Tuberous sclerosis

Last revised by Dr Tom Foster on 17 Oct 2021

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:

  1. seizures: absent in one-quarter of individuals
  2. intellectual disability: up to half have normal intelligence
  3. 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.

See tuberous sclerosis diagnostic criteria 2.

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:

  • renal angiomyolipoma(s)
    • 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
  • renal cell carcinoma and oncocytomas
    • 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
  • retroperitoneal lymphangiomyomatosis (LAM)
    • histologically identical to pulmonary LAM
    • retroperitoneal cystic lesions
    • chylous ascites, enlarged lymph nodes, dilatation of the thoracic duct
  • gastrointestinal polyps
  • pancreatic neuroendocrine tumors 12
  • hepatic angiomyolipoma(s)
  • lymphangioleiomyomatosis (LAM)
    • rare (1%)
    • some studies have described a lymphangiomyomatosis-like change to be present in 25-40% of female patients with tuberous sclerosis
    • indistinguishable from sporadic LAM
    • pneumothorax and chylous pleural effusions common
    • ~80% 10-year survival
  • multifocal micronodular pneumocyte hyperplasia (MMPH)
    • rare
    • characterized by multicentric well-demarcated nodular proliferation of type II pneumocytes
    • benign, non-progressive
    • differential diagnoses: miliary pulmonary opacities
  • cardiac rhabdomyomas
    • 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
  • sclerotic bone lesions: 40-66% 1
  • hyperostosis of the inner table of the calvaria
  • periosteal new bone
  • scoliosis
  • 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 fibroma (Koenen tumors): 20% of patients

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

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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Cases and figures

  • Case 1: with subependymal nodules
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  • Case 2: with cortical tubers
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  • Case 3: renal angiomyolipomata
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  • Case 4: cardiac rhabodmyomas
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  • Case 5: with renal angiomyolipomata
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  • Case 6: with subependymal nodules
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  • Case 7: mulitple angiomyolipomata
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  • Case 8
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  • Case 10
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  • Case 11
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  • Case 12
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  • Case 12: showing renal AML
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  • Case 13
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  • Case 14
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  • Case 15
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  • Case 16
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  • Case 17: with retinal phakomas
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  • Case 18: enhancing tubers
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  • Case 19
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  • Case 20
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  • Case 21: with subependymal calcified hamartomas
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  • Case 22: with calcified subependymal nodules and sclerotic bone lesions
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  • Case 23
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  • Case 24
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  • Case 25: prenatal cardiac rhabdomyomas in tuberous sclerosis (prenatal and neonatal findings)
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  • Case 26
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  • Case 27: with cortical tubers and radial bands
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  • Case 28: with LAM
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  • Case 29
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