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A variety of genetic disorders of known etiology present with behavioral profiles similar to that described in autism spectrum disorders (ASDs). Although some of these disorders are more likely to be associated with a comorbid ASD diagnosis, there exist cases in which there is a lack of empirical evidence to support a dual diagnosis. Two disorders, Williams syndrome (WS) and 15q13.3 deletion syndrome, have both been reported in the literature as examples of this phenotypic overlap. We present a case study of a young child with both WS and 15q13.3 deletion syndrome and significant ASD-related symptomatology. The results of a developmental evaluation, specifically the rationale for ruling out a comorbid ASD, are the focus of the present report. Implications for careful diagnostic consideration in cases of patients with known genetic conditions are also discussed. [ABSTRACT FROM AUTHOR]

Children with neurofibromatosis-1 (NF1), a neurodevelopmental disorder resulting from a mutation of the NF1 gene (17q11.2), often have difficulties with learning and attention, but there is little research in the early childhood years. In this study, the cognitive and psychosocial functioning of 40 young children with NF1 (ages 3 through 6) was examined and compared both to normative data and to a contrast group comprised of unaffected siblings and community members matched for age and socio-economic status (n = 37). Children with NF1 showed significantly weaker cognitive abilities across all domains and for the vast majority of subtests. Consistent with research in older children, a variety of patterns of intra-individual strength and weakness were present for young children with NF1. Few significant group differences in psychosocial functioning were observed, but the children with NF1 showed significantly greater functional communication problems than did the unaffected group. Overall, the results indicate that in participant groups matched for age and socioeconomic status, cognitive vulnerabilities are evident for close to half of young children with NF1, with some relations to psychosocial functioning, particularly functional communication, attention problems and social skills. (JINS, 2014, 1, 1–11) [ABSTRACT FROM AUTHOR]

The present study investigated the performance of children with neurofibromatosis type 1 on computerized assessments of attention and executive function. Relations to ADHD symptomatology were also examined. Participants included 37 children (20 male) with NF1 (9–13 years; Mage = 11.02). Participants completed the NIH Toolbox Dimensional Change Card Sort, List Sort Working Memory (LSWM), and Flanker tasks, as well as Cogstate Identification and One Back tests. ADHD symptomatology was assessed using the K-SADS. Average performance was significantly different from the normative mean on every measure, except LSWM. The NIH Toolbox Flanker and Cogstate Identification tasks detected the highest proportion of participants with at least mild difficulty, and the Cogstate Identification task detected the highest proportion of participants with severe difficulty. Analyses revealed significant relations with ADHD symptomatology for two NIH toolbox tasks. The various computerized measures of attention and executive function offer different information when working with school age children with NF1. The NIH Flanker may offer the most room for change and offers face validity, which may be beneficial for clinical trials research. However, the LSWM shows most support for relations with behavioral indicators of attention and executive challenges. [ABSTRACT FROM AUTHOR]

There has been a good deal of attention on elevated rates of autism spectrum disorder (ASD) among individuals with neurofibromatosis type 1 (NF1).1,2 Morotti et al.3 argue for a reconsideration of the interpretation of data about ASD symptoms in NF1, based both on a methodological critique of the current literature and on empirical examination of ASD and behavior problem symptom patterns in comparison to children with idiopathic ASD. However, if ASD symptomatology in NF1 is generally differentially related to problem behavior then it is worth considering that observed difficulties on measures of ASD may not be reflective of ASD per se. J Child Psychol Psychiatry 2013; 54: 216 - 24. 5 Grzadzinski R, Dick C, Lord C, Bishop S. Parent-reported and clinician-observed autism spectrum disorder (ASD) symptoms in children with attention deficit/hyperactivity disorder (ADHD): Implications for practice under DSM-5. [Extracted from the article]

Objective: The purpose of the present study is to characterize the trajectory of internalizing and externalizing behaviors in children with NF1 longitudinally from the early childhood period to the school age period on a broad psychosocial norm-referenced measure using linear mixed model growth curves. Participants and Methods: Children with NF1 (n=28) were seen at least once between the ages of 3-8 years old and then again between the ages of 9-13 years old. Parents completed the Behavior Assessment System for Children (BASC) Second Edition; the version of the BASC administered depended on age (i.e., preschool form or child form). Linear mixed model growth curve analyses were used to examine the developmental trajectories of children with NF1 on the following scales, which were selected due to findings in the literature: Externalizing Problems, Internalizing Problems, Hyperactivity, Anxiety, Depression, Attention, and Executive Function. T-scores (M=50, SD=10) were used. Higher scores indicate more challenges. Results: By using loess lines to qualitatively describe the patterns of ratings across time, it is evident that most scales (Externalizing Problems, Internalizing Problems, Hyperactivity, Attention Problems, Executive Function) demonstrated curvilinear trajectory patterns, with scores peaking in the 8-10-year-old range, then decreasing again. However, there was no statistically significant effect of age on any of the scales. Notably, trajectories largely included standard scores within the normative range (T-scores between 45-55). Conclusions: Overall, the models also suggest that most children with NF1 are within the average range of functioning on all scales examined across the childhood period. Furthermore, with the exception of the Depression and Anxiety scales, ratings tend to peak around the 8-10-year period, and then decrease into early adolescence. Thus, when working with patients with NF1, it may be the case that clinicians note relative increases in challenges across these domains in late childhood, though these challenges may decrease over time during this age range. Linear growth curve modeling identified that the developmental trajectories of internalizing and externalizing behaviors of children with NF1, as rated by parents, remain stable across the childhood period. Importantly, low power may have contributed to the lack of observed age effects. Longitudinal research would be beneficial to capture patterns that may emerge in adolescence or adulthood. [ABSTRACT FROM AUTHOR]

