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Arch Ophthalmol. 2004;122:413-415.

The PHACE syndrome is a neurocutaneous syndrome that includes the following primary features: posterior fossa malformations of the brain, large facial hemangiomas, arterial anomalies, cardiac anomalies and aortic coarctation, and eye abnormalities.^1-2 It occurs almost exclusively in girls. Several recent reports have documented an association between orofacial hemangioma and excavated optic disc anomalies (morning glory disc anomaly and peripapillary staphyloma) in girls. Metry et al² recently proposed that this association falls within the spectrum of PHACE syndrome. We document ipsilateral intracranial vascular abnormalities in 2 girls with juvenile orofacial hemangioma and excavated optic discs to provide further evidence that these patients fall within the spectrum of PHACE syndrome.

Report of Cases
Case 1

A 6-year-old girl was referred for evaluation of unilaterally decreased vision in the right eye. She was born full term, and her perinatal course was uneventful. At 2 weeks of age, she developed multiple hemangiomas involving the face, lip, parotid gland, and throat on the right side. At 1 month of age, these hemangiomas began to grow rapidly (Figure 1A). Magnetic resonance imaging confirmed massive hemangiomatous involvement of the right parotid gland and right side of the face. Results of a cardiology evaluation with echocardiography were normal. The hemangiomas continued to enlarge until the patient was 9 months of age. Treatment with oral steroids and multiple laser treatments to the gingival mucosa and the parotid gland produced regression of the tumor. At 1 year of age, she was noted to have an esotropia of the right eye.

View larger version (39K): [in this window] [in a new window] Figure 1. Case 1. A, Large orofacial hemangioma. B, Morning glory disc anomaly. C, Magnetic resonance angiogram shows tortuousity of the right internal carotid artery (open arrow) and narrowing of the proximal right middle cerebral artery (closed arrow).

Visual acuity was 20/160 OD and 20/20 OS. Both pupils reacted briskly to light, and there was a mild right afferent pupillary defect. Extraocular movements were full. Fixating near, she had 16 prism diopters of esotropia and fixated eccentrically with the right eye. Results of slitlamp examination were normal. Cycloplegic refractive error was +2.00 OD and +2.75 OS. Retinal examination disclosed a morning glory disc anomaly in the right eye with an elevated pigmented area of juxtapapillary scarring temporal to the disc (Figure 1B). Magnetic resonance angiography demonstrated marked tortuosity of the supraclinoid right internal carotid artery and narrowing of the proximal right middle cerebral artery (Figure 1C).

Case 2

A 6-week-old girl was evaluated for right-sided epiphora. Her perinatal course had been complicated by respiratory difficulties requiring temporary resuscitation. External examination disclosed a large capillary hemangioma on the right upper eyelid; tip of the nose; and right cheek, neck, and shoulder. In the ensuing weeks, the patient developed respiratory insufficiency requiring intubation. Results of a cardiology evaluation with echocardiography were normal. Magnetic resonance imaging disclosed several large hemangiomas in the chest, with extension to the upper aorta, displacement of the right upper lobe of the lung, and displacement of the trachea and larynx. The orofacial component of the hemangioma involved the right masseter muscle, parotid gland, orbit, and soft tissues of the tongue and lips on the right side.

Ophthalmologic examination of the patient at age 6 months showed esotropia and dense amblyopia of the right eye. A small conjunctival hemangioma was localized to the 3-o'clock position, the pupil was slightly eccentric, the iris stroma was moderately atrophic, and a persistent pupillary membrane was noted. Retinal examination showed excavation of the peripapillary retina.

She was treated with oral steroids and interferon, and the hemangioma regressed during the next 2 years. At 7 years of age, however, orofacial remnants of the hemangioma were still evident (Figure 2A). Visual acuity was 20/80 OD and 20/20 OS. Cycloplegic refraction was –11.75 +2.00 x95° OD and +3.00 +1.50 x110° OS. Retinal examination disclosed a large peripapillary staphyloma in the right eye, which enclosed a normal-appearing optic disc (Figure 2B). The macula was situated at the border of the staphyloma. Examination of the left optic disc and retina disclosed no abnormalities. Magnetic resonance angiography disclosed a developmental vascular anomaly of the origin of the right ophthalmic artery (Figure 2C).

View larger version (45K): [in this window] [in a new window] Figure 2. Case 2. A, Residual orofacial hemangioma. B, Peripapillary staphyloma. C, Magnetic resonance angiogram shows developmental vascular anomaly of the origin of the right ophthalmic artery (arrow).

Comment
In 1998, Holmstrom and Taylor³ described an association of facial capillary hemangioma with morning glory disc anomaly in 3 girls. Kirath et al⁴ subsequently reported peripapillary staphyloma in a girl with a large ipsilateral orofacial hemangioma. Our 2 cases demonstrate that these findings may also be associated with ipsilateral cerebral vascular dysgenesis.

