Toward better characterization of restricted and repetitive behaviors in individuals with germline heterozygous PTEN mutations

Abstract

This study aimed to further our understanding of restricted and repetitive behaviors (RRB) among individuals with germline pathogenic mutations in PTEN by providing multimethod characterization and comparison of key RRB subdomains across individuals with PTEN mutations with autism spectrum disorder (ASD) (PTEN‐ASD), with PTEN mutations without ASD (PTEN‐No ASD) and with ASD and macrocephaly but without PTEN mutations (Macro‐ASD). Of 86 total research participants, 38 had PTEN‐ASD (Mage = 8.93 years, SDage = 4.75), 25 Macro‐ASD (Mage = 11.99 years; SDage = 5.15), and 23 PTEN‐No ASD (Mage = 8.94 years; SDage = 4.85). The Repetitive Behavior Scale‐Revised (RBS‐R) and the Autism Diagnostic Interview‐Revised (ADI‐R) were used as measures of distinct RRB domains. There were significant group differences in the RBS‐R repetitive motor behaviors (RMB; F = 4.52, p = 0.014, ω2 = 0.08), insistence on sameness (IS; F = 4.11, p = 0.02, ω2 = 0.05), and circumscribed interests (CI; F = 7.80, p = 0.001, ω2 = 0.14) scales. Post hoc comparisons showed that the PTEN‐No ASD group had significantly lower RMB, IS, and CI scores compared to both PTEN‐ASD and Macro‐ASD groups. Importantly, PTEN‐No ASD group still showed elevated RRB levels. Furthermore, there was a portion of individuals in PTEN‐No ASD group whose Full‐Scale Intelligence Quotient (FSIQ) was >70 that did not show floor level scores in the RMB domain. After adjusting for age and FSIQ scores, group differences were no longer statistically significant. RMB, IS, and CI domains showed distinct association patterns with sex, age, and FSIQ. This investigation provides the largest and most comprehensive characterization of distinct RRB domains in individuals with PTEN mutations to date. Despite the limitations, our findings have important assessment and treatment implications.

Development of informant‐report neurobehavioral survey scales for PTEN hamartoma tumor syndrome and related neurodevelopmental genetic syndromes

“…The pronounced variability and complexity in the profiles of NDD and NPD symptoms, cognitive processing, and adaptive abilities seen in individuals with PHTS (Balci et al, 2018; Busch et al, 2013, 2019; Frazier et al, 2015; Frazier et al, 2021; Hansen‐Kiss et al, 2017; Hobert et al, 2014; Steele et al, 2021; Uljarevic et al, 2021a, 2021b) and other NDGS (Agarwal et al, 2019; Arnett et al, 2018; Berryer et al, 2013; Jimenez‐Gomez et al, 2019; Mulder et al, 2020; Parker et al, 2015; Rai et al, 2018) present a significant assessment challenge. Although a range of currently available and widely‐used instruments have been developed to capture discrete clinical presentations in PHTS and other NGDS, including ASD, ADHD, internalizing and externalizing symptoms, these tools tend to evaluate either a single broad construct or only a subset of relevant symptoms or behaviors.…”

“…Social communication/interaction, daily living skills, executive functioning, and quality of life levels tended to fall 1-2SD below the control mean, and motor skills fell more than 3SD below the control mean. The pronounced variability and complexity in the profiles of NDD and NPD symptoms, cognitive processing, and adaptive abilities seen in individuals with PHTS (Balci et al, 2018;Busch et al, 2013Busch et al, , 2019Frazier et al, 2015;Frazier et al, 2021;Hansen-Kiss et al, 2017;Hobert et al, 2014;Steele et al, 2021;Uljarevic et al, 2021aUljarevic et al, , 2021b and other NDGS (Agarwal et al, 2019;Arnett et al, 2018;Berryer et al, 2013;Jimenez-Gomez et al, 2019;Mulder et al, 2020;Parker et al, 2015;Rai et al, 2018) present a significant assessment challenge. Although a range of currently available and widely-used instruments have been developed to capture discrete clinical presentations T A B L E 2 Factor analysis results by survey scale.…”

“…The heterogenous PHTS clinical phenotype and pronounced variability and interplay between NDD and NPD symptoms, cognitive processing, and adaptive functioning present a particular assessment challenge. For instance, a recent study found that individuals with PHTS exhibited highly variable but significantly elevated levels of restricted and repetitive behaviors (RRB), regardless of the primary diagnosis (e.g., presence or absence of ASD) and cognitive functioning level (Uljarevic et al, 2021b). Levels of RRB and other clinical symptoms, including anxiety, have also been linked to difficulties in executive functioning in PHTS (Uljarevic et al, 2021a), emphasizing the need for simultaneous assessment of multiple domains.…”