The behavioral profile of 49,XXXXY and the potential impact of testosterone replacement therapy

49,XXXXY (1:85,000-100,000) is a rare sex chromosome aneuploidy that often presents with complex musculoskeletal abnormalities, decreased cognitive capabilities, speech and language dysfunction, and behavioral complications. Hormonal replacement therapy, or testosterone replacement therapy, is associated with improved neurodevelopmental and behavioral outcomes in males with 49,XXXXY. Two forms of testosterone replacement therapy, early hormonal treatment (EHT) and hormonal booster therapy (HBT), are associated with improved neurodevelopmental and behavioral outcomes in these boys. This study investigates the impact of EHT and HBT on behavioral symptoms in males with 49,XXXXY.

A total of 59 individuals were divided into 4 groups: 19 no testosterone (no-T), 23 EHT, 6 HBT, and 11 EHT and HBT. An analysis of variance examined group differences on the Child Behavior Checklist and the Behavior Rating Inventory of Executive Function ranging from 5 to 18 years.

Although no differences were identified on the Behavior Rating Inventory of Executive Function, the 3 hormonal replacement therapy groups presented with decreased complications on numerous variables on the Child Behavior Checklist; these include somatic complaints (P = .0095), somatic problems (P = .041), internalizing problems (P = .034), externalizing problems (P = .0001), and withdrawn/depression (P = .025).

This study presents evidence that HBT may be a beneficial treatment for individuals with 49,XXXXY.