In children with a dual diagnosis of DS + ASD, multiple medical comorbidities including infantile spasms, constipation, and behavioral feeding difficulties were more likely to be present than in children with DS alone, identifying for the first time that higher rates of particular medical conditions exist in persons with DS + ASD in childhood. This study builds on previous evidence that a history of epilepsy and/or infantile spasms places a child with DS at significantly higher odds of being diagnosed withASD.(20–22)
Individuals with DS + ASD in this study had twice the odds of being male, consistent with previously published, smaller studies(4, 23) and with the well documented increased incidence of ASD in males in the general population. There are many theories for this sex difference; some point to inherent bias in our diagnostic criteria,(24) while others implicate biological factors such as the influence of Y chromosome haplotypes,(25) elevated fetal testosterone(26) and prenatal maternal immune activation affecting neural development leading to ASD phenotypes.(27) The widespread use of non-invasive prenatal testing offers an opportunity to prospectively study these factors in the DS population.
Children with DS + ASD had significantly higher odds of a diagnosis of gastroesophageal reflux and constipation, consistent with findings in idiopathic ASD.(28, 29) For children with idiopathic ASD, multiple hypotheses have been proposed for the increased frequency of GI complaints, including disruption of the gut-brain axis and alteration in microbiota.(30) The shared pathophysiological links between GI disturbances and ASD are an area of active research. Further investigation is needed to determine if gut biomarkers studied in individuals with idiopathic ASD(31) are also found with higher prevalence in individuals with DS + ASD.
While several findings in this study are consistent with what has been described in the idiopathic ASD population, there are a few key differences to highlight. Idiopathic ASD occurs with increased frequency in patients with a history of CHD,(15) including those with atrial septal defects, while individuals with DS + ASD in this study had lower odds of having a history of either. In this study, rates of prematurity were not significantly different between the two groups, while it is well documented that prematurity increases the risk of idiopathic ASD.(32) Assessment of the true impact of CHD on the development of ASD is likely underpowered in this single center design and may be best elucidated in a multi-center study. Additionally, while a variety of MH conditions occur with an increased prevalence in individuals with idiopathic ASD as compared with the general population,(33) and there is an increased incidence of impulsivity and anxiety symptoms in patients with DS + ASD,(6, 23, 34) this study did not find a statistically significant difference in the frequency of anxiety, ADHD, or depression between the two groups. This may be due to the small number of individuals with these diagnoses among our study participants, and further research is needed.
There was a significant difference in ages between the two groups, with the DS group being younger than the DS + ASD group. However, the difference was small (1.5 years) and could have been a function of excessive power in the DS only group (N = 490, versus N = 72 in the DS + ASD group). We feel that the age difference found between the two groups is not clinically significant, as its impact on rates of acquired conditions is likely minimal, and it does not affect the rates of congenital conditions.
This study is not without limitations, and the following should be considered when interpreting our findings. The retrospective and non-controlled nature of this study limits generalizability and introduces a potential for selection bias. Generalizability is also affected by the fact that the data was collected from a single tertiary care center. Further, this study relied on parental report of medical history which may have been influenced by recall bias at the time of assessment. As such, some respondents left fields blank, limiting ability to definitively assess if a patient had or did not have a particular condition. This was potentially remedied by obtaining data from multiple encounters and utilizing an “if ever” approach to the conditions (especially as some may resolve). Although the BCH DSP has one of the highest volume pediatric DS centers in the country, ASD is only present in a minority of persons with DS and thus this study may have been underpowered to detect more nuanced medical contributions to ASD in children with DS, specifically in more rare conditions. This is further compounded by the fact that some medical conditions, such as autoimmune conditions, develop later in childhood and thus may have not yet been diagnosed in some of the younger patients included in this study. Future research should employ data gathered from a clinician using a systematic method to obtain a more complete picture of medical conditions impacting individuals with DS.