This study describes and compares attention-deficit hyperactivity disorder (ADHD) symptoms in a large cohort of children and adolescents with 4 different types of sex chromosome aneuploidy (SCA). Overall, the results show that ADHD symptoms are very common in all SCA groups and that the rates of individuals meeting DSM-IV criteria for ADHD based on parent report rating scales (ranging from 34% in XXY to 76% in XYY) are considerably higher than the 3% to 10% rate of ADHD estimated in the general population. Symptoms seen in the inattentive subtype of ADHD were the most common across all groups; however, males with XYY and XXYY were more likely to also have symptoms of hyperactivity and impulsivity.
It is important to note that current recommendations for establishing a diagnosis of ADHD include obtaining rating scales of a child’s behavior from both a parent/primary caregiver and 1 or more other adults familiar with the child’s behavior (usually a teacher) to establish that symptoms are present in more than 1 setting.13
In this study, results of parent report rating scales were used to classify whether patients had scores that met DSM-IV criteria for ADHD. Thus, it is important to recognize that the rates and subtype classifications are based on parent rating scale results and may overestimate the percentages that would meet criteria based on more comprehensive clinical assessment. Although results of the optional teacher rating scales were available only in 45% of cases, there were high agreement rates and a similar profile of symptoms when comparing parent and teacher responses. Further, consideration of other possible diagnoses or comorbid conditions is important before assigning a clinical ADHD diagnosis.13
Of the subgroup of 81 patients subsequently seen for clinical diagnostic evaluation, the classification of ADHD versus no ADHD on parent questionnaire was consistent with the final clinical diagnosis in 90% (73/81), although other clinical diagnoses may have also been applied. Thus, in this study group, it seems that classification of ADHD based on parent-report rating scales closely estimated final ADHD diagnosis.
There are only 2 previous studies that have evaluated rates and subtypes of ADHD based on parent-report of DSM-IV criteria in children with XXY/Klinefelter syndrome (KS). In 2009, Bruining et al6
found ADHD in 63%, which is somewhat higher than the 34% in our XXY group. Their sample had lower cognitive scores (Full Scale IQ [FSIQ] mean = 80) compared with our sample (FSIQ mean = 97) and somewhat higher rates of other psychological disorders such as autism spectrum disorders (14% vs 4%), depression or anxiety (56% vs 29%), and psychotic disorders (12% vs 2%). The more significant cognitive and psychological involvement in the study by Bruining et al6
might explain the higher rate of ADHD symptoms in their cohort. The second comparison study by Lee et al7
reported an ADHD rate of 41% in a sample of 27 males with XXY with a mean FSIQ of 101, which is more consistent with our findings. Both the other studies also found an increased likelihood of the inattentive subtype of ADHD in XXY, also similar to our study results.
As this study is the first to directly apply ADHD DSM-IV criteria in XYY, XXX, and XXYY, there are no direct comparison studies for these groups. However, previous case series have described previous ADHD diagnoses in XYY and XXYY at rates higher than those seen in the general population,5,9
which converges with our findings of significantly increased risk of ADHD in all SCA subgroups.
The most comprehensive studies on the psychological phenotypes of SCA subgroups were a group of studies conducted in the 1970s to 1990s at multiple sites around the world where samples were ascertained by newborn screening and followed closely into adulthood.8,10,14,15
These longitudinal studies provided information on an unselected sample of individuals with SCA, and the results of these prospective studies identified the elevated rates of language-based learning disabilities and psychosocial difficulties that characterize the behavioral phenotype of the SCA groups.16–18
When reviewing the findings from these studies, there were few reports of ADHD diagnoses; however, multiple study sites reported descriptions of problems with attention, distractibility, impulsivity, behavioral regulation, and executive function (EF). The discrepancy in rates of ADHD diagnosis between our study and these earlier studies may be due to the difference in time period, as there has been increased awareness about ADHD as a diagnosis and research in ADHD since the 1980s and early 1990s, at which point many of these patients were beyond school age. In addition, the strength of the newborn screening studies was in the ascertainment of an unselected sample followed from birth. In contrast, our sample contains a majority of individuals ascertained in the postnatal period due to developmental delays or cognitive impairments; thus, the ascertainment bias in our sample may also contribute to the elevated rates of ADHD symptoms compared with these previous studies.
Ascertainment bias must be addressed in any study on groups of individuals with SCA due to the large spectrum of involvement in these conditions and the low rate of lifetime diagnosis. It is important to point out that participants in this study were recruited primarily through advocacy groups and developmental-behavioral pediatrics clinics where patients with learning and behavioral difficulties are more likely to present. Thus, the rates of ADHD reported in this study are not being presented as the prevalence of ADHD in all individuals (diagnosed and/or undiagnosed) with SCA. If all individuals with SCA were ascertained at birth and evaluated for ADHD, the rates would most likely be much lower than in our sample. However, in the subset of the SCA population presenting for clinical care, ADHD is an important diagnostic consideration, and recognition of these symptoms by professionals is critical.
It should be noted that the mean IQ scores for each of the SCA types reported in this study are quite similar to what has been reported previously in the literature. In a meta-analytic review, Leggett et al (2010) reported mean Verbal IQs (VIQs) of 95, 99, and 80 and mean Performance IQs (PIQs) of 100, 106, and 85 for participants with XXY, XYY, and XXX, respectively.19
A review of XXYY syndrome describes a mean VIQ of 74 and PIQ of 87 in a large cohort.4
The mean IQs from these studies are quite similar to those reported in this article for each of the SCA types (), indicating that our samples are representative of patient populations with these disorders with regard to cognitive ability.
