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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
Author(s) -
Gripp Karen W.,
Hopkins Elizabeth,
Doyle Daniel,
Dobyns William B.
Publication year - 2010
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.33391
Subject(s) - macrocephaly , syringomyelia , megalencephaly , medicine , costello syndrome , hras , chiari malformation , hydrocephalus , pathology , anatomy , magnetic resonance imaging , radiology , colorectal cancer , cancer , kras
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 with mouse model data, delineating abnormal genesis of neurons and glia, resulting in an increased number of astrocytes and enlarged brain volume. In Costello syndrome and macrocephaly‐capillary malformation syndrome disproportionate brain growth is the main factor resulting in postnatal CBTH and Chiari 1 malformation. © 2010 Wiley‐Liss, Inc.