PHACE Syndrome – Causes, Symptoms, Diagnosis, Treatment

Although researchers have been able to establish diagnostic criteria with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the relatively small number of identified cases, the lack of large clinical studies, and the possibility of multiple genes influencing the phenotype prevent physicians from developing a “one size fits all” description of PHACE and its prognosis. Therefore, it is important to note that every person is unique and that most affected individuals will not have all of the symptoms discussed below.

The most noticeable sign associated with PHACE syndrome is often a hemangioma, which is an overgrowth of blood vessels that may appear as a red, purple, or blue birthmark. In these children, a hemangioma most often occurs on the face, head or neck. They may not be present or may be barely noticeable at birth, and become apparent and grow, sometimes quickly, in the weeks to months after birth. They usually become large, measuring more than 5 centimeters (approximately 2 inches). They can be one large area of discoloration or can consist of many smaller lesions in one area of the face, head, or neck. Hemangiomas can damage the skin causing sores (ulceration) or alter the appearance of facial features. If a hemangioma breaks open, it can be extremely painful.

Hemangiomas can be superficial (only affecting the upper layers of the skin) or deep (extending deeper in the skin or in the fat layers). Hemangiomas may also be found in the internal organs of the body. Depending on the exact location of a hemangioma, it can affect vision, hearing or breathing. A hemangioma located near the subglottic airway, the area of the throat just below the vocal cords, can cause potentially life-threatening airway obstruction. Affected individuals may have a wheezing or noisy way of breathing (stridor).

Some affected infants and children will have structural abnormalities of the brain, particularly in a region of the brain known as the posterior fossa. The posterior fossa is located near the base of the skull and contains the cerebellum, pons, and medulla oblongata. The cerebellum is the area of the brain that controls coordination and balance, and is also involved in cognition and behavior. Underdevelopment of the cerebellum, called cerebellar hypoplasia, is common. Cerebellar hypoplasia usually occurs on the same side of the body as the hemangioma (ipsilateral).

Another common structural brain abnormality is a Dandy-Walker malformation (DWM), which occurs during embryonic development of the cerebellum and 4th ventricle. The 4th ventricle is a space around the cerebellum that channels fluid from inside to around the outside of the brain. DWM is characterized by underdevelopment (small size and abnormal position) of the middle part of the cerebellum known as the cerebellar vermis, cystic enlargement of the 4th ventricle, and enlargement of the posterior fossa. DWM is sometimes (20-80%) associated with hydrocephalus, in which blockage of the normal flow of spinal fluid leads to excessive amounts of fluid accumulating in and around the brain. This leads to abnormally high pressure within the skull and swelling of the head and can lead to neurological impairment.

Abnormalities affecting the cerebral arteries are another common finding. Arteries are major blood vessels in the body; they carry oxygen-filled blood away from the heart to the rest of the body. Approximately 80-90% of individuals have abnormalities of the medium-sized arteries of the head and neck. These abnormalities include malformation (dysplasia) or narrowing of the blood vessels. Sometimes, a blood vessel may follow an abnormal (aberrant) path through the head and neck. Specific abnormalities can include severe underdevelopment or absence (agenesis) of the carotid or vertebral arteries or abnormal persistence of embryonic blood vessels. The two carotid arteries are the main blood vessels that supply blood to the front and middle parts of the brain.

Narrowing of the arteries may get progressively worse, putting affected children and individuals at risk for a stroke due to a lack of blood flow to the brain. Sometimes, seizures or loss of feeling on one side of the body (hemiparesis) can be the initial sign of blood vessel problems.

The abnormalities affecting the arteries may progress to resemble a disorder called Moyamoya disease. This is a progressive disorder that affects the blood vessels in the brain (cerebrovasculature). It is characterized by the narrowing (stenosis) and/or closing (occlusion) of the carotid artery inside the skull, a major artery that delivers blood to the brain. At the same time, tiny blood vessels at the base of the brain open up in an apparent attempt to supply blood to the brain distal to the blockage. Inadequate blood supply then leads to reduced oxygen delivery to the brain. One of the outcomes can be a stroke, symptoms of which include paralysis of the face, arms, or legs, loss of speech, etc., or temporary loss of neurologic function of body parts or speech (transient ischemic attack, or TIA). Twitching or seizures can also result.

Some affected infants and children have abnormalities affecting the heart and aortic arch. The aortic arch is where the aorta is connected to the heart; the aorta travels upward away from the heart before traveling downward (forming an arch). Common abnormalities can include coarctation of the aorta, aberrant subclavian artery, and ventricular septal defects. Coarctation of the aorta is a condition in which there is a narrowing of the aorta, the main artery that supplies blood to the body. The severity of the condition can range from mild to severe. Coarctation of the aorta can cause high pressure in the left ventricle, the chamber of the heart that pumps blood into the aorta. Because the heart is forced to work harder to try and pump blood, this can lead to overgrowth (hypertrophy) of and damage to the heart muscle.

