Williams syndrome (WS) is a neurodevelopmental disorder that results from a heterozygous microdeletion on chromosome 7q11.23. Most of the time, the affected region contains ~1.5 Mb of sequence encoding approximately 24 genes. Some 5–8% of patients with WS have a deletion exceeding 1.8 Mb, thereby affecting two additional genes, including GTF2IRD2. Currently, there is no consensus regarding the implications of GTF2IRD2 loss for the neuropsychological phenotype of WS patients. Objectives: The present study aimed to identify the role of GTF2IRD2 in the cognitive, behavioral, and adaptive profile of WS patients. Methods: Twelve patients diagnosed with WS participated, four with GTF2IRD2 deletion (atypical WS group), and eight without this deletion (typical WS group). The age range of both groups was 7–18 years old. Each patient’s 7q11.23 deletion scope was determined by chromosomal microarray analysis. Cognitive, behavioral, and adaptive abilities were assessed with a battery of neuropsychological tests. Results: Compared with the typical WS group, the atypical WS patients with GTF2IRD2 deletion had more impaired visuospatial abilities and more significant behavioral problems, mainly related to the construct of social cognition. Conclusions: These findings provide new evidence regarding the influence of the GTF2IRD2 gene on the severity of behavioral symptoms of WS related to social cognition and certain visuospatial abilities. (JINS, 2018, 24, 896–904)

Objective: While individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk for a variety of functional impairments and psychiatric disorders, including psychosis, not all individuals with 22q11DS experience negative outcomes. Efforts to further understand which childhood variables best predict adult functional outcomes are needed, especially those that investigate childhood executive functioning abilities. Methods: This longitudinal study followed 63 individuals with 22q11DS and 43 control participants over 9 years. Childhood executive functioning ability was assessed using both rater-based and performance-based measures and tested as predictors of young adult outcomes. Results: Childhood global executive functioning abilities and parent report of child executive functioning abilities were the most consistent predictors of young adult outcomes. The study group moderated the relationship between child executive functioning and young adult outcomes for several outcomes such that the relationships were stronger in the 22q11DS sample. Conclusion: Rater-based and performance-based measures of childhood executive functioning abilities predicted young adult outcomes in individuals with and without 22q11DS. Executive functioning could be a valuable target for treatment in children with 22q11DS for improving not only childhood functioning but also adult outcomes. (JINS, 2018, 24, 905–916)

Objectives: Past research suggests that youth with sex chromosome aneuploidies (SCAs) present with verbal fluency deficits. However, most studies have focused on sex chromosome trisomies. Far less is known about sex chromosome tetrasomies and pentasomies. Thus, the current research sought to characterize verbal fluency performance among youth with sex chromosome trisomies, tetrasomies, and pentasomies by contrasting how performance varies as a function of extra X number and X versus Y status. Methods: Participants included 79 youth with SCAs and 42 typically developing controls matched on age, maternal education, and racial/ethnic background. Participants completed the phonemic and semantic conditions of a verbal fluency task and an abbreviated intelligence test. Results: Both supernumerary X and Y chromosomes were associated with verbal fluency deficits relative to controls. These impairments increased as a function of the number of extra X chromosomes, and the pattern of impairments on phonemic and semantic fluency differed for those with a supernumerary X versus Y chromosome. Whereas one supernumerary Y chromosome was associated with similar performance across fluency conditions, one supernumerary X chromosome was associated with relatively stronger semantic than phonemic fluency skills. Conclusions: Verbal fluency skills in youth with supernumerary X and Y chromosomes are impaired relative to controls. However, the degree of impairment varies across groups and task condition. Further research into the cognitive underpinnings of verbal fluency in youth with SCAs may provide insights into their verbal fluency deficits and help guide future treatments. (JINS, 2018, 24, 917–927)

Objectives: To examine academic performance in dystrophinopathy as a function of dystrophin gene mutation position as well as intellectual function, executive skills, socioeconomic status (SES), behavior, and physical ability. Methods: In a cross-sectional study, boys with dystrophinopathy (ages 5–17; n=50) completed tests of academics (Woodcock-Johnson-III: spelling, reading, calculation and total scores), executive functioning (selective attention/inhibitory control, set shifting, working memory, and processing speed), single word comprehension and nonverbal reasoning. Motor skills were assessed and parents provided demographic information and child behavioral assessments. Dystrophin gene mutation positions were dichotomized into groups (upstream versus downstream of exon 43, location of isoforms previously linked to intellectual impairment). Genetic mutation groups were compared on measures of academic achievement, and multiple regression analyses examined unique and joint contributions of executive skills, intelligence quotient (IQ), SES, motor abilities, behavior, and mutation positions to academic outcomes. Results: Academic performance was slightly, yet significantly, lower than IQ and varied as a function of dystrophin gene position, wherein boys possessing the downstream mutation exhibited greater impairment than boys with the upstream mutation. Digit span forward (indexing verbal span), but no other measure of executive function, contributed significant variance to total academic achievement, spelling and calculation. Conclusions: Weak academic performance is associated with dystrophinopathy and is more common in downstream mutations. A specific deficit in verbal span may underlie inefficiencies observed in children with dystrophinopathy and may drive deficits impacting academic abilities. (JINS, 2018, 24, 928–938)

