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Last updated: May 30, 2018
Years published: 2018
NORD gratefully acknowledges Nikki Stefanko, MD, PHACE Foundation of Canada Pediatric Dermatology Research Fellow, Department of Dermatology, Medical College of Wisconsin, Beth Drolet MD, Professor of Dermatology, Medical College of Wisconsin, Medical Director of Vascular Anomalies, Childrenโs Hospital of Wisconsin, and the PHACE Syndrome Community, for assistance in the preparation of this report.
Summary
PHACE syndrome is a rare disorder that affects multiple systems of the body. This disorder is characterized by an association of several different abnormalities that occur together with greater frequency than would otherwise be expected. The term PHACE is an acronym; each letter stands for a word. The acronym comes from the first letter of some of the more common signs and symptoms of this disorder. PHACE stands for: (P)osterior fossa and other structural brain malformations; large (H)emangiomas of the face, neck, and/or scalp; anatomical anomalies of the cerebral or cervical (A)rteries; (C)ardiac anomalies/(C)oarctation of the aorta; and (E)ye abnormalities. If sternal anomalies are present, sometimes the term PHACES syndrome is used, with (S) standing for (S)ternal anomalies. The disorder occurs with much greater frequency in girls than boys. The specific symptoms and their severity can vary greatly from one individual to another. Most affected children will not exhibit all of the major symptoms potentially associated with this disorder. Some children with only develop mild problems associated with the disorder, while others will develop serious complications that greatly impact quality of life. The exact cause of PHACE syndrome is not known. PHACE syndrome was first identified in the medical literature in 1996.
Although researchers have been able to establish diagnostic criteria with characteristic or โcoreโ 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 โone size fits allโ 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 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 โTIAโ). 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 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. A vascular 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 โholeโ in the membrane (septum) that separates the two lower chambers of the heart, called the ventricles. The size of this โholeโ 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 โpushing outโ 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 โmorning glory.โ Morning glory disc anomaly can cause poor vision and poor clarity of vision.
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.
The exact cause of PHACE syndrome is unknown. It appears to occur randomly (sporadically) for no known reason. There have not been reports of the disorder occurring in multiple members of the same family.
Some researchers believe that the disorder results from an unknown postzygotic somatic mosaic mutation. A somatic mutation is a change in a gene that occurs in any cell of the body except the sex cells, namely the sperm and the egg. In PHACE syndrome, the affected gene(s) is unknown. A somatic mutation usually occurs in the body in a mosaic pattern, which means that some cells will have a normal copy of the gene and some cells will have an altered copy of the gene. This may be referred to as having two distinct cell lines in the body. The variability in symptoms and severity would be due, in part, to the ratio of healthy cells to altered cells. Some researchers believe that a somatic mutation in PHACE syndrome may affect a gene vital to health and function of neural crest cells. These cells form very early during embryonic development and give rise to most of the bone and cartilage underlying the face. Somatic mutations are not inherited and are not passed on to children. Researchers have also hypothesized that PHACE syndrome may be due to a de novo gene mutation. A de novo mutation is a new genetic change occurring for the first time in a family member due to a mutation in an egg or sperm from a parent or a mutation that occurs later, after the egg is fertilized.
PHACE syndrome may be a multifactorial disorder, which means that the disorder develops through the interaction of several genetic and environmental factors. Researchers are trying to determine the specific, underlying factors that play a role in the development of the disorder.
PHACE syndrome affects more females than it does males, although researchers are not exactly sure why this is the case. It has been described affecting many different ethnic groups. The exact incidence or prevalence of the disorder is unknown. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population.
A diagnosis of PHACE syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. There are consensus-based diagnostic criteria that have been established by medical experts for PHACE syndrome. These were first published in 2009 (Garzon et al.) and updated in 2016 (Metry et al.). These diagnostic guidelines break down the symptoms of PHACE syndrome into major and minor criteria. A diagnosis is based on the presence of a hemangioma of the head or scalp that is greater than 5 centimeters in diameter (about 2 inches) that occurs along with one major or two minor criteria or the presence of a hemangioma of the neck, upper trunk or trunk and proximal upper extremity plus two major criteria.
Clinical Testing and Workup
Affected individuals will also undergo periodic screening to detect potential signs and symptoms associated with this disorder. However, medical institutions and physicians may differ on how often screening tests are necessary.
Specialized imaging techniques may be used to screen for potential signs associated with the disorder. These tests include magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and echocardiogram. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An MRI of the head and neck region can detect structural abnormalities of the brain associated with PHACE syndrome. An MRA uses the same equipment used for an MRI in order to evaluate the health and function of blood vessels. In some instances, before the scan, an intravenous line is inserted into a vein to release a special dye (contrast). This contrast highlights the blood vessels, thereby enhancing the results of the scan. An echocardiogram is a test that uses reflected sound waves to create images of the heart, and can reveal structural heart defects associated with the disorder.
An eye doctor will conduct a thorough, extensive eye examination to look for eye abnormalities that may be associated with PHACE syndrome.