Background: Interventions for social difficulties have not been investigated in the neurofibromatosis type 1 (NF1) population despite observations of elevated rates of social difficulties. In this pilot study, the effectiveness of a 14-week telehealth PEERS® intervention with nineteen adolescents with NF1 (Mage=13.79 years, SD = 1.32) with social skills difficulties was examined. Measures of social outcomes were completed at three timepoints (before, immediately after, and at 14-week follow-up). Results: Caregiver-reported social-emotional skills, social impairment, caregiver-reported number of adolescent get-togethers, and teen social knowledge showed significant improvement following the intervention. Conclusions: The PEERS® intervention is promising to support the social and friendship skills of adolescents with NF1 who have social difficulties. [ABSTRACT FROM AUTHOR]

A systematic review was conducted to determine the scope and nature of the literature for adolescents with neurofibromatosis type 1 (NF1) by (1) characterizing the NF1 cognitive and psychosocial literature focusing on adolescence; (2) examining the risk of bias within the available literature; and (3) describing the extent to which the literature provides demographic information. Forty articles included adolescents in their samples, though most did not focus on adolescence specifically. This review underscores gaps in our understanding of cognitive and behavioral functioning and in reporting relevant demographic information at this critical developmental timepoint. [ABSTRACT FROM AUTHOR]

Objective: Social functioning patterns vary across measures in children with neurofibromatosis type 1 (NF1; Glad et al., 2021) with broad psychosocial screening measures having shown no impairment (Klein-Tasman et al., 2014; Martin et al., 2012; Sangster et al., 2011) while a more specific social functioning measure indicated poorer social skills (Barton & North, 2004; Huijbregts & de Sonneville, 2011; Loitfelder et al., 2015). The current aims were to characterize caregiver-reported social skills using three different measures and determine which measure appears to best capture social difficulties for young children with NF1. Participants and Methods: Fifty children with NF1 (31 males; M=3.96, SD=1.05) and 20 unaffected siblings (11 males; M =4.34, SD =0.88) in early childhood (ages 3-6) were rated by a caregiver on one social functioning measure (the Social Skills scale on the Social Skills Rating System (SSRS)) and two broader functioning measures that include assessment of social functioning (the Social Skills scale on the Behavior Assessment System for Children-Second Edition (BASC-2), Social Interaction and Communication domain on the Scales of Independent Behavior-Revised (SIB-R)). Results: For children with NF1, the SSRS mean standard score was significantly lower than the BASC-2 and SIB-R (f=-5.11, p<.001; f=-4.63, p<.001) while there was no significant difference between the BASC-2 and SIB-R. No significant differences emerged between measures for unaffected siblings. No significant group differences in mean standard score were found for the SSRS, BASC-2 or SIB-R. Fisher's exact tests revealed the NF1 group had significantly more frequent difficulties than unaffected siblings on the BASC-2 (p=.017) but not on the SSRS or SIB-R. For both groups, Cochran's Q tests determined a significant difference in the proportion of identified social difficulties across measures (NF1: X2(2)=16.33, p<.001; Siblings: X2(2)=9.25, p=.01). Follow up McNemar's tests demonstrated significantly more difficulties reported on the SSRS compared to the BASC-2 for both groups (NF1: p<.001; Siblings: p=.016). Significantly more frequent difficulties were also reported on the SSRS compared to the SIB-R for the NF1 group (p=.002) but not for the unaffected siblings group. No difference in the frequency of difficulties was evident between the BASC-2 and SIB-R for either group. Conclusions: Social skills difficulties appear to be best captured using the SSRS in young children, particularly for children with NF1 as this measure resulted in the lowest mean score and the greatest frequency of difficulties observed within the NF1 group. However, it is notable that group differences in comparison to unaffected siblings were not observed in mean score or frequency of difficulties, such that these young children with NF1 are not showing marked social challenges but rather, social difficulties may be mild when present at this age. Nevertheless, using a measure that specifically targets social functioning, rather than a measure where social functioning is merely a component of a broad measure, appears beneficial to capturing social difficulty. Using measures that best capture social difficulties will contribute to early identification and assessment of intervention effectiveness. Further work with additional age ranges and longitudinal trajectory is needed. [ABSTRACT FROM AUTHOR]

