Neurological and Vision publications

Your CostelloKids online research library

Neurological and vision publications

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,1* Elizabeth Hopkins,1 Daniel Doyle,2 and William B. Dobyns3

1 Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware

2 Division of Endocrinology, A. I. duPont Hospital for Children, Wilmington, Delaware

3 Departments of Human Genetics, Neurology and Pediatrics, The University of Chicago, Chicago, Illinois

Costello syndrome is a rasopathy caused by germline mutations in the proto-oncogene HRAS. Its presentation includes failureto- 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 1malformation (32%), and syrinx formation (25%). Our data reveal macrocephaly with progressive frontal bossing andCBTH, 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. InCostello syndrome and macrocephaly capillary malformation syndrome disproportionate brain growth is the main factor resulting in postnatal CBTH and Chiari 1 malformation.

Keratoconus in Costello Syndrome

Karen W. Gripp1* and Laurie A. Demmer 2

1 Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware

2 Division of Clinical Genetics, Levine Children’s Hospital, Charlotte, North Carolina

Keratoconus is a corneal dystrophy with progressive corneal thinning resulting in abnormal corneal shape and astigmatism. Corneal hydrops and rupture can occur and corneal transplant may become necessary. While keratoconus is rare in the general population occurring in about 1/2,000 individuals, it is more common in individuals with intellectual disability and syndromic conditions. Connective tissue abnormalities, most typically brittle cornea syndrome, have frequently been reported in association with keratoconus. Here, we report on bilateral keratoconus with acute hydrops in the left eye of a 24-year-old male with Costello syndrome. The patient was treated medically. After resolution of the hydrops, he had significant visual impairment from the resulting irregular astigmatism and scarring. This is the second report of keratoconus in Costello syndrome, suggesting an increased risk for this corneal dystrophy in individuals with Costello syndrome. Ongoing ophthalmological surveillance may be necessary for adult individuals with Costello syndrome, and apparent vision changes should be evaluated expediently.

Costello Syndrome and Neurological Abnormalities

Clinical Report

PediatriMarie-Ange Delrue, Jean-Franc¸ois Chateil, Benoit Arveiler,1 and Didier Lacombe 

Costello syndrome is a rare but increasingly recognized syndrome of unknown etiology. Neurological abnormalities are not rare in this syndrome and consist of structural and electrophysiological disorders. Ventricular dilatation is observed in more than 40% of cases. Other reported cerebral anomalies  are brain atrophy, Chiari malformation and syringomyelia. Although there is insufficient data to propose strict guidelines, it seams reasonnable to have a low threshold for neuroimaging, in general, and particularly when neurologic signs or symptoms are present. Screening including cerebral MRI and EEG should be proposed after a dianosis of Costello syndrome. The frequency of testing in such children should be guided by neurological follow-up.