page_title: Timeline of tuberous sclerosis
section_title: Early 20th century
hierarchical_section_title: Timeline of tuberous sclerosis / Early 20th century
caption_attribution_description: retinal changes visible in fundoscopy in patient with tuberous sclerosis (Bourneville disease). Drawing from van der Hoeve's classic paper
context_page_description: The history of tuberous sclerosis research spans less than 200 years. TSC is a rare, multi-system genetic disease that can cause benign tumours to grow on the brain or other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioural problems and skin abnormalities, as well as lung and kidney disease. TSC is caused by mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively. These proteins act as tumour growth suppressors and regulate cell proliferation and differentiation. Originally regarded as a rare pathological curiosity, it is now an important focus of research into tumour formation and suppression.
  The history of TSC research is commonly divided into four periods. In the late 19th century, notable physicians working in European teaching hospitals first described the cortical and dermatological manifestations; these early researchers have been awarded with eponyms such as "Bourneville's disease" and "Pringle's adenoma sebaceum". At the start of the 20th century, these symptoms were recognised as belonging to a single medical condition.
context_section_description: 1901
  Italian physician GB Pellizzi studied the pathology of the cerebral lesions. He noted their dysplastic nature, the cortical heterotopia and defective myelination. Pellizzi classified the tubers into type 1 (smooth surface) and type 2 (with central depressions).
  1903
  German physician Richard Kothe described periungual fibromas, which were later rediscovered by the Dutch physician Johannes Koenen in 1932 (known as Koenen's tumours).
  1906
  Australian neurologist Alfred Walter Campbell, working in England, considered the lesions in the brain, skin, heart and kidney to be caused by one disease. He also first described the pathology in the eye. His review of 20 reported cases led him to suggest a diagnostic triad of symptoms that is more commonly attributed to Vogt.
  1908
  German paediatric neurologist Heinrich Vogt established the diagnostic criteria for TSC, firmly associating the facial rash with the neurological consequences of the cortical tubers. Vogt's triad of epilepsy, idiocy, and adenoma sebaceum held for 60 years until research by Manuel Gómez discovered that fewer than a third of patients with TSC had all three symptoms.
  1910
  J. Kirpicznick was first to recognise that TSC was a genetic condition. He described cases of identical and fraternal twins and also one family with three successive generations affected.
  1911
  Edward Sherlock, barrister-at-law and lecturer in biology, reported nine cases in his book on the "feeble-minded". He coined the term epiloia, a portmanteau of epilepsy and anoia (mindless). The word is no longer widely used as a synonym for TSC. The geneticist Robert James Gorlin suggested in 1981 that it could be a useful acronym for epilepsy, low intelligence, and adenoma sebaceum.
  1913
  H. Berg is credited with first stating that TSC was a hereditary disorder, noting its transmission through two or three generations.
  1914
  P. Schuster described a patient with adenoma sebaceum and epilepsy but of normal intelligence. This reduced phenotypic expression is called a forme fruste.
  1918
  French physician René Lutembacher published the first report of cystic lung disease in a patient with TSC. The 36-year-old woman died from bilateral pneumothoraces. Lutembacher believed the cysts and nodules to be metastases from a renal fibrosarcoma. This complication, which only affects women, is now known as lymphangioleiomyomatosis (LAM).
  1920
  Dutch ophthalmologist Jan van der Hoeve described the retinal hamartomas (phakoma). He grouped both TSC and neurofibromatosis together as "phakomatoses" (later called neurocutaneous syndromes).
  1924
  H. Marcus noted that characteristic features of TSC such as intracranial calcifications were visible on x-ray.
caption: Jan van der Hoeve's retinal phakoma.
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