Treatment
The treatment of PHACE syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians; specialists in diagnosing and treating skin disorders (dermatologists); specialists in diagnosing and treating eye disorders (ophthalmologists); specialists in diagnosing and treating heart or blood vessel disorders in children (pediatric cardiologists); specialists in diagnosing and treating disorders of the endocrine system (endocrinologists); specialists in diagnosing and treating disorders of the brain and central nervous system (neurologists and neurosurgeons); specialists in diagnosing and treating disorders of the ear, nose, and throat (otolaryngologists); dental specialists; speech pathologists; psychiatrists; and other healthcare professionals may need to systematically and comprehensively plan an affected childโs treatment. Psychosocial support for the entire family is essential as well.
Genetic counseling is recommended for affected individuals and their families.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disorder, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with PHACE syndrome.
Surgery may be necessary to treat some of the complications of PHACE syndrome including hemangiomas, certain heart defects, and blood vessel abnormalities. Hearing aids or restorative hearing surgery may be necessary to treat hearing loss.
In 2014, the U.S. Food and Drug Administration (FDA) approved the drug propranolol for the treatment of infantile hemangiomas. However, its use in infants or children with PHACE syndrome is controversial. The use of propranolol in individuals with heart or blood vessel problems requires caution because of the risk of stroke. Sometimes, physicians recommend the use of the drug in PHACE syndrome with hemangiomas that threaten function or other serious complications. There are case reports of safe and effective use of propranolol in individuals with PHACE syndrome.
Propranolol is a type of medication called a beta blocker. There are reports of topical beta blocker solutions such as topical timolol being used to treat superficial hemangiomas in some affected individuals. More research is necessary to determine the long-term safety and effectiveness of medications like propranolol for the treatment of PHACE syndrome.
Daily aspirin may be recommended for children at risk of stroke. Headaches are treated with pain medications. If these medications are ineffective, then a thorough evaluation for an underlying cause of the headaches such as disease of the blood vessels or lack of blood flow (ischemia) to the brain should be done.
Growth hormone supplementation has been used to treat individuals who exhibit growth deficiency due to endocrine abnormalities.
The Childrenโs Hospital of Wisconsin maintains a research registry for PHACE syndrome. A registry is a special database that contains information about individuals with a specific disorder or group of conditions. The collection of data about rare disorders may enable researchers to increase the understanding of such disorders, expand the search for treatments, and accelerate clinical trials for specific treatment options. For more information, visit: https://www.chw.org/medical-care/birthmarks-and-vascular-anomalies-center/conditions/phace-syndrome/phace-syndrome-registry
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Disse SC, Zemlin M, Mueller C, Meyer S. PHACE syndrome โ before and after propranolol therapy. J Pediatr. 2018;193:275. https://www.ncbi.nlm.nih.gov/pubmed/29221694
Wan J, Steiner J, Baselga E, et al. Prenatal risk factors for PHACE syndrome: a study using the PHACE Syndrome International Clinical Registry and Genetic Repository. J Pediatr. 2017;190:275-279. https://www.ncbi.nlm.nih.gov/pubmed/28867065
Tortora D, Severino M, Accogli A, et al. Moyamoya vasculopathy in PHACE syndrome: six new cases and review of the literature. World Neurosurg. 2017;108:291-302. https://www.ncbi.nlm.nih.gov/pubmed/28887276
Bangiyev JN, Gurgel R, Vanderhooft SL, Grimmer JF. Reversible profound sensorineural hearing loss due to propranolol sensitive hemangioma in an infant with PHACE syndrome. Int J Pediatr Otorhinolaryngol. 2017;103:55-57. https://www.ncbi.nlm.nih.gov/pubmed/29224766
Garzon MC, Epstein LG, Heyer GL, et al. PHACE syndrome: consensus-derived diagnosis and care recommendations. J Pediatr. 2016;178-24-33. https://www.ncbi.nlm.nih.gov/pubmed/27659028
Metry D, Heyer G, Hess C, et al. Consensus statement on diagnostic criteria for PHACE syndrome. Pediatrics. 2009;124:1447-1456. https://www.ncbi.nlm.nih.gov/pubmed/19858157
Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol. 1996;132:307-311. https://www.ncbi.nlm.nih.gov/pubmed/8607636
INTERNET
Siegel DH. PHACE syndrome. UpToDate, Inc. 2017 Jun 19 Available at: https://www.uptodate.com/contents/phace-syndrome Accessed February 28, 2018.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:606519; Last Update:02/09/2015. Available at: https://omim.org/entry/606519 Accessed February 28, 2018.
Alvarez H, Lasjaunias P. PHACE Syndrome. Orphanet Encyclopedia, March 2007. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=42775 Accessed February 28, 2018.
PDQ Pediatric Treatment Editorial Board. Childhood Vascular Tumors Treatment (PDQยฎ). PDQ Cancer Information Summaries [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK343452/ Updated January 26, 2018. Accessed February 28, 2018.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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