Costello syndrome: Clinical phenotype, genotype, and management guidelines

Am J Med Genet A. 2019 Sep;179(9):1725-1744. doi: 10.1002/ajmg.a.61270. Epub 2019 Jun 20.


Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.

Keywords: Costello syndrome; HRAS mutation; RAS/MAPK; RASopathy; management guidelines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / physiopathology
  • Costello Syndrome / genetics*
  • Costello Syndrome / physiopathology
  • Costello Syndrome / therapy
  • Developmental Disabilities / genetics
  • Developmental Disabilities / physiopathology
  • Disease Management
  • Face / abnormalities
  • Gene Expression Regulation / genetics
  • Genotype
  • Germ-Line Mutation / genetics
  • Guidelines as Topic
  • Heart / physiopathology*
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / physiopathology
  • Humans
  • Phenotype
  • Proto-Oncogene Proteins p21(ras) / genetics*


  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)