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Case Report

Safe Use of Propranolol in a Patient With PHACES Syndrome: A Case Report

Ferreira, João Euzébio Encarnaçãoa; Ferreira, Marina Vilela Chagasa; Zatz, Rafaela; Foronda, Gustavob; Gemperli, Rolfa; Goldenberg, Dov Charlesa

Author Information
Journal of Vascular Anomalies: September 2021 - Volume 2 - Issue 3 - p e023
doi: 10.1097/JOVA.0000000000000023
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Abstract

Introduction

Infantile hemangioma (IH) is the most common vascular tumor of childhood, with an incidence of 4%–5% of births.1 In 1996, Frieden minted the term PHACE to describe a set of malformations that may be associated with IH presenting with segmental distribution in the face and scalp: structural malformations in the posterior fossa (P), arteries (A), heart (cardiac [C]), and eyes (E).2 Later, sternal malformation (S) was added, culminating in the mnemonic PHACES syndrome. It is more frequent in women, with a proportion of 4.2:1 and the incidence among patients with IH is 2.3%.1,3

Ninety-eight percent of the published cases of PHACES syndrome present with facial hemangioma, the majority of which are large and segmental hemangiomas.4 Among extracutaneous malformations, cerebrovascular malformations are the most frequent. An adequate neurological investigation is essential before instituting any treatment for large facial hemangiomas, to reduce the risk of ischemic events and neurological sequelae.3

While treatment with beta-blockers is well established for the treatment of IH,4,5 patients with cerebrovascular and arterial malformations could experience deleterious effects with the use of this medication. Theoretically, its negative chronotropic and inotropic effect could predispose to ischemic events in patients with stenotic vessels, occluded, absent, with little collateral circulation. Therefore, special attention should be given to the pharmacological treatment of the hemangioma in this syndrome.

The goal of this case presentation is to report the use of oral beta-blockers to treat a large hemangioma in a child who had PHACES syndrome with an arterial and cerebral malformation component, requiring concurrent cardiovascular surgical procedures. A retrospective analysis of a case attended was made. Survey of medical records, complementary exams and analysis of photographic records were carried out in successive outpatient evaluations. The patient was followed from 3 months to 2 years old.

Case report

A 3-month-old female patient was admitted to the Pediatric Plastic Surgery outpatient clinic. She was referred with an initial diagnosis of infantile hemangioma.

Her parents reported delivery at term, after a low-risk pregnancy, without complications or reports of smoking, alcoholism, or use of other substances. At birth, she had a very low birth weight (1410 g) and remained in the Intensive Care Unit for 9 days to treat bloodstream infection. At this time, a flat, hypochromic spot on her upper right hemiface was reported. From the second week of life onward, the lesion showed accelerated growth, increasing in volume, and acquiring a violet color, progressively preventing eye-opening. Until then, she had not received any kind of drug treatment for her hemangioma.

The parents also reported difficulty gaining weight (weighed 3410 g at 3 months of age). In the initial examination of the face, segmental infantile hemangioma was observed in the scalp, forehead, orbit, temporal and parietal region on the right side, as well as the dorsum of the nose, glabella, small extension of the tip of the nose, columella, lower lip, and mental region. She presented with obstruction of the visual axis, and the right eye could not be visualized in the resting position since it was covered by a fold of the hemangioma (Figure 1). There were no changes in the sternum. The distal pulses in the lower limbs were not palpable and the extremities were noted to be cold in the first evaluation by our team.

Figure 1.
Figure 1.:
Aspect at the time of initial assessment, at 3 mo of age.

The echocardiogram showed interruption of the aortic arch between the left common carotid artery and the left subclavian artery (type B, subtype 2 Celoria-Patton Classification), with an aberrant origin of the right subclavian artery. Also, there was a communication between the right and left subclavian arteries. A patent foramen ovale, enlarged left chambers, and significant mitral regurgitation were diagnosed. The laboratory and electrocardiographic evaluation did not show any relevant alterations.

Magnetic resonance angiography also confirmed the diagnosis of PHACES syndrome, demonstrating cerebrovascular and arterial abnormalities: a hypoplastic right internal carotid artery and interruption of the aortic arch, without signs of cerebral ischemia. Additionally, there were lesions in the pontocerebellar angle, internal auditory canal, cavernous sinus, and medial wall of the right middle fossa, compatible with schwannomas (Figure 2).

Figure 2.
Figure 2.:
On the left, a computed tomography scan of the skull with intravenous contrast in the axial section, showing the absence of the right internal carotid artery. On the right, the coronal section of the same examination is shown.

She went through multidisciplinary evaluation right after hospital admission. The ophthalmology team examined her and found that she had loss of visual field that resolved during long-term follow-up, leaving no sequelae such as blindness or astigmatism. Audiological screening tests were normal and the neurology team followed her during all hospital stay and did not find any neurological impairment.

