SWF Funded Research

2007 - Guo-Yuan Yang, M.D., Ph.D.; University of California, San Francisco "Development of Cerebrovascular Dysplasia Model for SWS Study", $30,000

This new application will focus on mechanistic studies that are manipulated to approximate key components of the human SWS phenotype. Based on published experience by our group and others, an animal model of growth factor stimulation against varying genetic backgrounds can approximate aspects of SWS to further understand its pathophysiology. Coupled with ongoing research into tissue expression pattern, we hope to better understand the interplay of signaling pathways and underlie the clinical phenotype. Our long term goal is to: 1. develop a feasible and reproducible focal brain leptomeningeal capillary dysplasia model, which mimics brain lesions in SWS patients; and 2. understand the mechanisms of the development and maturation of abnormal brain capillary in the SWS patient's brain.

2006 - Anita N. Haggstrom; University of Indiana " Facial Port Wine Stains and Infantile Segmental Hemangiomas Associated with Neurocutaneous Disorders: Implications of Facial Patterns”, $ 30,000

This study seeks to determine the significance of the specific location and pattern of infantile segmental hemangiomas in individuals with PHACES syndrome and port wine stains in individuals with Sturge-Weber syndrome (SWS). Researchers believe that the distribution of port wine stains (PWS), like hemangiomas, is not random, but actually corresponds with embryologic facial prominences – small protrusions or buds of tissue in the embryo from which various facial structures develop.

2006 - PD Dr. Franz Grus, PhD, MD; University of Mainz Germany"Analysis of Antibody Profiles in SWS Patients Compared to Glaucoma Patients”, $30,000

The new study will analyze antibody profiles in individuals with SWS versus individuals with glaucoma. The study will also seek to identify antibody biomarkers in SWS. Biomarker is a general term for any biological or chemical substance that is an indicator of an underlying process (such as an autoimmune process). If antibody biomarkers are found, researches would seek to determine their role in the development of SWS, which, in turn, could eventually open new pathways for future treatments for SWS.

2006 - Margarita Zeichner-David, PhD; University of Southern California ”A Molecular Approach to Understand the Oral Manifestations of Sturge- Weber Syndrome”, $30,000

This proposal will seek to learn more about the oral symptoms and findings associated with SWS through the molecular study of cells collected from oral tissue and extracted teeth.

2006 - "Angiogenesis in the Nervous System" NINDS, ORD, SWF; Bethesda, MD, $7,500

The SWF co-hosted this workshop on angiogenesis and ½ day satellite meeting to discuss the genetics and vascular phenotypes in Sturge-Weber syndrome. The workshop discussed development of the vascular system, angiogenic remodeling in adults, angiogenesis in the aging brain, disorders of vascular development and therapeutic approaches.

2005 Kristen Kelly, MD, University of CA, Irvine, "Photodynamic & Photothermal Port Wine Stain Treatment", $20,000

This study will evualte photodynamic therapy (PDT) alone and in combination with pulsed dye laser (PDL) as a therapeutic alternative for port wine stain birthmakrs. The successful implementation of this approach should: 1. improve degree of PWS blanching, 2. reduce the number of treatment sessions, and 3. improve safety.

2005- Emily Germaine-Lee, MD, John Hopkins University Hospital, Baltimore, MD, $30,000

The SWF reviewed patient records with consent and patient participation in a study on hormone abnormalities in Sturge-Weber syndrome. It is felt that based upon the risk factors associated with the general population and those identified preliminarily in SWS, there is a higher risk of hormone abnormalities in the SWS population.

2004 Seuphy Chen, "Burden of Disease in Sturge-Weber Patients & Families " , Emory University School of Medicine, Atlanta, GA $30,000

This study will measure the quality of life (QOL), financial and health care utilization burden of patients and families with SWS.

Final Conclusions: The impact of SWS is significant. Scores for vision indicate that impact highly associated with depressive symptoms. Parents have an overall perception of their children’s health as poor or limited. The port wine birthmarks greatly impacted both parents and patients although the latter were more likely to report that having a port wine birthmark interferes with making friends. While a low frequency of doctor visits was reported, SW patients generally visited the ophthalmologist most often and had relatively high prescription drug expenditures.

