N-type calcium channel v2.2 is a target of TCF21 in adrenocortical carcinomas.

Transcription factor 21 (TCF21) directly binds and regulates SF1 mRNA expression in tumor and normal adrenocortical cells, and both are involved in the development and steroidogenesis of the adrenal cortex. TCF21 is a tumor suppressor gene and its expression is reduced in malignant tumors. In adrenocortical tumors, it is less expressed in adrenocortical carcinomas (ACC) than in adrenocortical adenomas (ACA) and normal tissues. However, a comprehensive analysis to identify TCF21 targets has not yet been conducted in any type of cancer. In this study, we performed Chromatin Immunoprecipitation and Sequencing (ChIP-Seq) in an adrenocortical carcinoma cell line (NCI-H295R) overexpressing TCF21, with the aim of identifying TCF21 new targets. The five most frequently identified sequences corresponded to the PRDM7, CNTNAP2, CACNA1B, PTPRN2, and KCNE1B genes. Validation experiments showed that, in NCI-H295R cells, TCF21 negatively regulates the expression of the CACNA1B gene. Recently, it was observed that the N-type calcium channel v2.2 (Cav2.2) encoded by the CACNA1B gene is important in Angiotensin II signal transduction for corticosteroid biosynthesis in NCI-H295R adrenocortical carcinoma cells. Indeed, TCF21 inhibits CACNA1B and Cav2.2 expression in NCI-H295R. In addition, in a cohort of 55 adult patients with adrenocortical tumors, CACNA1B expression was higher in ACC than ACA and was related to poor disease-free survival in ACC patients. These results suggest a mechanism of steroidogenesis control by TCF21 in adrenocortical tumor cells, in addition to the control observed through SF1 inhibition. Importantly, steroid production could impair tumor immunogenicity, contributing to the immune resistance described in adrenal cancer.

Management of functioning pediatric adrenal tumors.

AIM: The aim of this study is to present our experience in the management of hormonally active adrenal tumors in children. MATERIAL AND METHODS: We did a retrospective chart review of all children with hormonally active adrenal tumors evaluated at the endocrinology clinic and operated at our institution between 1983 and 2019. RESULTS: There were 75 patients included in the study, 58 with adrenocortical tumors (ACTs) and 17 with pheochromocytomas (PCCs). Within the group of patients with ACTs, there were 41 females and 17 males. The mean age was 58.3 (SD: 87.9; range: 9-211) months. The clinical manifestation of the tumor's hormonal activity was virilization in 37 cases, Cushing syndrome in 5, and mixed in 16. A positive family history was present in 11 patients (18.9%). The mean tumor size was 48.2 (SD: 22.4; range: 7-120) mm. The pathological diagnosis was adenoma in 42 cases, carcinoma in 15 cases, and macronodular hyperplasia in 1. Median follow-up was 192 (range: 50-290) months. Tumor recurrence occurred in 6 patients (10.3%), and there were three disease-related deaths (5%). Within the group of patients with PCCs, there were 11 males and 6 females. The mean age was 146.7 (SD: 71.2; range: 60-216) months. A positive family history was present in 7 patients (41.2%). The mean tumor size was 36.6 (SD: 16.7; range: 7-120) mm. The pheochromocytoma was classified as benign in 15 cases and as malignant in 2. During a median follow-up of 180 (range: 127-300) months, recurrence was observed in 6 cases (35.3%) and disease-related death in 1 case (5.9%). CONCLUSIONS: Proper diagnosis and management at our referral center were associated with a high cure rate, even in cases of malignant tumors. Familial surveillance is highly recommended. LEVEL OF EVIDENCE: Level IV.

Choroidal and Retinal Abnormalities by Optical Coherence Tomography in Endogenous Cushing's Syndrome.

CONTEXT: Cortisol has been suggested as a risk factor for choroidal thickening, which may lead to retinal changes. OBJECTIVE: To compare choroidal thickness measurements using optical coherence tomography (OCT) in patients with endogenous active Cushing's syndrome (CS) and to evaluate the occurrence of retinal abnormalities in the same group of patients. DESIGN: Cross-sectional study. SETTING: Outpatient clinic. PATIENTS: Eleven female patients with CS in hypercortisolism state as determined by the presence of at least two abnormal measurements from urinary cortisol 24 h, no suppression of cortisol with low dose dexamethasone suppression test, and nocturnal salivary cortisol levels and 12 healthy controls. METHODS: Choroidal and retinal morphology was assessed using OCT. MAIN OUTCOME MEASURES: Choroidal thickness measurements and the presence of retinal changes. RESULTS: The mean subfoveal choroidal thickness was 372.96 ± 73.14 µm in the patients with CS and 255.63 ± 50.70 µm in the control group (p < 0.001). One patient (9.09%) presented with central serous chorioretinopathy and one patient (9.09%) with pachychoroid pigment epitheliopathy. CONCLUSION: Choroidal thickness is increased in the eyes of patients with active CS compared to healthy and matched control. Also, 18.18% of patients presented with macular changes, possibly secondary to choroidal thickening. While further studies are necessary to confirm our findings, excess corticosteroid levels seem to have a significant effect on the choroid and might be associated with secondary retinal diseases.