The history of tuberous sclerosis (TSC) 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. Further organ involvement was discovered, along with a realisation that the condition was highly variable in its severity. The late 20th century saw great improvements in cranial imaging techniques and the discovery of the two genes. Finally, the start of the 21st century saw the beginning of a molecular understanding of the illness, along with possible non-surgical therapeutic treatments.
19th century
1835 French dermatologist Pierre François Olive Rayer published an atlas of skin diseases. It contains 22 large coloured plates with 400 figures presented in a systematic order. On page 20, fig. 1 is a drawing that is regarded as the earliest description of tuberous sclerosis. Entitled "végétations vasculaires", Rayer noted these were "small vascular, of papulous appearance, widespread growths distributed on the nose and around the mouth". No mention was made of any medical condition associated with the skin disorder. 1850 English dermatologists Thomas Addison and William Gull described, in Guy's Hospital Reports, the case of a four-year-old girl with a "peculiar eruption extending across the nose and slightly affecting both cheeks", which they called "vitiligoidea tuberosa". 1862 German physician Friedrich Daniel von Recklinghausen, who was working as an assistant to Rudolf Virchow in the Institute for Pathological Anatomy in Berlin, presented a case to the city's Obstetrical Society. The heart of an infant who "died after taking a few breaths" had several tumours. He called these tumours "myomata", one of which was the "size of a pigeon's egg". He also noted the brain had "a great number of scleroses". These were almost certainly the cardiac rhabdomyomas and cortical tubers of tuberous sclerosis. He failed to recognise a distinct disease, regarding it as a pathological-anatomical curiosity. Von Recklinghausen's name would instead become associated with neurofibromatosis after a classic paper in 1881. 1864 German pathologist Rudolf Virchow published a three-volume work on tumours that described a child with cerebral tuberous sclerosis and rhabdomyoma of the heart. His description contained the first hint that this may be an inherited disease: the child's sister had died of a cerebral tumour. 1880 French neurologist Désiré-Magloire Bourneville had a chance encounter with the disease that would bear his name. He was working as an unofficial assistant to Jean Martin Charcot at La Salpêtrière. While substituting for his teacher, Louis J.F. Delasiauve, he attended to Marie, a 15-year-old girl with psychomotor retardation, epilepsy and a "confluent vascular-papulous eruption of the nose, the cheeks and forehead". She had a history of seizures since infancy and was taken to the children's hospital aged three and declared a hopeless case. She had learning difficulties and could neither walk nor talk. While under Bourneville's care, Marie had an ever-increasing number of seizures, which came in clusters. She was treated with quinquina, bromide of camphor, amyl nitrite, and the application of leeches behind the ears. On 7 May 1879 Marie died in her hospital bed. The post-mortem examination disclosed hard, dense tubers in the cerebral convolutions, which Bourneville named Sclérose tubéreuse des circonvolutions cérébrales. He concluded they were the source (focus) of her seizures. In addition, whitish hard masses, one "the size of a walnut", were found in both kidneys. 1881 German physician Hartdegen described the case of a two-day-old baby who died in status epilepticus. Post-mortem examination revealed small tumours in the lateral ventricles of the brain and areas of cortical sclerosis, which he called "glioma gangliocellulare cerebri congenitum".
1881 Bourneville and Édouard Brissaud examined a four-year-old boy at La Bicêtre. As before, this patient had cortical tubers, epilepsy and learning difficulties. In addition he had a heart murmur and, on post-mortem examination, had tiny hard tumours in the ventricle walls in the brain (subependymal nodules) and small tumours in the kidneys (angiomyolipomas). 1885 French physicians Félix Balzer and Pierre Eugène Ménétrier reported a case of "adénomes sébacés de la face et du cuir" (adenoma of the sebaceous glands of the face and scalp). The term has since proved to be incorrect as they are neither adenoma nor derived from sebaceous glands. The papular rash is now known as facial angiofibroma. 1885 French dermatologists François Henri Hallopeau and Émile Leredde published a case of adenoma sebaceum that was of a hard and fibrous nature. They first described the shagreen plaques and later would note an association between the facial rash and epilepsy. 1890 Scottish dermatologist John James Pringle, working in London, described a 25-year-old woman with subnormal intelligence, rough lesions on the arms and legs, and a papular facial rash. Pringle brought attention to five previous reports, two of which were unpublished. Pringle's adenoma sebaceum would become a common eponym for the facial rash.
Early 20th century
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