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Carole A Samango-Sprouse,1–3 Debra R Counts,4 Selena L Tran,3 Patricia C Lasutschinkow,3 Grace F Porter,3 Andrea L Gropman5,6 1Department of Pediatrics, George Washington University, Washington, DC, USA; 2Department of Human and Molecular Genetics, Florida International University, Miami, FL, USA; 3The Focus Foundation, Davidsonville, MD, USA; 4Pediatric Endocrinology, Sinai Hospital, Baltimore, MD, USA; 5Department of Neurology, George Washington University, Washington, DC, USA; 6Division of Neurogenetics and Developmental Pediatrics, Children’s National Medical Center, Washington, DC, USACorrespondence: Carole A Samango-SprouseThe Focus Foundation, 820 W. Central Ave. #190, Davidsonville, MD 21035, USATel +1 443-223-7323Fax +1 855-550-8696Email cssprouse@email.gwu.eduAbstract: 47,XXY (Klinefelter syndrome [KS]) is the most common sex chromosomal aneuploidy (1:660), yet, despite this, only 25% of the males are ever diagnosed. Males with 47,XXY present with characteristic symptoms throughout their lifetime with typical physical and neurodevelopmental manifestations focused in growth, cognitive development, endocrine function, and reproduction. Studies have demonstrated that optimal outcomes are dependent on early detection combined with consistent and targeted neurodevelopmental treatment throughout the lifespan. During infancy and into the preschool years, individuals with 47,XXY commonly face deficits in growth and development in the areas of early hormonal, motor, speech, and behavioral development. As they transition into school, the primary neurodevelopmental concerns include language difficulty, executive dysfunction, behavior, and learning and reading deficits. Adults with 47,XXY often present with taller than average height, low levels of fertility, azoospermia, and elevated gonadotropin levels. These presentations may persist from early childhood through adulthood but can be mitigated by appropriate interventions. Early neurodevelopmental and hormonal treatment has been shown to have a minimizing effect on the physical and neurodevelopmental manifestations in individuals with 47,XXY. With innovative and current research studies, the features common to the neurodevelopmental profile of 47,XXY have been further expanded and defined. Further research is necessary to elucidate and understand the relationship between the brain, behavior, and the phenotypic profile of 47,XXY.Keywords: 47, XXY, Klinefelter syndrome, neurodevelopment, hormonal treatment

The primary aim of this study was to evaluate the convergent validity of the Motor domain (MOT) of PediaTrac TM v3.0, an online developmental tracking instrument based on caregiver reports, with fine and gross motor domains (ASQ-FM and ASQ-GM) of the Ages and Stages Questionnaire (ASQ-3) in infants between 2- and 9 months of age. Participants were caregivers of 571 infants born term or preterm (gestational age <37 weeks) enrolled in a multi-site psychometric study of PediaTrac TM . Findings revealed significant correlations between MOT and ASQ-3 scores at 2, 4, 6, and 9 months across time periods, term-preterm status, and biological sex. A significantly higher percentage of infants born preterm, compared with those born at term, was identified as a moderate or high risk on both the ASQ-3 and PediaTrac. Future investigations are warranted to further examine the psychometric properties of the MOT domain, including sensitivity, specificity, and positive and negative predictive value., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46 th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors-ZFX and ZFY-encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Selective mutism (SM) is a severe but understudied childhood anxiety disorder. Most epidemiological research on SM was conducted decades ago and is limited by small sample sizes. This study analyzes parent-reported clinical data from 230 children with diagnosed and suspected SM to provide current information about the presentation of this disorder. Overall, anxiety and social anxiety symptoms were elevated. Gender ratio, comorbidities and family history of psychopathology were generally aligned with previous research. However, age of onset and diagnosis were both earlier than previously reported, with an average delay of 2 years between onset and diagnosis. The majority of children received therapy and school accommodations for their SM, yet there was large variability in types of interventions. This is the largest survey of children with SM conducted primarily within the US and it constitutes the first systematic inquiry into interventions and accommodations received within clinical and school settings., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46 th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex-chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors - ZFX and ZFY - encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes., Competing Interests: Declaration of interests: The authors declare no competing interests.

