Down syndrome (DS) is the most frequent chromosomal condition, affecting 1 in every 787 live born babies (de Graaf et al., 2015, 2017) and the most common genetic cause of intellectual disability. DS is associated with increased risk of several medical issues, such as congenital heart disease, obstructive sleep apnoea, celiac disease, and endocrine abnormalities, including thyroid dysfunctions (Antonarakis et al., 2020). Individuals with DS exhibit a range of thyroid dysfunctions that encompass congenital hypothyroidism, subclinical hypothyroidism (SH), acquired hypothyroidism (autoimmune/non autoimmune), and hyperthyroidism (Pierce et al., 2017; Valentini et al., 2021). For example, higher rates of hypothyroidism have been documented, with estimated prevalence of 23.5% in pediatric age and 39–61% in adult age (Carroll et al., 2008; Tsou et al., 2020). Another thyroid dysfunction particularly frequent in DS is SH, whose prevalence in this population has been estimated up to 87% (O’Grady and Cody, 2011; Szeliga et al., 2022), remarkably higher than the prevalence reported in general population (5%) (Chiovato et al., 2019). SH diagnosis is possible when serum thyroid-stimulating hormone (TSH) is slightly elevated and the levels of total or free thyroxine and triiodothyronine are normal (O’Grady and Cody, 2011). It has been proposed that the increased prevalence of thyroid dysfunctions in youth with DS could be determined by a delayed maturation of the hypothalamic–pituitary-thyroid axis; this would result in a temporary process not necessitating treatment (Sharav, 1988, 1991). Accordingly, literature suggests that only a limited percentage of individuals with DS and SH develops an overt hypothyroidism, particularly females with mostly positive titer of antithyroid autoantibodies (Szeliga et al., 2022).

Research on general population suggests SH is associated with increased prevalence of psychopathological symptoms. In particular, individuals with SH tend to exhibit significantly higher levels of depressive symptoms than individuals without SH (Gulseren et al., 2006; Almeida et al., 2007; Chueire et al., 2007; Demartini et al., 2014). An association between SH and depression symptoms has also been reported in animal models of SH (Ge et al., 2014). Moreover, some authors found that depression symptoms are observed more frequently among individuals with SH than those with overt hypothyroidism (Chueire et al., 2007); however, these results were not confirmed by a recent meta-analysis reporting a stronger association between depression and overt hypothyroidism than with SH (Bode et al., 2021). Literature also suggests associations between SH and anxiety symptoms. A systematic review on the topic highlighted that individuals with an anxiety disorder seem to be significantly more likely to have a co-occurring thyroid disorder (Fischer and Ehlert, 2018). Intriguingly, a recent study explored the relationship between SH and anxiety symptom in young first-episode and drug-naïve patients with major depressive disorder (Wu et al., 2023). The authors reported that high serum TSH level was associated with anxious major depressive disorder in young first-episode and drug-naïve individuals with major depressive disorder and SH, thus suggesting serum TSH level could be a possible biomarker for predicting anxiety symptoms, at least for the population considered in the study.

It has been also suggested that SH could be associated with sleep difficulties. Indeed, individuals with SH seem to exhibit poorer sleep quality in comparison with individuals without thyroid dysfunction (Song et al., 2019; Wu et al., 2021). Results from these studies were in contrast to previous reports suggesting no relationship between SH and sleep quality (Akatsu et al., 2014). Another research, involving 4,945 participants older than 19 years of age, reported significant associations between SH and sleep duration (Kim et al., 2019). Moreover, there are reports of higher frequency of SH among individuals with restless legs syndrome (Geng et al., 2022). On the other hand, contrasting findings have been reported about the existence of relationships between obstructive sleep apnoea and SH (Resta et al., 2005; Ozcan et al., 2014; Petrone et al., 2016; Zhang et al., 2016). As concerns population with DS, thyroid dysfunctions have been associated with behavioral sleep disturbances in adults, such as early awakenings (Esbensen, 2016).

Despite the well-described high prevalence of SH in individuals with DS, poor is known about possible, specific emotional and behavioral correlates of SH in such population, as also underlined by a recent review (Hirsch and Gaultney, 2023). Therefore, the first aim of the current study was to investigate differences in emotional and behavioral profiles between a group of children with DS exhibiting co-occurring SH and a group of age and body mass index (BMI)-matched children with DS without co-occurring SH. The second aim of the present study was to investigate differences in sleep disturbances between these groups. Based on literature, we hypothesized that participants with co-occurring SH would exhibit more internalizing symptoms (i.e., anxiety and depression symptoms) as well as more sleep difficulties than participants without SH did, in particular for insomnia-related difficulties.