2002 Anne Comi, Johns Hopkins Hospital/Kennedy-Krieger Institute Sturge-Weber Syndrome Center of Excellence, $50,000

Provides multidisciplinary clinical evaluation to patients with SWS and simultaneously jumpstarts clinical research efforts to further our understanding of SWS.

2001 Heather Etchevers, M.D. Institut d' Embryologie "Multipotency of Neural Crest-Derived Pericytes" $30,000-one year grant

The diverse cutaneous, vascular and neurological symptoms of Sturge-Weber syndrome may arise from a defect in the differentiation of the neural crest cell-derived pericyte. The long-term objective of this project is to define the capacity of purified pericytes to differentiate into other, characterized cell types. During embryonic life, cephalic NCC normally yield vascular pericytes as well as bone, cartilage, smooth muscle, fat, other connective tissues and neural and dermal cell types in the head. Pilot work for this proposal has established a protocol for the purification of embryonic NCC-derived pericytes and their maintenance under defined culture conditions.

2001 Douglas Marchuk, PhD. Duke University Medical Center, "Molecular Genetic Analysis of Port-Wine Stains in Sturge-Weber syndrome" $30,000-one year grant

The sporadic occurrence of Sturge-Weber syndrome, and distribution of lesions in a scattered or asymmetrical patter suggests the occurrence of a somatic mutation in an otherwise essential gene, leading to mosaicism for the mutation, as first postulated by Happle for this and similar syndromes. Our proposal is also based on the original observation of Smoller and Rosen that port-wine stains show a significant decrease in the density of nerves associated with blood vessels in the lesion. This observation, subsequently also described by others, suggests that a lack of innervation may be the primary defect of PWS, resulting in incomplete neural modulation of vascular flow. The extent of the vascular anomalies may depend on the time during development when this deficiency began, such that early events may predispose to some of the neurological problems associated with SWS. Our basic hypothesis is that the lack of innervation associated with PWS and SWS is due to somatic mutation of one of the receptors guiding axonal association in conjunction with vasculature system.

2000 Mahbubul Huq, M.D., Ph.D. Children's Hospital of Michigan: "Identification of Genetic Lesions in Sturge-Weber Syndrome" $30,000-one year grant

Our long range goal is to understand the pathogenesis of Sturge-Weber syndrome (SWS) and to use that knowledge to develop potent and novel therapy. The objective of this application, which is the next step in the pursuit of that goal, is to determine the genetic lesions in SWS. We hypothesize that SWS could arise from a somatic mutation that results in a single vascular abnormality of primordial vascular plexus in 4-mm embryo at 4 to 5weeks of gestation, when the visual cortex is juxtaposed to the optic vesicle and the upper part of the embryonic face. The mutation may reside in mesodermal or ectodermal cells that give rise to the primordial vascular plexus or that secondarily affect its generation and remodeling. SWS is characterized by sporadic occurrence, distribution of lesions in an asymmetrical pattern, variable extent of involvement, lack of diffuse involvement of entire body and or an organ, and almost equal sex ratio.

2000 Satoshi Hirakawa, M.D. Harvard Medical School: "The Role of Thrombospondin-2 in the Development of Hemangiomas Associated with Sturge-Weber syndrome" $30,000-one year grant

Our hypothesis is that the endogenous angiogenesis inhibitor TSP-2 plays an important role in the pathogenesis of hemangiomas associated with Sturge-Weber syndrome. Therefore, we expect that tSP-2 is down-regulated at both messenger RNA and protein level. We also expect that crosses of k14/VEGF transgenic mice with TSP-2 knock-out mice, and crosses of K14/angiopoietin-1 transgenic mice with TSP-2 knock-out mice, will show highly increased skin vascularization and hemangioma development and might serve as new in vivo models for cutaneous hemangiomas. We also expect that treatment of cutaneous hemangiomas with TSP-2 will decrease the size and formation of hemangiomas in vivo.

