This is the largest study to date of medical and psychological features of children and adults with XXYY syndrome. This cohort was primarily Caucasian, and all but two individuals were ascertained in the postnatal period due to a variety of neurodevelopmental problems or physical features. In contrast to XXY, where it is estimated that only approximately 3.6% of individuals diagnosed in the postnatal period are identified prior to age 10 [Abramsky and Chapple, 1997
], over 70% of individuals with XXYY in this cohort were diagnosed prior to age 10. This difference is due to the greater severity of developmental delays, dysmorphisms, medical problems, and neurodevelopmental disorders in children with XXYY compared to XXY leading to genetic testing. It is also an interesting contrast to the 11.3% of individuals with XXYY syndrome diagnosed prior to age 10 described in the last major case series published in 1970 [Borgaonkar et al., 1970
], most likely due to the increased practice of genetic testing in children with developmental delays and neurodevelopmental disorders over the past 35 years.
Stature in childhood is variable, with some children falling in the lower centiles and others having tall stature, consistent with previous reports [Borgaonkar et al., 1970
]. However, stature above the mean increases with age, and tall stature in adulthood is a characteristic feature. This is consistent with growth patterns in XXY [Aksglaede et al., 2008
]; however, the mean final adult height in XXYY (192.4 cm) is slightly taller than in XXY (188 cm). Our findings of a mean adult height of 192.4 cm (75.7 in) and almost two thirds (62%) of the adults falling above the 90th centile are more remarkable than the previously reported mean of 72 inches and only 30% above the 90th centile [Hunter, 1966
; Borgaonkar et al., 1970
]. Previous reports estimate gynecomastia in 62% of adult cases [Borgaonkar et al., 1970
]; however, in our study only 25% of adolescents and 41% of adults had palpable gynecomastia. Again, this difference is likely due to our current ascertainment of a larger percentage of individuals with a milder phenotype due to increased genetic testing for early developmental delays or behavioral problems that were not screened in the 1960s and 1970s.
In contrast to XXY, there are characteristic facial features in XXYY syndrome (). The most common facial features in childhood included hypertelorism with epicanthal folds, and narrow, upslanting palpebral fissures. Although our study is cross-sectional, some facial features seem to emerge with age, with the development of a more prominent brow and jaw. It is interesting that this progression has also been described in previous individual case reports [Spencer et al., 1969
; Davies, 1970
; Yamane et al., 1993
]. Dental problems including late or atypical dental eruption, thin enamel, taurodontism, crowding, malocclusion, multiple caries, and the need for dental surgery and orthodontia were almost universal in this population. Clinodactyly, flat feet, and tremor were also very common. The discrepancy between those with limited supination and pronation on physical examination (61%), and those with confirmed radioulnar synostosis or congenital elbow dislocation (17%) on radiograph suggests undiagnosed cases, especially since 70% of those who had been radiographed (n = 23) were found to have abnormalities. The high rates of asthma, allergies, and hospitalizations for respiratory infections are also higher than expected for the general pediatric population and raise the possibility of immunologic and/or pulmonary function abnormalities in this group.
Tremor has been previously reported in XXYY, as well as in other males with SCA [Baughman, 1969
; Boltshauser et al., 1978
; Telfeian et al., 2000
], and has generally been classified as essential tremor. Although essential tremor is common in the general adult population (4%) [Benito-Leon and Louis, 2006
], it is rare in children and it is interesting that essential tremor is estimated to present in 1/500 children [Jankovic et al., 2004
], the same general estimated prevalence of SCA in the population [Hook and Hamerton, 1978
]. Although clearly not all children with essential tremor have SCA, the presence of essential tremor in a child with a history of learning disabilities, developmental delays, or associated physical features should prompt genetic testing. The etiology, underlying neurophysiology, and treatment of tremor in this population needs further research and may shed light onto genes contributing to essential tremor in the general population.
