Neurocognitive, adaptive, and behavioral functioning of individuals with Costello syndrome: a review

Am J Med Genet C Semin Med Genet. 2011 May 15;157C(2):115-22. doi: 10.1002/ajmg.c.30299. Epub 2011 Apr 14.


Costello syndrome is a rare rasopathy resulting from germline mutations of the proto-oncogene HRAS. Its phenotype includes severe failure-to-thrive, cardiac abnormalities, a predisposition to benign and malignant tumors, hypotonia, and developmental delay. Costello syndrome is associated with cognitive impairment, including intellectual functioning generally in the mild to moderate range of disability, commensurate adaptive functioning, and increased anxiety. Relative strengths have been found for nonverbal fluid reasoning (FR). Gender effects have been reported, with females showing better adaptive functioning across domains. Developmentally, nonverbal skills plateau in late childhood/early adolescence, whereas the rate of vocabulary acquisition may increase in adolescence into early adulthood. Here we review the literature assessing cognitive, adaptive, and behavioral functioning in Costello syndrome, and we provide data from an ongoing longitudinal study. Severity of cognitive impairment may depend upon the specific HRAS mutation, as three individuals with the p.G13C change showed average nonverbal FR skills and borderline-to-low average overall nonverbal IQ. Further, separation anxiety is more common in Costello syndrome than in the general population, affecting 39% of this cohort, and males are more often overly anxious than females. Interrelations between anxiety and cognitive and adaptive functioning were found, pointing to functional difficulties as a likely source of stress and anxiety. Taking into account data from animal models, cognitive and behavioral changes likely originate from abnormal differentiation of neuronal precursor cells, which result in structural and functional brain differences.

Publication types

  • Review

MeSH terms

  • Adaptation, Psychological / physiology*
  • Anxiety Disorders / physiopathology*
  • Behavioral Symptoms / physiopathology*
  • Cognition Disorders / physiopathology*
  • Costello Syndrome / genetics
  • Costello Syndrome / physiopathology*
  • Female
  • Humans
  • Male
  • Mutation / genetics
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Sex Factors


  • MAS1 protein, human
  • Proto-Oncogene Mas
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)