The pediatric cardiology team admitted the patient to intensive care, simultaneously starting treatment for the infantile hemangioma and preparing the patient for surgery to correct the aortic coarctation. Propranolol was introduced with an initial dose of 1 mg/kg/d and gradually increased up to a dose of 2 mg/kg/d in the first week. After 18 days, the medication was held while the patient underwent aortic coarctation correction using a bovine pericardial graft. With good postoperative recovery, propranolol was carefully reintroduced in the same fashion, starting with 1 up to 2 mg/kg/d after a week. The patient was being continually monitored in the intensive care ward during the introduction of propranolol. There were no adverse events or electrocardiogram alterations related to the medication and she was discharged after 20 days of hospitalization.

Propranolol was maintained for 18 months. A progressive reduction in the hemangioma’s volume was noticed, appearing less intense in color and allowing partial eye-opening (Figures 3 and 4). The patient had no adverse effects related to the medication. Considering the hemangioma evolution curve, further natural involution is expected. At the time of her latest evaluation, she was 2 years old and had been off propranolol treatment for 3 months, with no signs of regrowth or recurrence. When the lesion achieves stability, we plan to resect skin excess.

Figure 3.
Figure 3.:
Evolution after introduction of propranolol. From left to right: 10 d, 1 mo, and 5 mo.
Figure 4.
Figure 4.:
Facial hemangioma aspect at 2 y of age, 3 mo after interrupting propranolol therapy

Discussion

The biological behavior of infantile hemangioma has been better understood in recent decades. There has been a significant advance in pharmacological treatment with the introduction of beta-blockers.4 Many cases are effectively treated with medication alone, avoiding surgical procedures. In PHACES syndrome, pharmacological therapy should be used more carefully, given the systemic effects of medication and risks associated with cerebrovascular malformations.

Although the current consensus points toward the use of beta-blockers,6 there is little information in the literature regarding its use in children with PHACES syndrome. A systematic review identified 22 cases of stroke in children with the syndrome. Only one of them was using propranolol and it is not clear whether it was a factor for stroke in that case.7 On the other hand, some studies show its safety: a multicentric retrospective study by Olsen et al8 with 76 patients reported no severe adverse effects (stroke, transient ischemic attack, or cardiovascular events). The side effects reported were mild, such as sleep disturbances and minor gastrointestinal tract and respiratory tract symptoms. Besides, in a case series by Hernandez-Martin et al,9 7 patients who underwent imaging tests had no alteration in cerebral perfusion after 6 months of treatment.

In this case report, the patient had obstruction of the visual axis, an indication for surgery.10 However, arterial malformations were of therapeutic priority, and the combined approach would increase the patient’s morbidity. Pharmacological therapy with propranolol was effective, since it cleared the visual axis and allowed the patient to develop properly, without the need for surgery or any clinical repercussions. Corticosteroids such as prednisolone could increase hydrosaline retention and cause cardiac overload11 and were contraindicated in her case and discouraged by her pediatric cardiologists

The use of beta-blockers in cases of facial hemangioma in children with PHACES syndrome is an effective and safe treatment option, with few side effects. In this particular case, the patient had life-threatening arterial malformation, but a multidisciplinary approach and gradual dosing of the medication helped to achieve satisfactory results. Functional and cosmetic aspects have improved drastically, reducing and delaying the need for surgical intervention.

In addition, it is important to emphasize the need for early referral when there is a suspicion of PHACES syndrome. The hemangioma was aggressively proliferating before referral and the ultimate result could have been improved had propranolol been introduced earlier.

References

1. Kilcline C, Frieden IJ. Infantile hemangiomas: how common are they? A systematic review of the medical literature. Pediatr Dermatol. 2008;25:168–173.
2. Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol. 1996;132:307–311.
3. Metry DW, Haggstrom AN, Drolet BA, et al. A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications. Am J Med Genet A. 2006;140:975–986.
4. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131:128–140.
5. Léauté-Labrèze C, De La Roque ED, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–2651.
6. Garzon MC, Epstein LG, Heyer GL, et al. PHACE syndrome: consensus-derived diagnosis and care recommendations. J Pediatr. 2016;178:24–33.e2.
7. Siegel DH, Tefft KA, Kelly T, et al. Stroke in children with posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome: a systematic review of the literature. Stroke. 2012;43:1672–1674.
8. Olsen GM, Hansen LM, Stefanko NS, et al. Evaluating the safety of oral propranolol therapy in patients with PHACE syndrome. JAMA Dermatol. 2020;156:186–190.
9. Hernandez-Martin S, Lopez-Gutierrez JC, Lopez-Fernandez S, et al. Brain perfusion SPECT in patients with PHACES syndrome under propranolol treatment. Eur J Pediatr Surg. 2012:22;54–59.
10. Goldenberg DC, Hiraki PY, Marques TM, Koga A, Gemperli R. Surgical treatment of facial infantile hemangiomas: an analysis based on tumor characteristics and outcomes. Plast Reconstr Surg. 2016;137:1221–1231.
11. Yasir M, Sonthalia S. Corticosteroid Adverse Effects [Internet]. Treasure Island, FL: StatPearls Publishing; 2019. http://www.ncbi.nlm.nih.gov/pubmed/30285357. Accessed March 8, 2021.
Keywords:

Hemangioma; Adrenergic beta-antagonists; Aortic coarctation; Facial neoplasms

Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Society for the Study of Vascular Anomalies.