48,XXYY syndrome is a sex chromosome anomaly in which males have an extra X and Y chromosome. Human cells usually contain two sex chromosomes, one from the mother and one from the father. Usually, females have two X chromosomes (XX) and males have one X and one Y chromosome (XY). The appearance of at least one Y chromosome makes a male. Therefore, XXYY only affects males. Males affected with XXYY syndrome have 48 chromosomes instead of the typical 46. This is why XXYY syndrome is sometimes written as 48,XXYY syndrome. It is estimated that XXYY affects one in every 18,000-40,000 male births.[1]
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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.[2] It was described in a 15-year-old mentally challenged boy who had signs of Klinefelter syndrome, however his chromosome testing showed 48,XXYY instead of 47,XXY.
XXYY syndrome was originally considered to be a variation of Klinefelter syndrome (47,XXY) because of shared physical and medical features resulting from the presence of an extra X chromosome including tall stature, the development of testosterone deficiency in adolescence and/or adulthood (hypergonadotropic hypogonadism), and infertility. However, recent research shows some important differences in males with 48,XXYY compared to 47,XXY.[3] 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 attention deficit hyperactivity disorder (ADHD) or autism spectrum disorders, and psychological/behavioral problems including anxiety, depression, and mood dysregulation. Also, a larger percentage of males with XXYY have additional medical problems such as seizures, congenital elbow malformations (radioulnar synostosis), and tremor compared to males with XXY. XXYY is still considered a variation of Klinefelter syndrome by some definitions, mainly because the pathophysiology of the testicular dysfunction has not been shown to differ from 47,XXY, and the most current research does not suggest that there should be any differences in the evaluation and treatment of testosterone deficiency in 48,XXYY compared to 47,XXY.[4] 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. There is significant variability between individuals in the number and severity of the medical and neurodevelopmental problems associated with XXYY, and some individuals have mild symptoms while others are more significantly affected.[1]
A karyotype is done to diagnose XXYY syndrome. Treatment consists of medications, behavioral therapies and intensive community support.[5]