NDLI: 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.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Gripp, Karen W. Hopkins, Elizabeth Doyle, Daniel Dobyns, William B.
Description	Country affiliation: United States Author Affiliation: Gripp KW ( Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, DE 19899, USA. kgripp@nemours.org)
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 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.
File Format	HTM / HTML
ISSN	15524825
e-ISSN	15524833
DOI	10.1002/ajmg.a.33391
Journal	American Journal of Medical Genetics Part A
Issue Number	5
Volume Number	152A
Language	English
Publisher	Wiley-Blackwell
Publisher Date	2010-05-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Genetics Cerebellum Abnormalities Growth & Development Costello Syndrome Epidemiology Genetics Mutation Proto-oncogene Proteins P21(ras) Spinal Cord Surgery Infant, Newborn Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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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

Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation.

Increased sleep spindle activity in patients with Costello syndrome (HRAS gene mutation).

An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences.

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome.

Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism.

Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline.

Comprehensive genetic analysis of overlapping syndromes of RAS/RAF/MEK/ERK pathway

Recurrent duplication mutation in HRAS causing mild Costello syndrome in a Chinese patient.

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.

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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

Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation.

Increased sleep spindle activity in patients with Costello syndrome (HRAS gene mutation).

An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences.

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome.

Male-to-male transmission of Costello syndrome: G12S HRAS germline mutation inherited from a father with somatic mosaicism.

Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline.

Comprehensive genetic analysis of overlapping syndromes of RAS/RAF/MEK/ERK pathway

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