Alterations in cortical and subcortical neuroanatomy and associations with behavior in females with fragile X syndrome.

AIM: To address substantial gaps in the literature on neuroanatomical variations in females with fragile X syndrome (FXS). METHOD: Surface-based modeling techniques were applied to the magnetic resonance imaging of 45 females with FXS (mean age = 10 years 9 months, range 6 years-16 years 4 months, SD = 2 years 9 months) and 33 age-matched and developmentally matched females without FXS to elucidate differences in cortical gray matter volume, surface area, and thickness. Gray matter volumes in subcortical regions were examined to ascertain differences in subcortical volume. RESULTS: In females with FXS, cortical volume was greater bilaterally in the occipital pole and smaller in the right postcentral gyrus. Seven regions demonstrated lower surface area in participants with FXS, while cortical thickness was significantly greater over the posterior and medial surfaces in the group with FXS. Subcortical region of interest analyses demonstrated greater volume in the caudate nucleus, globus pallidus, and nucleus accumbens in the group with FXS. Global gray matter volume, pial thickness, and surface area were associated with behavioral outcomes in the group with FXS but not in the comparison group. INTERPRETATION: Females with FXS demonstrated unique cortical and subcortical gray matter anatomy relative to a matched comparison group. These findings may be relevant to the pathogenesis of the FXS behavioral phenotype and provide insights into behavioral interventions targeted to this population.

Longitudinal investigation of cognition, social competence, and anxiety in children and adolescents with Turner syndrome.

Turner syndrome (TS), a common neurogenetic disorder caused by complete or partial absence of an X chromosome in females, is characterized by distinct physical, cognitive, and social-emotional features. Girls with TS typically display average overall intellectual functioning with relative strength in verbal abilities and weaknesses in visuospatial processing, executive function (EF), and social cognition. This study was designed to better understand longitudinal trajectories of cognitive and social-emotional domains commonly affected in TS. Participants included 57 girls with monosomic 45,X TS and 55 age- and verbal-IQ matched girls who completed behavioral, child-report, and parent-report measures across four timepoints. Group differences in visuospatial processing, EF, social cognition, and anxiety were assessed longitudinally. Potential effects of estrogen replacement therapy (ERT) were assessed cross-sectionally on an exploratory basis. The TS group showed poorer performance on measures of visuospatial processing, EF, and social cognition, but not anxiety, compared to controls throughout childhood and adolescence. There were no significant group differences in the trajectory of skill development over time. Exploratory analyses within the TS group revealed that girls who were receiving ERT showed better performance on measures of overall IQ, expressive vocabulary, and visuospatial processing compared to those not receiving ERT. Consistent with existing literature, weaknesses in visuospatial processing, EF, and social competence among girls with TS persisted throughout childhood and adolescence. Exploratory analyses suggest that ERT may help improve some aspects of cognitive function in TS, although other pre-existing, nonhormonal differences between the two TS subgroups may alternatively explain these findings, given our study design. Future studies are needed to examine potential impacts of ERT on cognitive and social-emotional development in TS.

Social gaze behavior and hyperarousal in young females with fragile X syndrome: A within-person approach.

Children with fragile X syndrome (FXS) often avoid eye contact, a behavior that is potentially related to hyperarousal. Prior studies, however, have focused on between-person associations rather than coupling of within-person changes in gaze behaviors and arousal. In addition, there is debate about whether prompts to maintain eye contact are beneficial for individuals with FXS. In a study of young females (ages 6-16), we used eye tracking to assess gaze behavior and pupil dilation during social interactions in a group with FXS (n = 32) and a developmentally similar comparison group (n = 23). Participants engaged in semi-structured conversations with a female examiner during blocks with and without verbal prompts to maintain eye contact. We identified a social-behavioral and psychophysiological profile that is specific to females with FXS; this group exhibited lower mean levels of eye contact, significantly increased mean pupil dilation during conversations that included prompts to maintain eye contact, and showed stronger positive coupling between eye contact and pupil dilation. Our findings strengthen support for the perspective that gaze aversion in FXS reflects negative reinforcement of social avoidance behavior. We also found that behavioral skills training may improve eye contact, but maintaining eye contact appears to be physiologically taxing for females with FXS.