The "inactive" X chromosome (Xi) has been assumed to have little impact, in trans , on the "active" X (Xa). To test this, we quantified Xi and Xa gene expression in individuals with one Xa and zero to three Xis. Our linear modeling revealed modular Xi and Xa transcriptomes and significant Xi-driven expression changes for 38% (162/423) of expressed X chromosome genes. By integrating allele-specific analyses, we found that modulation of Xa transcript levels by Xi contributes to many of these Xi-driven changes (≥121 genes). By incorporating metrics of evolutionary constraint, we identified 10 X chromosome genes most likely to drive sex differences in common disease and sex chromosome aneuploidy syndromes. We conclude that human X chromosomes are regulated both in cis , through Xi-wide transcriptional attenuation, and in trans , through positive or negative modulation of individual Xa genes by Xi. The sum of these cis and trans effects differs widely among genes., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Motor disturbance and altered motor networks are commonly reported in individuals with autism spectrum disorder (ASD). It has been suggested that electroencephalogram (EEG) can be used to provide exquisite temporal resolution for understanding motor control processes in ASD. However, the variability of study design and EEG approaches can impact our interpretation. Here, we conducted a systematic review on recent 11 EEG studies that involve motor observation and/or execution tasks and evaluated how these findings help us understand motor difficulties in ASD. Three behavior paradigms with different EEG analytic methods were demonstrated. The main findings were quite mixed: children with ASD did not always show disrupted neuronal activity during motor observation. Additionally, they might have intact ability for movement execution but have more difficulties in neuronal modulation during movement preparation. We would like to promote discussions on how methodological selections of behavioral tasks and data analytic approaches impact our interpretation of motor deficits in ASD. Future EEG research addressing the inconsistency across methodological approaches is necessary to help us understand neurophysiological mechanism of motor abnormalities in ASD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Difficulty with implicit learning plays an important role in the symptomology of autism spectrum disorder (ASD). However, findings in motor learning are inconsistent. This study evaluated implicit sequence learning and its relationship with motor ability in children with and without ASD. We adopted a classic serial reaction time task with a retention task and three awareness tests. The Movement Assessment Battery for Children was administered to assess children's motor ability. Significant learning differences between children with and without ASD were only found in retention but not immediately after the serial reaction time task. These findings suggest that the impaired implicit learning in ASD is characterized as impaired consolidation where the relatively permanent changes are missing. Exploratory moderation analyses revealed a significant relationship between implicit learning and motor ability for individuals with faster response time. We argue the importance of response speed for optimal learning and should be weighted more for future intervention in children with ASD.

49,XXXXY is a rare chromosomal variation characterized by deficits in motor, language, and cognitive domains. This study reports on the neurological function and dysmorphic features in the largest cohort to date. Seventy-two boys with 49,XXXXY were evaluated on a variety of domains including a neurological examination and neuromotor assessments including the Beery Buktenica Developmental Test of Visual-Motor Integration, Sixth Edition, the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), and the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition. Results supported previous literature by describing high occurrences of truncal and extremity hypotonia, which significantly impacts on motor milestones and ambulation in this population. The boys presented with dysmorphic features including epicanthal folds, frontal bossing, and synophrys. Visual perception skills were mildly impaired and cranial nerves were typically intact, however capabilities in motor coordination and fine motor precision were greatly delayed, supporting deficits in refined and controlled hand movements versus widespread visual deficits. Preschool boys treated with testosterone replacement had significantly increased scores when compared to the untreated group on the BSID-III Psychomotor Development Index, further supporting previous research indicating that testosterone replacement may have a positive impact on neurodevelopmental outcomes in males with additional X chromosomes. Boys with 49,XXXXY may benefit from hormonal treatment in conjunction with early intervention services to address their significant motor deficits., (© 2020 Wiley Periodicals LLC.)

