Infantile hemangiomas (IHs), occurring in 4–12% of infants, represent the most frequent benign tumors in this age group.1,2 PHACES syndrome (posterior fossa malformations, hemangioma, arterial anomalies, coarctation of the aorta/cardiac defects, eye abnormalities, and sternal malformations), classified as a neuro-cutaneous syndrome, was initially identified by Frieden and colleagues in 1996.3 This syndrome is observed in 2% of patients with segmental hemangiomas on the cervicofacial distribution, particularly in the frontotemporal or maxillary/mandibular regions. This condition is associated with various anomalies, including posterior fossa abnormalities, facial hemangiomas, arterial cerebrovascular anomalies, cardiac anomalies, coarctation, ocular anomalies, and sternal defects.4,5 The arteriopathy accompanying PHACES syndrome poses a significant concern in the treatment of patients with high-risk vascular anomalies who may require propranolol therapy. This arteriopathy carries the potential to initiate ischemic strokes, making it a primary focus in patient management. It is essential to exercise caution when considering propranolol therapy for individuals with high-risk vascular anomalies associated with PHACES syndrome, as there is a possibility that the use of propranolol could increase the risk of stroke in such cases. We describe the clinical and radiological characteristics of three patients with PHACES syndrome who exhibited cerebrovascular arteriopathy. Our focus is on the treatment challenges and clinical outcomes. The clinico-radiological findings of the three cases are summarized in Table 1.

Written consent for publication was obtained from all patients' parents.

Case Report

Case one

A three-week-old late preterm neonate presented with a segmental infantile hemangioma that affected the right neck, face, and scalp. The extent of the hemangioma raised suspicion of PHACES syndrome [Figure 1]. A magnetic resonance angiogram (MRA) was performed using a time-of-flight technique and revealed a congenital absence of the right internal carotid artery (ICA) in both cervical and intracranial segments, without any significant intracranial abnormalities [Figure 1]. The patient underwent ophthalmology and cardiology evaluations, which showed no abnormalities. A magnetic resonance imaging (MRI) perfusion study was attempted but was unsuccessful due to technical limitations. The multidisciplinary team decided to monitor the patient since he was asymptomatic and had a high stroke risk. During follow-up, the patient's hemangioma showed minimal growth with no complications. As a prophylactic measure, aspirin was initiated to prevent stroke.

Case two

An 11-week-old male infant born at term presented with progressive right facial swelling at the age of five weeks. The main presenting symptom was noisy breathing, without any stridor or shortness of breath. Clinical examination revealed a well-circumscribed, soft, 5 cm right cheek swelling with telangiectatic changes [Figure 2]. Ultrasound imaging revealed a hypervascular heterogeneously hypoechoic lesion over the right cheek consistent with a high-flow soft tissue hemangioma. Given the segmental appearance of the hemangioma, PHACES syndrome was suspected. MRI of the head and neck showed a right cheek mass and multiple other lobular lesions in the posterior paraspinal muscles from C1-C3, all of which had signal characteristics and an enhancement pattern consistent with hemangiomas [Figure 2]. No evidence of extension into the spinal canal was noted. MRA revealed that the left internal carotid artery had a smaller caliber compared to the right side, with focal mild to moderate stenosis of the left internal carotid artery just distal to the carotid bifurcation. The vertebral arteries had a mildly tortuous course. Cardiac and ophthalmology assessments were normal. The decision to initiate propranolol was debatable due to the high risk of stroke associated with intracranial arterial anomalies, leading to a multidisciplinary discussion that ultimately preferred to proceed with sclerotherapy as the best option for this infant. Several challenges delayed the intervention, given the patient's age and weight, including the unavailability of a small catheter size. Therefore, the team decided to start low-dose propranolol (1 mg/kg/day) while awaiting sclerotherapy. The infant showed a good response and improvement in symptoms while on low-dose propranolol, which was eventually tapered and discontinued after the right cheek lesion had regressed during follow-up at 12 months of age.

