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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Tseng, Hung H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Medical College of Wisconsin
Schools of Medicine
United States
Zip Code
Steiner, Jack E; McCoy, Garrett N; Hess, Christopher P et al. (2018) Structural malformations of the brain, eye, and pituitary gland in PHACE syndrome. Am J Med Genet A 176:48-55
Kim, M E; Cancel, M; Metry, D et al. (2017) Evaluation of maternal history of miscarriage, infertility and in vitro fertilization as associated factors in PHACE. Br J Dermatol 177:e90-e91
Schilter, Kala F; Steiner, Jack E; Demos, Wendy et al. (2017) RNF213 variants in a child with PHACE syndrome and moyamoya vasculopathy. Am J Med Genet A 173:2557-2561
Wan, Joy; Steiner, Jack; Baselga, Eulalia et al. (2017) Prenatal Risk Factors for PHACE Syndrome: A Study Using the PHACE Syndrome International Clinical Registry and Genetic Repository. J Pediatr 190:275-279
Garzon, Maria C; Epstein, Leon G; Heyer, Geoffrey L et al. (2016) PHACE Syndrome: Consensus-Derived Diagnosis and Care Recommendations. J Pediatr 178:24-33.e2
Yu, JiaDe; Siegel, Dawn H; Drolet, Beth A et al. (2016) Prevalence and Clinical Characteristics of Headaches in PHACE Syndrome. J Child Neurol 31:468-73
Chiu, Yvonne E; Siegel, Dawn H; Drolet, Beth A et al. (2014) Tooth enamel hypoplasia in PHACE syndrome. Pediatr Dermatol 31:455-8