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Ramappa M.,Medical University of South Carolina | Ramappa M.,L V Prasad Eye Institute | Wilson M.E.,Medical University of South Carolina | Rogers R.C.,Greenwood Genetics Center | Trivedi R.H.,Medical University of South Carolina
Journal of AAPOS | Year: 2014

We report a 6-week-old white boy of nonconsanguineous parents who presented with bluish scleral discoloration, thin corneas, and progressive high myopia. A diagnosis of brittle cornea syndrome was confirmed by molecular analysis and prompt measures were taken to manage the condition. Long-term follow-up of children diagnosed with brittle cornea syndrome is important to minimize the risks of corneal rupture and for detecting late-onset systemic conditions. Copyright © 2014 by the American Association for Pediatric Ophthalmology and Strabismus. Source

Hunter A.G.W.,Greenwood Genetics Center | Nezarati M.M.,Genetics Program | Velsher L.,Genetics Program
American Journal of Medical Genetics, Part A | Year: 2010

Facial angiofibromas are a major diagnostic sign for tuberous sclerosis (TS) and MEN1, and the former is probably the first disease to be considered by a geneticist when such lesions are found. They occur in up to 90% of persons with TS and 40-80% of individuals with MEN1. Early onset facial angiofibromas that are not associated with any other systemic sign appear to be unusual, and their occurrence can leave the clinician with some uncertainty as to their significance, as well as how to proceed. In this article we describe four patients with what appear to be isolated, bilateral facial angiofibromas. We discuss the significance of these lesions with respect to the conditions in which they have been seen, review prior reports of apparently isolated angiofibromas, and provide some rough calculations as to how likely it would be for an underlying systemic condition to be overlooked after different levels of investigation have been performed. We also look at some aspects of the financial cost/benefit ratio of further investigation of TS beyond a clinical examination. © 2010 Wiley-Liss, Inc. Source

Fisch G.S.,New York University | Carpenter N.,Center for Genetic Testing | Howard-Peebles P.N.,Genetics and IVF Institute | Holden J.J.A.,Queens University | And 3 more authors.
American Journal on Intellectual and Developmental Disabilities | Year: 2012

Few studies exist of developmental trajectories in children with intellectual disability, and none for those with subtelomeric deletions. We compared developmental trajectories of children with Wolf-Hirschhorn syndrome to other genetic disorders. We recruited 106 children diagnosed with fragile X, Williams-Beuren syndrome, or Wolf-Hirschhorn syndrome, assessing their intellectual and adaptive behavior abilities. We retested 61 children 2 years later. We compared Time 1 and Time 2 difference scores related to genetic disorder, age, initial IQ, or adaptive behavior composite. Results show genetic disorder and initial IQ score were significant factors for IQ differences, but only genetic disorder affected adaptive behavior differences. Results suggest different gene-brain-behavior pathways likely exist for these genetic disorders. Different developmental trajectories will influence the type and intensity of intervention implemented by caregivers. © EAAIDD. Source

Lindhurst M.J.,U.S. National Institutes of Health | Parker V.E.R.,University of Cambridge | Payne F.,Wellcome Trust Sanger Institute | Sapp J.C.,U.S. National Institutes of Health | And 27 more authors.
Nature Genetics | Year: 2012

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110Î ± catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP 3) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target. © 2012 Nature America, Inc. All rights reserved. Source

Sadler T.W.,Greenwood Genetics Center | Sadler T.W.,University of Utah
American Journal of Medical Genetics, Part A | Year: 2015

To date the etiology of the association called VACTERL remains a mystery. Interestingly, clues as to the origin of this collection of defects may reside in an old hypothesis concerning the midline as a developmental field as postulated by Dr. John Opitz. This theory suggested that the midline was not a separate entity, but could be influenced by other developmental signals. With new information concerning the origin of the left-right axis (laterality) and the importance of communications between this axis and the cranio-caudal (anterior-posterior) axis for normal development, it has become clear that coordination of the molecular signals responsible for specification of these domains is essential for normal development. In fact, if the signals regulating laterality are disrupted, then midline and other defects can occur as has been observed in cases of heterotaxy, presumably because of a disruption in this coordinated signaling effort. Thus, the origins of the defects commonly observed in the VACTERL association may be due to altered signaling responsible for establishing the left-right axis. © 2015 Wiley Periodicals, Inc. Source

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