Comprehensive Genomic Analysis of Noonan Syndrome and Acute Myeloid Leukemia in Adults: A Review and Future Directions

Acta Haematol. 2020;143(6):583-593. doi: 10.1159/000505715. Epub 2020 Jun 15.


Acute myeloid leukemia (AML) in the setting of Noonan syndrome (NS) has been reported before without clear guidelines for treatment or prognosis in these subgroups of patients, most likely due to its rarity and incomplete understanding of the pathogenesis of both diseases. In the current era of next-generation sequencing-based genomic analysis, we can better identify patients with NS with more accurate AML-related prognostic markers. Germline mutations in PTPN11 are the most common cause of NS. Somatic mutations in NPM1 occur frequently in AML. Here, we describe a young adult patient with a novel combined germline PTPN11 and somatic NPM1, IDH1,and BCL6 mutations who presented with fatal AML. In addition, a 50.5-Mb interstitial deletion of 7q21.11-q33 in tumor DNA was detected by chromosomal microarray analysis. While mutations in the transcriptional repressor BCL6 are known to contribute to the pathogenesis of diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), its novel identification in this patient suggests an expanded role in aggressive AML. The identification of key molecular aberrations including the overexpression of SHP2, which drives leukemogenesis and tumorigenesis, has led to the development of novel investigational targeted SHP2 inhibitors.

Keywords: Acute myeloid leukemia; B cell lymphoma/leukemia 6; Leukemogenesis; Noonan syndrome; SNP microarray; Whole-exome sequencing.

Publication types

  • Case Reports
  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adult
  • Germ-Line Mutation*
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Noonan Syndrome / genetics*
  • Noonan Syndrome / metabolism
  • Noonan Syndrome / pathology
  • Nuclear Proteins / genetics*
  • Nucleophosmin
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
  • Proto-Oncogene Proteins c-bcl-6 / genetics*


  • BCL6 protein, human
  • NPM1 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • Nucleophosmin
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11