Phacing the future: When patients with PHACE syndrome grow up

By Warren R. Heymann, MD
June 24, 2020
Vol. 2, No. 25

The acronym PHACE syndrome, emphasizing the characteristic findings of this neurocutaneous syndrome: posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities, was initially proposed by Frieden et al in 1996. They detailed two patients (and 41 similar cases) with large facial hemangiomas, congenital cataracts, and structural arterial abnormalities, particularly of the central nervous system vasculature. One of these infants also had a Dandy-Walker malformation. (1) Subsequently an “S” was added to denote sternal defects (PHACES). In 2009, diagnostic criteria were elaborated for the syndrome (2), which were updated in 2016. The basis for diagnosing PHACE syndrome is the presence of facial hemangioma [segmental, infantile] > 5cm with one major criterion or two minor criteria. A possible diagnosis of PHACE syndrome requires a cervicofacial hemangioma with one minor criterion (see below for major and minor criteria). PHACE syndrome is considered a sporadic disorder of uncertain etiology, without a genetic predisposition, despite its overwhelming female predominance. (3)

As Garzon et al eloquently state: “As patients with PHACE have been followed over time, new age-related comorbidities have been recognized, including headaches, as well as endocrinologic, hearing, and dental anomalies. Evidence-based data for screening and monitoring these potentially progressive morbidities do not exist so clinicians must rely on their individual experiences with a limited number of patients to guide management decisions.” (2)

There is remarkably little literature on adults with PHACE syndrome, as one might expect. Dr. Frieden’s index cases are now at least in their mid-20s, yet PHACE syndrome has been present for far longer, prior to its recognition as a distinct neurocutaneous syndrome. Recent articles describing the diagnosis of PHACE syndrome in adults are primarily based on the presence of a history of facial infantile hemangiomas that have subsequently regressed. Examples include a 35-year-old woman with a distal aortic arch aneurysm with a purple-red hemangioma that regressed after age 1 year (4); a 65-year-old woman with a transient ischemic attack and a history of a facial “vascular birthmark” treated by radiation during childhood (5); a 23-year-old woman with limb-shaking transient ischemic attacks, with a hemangioma of her neck that appeared shortly after birth, but spontaneously regressed (6); and a 29-year-old woman with a Dandy-Walker malformation, stroke, and remnant of a forehead hemangioma above her left eye. (7)

These cases were diagnosed retrospectively in adults. Today, when a child is born, the diagnosis of PHACE syndrome is likely to be established expediently. Anxious parents will ask the obvious questions — What will happen to my child when she grows up? What can we do to help her?

Stefanko et al surveyed a cohort of 18 adult PHACE syndrome patients, at least 18 years of age (range 18 to 59 years, mean age 24 years), derived from a PHACE syndrome registry and a Vascular Anomalies Clinic Database. Eighty-nine percent reported experiencing headaches, and 17% experienced acute but transient symptoms mimicking acute ischemic stroke, subsequently diagnosed as atypical migraines. Thirty-three percent reported hearing loss, and 67% had dental issues (cavities, enamel problems, malocclusion, premature eruption of permanent teeth, nerve pain and missing teeth). One patient experienced two arterial dissections. Three-fourths who attempted conception were successful, and none of their children had clinical features of PHACE. (8) As these women are now of childbearing age, special attention must be given to those considering pregnancy. Especially for those undergoing Caesarian section, anesthesia management focusing on maintaining a patent airway is essential. (9) Arguably, perhaps the most aggravating correlates of PHACE syndrome may be anxiety, depression, and diminished quality of life. (8)

Much remains to be learned about PHACE syndrome — its pathogenesis, complications, management, and treatment. (For an outstanding overview these considerations such as when to image, use propranolol, etc. are thoroughly articulated in reference 2.) What is clear is that the implications and risks are lifelong — patients and physicians must phace up to that.

Point to Remember: PHACE syndrome may present dramatically in the newborn period, but patients must be followed for a lifetime.

