Klinefelter syndrome affects approximately 1 in 700 men and is the most commom sex chromosomal disorder. Men with this syndrome have an extra X chromosome, giving rise to the XXY chromosomal pattern. This sex chromosomal aneuploidy results in a variety of phenotypes including hypogonadism, androgen deficiency and infertility (Lanfranco et al. 2004
). Cognitive and behavioral dysfunctions in Klinefelter syndrome have generally been under-appreciated relative to endocrinological and physical features. However, there is an awareness of behavioral and cognitive abnormalities (Boone et al. 2001
; Geschwind et al. 2000
). Although there is a general impression that men or boys with Klinefelter syndrome often struggle with social situations (for example at school or at work), knowledge of the social behavioral phenotype of Klinefelter syndrome is limited. Previous studies have predominantly assessed global functioning (for example academic achievement, occupation or marital status) rather specific social abilities. Some studies have specifically focused on social adjustment in adolescents and men with Klinefelter syndrome, but these studies have primarily collected categorical data (for example, someone can be either sociable, passive or shy) or the studies included small sample sizes or lacked control data from individuals from the general population. These studies suggest that individuals with Klinefelter syndrome are at risk for psychosocial and emotional problems such as social withdrawal, social anxiety, shyness, impulsivity and inappropriate social behavior (Bender et al. 1999
; Geschwind et al. 2000
; Geschwind and Dykens 2004
; Ratcliffe 1999
; Simm and Zacharin 2006
). In early adulthood a significant portion of the XXY men report having few or no friends, poor relations with siblings and parents, little energy and initiative, and few or no sparetime interests (Nielsen et al. 1980
Although speculative, difficulties in coping with the social environment may be indicative of an increased vulnerability for autistic traits in boys and men Klinefelter syndrome. Tentative support for this hypothesis comes from recent case studies of individuals with Klinefelter syndrome diagnosed with an autism spectrum disorder (Jha et al. 2007
; Merhar and Manning-Courtney 2007
). Also, population based studies investigating genetic disorders in individuals with autism have commented on the co-occurance of autism and the XXY pattern (Kielinen et al. 2004
; Konstantareas and Homatidis 1999
). However, to our knowledge, there has been no study of autism features in a large sample individuals with Klinefelter syndrome.
The aim of our study was to investigate specific social abilities in a large sample of adult men with Klinefelter syndrome and assess whether Klinefelter syndrome may be associated with increased levels of autistic traits. In an attempt to improve our understanding of the social behavioral phenotype of Klinefelter syndrome, our study included a quantitative measure of the degree to which XXY men participate in specific social behaviors and at the same time the degree to which XXY men are distressed during these social situations as compared to men from the general population. Importantly, this measure allows a quantification of social capacities that are normally distributed in the general population. Also, it has shown to be sensitive to the effects of social skills training, indicating that it is a sensitive measure of individual differences in social behavior.
The aim of this study was to assess social difficulties in adult men with Klinefelter syndrome and explore the extend to which social disabilities reflect increased levels of features that belong to the autism phenotype. Our main findings were that compared to men from the general population, men with Klinefelter syndrome reported more distress during specific social situations and were characterized by increased levels of autistic features across all dimensions of the autism phenotype.
In the Klinefelter group, increased levels of distress during social interactions were observed in various domains of social behavior, namely: expressing of negative emotions to others, expressing and dealing with personal limitations and initiating contact with others. Although overall frequency of participating in social interactions in XXY men was not different from men from the general population, significant differences in specific domains of social behavior were observed. XXY men reported to less often engage in social behavior dealing with expression of negative emotions, such as refusing a request or standing up for one’s rights in a public situation.
