Phace Association

Description

PHACE is an acronym for a neurocutaneous syndrome encompassing the following features: posterior fossa brain malformations, hemangiomas of the face (large or complex), arterial anomalies, cardiac anomalies, and eye abnormalities. The association is referred to as PHACES when ventral developmental defects, such as sternal clefting or supraumbilical raphe, are present (summary by Bracken et al., 2011).

Diagnosis

In a consensus statement regarding diagnostic criteria for PHACE syndrome (Metry et al., 2009), the criteria were stratified into 2 categories, PHACE syndrome and possible PHACE syndrome. Definite PHACE syndrome requires the presence of a characteristic segmental hemangioma or hemangioma greater than 5 cm in diameter on the face or scalp plus 1 major criterion or 2 minor criteria involving the cerebrovascular, cardiovascular, or ocular organ systems, the brain structure, or ventral or midline defects. Possible PHACE requires the presence of a hemangioma greater than 5 cm in diameter on the face or scalp plus 1 minor criterion; hemangioma of the neck or upper torso plus 1 major criterion or 2 minor criteria; or no hemangioma plus 2 major criteria.

Clinical Features

Frieden et al. (1996) reported 2 cases of infants with large facial hemangiomas, congenital cataracts, and structural arterial anomalies, particularly of the central nervous system. They also reviewed 41 cases with similar findings from the literature, and proposed the use of the acronym PHACE syndrome.

Coats et al. (1999) described the ophthalmologic features of PHACE syndrome. Their review of the literature revealed that approximately one-third of patients have ocular manifestations, including choroidal hemangiomas, cryptophthalmos, exophthalmos, colobomas, posterior embryotoxon, optic atrophy, microphthalmos, strabismus, and optic nerve hypoplasia. The patient they reported had congenital glaucoma, a feature not previously reported in association with PHACE syndrome, which required surgical management.

Raas-Rothschild et al. (2000) described a baby girl with giant congenital aortic aneurysm, bifid cleft sternum covered with atrophic skin, a midline raphe extending from the abnormal sternum to the umbilicus, and hemangiomas of the lower lip and right ear. They reviewed 2 previously reported cases of giant aortic aneurysm; both had hemangioma and sternal cleft, and one had supraumbilical raphe. Schieken et al. (1987) described a neonate with sternal cleft, cutaneous hemangioma, occlusion of the right innominate artery, and aneurysm of the ascending aorta. This child underwent successful repair of the aneurysm at age 17 months. Pasic et al. (1993) described an adult with aneurysm of the proximal aortic arch involving the innominate artery and the left carotid artery and a sternal cleft with supraumbilical midline raphe, hemangioma of the face and neck, and micrognathia. The patient was still asymptomatic at age 45 years.

Metry et al. (2001) evaluated the spectrum of disease in 14 patients they had evaluated and 116 reported patients meeting criteria for the syndrome. Because 115 of the patients were female, the authors suggested that the disorder may be X-linked dominant with lethality in males. Seventy percent of the patients had only 1 extracutaneous manifestation of the syndrome, most commonly structural or arterial malformations of the brain; however, complete investigations, including MRI and MR angiography, had not been performed in all patients. Several cases of PHACE association had also been misdiagnosed as Sturge-Weber syndrome (185300) when the patients' hemangiomas were mistaken for capillary malformations or port-wine stains. The authors concluded that PHACE association should be considered in any patient with a large, segmental, plaque-like facial hemangioma, and that these patients should have ophthalmologic, neurologic, and cardiac evaluations.

Slavotinek et al. (2002) described a 17-year-old female with possible PHACE syndrome who had a scalp hemangioma, cleft uvula, defect in the upper third of the sternum, cerebral vascular malformations, and rupture of an aortic aneurysm. Oral facial clefting and aortic aneurysms had rarely been reported in PHACE syndrome previously. The aortic aneurysm ruptured after minor trauma at 11 years of age. At 17 years of age, elective repair of a dilated, ectatic aorta was complicated by cerebral ischemia. Vascular anomalies included an aneurysm of the left subclavian artery, atresia of the right carotid artery, and calcified cerebral aneurysms. Although the patient had arachnodactyly and some of the other features associated with Marfan syndrome (154700), she did not fulfill the diagnostic criteria.

Kniestedt et al. (2004) reported 2 girls with a variant of PHACE syndrome with peripapillary excavation in the eye ipsilateral to the orofacial hemangioma: a morning glory disc in 1 girl and a peripapillary staphyloma in the other.

In a prospective cohort study of 1,096 children with hemangiomas, Metry et al. (2006) identified 25 (19.7%) who met the criteria for PHACE out of 127 infants with segmental facial hemangiomas. Compared to previous reports, these PHACE patients had a higher incidence of cerebrovascular and cardiovascular anomalies, 55% and 44%, respectively. Two patients developed acute arterial ischemic stroke during infancy, whereas 2 with cardiovascular anomalies showed documented evidence of normalization, suggesting that both progressive and regressive vascular phenomena may occur in this syndrome.

Hess et al. (2010) reviewed intracranial magnetic resonance angiography and/or computerized tomographic angiography images from 70 children meeting consensus criteria for PHACE syndrome who were known to have arterial lesions in the brain, head, or neck. Fifty-seven percent of the patients had more than 1 form of arteriopathy, with dysgenesis being the most common abnormality (56%), followed by anomalous course or origin (47%), narrowing (39%), and nonvisualization (20%). Primitive embryonic carotid-vertebrobasilar connections were present in 20% of children. Hemangiomas were ipsilateral to arteriopathy in all but 1 case. The frontotemporal and/or mandibular facial segments were involved in 97% of cases, but no other specific associations between arteriopathy location and hemangioma sites were detected. All cases with posterior fossa anomalies had either ICA anomalies or persistent embryonic carotid-basilar connections.

Bracken et al. (2011) performed a retrospective review of clinical and imaging records of a consecutive series of 12 patients, 10 female and 2 male, diagnosed with PHACE syndrome between 1998 and 2009. All patients had a segmental craniofacial hemangioma, which involved the frontotemporal segment in 12 patients, the maxillary segment in 8, mandibular in 5, and frontonasal in 1. The most common extracutaneous abnormalities were neurovascular anomalies, which were present in 10 patients, many of whom had multiple anomalies. The spectrum of arterial anomalies ranged from hypoplasia (9 patients) to ectasia (3 patients), anomalous origin or course (2 patients), and persistent fetal anastomosis (2 patients). Other anomalies found included cardiac anomalies in 3 patients, coarctation of the aorta in 2 patients, and a posterior fossa anomaly and a sternal region anomaly in 1 patient each. Bracken et al. (2011) concluded that intracranial anomalies are the most common extracutaneous feature of PHACE syndrome.

History

The relationship between large facial hemangiomas and underlying cerebrovascular and facial arterial anomalies was first recognized by Pascual-Castroviejo (1978), who reported 7 female patients with facial and scalp hemangiomas. Pascual-Castroviejo (1978) also noted that the hemangiomas were associated with brain anomalies, usually involving the cerebellum, and congenital heart disease. The most severe vascular anomalies occurred on the same side as the hemangiomas.