Behavioral phenotype of 49,XXXXY syndrome: Presence of anxiety‐related symptoms and intact social awareness

Abstract

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. K E Y W O R D S 49,XXXXY, anxiety disorders, behavioral dysfunction, communication deficits, sex chromosome abnormalities and aneuploidies, X and Y chromosomal variations

DNA methylation and behavioral dysfunction in males with 47,XXY and 49,XXXXY: a pilot study

“…The objective of this pilot study was to assess the relationship among the number of supernumerary X chromosomes, CpG methylation at different loci on the X chromosome, and parent report of behavior in males. In two parental questionnaires, the BRIEF and CBCL, significant differences were observed in both internalizing and externalizing behaviors between the 49,XXXXY group and both the 47,XXY and neurotypical 46,XY groups, which is consistent with a previous study by our group [ 15 ]. However, there were no significant differences between the 47,XXY and the 46,XY groups on the BRIEF and CBCL, which is in contrast to another study [ 11 , 38 ].…”

“…Primers were designed against regions as described in Additional file 2: Table 1. Whenever possible, we included regions experimentally verified as binding sites for the glucocorticoid receptor, or glucocorticoid response elements (GREs) [ 25 ], since anxiety is a common feature in the SCA disorder [ 11 , 15 ]. For each region, 2 sets of primers were designed.…”

“…In a recent study, infants with 49,XXXXY who received EHT scored higher on the Bayley Scales of Infant Development compared to their untreated counterparts [ 7 ]. While such studies suggest global improvement in these populations with testosterone treatment, the etiology of these behaviors has not been investigated from a genetic perspective [ 13 , 15 ].…”

Neurocognitive development and capabilities in boys with 49,XXXXY syndrome

“…Such difficulties may serve as mediating factors in the variable performance in the cognitive abilities of children with 49,XXXXY. In addition, recent research has described the presence of pervasive anxiety symptoms in 49,XXXXY (Lasutschinkow, Gropman, Porter, Sadeghin, & Samango‐Sprouse, 2020). The impact that anxiety symptoms have on the comfort of the child, as well as the ability to attend to or complete assessment, can be quite influential on any and all cognitive testing.…”

Introduction: Comprehensive investigation into an international cohort of boys with 49,XXXXY

“…Each article addresses one particular area of interest in relation to the 49,XXXXY phenotype; specifically, neuromotor and neurologic function, musculoskeletal, endocrinological function, speech and language, neurocognition and behavior. Two of the articles, Tosi et al, 2020 and Lasutschinkow et al, 2020, which address the musculoskeletal and behavioral phenotypes of 49,XXXXY respectively, were published ahead of this section and can be found in the online version of this special section. These articles provide evidence of the similar effect of testosterone replacement on the 49,XXXXY population as compared to the 47,XXY population.…”