Coffin-Lowry Syndrome

Coffin-Lowry syndrome is an X-linked disorder caused by pathogenic variants in RPS6KA3, with severe intellectual disability in males, short stature, coarse face, tapered fingers and stimulus induced drop episodes. Females show a range from mild to severe disease because of X-inactivation.

Pathophysiology. RPS6KA3 encodes RSK2, a kinase of the MAPK signalling cascade needed for synaptic plasticity and skeletal growth. Loss of function impairs these processes.

About 70% to 80% of cases are de novo, and the rest are inherited from carrier mothers.

Males with loss-of-function variants have the full disorder, and the course is progressive in skeleton and mobility.

• Severe intellectual disability in males, with very limited speech
• Short stature and microcephaly
• Coarse face with prominent forehead, hypertelorism, downslanting fissures, thick lips and a wide nose
• Soft, fleshy hands with tapered fingers, hypermobile joints
• Kyphoscoliosis and pectus deformity
• Stimulus induced drop episodes (sudden falls on startle) in about a third of males
• Hearing loss, dental anomalies and hypodontia
• Cardiac anomalies such as mitral valve prolapse
• Seizures in a minority
• Females: variable features, often mild learning difficulty with a characteristic hand and face

• RPS6KA3 sequencing with deletion and duplication analysis.
• Skeletal radiographs: spine, hands, and skull for characteristic changes.
• Hearing assessment, dental imaging, echocardiography.
• Developmental assessment.
• Testing of female relatives for carrier status, with X-inactivation not predictive of severity.

• Stimulus induced drop episodes: reassure and protect from injury. Treat with clonazepam 0.01 to 0.03 mg/kg daily in two to three divided doses (adults 0.5 mg twice daily increasing to 2 mg twice daily), or valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily, or clomipramine 10 to 25 mg at night increasing to 75 mg in adults. Use falls protection with a helmet and supervision.
• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, or other antiseizure drugs by seizure type.
• Orthopaedic care: spinal bracing and fusion for progressive scoliosis, with monitoring of cervical spine, and physiotherapy.
• Cardiac care: echocardiography at diagnosis and every 3 to 5 years, or more often if abnormal.
• Hearing and dental care: hearing aids, audiology every 12 months, and regular dental review.
• Development and communication: early intervention, speech therapy and augmentative communication, occupational therapy and special education.
• Behaviour and mental health: behavioural support, and treatment of anxiety, aggression or self-injury as needed.
• Genetic counselling: an affected mother has a 50% chance of transmitting the variant to each child; a carrier daughter may be affected, and an affected son's daughters are all carriers.

Special groups.

• Female carriers: examine for mild features and offer reproductive counselling.
• Anaesthesia: prepare for possible cervical spine instability and drop episodes.

Monitoring. Development and seizures every 6 to 12 months. Spine review every 6 months during growth, hearing yearly, and echocardiography every 3 to 5 years.

Referral and escalation. Refer to clinical genetics, paediatric neurology and orthopaedics. Urgent for rapid spinal deformity, repeated falls with injury, or seizures.