Objectives: As the number of adolescents and young adults (AYAs) surviving congenital heart disease (CHD) grows, studies of long-term outcomes are needed. CHD research documents poor executive function (EF) and cerebellum (CB) abnormalities in children. We examined whether AYAs with CHD exhibit reduced EF and CB volumes. We hypothesized a double dissociation such that the posterior CB is related to EF while the anterior CB is related to motor function. We also investigated whether the CB contributes to EF above and beyond processing speed. Methods: Twenty-two AYAs with CHD and 22 matched healthy controls underwent magnetic resonance imaging and assessment of EF, processing speed, and motor function. Volumetric data were calculated using a cerebellar atlas (SUIT) developed for SPM. Group differences were compared with t tests, relationships were tested with Pearson’s correlations and Fisher’s r to z transformation, and hierarchical regression was used to test the CB’s unique contributions to EF. Results: CHD patients had reduced CB total, lobular, and white matter volume (d=.52–.99) and poorer EF (d=.79–1.01) compared to controls. Significant correlations between the posterior CB and EF (r=.29–.48) were identified but there were no relationships between the anterior CB and motor function nor EF. The posterior CB predicted EF above and beyond processing speed (ps<.001). Conclusions: This study identified a relationship between the posterior CB and EF, which appears to be particularly important for inhibitory processes and abstract reasoning. The unique CB contribution to EF above and beyond processing speed alone warrants further study. (JINS, 2018, 24, 939–948)

Objectives: Children with sickle cell anemia (SCA) are commonly reported to experience executive dysfunction. However, the development of executive function (EF) in preschool-age children without stroke in this patient population has not been investigated so it is unclear when and how these deficits emerge. Methods: This case-control study examines the feasibility of assessing the early development of executive functioning in 22 preschool children years with SCA in the domains of processing speed, working memory, attention, inhibitory control, and cognitive flexibility, as well as everyday function, in comparison to matched control children. Results: A pattern of potential deficits in early emerging executive skills was observed in the domains of inhibitory control and cognitive flexibility. Parents reported no differences for everyday EF and no significant differences were observed for working memory and processing speed. Conclusions: Results suggest that deficits in everyday executive difficulties, working memory, and processing speed, as commonly reported for older children with SCA, may not yet have emerged at this early developmental stage, despite specific deficits in cognitive flexibility and inhibitory control on behavioral measures. The feasibility of using available executive measures with preschool age children to characterize the development of early EF skills is discussed. (JINS, 2018, 24, 949–954)

Objectives: Down syndrome (DS) is a population with known hippocampal impairment, with studies showing that individuals with DS display difficulties in spatial navigation and remembering arbitrary bindings. Recent research has also demonstrated the importance of the hippocampus for novel word-learning. Based on these data, we aimed to determine whether individuals with DS show deficits in learning new labels and if they may benefit from encoding conditions thought to be less reliant on hippocampal function (i.e., through fast mapping). Methods: In the current study, we examined immediate, 5-min, and 1-week delayed word-learning across two learning conditions (e.g., explicit encoding vs. fast mapping). These conditions were examined across groups (twenty-six 3- to 5-year-old typically developing children and twenty-six 11- to 28-year-old individuals with DS with comparable verbal and nonverbal scores on the Kaufman Brief Intelligence Test – second edition) and in reference to sleep quality. Results: Both individuals with and without DS showed retention after a 1-week delay, and the current study found no benefit of the fast mapping condition in either group contrary to our expectations. Eye tracking data showed that preferential eye movements to target words were not present immediately but emerged after 1-week in both groups. Furthermore, sleep measures collected via actigraphy did not relate to retention in either group. Conclusions: This study presents novel data on long-term knowledge retention in reference to sleep patterns in DS and adds to a body of knowledge helping us to understand the processes of word-learning in typical and atypically developing populations. (JINS, 2018, 24, 955–965)

