Concurrent Mutations Might Have Contributed to Child’s Cushing’s

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Mutations in the GPR101 and USP8 genes might have contributed to the growth of a particularly large and aggressive pituitary tumor that caused Cushing’s disease in a young girl.

The case was described in the report, “Concurrent mutations of germline GPR101 and somatic USP8 in a pediatric giant pituitary ACTH adenoma: a case report,” published in BMC Endocrine Disorders.

Cushing’s disease is caused by a tumor in the brain’s pituitary gland. The tumor produces and releases a signaling molecule called ACTH, which prompts the adrenal glands atop the kidneys to produce large amounts of the stress hormone cortisol. High cortisol levels ultimately give rise to Cushing’s symptoms.

Scientists in China described the case of a girl with Cushing’s disease caused by a large and aggressive pituitary tumor.

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At age 9, the girl gained weight rapidly. This was accompanied by facial puffiness, acne, and unusually dark skin and body hair. Her parents reported that she had become dull and less talkative.

At age 10, the girl began having unexplained eye pain. She then developed blepharoptosis, a condition that causes the upper eyelid to remain partially closed even when the eyes are open, which impaired her vision. Soon after, her eyes failed to rotate properly in all directions.

The girl was admitted to the hospital and a physical exam revealed characteristic features of Cushing’s, such as a “moon face” and a “buffalo hump.” Laboratory tests indicated she had abnormally high ACTH and cortisol levels.

Imaging tests showed she had a very large pituitary adenoma, a type of tumor, that was pushing on the optic nerves, which carry information from the eyes to the brain.

Surgery to remove as much of the tumor as possible led to a decrease in ACTH levels, but these increased again a month later and the girl was referred for radiation therapy to control the residual tumor.

Genetic tests were done as “the early onset and invasive behavior of this tumor led to the consideration of whether there was a genetic defect,” the researchers wrote.

Results showed two noteworthy findings. She had a mutation in the USP8 gene, which is known to be important for regulating ACTH production in the pituitary gland. Based on its function, researchers speculated that this mutation might have contributed to ACTH production in the tumor.

A second mutation was identified in the GPR101 gene. While this mutation has not been reported before, researchers noted that other mutations in this gene have been shown to drive the growth of pituitary cancer cells, and computer models suggest this mutation has a similar disease-driving capacity.

The USP8 mutation was somatic while the GPR101 mutation was germline. Somatic mutations are not inherited and happen sporadically after conception, while germline mutations are inherited.

“We report a novel germline GPR101 and somatic USP8 mutation in a girl with an extremely giant pituitary ACTH adenoma. The concurrent mutations may lead to the growth and function of the tumor, respectively,” the researchers wrote noting that more investigation should be done to “verify the role of the concurrent mutations in the pathogenesis [development] of pediatric [Cushing’s disease].”