DermatologyTier 2Disease (DEADMAN)

Cutaneous manifestations of inherited disorders - tuberous sclerosis

Description

Tuberous sclerosis complex produces characteristic cutaneous findings from mutations in TSC1 (hamartin) or TSC2 (tuberin), tumour suppressor genes regulating the mTOR pathway - causing benign hamartomas across multiple organs, with distinctive skin findings often providing the earliest diagnostic clue

Autosomal dominant, though a substantial proportion of cases arise from de novo mutations rather than being inherited from an affected parent; variable expressivity means severity ranges widely between affected individuals, including within the same family

Loss of TSC1/TSC2 function removes normal inhibition of the mTOR pathway, driving excessive, dysregulated cell growth/proliferation - producing benign hamartomatous growths (not true malignancies, though some can cause significant local complications) across skin, brain, kidney, heart, and lung

Cutaneous diagnostic features: hypomelanotic macules ("ash-leaf spots") - often the earliest sign, sometimes present from infancy, best seen under Wood's lamp examination; facial angiofibromas (developing later, in childhood-adolescence); shagreen patches (a connective tissue naevus, typically lumbosacral); periungual fibromas (developing later, around puberty)
These cutaneous findings are incorporated into formal diagnostic criteria alongside major/minor features from other organ systems (cortical tubers, subependymal nodules on brain imaging, cardiac rhabdomyoma, renal angiomyolipoma)

mTOR inhibitors (e.g. everolimus) - a genuinely disease-modifying therapy, used for specific manifestations (subependymal giant cell astrocytoma, renal angiomyolipoma, and facial angiofibromas) given the direct mechanistic link to the dysregulated mTOR pathway
Regular surveillance for the major organ manifestations (renal imaging for angiomyolipoma, cardiac assessment for rhabdomyoma particularly in infancy, neurodevelopmental/seizure monitoring) given the multisystem nature of the condition
Genetic counselling given autosomal dominant inheritance, though many cases are de novo

Cortical tubers and epilepsy/infantile spasms, cardiac rhabdomyoma (often detected antenatally/in infancy, frequently regresses), renal angiomyolipoma, subependymal giant cell astrocytoma, autism spectrum disorder (increased prevalence)

The hypomelanotic "ash-leaf" macules can be present from birth/early infancy, well before the more classically recognised facial angiofibromas develop - Wood's lamp examination of an infant with new seizures (particularly infantile spasms) is a high-yield, simple bedside step that can support an early tuberous sclerosis diagnosis

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