The relationship between large facial hemangiomas and cerebrovascular and facial arterial anomalies was recognized by Pascual-Castroviejo⁵ in 1978. Although cardiac and cerebellar malformations are usually present, it is now believed that PHACE syndrome represents a spectrum of anomalies (Table 1) that vary considerably from one case to another. In 70% of reported cases, only 1 extracutaneous manifestation of the syndrome has been present, with extracutaneous manifestations biased toward the specialty for which the article was written.²

View this table: [in this window] [in a new window] Systemic Anomalies Associated With PHACE Syndrome*

The orofacial hemangiomas seen in PHACE syndrome are characteristically large, segmental, and plaquelike.^1-2 The pathogenesis of PHACE syndrome is unknown. The clinical manifestations of PHACE syndrome conform to a developmental field defect, which results from errors within morphoregulatory genes that determine a constellation of developmental anomalies in a spatially coordinated, temporally synchronous manner.^{2, 6} Its confinement to girls raises the possibility of an X-linked lethal mutation.² To our knowledge, no familial cases of PHACE syndrome have been reported.

Other clinical features of PHACE syndrome are in Table 1.² The most common central nervous system abnormalities have involved the posterior fossa, most notably the Dandy-Walker malformation, characterized by a hypoplastic or absent cerebellar vermis and a posterior fossa cyst continuous with the fourth ventricle.^{1, 7}

Cerebellar atrophy and arachnoid cyst with cerebellar hypoplasia have also been reported, as have frequent alterations in the intracranial carotid vasculature.^{1, 8} Pascual-Castroviejo,⁷ who routinely performs carotid angiography in children with large facial hemangiomas, reports frequent alterations of the intracranial vasculature, particularly the carotid artery. Burrows et al⁹ reported cerebral infarction secondary to progressive occlusive arterial disease in 4 infants who were previously healthy. In addition to a variety of structural cardiac abnormalities and aortic coarctation, ventral developmental defects such as sternal pits, sternal clefting, and supra-abdominal raphe should be sought.^1-2

Metry et al² considered the co-occurrence of morning glory disc anomaly and ipsilateral facial hemangioma as falling within the spectrum of PHACE syndrome. The ipsilateral neurovascular abnormalities in the territory of the carotid circulation in our 2 cases supports this contention. The association of a unilateral morning glory disc anomaly or peripapillary staphyloma with ipsilateral facial hemangioma mandates a careful search for associated cardiac, aortic, and cerebrovascular anomalies.

This study was supported in part by a grant from Research to Prevent Blindness Inc, New York, NY.

AUTHOR INFORMATION

Christoph Kniestedt, MD; Klara Landau, MD
Zurich, Switzerland

Michael C. Brodsky, MD; Paula North, MD; Milton Waner, MD
Little Rock, Ark

Corresponding author: Michael C. Brodsky, MD, Ophthalmology and Pediatrics, Arkansas Children's Hospital, 800 Marshall St, Little Rock, AR 72202-3591 (e-mail: brodskymichaelc{at}uams.edu).

REFERENCES
1. 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. ABSTRACT 2. Metry DW, Dowd CF, Barkovich AJ, Frieden IJ. The many faces of PHACE syndrome. J Pediatr. 2001;139:117-123. FULL TEXT | ISI | PUBMED 3. Holmstrom G, Taylor D. Capillary haemangiomas in association with morning glory disc anomaly. Acta Ophthalmol Scand. 1998;76:613-616. FULL TEXT | ISI | PUBMED 4. Kirath H, Bozkurt B, Mocan C. Peripapillary staphyloma associated with orofacial hemangioma. Ophthalmic Genet. 2001;22:249-253. FULL TEXT | PUBMED 5. Pascual-Castroviejo I. Vascular and nonvascular intracranial malformations associated with external capillary hemangiomas. Neuroradiology. 1978;16:82-84. FULL TEXT | ISI | PUBMED 6. Opitz JM, Gilbert EF. CNS anomalies and the midline as a "developmental field." Am J Med Genet. 1982;12:443-455. FULL TEXT | ISI | PUBMED 7. Pascual-Castroviejo I. The association of extracranial and intracranial vascular malformations in children. Can J Neurol Sci. 1985;12:139-148. ISI | PUBMED 8. Coats DK, Paysse EA, Levy ML. PHACE: a neurocutaneous syndrome with important ophthalmologic implications. Ophthalmology. 1999;106:1739-1741. FULL TEXT | ISI | PUBMED 9. Burrows PE, Robertson RL, Mulliken JB, et al. Cerebral vasculopathy and neurologic sequelae in infants with cervicofacial hemangioma: report of eight patients. Radiology. 1998;207:601-607. FREE FULL TEXT

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