This group of individuals with XXYY syndrome showed the expected development of hypogonadism seen in males with X chromosome polysomy. There have been no studies directly comparing hypogonadism in XXY and XXYY, although clinical and laboratory characteristics of hypergonadotropic hypogonadism, and studies of testicular histology show similar findings to those seen in XXY [Leisti et al., 1964
; Tabata et al., 1964
]. Thus, for now we presume that clinical endocrinologic monitoring and initiation of testosterone treatment should be similar to adolescents with XXY syndrome until further research is completed.
Three of the adult subjects with XXYY had laboratory evidence and physical symptoms of hypogonadism, however they were not on testosterone due to concerns of worsening behavioral problems with a history of mood disorders and impulsivity. The behavioral effect of testosterone treatment in XXYY was a common question asked by families and physicians of study participants. There is one report describing the initiation of androgen replacement in a 32-year-old with XXYY with a history of behavioral problems, emphasizing that androgen treatment did not worsen behaviors, aggression or hypersexuality, and significantly improved fatigue, bone density, and apathy [Heuser et al., 1999
]. Sourial and Fenton 
also described a case of an adult with XXYY in which testosterone replacement significantly improved aggression and atypical sexual behaviors [Sourial and Fenton, 1988
]. However, Lee described a male with XXYY and schizophrenia treated with testosterone at age 31 who developed agitation and aggression [Lee, 1996
]. Our clinical experience with this group supports the view that testosterone treatment at standard doses generally improves or has no significant impact on behavior, although treatment was discontinued in two older individuals with significant mental heath problems due to increased agitation. Unfortunately, in both cases changes to other psychiatric medications occurred at the same time, making it difficult to determine if the testosterone indeed led to the agitation.
Interestingly, review of brain MR imaging showed a spectrum of nonspecific T2/Flair white matter hyperintensities in almost half of those who had brain MR performed. Some patients had a few tiny (1–2 mm) abnormal white matter foci whereas others had more diffuse and confluent (4–5 mm) abnormal white matter foci. The differential for these findings is broad and includes developmental, dysmyelination/demyelination, and gliosis or scar from remote insult (inflammation or trauma). This finding may also be underreported as neuroradiologists with predominantly adult practices may consider these to be normal findings. Warwick et al. 
described similar findings of “high-intensity signal foci” in 5/10 XXY, 3/11 XXX, and 1/10 XYY adult subjects compared to none in controls, postulating the increased susceptibility of developmentally abnormal brains to injury associated with aging. However, Boettger et al. 
describe similar findings in a 5-year-old male with XXY, and in our series these findings were present as early as 10 months of age and in three children 3 years of age. Thus, they may represent the sequelae of abnormal neurodevelopment and can provide clues to the pathology of the neurological/neurodevelopmental abnormalities seen in XXYY and other sex chromosome aneuploidies. In our series, the individuals with T2/Flair white matter hyperintensities did not differ in the presence of ID, seizures or tremor compared with those without reported MR findings, although larger sample sizes are needed.
Cognitive profiles with strengths in visuoperceptual skills relative to language-based tasks are consistent with previous reports, although the mean FSIQ of this group is almost 10 points higher than previously reported [Borgaonkar et al., 1970
]. This is likely related to increased ascertainment of higher-functioning individuals with the increasing genetic testing in children with developmental delays over the past 30 years. We also found that VIQ significantly decreased with age, and it is important to point out that this is a cross-sectional study in which most individuals in this older age group were ascertained 20–30 years ago when genetic testing was only obtained for significant dysmorphology or severe cognitive deficits. There was also a discrepancy between overall cognitive measures and adaptive functioning, with adaptive skills almost one standard deviation less than full-scale IQ scores. The striking rates of neurodevelopmental disorders such as ADHD and autism spectrum disorders, other psychological diagnoses, psychiatric hospitalizations, and psychopharmacologic medication use emphasize the significance of the behavioral phenotype in XXYY syndrome and the need for further study in etiologies and treatments for these associated problems.