Case three

A three-month-old female neonate born at full-term presented with segmental hemangioma, which first appeared as a telangiectatic patch on the right periorbital area and forehead at two weeks of age. The lesion progressed to redness and swelling over time [Figure 3]. A thorough evaluation for PHACES syndrome revealed hypoplasia of the right internal carotid artery via MRA [Figure 3], an optic disc anomaly, and normal cardiac assessment. During the same hospitalization, she developed intussusception and required laparotomy after unsuccessful pneumatic reduction. The intussusception was attributed to an ileum hemangioma, which was excised. Given the presence of hemangiomas in three critical sites (i.e., orbital, intracranial, and intestinal hemangioma), a low dose of oral propranolol at 1.5 mg/kg/day was initiated. The treatment was effective, allowing for the gradual tapering and eventual cessation of propranolol by 24 months of age.

Discussion

PHACES syndrome is a rare disorder of unknown etiology and pathogenesis. The extracutaneous manifestations of this syndrome are well-documented and include cerebrovascular anomalies, which are associated with potential comorbidities such as seizures and ischemic strokes.4,6 The documented arteriopathy predominantly affects the medium and large-caliber cerebral vessels, giving rise to stenosis, occlusion, agenesis, hypoplasia, or anomalous origin/course of the main cerebral arteries, saccular aneurysms, and arterial dysplasia.7,8 Furthermore, intracranial vasculopathy such as Moyamoya syndrome may cause arterial ischemic stroke.5,9

Patients with PHACES syndrome who present with significant narrowing (> 25%) or occlusion, aplasia or hypoplasia of main cerebral vessels, tandem or multiple arterial stenoses that diminish cerebral perfusion, and/or imaging findings suggesting chronic or silent brain ischemia are considered to be at high risk for arterial ischemic stroke.10,11 In this context, initiating of treatment for segmental hemangioma, which often occurs within the first few months of life, is crucial given its aggressive proliferation, and propranolol treatment is considered the gold standard therapy for visual impairment or airway obstruction.10,11

However, the presence of vasculopathy in children affected by PHACES syndrome raises concerns about the potential increased risk of stroke associated with beta-blocker use, especially in those with major or multiple arterial anomalies.12 While arterial anomalies are commonly observed in PHACES syndrome cases, there is limited information on the clinical outcomes of these changes after propranolol use. Two patients have reported stroke while receiving propranolol. The hypotension-induced reduction in blood flow in the stenotic, occluded, hypoplastic, or absent artery is the proposed mechanism by which propranolol may trigger ischemic stroke.12

Several reported cases of PHACES syndrome associated with strokes, with the average age of stroke occurrence being 13.6 months, and the most common presenting symptoms being seizure and hemiparesis, emphasize the challenges of starting oral propranolol in patients with arterial anomalies and the need for careful consideration of the potential risk of stroke.5

Our three cases highlight the multifaceted nature of propranolol therapy decisions in PHACES syndrome, emphasizing the importance of meticulous case evaluation and a multidisciplinary approach to treatment decision-making. In case one, the decision not to administer propranolol and instead opt for clinical observation was based on the assessment that the patient had a notable stroke risk, while the hemangioma did not induce functional abnormalities. For cases two and three, the high indication for propranolol therapy was driven by the potential for functional abnormalities arising from the hemangioma's location, coupled with a lower vascular stroke risk compared to case 1.

In summary, propranolol remains a key therapeutic option for managing segmental hemangioma in PHACES syndrome, but its use must be approached with caution, especially in patients with significant arterial anomalies. The potential risk of stroke underscores the importance of thorough evaluation and a multidisciplinary approach to treatment decision-making.

Conclusion

This case series involving three PHACES syndrome patients brings to light the challenging task of deciding on propranolol administration in those with cerebrovascular anomalies due to the increased susceptibility to stroke. It emphasizes the paramount importance of interdisciplinary discussions. Regrettably, the utility of brain perfusion study to assess cerebral blood flow before propranolol initiation as a potential predictor of stroke risk remains unclear. Additional research is imperative to determine the role of perfusion studies in the algorithm for propranolol administration in
these patients.

Disclosure

The authors declared no conflicts of interest.

References

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