A Novel Pathogenic Variant of DICER1 Gene in a Young Greek Patient with 2 Different Sex-Cord Ovarian Tumors and Multinodular Goiter

Abstract

DICER1 syndrome (DICERs) represents a tumor predisposition genetic syndrome, inherited in an autosomal dominant manner. Germline loss-of-function variants of the DICER1 gene lead to impaired processing of microRNA, gene expression, and increased risk of tumorigenesis. Although pleuropulmonary blastoma (PPB) is the hallmark of the syndrome, multiple extrapulmonary malignant and non-malignant conditions have also been described, including multinodular goiter (MNG) and sex-cord stromal tumors. MNG is one of the most common components and is associated with an increased risk of thyroid carcinoma. Sertoli-Leydig cell tumor (SLCT) represents the most prevalent type of sex-cord stromal tumor associated with the syndrome, whereas juvenile granulosa cell tumor (JGCT) is considered to be a very rare phenotype. They both may present with abdominal pain due to mass effect and menstrual irregularities in case of hormone production. Although they exhibit low rates of mortality, recurrence rates highly depend on the grade of malignancy. Herein, we report a novel pathogenic DICER1 variant associated with MNG, bilateral ovarian SLCT, and JGCT in a young Greek patient. Clinicians should be aware of a potential germline DICER1 variant when evaluating MNG in young patients, especially if it coexists with other neoplasms.

Keywords: DICER1 gene; DICER1 syndrome; Sertoli–Leydig cell tumor; hyperandrogenemia; juvenile granulosa cell tumor; multinodular goiter; novel DICER1 variant.

Figure 1

The role of DICER1 protein in the microRNA (miRNA) generation pathway. Initially, RNase II in the nucleus converts longer precursors from DNA into primary RNAs (pri-miRNAs). Pri-miRNA is broken down by Drosha and Pasha/DGCR8 (DiGeorge critical region 8) into pre-miRNA, which is a “hairpin structure”. After it is exported from the nucleus via exportin 5, 3p and 5p miRNAs are cleaved by the DICER1 protein, forming a short miRNA duplex molecule that is later degraded into a single-strand miRNA (mature miRNA). Then, one strand of the miRNA duplex is combined with other proteins, such as members of the Argonaute (AGO) family, to form an RNA-induced silencing complex (RISC) that targets and controls messenger RNA, regulating suppression of gene expression.

Figure 2

Immunostaining results of moderately differentiated bilateral ovarian Sertoli–Leydig cell tumor (SLCT). (A) Diffuse sheet-like pattern (H/E ×10). (B) Inhibin-a (×10) highlights Sertoli cells. (C) Calretinin (×10) immunostaining reveals positive staining in Sertoli cells. (D) WT-1 (×10) immunostaining uniformly highlights the Sertoli cells. (E) Melan-A (×10) immunostaining shows weak positivity in Leydig cells. (F) Diffuse positivity in Vimentin (×10) staining in SLCT cells (a scale of 240 pixels has been used).

Figure 3

Immunostaining results of juvenile granulosa cell tumor (JGCT) of the right ovary. (A) JGCT with diffuse growth pattern, round hyperchromatic nuclei, with small nucleoli and irregular nuclear contours and rare grooves (H/E ×10). (B) Inhibin-a (×10) highlights juvenile granulosa cells. (C) Calretinin (×10) immunostaining reveals rare immunoreactivity in cells of JGCT. (D) WT-1 (×10) immunostaining scattered in JGCT cells. (E) CD-99 (×10) reveals positive stain in JGCT cells. (F) Diffuse positivity in Vimentin (×10) staining in JGCT cells (a scale of 240 pixels has been used).

Figure 4

The timeline of our patient’s history.