Extraskeletal chondroma of the toe in a child with DICER1 tumor predisposition syndrome: support for a dominant negative mechanism

Dylan Pelletier; Nelly Sabbaghian; Anne-Laure Chong; John R Priest; Yomna Elsheikh Ahmed; Gabriel P Fox; Marc R Fabian; William D Foulkes

doi:10.1007/s00428-024-03759-y

Extraskeletal chondroma of the toe in a child with DICER1 tumor predisposition syndrome: support for a dominant negative mechanism

Virchows Arch. 2024 Feb 14. doi: 10.1007/s00428-024-03759-y. Online ahead of print.

Authors

Dylan Pelletier^{1

2

3}, Nelly Sabbaghian^{1

2}, Anne-Laure Chong^{1

2}, John R Priest⁴, Yomna Elsheikh Ahmed^{5

6

7}, Gabriel P Fox^{6

7}, Marc R Fabian^{2

8}, William D Foulkes^{9

10

11

12}

Affiliations

¹ Department of Human Genetics, Medicine, McGill University, Montreal, QC, Canada.
² Cancer Axis, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
³ Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
⁴ , Minneapolis, USA.
⁵ Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
⁶ Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen, Bahrain.
⁷ King Hamad University Hospital, Al Sayh, Bahrain.
⁸ Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
⁹ Department of Human Genetics, Medicine, McGill University, Montreal, QC, Canada. william.foulkes@mcgill.ca.
¹⁰ Cancer Axis, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada. william.foulkes@mcgill.ca.
¹¹ Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada. william.foulkes@mcgill.ca.
¹² Cancer Research Program, Research Institute of the McGill University Health Center, Montreal, QC, Canada. william.foulkes@mcgill.ca.

PMID: 38355738
DOI: 10.1007/s00428-024-03759-y

Abstract

DICER1 tumor predisposition syndrome is a pleiotropic disorder that gives rise to various mainly pediatric-onset lesions. We report an extraskeletal chondroma (EC) of the great toe occurring in a child who, unusually, carries a germline "hotspot" missense DICER1 variant rather than the more usual loss-of-function (LOF) variant. No heterozygous LOF allele was identified in the EC. We demonstrate this variant impairs 5p cleavage of precursor-miRNA (pre-miRNA) and competes with wild-type (WT) DICER1 protein for pre-miRNA processing. These results suggest a mechanism through which a germline RNase IIIb variant could impair pre-miRNA processing without complete LOF of the WT DICER1 allele.

Keywords: DICER1 syndrome; Extraskeletal chondroma; Pediatric oncology; Rare tumors; miRNA biogenesis.

Abstract

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