We report the case of a 29-week preterm infant with PHACE (posterior fossa malformations, hemangionas, arterial anomalies, cardiac anomalies, eye anomalies) syndrome. PHACE syndrome is a neurocutaneous disorder with large facial segmental hemangionas associated with anomalies of the brain, eye, heart and aorta. The hemangiomas in our patient were problematic, distorting the airway and interfering with respirations to the point of requiring mechanical ventilation. Consultation with several different centers with medical expertize in treatment of congenital hemangiomas revealed different views on the best management strategy. In this infant, the hemangiomas progressed with failure to involute despite currently recommended therapy including corticosteroids and vincristine. Therefore, the infant was treated with propranolol and had significant regression of the hemangiomas. The use of propranolol for the treatment of infantile hemangiomas is reviewed.
Infantile hemangiomas are common tumors of the vascular endothelium. The natural history of these hemangiomas is that they often grow during the early months and then spontaneously regress until they are completely gone by 1–2 years of age. Hemangiomas are segmental when their distribution corresponds to developmental units such as mandibular and maxillary prominences (covering anatomic territory). PHACE syndrome is an acronym (posterior fossa malformations, hemangionas, arterial anomalies, cardiac anomalies, eye anomalies) for a more extensive, neurocutaneous disorder with large facial segmental hemangionas associated with anomalies of the brain, eye, heart and aorta.
The definition of PHACE syndrome, based on the recent Consensus Statement on Diagnostic Criteria for PHACE syndrome requires a large facial hemangioma (>5 cm diameter) plus one major criteria (a subset of cerebrovascular, structural brain, ocular or ventral/midline anomalies).1 No specific chromosomal or genetic abnormality has been identified. Although most hemangiomas are benign and do not cause any morbidity or mortality, they may occasionally, impinge on vital structures. Permanent significant structural abnormalities may result when hemangiomas involve facial structures, particularly the nasal tip, lips and ears. Although oral corticosteroids are first-line therapy for such complex hemangiomas, there is no consensus about subsequent therapies in the event of failure of corticosteroids to control the progression of these lesions.
A 29-week preterm infant was transferred on day of life 25 for rapidly enlarging segmental facial hemangiomas. The infant was delivered via emergency C-section at 29 weeks because of the pregnancy-induced hypertension. The infant had Apgars of 5 and 8 at 1 and 5 min, respectively. She was intubated, received one dose of surfactant for respiratory distress, and was subsequently extubated to nasal cannula continuous positive airway pressure. Full enteral feeds were achieved by day of life 2.
The infant was noted to have purple discoloration of the upper and lower lips at birth that subsequently evolved into confluent plaques or ‘port wine stains’ of the left orbit, bilateral cheeks, neck and lips. By day of life 25, the areas of discoloration had evolved into extensive hemangiomas, involving the forehead, face and neck (Figure 1). The baby was started on dexamethasone at the referring facility and baby was transferred to our neonatal intensive care unit for further evaluation and management.
Diagnostic studies included an echocardiogram that showed a small atrial septal defect. Magnetic resonance imaging of the brain, orbit, neck and mediastinum showed cerebellar vermis hypoplasia, agenesis of the corpus callosum and a tortuous tangle of arteries in the brain composed of the left internal carotid, left middle cerebral and left posterior cerebral arteries. Ophthalmological exam showed a descematocele of the left eye. These additional findings confirmed diagnosis of PHACE.
The infant continued to receive intravenous dexamethasone at a dose of 0.5 mg kg−1 per day; equivalent to 3 mg kg−1 per day of prednisone. The steroid was changed to prednisone at 3 mg kg−1 per day when the infant was started on oral feeds. The size, extent and appearance of the hemangiomas were monitored. Despite steroid therapy, the hemangiomas continued to enlarge with ulceration, excoriation and necrotic areas. The infant developed airway compromise requiring intubation and assisted ventilation. After consultation with several specialists vincristine was started at this point, as a desperate measure at a dose of 15 mcg kg−1 per week. It was an attempt to slow cell proliferation and was continued for 6 weeks. The infant continued to require mechanical ventilation. Attempts to reduce ventilatory support were unsuccessful. Bronchoscopy did not show any hemangiomas in the airways.
After reviewing the case report by Léauté-Labrèze2, 3 and discussion with specialists, propranolol was started at a dose of 0.5 mg kg−1 per day and advanced to 1 mg kg−1 per day in 1 week to a maximum dose of 2 mg kg−1 per day the following week. Within a week of starting propranolol, there was significant regression of the lesions with decrease in size, flattening of the contours and softening of the hemangioma (Figure 2). The baby did not develop systemic hypotension, bradycardia or hypoglycemia at this dosage. The infant was successfully extubated the following week. She continued to do well on propranolol and prednisone, which was slowly weaned. She was discharged home on these medications and was followed by the pediatric dermatologist. Follow-up visit at 6 months of chronological age and 3½ months adjusted age showed continued regression and re-epithelization of the hemangiomas on this regimen.
