PHACE association is a rare neurocutaneous syndrome that may include posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities, and sternal defects. The arterial abnormalities may be developmental or acquired and usually involve the cervical and cerebral vasculature. We believe that infants with PHACE association are at increased risk of arterial ischemic stroke and describe 5 infants with facial hemangiomas and structural and acquired arterial anomalies, all of whom suffered an arterial ischemic stroke during infancy.
In 1978, Pascual-Castroviejo1 described the association of large cutaneous hemangiomas of the head and anomalies of the cerebral vasculature. Frieden et al2 subsequently coined the acronym PHACE association (Online Mendelian Inheritance in Man database No. 606519) to expand on the spectrum of anomalies that may occur in infants with large facial hemangiomas (Table 1). The etiology and significance of the associated arterial anomalies is poorly defined. Recent literature has suggested that the cervical and cerebral arterial anomalies may be progressive and that infants with PHACE association are at risk for arterial ischemic stroke (AIS).3 We believe that this phenomenon is underrecognized and describe 5 additional infants with facial hemangiomas and progressive cervical and cerebral vasoocclusive disease that resulted in AIS.
A 3-week-old term girl presented for evaluation of an enlarging facial hemangioma. On examination there was an extensive bright-red, slightly elevated plaque involving the left scalp and forehead, left upper eyelid, and the anterior left and central posterior neck. There was proptosis and exotropia of the left eye. Magnetic resonance imaging (MRI) showed an extensive infiltrating hemangioma involving the left face, deep soft tissues of the neck, and the upper mediastinum. Echocardiography revealed mild narrowing of the transverse aortic arch. Systemic steroid therapy was initiated (2.4 mg/kg per day), and response was initially dramatic; however, repeated attempts to taper her systemic steroid dose were unsuccessful because of persistent growth of the retrobulbar hemangioma.
At 5 months of age, she developed meningitis; her cerebrospinal fluid grew Listeriamonocytogenes. During her hospitalization, she exhibited prolonged seizure activity and right-sided hemiparesis. MRI revealed extensive cerebral edema suggestive of an acute infarct in the distribution of the entire left middle cerebral artery and the bilateral anterior cerebral arteries. Magnetic resonance angiography (MRA) demonstrated narrowing of the circle of Willis with no flow within the right posterior communicating artery and significant stenosis of the left internal carotid artery. A thorough evaluation for prothrombotic disorders (factor V Leiden mutation, methylenetetrahydrofolate reductase mutation, prothrombin gene defect, antiphospholipid antibodies, and deficiencies of protein C, protein S, and antithrombin) was performed; although there were mild alterations during the period of sepsis, none of these persisted when retested. Repeat MRI demonstrated extensive encephalomalacia of the left hemisphere, bilateral subdural effusions, and an increase in the size of the hemangioma. She was treated with 40.5 mg of aspirin per day. Her facial hemangioma continued to proliferate (Fig 1), and vincristine 2 mg/m2 per week was begun with an excellent response. Cerebral MRI/MRA at 5 years of age revealed the old left hemispheric infarction and complete occlusion of the right vertebral artery and left anterior cerebral artery, stenosis of the left internal carotid artery, left middle cerebral artery, and right anterior cerebral artery. She is developmentally delayed and has persistent right hemiparesis.
