Paeds · genetics-dysmorphology-and-metabolism
Tuberous sclerosis complex
Also known as Tuberous sclerosis · TSC · Bourneville disease · Epiloia · Phakomatosis · mTOR-opathy
A fellowship approach to tuberous sclerosis complex: recognise the infant with hypomelanotic macules and infantile spasms or the fetus with a cardiac rhabdomyoma as having TSC, confirm with the 2012 international consensus criteria and TSC1/TSC2 testing, explain the hamartin-tuberin-Rheb-mTORC1 mechanism, build organ-by-organ surveillance, and offer everolimus for growing subependymal giant cell astrocytoma and refractory epilepsy.
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- An infant with infantile spasms (West syndrome) and hypomelanotic macules has tuberous sclerosis complex until proven otherwise
- A fetus or neonate with a cardiac rhabdomyoma should be screened for TSC, as it is the most common cardiac tumour of infancy
- A growing subependymal giant cell astrocytoma near the foramen of Monro threatens obstructive hydrocephalus and needs urgent imaging and neurosurgical or mTOR-inhibitor intervention
- New or worsening seizures, especially refractory focal epilepsy, warrant reassessment of brain lesions and consideration of everolimus or epilepsy surgery
- A large renal angiomyolipoma carries a risk of life-threatening haemorrhage and needs mTOR-inhibitor therapy or prophylactic embolisation
- A first-degree relative of a confirmed case who has not had genetic assessment needs cascade testing, as penetrance is effectively complete
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- Tuberous sclerosis complex diagnostic criteria
- Recognition of ash-leaf macules and infantile spasms
- Indications for TSC1/TSC2 genetic testing
- TSC1/TSC2-hamartin/tuberin-mTORC1 molecular mechanism
- Multidisciplinary surveillance and everolimus therapy for SEGA and epilepsy
- Distinguishing TSC from other phakomatoses and causes of infantile spasms
- Assessing a child with suspected tuberous sclerosis
- Genetic counselling of an autosomal-dominant tumour-predisposition syndrome
- Coordinating neurology, nephrology and developmental support
- Long case of a child with epilepsy, developmental delay and skin lesions
- Counselling a family on TSC inheritance and reproductive risk
- Genetic causes of neurodevelopmental disability and epilepsy
- Communication and safeguarding in lifelong chronic genetic disease
- Transition to adult care
- Tuberous sclerosis complex genetics and diagnostic criteria
- Infantile spasms and the phakomatoses
- Everolimus for subependymal giant cell astrocytoma and refractory epilepsy
- Skin and dysmorphology examination of the child with TSC
- Counselling on genetic testing and surveillance results
- Tuberous sclerosis complex
- Evaluation of the child with infantile spasms
- Cardiac rhabdomyoma and genetic counselling
- Phakomatoses and neurocutaneous syndromes
- Multidisciplinary care of chronic multisystem genetic disease
- Infantile spasms and West syndrome
- Everolimus and mTOR-inhibitor therapy
The mark-winning candidate keeps three layers in view at once. The first is the child in front of you: their seizures, their skin, their development, and the hamartomas that are and are not there across every organ. The second is the molecular mechanism: a lost tumour-suppressor brake that fails to restrain mTORC1-driven cell growth, and which a drug can restore downstream. The third is the family: an autosomal-dominant condition with 50 per cent transmission means every first-degree relative deserves assessment and counselling. [1] [2]
Overview & Definition
Tuberous sclerosis complex is an autosomal-dominant disorder caused by loss-of-function variants in either of two genes: TSC1 on chromosome 9q34, which encodes hamartin, and TSC2 on chromosome 16p13.3, which encodes tuberin. These two proteins join to form a complex that restrains cell growth by braking the mTORC1 signalling pathway. When the complex is lost, cells in the skin, brain, kidney, heart and lung proliferate without control and form the hamartomas and benign tumours that define the condition. [1]
The name "tuberous sclerosis" comes from the cortical tubers, the potato-like brain malformations first described by Bourneville in 1880, but the disease is far more than a brain disorder. It is a tumour-predisposition and malformation syndrome that declares itself differently at every age: a fetal cardiac rhabdomyoma, an infant with spasms, a preschool child with autism, and an adult woman with cystic lung disease can all be the same condition. [2]
TSC is one of the phakomatoses, the neurocutaneous syndromes shared with neurofibromatosis, Sturge-Weber syndrome and von Hippel-Lindau disease, but it is the only one driven by the mTOR pathway. Recognising the cluster of seizures, skin lesions and multi-organ hamartomas, and confirming it with the consensus criteria and molecular testing, sets the surveillance schedule and opens the door to targeted therapy. [1] [2]
References10ShowHide
- [1]Henske EP, Jóźwiak S, Kingswood JC, et al. Tuberous sclerosis complex. Nat Rev Dis Primers, 2016.PMID 27226234
- [2]Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet, 2008.PMID 18722871
- [3]Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Group. Pediatr Neurol, 2013.PMID 24053982
- [4]Krueger DA, Northrup H; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Group. Pediatr Neurol, 2013.PMID 24053983
- [5]Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol, 2014.PMID 25456370
- [6]French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis complex (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet, 2016.PMID 27613521
- [7]Curatolo P, Franz DN, Lawson JA, et al. Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial. Lancet Child Adolesc Health, 2018.PMID 30169322
- [8]de Vries P, Humphrey A, McCartney D, et al. Consensus clinical guidelines for the assessment of cognitive and behavioural problems in Tuberous Sclerosis. Eur Child Adolesc Psychiatry, 2005.PMID 15981129
- [9]Overwater IE, Swenker R, van der Ende EL, et al. Genotype and brain pathology phenotype in children with tuberous sclerosis complex. Eur J Hum Genet, 2016.PMID 27406250
- [10]Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med, 2010.PMID 21047224