that show the deregulation of X-linked genes correlated to verbal cognition. Additional evidence from mouse models of XXY that show behavioural traits similar to human XXY demonstrates that differences from wild-type mice persist after castration and do not improve with TRT. Nonetheless, cognitive profiles of mosaic XXY do not differ significantly from patients with classical XXY, while androgen levels at early developmental stages have been shown to play a role in neurodevelopment and brain lateralization, making it difficult to distinguish hormonal from genomic contribution in the phenotype.

Concerning metabolic abnormalities in XXY, the role of hypogonadism is central as it may perpetuate a vicious circle of insulin resistance, dyslipidemia and obesity, which in turn is responsible for the progression of hypogonadism itself. Nevertheless, abdominal obesity usually precedes puberty and, in XXY subjects, is only partially ameliorated by TRT, suggesting that a genetic component is also to be considered.

There is a body of evidence that this relative resistance to TRT may be attributed to a high prevalence of aberrations of the CAG polymorphism of the AR gene reported among XXY.

Cardiovascular Morbidity

The role of CV morbidity is pivotal for the increased overall morbidity and mortality observed in XXY. Interestingly, data on the prevalence of coronary artery disease are conflicting and definitely not as frequent as might have been expected in relation to the reported metabolic derangement. Moreover, alterations in biomarkers of CV dysfunction, such as increased CRP levels, have not always been confirmed by other parameters, such as carotid intima-media thickness or flow-mediated dilation of the brachial artery. Consideration of these findings should be cautious as the same study by Foresta et al. has shown that the main arteries of XXY subjects are smaller in diameter compared to controls independently of hormonal status, metabolic parameters, anthropometric measures and the length of CAG(n) repeats. Moreover, of note, XXY is not associated with arterial hypertension, a finding that has been attributed to the protective role of normal levels of adiponectin that these patients have despite the presence of MetS.

In search of factors that may contribute to increased CV morbidity, one may note the impaired cardiopulmonary performance occasionally observed in XXY. This may be a result of subclinical systolic and diastolic dysfunction, especially when associated with chronotropic incompetence i.e. the inability of the heart to increase its rate as a response to increased activity or demand. This anomaly is associated with exercise intolerance as evidenced by a reduced peak oxygen uptake (VO2 max) in XXY patients and is an independent predictor of major adverse cardiovascular events and overall mortality in an asymptomatic population.

Moreover, resting ECG evaluation may reveal a QTc interval shorter than in euploid men and women, which may be associated with fatal arrhythmias. This phenomenon is more pronounced in KS men with paternal origin of the excessive X-chromosome and is related to the presence of metabolic syndrome.

XXY patients also appear to be at a higher risk of congenital heart diseases, which may lead to higher mortality. Several abnormalities have been reported to co-exist with XXY, including a higher prevalence of mitral valve prolapse, atrial and ventricular septal defects with patent ductus arteriosus, bilateral hypoplasia of the internal carotid arteries with dilatation of the vertebral arteries and anomalous pulmonary venous connection.

Breast Cancer Risk among Patients with KS

The incidence of breast cancer, an otherwise rare type of cancer among males (1:100,000), is increased up to 30-fold in XXY. A recent review of the literature, including case series and epidemiologic studies that have evaluated breast cancer risk among KS patients, has estimated this risk to be 19-fold. This figure is lower than previously believed and still 30% inferior to the corresponding risk among females, contrary to older studies suggesting a propensity to breast cancer equal to that of females. This figure might be even lower if Klinefelter cases identified after a diagnosis of male breast cancer were excluded.

Nevertheless, KS remains the strongest independent risk factor for male breast cancer, and this risk is particularly elevated among patients with mosaic karyotypes. Breast cancer is a late event in the evolution of the KS phenotype as it is usually diagnosed in the 7th decade of life (range 58–82 and is associated with increased mortality compared to normal men.

Relatively elevated levels of estrogens have been implicated in the pathogenesis of breast cancer; however, gynecomastia does not present a risk factor despite being observed in almost 40% of Klinefelter patients. On the other hand, long-term TRT has also been associated with an increased risk for male breast cancer, whereas genetic reasons attributed to the supernumerary X chromosome cannot be excluded.

