Smith-Kingsmore Syndrome

Smith-Kingsmore syndrome is an autosomal dominant disorder caused by activating missense variants in MTOR, with macrocephaly or megalencephaly, intellectual disability, seizures and autism. It is one of the mTORopathies, and the drug target is mTOR itself.

Pathophysiology. Activating variants in the kinase domain of MTOR raise mTORC1 and mTORC2 signalling, driving cell growth and abnormal cortical development. Germline variants cause the syndrome, while somatic mosaic variants cause focal cortical dysplasia and hemimegalencephaly.

Most cases are de novo, and recurrent variants (for example p.Glu1799Lys) account for many.

Seizures are often drug resistant, and mTOR inhibitors are used in selected patients.

• Macrocephaly or megalencephaly, often present at birth
• Intellectual disability of variable severity, with speech delay
• Epilepsy (about 70%) with focal or generalised seizures, and infantile spasms in some
• Autism spectrum disorder and behavioural problems
• Hypotonia, ataxia and an unsteady gait
• Facial features: frontal bossing, down slanting palpebral fissures, and a depressed nasal bridge
• Brain MRI: megalencephaly, ventriculomegaly, cortical dysplasia, and thick corpus callosum
• Skin findings: pigmentary changes, and haemangiomas
• Hypoglycaemia and endocrine problems in some, and an increased risk of tumours reported in a few

• MTOR sequencing, or a megalencephaly gene panel or exome sequencing. Blood testing may miss mosaic variants, so tissue testing is useful.
• Brain MRI to define megalencephaly and cortical malformation.
• EEG and seizure characterisation.
• Developmental and autism assessment.
• Parental testing to confirm de novo origin.
• Echocardiography, renal ultrasound, ophthalmology and audiology assessment.

Differential diagnosis.

• Tuberous sclerosis complex (TSC1 and TSC2)
• PIK3CA-related overgrowth spectrum (megalencephaly capillary malformation)
• PTEN hamartoma tumour syndrome
• Sotos syndrome and Weaver syndrome
• Fragile X syndrome
• Hemimegalencephaly of somatic origin

• Epilepsy: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily, vigabatrin for infantile spasms (50 mg/kg daily increasing to 100 to 150 mg/kg daily), and 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.
• mTOR inhibition in refractory epilepsy or severe features: everolimus 4.5 mg/m2 orally once daily, or sirolimus 0.8 mg/m2 orally twice daily in children, adjusted to a trough level of 5 to 15 ng/mL, in specialist care. Evidence in this syndrome comes from case reports and small series.
• Monitoring on mTOR inhibitors: blood count, lipids, glucose, creatinine, and liver tests every 3 months, and watch for mouth ulcers, infection and impaired wound healing.
• Epilepsy surgery for a focal resectable lesion in refractory epilepsy.
• Development and behaviour: early intervention, speech therapy, applied behavioural support, and special education.
• Hydrocephalus or raised pressure: neurosurgical assessment if progressive ventriculomegaly.
• Endocrine care: monitor glucose, especially in infancy.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Infants on mTOR inhibitors: avoid live vaccines during treatment and ensure other vaccines are complete before starting.

Monitoring. Seizures and development every 3 to 6 months. Head circumference at each visit, and MRI as clinically indicated. Blood tests every 3 months on mTOR inhibitors.

Referral and escalation. Refer to clinical genetics, paediatric neurology and epilepsy surgery. Urgent for prolonged seizures, raised intracranial pressure or infection on an mTOR inhibitor.