AM Report 11/22/2016: Tuberous Sclerosis

Remember the 3 large distinctions of anemia types and potential etiologies:
Microcytic (MCV < 80)
Normocytic (MCV 80-100)
Macrocytic (MCV >100)


Know how to interpret an iron panel in a medically ill patient:

1) Ignore the transferrin saturation

  • Reason: does not discriminate between anemia of inflammation and iron deficiency

2) Assess ferritin

  • <20: Iron deficiency
  • 20-100: Iron deficiency likely if inflammation, chronic viral infection, etc.
  • 100-800: Unlikely iron deficiency (unless hepatitis, chronic HD)
  • >800: Extremely unlikely iron deficient

3)Assess the TIBC (preferred over transferrin level)

  • >400: Iron deficient
  • 300-400: Likely a component of iron deficiency
  • 200-300: Unlikely iron deficient
  • <200: Very unlikely iron deficient, usually inflammation, liver failure

Tuberous Sclerosis:

  • Autosomal dominant genetic disorder due to a mutation in either TSC1 or TSC2 gene.
  • Incidence of 1 in 5000-10000 live births
  • De novo mutations account for ~ 80% of TSC cases
  • TSC is highly variable in expression – thus the severity of disease can vary substantially among affected individuals within the same family
  • TSC is characterized by the development of a variety of benign tumors in multiple organs: brain, heart, skin, kidney, lung, and liver

81-95% of TSC patients have on the characteristic skin lesions:

  • Angiofibromas ~ typically on the malar region of the face
  • Hypopigmented macules AKA ash-leaf spots ~ elliptic in shape
  • Shagreen patches ~ usually over the lower trunk
  • A distinctive brown fibrous plaque on the forehead ~ usually the first and most readily recognized feature of TSC
  • Periungual/subungual fibromas develop during adolescence or adulthood; toenails > fingernails

CNS lesions characteristic of TSC include:

  • Glioneuronal hamartomas (corticol tubers)
  • Subependymal nodules
  • Subependymals giant cell tumors (SGCTs): the characteristic brain tumor of TSC with a prevalence of ~ 5-20%, with 6-9% symptomatic

Neurological complications include:

  • Seizures ~ 79-90% of patients, most often in the 1st year of life
  • Cognitive deficits ~ 44-65%, associated with a history of infantile spasms or refractory seizures
  • Behavioral problems ~ 40-90%; typically hyperactivity, inattention, and self-injury

Cardiovascular complications include:

  • Rhabdomyoma: a benign tumor that often presents as multiple lesions
  • No evidence for malignant transformation; no treatment is necessary for asymptomatic tumors
  • Unlike other lesions of TSC, cardiac rhabdomyomas often disappear in later life spontaneously

Renal complications include:

  • Angiomyolipomas ~ 55-75% (estimated incidence)
  • Benign tumors composed of abnormal vessels, immature smooth-muscle cells, and fat cells
  • Due to the abnormal vasculature and potential for aneurysms, spontaneously life-threatening bleeding is a potential complication

Pulmonary complication of TSC:

  • Lympangiomyomatosis (LAM); Women (almost exclusively) – Widespread pulmonary proliferation of abnormal smooth-muscle cells and cystic changes within the lung parenchyma
  • Two common intial manifestations of LAM: dyspnea and spontaneous pneumothroax


Diagnostic criteria for TSC:

Diagnosis is based on either genetic testing results and/or clinical findings

Genetic criteria:

  • Identification of either a TSC1 or TSC2 pathogenic mutation (i.e. a mutation that clearly inactivates the function of TSC1/2 proteins)

Clinical criteria:

  • 11 major and 6 minor features
  • Definite diagnosis requires 2 major or 1 major/>2 minor features


Management of TSC:

  • Requires a multidisciplinary approach of specialists including: neurologists, dermatologists, geneticists, and pulmonologists
  • Referral to a TSC clinic is recommended given the complexity of the disease (next slide)
  • Long-term follow-up including monitoring of lesion growth (angiomyolipomas and SGCTs); no conclusive guidelines exist
    • Standard practice: brain/abdominal imaging every 3 years; more frequently with known lesions
    • Genetic counseling for family planning (risk of affected child is 50%)

Therapeutic Options:

  • Sirolimus (mTOR inhibitor) has been identified as a potential option given tumor cells from patients with TSC active mTOR (studies ongoing)

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