The subclavian arteries are the arteries that supply blood to the arms. Aberrant subclavian arteries do not follow the normal path in the body that these arteries usually follow. This condition can potentially cause serious complications including a vascular ring. The avascular ring is an abnormality in which the aorta or one of its branches forms a ring around the windpipe (trachea) and the tube that carries food from the mouth to the stomach (esophagus). There are different types of vascular rings. Some symptoms that can occur include difficulty swallowing, difficulty eating or drinking, noisy breathing, difficulty breathing, or a persistent cough.

A ventricular septal defect is when there is a ‘hole’ in the membrane (septum) that separates the two lower chambers of the heart, called the ventricles. The size of this ‘hole’ will determine whether any symptoms are present, and how severe these symptoms may be.

Individuals with PHACE syndrome are at risk of developing an aneurysm. This is when the walls of an artery bulge or balloon outward. Depending on its size and location, an aneurysm can cause a variety of symptoms. Aneurysms can also rupture, which can cause serious complications.

Individuals with PHACE syndrome may also have a variety of eye abnormalities including underdevelopment of the main nerve that transmits nerve impulses from the eye to the brain to form images (optic nerve), morning glory disc anomaly, persistent hyperplastic primary vitreous, and the formation of a staphyloma, which is the abnormal protrusion or ‘pushing out’ of uveal tissue through a weak point in the eyeball. The uvea is the middle, colored (pigmented) layer of tissue of the eye.

Morning glory disc anomaly is a birth defect involving the optic disc, the raised area where the optic nerves leave the retina. It is characterized by an abnormally-shaped optic disc, which ends up resembling a flower called a “morning glory.” Morning glory disc anomaly can cause poor vision and poor clarity of vision.

The persistent hyperplastic primary vitreous is a birth defect in which embryonic blood vessels within the eye do not regress as they normally do. This can potentially cause vision problems.

Less common findings include abnormally small eyes (microphthalmia), congenital cataracts, improper development of the cornea in which it blends into the white of the eye (sclerocornea), and a cleft of missing tissue in the colored portion of the eye (iris), which is called a coloboma.

Third nerve palsy and Horner syndrome have also been reported in children with PHACE syndrome. The third cranial nerve controls muscles that move the eye and also controls the constriction of the pupil, position of the upper eyelid, and the ability of the eye to focus. Symptoms of third nerve palsy can include double vision and drooping of the upper eyelid. Horner syndrome is a condition caused by abnormalities of the nerve pathway that runs from the brain to the eye and face on one side of the body. Horner syndrome is characterized by a persistently small pupil (miosis), drooping of the eyelid (ptosis), and little to no sweating on the affected side of the face (anhidrosis).

PHACE syndrome can be associated with abnormalities affecting the breastbone (sternum) including partial or complete absence of the sternum. Sometimes, there is a split or groove in the sternum (sternal cleft) usually due to the sternum failing to fuse properly. On the skin of the breastbone, there may be small indentations or pits, or small, raised bumps (papules). Some infants or children have a scar-like line that extends upward from the bellybutton (supraumbilical raphe).

Affected infants and children may experience delays in attaining speech and language abilities or difficulty swallowing (dysphagia). Children with PHACE syndrome often experience headaches. These headaches tend to be more severe and more frequent than in children without the disorder. Migraines may also occur and can result in vomiting and sensitivity to light (photophobia). Some individuals have dental problems including underdevelopment (hypoplasia) of the enamel of the teeth, discoloration of the enamel, and enamel that may chip easily.

Affected individuals may also have endocrine abnormalities. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Affected individuals may experience decreased production of hormones made by the pituitary gland (hypopituitarism) or hormones made from the thyroid gland (hypothyroidism). Hypothyroidism may be present at birth or may be acquired during infancy or childhood and is characterized by poor growth (growth deficiency). Other signs of hypothyroidism can include weakness, fatigue, cold intolerance, and weight gain. Hypopituitarism is characterized by underdevelopment of the ovaries in females and the testes in males (hypogonadotropic hypogonadism) and late-onset adrenal insufficiency, in which the adrenal gland does not produce enough of the hormone cortisol. This can cause unintended weight loss, muscle weakness, fatigue, and low blood pressure.

Some individuals may develop hearing loss. This may be because of a hemangioma forming in the auditory canal or affecting the auditory nerve. They are two main types of hearing loss: conductive and sensorineural. Conductive hearing loss is when there is a failure of sound to be conducted from the outer ear to the middle ear. Sensorineural hearing loss is when there is an impaired ability of the nerves of the ear to transmit sensory input from the inner ear to the brain. Mixed hearing loss is a combination of both.

There are additional abnormalities that have been reported in individuals with PHACE syndrome. These additional abnormalities include Tetralogy of Fallot, ectopia cordis, and patent foreman ovale; arteriovenous malformations or arteriovenous fistula; malformations in the development of the outer layer of the cerebrum (abnormal cortical development); and the presence of thyroid tissue outside of its normal location (ectopic thyroid). For more information on these conditions, choose the specific condition name as your search term in the Rare Disease Database, or visit the organizations listed in the Resources section of this report.