Background: 7q11.23 duplication (Dup7) is one of the most frequent recurrent copy number variants (CNVs) in individuals with autism spectrum disorder (ASD), but based on gold-standard assessments, only 19% of Dup7 carriers have ASD, suggesting that additional genetic factors are necessary to manifest the ASD phenotype. To assess the contribution of additional genetic variants to the Dup7 phenotype, we conducted whole-genome sequencing analysis of 20 Dup7 carriers: nine with ASD (Dup7-ASD) and 11 without ASD (Dup7-non-ASD).Results: We identified three rare variants of potential clinical relevance for ASD: a 1q21.1 microdeletion (Dup7-non-ASD) and two deletions which disrupted IMMP2L (one Dup7-ASD, one Dup7-non-ASD). There were no significant differences in gene-set or pathway variant burden between the Dup7-ASD and Dup7-non-ASD groups. However, overall intellectual ability negatively correlated with the number of rare loss-of-function variants present in nervous system development and membrane component pathways, and adaptive behaviour standard scores negatively correlated with the number of low-frequency likely-damaging missense variants found in genes expressed in the prenatal human brain. ASD severity positively correlated with the number of low frequency loss-of-function variants impacting genes expressed at low levels in the brain, and genes with a low level of intolerance.Conclusions: Our study suggests that in the presence of the same pathogenic Dup7 variant, rare and low frequency genetic variants act additively to contribute to components of the overall Dup7 phenotype. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to explore relations between speech sound disorder severity and selective mutism in a group of children with 7q11.23 duplication syndrome (Dup7), a genetic condition predisposing children to childhood apraxia of speech (CAS) and other speech sound disorders and to anxiety disorders, including selective mutism and social anxiety disorder., Method: Forty-nine children aged 4-17 years with genetically confirmed Dup7 completed the Goldman-Fristoe Test of Articulation-Second Edition (GFTA-2), the Expressive Vocabulary Test-Second Edition (EVT-2), and the Differential Ability Scales-Second Edition (DAS-II). Parents completed the Anxiety Disorders Interview Schedule-Parent (ADIS-P)., Results: Mean standard scores (SSs) were 65.67 for the GFTA-2, 92.73 for the EVT-2, and 82.69 for the DAS-II General Conceptual Ability (GCA; similar to IQ). Standard deviations for all measures were larger than for the general population. GFTA-2 SS was significantly correlated with both EVT-2 SS and DAS-II GCA. Based on the ADIS-P, 22 participants (45%) were diagnosed with selective mutism and 29 (59%) were diagnosed with social anxiety disorder. No significant differences in performance on any of the measures were found either between the group with a selective mutism diagnosis and the group that did not have selective mutism or between the group with a selective mutism and/or social anxiety disorder diagnosis and the group that did not have either disorder., Conclusions: For children with Dup7, neither the diagnosis of selective mutism nor the diagnosis of selective mutism and/or social anxiety disorder was related to severity of speech sound disorder, expressive vocabulary ability, or overall intellectual ability. Accordingly, treatment for speech sound disorder alone is unlikely to lead to remission of selective mutism or social anxiety disorder. Instead, selective mutism and/or social anxiety disorder should be treated directly. Further research is needed to determine if these findings generalize to other populations, such as children with idiopathic CAS.

