Helsmoortel-Van der Aa Syndrome

Helsmoortel-Van der Aa syndrome (ADNP syndrome) is a neurodevelopmental disorder caused by de novo heterozygous variants in ADNP, with autism spectrum disorder, intellectual disability, hypotonia and a recognisable set of dental, visual and gastrointestinal features. This article concentrates on clinical care through childhood and adulthood.

Pathophysiology. ADNP is a chromatin regulator that interacts with the BAF complex and is needed for neuronal differentiation and synapse function. Most pathogenic variants are truncating changes in the last exon.

Clinical severity varies, and symptoms continue into adulthood.

Developmental, behavioural and sensory needs form the core of care.

• Autism spectrum disorder in most, with social communication difficulty
• Intellectual disability (mild to severe) and speech delay, and poor expressive language
• Hypotonia, motor delay and an unsteady gait
• Early eruption of primary teeth (before 4 months) and later dental crowding
• Hypermetropia, strabismus, cortical visual impairment, and nystagmus
• Constipation, reflux and feeding difficulty
• Sleep disturbance, high pain threshold, and sensory sensitivity
• Anxiety, ADHD and self-injury
• Seizures in a minority
• Congenital heart disease and hearing loss in some

• ADNP sequencing, within an autism gene panel or exome sequencing.
• Peripheral blood DNA methylation (episignature) analysis to classify uncertain variants.
• Parental testing to confirm de novo origin.
• Developmental and autism assessment.
• Ophthalmology, audiology and dental assessment.
• Echocardiography and thyroid function.

• Autism and communication: early intensive behavioural and communication therapy, picture and electronic communication aids, and a structured routine.
• Sleep: sleep hygiene and melatonin 2 to 5 mg orally 30 to 60 minutes before bed (up to 10 mg if needed).
• Gastrointestinal care: macrogol 0.4 to 0.8 g/kg daily (adults 1 to 3 sachets) for constipation, and omeprazole 0.7 to 1 mg/kg daily for reflux.
• Vision and dental care: spectacles, strabismus treatment, and early dental review.
• Behaviour and mental health: treat ADHD with methylphenidate 5 mg orally once or twice daily increasing weekly by 5 to 10 mg to a usual maximum of 60 mg daily after cardiac review, and anxiety with sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily. Use risperidone 0.25 mg daily increasing to 1 to 2 mg daily for severe irritability, with metabolic monitoring.
• Safety: watch for unrecognised injury and illness because of high pain threshold.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: continue behavioural support, mental health care and supported living arrangements.

Monitoring. Development, sleep and behaviour every 6 to 12 months. Vision, hearing and thyroid function yearly, dental review every 6 months, and metabolic monitoring if on risperidone.

Referral and escalation. Refer to clinical genetics, developmental paediatrics and child psychiatry. Urgent for self-injury, regression or seizures.