COVID-19 Pandemic: Mental Health in Girls With and Without Fragile X Syndrome.

OBJECTIVE: Children and adolescents, who have less developed coping skills, are affected by natural disasters and other traumatic events differently than adults. Emotional and behavioral effects are particularly pronounced during a pandemic-related disaster, when support networks that typically promote healthy coping, such as friends, teachers, and family members, may be less available. Children and adolescents with fragile X syndrome (FXS), who are at increased risk for developing anxiety and depression, may be particularly vulnerable to behavioral or emotional difficulties during a pandemic. This study examined the mental health outcomes of school-aged girls with FXS during the COVID-19 pandemic and associated stay-at-home orders. METHODS: Participants included 47 school-aged girls with FXS and 33 age- and developmentally matched comparison girls. Associations between COVID-19 behavioral and emotional outcomes and prior academic, adaptive, behavioral, and emotional functioning as well as prior maternal mental health and characteristics of the mother-child relationship were examined. Qualitative data from the parental report of emotional and behavioral responses to the pandemic were also obtained. RESULTS: Results indicate that school-aged girls with FXS demonstrate a distinct profile of COVID-19 related associations compared to the comparison group, such that pandemic-related worries and emotional impact of pandemic restrictions were predicted by prior mental health factors for the comparison group but by prior social, behavioral, and relational factors for the FXS group. CONCLUSIONS: Findings provide insight into factors that may confer risk or resilience for youth with special needs, suggesting potential therapeutic targets and informing public health initiatives in response to the pandemic.

Cognitive and Social-Emotional Development in Girls With Fragile X Syndrome.

OBJECTIVES: To evaluate the developmental trajectory of key cognitive, social, and emotional features in girls with fragile X syndrome (FXS). METHODS: This longitudinal, parallel cohort study collected data between January 2018 and December 2022. Participants were evaluated 3 times with ∼12-18 months between visits. Participants included 65 girls with FXS, 6 to 16 years, and 52 age- and developmentally-matched girls without FXS. Participants' scores from direct assessment and caregiver report evaluated 3 cognitive domains (verbal abilities, nonverbal abilities, executive function) and 4 social-emotional domains (depression, general anxiety, social behavior, and social anxiety). RESULTS: Participants included 117 girls (mean [M] [SD] age at study entry: FXS M = 10.59 [3.00]; comparison M = 10.45 [2.40])). Omnibus tests showed 4 domains with significant group differences: Verbal (P < .0001, eg, Differential Abilities Scale-II(DAS-II), Picture Vocabulary (-6.25 [1.87])), nonverbal (P < .0001, eg, Kaufman Test of Educational Achievement, Third Edition, Brief Form, Math (-8.56 [2.90])), executive function (P < .0001, eg, NIH Toolbox List Sorting (-6.26 [1.48])), and social anxiety (P < .03, eg, Anxiety, Depression, and Mood Scale (ADAMS) Social Avoidance (1.50 [0.65])). Three domains had significant group by age interaction: Verbal (P < .04, eg, DAS-II, Word Definitions (-1.33 [0.55])), social behavior (P < .01, eg, Social Responsiveness Scale-2 Social Communication (1.57 [0.51])), and social anxiety (P < .01, eg, ADAMS Social Avoidance (0.46 [0.19])). CONCLUSIONS: These findings support the development of early, disorder specific interventions for girls with FXS targeting verbal and nonverbal skills, executive function, social behavior, and social anxiety.

Cognition, Academic Achievement, Adaptive Behavior, and Quality of Life in Child and Adolescent Boys with Klinefelter Syndrome.

