USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 3-year-old girl with a history of seizures comes to the emergency department because of headaches and more frequently occurring seizures. Her social, behavioural, and mental development has lagged significantly behind that of her peers. Her temperature is 37.5°C (99.5°F), pulse is 70/min, respirations are 14/min, and blood pressure is 118/75 mmHg . Physical examination shows patches of leathery-appearing and hypopigmented skin lesions scattered over her body. A subungual nodule is found on her left thumb. CT-scan of the brain shows subependymal nodules, cortical foci with loss of the gray-white matter distinction,and a nodule partially obstructing the cerebral aqueduct. Which of the following is the most likely cause of the patient’s symptoms?
Tuberous sclerosis is a genetic condition that causes growths to form in various body organs. Most commonly affecting the brain, skin, kidneys, lungs, and eyes.
TSC1 encodes the protein hamartin and TSC2 encodes the protein tuberin.
Both of these proteins, are tumor suppressors, meaning they help slow down cell growth and prevent tumors.
They do this by combining to form a hamartin-tuberin protein complex, which binds to and inhibits another protein called mechanistic target of rapamycin, or mTOR.
mTOR activity speeds up the cell cycle and increases cell proliferation mainly thanks to its effect on protein synthesis.
So when mTOR is switched off by the hamartin-tuberin protein complex, it slows growth and division of cells throughout the body.
Individuals with tuberous sclerosis have a mutation in either the gene TSC1 or TSC2, and these mutations have an autosomal dominant inheritance pattern.
The mutations lead to an altered hamartin-tuberin protein complex that’s unable to switch off mTOR.
Because of that, benign tumors and growths called hamartomas form throughout the body.
Hamartomas are kind of like tumors, but they’re made of a variety of cell types from the tissue where they arise, rather than a single cell type.
In fact, if we think of the tissue like a sheet of fabric, a hamartoma is like a knot in the sheet.
Benign tumors and hamartomas can form in any tissue, but the brain and the skin are usually affected the most, along with the kidneys, lungs and eyes.
On top of that the lifetime risk of cancer is increased in individuals with tuberous sclerosis.
That’s because the rapidly dividing cells can develop additional mutations that eventually make these growths expand beyond the basement membrane and invade neighboring tissues.
In the brain, the most common growths are glioneural hamartomas, also known as a cortical tubers. They arise from supportive glial cells as well as neurons.
Next most common are subependymal nodules, which are hamartomas that form under the ependyma, the thin membrane that lines the ventricles in the brain.
Individuals are also at an increased risk of developing a subependymal giant cell astrocytoma, or SEGA, which is a type of cancer that can arise from the subependymal nodules.