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A 3-year-old girl is brought to the office by her parents because of strange movements for a week. Her parents state that she first seemed wobbly on her feet, and then they noticed her head and hands shook from side to side when she tried to sit up on her own. Three days ago, her parents also noticed that her "eyes were dancing" and her limbs moved in strange jerky motions. Now, she is so unsteady on her feet that she cannot walk. Medical history includes normal development. Which of the following diagnoses is this condition commonly associated with in children?
Neuroblastoma is the most common cancer in infants, and it’s only rarely seen in children over five years old.
When a fetus is in its 5th week of development, special cells called neural crest cells start migrating along the spine.
In the thoracic region of the spine, neural crest cells differentiate into the neurons of the sympathetic chain, lying on either side of the entire spinal cord.
In the lumbar region, neural crest cells differentiate into the cells of the adrenal medulla, the inner part of the adrenal gland that sits atop the kidneys.
Together, the sympathetic chain and adrenal medulla form the sympathetic nervous system, connecting the brain and central nervous system to various organs including the heart and blood vessels.
So, when you’re under some sort of stress, like playing a competitive sport like badminton, the sympathetic nervous system kicks into action.
These hormones bind to receptors in various tissues like the blood vessels, the heart, and the lungs, redirecting blood flow to your muscles, make your heart pump faster, and expanding the airways in your lungs, all of which can help you make the winning hit.
After the game is over, and the hormones are no longer needed, epinephrine and norepinephrine break down into metabolites like homovanillic acid or HMA, and vanillylmandelic acid, or VMA.
In neuroblastoma, some neural crest cells in the sympathetic chain or adrenal medulla don’t differentiate properly during fetal development, and these cells ultimately go on to form a tumor, which most often form in the adrenal medulla, but can also develop in other areas of the sympathetic chain.
While no one knows exactly how it happens, this abnormal cell differentiation has been associated with mutations in the MYCN oncogene, Anaplastic lymphoma kinase ALK fusion oncogenes, and mutations in tumor suppressor genes, like the Paired-like homeobox 2b or PHOX2B, and other tumor suppressor genes on chromosome 1 and 11.
Oncogenes help cells grow and proliferate, while tumor suppressor genes slow down cell growth and proliferation.
So both an MYCN amplification or ALK gene fusion, where the oncogene is “turned on,” or a PHOX2B and chromosome 1 and 11 deletions, where tumor suppressor genes are “turned off,” can potentially cause uncontrolled cell growth.
There are three types of neuroblastomas, and they’re categorized based on the size and shape of the tumor cells: undifferentiated, poorly differentiated, and differentiating neuroblastoma.
An undifferentiated neuroblastoma is mostly comprised of neural crest cells, which are sometimes called small round blue cells, due to a lack of cytoplasm, and a large blue nuclei.
A poorly differentiated neuroblastoma is composed of slightly more differentiated cells, with smaller nuclei and a bit more cytoplasm.
In addition, the cells of a poorly differentiated neuroblastoma may be surrounded by a substance called neuropil, which is a dense network of interwoven nerve fibers, like axon and dendrite branches.
Finally, a differentiating neuroblastoma is composed of cells with lots of cytoplasm, and is often surrounded by a substance called Schwannian stroma.
Schwannian stroma is a connective tissue from non-neuronal cells that forms myelin, which insulates the axons of the mature neurons.
When any type of neuroblastoma forms, cells in the surrounding tissue release chemokines called CXCL12 and that stimulates nearby immune cells.
CXCL12 is normally produced by some organs like the lymph nodes, liver, bones, and especially the bone marrow, but gets produced in higher amounts when tissue is damaged.