49,XXXXY is the rarest X and Y chromosomal variation and is frequently characterized by expressive and receptive language dysfunction, low muscle tonus, and intellectual deficits. Due to the low incidence of this disorder, comprehensive studies analyzing the specific aspects of the speech and language phenotype in these boys have been uncommon. This is the first in-depth investigation of the speech and language profiles in a large cohort of boys with 49,XXXXY. Based on the clinical judgment of speech and language pathologists, there was an increased incidence (91.8%) of Childhood Apraxia of Speech (CAS), which has not been previously described in this disorder. In preschool boys, some significant differences were demonstrated between boys who received early hormonal treatment (n = 16) and untreated boys (n = 4) on the language scales (p = .047) on the Bayley Scales of Infants and Toddlers, as well as significant differences between treated (n = 13) and untreated boys (n = 8) on the Expressive One Word Picture Vocabulary Test (p = .008). No significant differences between treatment groups were found in school age children, however, treated groups demonstrated less discrepancies between expressive and receptive language. More research and larger samples are needed to determine the extent of the impact of testosterone treatment on boys with 49,XXXXY. This study identifies CAS as a potential explanation for the significant expressive language dysfunction and subsequent behavioral dysfunction. These findings may assist in facilitating more targeted treatment and improved outcomes for boys with 49,XXXXY., (© 2020 Wiley Periodicals LLC.)

49,XXXXY is the rarest X and Y chromosomal variation, with an incidence of 1 in 80,000-100,000 live male births and has been associated with numerous musculoskeletal abnormalities. Data was collected from an international cohort of boys with 49,XXXXY over 10 years. Children were evaluated by a multidisciplinary team consisting of a pediatric orthopedist, a neurogeneticist, a neurodevelopmentalist, and two physical therapists. Increased rates of torticollis (32.4%), hamstring tightness (42%), radioulnar synostosis (67.6%), pes planus (65.2%), and other foot abnormalities (86.9%) were observed. Several anomalies increased with age, specifically hamstring tightness, kyphosis, and scoliosis. The elucidation of the orthopedic profile of this population is necessary in order to provide healthcare providers with current medical information. This research further supports the necessity for the comprehensive multidisciplinary treatment of boys with 49,XXXXY., (© 2020 Wiley Periodicals, Inc.)

49,XXXXY was previously associated with profound to severe intellectual deficits. However, prior research papers on the cognitive profiles of this population were confounded by small samples sizes, wide age spreads, and incomplete histories of testosterone replacement therapy. This study is the first comprehensive, international investigation of the neurocognitive aspects of 49,XXXXY, and the potential effects of biological treatment on this profile. Sixty-seven boys from infancy to 11 years of age were enrolled in this longitudinal study, with the majority of boys postnatally diagnosed though chromosomal analysis. These boys received a comprehensive neurocognitive evaluation tailored to specific language-based deficits and cognitive challenges. Results revealed higher neurocognitive capacities, both verbally and nonverbally, than previously reported in this disorder. Infant boys with 49,XXXXY who received early hormonal therapy (EHT) had significantly higher scores on the cognitive domain of the Bayley Scales of Infant Development than untreated infants (p = .013). In addition, treated school-aged participants had significantly better scaled scores than untreated boys in form completion (p = .042), a task that requires deductive reasoning, on nonverbal testing on the Leiter International Performance Scales. This study indicates greater cognitive capacities with a wide range of abilities in the child with 49,XXXXY, thus warranting further investigation to identify and understand the critical influences on the etiology and the variability of those capacities., (© 2020 Wiley Periodicals LLC.)

49,XXXXY is an X and Y chromosome variation that occurs in 1:85,000 to 1:100,000 live male births. Previous case studies have described boys with this disorder to be shorter than average when compared with boys with only one extra chromosome and with the mean stature in a small cohort reported to range from the seventh to 33rd percentile. The origin behind the possible differences in height between boys with 47,XXY and 49,XXXXY is currently unknown, however one study hypothesized that it was due to a difference in the expression of the SHOX gene. This study reports on the anthropometric measurements of 84 boys with 49,XXXXY. Forty-five percent of children with 49,XXXXY were found to be below the third percentile in height at the time of evaluation. In addition, 7.14% of the cohort were diagnosed and given treatment for growth hormone deficiency (GHD). The analysis of this cohort demonstrates that the below average heights seen throughout childhood in this population potentially begins prenatally and suggests that boys with 49,XXXXY may be at a higher risk for intrauterine growth restriction (IUGR) and GHD. Future research is needed to investigate the etiology of the poor growth in boys with 49,XXXXY and evaluate the incidence of GHD and IUGR in this population., (© 2020 Wiley Periodicals LLC.)

