see also:

• tuberous sclerosis complex (TSC) is a rare, multi-system, genetic disorder with many potential clinical features
• the “tubers” refers to hard swellings in the brains of patients first described by French neurologist Désiré-Magloire Bourneville in 1880
• caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively.
• TSC2 mutations are more frequent (55-90% of cases) and have usually more severe symptoms
• these proteins act as tumor growth suppressors, regulating cell proliferation and differentiation, thus functional loss results in increased risk of benign tumors.

• autosomal dominant inheritance with variable expressivity, and high but incomplete penetrance
• however 2/3rds of cases are de novo spontaneous mutations
• prevalence is estimated to be 7 to 12 in 100,000

• excessive benign tumour growths
  • hamartia (malformed tissue such as the cortical tubers)
    • intracerebral tubers which may cause seizures, intellectual disability, developmental delay, and behavioral problems
  • hamartomas
    • benign growths such as facial angiofibroma and subependymal nodules
  • renal angiomyolipomas (AMLs)
  • etc

• possible intellectual impairment
  • 40–50% have a normal IQ (more likely in TSC1 mutations) however, there are often specific learning disorders such as dyscalculia
  • ~half of cases when assessed for neuropsychological skills, are in the bottom 5th percentile in some areas, especially attention, memory, and executive functions of planning, etc
  • profound intellectual disability is seen in a third of TSC2 mutation patients
• almost all have dental enamel pits
• 90% have hypomelanic macules (“ash leaf spots”)
  • usually the only visible sign of TSC at birth
  • may require a Wood's lamp to see them
  • scalp lesions may be a white patch of hair (poliosis)
  • patches smaller than 3mm are known as “confetti” skin lesions
• 75% have facial angiofibroma which usually appears as mainly malar butterfly distribution papular growths which appear during childhood
• adults may have ungual fibromas (Koenen's tumors) nail bed growths which may cause nail deformities especially in toes
  • tend to develop after age 15yrs especially in women and are more commonly seen in middle age (rare in childhood)
• 50% have Shagreen patches - pigmented areas of thick leathery skin that are dimpled like an orange peel usually found on the lower back or nape of the neck, or scattered across the trunk or thighs and more common with age
• 20-50% of adults have intraoral fibromas are small surface-tumours found in the gums, inside the cheeks or tongue
• 25% have fibrous cephalic plaques on their forehead
• >80% of children under age 2 years have cardiac rhabdomyomas
  • 80% of children under two-years-old with TSC have at least one rhabdomyoma, and about 90% of those will have several
  • some may cause heart failure in the foetus or first year of life
  • only around 20% of children over two years old have residual cardiac rhabdomyomas but can cause arrhythmias
  • vary in size from a few millimetres to several centimetres and are usually in the ventricles
• 26-80% have renal angiomyolipomas (AMLs)
  • often multiple
  • often present at a younger age (mean age 31yrs) than sporadic AMLs (mean age 54yrs)
  • often are larger (mean size 8cm vs 4.5cm for sporadic) and more likely to result in sudden catastrophic haemorrhage when greater than 4.5cm
  • more likely to require surgical intervention (50% vs 28% for sporadic cases)
• retinal astrocytic hamartomas (or “phakomas”) may calcify and be seen on CT scan
• angiofibroma of eyelids
• coloboma
• may also cause:
  • subependymal nodules which form in the walls of cerebral ventricles and tend to calcify as the patient ages
    • rarely, these can transform into giant cell astrocytoma which typically develops in the region of the foramen of Monro and can block CSF flow causing hydrocephalus
  • lymphangioleiomyomatosis (LAM) of the lung
    • progressive replacement of the lung parenchyma with multiple cysts
    • these are apparently monoclonal metastasis from a coexisting renal angiomyolipoma
  • rarely, pancreatic neuroendocrine tumours
  • very rarely, cancerous hamartoblastomas
  • 2% of individuals with TSC also develop polycystic kidney disease in childhood as the PKD1 gene which causes polycystic kidney disease is contiguous with TSC2 gene hence a gross mutation of both genes can occur

• there isn't one sign that is pathognomonic to TSC, nor are all signs seen in all individuals
• can be first diagnosed at any stage of life
• an individual with two major features, or one major feature and at least two minor features can be given a definite diagnosis of TSC

• at least three hypomelanotic macules > 5mm in size
• at least three facial angiofibromas
• at least two ungual fibromas
• a Shagreen patch
• multiple retinal nodular hamartomas
• cortical dysplasias
• subependymal nodule
• subependymal giant cell astrocytoma
• cardiac rhabdomyoma
• lymphangioleiomyomatosis of lung
• at least two renal angiomyolipomas

• “Confetti” skin lesions
• at least three dental enamel pits
• at least two intraoral fibromas
• retinal achromic patch
• multiple renal cysts
• nonrenal hamartoma eg. liver, spleen, etc