Literature ReviewMoyamoya Vasculopathy in PHACE Syndrome: Six New Cases and Review of the Literature
Introduction
PHACE syndrome (OMIM 606519) is a rare neurocutaneous vascular disorder with an estimated prevalence of <1 in 1,000,000, characterized by Posterior fossa malformations, large cervicofacial infantile Hemangiomas, Arterial anomalies, aortic coarctation and Cardiac abnormalities, and Eye abnormalities.1, 2, 3, 4, 5 Of note, cerebrovascular anomalies are the most frequent extracutaneous manifestation of the disease,6 including the persistence of primitive embryonic arteries, arterial dolichoectasia or aneurysmatic dilatations, and agenesis or stenosis of the internal carotid artery (ICA) and vertebral artery, variably associated with a network of collaterals from the external carotid arteries (carotid rete mirabile) or quasi-moyamoya disease (quasi-MMD).1, 2, 6, 7, 8, 9, 10, 11 No genetic cause has been identified in PHACE syndrome to date. Interestingly, Schilter et al.12 recently have described compound RNF213-heterozygous variants in a child with PHACE and moyamoya vasculopathy, thus suggesting a potential role of this gene as a modifier of the vascular phenotype seen in PHACE.
Although the natural history of PHACE vascular anomalies remain unknown, their impact on the long-term neurologic outcomes is particularly relevant, with up to 50% of patients becoming symptomatic due to the progressive intracranial arteriopathy.4, 7 Therefore, a recent consensus statement has delineated the criteria necessary for the diagnosis and care of PHACE syndrome, categorizing the associated arteriopathies based on the risk of acute ischemic stroke into low-, intermediate-, and high-risk PHACE vasculopathies.13 Accordingly, pediatric neurologist referral and short-term imaging surveillance at 6 months and 1 year are recommended for high-risk vasculopathies, whereas longer imaging follow-up should be determined on a case-by-case basis by a multidisciplinary team. Prophylactic aspirin therapy should be considered for high-risk patients, but no specific recommendations have been provided for surgical treatment of moyamoya vasculopathy.13 Indeed, despite the numerous reports on PHACE, only few cases with moyamoya vasculopathy have been described so far.5, 6, 7, 11, 12, 14, 15, 16, 17
Here, we report 6 patients with PHACE syndrome and quasi-MMD, focusing on the surgical management and clinical outcome of the 3 children who were treated with encephaloduroarteriosynangiosis (EDAS) and encephalomyosynangiosis (EMS). In addition, we systematically reviewed the radiologic, clinical, and surgical aspects of moyamoya vasculopathy in PHACE syndrome, providing information on 15 additional published cases.
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Methods
The population considered for inclusion in this case series consisted of a historic cohort of 50 children clinically diagnosed as definitive or possible PHACE syndrome, according to the last revised classification.13 Subjects were evaluated in the pediatric dermatology clinics at our Institution from 2006 to 2017. All patients underwent magnetic resonance imaging (MRI) of the brain and at least one radiologic evaluation of the cerebral vasculature, including magnetic resonance angiography (MRA)
Literature Review
Table 1 reports the clinicoradiologic findings and medical and/or surgical management of our 6 patients and the 15 PHACE cases with quasi-MMD identified from the literature.5, 6, 7, 11, 12, 14, 15, 16, 17 Following the new classification, 18 of 21 cases could be retrospectively defined as definite PHACE, whereas the remaining 3 of 21 cases were defined as possible PHACE.13 Mean age at diagnosis was 22.7 months (range 1 month to 14 years). Mean age t the onset of neurologic symptoms was 33.6
Discussion
From the first description of the association of facial hemangiomas and cerebrovascular anomalies by Pascual-Castroviejo in 19962 and the definition of the PHACE acronym by Frieden in the same year,1 the clinical description of this neurovascular disorder has evolved significantly, resulting in what is now known as PHACE syndrome.3 Indeed, after the first diagnostic criteria were proposed in 2009, several inclusions and modifications were suggested, leading to new consensus-derived diagnosis
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.