An ideal study of this population would include prospective studies of a cohort identified prior to or at birth to eliminate ascertainment bias and to study changes in health, cognition and adaptive functioning related to age. Cases identified in the prenatal period and carried to term are rare, with only two such cases in our cohort. There are no studies describing termination rates in early XXYY pregnancies; however, considering the recently reported termination rate of 70% in XXY fetuses by women electing prenatal genetic testing [Shaffer et al., 2006
], it is most likely higher in XXYY due to the association with more significant cognitive and psychological problems in the current medical literature. Our two cases identified in the prenatal period did not have significant differences in physical features, medical problems, or cognitive/psychological features compared to the rest of the group. Screening of newborns to identify unselected cases would require a very large collaborative study to obtain sufficient samples sizes due to the low prevalence of XXYY.
It is posited that XXYY syndrome results from a double nondisjunction during meiosis in spermatogenesis. Very few studies have reported on further molecular investigations in XXYY males. The parent-of-origin of the extra chromosomes has been evaluated in six cases, and all have identified the extra chromosomes as being paternal in origin [Rinaldi et al., 1979
; Leal et al., 1994
; Iitsuka et al., 2001
]. It is believed that the phenotypic differences in XXYY syndrome and other SCAs likely result from gene dosage effects of genes in the pseudoautosomal regions (PAR) of the X and Y chromosomes that escape X-inactivation. Thus, in XXYY males, genes in the PAR regions would be expressed from the four sex chromosomes, compared to the two sex chromosomes in 46,XY males. Overexpression of other X chromosome genes that escape X-inactivation or Y chromosome genes may also be involved. The phenotypic differences may be also be related to polymorphisms in selected X and Y chromosome genes, and other recent research has suggested that the presence of supernumerary sex chromosomes may lead to alterations in DNA methylation at various loci in the genome, leading to altered gene expression and subsequent phenotypic differences [Coffee et al., 2007
To date, only two specific genes on the X and Y chromosomes have been described that may be associated with the phenotype of SCA. It is postulated that the tall stature of individuals with supernumerary sex chromosomes is related to overexpression of the SHOX
gene, a pseudoautosomal gene that escapes X-inactivation and is highly expressed in growth plates of long bones where it plays a role in bone growth and maturation [Rao et al., 1997
; Munns et al., 2004
]. Haploinsufficiency of SHOX
has been shown to be related to short stature in Turner syndrome [Clement-Jones et al., 2000
], microdeletions of SHOX
have been shown to be associated with short stature [Rao at al., 1997
], and duplications of SHOX
have been associated with tall stature [Ogata et al., 2000
]. Thus, the tall stature in XXYY may be related to an overexpression of SHOX
. Gene dosage effects of a potential growth control gene on the Y chromosome (GCY) has also been proposed and may be involved in the additional height in XXYY [Kirsch et al., 2004
A polymorphism in the androgen receptor (AR
) gene on the X chromosome gene has also been found to be related to phenotypic differences in XXY in some studies. The CAG-repeat length of the AR
gene is associated with taller adult height and more gynecomastia in adult males [Zitzmann et al., 2004
], and with shorter penile length in children with XXY [Zinn et al., 2005
]. The longer CAG-repeat polymorphism codes for a receptor that is less responsive to androgen, thus perhaps low receptor responsiveness coupled with mild-moderate androgen deficiency contributes to the more severe phenotype in XXY. Studies of the genotype–phenotype relationship of the AR
gene polymorphism in a sample of this XXYY population are currently underway. Also, future study of the two sets of twins with XXYY in this report comparing DNA methylation patterns and gene expression to their phenotypes may provide interesting data about the role of epigenetics in XXYY and other forms of SCA.
In summary, there are many important comparisons between the phenotypes of XXYY syndrome and XXY. In most cases, the number of congenital malformations, dysmorphic features, and associated medical problems are more significant in XXYY, along with a taller final adult height. However, features of hypergonadotropic hypogonadism are similar, and testosterone treatment is indicated when laboratory evidence or clinical symptoms of androgen deficiency present. The most important distinctions lay in the differences in the behavioral phenotype, where males with XXYY have more significant developmental delays, language-based cognitive deficits, and problems with adaptive functioning. Neurodevelopmental disorders such as autism spectrum disorders and ADHD, as well as other psychological comorbidities are also more common in XXYY compared to XXY. However, as in XXY, there is considerable variation in the phenotype, with the genetic and environmental factors underlying this variation yet to be identified.