A 6-week-old girl presented with an enlarging left facial hemangioma distributed over the left forehead, upper and lower left eyelids, left cheek, upper and lower lip, parietal scalp, and anterior and posterior neck (Fig 2). Prednisone was initiated at 3 mg/kg per day to prevent ocular compromise. MRI of the head and neck revealed a left facial and orbital hemangioma and a small, deep, left neck hemangioma that extended into the upper mediastinum. A screening echocardiogram demonstrated a massive saccular aneurysm of the transverse portion of the aortic arch. An angiogram of the great vessels confirmed the aneurysm and demonstrated complete occlusion of the descending aorta with multiple collateral vessels supplying the lower extremities. The right and left common carotid arteries arose anomalously proximal to the aneurysm. She underwent corrective surgery for the aortic aneurysm with Gortex graft placement. At 3 months of age, she presented with nystagmus and seizures. MRI of the head demonstrated an acute infarct in the left posterior temporal and occipital regions; MRA was not performed. Phenytoin and 40.5 mg of aspirin per day were started. The results of an extensive prothrombotic workup were normal (factor V Leiden mutation, methylenetetrahydrofolate reductase mutation, prothrombin gene defect, antiphospholipid antibodies, and deficiencies of protein C, protein S, and antithrombin). Repeat MRI/MRA at 5 months of age revealed mild encephalomalacia in the regions of prior edema, stenosis of the left internal carotid artery, slow flow in the right middle cerebral artery, and narrowing of the left vertebral artery. At 8 months of age MRA revealed progressive stenosis of both internal carotid arteries. Angiography of the head and neck demonstrated multiple anomalous vessels. The right common carotid was the first vessel to come off the aortic arch and supplied most of the intracranial structures. The right internal carotid was dilated and tortuous (Fig 3). There was complete occlusion of the majority of the left internal carotid artery and a segment of the left vertebral artery. Several collateral arteries were noted to supply the superior internal carotid artery and left subclavian artery. The A1 segment of the anterior cerebral artery was missing. She is now 3 years of age and continues to have intermittent seizures, motor delay, and severe verbal developmental delay.
A 4-week-old term girl was evaluated by dermatology for a rapidly enlarging hemangioma of the right upper lip. Despite 2.6 mg/kg per day of oral prednisone therapy, it extended to involve the entire right side of the face and nose, with extensive ulceration of the upper lip and right hard palate. Oral prednisone was increased to 5 mg/kg per day. MRI of her head and chest showed extensive enhancement of the soft tissue involving the midface, cheeks, the deep masticator space, right orbital and supraorbital regions, and right side of the neck, extending inferiorly into the superior mediastinum and anterior chest wall. There was no evidence of cerebellar hypoplasia or structural anomalies of the central nervous system; MRA was not performed. Intravenous methylprednisolone 4 mg/kg per day and subcutaneous interferon α2b were initiated, with temporary arrest of the ulcerative process, but hypertension and extreme elevation of liver transaminases (>1000 U) necessitated discontinuation. Intravenous vincristine was initiated, with eventual cessation of the centrofacial ulcerative process.
At 5 months of age she presented with new-onset seizures. MRI demonstrated a cerebral infarction of the right occipital and posterior parietal lobes; no MRA was done at that time. Fosphenytoin was initiated for seizures, and she was started on 40.5 mg of aspirin per day. There was no factor V Leiden mutation, prothrombin gene defect, or antiphospholipid antibodies, and protein C, protein S, and antithrombin levels were normal. On repeat MRI studies at 9 months of age, interval evolution of the infarct was noted with postinfarct encephalomalacia and enlargement of cerebrospinal fluid spaces. The patient underwent extensive reconstructive surgery of the right face. Gadolinium-enhanced MRI and MRA performed at 32 months of age demonstrated narrowing of the entire right internal carotid artery and tortuosity of the basilar artery. At 36 months of age, she had not had additional seizures, and was taking small amounts of food orally. Her gross motor development is mildly delayed, but her cognitive development seems normal.
