Triple X Syndrome

Triple X syndrome (47,XXX) is a sex chromosome aneuploidy in females, with tall stature, a range of learning and language difficulties, and variable psychiatric and physical features. It affects about 1 in 1000 female births, and many cases are never diagnosed.

Pathophysiology. An extra X chromosome arises from maternal meiotic non-disjunction in most cases, with risk rising with maternal age. Gene dosage from the extra X, which escapes inactivation for some genes, affects growth, neurodevelopment and ovarian function.

Phenotype ranges from normal to marked developmental delay, and cannot be predicted from prenatal diagnosis.

Fertility is usually normal, though premature ovarian insufficiency occurs.

• Tall stature, with accelerated growth in childhood
• Hypotonia and motor delay in infancy
• Speech and language delay, learning difficulties, reduced average IQ
• Attention deficit hyperactivity disorder, anxiety, depression and social difficulties
• Premature ovarian insufficiency in some
• Seizures, and renal and genitourinary anomalies in a minority
• Scoliosis, clinodactyly, hypertelorism and epicanthal folds
• Often no obvious features

• Karyotype or chromosomal microarray showing 47,XXX (or mosaic form).
• Prenatal detection: incidental finding on cell free DNA screening or amniocentesis, confirmed by invasive testing.
• Developmental assessment: speech, language, motor skills and cognitive testing.
• Endocrine evaluation: pubertal assessment, and FSH and AMH in adolescence if irregular periods.
• Renal ultrasound and spine examination when indicated.
• Psychiatric assessment when behavioural concerns arise.

• Developmental surveillance: early speech and language therapy, occupational therapy and physiotherapy for hypotonia, and educational support.
• Behavioural and mental health care: assess for ADHD, anxiety and depression, and treat in the usual way. For ADHD, methylphenidate 5 mg orally once or twice daily increasing weekly by 5 to 10 mg to a usual maximum of 60 mg daily (up to 100 mg in adults under specialist care), with growth and blood pressure monitoring.
• Puberty and fertility: monitor pubertal timing and menses. In premature ovarian insufficiency give hormone replacement (oestradiol 1 to 2 mg daily with progestogen) until about 51 years, and offer fertility counselling and preservation.
• Contraception and sexual health: routine counselling, with attention to premature ovarian insufficiency.
• Bone health: calcium and vitamin D, weight bearing exercise, and DXA scan if ovarian insufficiency.
• Renal and orthopaedic care: treat anomalies if found, and monitor scoliosis.
• Seizures: choose antiseizure medication by seizure type.
• Counselling: reassure that most women have a normal life, low recurrence risk, and children are usually chromosomally normal.

Special groups.

• Prenatal diagnosis: provide balanced counselling stressing the wide range of outcomes.
• Children with school difficulties: early neuropsychological testing allows tailored support.

Monitoring. Review growth, development, school progress and mood every 6 to 12 months. Menstrual and ovarian function review from puberty.

Referral and escalation. Refer to clinical genetics, paediatric development services and endocrinology. Urgent for self-harm risk, seizures, or primary amenorrhoea.