To decrease the effect of ascertainment bias on study results and to aid in prenatal genetic counseling of these conditions, previous studies in SCA also compare individuals diagnosed in the prenatal period to those in the postnatal period.5,11,20
A prenatally diagnosed sample is less biased toward individuals ascertained due to developmental problems, and previous literature supports the finding that those with a prenatal diagnosis have improved outcomes compared with those diagnosed in the postnatal period.12
The latter is likely due, in part, to higher socioeconomic status and improved opportunities for early intervention therapies. In our sample, those with a prenatal diagnosis of XXY were less likely to meet criteria for ADHD compared with the postnatally diagnosed group, and there was a similar trend in the XXX and XYY groups as well. Overall, the data suggest that genetic counselors should describe that children with SCA diagnosed in the prenatal period are less likely to have ADHD later in life; however, the rates of ADHD in a prenatally diagnosed sample are still higher than in the general population.
When we compared the pooled group of children with trisomy SCA with ADHD to those without ADHD, there were no significant differences in FSIQ scores between groups. However, the group with ADHD had significantly lower adaptive functioning abilities compared with those without ADHD. These results suggest that the effects of ADHD symptoms extend beyond the academic setting and are likely affecting overall functioning across multiple domains of daily functioning.
This study has important clinical implications in that it calls attention to the high rates of ADHD symptoms in the SCA conditions and supports the need for screening for ADHD in all children with SCA. As the hyperactive/impulsive symptoms are not as prominent in the XXY and XXX subgroups, it is sometimes easy to miss problems with attention and distractibility as being significant contributing factors affecting educational performance and daily living skills. Although comorbidities of learning, language, and social-emotional disorders may make the picture more complex, the diagnosis of ADHD is important to establish, if present, because it has implications in the educational setting. Most educational settings do not recognize the specific features and learning profiles of each genetic condition, but an ADHD diagnosis will often lead to additional educational interventions and accommodations via an individualized educational plan or other support plan. Strategies designed for children and adolescents with ADHD can also be implemented in the home setting to support daily living skills and social interactions.
The general approach to ADHD evaluation and treatment in the SCA conditions is not significantly different compared with the general population; however, an understanding of medical and other psychological features of the SCA conditions is important when evaluating the patient and developing a treatment plan. In adolescents with XXY/KS and XXYY, testosterone deficiency can lead to decreased energy levels and may contribute to attentional difficulties. Thus, evaluation of testosterone levels must be considered and treatment optimized. Risks for hypothyroidism, seizure disorders, and sleep apnea are slightly elevated in all SCA groups compared with the general population and should be screened for a possible contribution to attentional and academic difficulties. This study, along with previous SCA literature, shows that ADHD symptoms are often accompanied by other cognitive and psychological difficulties, so a full psychological assessment is recommended before assigning an ADHD diagnosis or starting on medication treatment. A psychological or neuropsychological assessment will help determine whether other learning disabilities, speech/language disorders, or emotional symptoms are present, which may need to be included as part of a comprehensive treatment plan. Patients previously diagnosed with ADHD who do not seem to respond to treatment may have increased rates or severity of these comorbid factors, which may not have been fully appreciated or addressed. Furthermore, comorbid learning and social-emotional symptoms, just like ADHD symptoms, often present differently across the life span, so periodic reevaluation may be necessary.
Finally, the results of the medication review show that more than 70% of children and adolescents with SCA and ADHD responded to standard stimulant medications, with a relatively low rate of significant side effects. Increased irritability was the most common side effect leading to discontinuation of medication, so low starting doses with gradual increases are recommended to decrease impact of irritability symptoms. The response rates to pharmacological intervention for ADHD are included in this article because of the lack of data in the literature on ADHD treatment in SCA beyond a few case reports. It should be noted, however, that the results presented here are based on a retrospective chart review. A more rigorous study design is needed to better understand medication responses in SCA compared with general ADHD. There were no sufficient data to draw firm conclusions about the response rates to nonstimulant medications, although based on this small series of cases, they are generally effective and well tolerated across all SCA subgroups and thus appropriate to try whether other clinical symptoms, parental preferences, or stimulant side effects lead to selection of these medications.
Other weaknesses of this study include the variability in measures used for assessment of cognitive and adaptive functioning. In addition, current best practice in ADHD diagnosis includes obtaining information about symptoms in more than 1 setting, so classification of ADHD diagnosis based on both parent and teacher responses for all subjects would have strengthened study results.
Although it is important to identify ADHD as a clinical diagnosis, additional research is needed to deconstruct the neuropsychological deficits leading to the behavioral symptoms of ADHD in the SCA population. Although FSIQ was not related to ADHD diagnostic rates in this study, it is possible that increased rates of language-based learning disabilities, EF deficits, and social emotional disorders underlie some of the behavioral ADHD symptoms. Specifically, EF impairments have been described in small cohorts of children and adults with XXY/KS, with these studies showing impairment in various EF subdomains, including inhibition, verbal working memory, processing speed, attention, and other frontal-executive deficits.21–26
The sample sizes, assessments used, and ages of the participants in these studies have varied, and thus more carefully designed prospective studies of EF and how they relate to ADHD and other neuropsychological features in larger cohorts of individuals with SCA are an important next step for researchers.