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Germline USP8 mutation associated with pediatric Cushing disease and other clinical features: a new syndrome.

BACKGROUND
Somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene are common in corticotropinomas of children with Cushing disease (CD). We present a unique patient with a germline USP8 mutation, who presented with CD and a constellation of other findings that constitute a new genetic syndrome.


CASE DESCRIPTION
We describe a 16-year-old female with CD, developmental delay, dysmorphic features, ichthyosiform hyperkeratosis, chronic lung disease, chronic kidney disease, hyperglycemia, dilated cardiomyopathy with congestive heart failure (CHF), and previous history of hyperinsulinism and partial growth hormone (GH) deficiency. She was diagnosed with CD at 14 years old and underwent trans-sphenoidal surgery. Despite initial improvement, she developed recurrent CD.


METHODS
DNA was extracted from peripheral blood and tumor DNA; whole-exome and Sanger confirmatory sequencing were performed. Immunohistochemistry was performed on the resected adenoma.


RESULTS
A de novo germline heterozygous USP8 mutation (c.2155T>C, p.S719P) in the critical 14-3-3 binding motif hotspot locus of the gene was identified in both the peripheral blood and tumor DNA. Histopathologic evaluation of the resected tumor confirmed an ACTH-secreting adenoma.


CONCLUSIONS
Somatic USP8 mutations are common in adenomas causing CD, but to date no germline defects have been reported. We describe a patient with a de novo germline USP8 mutation with recurrent CD and multiple other medical problems. This unique patient informs us of the multitude of signaling events that may be controlled by USP8.