The first aim of the present work was to investigate differences in emotional and behavioral problems between a group of children with DS exhibiting co-occurring SH and a group of children with DS without co-occurring SH. Contrary to our hypothesis, we did not observe any group difference on internalizing problems as detected by the CBCL. Instead, participants in the SH group exhibited higher scores in several scales indicating externalizing symptomatology, as detected by the CPRS, namely: ADHD index; CGI: restlessness; CGI: emotional instability; CGI: total. These findings then suggest that, in children and adolescents with DS, the presence of SH is associated with externalizing rather than internalizing problems, taking into account confounding factors such as age, BMI or sex. Although most of the available evidence in typical population points to an association between SH and internalizing problems, it is possible to identify some indications of externalizing symptomatology in association with hypothyroid conditions. For instance, there are indications for a higher prevalence of SH in children and adolescents with behavioral dysregulation (Holtmann et al., 2010). Another study conducted on a sample of 224 children with SH aged 11–19 years reported impaired emotional intelligence quotients, including worse self-control than controls (Arianas et al., 2022). Intriguingly, these studies focused exclusively on pediatric age, similar to the present research. Preclinical studies also suggest that juvenile hypothyroidism is associated with hyperactive locomotor behavioral patterns (Van Wijk et al., 2008; Umezu et al., 2019). Our findings provide preliminary evidence for considering SH-related problems in children with DS who exhibit behavioral changes associated with hyperactivity.

The second aim of the current study was to investigate differences in sleep problems between children with and without co-occurring SH. We found that participants in the SH group did not exhibit significantly higher scores at the SDSC compared to participants in the control group. This finding is inconsistent with some studies that suggest an association between SH and sleep difficulties (Iodice et al., 2019; Kim et al., 2019; Song et al., 2019; Green et al., 2021; Geng et al., 2022). Such inconsistency could be explained, at least in part, by differences in the method used to detect the presence of sleep disorders: some studies used self-report questionnaires specifically designed for the research, others used standardized questionnaires, and still others employed objective measures, such as polysomnography. However, the association between SH and sleep disturbances has not been unequivocally reported in the literature. For instance, the study by Gencer et al. (2022) included 120 participants, of whom 60 had newly diagnosed SH and 60 had normal thyroid functions; the authors did not detect any significant difference in the frequency and severity of obstructive sleep apneas measured by polysomnography (Gencer et al., 2022). The absence of group differences in an indirect index of sleep-related breathing disorders, as provided by SBD scale scores of the SDSC, could be explained by two reasons. The first one relates with the general vulnerability of individuals with DS to sleep-related breathing difficulties, such as sleep apneas (Hirsch and Gaultney, 2023), as also confirmed by the mean scores of the SBD scale that fall into borderline range for both groups. Moreover, the BMI matching between SH and CON groups could contribute in explaining the lack of group differences at SBD scores, since obesity could be a confounding factor in the association between SH and sleep apneas, as previously suggested (Zhang et al., 2016). However, participants included in the current research did not undergo polysomnography; we only collected parent-reported information on child’s sleep. Therefore, the comparison between the results emerging from the present study and those reported in the literature is limited by methodological differences.

This study is not without limitations. The first one is the restricted sample size, which limits the generalizability of the results. The second limitation is the wide age range of the participants included: since the risk of hypothyroidism increases with age in individuals with DS (Bull et al., 2022), future research should focus on specific age ranges in order to better characterize emotional and behavioral features associated with SH across development. The use of parent-report questionnaires to evaluate emotional and behavioral problems, as well as sleep difficulties, represents another limitation of this study. Future studies should include additional tools for psychological assessment, such as clinical interviews, and utilize objective measures to detect sleep disturbances, such as polysomnography and actigraphy.

Despite these limitations, the present research provides evidence of specific emotional and behavioral features associated with SH in children and adolescents with DS. Recently developed guidelines suggest evaluating for medical problems that can be associated with behavior changes, including thyroid abnormalities, for children with DS aged 5–12 years (Bull et al., 2022). This study has useful clinical implications, given that it offers specific indications for clinicians involved in the follow-up of children with DS about the need to pay attention to the development of behavioral problems in children with DS and co-occurring SH. A multidisciplinary approach that includes diverse professionals, such as pediatricians, psychologists, neuropsychiatrists, and endocrinologists, is essential to for the healthcare of children and adolescents with DS.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ospedale Pediatrico Bambino Gesù. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants' legal guardians/next of kin.

EF: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. FC: Conceptualization, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. PG: Data curation, Investigation, Writing – original draft. LC: Data curation, Writing – original draft. AV: Writing – review & editing. DV: Conceptualization, Writing – review & editing. SV: Conceptualization, Project administration, Supervision, Writing – review & editing.