Our findings of difficulties in coping with social situations in XXY men, especially high levels of distress during social interactions, are consistent with reports of social anxiety, social withdrawal and shyness in individuals with the XXY karyotype (Bender et al. 1999
; Ratcliffe 1999
). Difficulties in social adjustment have primarily been reported for children or adolescents with Klinefelter syndrome. Our data suggest that social difficulties may persist into adulthood, with social distress more prominent than a general reduction in engagement in social interactions. It has been proposed that social difficulties may arise as a consequence of language based learning difficulties (Geschwind et al. 2000
), social cognitive impairments (Van Rijn et al. 2006
) and verbal disabilities (Rovet et al. 1996
) in Klinefelter syndrome.
The high levels of autism traits in XXY men suggest that Klinefelter syndrome may be associated with an increased genetic vulnerability for autistic features. Interestingly, our finding of high rates of autistic traits across all dimensions of the autism phenotype suggest that vulnerability for autistic features in Klinefelter syndrome may not be restricted to impairments in social behavior and communication, but may extend to other aspects of the phenotype as well. Although this observation suggests that XXY men may display the specific combination of various individual traits that are all part of the autism phenotype, some of the traits and symptoms of autism are not specific for the autism phenotype, but may also be seen in individuals with other psychiatric disorders. Therefore, it is possible that men with Klinefelter may not only have an increased vulnerability for autism, but also for other psychiatric disorders.
The significance of the present findings is illustrated by the observation that on the autism questionnaire 15 (48%) of the XXY men scored above the cut-off for Asperger syndrome in a clinical population and 2 (6%) of the XXY men had a score above the cut-off for high functioning autism/Asperger syndrome in the general population. In the Klinefelter group, higher levels of autism traits were associated with more distress during social interactions and less frequent engagement in social interactions. Interestingly, social difficulties and autistic features in XXY men were observed in the face of spared intellectual abilities. In the XXY group, verbal- and performal-intelligence as measured with the WAIS was within the normal range and performance of the XXY group on Raven’s matrices and the NART did not significantly differ from control men. The findings of relatively spared intellectual functioning in the XXY group underscore the particular significance of the results with regard to social difficulties and high levels of autistic traits.
Our findings fit with the concept of a ‘broad phenotype’ of autism, which refers to the mild autistic-like features that are seen in individuals that are genetically related to an individual with autism (Bailey et al. 1998
; Bishop et al. 2004
). Using the same measure for autism traits (the AQ), increased levels of autism traits have also been found in biological relatives of subject with autism. In a study by Bishop et al. (2004
), parents of individuals with autism had significantly higher scores as compared to control parents on the subscales ‘social skills’ and ‘communication’. Mean score for ‘social skills’ in the group of parents of individuals with autism was 3.0, whereas in our study this was 4.8 for the XXY group. Similarly, mean score for ‘communication’ in the group of parents of individuals with autism was 2.75, whereas in our study this was 4.4 for the XXY group. Although it has been suggested that the typical clinical phenotype of autism as seen in subjects with the disorder and the broader subclinical phenotype of autism as seen in biological relatives may share a genetic origin (Rutter 2000
), the degree to which the mild autistic-like phenotype in men with Klinefelter syndrome and the broad phenotype of autism share a common genetic remains as yet unclear. However, because Klinefelter syndrome is defined by an X chromosomal abnormality (47,XXY) we may speculate that the X chromosome might be one of many genetic factors that play a role in the etiology of autism-like behaviors. Support for this hypothesis is derived from studies in Turner syndrome, another X chromosomal disorder characterized by a partial or complete absence of one of the X chromosomes in females (45,XO). Turner females also display difficulties in the social domain and the estimated risk of autism spectrum disorders is much higher as compared to women from the general population (Creswell and Skuse 1999
; Mazzocco et al. 1998
; McCauley and Sybert 2006
; Skuse 2000
With regard to the exact genetic mechanisms that may underlie the effects of an extra X chromosome on the social behavioral phenotype, we can merely speculate. Isles et al. (2006
) have argued that parental origin of a gene impacts the development of social behavior. The differential expression of a gene depending on the parental origin of the gene is referred to as genomic imprinting. Evidence for X-linked imprinting effects on social behavior and underlying brain development has been reviewed by Davies et al. (2006
). Badcock et al. (2006
) have also reviewed evidence supporting the importance of genomic imprinting in explaining social behavioral phenotypes, and more specifically the autism phenotype. Their ‘imprinted brain theory of autism’ poses that an imbalance in brain development driven by genomic imprinting gives rise the autism phenotype.