Infantile hemangiomas are common tumors of the vascular endothelium occurring in 2.5–10% of infants. The incidence of infantile hemangiomas is ∼22–30% in preterm infants with birth weight <1 kg.4 The incidence in preterm infants with birth weight >1.5 kg is the same as term infants. In a large cohort study of 1096 children with hemangiomas, 25 met criteria for PHACE. These 25 patients represented 20% of infants with segmental facial hemangiomas.5 In another multicenter prospective study of 108 infants who had large facial hemangiomas, 33 (33%) had PHACE syndrome.6
PHACE occurs more frequently in females (9:1) and an increased incidence has been reported in infants of non-Hispanic Caucasian and Hispanic ethnicity. No specific chromosomal or genetic abnormality has been identified. Several cases of PHACE syndrome have been misdiagnosed as Sturge-Weber when the hemangiomas were mistaken for capillary malformations or port wine stains. However, the port wine stains in Sturge-Weber do not proliferate or regress in infancy.7, 8, 9 Oral corticosteroids (prednisone up to 2 mg kg−1 per day) are the recommended first-line therapy for hemangiomas that are enlarging rapidly or compromising vision or airways. Corticosteroids are not approved by Food and Drug Administration Agency for the hemangiomas of infancy and their use is off label. Use of oral corticosteroids in this setting has been associated with growth failure, osteoporosis, opportunistic infections, developmental delay and hypertension.10 Vincristine slows cell proliferation and may take a long time to work, about 4 to 6 months. Interferon-α is used infrequently because of potential neurotoxicity.
Although there have been several case reports of the use propranolol in the treatment of capillary hemangiomas, there is no definitive guideline for the usage of this medication in PHACE syndrome, and to date there are no published clinical trials. Propranolol is a non-selective β-blocker. The mechanism of action to cause involution of infantile hemangiomas is not completely understood. Proposed mechanisms may include vasoconstriction, noted as change in color and softening of hemangioma. Capillary endothelial cells express β2 adrenergic receptors, which modulate the release of nitric oxide causing endothelium-dependant vasodilatation. There is decreased expression of two proangiogenic genes (1) basic fibroblast growth factor and (2) vascular endothelial growth factor resulting in apoptosis of vascular endothelium. Although our infant had been on corticosteroids for 3 weeks and showed no regression, there was significant regression of the facial hemangiomas that was apparent within several days of starting this treatment. In this infant propranolol was started at the dose of 0.5 mg kg−1 per day, advanced to 1 mg kg−1 per day in 1 week to a maximum dose of 2 mg kg−1 per day.
The case report by Léauté-Labrèze indicated that they started the propranolol at 2 mg kg−1 per day. Consultation with several different centers with medical expertize in treatment of congenital hemangiomas revealed different views on the best management strategy. There was no consensus on the use of propranolol in the treatment of hemangiomas. There is also no consensus on the dosage at initiation and treatment or duration of using propranolol. Further, there were concerns about adverse effects of propranolol, such as bradycardia, hypotension, hypoglycemia and bronchospasm. High-output cardiac failure can occur in infants with very large infantile hemangiomas, PHACE syndrome, PELVIS (perineal hemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate) syndrome and diffuse neonatal hemangiomatosis (miliary type). There is a risk of stroke or vascular ‘steal’ syndrome in infants with PHACE who have intracranial vascular malformations particularly on starting propranolol.11 Hence, imaging of brain is required before starting propranolol. Our baby did not demonstrate any adverse side effects in terms of cardiovascular function or outflow. The infant continued to do well on propranolol and prednisone and was discharged home on these medications. She is being followed to assess the long-term course of her hemangiomas treated with propranolol. Another case report of an infant born at 28 weeks with large thoracic hemangiomas was published by Mousa et al.12 with similar results.
Propranolol seems to have had impressive effects in this patient and may hold promise for the future; however, its use for this disorder is currently not approved by the Food and Drug Administration. Large multicenter trials are required to assess the adverse effects, as well, as long-term follow-up for recurrence of hemangioma; however, the infrequent occurrence of PHACE syndrome may preclude such trials. There also needs be a consensus on the dosage guideline for initiation and treatment. A prospective, randomized, multicenter adaptive phase II/III study comparing dosing regimens of propranolol with placebo is underway, although not specifically those reported with PHACE syndrome.13
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The authors declare no conflict of interests.
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Solomon, T., Ninnis, J., Deming, D. et al. Use of propranolol for treatment of hemangiomas in PHACE syndrome. J Perinatol 31, 739–741 (2011). https://doi.org/10.1038/jp.2011.28
- infantile hemangiomas
- PHACE syndrome
- facial hemangiomas
- segmental hemangiomas
American Journal of Clinical Dermatology (2013)