Objectives: As surprisingly little is known about the developing brain studied in vivo in youth with Down syndrome (DS), the current review summarizes the small DS pediatric structural neuroimaging literature and begins to contextualize existing research within a developmental framework. Methods: A systematic review of the literature was completed, effect sizes from published studies were reviewed, and results are presented with respect to the DS cognitive behavioral phenotype and typical brain development. Results: The majority of DS structural neuroimaging studies describe gross differences in brain morphometry and do not use advanced neuroimaging methods to provide nuanced descriptions of the brain. There is evidence for smaller total brain volume (TBV), total gray matter (GM) and white matter, cortical lobar, hippocampal, and cerebellar volumes. When reductions in TBV are accounted for, specific reductions are noted in subregions of the frontal lobe, temporal lobe, cerebellum, and hippocampus. A review of cortical lobar effect sizes reveals mostly large effect sizes from early childhood through adolescence. However, deviance is smaller in adolescence. Despite these smaller effects, frontal GM continues to be largely deviant in adolescence. An examination of age-frontal GM relations using effect sizes from published studies and data from Lee et al. (2016) reveals that while there is a strong inverse relationship between age and frontal GM volume in controls across childhood and adolescence, this is not observed in DS. Conclusions: Further developmentally focused research, ideally using longitudinal neuroimaging, is needed to elucidate the nature of the DS neuroanatomic phenotype during childhood and adolescence. (JINS, 2018, 24, 966–976)

Objectives: Neurofibromatosis type 1 (NF1) is a genetic disorder in which the most frequent complication in children is learning disabilities. Over the past decade, growing arguments support the idea that executive dysfunction is a core deficit in children with NF1. However, some data remain inconsistent. The aim of this study was to determine the magnitude of impairment for each executive function (EF) and clarify the impact of methodological choices and participant’s characteristics on EFs. Methods: In this meta-analysis, 19 studies met the selection criteria and were included with data from a total of 805 children with NF1 and 667 controls. Based on the Diamond’s model (2013), EF measures were coded separately according to the following EF components: working memory, inhibitory control, cognitive flexibility, planning/problem solving. The review protocol was registered with PROSPERO (International prospective register of systematic reviews; CRD42017068808). Results: A significant executive dysfunction in children with NF1 is demonstrated. Subgroup analysis showed that the impairment varied as a function of the specific component of executive functioning. The effect size for working memory and planning/problem solving was moderate whereas it was small for inhibitory control and cognitive flexibility. Executive dysfunction seems to be greater with increasing age whereas assessment tool type, intellectual performance, attention deficit hyperactivity disorder and control group composition did not seem to affect EF results. Conclusions: EF deficits are a core feature in children with NF1 and an early identification of executive dysfunctions is essential to limit their impact on the quality of life. (JINS, 2018, 24, 977–994)

Objectives: Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder caused by insufficient expression of the TCF4 gene. Most cases are characterized by severe intellectual disability, absent speech, motor delays, and autism spectrum disorder. Many have abnormal brain imaging, dysmorphic facial features, and medical comorbidities: myopia, constipation, epilepsy, and apneic spells. The present case study expands existing understanding of this disorder by presenting a unique phenotype with higher cognitive abilities and fewer medical comorbidities. Methods: The present case study reports on a 13-year-old, Caucasian male with a recent diagnosis of PTHS following genetic testing (i.e., whole exome sequencing). He was referred for a neuropsychological evaluation to document his neurocognitive functioning to assist with intervention planning. Results: Evaluation of intellectual, attention/executive, memory, visual-motor/fine-motor, academic, adaptive, and emotional/behavioral functioning revealed global impairment across all areas of functioning. However, he demonstrated abilities beyond what has been detailed in the literature, including use of full sentences, capacity to learn and solve novel problems, basic academic functioning, and independent ambulation. Conclusions: Children with PTHS may demonstrate a spectrum of abilities beyond what has been documented in the literature thus far. Failure to recognize this spectrum can result in late identification of an accurate diagnosis. (JINS, 2018, 24, 995–1002)

Objectives: Although the spacing effect has been investigated extensively in a variety of populations, few studies have focused on individuals with hippocampal amnesia and none, to our knowledge, have investigated differences in performance as a function of spacing schedule in these cases. In the current study, we investigated the benefit of expanding and equal-interval, compared to massed, spacing schedules in a developmental amnesic person, H.C., who shows congenitally based abnormal development of the hippocampal memory system. Methods: Given the possibility of plasticity and reorganization in the developing brain, we investigated whether H.C. would benefit more from an expanding versus equal-interval schedule using a continuous recognition paradigm, even though this task has been shown to recruit structures within the medial temporal lobe, including the hippocampus. Results: H.C. and matched controls both showed a clear spacing effect, although neither group benefited more from an equal-interval or expanding spacing schedule. Conclusions: The results of the current study show that the spacing effect is an effective and clinically meaningful memory intervention technique that may be applied to clinical conditions known to affect hippocampal function and episodic memory early in life. (JINS, 2018, 24, 1003–1012)