Juvenile xanthogranuloma in Noonan syndrome

Am J Med Genet A. 2021 Oct;185(10):3048-3052. doi: 10.1002/ajmg.a.62353. Epub 2021 May 25.


Noonan syndrome (NS) is one of the common RASopathies. While the clinical phenotype in NS is variable, it is typically characterized by distinctive craniofacial features, cardiac defects, reduced growth, bleeding disorders, learning issues, and an increased risk of cancer. Several different genes cause NS, all of which are involved in the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. Juvenile xanthogranuloma (JXG) is an uncommon, proliferative, self-limited cutaneous disorder that affects young individuals and may be overlooked or misdiagnosed due to its transient nature. A RASopathy that is known to be associated with JXG is neurofibromatosis type 1 (NF1). JXG in NF1 has also been reported in association with a juvenile myelomonocytic leukemia (JMML). As RASopathies, both NS and NF1 have an increased incidence of JMML. We report a 10-month-old female with NS who has a PTPN11 pathogenic variant resulting in a heterozygous SHP2 p.Y62D missense mutation. She was found to have numerous, small, yellow-pink smooth papules that were histopathologically confirmed to be JXG. In understanding the common underlying pathogenetic dysregulation of the Ras/MAPK pathway in both NS and NF1, this report suggests a possible molecular association for why NS individuals may be predisposed to JXG.

Keywords: Noonan syndrome; PTPN11; RASopathy; Ras/MAPK pathway; juvenile myelomonocytic leukemia; juvenile xanthogranuloma.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Infant
  • Leukemia, Myelomonocytic, Juvenile / complications
  • Leukemia, Myelomonocytic, Juvenile / genetics*
  • Leukemia, Myelomonocytic, Juvenile / pathology
  • Mutation, Missense / genetics
  • Neurofibromin 1 / genetics
  • Noonan Syndrome / complications
  • Noonan Syndrome / genetics*
  • Noonan Syndrome / pathology
  • Phenotype
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics*
  • Xanthogranuloma, Juvenile / complications
  • Xanthogranuloma, Juvenile / genetics*
  • Xanthogranuloma, Juvenile / pathology
  • ras Proteins / genetics


  • NF1 protein, human
  • Neurofibromin 1
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • ras Proteins