Extra copies of genes on the X chromosome interfere with male sexual development, preventing the testes from functioning normally and reducing the levels of testosterone.

[4][5] The condition 48,XXYY is not inherited; it usually occurs as a random event during the formation of reproductive cells (eggs and sperm).

[citation needed] In a small percentage of cases, 48,XXYY syndrome results from nondisjunction of the sex chromosomes in a 46,XY embryo very soon after fertilization has occurred.

If hypogonadism is present, testosterone treatment should be considered in all individuals regardless of cognitive abilities due to positive effects on bone health, muscle strength, fatigue, and endurance, with possible mental health/behavioral benefits, as well.

Poor fine-motor coordination and the development of intention tremor can make handwriting slow and laborious, and occupational therapy and keyboarding should be introduced at an early age to facilitate schoolwork and self-help skills.

[8][4] The first published report of a boy with a 48,XXYY karyotype was by Sylfest Muldal and Charles H. Ockey in Manchester, England in 1960.

Shared physical and medical features resulting from the presence of an extra X chromosome include tall stature, the development of testosterone deficiency in adolescence and/or adulthood (hypergonadotropic hypogonadism), and infertility.

[6] The most important differences result from the effects of the extra X and Y chromosome on neurodevelopment, leading to higher rates of developmental delays in early childhood, learning disability or intellectual disability, adaptive functioning (life skills) difficulties, neurodevelopmental disorders such as ADHD or autism spectrum disorders, and psychological/behavioral problems including anxiety, depression, and mood dysregulation.

[10] However, for the psychological and behavioral symptoms of XXYY syndrome, more extensive evaluations, interventions, and supports are usually needed compared to 47, XXY due to more complex neurodevelopmental involvement.