1999 Anne Comi, MD/Co-Investigator Jonathan Pevsner, PhD- Kennedy Krieger Research Institute: Gene Expression "Microarray Analysis of Gene Expression in Sturge-Weber syndrome" $30,000- one year grant

Sturge-Weber is a neurocutaneous disorder defined by the presence of a facial cutaneous angioma and clinical signs or radiologic evidence of a leptomeningeal angioma. The majority of individuals with SWS experience deterioration in neurologic function including hemiplegia and intellectual impairment. One model for understanding the often progressive neurologic pathology & clinical deficits in SWS proposes a complex interaction between abnormal angiogenesis, hypoxia, seizures and abnormal metabolism with energy failure. We propose to examine profiles of RNA expression in surgical tissue from subjects with SWS by cDNA microarray analysis. Microarray analysis would allow the identification of novel genes relevant to this disorder in addition to the simultaneous study of several hypothesized pathologic factors.

1999 Karl Heinz Plate, MD Friedrich-Alexander University: Angiogenesis "Regulation of Angiogenesis in Sturge-Weber syndrome" $30,000- one year grant

Failure of proper vascular development most likely is an underlying cause of SWS. These malformed blood vessels, or hemangiomas, may lead to port wine stain, epilepsy, and glaucoma, depending on location. We plan to examine expression of angiogenesis factors (such as VEGF & angiopoietins), their receptors (VEGFR's and TIE's) and putative regulatory molecules (such as hypoxia-inducible transcription factors, HIF's), by Northern analysis, immunohistochemistry, and in situ hybridization. In addition, we plan to test whether SWS could be a viral disease.

SWF Facilitated Clinical Research

Ongoing - Kevin Whitehead, MD, Howard Hughes Institute , Salt Lake City, Utah

The SWF has been working with Dr. Whitehead and colleagues at the Howard Hughes Institute to investigate and identify the inherited causes of SWS and KT. The SWF identifies patients with SWS and congenital cardiovascular problems for inclusion in the study and then facilitates participation. The chromosomes in the DNA taken from blood samples are examined. The scientists are particularly interested in families with multiple family members with a port wine stain.

2003 Eric Kossoff, MD; Carol Buck; and John M. Freeman, MD"Outcomes of 32 hemispherectomies for Sturge-Weber syndrome worldwide" Johns-Hopkins, Baltimore, MD

Epilepsy affects 80% of patients with Sturge-Weber syndrome; the majority of seizures begin before the age of 1. When seizures are intractable to medications and unihemispheric, hemispherectomy is often advised. In this study, The mean age at onset of seizures was 4 months, and the median age at surgery was 1.2 years. Children failed to respond to 3.7 anticonvulsants prior to surgery and averaged 387 seizures/month. Forty-seven percent had complications (e.g., hemorrhage and hypertension) in the perioperative period; however, 81% are currently seizure-free, with 53% off anticonvulsants. Hemispherectomy type (anatomic versus functional versus hemidecortication) did not influence outcome. Age at onset of seizures did not predict seizure freedom; however, an older age at hemispherectomy was positively correlated. Postoperative hemiparesis was not more sever than before surgery. Cognitive outcome was not related to the age at operation, side of operation, or seizure freedom. CONCLUSIONS: Children undergoing hemispherectomy presented at a young age and had frequent seizures for approximately 1 year but are now mostly seizure-free. Age at surgery did not have an adverse effect on either seizure or cognitive outcomes.

A. Rebarber, MD; A. S. Roman, MD, MPH; D. Roshan, MD; F. Blei, MD. NYU School of Medicine, Departments of Obstetrics / Gynecology, Pedriatrics, and Plastic Surgery, " Obstetrical Management of Patients with Klippel-Trenaunay Syndrome"

Successful pregnancy outcomes can be safely achieved in patients with Klippel-Trenaunay syndrome. Successful pregnancy outcome was achieved in all pregnancies with delivery at or beyone 36 weeks of gestation. One of the four pregnancies was cmplicated by pulmonacy embolism. Hereditary thrombophilia evaluation in two of the three patients was significant for heterozygous prothrombin gbene mutation. Secondarily, we rfeviewed 62 respondents to our questionnaire. There were 20 women who had a total of 33 successful deliveries. Obstetrical complications in this cohort included an increased rate of preeclampsia (20% versus 7@ in the general population), an increased frequency of thromboembolic events, and an increased rate of cesarean delivery (50% versus 18%).