High incidence of progressive postnatal cerebellar enlargement in Costello syndrome: Brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities

Karen W. Gripp, Elizabeth Hopkins, Daniel Doyle, William B Dobyns

Research output: Contribution to journalArticlepeer-review

Abstract

Costello syndrome is a rasopathy caused by germline mutations in the proto-oncogene HRAS. Its presentation includes failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. In a systematic review we found absolute or relative macrocephaly (100%), ventriculomegaly (50%), and other abnormalities on brain and spinal cord imaging studies in 27/28 individuals. Posterior fossa crowding with cerebellar tonsillar herniation (CBTH) was noted in 27/28 (96%), and in 10/17 (59%) with serial studies posterior fossa crowding progressed. Sequelae of posterior fossa crowding and CBTH included hydrocephalus requiring shunt or ventriculostomy (25%), Chiari 1 malformation (32%), and syrinx formation (25%). Our data reveal macrocephaly with progressive frontal bossing and CBTH, documenting an ongoing process rather than a static congenital anomaly. Comparison of images obtained in young infants to subsequent studies demonstrated postnatal development of posterior fossa crowding. This process of evolving megalencephaly and cerebellar enlargement is in keeping withmouse model data, delineating abnormal genesis of neurons and glia, resulting in an increased number of astrocytes and enlarged brain volume. In Costello syndrome and macrocephalycapillary malformation syndrome disproportionate brain growth is the main factor resulting in postnatal CBTH and Chiari 1 malformation.

Original languageEnglish (US)
Pages (from-to)1161-1168
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume152
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

Keywords

  • Cardio-facio-cutaneous (CFC) syndrome
  • Macrocephaly-capillary malformation (M-CM) syndrome
  • Megalencephaly- polydactyly-polymicrogyria-hydrocephaly (MMPH) syndrome
  • NF1
  • Noonan syndrome
  • Rasopathy

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