Background: PHACE syndrome is the association of large segmental facial hemangiomas and congenital birth defects, such as posterior fossa malformations. The vast majority of cases are sporadic, suggesting de novo or postzygotic somatic mutations may be the pathogenic mechanism. Gap: There is a fundamental lack of knowledge about the pathogenesis and natural history of the developmental anomalies in this hemangioma syndrome. Goal: Our primary objective is to elucidate the critical developmental genetic pathway involved in this hemangioma syndrome. Our secondary objective is to correlate the most severe clinical features (coarctation of the aorta, cerebrovascular anomalies and stroke) with the genotype.
Aims : 1) We will use next generation high-throughput sequencing technology, custom designed analysis pipelines, and standard validation methods to identify mosaic mutations in PHACE. 2) We will capitalize on our rigorously phenotyped clinical PHACE registry and extensive preliminary data defining the clinical characteristics of PHACE syndrome to determine genotype-phenotype correlations. Significance: The contribution of the proposed research is expected to be an understanding of the genetic underpinnings of PHACE syndrome and phenotypic correlation with the associated developmental anomalies. This knowledge will be significant as it will drive strategies for prevention and provide critical targets for new therapeutic agents. Collaborators: Our multi-disciplinary study team includes expertise in dermatology (Siegel, Drolet and Frieden), medical genetics and child neurology (Dobyns), bioinformatics (Worthey), genomics (Worthey, Jacob and Shendure), statistics (Hoffman) and cell biology (Rafiee).

Public Health Relevance

Large hemangiomas on the face can be associated with developmental anomalies involving multiple systems, including the eye, brain (Dandy-Walker malformation), heart, and blood vessels. Identifying the cause of PHACE syndrome will provide valuable clues about the pathogenesis and outcomes of hemangiomas and associated birth defects and impact many fields of medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR064258-01A1
Application #
8694346
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Tseng, Hung H
Project Start
2014-04-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$643,954
Indirect Cost
$220,478
Name
Medical College of Wisconsin
Department
Dermatology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226