AUTHOR=Martínez de LaPiscina Idoia , Hernández-Ramírez Laura C. , Portillo Nancy , Gómez-Gila Ana L. , Urrutia Inés , Martínez-Salazar Rosa , García-Castaño Alejandro , Aguayo Aníbal , Rica Itxaso , Gaztambide Sonia , Faucz Fabio R. , Keil Margaret F. , Lodish Maya B. , Quezado Martha , Pankratz Nathan , Chittiboina Prashant , Lane John , Kay Denise M. , Mills James L. , Castaño Luis , Stratakis Constantine A. 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2020.00433

DOI=10.3389/fendo.2020.00433

ISSN=1664-2392

ABSTRACT=<p><bold>Context:</bold> The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the <italic>DICER1</italic> gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushing's disease (CD). The role of <italic>DICER1</italic> in other corticotropinomas, however, remains unknown.</p><p><bold>Objective:</bold> To perform a comprehensive screening for <italic>DICER1</italic> variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype.</p><p><bold>Design, setting, patients, and interventions:</bold> We included 192 CD cases: ten young-onset (age &lt;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.</p><p><bold>Results:</bold> Rare germline <italic>DICER1</italic> variants were found in seven pediatric patients with no other known disease-associated germline defects or somatic <italic>DICER1</italic> 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.</p><p><bold>Conclusions:</bold> Our findings suggest that <italic>DICER1</italic> gene variants may contribute to the pathogenesis of non-syndromic corticotropinomas. Clarifying whether <italic>DICER1</italic> loss-of-function is disease-causative or a mere disease-modifier in this setting, requires further studies.</p><p><bold>Clinical trial registration:</bold><ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>: NCT00001595.</p>