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Tuberous sclerosis (TS), also known as tuberous sclerosis complex (TSC) or Bourneville disease, is a phakomatosis (neurocutaneous disorder) characterized by the development of multiple benign tumors of the embryonic ectoderm (e.g. skin, eyes, and nervous system).
Tuberous sclerosis has an incidence of 1:6000-12,000, with most being sporadic (see below) 1.
Tuberous sclerosis was classically described as presenting in childhood with a pathognomonic triad (Vogt triad) of:
seizures: absent in one-quarter of individuals
intellectual disability: up to half have normal intelligence
adenoma sebaceum: only present in about three-quarters of patients 1
The full triad is only seen in a minority of patients (~30%). Therefore, diagnostic criteria have been developed to aid the diagnosis of tuberous sclerosis.
When patients do not meet these criteria, they are sometimes referred to as manifesting a forme fruste of the condition.
Spontaneous mutations account for 50-86% of cases 3, with the remainder inherited as an autosomal dominant condition. In the majority of such cases (80%) the mutation has been narrowed down to two tumor suppressor genes, both part of the mTOR pathway 3,13:
TSC1: encoding hamartin, on chromosome 9q32-34
TSC2: encoding tuberin, on chromosome 16p13.3 (accounts for most cases)
Tuberous sclerosis has a significant number of manifestations, involving many organ systems. The most common radiographic manifestations are:
cortical or subependymal tubers and white matter abnormalities
A mnemonic to remember these manifestations is HAMARTOMAS.
cortical/subcortical tubers: 50% are in the frontal lobe; high T2 and low T1 with only 10% of tubers showing enhancement; frequently calcify after two years of age
88% are associated with calcification, although calcification absent in early childhood
visible within the first six months of age 4
variable signal, frequently high T1 and iso to high T2
enhancement is variable and is not a useful feature in distinguishing them from subependymal giant cell astrocytomas (SGCA); only serial growth is reliable 5,6
peak occurrence 8-18 years
tend to be large and demonstrate growth 5,6
tend to have intense enhancement
white matter abnormalities
variable appearance, with nodular, ill-defined, cystic and band-like lesions seen
radial bands are thought to be relatively specific for TS 7
tuberous sclerosis accounts for 20% of all angiomyolipomas 3
angiomyolipomas are seen in 55-75% of patients with tuberous sclerosis
tend to be multiple, large and bilateral
tend to grow and require surgical treatment, as the probability of hemorrhage is proportional to the size
micro and macro aneurysms may be present 3
fat may not be visible in up to 4.5% 1
renal cysts: the TSC2 gene is located adjacent to the PCKD1 gene 3
18-53% of patients with tuberous sclerosis 1
although rates of renal cell carcinoma are the same as in the general population, in patients with tuberous sclerosis, renal cell carcinoma tends to occur at a younger age 1
histologically identical to pulmonary LAM
retroperitoneal cystic lesions
chylous ascites, enlarged lymph nodes, dilatation of the thoracic duct
pancreatic neuroendocrine tumors 12
characterized by multicentric well-demarcated nodular proliferation of type II pneumocytes
differential diagnoses: miliary pulmonary opacities
benign striated muscle tumor characterized by the presence of spider cells
seen in 50-65% of patients with tuberous sclerosis
40-80% of patients with cardiac rhabdomyomas have tuberous sclerosis
multiple or single
typically involve the ventricular septum
occur before the age of 1 year (75% of cases) 1
typically regress before birth with spontaneous regression in 70% of children by age 4
thoracic duct and aortic/pulmonary artery aneurysm
myocardial fatty foci 14 / cardiac fat containing lesions 20
sclerotic bone lesions: 40-66% 1
hyperostosis of the inner table of the calvaria
periosteal new bone
bone cysts 8
Cutaneous lesions are present in ~95% of cases, but are rarely appreciated radiographically 8:
hypopigmented macules (ash leaf spots): seen in 90% of patients 1
facial angiofibromas (Pringle nodules or adenoma sebaceum); seen in 75% of patients
these skin lesions are neither adenomas nor sebaceous in origin 19
fibrous plaques of the forehead (15-20%)
confetti lesions: variant of leukoderma spots
shagreen patches: seen in 20-30% of patients
periungual angiofibroma (Koenen tumors): 20% of patients
Treatment and prognosis
Treatment of seizures is essential and depending on the degree of intellectual disability, supportive care may be required. Treatment will be dictated by individual manifestations (e.g. subependymal giant cell astrocytomas, or retroperitoneal hemorrhage from renal angiomyolipoma).
Approximately 40% of patients die by age 35 from complications of one or more of the manifestations mentioned above 1.
History and etymology
Historically, the disease was also called Bourneville disease, or even Bourneville-Pringle disease, although both names are still occasionally seen 15,16.
Désiré-Magloire Bourneville (1840-1909) was a French neurologist that is notable for his initial description of tuberous sclerosis (“Bourneville disease”) in 1880. His own medical training included apprenticeship to the renowned French neurologist, Jean Martin Charcot 16.
John James Pringle (1855-1922) was a Scottish dermatologist that also studied this disease leading some books to refer to it as "Bourneville-Pringle disease” 17.
Heinrich Vogt (1875-1957) was a German neurologist who is notable by establishing that the simultaneous presence of three clinical signs was pathognomonic for tuberous sclerosis; this became known as "Vogt triad” 18.
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