Introduction to PHACE Syndrome

What is PHACE syndrome?

A syndrome is defined as a recognizable pattern of medical conditions that occur together. PHACE syndrome is a disorder characterized by large infantile hemangiomas of the face, scalp and neck associated with developmental defects of the brain, blood vessels, eyes, heart and chest wall.

History of PHACE syndrome

PHACE syndrome is a relatively newly discovered entity and was first described in 1996 by an astute physician who recognized a pattern of problems in babies with large facial hemangiomas. Dr. Ilona Frieden and colleagues published a medical paper detailing 5 babies with large facial hemangiomas and anomalies of the brain, aortic arch, eye and arteries. Frieden created the term PHACE, which is an acronym (a word formed from the first letters of the several words in the name) which refers to Posterior fossa anomalies, Hemangioma, Arterial lesions, Cardiac abnormalities/Coarctation of the aorta, and Eye anomalies. A physician in Spain also noted a similar constellation of findings (Pascual Castroviejo type II syndrome).

In that same paper, Frieden also reviewed previously published papers that described similar conditions. We believe that many children had PHACE syndrome in the past but were unrecognized or were misdiagnosed as another syndrome. Even though it has been recognized for almost 15 years, in medical terms this is still considered a very new syndrome and we have much more to learn. Since this report, many more cases of PHACE syndrome have been identified; with every child diagnosed with PHACE syndrome, we discover more about this condition.

Every child diagnosed with PHACE syndrome has a different combination of abnormalities associated with the syndrome. Not every affected child has all of the same symptoms, and there is a spectrum of severity. In most cases, there is no history of PHACE syndrome or similar medical conditions in the family. For reasons we do not understand, girls are more likely to get PHACE syndrome when compared to boys, but the severity of the disease does not seem to be worse in either sex. At this point, little is known about what problems may occur as children with PHACE syndrome get older. The cause of PHACE syndrome remains unknown. However, nationwide research efforts are beginning to provide valuable information about PHACE syndrome with the goal of improving clinical care for these children.

How common is PHACE syndrome?

Although relatively uncommon, more than 400 cases of PHACE syndrome have been reported in the medical literature. This number, however, is most likely an underrepresentation of the true number of PHACE syndrome cases due to a variety of reasons. First, the reported cases found in the literature often have the most severe abnormalities associated with PHACE syndrome. Thus, children who have a more mild form of PHACE syndrome may not be reported in medical journals. Second, some children that were previously misdiagnosed with other diseases, most notably Sturge-Weber Syndrome, may actually have PHACE syndrome. As understanding and recognition of PHACE syndrome increases, the reported number of patients diagnosed with the syndrome is expected to increase.

How is PHACE syndrome diagnosed?

The identification of PHACE syndrome is made by a clinical diagnosis. This means there is no one sign or symptom that will indicate a diagnosis of PHACE syndrome. Currently, there is no blood test or genetic test for PHACE syndrome. Physicians use a combination of signs and symptoms called diagnostic criteria to make the diagnosis (see Tables 1 and 2). Most children with PHACE syndrome have a large hemangioma on the face, scalp or neck. One study found that 31 percent of children with large infantile hemangiomas on the face or scalp have PHACE syndrome. Rarely, children with large hemangiomas of the arm and/or trunk may also have PHACE syndrome. Children with a large segmental hemangioma (see Infantile Hemangioma section) of the head and neck should undergo a thorough evaluation, especially of the brain, heart, blood vessels and eyes. If a child is at risk for PHACE syndrome, certain tests and examinations should be considered.

What tests need to be done to diagnose PHACE syndrome?

It is recommended that infants at risk for PHACE syndrome with large (greater than 24 cm squared) hemangiomas of the face or scalp undergo several tests to evaluate their brain, neck, chest, heart and eyes. These tests may include:

  • A history and physical examination is a comprehensive evaluation of the patient by a physician. During this examination the physician gathers information about the infant's past medical problems, problems experienced during the pregnancy, and an overview of medical conditions that may or may not run in the family. Additionally, the physician will perform a physical examination of the infant. The information gathered will help to guide future consultations and examinations as well as treatment planning. This initial assessment will supply information to the physician that provides guidance on further consultations and studies.
  • An ophthalmic (eye) exam is performed by an ophthalmologist (eye doctor) to check vision and the health of the eyes. During this examination the ophthalmologist may check eye movements, reaction to light, and use an ophthalmoscope to check the deep and surface anatomy of the eye. This examination may be used to look for the eye abnormalities of PHACE syndrome. For more information about ophthalmic exams, please refer to the Eye Abnormalities section.
  • An echocardiogram (echo) is an ultrasound test that uses sound waves to create a moving picture of the heart and large blood vessels arising from the heart. This test is similar to the sonogram or ultrasound used to observe a baby while pregnant. This picture is much more detailed than an X-ray image and involves no radiation exposure. An echocardiogram allows doctors to diagnose, evaluate, and monitor the heart and aortic abnormalities associated with PHACE syndrome. For more information about heart abnormalities or echocardiograms, please refer to the Congenital Heart Abnormalities section.
  • A magnetic resonance imaging (MRI) and magnetic resonance angiogram (MRA) of the head and neck should be ordered if PHACE syndrome is suspected. These tests can provide important information needed to diagnose certain conditions associated with PHACE syndrome such as abnormal arterial blood vessels and abnormalities of the brain. Both MRI and MRA use a magnetic field and a computer to provide a detailed image of the body and internal organs. An MRI of the brain provides detailed pictures that allow doctors to look for findings of PHACE syndrome. An MRA of the head, neck, and chest provides detailed pictures of the arterial blood vessels through the use of a contrast agent. An intravenous (IV) line needs to be inserted so that the contrast material can be injected into the bloodstream. The same machine is used for both an MRI and an MRA and in most cases these tests are done at the same time. There is no radiation exposure during an MRI or MRA. Because slight movements may interfere with the quality of the images, infants and young children may need to be sedated so they do not move. For more information about brain abnormalities, please refer to the Intracranial Hemangiomas, Cerebrovascular Abnormalities, Brain Abnormalities, and Neurologic Abnormalities sections.
  • Occasionally, a computed tomography angiogram (CTA) may be used to look at blood vessels of the brain, neck, and chest. This is a special type of CT scan that uses intravenous (IV) dye to highlight the body's blood vessels.

