Tuberous Sclerosis complex | EPILOIA

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EPILOIA: Epilepsy, Low Inteligence, Adenoma Sebaceum
  • Epidemoliologia
    • IncidĂŞncia 1 em 10.000
  • Inheritance pattern
    • AD
    • 75% are due to de novo mutations
    • Segmental disease may occur
    • 95% penetrance
    • Variable expression
  • Mutation
    • Mutations in hamartin (TSC1) or tuberin (TSC2)
      • Encode tumor suppressor gene, inhibit mTOR pathway → treatment implication
      • TSC2 mutation more common and more severe disease
    • TS Complex caused by constitutive activation of mTOR
      • → Increased/abdnormal cell differentiation, proliferation, migration
          • notion image
  • Clinical findings
      • Alikhan Review of Dermatology
      Alikhan Review of Dermatology
    • Cutaneous
      • First skin finding: ≥3 hypopigmented macules in neonates/infancy
        • More specific: confetti, ash leaf (lancet shape)
        • More common: polygonal, thumbprint shape
        • Wood’s lamp may aid in diagnosis
      • Angiofibromas (mais tarde)
        • May be confused with acne
        • Benign tumor composed of blood vessels and fibrous connective tissue
        • Age of onset: between 3–4 years of age; development of lesions increases during adolescence
        • Mostly located around the nose and cheeks
        • Distribution resembles a butterfly shape
        • Also in Multiple Endocrine Neoplasia type 1 (Wermer Syndrome)
      • Shagreen patch
        • Connection tissue nevus/hamartoma
        • Orange peel surface
        • “Cobblestone” nevus
        • Lower back
      • Fibrous cephalic plaque (anunciadora)
      • Dental pits
      • Ungueal fibromas or Koenen tumors
        • Subungueal or periungueal flesh colored papules
    • Other organs
      • Neurologic
        • Benign tumors in the brain → may cause obstruction, seizures, neurodevelopmental issues
          • Infantile spasms (West syndrome) → Children with infantile spasm of unknown etiology are often worked-up for tuberous sclerosis - woods light and skin imaging helps
          • Brain tumors
            • Hamartomas: can be cortical (glioneuronal hamartoma or tuber), subcortical, and/or subependymal
            • Giant cell astrocytoma
      • Bone damage
        • Pseudocystic phalanges
        • Areas of osteosclerosis with pagetoid features of the cranial vault
        • Localized gigantism
        • Rib hypertrophy
      • Cardiac rhabdomyomas most patients
        • May spontaneous regress
        • May cause symptoms of mitral regurgitation and/or obstructive heart failure
      • Lung involvement - Lymphangiomyomatosis - common in women
      • Kidneys Angiomyolipomas, cysts or renal carcinoma
        • May cause: hypertension, hematuria, proeinuria
        • Malignant transformation is rare
      • Vascular Aneurysms of large arteries
        • đź’ˇ
        HAMAARTOMASS: Hamartomas, Ash leaf spots, Mind (intellectual disability), Adenoma sebaceum, renal Angiomyolipoma, Rhabdomyoma, Tumor suppressor genes (TSC1 gene and TSC2 gene), autosomal dOminant, Mitral regurgitation, Astrocytomas, Seizures, and Shagreen patches.
        DOI 10.1038/nrdp.2016.35
        DOI 10.1038/nrdp.2016.35
      notion image
  • DDx
    • Conditions associated with ash-leaf spots
      • Nevus anemicus
      • Hypomelanosis of Ito
      • Vitiligo
      • Piebaldism
    • Conditions associated with angiofibroma
    • Conditions associated with shagreen patch
      • Birt-Hogg-Dube syndrome
      • MEN-1 syndrome
    • Other hamartoma syndromes
      • Cowden syndrome
      • Juvenile polyposis syndrome
      • Peutz-Jeghers syndrome
      • Gorlin syndrome
  • DiagnĂłstico
    • Genetic criteria: identification of a pathogenic mutation in either TSC1 or TSC2 in DNA from normal tissue is sufficient to make a definitive diagnosis
      • BUT, the absence of a mutation doesn’t exclude the diagnosis → mosaics are common
    • Clinical criteria
      • notion image
      Alikhan Review Dermatology
      Alikhan Review Dermatology
  • Abordagem (rever - AMBOSS)
    • ECG: cardiac rhabdomyoma can cause ventricular hypertrophy and arrhythmias
    • EEG: seizure activity
    • Imaging
      • Echocardiography: rhabdomyoma (common in the apex of the left ventricle)
      • Abdominal MRI: renal cyst, angiomyolipoma, and/or carcinoma
      • Contrast cerebral CT/MRI
        • Tumors (e.g., giant cell astrocytomas)
        • Enlarged ventricles (tumors in the periventricular area commonly cause obstructive hydrocephalus)
    • Genetic testing: mutation of TSC1 or TSC2 gene
  • Treatment with mTOR inhibitors
    • Angiofibromas, cephalic plaques may be treated by destructive modalities (laser, electrosurgery) & topical mTOR inhibitors
    • Everolimus is for renal angiomyolipomas and SEGA (Subependymal Giant Cell Astrocytoma)
    • Sirolimus (rapamycin) is for LAM (lymphangioleiomyomatosis)
    • Sirolimus cream for facial angiofibromas → 600€ a tube
    • Cardiac rhabdomyomas spontaneously regress
    • Seizure control
      • Infantile spasms: vigabatrin or ACTH
      • Anticonvulsants
  • Prognosis
    • Renal disease and epilepsy are the most common causes of death.
    • Life expectancy depends on severity of disease but can be normal if symptoms are mild and complications are treated accordingly.
  • Follow up
    • Annual renal ultrasound or MRI
    • Annual chest CT in women ≥30 yo to screen for lymphangioleiomyomatosis
    • Controversial: regular brain MRI until 20 years old to screen for SEGA (subependymal giant cell astrocytoma)
  • Genetic counceling
    • Difficult due to the high phenotypic variability
    • Frequency and significance of neurological involvement must be emphasized