TY - JOUR
T1 - High incidence of progressive postnatal cerebellar enlargement in Costello syndrome
T2 - Brain overgrowth associated with HRAS mutations as the likely cause of structural brain and spinal cord abnormalities
AU - Gripp, Karen W.
AU - Hopkins, Elizabeth
AU - Doyle, Daniel
AU - Dobyns, William B.
PY - 2010/5
Y1 - 2010/5
N2 - 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.
AB - 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.
KW - Cardio-facio-cutaneous (CFC) syndrome
KW - Macrocephaly-capillary malformation (M-CM) syndrome
KW - Megalencephaly- polydactyly-polymicrogyria-hydrocephaly (MMPH) syndrome
KW - NF1
KW - Noonan syndrome
KW - Rasopathy
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U2 - 10.1002/ajmg.a.33391
DO - 10.1002/ajmg.a.33391
M3 - Article
C2 - 20425820
AN - SCOPUS:77951745198
SN - 1552-4825
VL - 152
SP - 1161
EP - 1168
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 5
ER -