What are the diagnostic criteria for PHACE syndrome?

The diagnosis of PHACE syndrome is made by using a combination of major and minor criteria. Major criteria are findings that are common in PHACE syndrome but rare in other medical conditions. Minor criteria are findings that are seen in PHACE syndrome but can also be found in other conditions. There are additional features of PHACE syndrome that are not included in the diagnostic criteria but are still very important to the health and management of children with PHACE syndrome. We cover these additional features in the last few chapters.

Affected children are classified into two categories, definite PHACE syndrome and possible PHACE syndrome, based on the nature and number of criteria met. Definite PHACE syndrome requires the presence of a characteristic segmental hemangioma greater than 5 cm in diameter on the face (or scalp) plus one of the major criterion or two minor criteria listed in Table 1. Possible PHACE syndrome can be diagnosed in one of three different combinations: a) Facial hemangioma greater than 5 cm in diameter plus 1 minor criterion; b) hemangioma of the neck or upper torso plus 1 major criterion or 2 minor criteria; or c) no hemangioma plus 2 major criteria. Note that more than one anomaly in one organ system (for example, two heart conditions) only counts for one criterion.

Table 1: Diagnostic criteria for PHACE syndrome

 

Organ system 
 
Major criteria 
 
Minor criteria 
 

Cerebrovascular

  • Anomaly of major cerebral arteries
  • Dysplasia of the large cerebral arteries
  • Arterial stenosis or occlusion with or without moyamoya collaterals
  • Absence or moderate-severe hypoplasia of the large cerebral arteries
  • Aberrant origin or course of the large cerebral arteries
  • Persistent trigeminal artery
  • Saccular aneurysms of any cerebral arteries

 

  • Persistent embryonic artery other than trigeminal artery
  • Proatlantal intersegmental artery (types 1 and 2)
  • Primitive hypoglossal artery
  • Primitive otic artery
Structural Brain
  • Posterior fossa anomaly
  • Dandy-Walker complex or unilateral/bilateral cerebellar hypoplasia/dysplasia
  • Enhancing extra-axial lesion with features consistent with intracranial hemangioma
  • Midline anomaly
  • Neuronal migration disorder 
     
Cardiovascular
  • Aortic arch anomaly
  • Coarctation of aorta
  • Dysplasia
  • Aneurysm
  • Aberrant origin of the subclavian artery with or without a vascular ring

 

  • Ventricular septal defect
  • Right aortic arch (double aortic arch)
Ocular
  • Posterior segment abnormality
  • Persistent fetal vasculature (Persistent hyperplastic primary vitreous)
  • Retinal vascular anomalies
  • Morning glory disc anomaly
  • Optic nerve hypoplasia
  • Peripapillary staphyloma
  • Coloboma
  • Anterior segment abnormality
  • Sclerocornea
  • Cataract
  • Coloboma
  • Microphthalmia
Ventral or Midline 
 
  • Sternal defect
  • Sternal cleft
  • Supraumbilical raphe
  • Hypopituitarism
  • Ectopic thyroid

 

Table 2: Categories of PHACE syndrome

Definite PHACE syndrome

Facial hemangioma greater than 5 cm
PLUS
1 major OR 2 minor criteria

Possible PHACE syndrome

Facial hemangioma greater than 5 cm PLUS 1 minor criteria
Hemangioma of the neck or upper torso PLUS 1 major OR 2 minor criteria 2 major criteria without hemangioma

What causes PHACE syndrome?

Although there is research in progress to determine the cause of PHACE syndrome, still very little is known about the development and natural history of this syndrome. The abnormalities associated with this syndrome are thought to be due to errors that occur very early during development, but why the errors occur is unknown. There may be a genetic component involved and studies are underway to investigate this idea. No familial cases have been identified to date.

How many children will have PHACE syndrome within a family?

No cases of PHACE syndrome have been identified in the same family. However, if there is a suspicion of PHACE syndrome in any child, it is always best to visit a physician.

What doctors should evaluate a baby suspected to have PHACE syndrome?

If a child has been diagnosed with PHACE syndrome, we recommend that the child be evaluated by a multidisciplinary team (doctors from many different specialties) of physicians to ensure that all aspects of the child's health are evaluated and treated. These doctors should have experience in treating infants and children with PHACE syndrome. Depending on the child, a pediatrician, pediatric dermatologist, hematologist/oncologist, ophthalmologist, radiologist, neurologist, cardiac surgeon, plastic surgeon, general surgeon, geneticist, cardiologist, and otolaryngologist may need to be involved. This network of physicians will be critical in providing the most comprehensive care and support that the child may need in the future.