Objective: Elevated rates of social difficulties are evident for children and adolescents with neurofibromatosis type 1 (NF1) but the effects of social skills interventions have not been investigated for this population. The Program for the Education and Enrichment of Relational Skills (PEERS®), a widely established social skills intervention in autism spectrum disorders with expansion to other conditions, was recently modified to be offered virtually. This study examined the feasibility and acceptability of this telehealth intervention., Methods: 27 adolescents with NF1 with social skills difficulties and at least 1 caregiver enrolled in the study. 19 of those participants (Mage = 14.21 years, SD = 1.63; 7 females; 79% White) completed PEERS® via telehealth in a single-arm pilot study. Dropout rates, attendance records, helpfulness of the curriculum topics and caregiver-reported acceptability, including ratings on the Treatment Acceptability Questionnaire, were examined., Results: Low study drop out (30% of enrolled participants; 14% of participants who began the intervention) and high attendance rates were observed. Caregivers found sessions related to common, everyday interactions most helpful. Adolescents indicated sessions related to having get-togethers and social nuances (e.g., humor) as most helpful. Caregiver ratings indicated acceptability of the intervention., Conclusions: This investigation supported the feasibility and acceptability of telehealth PEERS®, a social skills intervention program, among adolescents with NF1 and their caregivers based on attendance patterns as well as appraisal of the curriculum and telehealth modality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Williams-Beuren syndrome (WBS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders caused by deletion and duplication of a 1.5 Mb region that includes at least five genes with a known role in epigenetic regulation. We have shown that CNV of this chromosome segment causes dose-dependent, genome-wide changes in DNA methylation, but the specific genes driving these changes are unknown. We measured genome-wide whole blood DNA methylation in six participants with atypical CNV of 7q11.23 (three with deletions and three with duplications) using the Illumina HumanMethylation450k array and compared their profiles with those from groups of individuals with classic WBS or classic Dup7 and with typically developing (TD) controls. Across the top 1000 most variable positions we found that only the atypical rearrangements that changed the copy number of GTF2IRD1 and/or GTF2I (coding for the TFII-IRD1 and TFII-I proteins) clustered with their respective syndromic cohorts. This finding was supported by results from hierarchical clustering across a selection of differentially methylated CpGs, in addition to pyrosequencing validation. These findings suggest that CNV of the GTF2I genes at the telomeric end of the 7q11.23 interval is a key contributor to the large changes in DNA methylation that are seen in blood DNA from our WBS and Dup7 cohorts, compared to TD controls. Our findings suggest that members of the TFII-I protein family are involved in epigenetic processes that alter DNA methylation on a genome-wide level., (© 2023. Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.)

Objective: 7q11.23 duplication syndrome (Dup7) is a genetic disorder with a variable phenotype associated with cognitive and behavioral characteristics including a high incidence of expressive language difficulties, social anxiety, and oppositional or disruptive behavior. Correlates of aggression and oppositionality were examined., Method: Participants were 63 children with genetically confirmed Dup7 between the ages of 4 and 17 years. A multimethod, multi-informant approach was used to assess aggression and oppositional behavior, and the contributions of cognitive functioning, expressive language, autism spectrum, social anxiety, and hyperactivity/impulsivity (H/I) symptomatology were considered., Results: Elevated levels of aggression and oppositional behavior were found. Cognitive functioning, expressive language, and autism spectrum disorder symptomatology were not significantly related to parent ratings of aggression, although young children who had language and nonverbal cognitive delays were most likely to demonstrate examiner-observed aggression. Social anxiety and H/I symptomatology were related to defiant/aggressive and oppositional behavior., Conclusion: Genes in the 7q11.23 region duplicated in Dup7, in transaction with the environment, may contribute to aggressive and oppositional behavior., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Children with neurofibromatosis type 1 (NF1) often demonstrate difficulties with attention and executive functioning that can be evident starting at a young age. There has been little research about which measures of attention are most suitable for use with young children with NF1. This pilot study explored several computerized measures of attention, a digits forward task, and parent report measures of attention to compare their reliability, validity, and the degree to which they capture attention difficulty in this population. Participants with NF1 ages 4 to 6 years were seen for one ( n= 2) or two ( n= 18) time points. Statistical analyses for evaluating evidence for test-retest reliability, convergent and discriminant validity, practice effects, and identification of difficulties were conducted. Each measure demonstrated relative strengths and weaknesses, and there may not be a "one size fits all" measure for use with young children with NF1. However, the Behavior Rating Inventory of Executive Function Preschool/Second Edition, Conners Early Childhood Inattention/Hyperactivity Scale, and the Conners Kiddie Continuous Performance Test Second Edition generally had the highest reliability and most evidence of validity. More specific recommendations are provided for the appropriate measure to use in clinical and research batteries., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to American Academy of Pediatric Neuropsychology 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Neurofibromatosis type 1 (NF1) is associated with neurocognitive deficits that can impact everyday functioning of children, adolescents, and adults with this disease. However, there is little agreement regarding measures to use as cognitive endpoints in clinical trials. This article describes the work of the Neurocognitive Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration. The goal of this committee is to identify standardized and specific cognitive assessment tools for use in NF clinical trials. The committee first identified cognitive domains relevant to NF1 and prioritized attention as the first domain of focus given prior and current trends in NF1 cognitive clinical trials. Performance measures and behavioral rating questionnaires of attention were reviewed by the group using established criteria to assess patient characteristics, psychometric properties, and feasibility. The highest rated tests underwent side-by-side comparison. The Digit Span subtest from the Wechsler scales was given the highest ratings of the performance measures due to its good psychometrics, feasibility, utility across a wide age range, and extensive use in previous research. The Conners scales achieved the highest ratings of the behavioral questionnaires for similar reasons. Future articles will focus on other cognitive domains, with the ultimate goal of achieving agreement for cognitive endpoints that can be used across NF clinical trials., (© 2016 American Academy of Neurology.)