title: 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.
abstract: BACKGROUND
  Ectopic ACTH/CRH syndrome is a rare cause of Cushing syndrome (CS), especially in children. The localization, work-up, and management of ACTH/CRH-secreting tumors are discussed.
  
  
  METHODS
  A retrospective study was conducted of patients under 21 years of age evaluated at the National Institutes of Health (NIH) for CS and diagnosed with ectopic ACTH/CRH-secreting tumors during the period 2009-2014.
  
  
  METHODS
  Seven patients with ectopic ACTH/CRH CS are included in this study with a median age 13.6 years (range 1-21), and 3 are female.
  
  
  METHODS
  Clinical, biochemical, radiological features, treatment, and histological findings are described.
  
  
  RESULTS
  Seven patients were found to have ACTH/CRH-secreting tumors, all with neuroendocrine features. The site of the primary lesion varied: pancreas (3), thymus (2), liver (1), right lower pulmonary lobe (1). PATIENTS underwent biochemical evaluation for CS, including diurnal serum cortisol and ACTH levels, urinary free cortisol levels (UFC), and CRH stimulation tests. All patients underwent radiological investigations including MRI, CT, and PET scan; imaging with octreotide and 68 gallium DOTATATE scans were performed in individual cases. Five patients underwent inferior petrosal sinus sampling; 4 patients had sampling for ACTH and CRH levels from additional sites. Three patients underwent trans-sphenoidal surgery (TSS), and 3 patients required bilateral adrenalectomy. Three patients (43%) died due to metastatic disease, demonstrating the high mortality rate. One of the unique findings in these seven patients is that in each case, their neuroendocrine tumors were ultimately proven to be co-secreting ACTH and CRH. This explains the enigmatic presentation, in which 3 patients initially thought to have Cushing's disease (CD) with corresponding pituitary hyperplasia underwent TSS prior to the correct localization of the causative tumor.
  
  
  CONCLUSIONS
  Ectopic ACTH/CRH co-secreting tumors are extremely rare in children and adolescents. The diagnosis of this condition is frequently missed and is sometimes confused with CD due to the effect of CRH on the pituitary.
authors.affiliation: Section on Endocrinology and Genetics (A.S.K., J.B., M.F.K., C.L., M.B.L., C.A.S.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Section of Radiology and Imaging Sciences (G.Z.P., N.J.P.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Pathology (M.M.Q., M.M.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; Thoracic and Gastrointestinal Oncology Branch (D.S.S.), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; Endocrine Oncology Branch (E.K.), Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; Randall Children's Hospital at Legacy Emanuel (M.K.H.), Children's Diabetes and Endocrine Center, Portland, Oregon 97227; Department of Pediatrics (M.R.A., L.P.K., A.E.B.), Section of Diabetes and Endocrinology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Karageorgiadis
authors.forename: Georgios Z
authors.initials: GZ
authors.lastname: Papadakis
authors.forename: Juliana
authors.initials: J
authors.lastname: Biro
authors.forename: Meg F
authors.initials: MF
authors.lastname: Keil
authors.forename: Charalampos
authors.initials: C
authors.lastname: Lyssikatos
authors.forename: Martha M
authors.initials: MM
authors.lastname: Quezado
authors.forename: Maria
authors.initials: M
authors.lastname: Merino
authors.forename: David S
authors.initials: DS
authors.lastname: Schrump
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Patronas
authors.forename: Maya K
authors.initials: MK
authors.lastname: Hunter
authors.forename: Mouhammad R
authors.initials: MR
authors.lastname: Alwazeer
authors.forename: Lefkothea P
authors.initials: LP
authors.lastname: Karaviti
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Balazs
authors.forename: Maya B
authors.initials: MB
authors.lastname: Lodish
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000182:ACTH Syndrome, Ectopic / Q000150:complications / Q000175:diagnosis*; D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000652:urine; D002648:Child; D003480:Cushing Syndrome / Q000175:diagnosis* / Q000209:etiology; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D008113:Liver Neoplasms / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D010190:Pancreatic Neoplasms / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D047748:Pituitary ACTH Hypersecretion / Q000175:diagnosis*; D013953:Thymus Neoplasms / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*
chemical_list: D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone