Rare Germline DICER1 Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?

the Spanish Corticotroph Adenomas Collaborative

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9 Scopus citations


Context: The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the DICER1 gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushing's disease (CD). The role of DICER1 in other corticotropinomas, however, remains unknown. Objective: To perform a comprehensive screening for DICER1 variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype. Design, setting, patients, and interventions: We included 192 CD cases: ten young-onset (age <30 years at diagnosis) patients were studied using a next generation sequencing panel, and 182 patients (170 pediatric and 12 adults) were screened via whole-exome sequencing. In seven cases, tumor samples were analyzed by Sanger sequencing. Results: Rare germline DICER1 variants were found in seven pediatric patients with no other known disease-associated germline defects or somatic DICER1 second hits. By immunohistochemistry, DICER1 showed nuclear localization in 5/6 patients. Variant transmission from one of the parents was confirmed in 5/7 cases. One patient had a multinodular goiter; another had a family history of melanoma; no other patients had a history of neoplasms. Conclusions: Our findings suggest that DICER1 gene variants may contribute to the pathogenesis of non-syndromic corticotropinomas. Clarifying whether DICER1 loss-of-function is disease-causative or a mere disease-modifier in this setting, requires further studies. Clinical trial registration: ClinicalTrials.gov: NCT00001595.

Original languageEnglish (US)
Article number433
Pages (from-to)433
JournalFrontiers in Endocrinology
StatePublished - Jul 3 2020

Bibliographical note

Funding Information:
This work was in part funded by the Intramural Research Program, NICHD, NIH. We would like to acknowledge Dr. Lyssikatos Charalampos and Ms. Maria de la Luz Sierra for their help with the collection and preparation of DNA and histopathological samples used in this study. Members of the Spanish Corticotroph Adenomas Collaborative Group include the following individuals and institutions: E Colino (Hospital San Rafael. Madrid), E Garc?a-Garc?a (Hospital Universitario Virgen del Roc?o. Sevilla), JP L?pez Siguero (Hospital Regional Universitario de M?laga. M?laga), F Moreno-Maci?n (Hospital Universitario y Polit?cnico de La Fe. Valencia), D Moure (Hospital Universitario Cruces, Barakaldo), C Villabona (Hospital Universitario Bellvitge. L'Hospitalet de Llobregat). In addition, we would like to thank the patients and their families for participating in our research. Funding. This work was supported by the Intramural Research Programs of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institute for Neurological Diseases and Stroke, National Institutes of Health, a grant from the Basque Department of Education (IT795-13), a grant from the Basque Department of Health (GV2018111082), the Merck Serono Research award from Fundaci?n Salud 2000 (15-EP-004) and the Jos? Igea 2018 grant, sponsored by Pfizer, from Fundaci?n Sociedad Espa?ola de Endocrinolog?a Pedi?trica (SEEP).

Publisher Copyright:
© Copyright © 2020 Martínez de LaPiscina, Hernández-Ramírez, Portillo, Gómez-Gila, Urrutia, Martínez-Salazar, García-Castaño, Aguayo, Rica, Gaztambide, Faucz, Keil, Lodish, Quezado, Pankratz, Chittiboina, Lane, Kay, Mills, Castaño and Stratakis.


  • Adolescent
  • Adult
  • Child
  • Cohort Studies
  • DEAD-box RNA Helicases/genetics
  • Female
  • Genetic Testing/methods
  • Germ-Line Mutation
  • Humans
  • Male
  • Pituitary ACTH Hypersecretion/diagnosis
  • Ribonuclease III/genetics
  • Young Adult

PubMed: MeSH publication types

  • Case Reports
  • Journal Article
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't


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