Kleefstra Syndrome

Kleefstra syndrome is a neurodevelopmental disorder caused by haploinsufficiency of EHMT1 at 9q34.3, either through a terminal deletion or an intragenic loss-of-function variant. It features intellectual disability, hypotonia, childhood facial features, autism and, in later life, regression and psychiatric disease.

Pathophysiology. EHMT1 encodes a histone methyltransferase that dimethylates histone H3 lysine 9 and represses gene expression, with roles in synaptic function and learning. Loss of one copy disturbs this chromatin regulation.

Most cases are de novo. Larger deletions add features beyond the EHMT1 phenotype.

Care is lifelong and changes from childhood to adulthood.

• Moderate to severe intellectual disability and severely limited speech
• Hypotonia in infancy, feeding difficulty
• Childhood facial features: brachycephaly, midface hypoplasia, synophrys, anteverted nares, everted lower lip
• Microcephaly
• Autism spectrum disorder, and later regression with apathy and catatonia like features in some
• Seizures in about a third
• Congenital heart disease, renal and urogenital anomalies
• Obesity in later childhood and adulthood
• Hearing loss, sleep disturbance
• Recurrent infections and airway problems
• Coarsening facial features with age

• Chromosomal microarray for 9q34.3 deletions including EHMT1.
• EHMT1 sequencing with deletion and duplication analysis when the microarray is normal.
• Parental testing to confirm de novo origin.
• Echocardiography, renal ultrasound, hearing and vision assessment.
• EEG if seizures.
• Developmental and autism assessment, with metabolic screening (weight, glucose, lipids) in older patients.

• Development and education: early intervention, speech therapy with augmentative communication, occupational therapy and special education.
• Epilepsy: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, with other agents by seizure type.
• Behaviour and mental health: structured behavioural support. Treat anxiety with sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily. In adolescents or adults with regression, catatonia or depression, assess promptly: lorazepam 0.5 to 1 mg orally or intramuscularly up to three times daily in catatonia, with specialist psychiatric input.
• Weight management: early dietary advice and structured exercise, with yearly glucose and lipid screening in obese patients.
• Cardiac and renal care: treat structural anomalies.
• Hearing and vision: audiology yearly, and treatment of hearing loss.
• Sleep: sleep hygiene and melatonin 2 to 5 mg orally 30 to 60 minutes before bed (up to 10 mg if needed).
• Respiratory care: vaccination and prompt treatment of infections.
• Genetic counselling: de novo deletions and variants carry low recurrence risk, unless a parent has a balanced rearrangement.

Special groups.

• Adolescents and adults: monitor for regression, catatonia, depression and psychosis, because these respond to early treatment.

Monitoring. Development, behaviour and growth every 6 to 12 months. Cardiac and renal review as advised, audiology yearly, and metabolic screening yearly.

Referral and escalation. Refer to clinical genetics, developmental paediatrics and, in adults, psychiatry. Urgent for loss of skills, catatonia, self-neglect or seizures.