Background Somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene are common in corticotropinomas of children with Cushing disease (CD). We report a unique patient with a germline USP8 mutation who presented with CD and a constellation of other findings that constitute an intriguing 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, and previous history of hyperinsulinism and partial GH deficiency. She was diagnosed with CD at 14 years old and underwent transsphenoidal 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 hot spot 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. Conclusion 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.

Summary Objective To investigate early signs of cardiovascular arterial remodelling in paediatric patients with Cushing syndrome (CS) in comparison with normative values from healthy children. Study Design The metrics used to assess cardiac health were from thoracic aorta and carotid MRI. Scans were performed on 18 children with CS (mean: 12.5 ± 3.1 years, range: 6.0‐16.8 years, 10 female). Pulse wave velocity (PWV), aortic distensibility (AD) and carotid intima‐media thickness (cIMT), well‐validated measurements of cardiac compromise, were measured from the images and compared to normative age‐matched values where available. Results Patients with CS had significantly higher PWV compared to age‐adjusted normal median control values (4.0 ± 0.7 m/s vs. 3.4 ± 0.2 m/s, respectively, P = 0.0115). PWV was positively correlated with midnight plasma cortisol ( r = 0.56, P = 0.02). Internal and common cIMT were negatively correlated with ascending AD ( r = −0.75, P = 0.0022, r = −0.69, P = 0.0068, respectively). Conclusion Pulse wave velocity data indicate that paediatric patients with CS have early evidence of cardiovascular remodelling. The results suggest the opportunity for monitoring as these changes begin in childhood.