Cervical and Intracranial Arterial Anomalies in 70 Patients with PHACE Syndrome

Discussion

This work confirms a strong association between the laterality of head and neck arteriopathy, cutaneous hemangiomas, and brain structural abnormalities in patients with PHACE syndrome and emphasizes the significant proportion of cases in which the ICA or its early embryologic branches or both are involved in the disorder. While the findings in large part concur with current ideas regarding the etiology of PHACE syndrome, they also raise the novel possibility that the variable phenotype of the disorder could, in part, be accounted for by alterations in blood flow caused by the development of arteriopathy during embryogenesis.

We found that the 2 most common forms of arteriopathy were dysgenesis and anomalous arterial origin and/or course. Estimates of frequencies for different types of arteriopathy in this work differ from those given in prior studies^6,7 in 3 important respects: First, arterial abnormalities were classified on the basis of primary review of cross-sectional imaging, rather than written descriptions extracted from medical records or published case reports. Second, the use of consensus criteria for the diagnosis of PHACE syndrome led to a more uniform group of patients for analysis. Finally, whereas prior estimates have been based on groups of patients both with and without cerebrovascular anomalies, our study was limited to only subjects with arteriopathy.

The frequent coexistence of different forms of arteriopathy suggests that the categories used for classification in this and other reports represent different pathologic end points of the same underlying process. The most likely candidate is a disruption in the normal histologic architecture of the arterial wall, which, as discussed by Bhattacharya et al,⁴ could result in reductions or increases in cross-sectional diameter, elongation, corkscrewing, and/or tortuosity. Corkscrewing and other forms of dysgenesis are exceedingly rare in children and are most often associated with disorders that have decreased elasticity of tissues such as Menkes disease.²⁰ Long-segment concentric narrowing of the ICA is similarly unusual because most secondary childhood stenosing arteriopathies—eg, Moyamoya disease, sickle cell vasculopathy, focal arteriopathy of childhood, and dissection—tend to cause more focal narrowing. To the authors' knowledge, there have been no tissue biopsies of the abnormal cervical or intracranial arteries in patients with PHACE syndrome, though the reported microstructural abnormalities in the arterial intima and media of the diseased aorta in 2 children undergoing aortic coarctation repair²¹ support the idea of dysgenetic vessels. Anomalous arterial origin and course, which, in some cases, corresponded to persistent embryonic arteries, and primitive embryonic carotid-vertebrobasilar connections suggest a different process, in which the normal pattern of vasculogenesis is altered during development of the cervical and intracranial arterial system.

As elegantly summarized by Krings et al,²² current hypotheses regarding the developmental errors that link the abnormalities in PHACE syndrome have focused on the role of the neural crest, the adjacent cephalic mesoderm, and even the neural plate in cases of brain structural lesions. Chimera studies in the avian embryo provide evidence that the muscular and connective tissue wall of the ICA and its branches are derived from cephalic neural crest cells, in contrast to the arterial wall of the basilar and vertebral arteries, which derive from the cephalic mesoderm.²³ The disproportionate frequency with which the anterior circulation is involved compared with the posterior circulation follows the embryologic division between neural crest and mesodermal-derived arteries. However, for reasons outlined by other authors, metameric disruption in the neural crest and adjacent cephalic mesoderm does not fully account for the spectrum of abnormalities in PHACE syndrome.^4,19,22

The primitive ICA is vital to the normal development of the brain and surrounding structures because it is the embryologic precursor to the MCA, the ACA, the PcomA arteries, the PCAs, the superior cerebellar arteries, and the upper BA and it is the primary source of blood to the developing vertebrobasilar system. According to Padget,²⁴ this artery is first seen as the cranial extension of the dorsal aorta at the 3-mm embryonic stage (22–23 days) and gives rise to its primary branches by the 16-to 18-mm stage (48–51 days). During this roughly 4-week period, the primitive ICA also supplies the posterior circulation through a series of transient intersegmental arteries that each normally develop and regress for 7–10 days until the vertebrobasilar system is fully developed. Blood supply to the cerebellum in particular is critically dependent on the ICA during this phase of embryogenesis.

While different brain structural anomalies observed in this study and previously associated with PHACE syndrome may individually be caused by a variety of factors, both the common posterior fossa abnormalities and the less frequent supratentorial abnormalities share in utero ischemia as a common potential cause. Before fusing and becoming the BA between 29 and 33 days' gestation, the paired dorsal longitudinal arteries are supplied mainly by the primitive ICA by means of the trigeminal arteries. It is not until nearly 6 weeks' gestation that the vertebral arteries become the major contributor to hindbrain blood supply. Compromised vascular blood flow within 1 longitudinal artery before this point could impair formation of the ipsilateral cerebellar hemisphere and vermis. Abrupt disruption of an otherwise normally developing cerebellum is suggested by the normal bony posterior fossa,⁴ consistent with an ischemic etiology for cerebellar anomalies. Similarly, transient or permanent vascular insult and in utero ischemia are well-established causes for polymicrogyria,²⁵ callosal dysgenesis,²⁶ heterotopia,²⁷ cerebellar hypoplasia,²⁸ and other malformations of cortical development.

Although almost all cases with intracranial arteriopathy have S1 or S3 segment hemangiomas, the lack of a significant association between the arteries involved and the segmental location of the facial hemangioma militates against a common metameric origin for the simultaneous development of both abnormalities. Recent work provides evidence that the endothelial progenitor cells that give rise to hemangiomas may ultimately derive from the neural crest,²⁹ though the cellular and molecular events that would induce the neural crest to differentiate along these lines have not yet been elaborated. At birth, most hemangiomas represent “precursor lesions” that subsequently proliferate. Alterations in blood flow or hypoxia may serve as the trigger that leads to the development of latent hemangioma precursors. Hemangiomas at all stages of evolution express glucose transporter 1,³⁰ an intrinsic cellular marker of tissue hypoxia, and the combination of hypoxia and estrogen demonstrates a synergistic effect on hemangioma endothelial cell proliferation.³¹

There are 2 important limitations of this study. First, because most patients underwent only MRA to study their arteries, it was not possible to distinguish between agenesis and occlusion or between stenosis and hypoplasia, which represent fundamentally different processes. This limitation hinders our ability to divide these anomalies from an embryologic standpoint. Second, the average age of children included in this work was relatively old with respect the diagnosis of PHACE syndrome. To the extent that arteriopathy may change with time, this ascertainment bias could lead to inaccuracies in the estimated frequencies of different types of arteriopathy.