XXXY

XXXY syndrome, also referred to as XXXY (karyotype 48,XXXY), is a rare sex chromosome aneuploidy that occurs in males. In 48,XXXY, there are three X chromosomes and one Y chromosome in each cell, two X chromosomes more than a typical male (46,XY). The condition generally results from nondisjunction events during parental gametogenesis, leading to a gamete carrying two extra X chromosomes that combines with a normal or abnormal sperm or egg.

Clinical features are variable but commonly include neurodevelopmental challenges and distinctive physical findings. Infants may present with low muscle tone (hypotonia) and delayed motor milestones, followed by speech and language delay and broader intellectual disability ranging from mild to moderate. Behavioral concerns such as attention problems or autism spectrum features may occur. Tall stature is often noted during adolescence due to delayed epiphyseal closure, while gonadal dysfunction is typical in adolescence and adulthood, with small testes and reduced fertility. Other frequent findings include limited facial and body hair, gynecomastia, and skeletal anomalies such as scoliosis or other bone-related issues. Congenital heart defects and renal anomalies are relatively uncommon.

Diagnosis is based on karyotype analysis from blood or other tissues; prenatal detection is possible through fetal testing. Management requires a multidisciplinary approach, including early intervention services, physical, occupational, and speech therapy, educational support, and endocrinologic care. Testosterone replacement may be considered during puberty to support secondary sexual characteristics and bone health. Genetic counseling is advised for families, and prognosis varies with severity and access to comprehensive care; many individuals achieve functional independence with appropriate support.