Abstract
Background/Objective
DICER1
‐related tumor predisposition is a rare hereditary tumor predisposition disorder characterized by autosomal dominant inheritance, reduced penetrance, and variable expressivity. This study is aimed at describing the clinical and molecular spectrum of
DICER1
‐related tumor predisposition in an Argentine pediatric cohort.
Design and Methods
Seventeen unrelated patients with
DICER1
‐related tumor predisposition and 54 relatives were evaluated at “Prof. Dr. J. P. Garrahan” Pediatric Hospital (Buenos Aires, Argentina) between 2014 and 2024. Germline and somatic
DICER1
variants were analyzed using Sanger or next‐generation sequencing. Functional assays were performed for selected intronic variants. Three samples of poorly differentiated thyroid carcinoma were also included.
Results
Sixteen distinct germline variants were identified in the 17 index cases, including 12 novel alterations (75%). One quarter of the variants were de novo. Thyroid involvement, particularly multinodular goiter and papillary thyroid carcinoma, was the most common presentation and frequently coexisted with ovarian Sertoli–Leydig cell tumors or embryonal rhabdomyosarcoma. Two novel intronic variants were confirmed to affect splicing by RT‐PCR. Somatic “hotspot” mutations in exons 24–25 (RNase IIIb domain) were detected in most tumors, consistent with the two‐hit model. The identification of asymptomatic carriers enabled early surveillance and preventive interventions.
Conclusions
This study expands the molecular spectrum of germline
DICER1
variants, reinforces the predominance of thyroid involvement, and highlights the value of molecular testing for diagnosis, genetic counseling, and early intervention. Ethical considerations regarding surveillance and management of asymptomatic carriers remain an important area in need of future guidance.