Endocrine Dysfunction

Premature failure of Leydig cell function is observed in KS subjects, however, at later stages. Thus, despite detecting a compensational elevation of luteinizing hormone (LH) and low INSL3 levels already from early puberty, hypogonadism is usually not evident before early adulthood.

In line with this, congenital anomalies of the genital organs driven by hypogonadism, such as micropenis, bifid scrotum or hypospadias, although more frequent in KS than in the general population, have an overall low prevalence.

Accordingly, the temporary surge in gonadotropins observed in early infancy, also known as “mini-puberty”, is usually present with FSH levels peaking at 2–3 months of age, followed by a subsequent rapid decline. This pattern agrees with that observed in 46,XY males and contrasts with the prolonged elevation observed in females.

There is a paucity of data regarding sex steroid secretion in XXY patients during childhood; however, one should anticipate similarities to normal boys as this is, in general, a period of minimal Leydig cell function. On the other hand, puberty in XXY subjects seems to occur in a timely fashion and follows a more or less normal course, with testosterone levels sufficient for satisfactory development of secondary sexual characteristics and able to trigger a growth spurt. Nevertheless, T levels are usually suboptimal to promote epiphyseal closure as in eugonadal boys, a fact that may contribute to the preponderance of tall stature among KS subjects and exacerbate the ratio between the trunk and the disproportionately long lower extremities.

As XXY patients progress to adulthood, hypogonadism tends to become more prevalent. Serum T levels fall into the low normal range beginning in early adulthood, and eventually, 65–85% of KS patients present overt hypogonadism after the age of 25. Moreover, the compensational elevation of LH activates aromatase, causing a relative increase in estrogen levels, which may contribute to the development of gynecomastia.

The great variability that characterises the phenotype of 47XXY is also evident regarding the virilization of adult patients, e.g. penile size, sexual hair density and fat distribution. This variability may be attributed to the magnitude of androgen deficiency or inherent differences in the sensitivity of AR and, particularly, the length of the CAG repeats polymorphism.

Recent studies have suggested that the observed low testosterone levels of XXY are not the result of diminished production but of defective release into the testicular bloodstream due to aberrations of the testicular vasculature.

Bone Density and Risk of Osteoporosis among XXY

KS patients present an increased prevalence of metabolic bone disorders, particularly reduced bone mineral density (BMD). A recent study found the combined proportion of XXY patients with osteopenia and/or osteoporosis to be 42.5%, a figure which is 8 times more frequent than in 46 XY age-matched males. Furthermore, two studies have assessed volumetric BMD, microarchitecture and estimated bone strength of the radius and the tibia, using quantitative computed tomography (pQCT). Their findings regarding volumetric BMD are divergent; however, both demonstrated reduced tibial cortical area and reduced trabecular density that, in combination, compromise the estimated bone strength. Reduced BMD is attributed to increased bone turnover and is accompanied by an increased risk of bone fractures, especially in the femoral area. Moreover, hip fractures in XXY are associated with an elevated mortality rate.

Although hypogonadism is a condition strongly related to BMD reduction, this may not be the case among XXY as no significant relationship has been demonstrated between testosterone levels and bone mass. In addition, TRT does not seem to normalize BMD in KS adults

These findings imply that variable degrees of hypogonadism occurring during the critical pubertal stages of bone development might account for an equally variable accrual of peak bone mass that cannot be modified later in adulthood. Finally, XXY patients seem to be particularly prone to 25OH-vitamin D fluctuations, as they present insufficient levels more frequently than controls, whereas vitamin D repletion has been demonstrated to be superior to TRT in improving BMD.

Autoimmunity among XXY

As early as the 1960s and 1970s, several reports described the concurrence of KS with autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis, psoriatic arthritis, polymyositis/ dermatomyositis, systemic sclerosis and mixed connective tissue disease; however, there is no substantial systematic evidence.

A recent retrospective study from England has demonstrated among XXY’s a significantly increased risk over controls regarding Addison’s disease, diabetes mellitus type, multiple sclerosis, acquired hypothyroidism, Sjogren’s syndrome and SLE.

Interestingly, the majority of the above conditions are more frequent among females, whereas no increased risk was found regarding autoimmune diseases that predominantly occur in men, such as ankylosing spondylitis and Goodpasture’s syndrome

Regarding hypothyroidism, it has to be noted that an increased presence of thyroid antibodies is debated among XXY, whereas there are studies suggesting a central component of hypothyroidism.

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