OBJECTIVE: Klinefelter syndrome (KS; 47, XXY), the most common sex chromosome aneuploidy in males, is characterized by testicular failure and testosterone deficiency as well as a variety of cognitive, social, and emotional challenges. In the current study, we aimed to clarify the cognitive-behavioral profile of peripubertal boys with KS using measures of cognition, academic achievement, adaptive behavior, and quality of life. METHOD: We compared 47 boys with KS (7-16 years of age) with 55 performance IQ-matched boys without KS on measures of cognition (WISC-V), executive function (BRIEF-2), academic achievement (KTEA-3), adaptive behavior (Vineland-3), and quality of life (PROMIS). In exploratory analyses, we examined associations among these measures and potential associations with pubertal metrics. RESULTS: Boys with KS demonstrated a significantly different profile of cognition, behavioral ratings of executive function, academic achievement, adaptive behavior, and quality of life compared with their typically developing peers, with, on average, lower functioning. The groups showed significantly different correlations between cognition and aspects of quality of life. No associations were observed between behavior and pubertal development. CONCLUSION: Taken together, these findings indicated that boys with KS are at increased risk for cognitive difficulties, which may affect academic achievement, adaptive behavior, and quality of life. Although initial exploratory analyses indicated that the magnitude of these alterations was not correlated with severity of testicular failure, longitudinal analyses currently being conducted by our group may help clarify the trajectory of these difficulties through the pubertal transition and testosterone replacement.

Cognition, academic achievement, and adaptive behavior in school-aged girls with fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism in males and females. Females with FXS typically display a milder cognitive phenotype than males, despite experiencing significant developmental, behavioral, and social-emotional issues. AIMS: To measure and distinguish the cognitive-behavioral profile of girls with FXS relative to verbal IQ-matched peers. METHODS AND PROCEDURES: Ninety-seven participants (NFXS=55, Ncomparison=42) six to 16 years of age completed assessments evaluating cognition, academic achievement, and adaptive behavior. The comparison group consisted of age-, sex-, and verbal IQ-matched peers. OUTCOMES AND RESULTS: Consistent with previous studies, the FXS group demonstrated mean cognitive skills, academic achievement, and adaptive behavior in the borderline to low average range. On average, the FXS group showed poorer nonverbal reasoning, visual pattern recognition, verbal abstraction, math abilities, attention, inhibitory control, and working memory than the comparison group. There were no significant group differences in adaptive behavior. Different patterns of associations between cognition and selected outcomes emerged in each group. CONCLUSIONS AND IMPLICATIONS: Results highlight the importance of identifying specific cognitive-behavioral profiles in girls with FXS to inform more targeted interventions for optimizing outcomes and quality of life in this population.

Anxiety, Depression, and Social Skills in Girls with Fragile X Syndrome: Understanding the Cycle to Improve Outcomes.

OBJECTIVE: Female patients with fragile X syndrome (FXS), a genetic condition associated with a mutation in the FMR1 gene, are at significantly elevated risk for developing anxiety and depression. This study is designed to better understand these symptoms in school-age girls, particularly as they relate to age, social skills, and functional outcomes. METHODS: We compared 58 girls aged 6 to 16 years with FXS with 46 age-matched, sex-matched, and developmentally matched peers without FXS on measures of anxiety, depression, social skills, adaptive behavior, and quality of life. RESULTS: Girls with FXS 10.5 years and older demonstrated significantly higher levels of depression, withdrawal, and social avoidance than girls younger than 10.5 years with FXS ( p -values < 0.01). Girls in the comparison group did not show any age-related differences on these measures. The older FXS cohort also showed associations between social communication and interaction skills, adaptive behavior, and measures of anxiety and depression ( p -values < 0.05) not seen in the comparison group, regardless of age. CONCLUSION: We found that age seems to play an important role in the development of mood symptoms and that such symptoms are uniquely correlated with social communication and reciprocal social interaction behaviors and adaptive functioning in girls with FXS after puberty. These data suggest a critical window of intervention for girls with FXS in the improvement of social interaction skills and the prevention of social avoidance and symptoms of anxiety and depression, with the ultimate goal of improving quality of life and promoting greater independence.