Endocrine Abstracts

JOINT1599

Purpose: DICER1 syndrome is an autosomal dominant familial tumor syndrome predisposing various benign or malignant tumors with incomplete penetrance and variable expressivity. Mutations in DICER1 on chromosome 14q32. 13 lead to truncated protein, impaired microRNA production, and dysregulated gene expression, resulting in tumor formation. DICER1 syndrome is associated with early-onset multinodular goiter and differentiated thyroid carcinoma. This study aimed to investigate the frequency of DICER1 mutations in patients with thyroid cancer and the clinical phenotypes of patients with DICER1 syndrome.

Methods: This study included 16 patients from 8 families with DICER1 syndrome through targeted gene panel sequencing or Sanger sequencing of DICER1. The targeted gene panel included 172 genes associated with hereditary tumor syndromes. Genetic testing was conducted for patients with a clinical features of DICER1 syndrome such as pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumors, early-onset thyroid cancer, or family history of DICER1 syndrome. Clinical phenotypes and mutation spectrum of the patients were reviewed retrospectively.

Results: Mutations in DICER1 were found in 7 probands with childhood-onset differentiated thyroid cancer, one with PPB, and two with rhabdomyosarcoma by targeted panel sequencing, and the other 6 first-degree relatives of DICER1 syndrome were diagnosed by Sanger sequencing. The mean age at diagnosis was 12. 4 years for probands and 26. 8 years for family members. Associated tumors included PPB (n = 4), thyroid carcinoma (n = 6), ovarian Sertoli-Leydig cell tumors (n = 1), cystic nephroma (n = 1), embryonal rhabdomyosarcoma (n = 2), and ectomesenchymoma (n = 1). Genetic analysis identified 9 nonsense mutations from 3 pedigrees, 5 frameshift mutations from 3 pedigrees, and 2 splice site mutations from 2 pedigrees, including three novel variants: c. 3747del (p. K1249Nfs*9), c. 1376+2T>C, and c. 3689del (p. Q1230Rfs*9).

Conclusions: Pediatric patients with thyroid cancer and associated tumors should be evaluated for DICER1 syndrome with family screening. Given the association of endocrine organ tumors with DICER1 syndrome, pediatric endocrinologists should be aware of the disease’s clinical spectrum to provide proper management and reduce its morbidities.