Our expert's viewpoint

Ilona J. Frieden, MD
Professor of Dermatology and Pediatrics
University of California, San Francisco

The acronym PHACE was first coined in 1996. In the intervening 20+ years, there have been hundreds of additional case reports. We also know that there were many cases of PHACE described prior to 1996 (often called “atypical Sturge-Weber syndrome"). While PHACE is not common, it is not extremely rare — arguably more common than Sturge-Weber syndrome, a much better known neurocutaneous disorder. There are now groups for parent support and patient advocacy and an international disease registry. Consensus criteria for diagnosis have been established, and we have continued to learn more and more about this condition. Unfortunately, despite attempts to find an etiology, its cause (or causes) have eluded discovery, but the search for what is likely a post-zygotic somatic mutation goes on.

What have we learned regarding the long-term outcome of individuals diagnosed with PHACE? We are now aware of certain medical issues which were not initially recognized, including potential dental anomalies, chronic headaches, and — in some cases — persistence or unexpected prolonged growth of the associated infantile hemangiomas. There is a minority — fortunately a fairly small minority — who develop strokes or other signs of brain ischemia. Stefanko et al have published a survey of outcomes in 18 adults with PHACE, but we know this is a small fraction of affected adults. Identifying a larger cohort and understanding the etiology would likely go a long way to helping us understand outcomes. Finding an etiology would like identify mechanisms of pathogenesis and most probably an even larger cohort of affected individuals who are affected either differently or more mildly than those diagnosed via consensus criteria. Fortunately, this research is ongoing, and there are many vascular anomalies centers and specialists with expertise re: PHACE. Over time we will likely to be able to add to our knowledge and management strategies for this condition.

Dr. Frieden had disclosed financial relationships with the following to the AAD at the time of publication: Pfizer, Venthera. Full disclosure information is available at coi.aad.org.

1. Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformation, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defect, and eye abnormalities. Arch Dermatol 1996; 132; 307-311.

2. Garzon MC, Epstein LG, Heyer GL, Frommeit PC, et al. PHACE syndrome: Consensus-derived diagnosis and care considerations. J Pediatr 2016; 178: 24-33.

3. Chamli A, Litaiem N. PHACE syndrome. Stat Pearls [Internet]. Treasure Island (FL): Stat Pearls Publishing ; 2019 Jan.

4. Tanaka C, Shimura, S, Cho Y, Ueda T. Distal aortic arch aneurysm in an adult case of PHACE syndrome. Interact Cardovasc Thorac Surg 2018; 27: 619-621.

5. Burch EA, Garzon MC, Parikh A, Meyers PM. A 65-year-old woman diagnosed with PHACE syndrome. Pediatr Dermatol 2013; 30: e153-e156.

6. Chou PS, Guo YC. Limb-shaking transient ischemic attacks in an adult PHACE syndrome: A case report and review of the literature. Neurol Sci 2012; 3: 305-307.

7. Arora SS, Plato, BM, Sattenberg RJ, Downs RK, et al. Adult presentation of PHACES syndrome. Interv Neuroradiol 2011; 17: 137-146.

8. Stefanko NS, Cossio ML, Powell J, Blei F, et al. Natural history of PHACE syndrome: A survey of adults with PHACE. Pediatr Dermatol 2019; 36: 618-622.

9. Martel C, Robertson R, Williman FB, Moore C, Clark A. Anesthetic management of a parturient with PHACE syndrome for Cesarean delivery. A&A Case Reports 2015; 5: 176-79884

Major and Minor Criteria for PHACE syndrome (reference 3)

Major criteria:

• Arterial: anomalies of major cerebral or cervical arteries, stenosis, occlusion, dysplasia, hypoplasia, persistent carotid-vertebrobasilar anastomosis

• Structural brain: posterior fossa anomalies: Dandy-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, cataract, sclerocornea, microphthalmia

• Ventral or midline: hypopituitarism, ectopic thyroid, midline sternal papule

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