USP8 mutations tied to worse outcomes in Cushing’s children
Study: Theses youngsters tend to have larger, more invasive tumors
Children with Cushing’s disease whose pituitary tumors carry USP8 gene mutations tend to have larger, more invasive tumors and face a higher risk of persistent or recurrent disease after surgery, a study reports.
While inherited mutations do not cause most pediatric cases, non-inherited mutations appear to influence tumor size and treatment outcomes, particularly in USP8.
“The description of the genetic causes of [pituitary tumors] will enhance our understanding on the mechanisms of pituitary [tumor development] and provide insight on the disease presentation,” researchers wrote.
The study, “Genetic evaluation of pediatric pituitary adenomas and USP8-related genotype-phenotype correlations in Cushing’s disease,” was published in the journal Pituitary.
2 types of genetic mutation may contribute to higher pituitary tumor risk
Cushing’s syndrome occurs when the body produces excessive amounts of the hormone cortisol, leading to symptoms such as weight gain, changes in hair or skin, and, in children, slowed growth. Cushing’s disease, a type of Cushing’s syndrome, is most often caused by pituitary adenomas — tumors that form in the pituitary gland at the base of the brain. These tumors overstimulate the production of adrenocorticotropic hormone, which in turn drives the adrenal glands to release excess cortisol.
Two distinct types of genetic mutation may contribute to a higher risk of pituitary tumors. These are germline mutations, which an individual inherits from a parent and are present from birth, and somatic mutations, which arise during life in individual cells and are not passed to offspring.
Although germline mutations rarely cause pituitary adenomas, some estimates suggest that up to around half of adults with these tumors have somatic mutations. Mutations in the USP8 gene are particularly common, causing about 35% of adult pituitary adenomas.
“Some genetic findings may predispose to … more or less aggressive [disease characteristics] and predict their response to treatment,” the researchers wrote, adding that understanding and identifying germline and somatic mutations could have clinical implications.
In the present study, the researchers aimed to identify genetic mutations in 47 children with Cushing’s disease. At the time of diagnosis, participants’ average age was 13. The team recruited participants through two large, observational clinical trials (NCT00001595 and NCT03206099).
Seven children with a different form of pituitary adenoma associated with excess production of growth hormones also participated. These tumors lead to acromegaly, also called gigantism, rather than Cushing’s.
Among Cushing’s participants with germline genetic testing results, one had a likely disease-causing mutation in the CDKN2A gene. Two of the children with excess growth hormone had disease-causing germline mutations.
Children with USP8 mutations had worse outcomes after surgery
In somatic genetic testing of tumor cells from 38 Cushing’s participants, the team found six cases of disease-causing USP8 mutations, representing 15.8% of the group. The researchers then compared disease features and outcomes for participants with and without these mutations.
Children with USP8 mutations had significantly larger tumors than their counterparts (9.5 mm vs. 6 mm) and were more likely to develop larger tumors, called macroadenomas. Those with a USP8 mutation also had a higher risk of tumors infiltrating the cavernous sinus, a channel within the skull, which can lead to further complications.
Taken together, our data support that USP8 [disease-causing] variants are a marker of worse prognosis in pediatric [Cushing’s disease] and should be suspected in patients with large invasive [pituitary tumors] of pediatric onset.
After surgery to remove the pituitary adenoma, children with USP8 mutations had worse outcomes. All children without USP8 mutations went into remission, meaning no visible signs of the tumor remained. In contrast, one-third of children with mutations did not achieve remission after surgery. Even among those who initially did, the disease was much more likely to return: 75% experienced a recurrence, compared with only 9.4% in the non-mutation group.
“Thus, patients with USP8 positive tumors had overall worse prognosis, most commonly due to larger tumors that tended to invade the cavernous sinus and recur even after initial remission,” the researchers wrote.
Although genetic mutations didn’t explain most of the pediatric cases in this study, the poorer outcomes among children with USP8 mutations suggest that understanding the influence of these mutations might be helpful clinically. However, “the long-term prognosis of these patients remains to be seen, and we acknowledge the potential limitations of the small sample size in this study,” the team wrote.
“Taken together, our data support that USP8 [disease-causing] variants are a marker of worse prognosis in pediatric [Cushing’s disease] and should be suspected in patients with large invasive [pituitary tumors] of pediatric onset,” the researchers concluded.
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