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

Large segmental infantile hemangiomas are a hallmark of PHACE (posterior fossa brain malformations, large facial hemangiomas, arterial anomalies, cardiac defects [including aortic coarctation], and eye abnormalities), as is a high prevalence of cerebral arterial abnormalities ipsilateral to the infantile hemangioma. Both infantile hemangioma and PHACE are characterized by a striking female predominance and a frequent gestational history of placental anomalies. Yet despite extensive study, the pathogenesis of both remains incompletely understood, and neither has been associated with a genetic mutation. We synthesize clinical, embryological, and molecular evidence to propose a unifying developmental framework. In this model, perturbation of neural‐crest‐cell‐derived mesenchyme disrupts normal craniofacial vascular patterning, while hypoxia‐driven and placental signaling drives endothelial proliferation and the hemangioma phenotype. Segmental distribution and ipsilaterality, internal carotid artery dysgenesis, persistence of embryonic carotid–basilar anastomoses, and the high incidence of moyamoya disease are accounted for, as is female predominance. This integrated framework reconciles previously disparate observations and suggests that PHACE represents a developmental arteriopathy within the spectrum of neurocristopathies.