Tuberous sclerosis complex

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]