PHACE Syndrome

Etiology

PHACE syndrome is considered a non-hereditary condition. The etiology is not fully understood. Most cases are sporadic, but suggestions exist that it may correlate to a mutation in the X-linked genes since its female predominance, with prenatal male lethality.[3] It corresponds with various genetic and phenotypic anomalies. Some authors suggest a developmental error between 6 and 8 weeks of gestation, before or during vasculogenesis.

Epidemiology

PS is more prevalent in the White and Hispanic populations. There is a female predominance with a female-to-male ratio of 9 to 1.[1] Approximately 20 % of children with facial hemangioma will develop one of the abnormalities of PS.[4] The risk of extracutaneous abnormalities increases with increasing hemangioma size and when the hemangioma involves multiple facial segments.[5]

Pathophysiology

The physiopathology of PHACE syndrome is different from that of isolated hemangioma. It is not fully understood and demonstrates no family inheritance pattern.

The ipsilateral malformation in PS suggests an abnormal embryonic or fetal development.

Also, the vascular abnormalities may result from regional arterial insufficiency and disruption of the normal arterial wall and, therefore, alteration in blood flow and hypoxia. Thus, these changes lead to the formation of hemangioma and abnormalities in brain structures.[3]

History and Physical

PHACE syndrome is a neurocutaneous disorder. Cutaneous anomalies are manifested by hemangioma, which can be absent, subtle at birth, or obvious after birth. It can be present at birth as premonitory lesions as an erythematous patch or a telangiectatic red macule. It is typically characterized by a large segmental cervicofacial hemangioma as red-bluish soft masses covering a broad cutaneous territory or manifests as confluent plaques or small individual papules clustered that assume a specific distribution. The pattern, in some cases, has a dermatomal involvement, occurring trigeminal patterns V1, V2, and V3 facial hemangioma is the most frequent localization. It can occur unilaterally or bilaterally. Lesions undergo a proliferative phase followed by slow involution often leading to complete regression. There are reports of a suspected link between the distribution of facial hemangioma and extracutaneous manifestations.

The face is divided into four segments related to the prominences of facial develo­pment: frontotemporal (segment 1), maxillary (segment 2), mandibular (segment 3), and frontonasal (segment 4). Hemangiomas on the frontotemporal and frontonasal segments have been reported with a higher risk of ocular, cerebrovascular, and brain involvement, whereas those on the mandibular segment correlate with a potential risk of midline and cardiovascular defects. However, these correlations have not been fully elucidated.[6]

Furthermore, the hemangioma may occur elsewhere in the body; the most common association is with the segmental hemangioma or the subglottic (airway hemangioma) and occasionally may be seen in the gastrointestinal tract.[7]

The extracutaneous manifestations include abnormalities of the brain, cerebral vasculature, aorta, eyes, and chest wall. The most common associated extracutaneous findings are cerebrovascular (91%), cardiovascular (67%), and brain (52%) abnormalities. Thereon, the cerebrovascular involvement is typically related to the ipsilateral internal carotid artery.  The most frequent cardiovascular abnormalities are aberrant subclavian artery and coarctation of the aorta, which are present in 20% of cases. Brain abnormalities mainly involve the posterior fossa and may include cerebral hypoplasia, cortical dysgenesis, and Danky-Walker malformation. Additionally, neurological symptoms are variable, depending on the associated territory of the occluded artery. The ophthalmologic manifestations include microphthalmia, glaucoma, and coloboma.[6][8][9]

Evaluation

PHACE syndrome should be suspected in the presence of cervicofacial infantile hemangioma over 5cm in size, and a systemic evaluation is required. Thus, history taking and careful physical examination are necessary. Imaging with magnetic resonance imaging (MRI) and/or magnetic resonance angiography (MRA) of the head and neck should be ordered if PS is suspected. Moreover, an ophthalmic evaluation should be performed to look for eye abnormalities associated with PS. Also, an echocardiogram should be performed, looking for heart and aortic abnormalities.

PS can be suspected during pregnancy. Antenatal ultrasound screening can detect abnormalities of the posterior fossa, and therefore, an MRI is recommended to assess the diagnosis in the antenatal period.[10] Additionally, an appropriate endocrinologic workup should be performed according to the clinical signs.

An interprofessional group of specialists has established the 2009 diagnostic criteria, which had an update in 2016. The diagnostic basis of definite PS is the presence of a facial hemangioma of more than 5 cm with one major criterion or two minor criteria. Possible PS requires the presence of cervicofacial hemangioma with one minor criterion.[11]

Major criteria:

• Arterial: anomalies of major cerebral or cervical arteries, stenosis, occlusion, dysplasia, hypoplasia, persistent carotid-vertebrobasilar anastomosis
• Structural brain: posterior fossa anomalies: Danky-Walker complex, unilateral or bilateral cerebral dysplasia or hypoplasia
• Cardiovascular: aortic arch anomalies, aneurysm, an aberrant origin of the subclavian artery
• Ocular: posterior segment anomaly, retinal vascular anomalies
• Ventral or midline: sternal defect, sternal cleft

Minor criteria:

• Arterial: aneurysm of cerebral arteries
• Structural brain: midline anomaly, malformation of cortical development, neuronal migration disorder
• Cardiovascular: ventricular septal defect, right aortic arch
• Ocular: anterior segment anomalies, cataracts, sclerocornea, microphthalmia
• Ventral or midline: hypopituitarism, ectopic thyroid, midline sternal papule[11]

Treatment / Management

The management should be multidisciplinary. There is no standardized treatment protocol for affected children. The treatment directs itself toward the specific symptoms in each patient. Patients with PS may need to be managed by cardiologists and neurologists, depending on their extracutaneous manifestations. The hemangioma is generally treated successfully with oral propranolol with caution because of the risk of stroke in patients with heart or blood vessel problems. Also, treatment of hemangioma may involve systemic steroids, surgery, or laser therapy. Therapy with aspirin is generally recommended to prevent ischemic accidents. Cardiovascular abnormalities may require early surgical intervention.[12]

Differential Diagnosis

• Sturge-Weber syndrome
• Infantile hemangioma
• Visceral hemangioma
• Wyburn-Mason syndrome
• LUMBAR syndrome[13]

Prognosis

The prognosis is variable. It depends on the associated manifestations. Neurological and cognitive impairments are very common, and they constitute the most significant source of morbidity.

Complications

• Hemangioma: ulceration, bleeding, visual compromise, cause issues with vital function
• Cardiovascular: coarctation of the aorta is the most common (14,5 %); other aortic arch abnormalities
• Neurological: migraine headaches, developmental delays, seizures, speech delays, and rarely ischemic strokes or hemorrhage
• Ophthalmological: cataract, glaucoma
• Occasionally, dental hypoplasia, impaired hearing, and endocrine abnormalities (hypopituitarism and hypothyroidism)