XXX (triple X), XXXX (tetrasomy X), and XXXXX (pentasomy X) syndromes

X-chromosome polysomy syndromes (XXX [triple X], XXXX [tetrasomy X], and XXXXX [pentasomy X] syndromes) are genetic disorders that can affect neurodevelopment, mental health, and multiple organ systems. These conditions typically occur as sporadic chromosomal abnormalities rather than as inherited disorders. They occur in females.

They can present with psychiatric features such as anxiety, depression, attention-deficit symptoms, social difficulties, behavioural problems, and, particularly in triple X syndrome, psychosis. Psychiatric manifestations may become apparent or clinically significant during adolescence or adulthood, including psychotic disorders in some individuals with triple X syndrome.

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

• Flat face (described in XXXXX syndrome)

• Midface retrusion (described in XXX and XXXX syndromes)

• Micrognathia (described in XXX and XXXX syndromes)

• Short neck (described in XXXXX syndrome)

• Widely spaced eyes (described in XXX and XXXX syndromes)

• Epicanthus

• Upslanted palpebral fissures

• Depressed nasal bridge (described in XXXXX syndrome)

• Clinodactyly of fifth fingers

Other characteristic features include developmental delay, intellectual disability of variable severity, speech and language difficulties, learning difficulties, hypotonia, motor-coordination difficulties, and seizures in some individuals. The phenotype generally becomes more pronounced with increasing numbers of X chromosomes, with tetrasomy X and pentasomy X more often associated with intellectual disability, short stature, craniofacial abnormalities, and congenital malformations.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

• Cardiovascular: congenital heart disease and other structural cardiac abnormalities, particularly in tetrasomy X and pentasomy X.

• Respiratory: recurrent respiratory infections may occur.

• Renal/electrolytes: renal and urinary tract abnormalities may occur.

• Endocrine: ovarian dysfunction, irregular or absent menstruation, premature ovarian insufficiency, and reduced fertility may occur; gonadal dysfunction tends to be more pronounced in the higher-order X-chromosome polysomies.

• Musculoskeletal: scoliosis, joint laxity or contractures, clinodactyly, radioulnar synostosis, and other skeletal abnormalities; short stature is particularly characteristic of pentasomy X, whereas triple X is more often associated with tall stature.

Early diagnosis is important to identify potentially treatable medical contributors to psychiatric, developmental, and cognitive presentations, recognize associated endocrine, cardiovascular, renal, musculoskeletal, and other systemic complications, guide appropriate developmental and educational support and medical surveillance, and enable timely treatment of psychiatric illness and other comorbidities.