50 Years Ago in The Journal of Pediatrics:

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Chao DH. J Pediatr 1959;55:447-459

“But it's no use going back to yesterday, because I was a different person then,” declared the heroine in Lewis Carroll's Alice's Adventures in Wonderland. Shortly after that 1865 classic, the French neurologist Bourneville described tuberous sclerosis. Fifty years ago in The Journal, Chao elaborated how tuberous sclerosis manifestations differ longitudinally in children. Nevertheless, Chao goes down the rabbit hole when acknowledging Vogt's triad—epilepsy, mental deficiency, and adenoma sebaceum—as requisite for diagnosis in the “defective” child who “rarely lives more than 25 years.” Pediatrics was a different field then.

Today we recognize tuberous sclerosis as an autosomal-dominant, progressive disorder that arises de novo in two thirds of cases. Defects in the TSC1 and TSC2 genes, which produce hamartin and tuberin, respectively, and inhibit the downstream mTOR-signaling complex, can be identified in 70% of individuals. Disease penetrance is highly variable, and genetic mosaicism plays a role. Seizures are the most common herald, because of tubers in the cerebral cortex. Patients can also harbor subependymal nodules or rarely subependymal giant cell astrocytomas. As the child ages, skin manifestations can include hypomelanotic macules (ash leaf spots), café-au-lait spots, facial angiofibroma (adenoma sebaceum), shagreen patches, and periungal fibromas. Some toddlers have cardiac rhabdomyomas, and others can have renal cysts or angiomyolipoma.

Diagnosis and management differ vastly from 50 years ago. Ash leaf spots, seen best by today's looking glass, the Wood's lamp, can establish the diagnosis in the toddler with seizures. More commonly, tuberous sclerosis is diagnosed after brain magnetic resonance imaging after seizures, especially infantile spasms. Vigabtrin can abate these spasms instead of adrenocorticotropic hormone. Epilepsy surgery can be an option for patients with refractory seizures localized to a single tuber. The mTOR inhibitor rapamycin can shrink subependymal giant cell astrocytomas without surgery. Contrary to Vogt's triad, cognitive outcomes are known to be highly variable, and some children normal and others autistic.

Can we prevent a child from becoming a different person than he was then? Preliminary reports indicate that rapamycin might reverse intellectual disability or prevent seizures in tuberous sclerosis.¹ As Alice mused, “It would be so nice if something made sense for a change.”

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Reference 

1. Crino PB. Do we have a cure for tuberous sclerosis complex?. Epilepsy Curr. 2008;8:159–162
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