A previously healthy 4-month-old boy was admitted for seizures and acute onset of right-sided hemiparesis. He had episodic eye deviation with horizontal nystagmus, with no facial asymmetry but profound weakness of the right upper extremity flexors and extensors. Deep-tendon reflexes were increased on the right arm compared with the left. There was an early systolic ejection murmur. A small 3.0 × 3.0-cm, soft, blue nodule was present on the left mandibular cheek, with a superimposed 1.0 × 1.0-cm red plaque. An echocardiogram demonstrated a patent foramen ovale but no aortic-arch anomalies. T2-weighted cerebral MRI demonstrated abnormal increased signal intensity in the left temporal lobe in the anterior and middle portion of the putamen, which was suggestive of an acute infarction in the left middle cerebral artery territory. MRA showed substantial narrowing of a long segment of the left internal carotid artery as it passed into the skull base, with increased stenosis at the supraclinoid region (Fig 4). There were irregularities and tapering of the left A1 and M1 segments of the anterior and middle cerebral arteries. An extensive prothrombotic workup was normal (factor V Leiden mutation, methylenetetrahydrofolate reductase mutation, prothrombin gene defect, antiphospholipid antibodies, and deficiencies of protein C, protein S, and antithrombin). Repeated imaging studies have demonstrated encephalomalacia of the affected left temporal lobe and slight progression of the narrowing of the left internal carotid. He was placed on 40.5 mg of aspirin per day and has no additional signs or symptoms of AIS. He is now 15 months old and has residual weakness of his right upper extremity with normal cognitive development.
A 6-week-old term girl presented for evaluation of a large, segmental, red plaque involving both periorbital regions, the entire right side of the face, and right lower lip. There was bilateral ptosis resulting from the retrobulbar involvement of the hemangiomas. At 8 weeks of life, MRI demonstrated multiple foci of hemangiomas within both orbits, the right parotid gland, retropharyngeal space, carotid space, and right supraglottis/glottis, with an external mass effect on the airway. MRA of the cerebral vasculature demonstrated bilateral abnormalities of the cervical and petrous internal carotid arteries, with redundancy and areas of narrowing. The right internal carotid and A1 segment of the right anterior cerebral artery were diminutive. The left posterior communicating artery was tortuous and redundant, with a corkscrew-like appearance. Results of an extensive prothrombotic laboratory investigation were normal except for a homozygous C677T mutation of the methylene tetrahydrofolate reductase (MTHFR) gene. She was started on high-dose folate at 0.5 mg orally per day. At 1 year of age she presented with an acute left hemiparesis. Computed tomography of the brain revealed acute right frontal lobe infarction and an old left temporal-parietal infarction, which had not been present on cranial computed tomography 3 months earlier. After discussion with her ear, nose, and throat surgeon, who thought that she was at relatively low risk of bleeding from her hemangiomas, she was started on 10 mg of aspirin per day and developed gradual improvement of her hemiparesis. She developed bruising when her dose was increased to 20 mg per day, so her dose has remained at 10 mg per day. At 16 months of age, she had a mild left hemiparesis and both motor and cognitive developmental delay.
Stroke in children is rare, particularly in infants beyond the perinatal period. The overall annual incidence of stroke in children <14 years of age is 2.5 to 3.5 per 100000 per year.4 Children with PHACE association seem to be a subgroup that is at unusually high risk of early stroke.
The risk factors for childhood arterial stroke differ from those observed in adults. In a British article describing a registry of 212 children with AIS, 5 patients (2.3%) were described as having “skin hemangiomas,” and 79% of patients had cervical or cerebral arterial abnormalities; it is unclear how many had both hemangioma and cerebrovascular abnormalities.5 Occlusion or narrowing of the terminal internal carotid and/or proximal segment of the anterior middle cerebral artery was the most frequent finding.5,6 In our series and previously described series, these are the most common cerebral vascular anomalies associated with PHACE association.
