| 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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MedLine Citation:
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PMID: 20425820 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Karen W Gripp; Elizabeth Hopkins; Daniel Doyle; William B Dobyns |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Review |
Journal Detail:
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Title: American journal of medical genetics. Part A Volume: 152A ISSN: 1552-4833 ISO Abbreviation: Am. J. Med. Genet. A Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-04-28 Completed Date: 2010-08-12 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101235741 Medline TA: Am J Med Genet A Country: United States |
Other Details:
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Languages: eng Pagination: 1161-8 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Wiley-Liss, Inc. |
Affiliation:
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Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, DE 19899, USA. kgripp@nemours.org |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cerebellum
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abnormalities*,
growth & development* Costello Syndrome / epidemiology*, genetics*, surgery Humans Incidence Infant, Newborn Mutation / genetics* Proto-Oncogene Proteins p21(ras) / genetics* Spinal Cord / abnormalities* |
| Grant Support | |
ID/Acronym/Agency:
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1R01-NS050375/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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EC 3.6.5.2/HRAS protein, human; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras) |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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