SUN-284 DICER1 Mutations in Adolescent Girls: Clinicopathological Findings and Genetic Correlation

Abstract

Background: The DICER1 syndrome is a rare tumor predisposition disorder associated with multinodular goiter (MNG), differentiated thyroid cancer, ovarian Sertoli-Leydig cell tumor, pleuropulmonary blastoma and pituitary blastoma (1,2). The DICER1 gene encodes the endoribonuclease protein of the ribonuclease III family which acts post-transcriptionally to downregulate messenger RNAs. Both germline and somatic mutations have been reported (3). We describe 2 previously healthy unrelated females referred for evaluation of thyroid nodules. Cases:Case 1: A 16yo female presented with spontaneous passage of polyps at her menstrual period. Histologic analysis revealed embryonal rhabdomyosarcoma. Her primary malignancy, confined to the cervix, was treated with surgical resection followed by chemotherapy. Staging evaluation revealed a left thyroid nodule. FNA of the nodule showed follicular patterned lesion with cytologic atypia; molecular testing was positive for DICER1 somatic mutation (c.5429A;p.D1810V). Peripheral blood genetic testing was positive for a heterozygous DICER1 germline mutation (1510-1G>A). She underwent left lobectomy; histology showed encapsulated papillary carcinoma. Case 2: A 13yo female developed a sudden non-tender neck mass. Ultrasound-guided FNA of the solid lesion in the left thyroid lobe revealed atypia of undetermined significance. Molecular studies identified a DICER1 gene mutation (c.5126A>G; p.D1709G). A peripheral blood sample showed heterozygous DICER1 mutation (c.1870C>T;pArg624*). Three 1st degree family members were also positive for the germline mutation. She underwent total thyroidectomy; pathology revealed MNG with a predominant hyperplastic nodule. Conclusion: Two adolescents with thyroid lesions were positive for DICER1 mutations (4). The prevalence of DICER1 mutations, natural history, and extent of phenotypic heterogeneity are unknown. Two mutations, one germline and one somatic, were identified in our patients. Enhanced molecular testing (ThyroSeqv3) is now available to identify mutations. Testing thyroid nodules for DICER1 mutations (5-7), followed by screening for germline mutations in positive cases is essential to identify patients at risk of other manifestations and to ensure surveillance. Scrutiny of cases will help elucidate the natural history of DICER1 syndrome and establish guidelines regarding the extent and frequency of screening.