PHACE Syndrome: an Exploration of Combined Phenotype Incidences and an Analysis of Proposed Causes

Abstract

PHACE Syndrome presents early in childhood and is characterized by vascular anomalies, the most prevalent being infantile hemangioma. The cause of PHACE Syndrome is unknown, and it remains highly uncertain whether a patient with PHACE will have long-term complications. PHACE Syndrome is more prevalent in females than males, but a connection between PHACE Syndrome and the X-chromosome has not been elucidated. Current research in the field suggests a connection between RAS pathway dysregulation and PHACE, offering a new area to be explored further to better understand the etiology of PHACE. The highly varied nature of PHACE Syndrome makes diagnosis more difficult. I have explored the very varied nature of PHACE Syndrome by compiling phenotypic data from PHACE Syndrome case studies. This data allowed for phenotype incidences to be calculated as well as phenotype combination incidences. Through this research, I have uncovered that certain phenotypes commonly appear together in PHACE Syndrome while they do not typically appear together in non-PHACE cases. These phenotype pairs include: absence of the internal carotid artery and aberrant subclavian artery, patent ductus arteriosus and atrial septal defect, and hypoplasia of the internal carotid artery and the vertebral artery. These phenotype combinations point to variations in these symptoms between PHACE and non-PHACE patients and further research concerning these phenotypes could point to an etiology of PHACE Syndrome. I also explored the possibility of male severity and lethality, as is common in X-linked conditions, and discovered that males could present with more severe symptoms, as demonstrated through the complications associated with Dandy-Walker malformation. The sex bias of Dandy-Walker malformation within PHACE Syndrome is an avenue for further research. I have also demonstrated that certain phenotypes, such as hearing loss, hypothyroidism, and atrial septal defect, have higher incidences within PHACE Syndrome than previously indicated. This leads to the recommendation for an update to the current PHACE Syndrome diagnostic criteria to include these phenotypes that have greater prevalence than previously indicated.