Testosterone replacement therapy (early hormonal treatment and hormonal booster therapy) was associated with decreased behavioral complications on numerous Child Behavior Checklist variables in males with 49,XXXXY, presenting evidence that HBT may be a beneficial treatment for these individuals.
Key Findings
Background
49,XXXXY is a rare sex chromosome aneuploidy with a prevalence of approximately 1 in 85,000-100,000 that presents with complex musculoskeletal abnormalities, decreased cognitive capabilities, speech and language dysfunction, and behavioral complications.
Prevalence is estimated at 1:85,000-100,000 live births.
The condition is associated with complex musculoskeletal abnormalities, decreased cognitive capabilities, speech and language dysfunction, and behavioral complications.
Two forms of testosterone replacement therapy studied were early hormonal treatment (EHT) and hormonal booster therapy (HBT).
Methods
A total of 59 individuals with 49,XXXXY were divided into four treatment groups for analysis of behavioral outcomes.
The four groups were: 19 no testosterone (no-T), 23 EHT, 6 HBT, and 11 EHT and HBT.
Participants ranged from 5 to 18 years of age.
Behavioral assessments included the Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function (BRIEF).
An analysis of variance (ANOVA) was used to examine group differences.
Results
The three hormonal replacement therapy groups showed significantly decreased somatic complaints compared to the no-testosterone group.
Somatic complaints differed significantly across groups (P = .0095).
Somatic problems also differed significantly (P = .041).
These differences were identified on the Child Behavior Checklist.
Results
The three hormonal replacement therapy groups showed significantly decreased internalizing and withdrawn/depressive problems compared to the no-testosterone group.
Internalizing problems differed significantly across groups (P = .034).
Withdrawn/depression differed significantly across groups (P = .025).
These findings were identified on the Child Behavior Checklist.
Results
The three hormonal replacement therapy groups showed significantly decreased externalizing problems compared to the no-testosterone group.
Externalizing problems differed significantly across groups (P = .0001), representing the most statistically significant behavioral difference found.
This finding was identified on the Child Behavior Checklist.
All three HRT groups (EHT, HBT, and EHT+HBT) presented with decreased complications on this variable.
Results
No significant differences were identified between groups on the Behavior Rating Inventory of Executive Function.
Despite significant findings on the CBCL, the BRIEF did not reveal group differences.
This suggests that testosterone replacement therapy may differentially affect behavioral versus executive function domains.
All four groups (no-T, EHT, HBT, EHT+HBT) were compared on the BRIEF.
Conclusions
Hormonal booster therapy (HBT) may be a beneficial treatment for individuals with 49,XXXXY.
The study presents evidence supporting HBT as a potentially beneficial treatment.
Both EHT and HBT were associated with improved neurodevelopmental and behavioral outcomes.
The HBT group had the smallest sample size (n = 6), which is a study limitation.
Samango-Sprouse C, Hamzik M, Gropman E, Brooks M, Powell S, Taylor A, et al.. (2023). The behavioral profile of 49,XXXXY and the potential impact of testosterone replacement therapy.. Genetics in medicine : official journal of the American College of Medical Genetics. https://doi.org/10.1016/j.gim.2023.100847