A neural‐crest‐driven developmental framework for PHACE : Infantile hemangioma and cerebral arterial dysgenesis

PHACE syndrome is a neurocutaneous disorder characterized by large segmental infantile hemangiomas, most often involving the face or scalp, together with congenital abnormalities of the cerebral arteries, posterior fossa, eyes, heart, or aortic arch. A striking feature is that the hemangioma and associated abnormalities usually occur on the same side. PHACE also predominantly affects females, yet no consistent causative genetic alteration has been identified. This review integrates clinical, embryological, and molecular evidence to propose that PHACE results from disturbed development of neural crest-derived tissues. During early embryogenesis, neural crest cells migrate into defined craniofacial territories and contribute to vascular smooth muscle and pericytes in the face, forebrain, and proximal internal carotid artery. They also contribute to the development of the eyes, aortic arch, cardiac outflow tract, and some posterior fossa structures. Disruption of a regional neural crest cell population could therefore explain the segmental and same-sided distribution of abnormalities, the particular vulnerability of the internal carotid artery, and the association with progressive moyamoya arteriopathy. The neural crest model is integrated with evidence linking infantile hemangiomas to placental abnormalities and fetal hypoxic stress. Placental dysfunction and hypoxia-related signaling may promote endothelial proliferation and the hemangioma phenotype, while altered neural crest development determines where lesions occur and which associated structures are affected. Sex-specific responses of neural crest cells to hypoxia-related signals could potentially contribute to the marked female predominance.