DDX3X Syndrome

DDX3X syndrome is an X-linked neurodevelopmental disorder caused by de novo variants in DDX3X, with intellectual disability, hypotonia, movement disorders, behavioural problems and corpus callosum hypoplasia. It is one of the commoner causes of intellectual disability in females, in whom variants are usually loss-of-function.

Pathophysiology. DDX3X encodes a DEAD-box RNA helicase involved in translation, RNA transport and Wnt signalling. In females, loss-of-function variants cause haploinsufficiency, and the effect of X inactivation (often skewed) modifies severity.

Males with hemizygous variants are less common; they usually carry missense variants that retain some function, and often inherit them from an unaffected or mildly affected mother.

Missense variants in the helicase domain tend to give more severe malformations.

• Hypotonia in infancy and motor delay
• Intellectual disability from mild to severe, and absent or limited speech in many
• Movement disorders: spasticity, dystonia, ataxia and stereotypies
• Behavioural problems: autism features, aggression, self-injury and anxiety
• Microcephaly or macrocephaly
• Corpus callosum hypoplasia and ventriculomegaly, with polymicrogyria in those with missense variants
• Epilepsy in a minority
• Feeding difficulty, reflux, constipation
• Vision problems, hearing loss and scoliosis
• Congenital heart disease, and precocious puberty in some

• DDX3X sequencing with deletion and duplication analysis, within an intellectual disability panel or exome sequencing.
• Parental testing: most variants are de novo; a male may inherit a missense variant from his mother.
• Brain MRI for corpus callosum and cortical malformation.
• EEG if seizures.
• Developmental, vision and hearing assessment.
• Echocardiography and endocrine review if puberty is early.

• Development and education: early intervention, physiotherapy, speech therapy with augmentative communication, and special education.
• Spasticity and dystonia: baclofen 0.3 mg/kg daily in divided doses increasing weekly to 2 mg/kg daily (maximum 60 mg), botulinum toxin for focal problems, and orthotics.
• Epilepsy: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, with other agents by seizure type. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Behaviour and mental health: structured behavioural support, sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily for anxiety, and risperidone 0.25 mg daily increasing to 1 to 2 mg daily for severe irritability, with metabolic monitoring.
• Feeding and gastrointestinal care: omeprazole 0.7 to 1 mg/kg daily and macrogol 0.4 to 0.8 g/kg daily.
• Sleep: sleep hygiene and melatonin 2 to 5 mg 30 to 60 minutes before bed (up to 10 mg if needed).
• Orthopaedic care: yearly spine and hip review, with bracing or surgery for progressive scoliosis.
• Endocrine care: assess for precocious puberty if secondary sexual characteristics appear before 8 years in girls or 9 years in boys.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism. A mother carrying a variant has a 50% risk of transmission in each pregnancy.

Special groups.

• Males with an inherited missense variant: test the mother and counsel on the 50% transmission risk.

Monitoring. Development, behaviour and seizures every 6 to 12 months. Spine, hips, vision and hearing yearly, and pubertal staging every year from 7 years.

Referral and escalation. Refer to clinical genetics, paediatric neurology and orthopaedics. Urgent for regression, self-injury or prolonged seizures.