Anomalies of the cervical and cerebral vasculature are now recognized as a frequent finding in PHACE association, but relatively few reports have noted an increased incidence of stroke. In 1998, Burrows et al3 reported 8 patients with large cervicofacial hemangiomas and associated cerebrovascular disease. Through serial neurologic imaging, these authors demonstrated that some of the arterial abnormalities previously described in association with large facial hemangiomas were not present at birth. They concluded that these infants seem to suffer from a progressive arterial vasculopathy characterized by corkscrew-like kinking and tortuosity, stenosis and/or occlusion, and extensive collateral vessel formation (“Moyamoya-like phenomenon”). In this series, 4 of the 8 children (50%) had AIS in the distribution of these acquired arterial changes. Espunes et al7 reported the death of a 5-year-old child with an extensive facial hemangioma who suffered a bilateral AIS; it is unclear whether the infarction was the result of PHACE association, a surgical complication and malfunction of a shunt for a Dandy-Walker anomaly, or a combination of factors. Several other small case series, most reported under the term PHACE association, describe the radiologic findings of the cervical and cerebral arterial anomalies observed in infants with large facial hemangiomas.8–13 Cerebrovascular arterial anomalies seem to be the most common noncutaneous abnormality, occurring in as many as 57% to 100% of patients.10 Metry et al13 reported their experience with 14 patients with PHACE association and reviewed an additional 116 cases reported in the literature. Cerebral arterial anomalies were present in 8 (57.1%) of 14 of their cases and reported in approximately one third of the cases in the literature. Many of the patients in these series did not undergo sensitive screening for arterial anomalies, so the true incidence may be significantly higher. Luo et al11 described 8 children with PHACE association and summarized the cervicocerebrovascular pathology. The arterial abnormalities seemed to fall into 2 categories: congenital or developmental anomalies of cervical and cerebral vessels and progressive or acquired changes often localized and perhaps in response to the congenital anomalies (Table 2).
Many of the cerebral abnormalities in PHACE association, such as “hypoplasia” or “encephalomalacia,” have not been documented as congenital and may be a result of stroke in utero or an unrecognized stroke in early childhood.8,12 Likewise, in utero vascular insufficiency might contribute to the pathogenesis of cerebral polymicrogyria-like changes, pachygryria, “cerebral dysplasia,” cerebellar hypoplasia, and ectopic gray matter, which also have been described in patients with PHACE association.9,14,15
Unilateral encephalomalacia is also a feature of Sturge-Weber syndrome. Critical review of patients reported under this eponym reveals that several infants described in older reports actually had a cutaneous hemangioma of infancy and features of PHACE association rather than a port-wine stain.16–18 These same patients were also reported to have AIS resulting in unilateral encephalomalacia. Thus, the longstanding confusion in the nomenclature surrounding vascular lesions has also contributed to the poor understanding of this phenomenon.
There are many factors that may contribute to the underrecognition of AIS in infants with PHACE association. The clinical diagnosis of stroke is often delayed in children.19 Headaches and aphasia are very difficult to appreciate in a child who has not yet developed language skills. Subtle neurologic changes, especially in patients with PHACE association and baseline neurologic impairment related to structural anomalies of the cerebellum, may not be appreciated. Many of the previously reported, nonspecific neurologic abnormalities of PHACE association (Table 3) could also be secondary to AIS. Seizures were the presenting sign of acute infarction in 3 of our patients and seizure and hemiplegia in 2. Lasky et al20 recently reported an infant with PHACE association and the acute onset of a left gaze preference and left hemiplegia. The article did not describe acute infarction on imaging, and the authors attributed the neurologic findings to interferon α2a-induced neurotoxicity; however, spastic diplegia is the only well-established neurologic adverse effect of this medication.
There has been a dramatic increase in the number of reports of PHACE association, and in our experience this is not a rare disorder.21 There seems to be a wide range of disease severity, and it is difficult to predict which infants are at greatest risk for the neurologic sequelae. We were unable to identify specific clinical features that may have placed these particular 5 infants with PHACE association at greater risk for AIS. Cerebrovascular abnormalities may not be the only explanation for this increased risk of stroke. Additional potential risk factors include sepsis from immunosuppressive therapy, hypertension secondary to the use of corticosteroid therapy, high-output cardiac failure, and associated cardiac and aortic-arch anomalies. These may have been contributory factors in our patients. The ischemic events seem to be lateralized to the same side as the facial hemangioma; patient 5 had bilateral hemangiomas and bilateral AIS. In all patients except patient 3, the infarct occurred in the distribution of the abnormal cervical and cerebral vessels. Four of our patients had very large facial hemangiomas and extensive anterior and posterior cervical involvement. One of our patients had a small, localized type of facial hemangioma; however, the ipsilateral location of both the infarction and the arterial stenosis at the distal internal carotid suggests that this is the same phenomenon. Most series of PHACE association report a marked female predominance, which is reflected in our case series of 4 girls and 1 boy. All 5 of our patients suffered from ulceration of the cutaneous hemangioma. Ulceration is the most common complication of hemangiomas and is frequently observed in the central facial region. It is conceivable that the severity and locations of these ulcerations are a marker of more severe involvement and increased risk of AIS; however, larger numbers of patients would be needed to confirm this association.
