The effects of early androgen treatment on neurodevelopmental performance in pre-pubertal boys with 47,XXY have not been well investigated. The influence of hormones on brain development in humans suggests that a positive effect on neurodevelopmental outcome in young boys with XXY may be plausible with hormone replacement therapy. The aim of the study was to investigate retrospectively if an early course of androgen treatment (three injections of testosterone enanthate, 25 mg, each) had an impact on specific domains of neurodevelopmental function in boys with 47,XXY at 36 and 72 months of age. One hundred one boys with a karyotype of 47,XXY had neurodevelopmental assessments. The retrospective chart review resulted in one group (n = 34) who had received androgen treatment during infancy and the second group was untreated (N = 67). Statistical analysis was completed to determine if there was a positive effect from treatment observed at 36 and at 72 months on multiple domains of development. There were significant differences in multiple cognitive domains in the group who received androgen treatment, including multiple measures of language, intellectual, and neuromotor skills. Improved function was observed in neurodevelopmental outcome in boys with 47,XXY at 36 and 72 months who had been treated with a short course of androgen treatment in infancy. Continued research is underway to expand our understanding of the relationship of androgen, brain function, and neurobehavioral and neurodevelopmental outcome in boys with 47,XXY.

49, XXXXY is a rare chromosomal syndrome due to double nondisjunction of the replicating X chromosome. Considered a severe variant of XXY or Klinefelter syndrome, boys with this chromosome constitution are assumed to have severe mental retardation (MR) in addition to craniofacial, genital, endocrine, and heart abnormalities. Here, we present a multidisciplinary analysis including the clinical and neurobehavioral aspects of this condition in 20 boys with 49, XXXXY who share a common phenotype and neurobehavioral profile. The phenotypic presentation of the boys with 49, XXXXY shares some characteristics with 47, XXY, but there are also other unique and distinctive features. Previously unappreciated intact nonverbal skills are evident in conjunction with moderate to severe developmental dyspraxia. Variability in clinical and cognitive functioning may reflect skewed X inactivation, mosaicism, or other factors that warrant further investigation.

47, XXY occurs in up to 1 in 650 male births and is associated with androgen deficiency, neurodevelopmental delays, and atypical social-behaviors. Previously, we showed that young boys with 47, XXY who received early hormonal therapy (EHT) had significantly improved neurodevelopment. The objective of this follow-up study was to examine the effects of EHT on social behavior in boys with 47, XXY. The study consisted of boys prenatally diagnosed with 47, XXY who were referred for evaluations. Twenty-nine boys received three injections of 25 mg testosterone enanthate and 57 controls did not receive EHT. Behavioral functioning was assessed using the Behavior Rating Inventory of Executive Function, Social Responsiveness Scale, 2nd Ed., and the Child Behavior Checklist for Ages 6-18. The hypothesis that EHT may affect behavior was formulated prior to data collection. Questionnaire data was prospectively obtained and analyzed to test for significance between two groups. Significant differences were identified between group's scores over time in Social Communication (P=0.007), Social Cognition (P=0.006), and Total T-score (P=0.001) on the SRS-2; Initiation (P=0.05) on the BRIEF; and Externalizing Problems (P=0.024), Affective Problems (P=0.05), and Aggressive Behaviors (P=0.031) on the CBCL. This is the third study revealing positive effects of EHT on boys with XXY. There was a significant improvements associated with the 47, XXY genotype in boys who received EHT. Research is underway on the neurobiological mechanisms, and later developmental effects of EHT.

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.

Our findings revealed improved function in several areas of development which had been severely delayed in boys with 49,XXXXY. Continued research is underway to expand our understanding of the relationship of androgen, brain function and behavioural outcome in boys with 49,XXXXY.

Objective The purpose of this paper is to provide an overview of the 47, XXY syndrome, which is the most commonly occurring X and Y chromosomal variation. This paper seeks to review what is currently known of noninvasive prenatal testing (NIPT) and 47, XXY and investigate potential risks and benefits of prenatal identification.Method A literature review of NIPT and 47, XXY was performed to identify limitations of current NIPT techniques.Results As NIPT becomes an increasingly more routine procedure, prenatal findings of 47, XXY may increase. Awareness of this disorder and appropriate genetic counseling is necessary.Conclusion X and Y chromosomal variations will be identified through this screening, and the benefits and limitations to this finding need to be thoughtfully considered.

Funding informationThe Focus Foundation 47,XXY (Klinefelter syndrome) is the most common X and Y chromosomal variation (1:660 males). The incidence of anxiety disorders and the impact of hormonal replacement therapy (HRT) is not well understood. Child Behavior Checklist and Screen for Childhood Anxiety Related Emotional Disorders were completed by parents of 80 boys with 47,XXY. Forty received HRT prior to 10 years of age while 40 did not. HRT (22.5%) received early hormonal treatment prior to 18 months. About 32.5% received hormone booster treatment between 5 and 10 years. The remaining 42.5% received both. There were fewer reported social (p = .015), thought (p = .012), and affective problems (p = .048) in treated boys when compared to untreated. Boys with both treatments demonstrated fewer symptoms on anxious/depressed scale (p = .001) compared to those with early treatment only. Within the treated group, prenatally diagnosed showed fewer indications of anxiety problems (p = .02) than their postnatal counterparts. This comparative, cross-sectional study expands previous findings on the possible positive effect of HRT in boys with 47,XXY. Anxiety disorders appear to be a penetrant aspect of the 47,XXY phenotype. Further investigation is warranted to explore the relationship between biological treatment and individual responses to HRT to develop more personalized and precise medicine. K E Y W O R D S anxiety disorders, hormonal replacement therapy, Klinefelter syndrome, sex chromosome abnormalities and aneuploidies, X and Y chromosomal variations, 47,XXY

47,XXY (KS) occurs in 1:650 male births, though less than 25% are ever identified. We assessed stability of neurocognitive features across diverse populations and quantified factors mediating outcome. Forty-four boys from the Netherlands (NL) and 54 boys from the United States (US) participated. The Wechsler Intelligence Scales assessed intellectual functioning; the ANT program evaluated cognitive function; and the CBCL assessed behavioral functioning. ANOVA was used for group comparisons. Hierarchical regressions assessed variance explained by each independent variable: parental education, timing of diagnosis, testosterone, age, and nationality. Parental education, timing of diagnosis, and hormonal treatment all played an important role in neurocognitive performance. The observed higher IQ and better attention regulation in the US group as compared to the NL group was observed with decreased levels of behavioral problems in the US group. Cognitive measures that were different between the NL and US groups, i.e., attention regulation and IQ scores, were also significantly influenced by external factors including timing of diagnosis, testosterone treatment, and parental education. On the ANT, a cognitive phenotype of 47,XXY was observed, with similar scores on 9 out of the 10 ANT subtests for the NL and US groups. This study lays additional features to the foundation for an algorithm linking external variables to outcome on various neurodevelopmental measures.