Pediatric Germline Predisposition to Myeloid Neoplasms

Curr Hematol Malig Rep. 2022 Dec;17(6):266-274. doi: 10.1007/s11899-022-00681-5. Epub 2022 Sep 19.


Purpose of review: Advances in the understanding of germline predisposition to pediatric cancers, particularly myeloid neoplasms, have increased rapidly over the last 20 years. Here, we highlight the most up-to-date knowledge regarding known pathogenic germline variants that contribute to the development of myeloid neoplasms in children.

Recent findings: This discussion enumerates the most notable myeloid neoplasm-causing germline mutations. These mutations may be organized based on their molecular underpinnings-transcriptional control, splicing and signal transduction control, and a group of heterogeneous bone marrow failure syndromes. We review recent findings related to the biochemical mechanisms that predispose to malignant transformation in each condition. Key genetic discoveries such as novel mutations, degrees of penetrance, principles of the two-hit hypothesis, and co-occurrence of multiple mutations are shared. Clinical pearls, such as information regarding epidemiology, natural history, or prognosis, are also discussed. Germline mutations predisposing to pediatric myeloid neoplasms are frequent, but underrecognized. They hold major clinical implications regarding prognosis, treatment strategies, and screening for other malignancies. Further research is warranted to better characterize each of these conditions, as well as identify additional novel germline pathogenic variants of interest.

Keywords: GATA2; Germline predisposition; Inherited bone marrow failure; Myeloid neoplasms; Pediatric; SMAD9 or SMAD9L.

Publication types

  • Review

MeSH terms

  • Child
  • Genetic Predisposition to Disease
  • Germ Cells / pathology
  • Germ-Line Mutation
  • Hematologic Neoplasms* / diagnosis
  • Hematologic Neoplasms* / genetics
  • Hematologic Neoplasms* / pathology
  • Humans
  • Myeloproliferative Disorders* / diagnosis
  • Myeloproliferative Disorders* / genetics
  • Neoplasms*