This cross-sectional study examined the neurodevelopment of a large, prenatally diagnosed population of boys with 47,XXY; investigated the potentially positive effects of early hormonal therapy (EHT) on language, cognition, and motor in this population; and identified novel at risk biomarkers associated with 47,XXY. Two-hundred and seventy two evaluations were collected from 148 prenatally diagnosed boys with 47,XXY between 0 and 36 months and separated into one of three groups, depending on visit age: Y1 (0-12 months; n = 100), Y2 (13-24 months; n = 90), and Y3 (25-36 months; n = 82). Those who received EHT (administered by 12 months) were further separated (Y1, n = 37; Y2, n = 34; Y3, n = 30). Neurodevelopmental evaluations consisted of Preschool Language Scales, Early Language Milestone Scale, and Bayley Scales of Infant and Toddler Development and evaluated the effect of EHT on auditory comprehension, expressive communication, receptive language, cognition, and motor. EHT was found to be associated with a positive effect within the first year of life in these domains, as well as in the second and third year of life. Additionally, three novel at-risk biomarkers were identified in this cohort: feeding difficulties in infancy, positional torticollis, and the need for orthotics. The positive effects of EHT observed in language, cognition, and motor at variable stages within the first 3 years of life provide additional evidence into the possible efficacy of early biological treatment for boys with 47,XXY to address the neurodevelopmental dysfunction., (© 2020 Wiley Periodicals, Inc.)

49,XXXXY is a rare X and Y chromosome variation that occurs in 1:85,000 to 1:100,000 live male births and is notable for variable motor, speech, and behavioral deficits. Case studies have described boys with this disorder as shy, impulsive, and aggressive with low frustration tolerances; however, previous studies have been limited due to cohort size. This study reports on the largest cohort of boys with 49,XXXXY to date with an emphasis on the prevalence of anxiety-related symptoms and sociability from preschool to adolescence. The Child Behavior Checklist, Behavior Rating Inventory of Executive Function, 2nd edition, and Social Responsiveness Scale, 2nd edition were completed by parents on a cohort of 69. The cohort demonstrated deficits in social cognition and communication beginning in preschool, however, presented with consistent social awareness and motivation for social activities not previously appreciated in this disorder. In addition, signs of anxiety presented during preschool years and increased in severity with age, particularly in internalizing problems. Boys with 49,XXXXY presented with wide behavioral variability across all ages and domains. Further research into the potential influences of culture, birth order, biological treatment, and frequency of services is needed to better define the behavioral phenotype of children with this disorder., (© 2020 Wiley Periodicals, Inc.)

Purpose of Review: Although 47,XXY (Klinefelter syndrome) was first discovered more than 50 years ago, there have been limited comprehensive studies on this disorder. The present review explains the study of neurodevelopmental dysfunction and the impact of testosterone replacement at specific junctions in the life of males with 47,XXY. The intricate relationship between testosterone, neurodevelopment, health, and well being warrants an in-depth investigation in order to achieve optimal outcomes., Recent Findings: Current literature suggests that the implementation of biological treatment has a positive impact on numerous areas of neurodevelopment. Further research is needed to determine ideal dosage, timing, and frequency of biological treatment for efficacy and safety of the child with 47,XXY., Summary: As noninvasive prenatal screening has detected increasing numbers of fetuses with 47,XXY, parents may benefit from both prenatal and postnatal counseling, including the latest innovative biological treatment, that may further optimize the child's outcome, especially when coupled with targeted early intervention services.

Objective: To investigate the attitudes of parents of children with a sex chromosome aneuploidy (SCA) regarding the impact of an early diagnosis and noninvasive prenatal testing (NIPT)., Method: A survey consisting of multiple choice and long response formatted questions was completed by parents of children with SCA(s)., Results: Fifty-five participants responded to the survey. A total of 88.1% of participants who received an early diagnosis expressed that it had a positive impact on their child's life. Of the 23 participants who utilized NIPT, 95.7% believed it was a decisive factor in their life because they could research the disorders prior to the birth of their child (35.3%), pinpoint valuable resources and interventions (38.2%), and determine possible risk factors of neurodevelopmental delays to be considered after delivery (20.6%)., Conclusion: This study documented parental perspectives on the impact of an early SCA diagnosis and attitudes towards NIPT use for identifying those at risk for SCAs. These informative and insightful results provide personal experiences that health care providers may want to consider when providing prenatal counseling on NIPT for expectant mothers. As this analysis is the first of its kind, ascertainment is limited, and future research should aim to expand these findings by investigating the different factors influencing attitudes towards NIPT., (© 2019 John Wiley & Sons, Ltd.)