ESPE Abstracts

Background: DICER1 is a member of the Ribonuclease III family that plays a crucial role in the biogenesis and the maturation of microRNAs. Pathogenic germline DICER1 variants cause a hereditary cancer predisposition syndrome with a variety of manifestations: in addition to first described pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumours, individuals may also develop benign (multinodular goiter MNG, cystic nephroma\.) or malignant tumours as differentiated thyroid carcinoma from infancy to adolescence and early adult. Average penetrance seems low to 15% except for MNG recently described as 15 to 75% at 40 years (male and female respectively).

Objective: To investigate whether MNG could be a pointer for familial DICER1variants screening

Methods: We report a families’ serie whose diagnosis for DICER1 syndrome was done on childhood MNG history (or in index patient or in siblings presenting with benign (15) and/or malignant (9) tumours). We screened germline DNA samples from probands and relatives for DICER1 variants using Next Generation Sequencing tools. For 3 families the unique manifestation over generations was related to MNG. Personal and family history, clinical examination, thyroid ultrasonography, thyroid function and autoimmunity were evaluated.

Results: We identified 8 different pathogenic DICER1 variants in 9 index patients and 25 relatives: In all cases but one, the germline DICER1 pathogenic variants associated to MNG have been already described in the literature or located in the enzymatic site of the enzyme. In one family, infant history of pulmonary cystic adenomatoid malformation in the context of MNG at 11 for the proband but also father and uncle, led us to explore the DICER1 gene and identified a novel heterozygous variant in the exon 20, c.3104C>G, p.Pro1035Arg. Histological sections rereading in view of the familial thyroid history corrected the initial diagnosis in PPB.

Conclusion: GMN is uncommon in children. Its diagnosis before adulthood, recurrence within a family or its association with children benign or malignant tumours should make them suspect of anomalies in the DICER1 protein as proposed in recent international recommendations. Children and adolescents diagnosed with GMN should be referred in genetic counselling.Early detection of DICER1 variants has important consequences in terms of tumour screening and therapeutic strategies.