Objective: Diagnostic workup of Cushing disease (CD) involves imaging evaluation of the pituitary gland, but in many patients no tumour is visualised. The aim of this study is to describe the association of magnetic resonance imaging (MRI) findings with the postoperative course of paediatric and adolescent patients with CD.Patients: Patients with a diagnosis of CD at less than 21 years of age with MRI evaluation of the pituitary before first transsphenoidal surgery were included.Measurements: Clinical, imaging and biochemical data were analysed.Results: One hundred and eighty-six patients with paediatric or adolescent-onset CD were included in the study. Of all patients, 127 (68.3%) had MRI findings consistent with pituitary adenoma, while the remaining had negative or inconclusive MRI. Patients with negative MRI were younger in age and had lower morning cortisol and adrenocorticotropin levels. Of 181 patients with data on postoperative course, patients with negative MRI had higher odds of not achieving remission after the first surgery (odds ratio = 2.6, 95% confidence intervals [CIs] = 1.1-6.0) compared to those with positive MRI. In patients with remission after first transsphenoidal surgery, long-term recurrence risk was not associated with the detection of a pituitary adenoma in the preoperative MRI (hazard risk = 2.1, 95% CI = 0.7-5.8).Conclusions: Up to one-third of paediatric and adolescent patients with CD do not have a pituitary tumour visualised in MRI. A negative MRI is associated with higher odds of nonremission after surgery; however, if remission is achieved, long-term risk for recurrence is not associated with the preoperative MRI findings.

Background: In Multiple Endocrine Neoplasia type 1 (MEN1) only about 2% of pituitary adenomas are ACTH-secreting. Cushing Syndrome due to ectopic ACTH or CRH secretion from neuroendocrine tumors (NETs), carcinoid tumors, or pheochromocytomas is very rare, though patients with MEN1 are at increased risk for these three types of tumors, as well as autonomous adrenal secretion of cortisol. The 10-year follow up of a previously-reported case of a child with MEN1 and metastatic pancreatic ACTH/CRH-secreting NET is presented. Clinical Case: A previously-reported (J Clin Endocrinol Metab, 2015) now 21 yo female presented to the National Institutes of Health (NIH) at 11 yo with persistent hypercortisolemia despite transsphenoidal surgery for suspected Cushing Disease. However, the resected tissue revealed pituitary hyperplasia, and she remained hypercortisolemic. A CRH test was consistent with an ectopic source, and abdominal CT, PET scan, and Octreotide scan revealed a mass in the pancreatic tail. The patient underwent partial pancreatectomy at 11 yo with the resected tissue staining positive for ACTH and CRH. However, she remained hypercortisolemic, so bilateral adrenalectomy was performed. At 12 yo metastases were found, so Octreotide therapy was initiated. She continued to have elevated ACTH levels > 1000 pg/mL (5-46). Additionally, a pituitary adenoma was noted at 12 yo, which has since increased in size. The patient also developed mild primary hyperparathyroidism, first noted at 19 yo. Sequencing of MEN1 for the patient and her parents revealed a de novo heterozygous c.1546dupC variant, consistent with sporadic MEN1. The patient also had a chromosome 8p23.2 duplication that was present in unaffected relatives. Conclusion: While 2% of patients with MEN1 may develop Cushing Syndrome due to an ACTH-secreting pituitary adenoma, it is also important to consider ectopic secretion of ACTH/CRH from MEN1-associated NETs, carcinoid tumors, or pheochromocytomas, as well as autonomous adrenal secretion of cortisol. Given the early age and severe presentation of MEN1 features in this patient, the c.1546dupC heterozygous variant of MEN1, which has been previously reported in multiple other cases of MEN1, may represent a higher-risk causative variant of MEN1. Alternatively, expression of this variant may have been affected by the concurrent presence of an otherwise apparently benign chromosomal variant. References: A. Karageorgiadis, G. Papadakis, J. Biro, M. Keil, C. Lyssikatos, M. Quezado, M. Merino, D. Schrump, E. Kebebew, N. Patronas, M. Hunter, M. Alwazeer, L. Karaviti, A. Balazs, M. Lodish, and C. Stratakis. Ectopic Adrenocorticotropic Hormone and Corticotropin-Releasing Hormone Co-Secreting Tumors in Children and Adolescents Causing Cushing Syndrome: A Diagnostic Dilemma and How to Solve It. Clin Endocrinol Metab, January 2015, 100(1):141–148