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Tuberous sclerosis

Tuberous sclerosis (TS), also known as tuberous sclerosis complex or Bourneville disease, is a neurocutaneous disorder (phakomatosis) characterized by development of multiple benign tumours of the embryonic ectoderm, e.g. skin, eyes, nervous system.

Epidemiology

Tuberous sclerosis has an incidence of 1:6000-12,000, with most being sporadic (see below) 6.

Clinical presentation

Tuberous sclerosis was classically described as presenting in childhood with a triad of:

  1. seizures: absent in one-quarter of individuals
  2. mental retardation: up to half have normal intelligence
  3. adenoma sebaceum: only present in about three-quarters of patients 6

The full triad is only seen in a minority of patients (~30%). Therefore, diagnostic criteria have been developed to aid the diagnosis of TS - see tuberous sclerosis diagnostic criteria. When patients do not meet these criteria they are sometimes referred to as manifesting a forme fruste of the condition. 

Pathology

Spontaneous mutations account for 50-86% of cases 4, with the remainder inherited as an autosomal dominant condition. In the majority of such cases (80%) the mutation has been narrowed down to two tumour suppressor genes:

  • TSC1: encoding HAMARTIN, on chromosome 9q32-34
  • TSC2: encoding TUBERIN, on chromosome 16p13.3 (accounts for most cases) 

Radiographic features

Tuberous sclerosis has a great number of manifestations, involving many organ systems. The most common manifestations are:

Neurological 
  • cortical/subcortical tubers: 50% are in the frontal lobe; high T2 and low T1 with only 10% of tubers showing enhancement; calcify frequently after 2 years of age
  • subependymal hamartomas:
    • 88% are associated with calcification, although calcification absent in early childhood
    • visible within the first 6 months of age 11
    • 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 9-10
  • subependymal giant cell astrocytomas (SGCA):
    • peak occurance 8-18 years
    • tend to be large and demonstrate growth 9-10
    • 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 12
  • retinal phakomas
  • rarer findings:
Abdominal 
  • renal angiomyolipoma(s):
    • TS accounts for 20% of all AMLs 4
    • AML's seen in 55-75% of patient with TS
    • tend to be multiple, large, bilateral.
    • tend to grow and require surgical treatment, as the probability of haemorrhage is proportional to the size
    • micro and macro aneurysms may be present 4
    • fat may not be visible in up to 4.5% 6
  • renal cysts: the TSC2 gene is located adjacent to the PCKD1 gene 4
    • 18-53% of patients with TS 6
  • renal cell carcinoma and oncocytomas:
    • although rates of RCC are the same as in the general population, in patients with tuberous sclerosis RCCs tend to occur at a younger age 6
  • retroperitoneal lymphangiomyomatosis 
    • histologically identical to pulmonary LAM
    • retroperitoneal cystic lesions
    • chylous ascites, enlarged lymph nodes, dilatation of thoracic duct
  • gastrointestinal polyps
Thoracic
  • lymphangiomyomatosis (LAM):
    • rare (1%)
    • some have studies have described lymphangiomyomatosis-like change to be present in 25-40% of female patients with TS
    • 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 proliferations of type II pneumocytes
    • benign, non-progressive
    • differential diagnoses: miliary pulmonary opacities
  • cardiac rhabdomyomas:
    • benign striated muscle tumour characterized by the presence of spider cells
    • seen in 50-65% of patients with TS
    • 40-80% of patients with cardiac rhabdomyomas have TS
    • multiple or single
    • typically involve the ventricular septum
    • occur before the age of 1 year (75% of cases) 6
    • typically regress before birth with spontaneous regression in 70% of children by age 4
  • thoracic duct and aortic/pulmonary artery aneurysm
Musculoskeletal
  • sclerotic bone lesions: 40-66% 6
  • hyperostosis of inner table of calvaria
  • periosteal new bone
  • scoliosis
  • bone cysts 5
Skin

Cutaneous lesions are present in ~95% of cases 7 :

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 haemorrhage from renal angiomyolipoma). 

Approximately 40% of patients die by age 35 from complications of one or more of the above mentioned manifestations 6

History and etymology

Désiré-Magloire Bourneville (1840-1909) was a French neurologist that is notable by early description of tuberous sclerosis (“Bourneville disease”) in 1880.

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”. 

Heinrich Vogt (1875-1936) was a German neurologist that is notable by establishing the three pathognomonic clinical signs for tuberous sclerosis that became known as "Vogt's triad”.


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