ESPE Abstracts (2018) 89 RFC14.4

aSection on Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA; bDepartment of Reproductive Endocrinology, Alexandra Hospital, University of Athens, Athens, Greece; cDepartment of Biochemistry, Institute of Child Health, Athens, Greece; dEndocrine Unit, 1st Department of Pediatrics, Medical School, University of Athens, Athens, Greece

Background: DICER1 is an endoribonuclease that acts post-transcriptionally by processing mRNA into siRNA and microRNA, thus leading to mRNA downregulation. DICER1 syndrome is usually caused by germline variants and is characterized by a variety of benign or malignant tumors: pleuropulmonary blastoma, ovarian Sertoli-Leydig cell tumor, cystic nephroma, pituitary blastoma and multinodular goitre. Patients with germline aberrations in the DICER1 gene may carry additional somatic missense DICER1 mutations within the associated tumors, located in the metal ion-binding residues of the RNase IIIb domain.

Patient: A 10 yo girl was evaluated for thyroid enlargement. Thyroid sonography revealed three nodules in the right lobe (diameter: 1.9, 2.3, and 3 cm, respectively). Thyroid function tests were normal and thyroid autoantibodies negative. Thyroidectomy was carried out and the lesions proved hyperplastic nonmalignant. She entered puberty at age 11 years and at age 12 years, both breast and pubic hair were Tanner stage IV. Ten months later, during follow-up, breast had regressed to Tanner stage I, hirsutism was present and her voice had notably deepened. Hormonal evaluation showed Testosterone 478 ng/dl, DHEAS 2480 ng/ml, 17OH-progesterone 11 ng/ml, Δ4 androstenedione 7.9 ng/ml, LH 10.7 mIU/ml, FSH 3.2 mIU/ml, Cortisol 3 μg/dl and ACTH 12.2 pg/ml. Ovarian sonography revealed an enlarged right ovary (12cc) while the left ovary was normal (3cc). Pituitary MRI was normal. Right salpingo-oophorectomy was carried out and biopsy revealed an ovarian Sertoli-Leydig cell tumor. Ten days postoperatively androgens had returned to normal levels.

Methods: Genetic analysis of the DICER1 gene in peripheral leukocytes and ovarian and thyroid tissues as well as immunohistochemistry of the tumors were carried out.

Results: A novel germline nonsense DICER1 mutation (p.W1481*, c.4443G>A) was detected, inherited from her father (in whom sonography revealed multinodular goiter). Further studies in the ovarian and thyroid tissues showed two different somatic missense mutations of the same codon. The ovarian tissue carried the missense mutation p.E1813D (c.5439G>T) in heterozygous state whereas, the thyroid tissue carried the missense variant p.E1813Q (c. 5437G>C) in heterozygosity. Immunohistochemistry revealed that within these tumors, the DICER1 protein expression was significantly decreased compared to normal tissue.

Conclusion: We report a novel DICER1 mutation (p.W1481*, c.4443G>A) and confirm that patients with germline DICER1 mutations can develop somatic mutations within the RNase IIIb domain. Our findings show that impaired DICER1 function affects the thyroid and ovarian tissue homeostasis and offer further proof that DICER1 is a tumorigenic driver during childhood.

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