Important empirical evidence for the role of imprinted genes in explaining the social behavioral phenotype comes from studies on Turner syndrome (X0). Females with the single X chromosome of maternal origin display more social difficulties than Turner females with the single X chromosome of paternal origin (Skuse et al. 1997
). Unfortunately, in the present study subgroups of XXY men with an extra X chromosome of maternal origin versus paternal origin were not of sufficient size for statistical analyses. Although genomic imprinting effects on social behavior have not yet been investigated in Klinefelter syndrome, parental origin of the extra X chromosome seems to influence at least some aspects of the phenotype of Klinefelter syndrome, such as impaired speech and motor developmental problems (Stemkens et al. 2006
). However, other genetic mechanism such as overexpression of genes on the X chromosome or abnormal X-inactivation may play a role as well (Vawter et al. 2007
). Future genetic studies may provide insight into the possible contribution of X-linked genetic mechanisms in explaining the social behavioral and autism-like phenotype in Klinefelter syndrome. Genetic studies investigating the link between X chromosomal mechanisms and autism features may especially be relevant considering the male preponderance in autism spectrum disorders (Volkmar et al. 1993
The degree to which the observed behavioral impairments in XXY men represent the effects of testosterone deficits is unclear. Although lower levels of testosterone can be seen after the onset of puberty (Salbenblatt et al. 1985
), there are studies showing that prenatal testosterone levels may not differ between individuals with Klinefelter syndrome and male controls (Ratcliffe et al. 1994
). Although speculative, support for the hypothesis that at least some aspects of the XXY phenotype may represent the effects of X chromosomal genetic pathology rather than low testosterone levels by itself, comes from individuals with X chromosomal aneuploidies that are not associated with low testosterone levels. For example, although females with the XXX karyotype are thought to have typical androgen levels, they do display impairments in the language domain and have decreased social adjustment (Bender et al. 1999
; Harmon et al. 1998).
Finally, we are aware of some limitations of the present study. As many men with Klinefelter syndrome remain undiagnosed and XXY men in our study were recruited with help from the Dutch Klinefelter Association, our sample may not be completely representative. In spite of this, we believe that the present effect sizes convincingly indicate a relationship between Klinefelter and autism traits, although the possibility that effect sizes might be attenuated in a more representative sample cannot be excluded. Also, the finding that the XXY group in our sample was relatively high functioning, as indicated by our measures of intellectual abilities, is in contrast with a bias towards including the more severe cases. Another limitation is that we included two control groups in this study for practical reasons. Therefore, we were not able to calculate correlations between autism traits and social abilities in the control sample. Furthermore, the use of self-report measures might have biased the degree of social disabilities in Klinefelter syndrome. However, studies showing that XXY men tend to overrate, rather than underrate, their own social adjustment (Bender et al. 1999
) suggest that our findings might rather be an underestimation than overestimation of social disabilities in Klinefelter syndrome.
Taken together, as compared to men from the general population, XXY men reported increased levels of distress during various types of social interactions and less engagement in those aspects of social behavior that deal with display of negative emotions. Interestingly, we observed considerably increased levels of autistic traits across all dimensions of the autism phenotype in XXY men. The observation that increased levels of autism traits were not only found in the subscales dealing with social skills and communication, but in all subscales of the autism questionnaire, call for a more thorough clinical investigation of vulnerability to autism spectrum pathology in Klinefelter syndrome in a larger and more representative sample in epidemiological terms. Although our findings require replication, Klinefelter syndrome might prove to serve as a useful model for studying a role of the X chromosome in social behavioral dysfunction and autism-like behavior.