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

Virchows Arch. 2024 Jun;484(6):1023-1027. doi: 10.1007/s00428-024-03759-y. Epub 2024 Feb 14.

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.

Publication types

  • Case Reports

MeSH terms

  • Child
  • Chondroma* / genetics
  • Chondroma* / pathology
  • DEAD-box RNA Helicases* / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation
  • Humans
  • Male
  • Ribonuclease III* / genetics
  • Toes / pathology

Substances

  • Ribonuclease III
  • DEAD-box RNA Helicases
  • DICER1 protein, human