Klinefelter syndrome (47,XXY), XXXY, and XXXXY syndromes

Klinefelter syndrome (47,XXY), XXXY, and XXXXY syndromes are sex-chromosome aneuploidies that typically result in a male phenotype, with Klinefelter syndrome being the most common form. The presence of additional X chromosomes is generally associated with progressively more pronounced physical, developmental, and intellectual manifestations. These chromosomal abnormalities usually occur sporadically as a result of abnormal chromosome separation during cell division and are not inherited. A distinctive presentation may include hypogonadism, characteristic facial and skeletal features, and developmental or intellectual difficulties, with more pronounced manifestations generally occurring in XXXY and XXXXY syndromes.

Klinefelter syndrome can present with psychiatric features such as ADHD, autism spectrum disorder (ASD), anxiety, depression, and other behavioural or emotional difficulties. Psychotic disorders, including schizophrenia, have also been reported at increased rates in individuals with XXY. Neuropsychiatric manifestations can occur during childhood, adolescence, and adulthood. Psychiatric and behavioural manifestations have also been described in XXXY and XXXXY syndromes, but these are less well characterised; reported features include attention difficulties, behavioural problems, anxiety, irritability, emotional dysregulation, and social difficulties.

From a morphologic lens perspective, other features include (but are not limited to):

• Flat face (XXXY and XXXXY)

• Prognathism (XXXY and XXXXY)

• Short neck (XXXY and XXXXY)

• Epicanthus (XXXY and XXXXY)

• Upslanted palpebral fissures (XXXY and XXXXY)

• Depressed nasal bridge (XXXY and XXXXY)

• Clinodactyly of fifth fingers (XXY, XXXY and XXXXY)

Other characteristic features include developmental delay or intellectual disability, speech and language impairment, executive-function and learning difficulties, hypotonia, and motor-coordination difficulties. Physical manifestations may include hypogonadism, small testes, infertility, gynecomastia, sparse facial and body hair, reduced muscle mass, and characteristic skeletal abnormalities. Additional X chromosomes are generally associated with more pronounced intellectual, speech and language, skeletal, and facial abnormalities, particularly in XXXY and XXXXY syndromes. Unlike XXY and XXXY syndromes, in which tall stature is common, individuals with XXXXY syndrome are often short. Other manifestations may include dental abnormalities, congenital heart defects, osteoporosis, and metabolic complications.

Early diagnosis is important to identify and manage developmental, educational, psychiatric, endocrine, reproductive, skeletal, and other medical complications; to guide appropriate management of hypogonadism; and to provide appropriate developmental, educational, and psychosocial support.