Sex Chromosome Trisomies Increase Neurodevelopmental, Mental Health Risks

Research study background

Despite occurring in approximately 1 in 500 live births, sex chromosome trisomies (SCT) — caused by an extra X or Y chromosome — have historically been underdiagnosed and under researched. Klinefelter syndrome (XXY), the most common SCT, occurs in 1 in 600 males but approximately one third of cases are never diagnosed. Trisomy X syndrome (XXX), which affects females, and double Y syndrome (XYY), which affects males, occur in approximately 1 in 1,000 live births. Of those, less than 10% will receive a diagnosis.

Past research linked SCT with several neurodevelopmental and mental health comorbidities, but since most report on small samples and lack control groups, it was unclear how the risk of these conditions compared to that of peers. SCT diagnoses are anticipated to significantly rise as non-invasive prenatal screening becomes standard, increasing the need for more robust SCT research to inform counseling and care.

This study, the first of its kind, was led by a multidisciplinary team of researchers at Children’s Hospital Colorado. The collaboration included experts from the eXtraordinarY Kids Clinic and Research Program, (one of the few centers pursuing clinical research in X and Y chromosome variation), the Department of Endocrinology and the Developmental Pediatrics Program.

Using PEDSnet data from patient encounters at six pediatric centers across the U.S. over 10 years, researchers compared the prevalence of neurodevelopmental and mental health diagnoses in 1,676 youth with XXY, XXX or XYY to a matched control pool.

The comparison found that individuals with SCT were six times more likely than sex and age-matched controls to have one or more neurodevelopmental diagnoses. The most common were motor delays, followed by speech and language disorders and attention-deficit/hyperactivity disorder. Although less frequent, youth with SCT were twice as likely to have a mental health diagnosis. Anxiety was most prevalent among all three sex chromosome variations, followed by mood disorders.

Researchers also evaluated interventions for diagnosed conditions among the two groups. More youth with SCT were prescribed psychotropic medications than matched controls. In both the SCT and control groups, stimulants were most commonly prescribed, followed by selective serotonin reuptake inhibitors and antipsychotics. Nearly half of all SCT youth had at least one behavioral health visit, compared to less than 20% in the control group. An encounter was seven times more likely for youth with XYY and XXX and four times more likely for youth with XXY.

Clinical implications

Findings from this large-scale analysis enhance existing literature from smaller studies. This study demonstrates that youth with SCT receiving care at high level pediatric centers in the U.S. have disproportionately high rates of neurodevelopmental and mental health conditions compared to matched controls. It also underscores the need for universal screening of children with SCT to promote early diagnosis and improve access to care.