Treating children with PHACE association and AIS presents a challenge to pediatricians and pediatric neurologists. These children are simultaneously at risk for bleeding from their hemangioma and for cerebral infarction from their arterial vasculopathy. Currently, there are no established guidelines for therapy for infants with PHACE association and AIS. In most cases, children with AIS are empirically treated with antithrombotic therapy; however, the use of aspirin to treat or prevent pediatric stroke has not been evaluated in randomized, controlled trials. The literature demonstrates at least a 6% risk of recurrent stroke in infants with AIS beyond 6 months of age; therefore, antiplatelet therapy was instituted in all our cases.22 Although there are no universally accepted guidelines for aspirin dosing in children, a dose of 3 to 5 mg/kg per day has been suggested.23 This dose is also used to treat children with Kawasaki's disease. Patient 5 received a lower dose because of bruising, and her weight was artificially high because of steroid therapy. None of our patients had significant bleeding related to aspirin therapy, and none have experienced a second thromboembolic event.
The serial clinical and radiologic changes observed in our patients support a multifactorial neurovascular disease resulting from both developmental structural malformations of the arterial vessels as well as acquired and progressive stenosis and tortuosity of the same or associated vessels. Given our current understanding of this phenomenon, baseline MRI and MRA of the head, neck, and chest are indicated for patients with large segmental facial hemangiomas. In addition, clinical monitoring for signs or symptoms of AIS in the first years of life is recommended.
Dr Drolet receives funding from the Dermatology Foundation, American Skin Association, and Children's Hospital of Wisconsin Foundation. Dr Golomb receives support from National Institutes of Health National Institute of Neurological Disorders and Stroke grant K23 NS048024 and Clarian Values grant VFR-171.
- Accepted July 27, 2005.
- Address correspondence to Beth A. Drolet, MD, Pediatric Dermatology, 9200 W Wisconsin Ave, Milwaukee, WI 53211. E-mail:
The authors have indicated that they have no relationships relevant to this article to disclose.
- ↵Kirkham FJ, Prengler M, Hewes DKM, Ganesan V. Risk factors for arterial ischemic stroke in children. J Child Neurol.2000;15 :299– 307
- ↵Pascual-Castroviejo I, Viano J, Moreno F, et al. Hemangiomas of the head, neck, and chest with associated vascular brain anomalies: a complex neurocutaneous syndrome. AJNR Am J Neuroradiol.1996;17 :461– 471
- ↵Aeby A, Guerrini R, David Rodesh G, Raybaud C, Van Bogaert P. Facial hemangioma and cerebral corticovascular dysplasia. Neurology.2003;60 :1030– 1032
- ↵Decker T, Jones K, Barnes P. Sturge-Weber syndrome with posterior fossa involvement. AJNR Am J Neuroradiol.1994;15 :389– 392
- ↵Gabis LV, Yangela R, Lenn NJ. Time lag to diagnosis of stroke in children. Pediatrics.2002;110 :924– 928
- ↵Frieden IJ, Haggstrom A, Drolet BA. Hemangioma subtype characterization: a cohort prospective study [abstract]. Presented at: 15th International Society for the Study of Vascular Anomalies Congress; 2004; Wellington, New Zealand. Abstract M9.2004
- Copyright © 2006 by the American Academy of Pediatrics