OR06-01 The Role of Germline Defects in Cushing’s Disease

Abstract J.L.M. and C.A.S. contributed equally. Introduction: Cushing’s Disease (CD) has been described as a component of a number of familial genetic syndromes. Yet, such cases may go largely unrecognized due to phenotypic variability, incomplete penetrance, and the rarity of the disease. We determined the frequency and type of germline genetic causes of CD and characterized their clinical phenotype in a large cohort of CD patients. Methods: We studied 245 unrelated CD patients (139 females, 60.4%), referred to our Center between 1997–2018, including 230 pediatric (≤18 years at disease onset, 93.9%) and 15 adult patients (6.1%). Germline genetic causes were identified by whole exome sequencing in 184 patients and by Sanger sequencing of specific genes in 39 patients; 22 patients did not undergo genetic testing, due to low quality or insufficient DNA. When available (n=66), corticotropinoma DNA was screened for USP8 hotspot variants using Sanger sequencing. Results: Eighteen patients (7.3%) had positive family history: nine presented as FIPA with unknown genetic cause, eight presented as MEN1 (seven had confirmed MEN1 variants), and one had a family history of pheochromocytoma/paraganglioma and pituitary adenoma with unknown genetic cause. Among the 227 sporadic patients (92.7%), 13 (5.7%) simplex cases had putative pathogenic variants in the following genes: CDKN1B (n=5), CABLES1 (n=3), AIP (n=1), PRKAR1A (n=1),TP53 (n=1),TSC2 (n=1), and USP8 (n=1). Altogether, cases with potentially inheritable genetic causes(familial and simplex) accounted for 12.7% (31/245) of all patients. There were no statistically significant differences in age at disease onset, age at diagnosis or tumor diameter between patients with potentially inheritable genetic defects and the rest of the cohort. In the pediatric subset, however, there was a non-significant higher frequency of macroadenomas among familial and simplex patients (21.4%), compared with sporadic patients (12.4%, P=0.19). Somatic USP8 hotspot mutations were found in 33.3% (12/36) of sporadic patients, but only in 3.3% (1/30) of familial and simplex (e.g. patients with a disease-associated germline defect, but no affected relatives) cases (P=0.0038). The global frequency of USP8 defects was 19.7% (13/66). Conclusions: Potentially inheritable cases of CD accounted for one-eighth of the patients in our cohort: 64.5% (20/31) of them are associated with defects in genes with a known involvement in CD. Patients with germline genetic causes of CD might present as apparently sporadic cases, due variability in disease penetrance. Unlike sporadic cases, somatic USP8 hotspot mutations are rare in those with inheritable causes of CD, suggesting different drivers for tumorigenesis in each group. Identifying the genetic causes of CD should lead to a more precise genetic testing and counselling and might aid in developing targeted therapeutic strategies.