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For members of the Texas Children's Hospital medical staff
PHACE syndrome: uncommon, but not rare
By Denise W. Metry, M.D.
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Newborn girl with a large, erythematous plaque of the left face, scalp and ear. |
Infantile hemangiomas (IH) are the most common benign tumors of infancy. Known risk factors for their development include female gender, Caucasian ethnicity, low birth weight and multiple gestation. Unique in their behavior, IH classically undergo an initial phase of growth, the majority of which often occurs within the first three to four months of life. This is followed by a period of slow regression, generally over years.(1) While the majority of IH remain uncomplicated and do not need treatment, a substantial minority can be associated with significant complications.
Recently, it has been recognized that complication risk can be correlated with lesion morphology, and that two morphologic types of hemangiomas exist: localized and segmental. Localized IH are by far the most common type, and consist of papules or nodules that appear to arise from a single focal point and demonstrate clear spatial containment. In contrast, segmental IH are plaque-like and show linear and/or geographic "patterning" over the skin (photo). The patterns observed in facial segmental IH do not appear to correspond to facial dermatomes or lines of Blaschko, but do correspond, at least partially, to developmental facial prominences.(2) While segmental IH show no histopathologic differences from localized lesions, they are much more likely to be associated with complications such as ulceration, birth defects and visceral hemangiomas. Segmental IH are also more likely to require more intensive and prolonged therapy, and have a poorer overall outcome.(3)
PHACE syndrome (OMIM #606519) is a neurocutaneous association. The acronym, first proposed in 1996 by Frieden et al, refers to the combination of large, segmental hemangiomas, most commonly located on the face, with one or more of the following congenital anomalies: posterior fossa or other structural brain malformations, arterial anomalies, coarctation of the aorta, cardiac defects, and/or eye abnormalities.(4) The syndrome is sometimes referred to as PHACES when ventral midline defects such as sternal clefting and/or supraumbilical raphe (typically a linear, scar-like lesion that extends upward from the umbilicus) are present. The diagnosis of PHACE requires the presence of a typical segmental, facial IH in association with only one other congenital anomaly, as affected infants rarely present with the complete spectrum.(5)
PHACE vs. Sturge-Weber
PHACE is uncommon, but not rare. It is now recognized that PHACE is probably even more common than Sturge-Weber syndrome, a disorder with which PHACE is sometimes confused. However, the vascular birthmark associated with Sturge-Weber syndrome is a port-wine stain which, unlike IH, is a capillary-like vascular malformation that is fully present at birth, shows no signs of proliferation during infancy, undergoes minimal (if any) expansion over time, and does not regress. Recent studies estimate that PHACE probably represents about 2-3 percent of patients with IH overall, and at least 20 percent of patients with segmental IH of the face. Notably, however, these numbers, as well as the incidence of reported PHACE anomalies (Table), are very likely underestimated since the vast majority of at-risk patients with segmental facial IH have not undergone complete evaluations.(6)
The list of PHACE anomalies continues to expand as the spectrum becomes more fully defined (Table). Structural and vascular anomalies of the brain are the most common features, followed by cardiovascular anomalies, ventral developmental defects, and ocular anomalies. Due to the potential for acute and chronic neurologic sequelae, brain anomalies are not only the most common association, but also the most potentially worrisome. Developmental delays (motor > language) can result from structural brain anomalies, possibly as a result of cerebellar defects. Cerebrovascular anomalies are also of concern because of known progressive vasculopathies that can occur within such anomalies, which can lead to seizures and/or acute arterial ischemic stroke (AIS), generally during infancy.(6) In fact, though the mechanism is unknown, it is now believed that PHACE may represent an under-recognized cause of pediatric AIS, which is overall a relatively rare event.(7)
Serial neuroimaging during infancy should be considered in PHACE patients with significant cerebrovascular anomalies (particularly those of the carotid artery), with the reasoning that if progressive cerebrovascular changes were identified early, neurosurgical revascularization procedures could be performed to potentially reduce AIS-related morbidity and mortality. In addition to cerebrovascular anomalies, a number of especially unique and complex aortic anomalies have been described in association with PHACE, and though the potential for progressive changes within these anomalies is also of concern, the real risk is not currently known. Of note, in addition to progressive vascular changes in PHACE, cases of regressive phenomena (normalization) of such anomalies have also been reported.(6)
IH connection
A correlation appears to exist between IH located over the upper half of the face ("fronto-temporal" and/or "frontonasal" distribution) and the presence of structural brain, cerebrovascular, and ocular anomalies. In contrast, a correlation also exists between ventral developmental defects (sternal defects and/or supraumbilical raphe) and IH located over the lower half of the face ("mandibular" distribution). Since such correlations are not absolute, with clear exceptions reported, it is currently recommended that all patients with segmental facial IH undergo complete evaluation for all potential anomalies, including MRI and MRA imaging of the head and neck vasculature, echocardiogram or MRI/MRA imaging of the cardiovasculature, and a formal ophthalmologic examination.(6) Prospective studies are currently ongoing in an effort to help further define the true scope of disease and correlate IH anatomic location with disease burden.
The pathogenesis of PHACE is poorly understood. In contrast to IH overall, the syndrome is even more common among female infants, with a nearly 90 percent female incidence, and tends to occur in term, singleton pregnancies of normal birth weight. A recent study of infant and maternal demographic features found no common factors that might suggest an environmental or other influence.(6) The spectrum of anomalies in PHACE, and general ipsilateral relationship between such anomalies and the cutaneous IH, strongly suggests a "developmental field defect," as proposed by Opitz et al, whereby an insult at a critical time in embryogenesis gives rise to similar developmental outcomes. The precise timing of such an insult in PHACE is speculative, but both the anatomic IH patterns corresponding to developmental prominences, and several of the associated structural abnormalities, points to timing early during the first trimester, probably within the first three to 12 weeks of gestation prior to or during early vasculogenesis.(5) Because PHACE has a reproducible pattern of structural and functional anomalies, it likely has a genetic basis. Based on recent findings that multi-organ syndromes are caused by micro deletions, it is hypothesized that PHACE may result from a very small (submicroscopic) copy number aberration, and molecular genetic studies for this are currently in progress. The marked female predominance is also of interest, suggesting the possibility of X-linked inheritance with lethality in males.(6) However, no vertical transmission has been reported, no chromosomal abnormalities have been detected in 15 cases studied, and males with PHACE do not appear to manifest a significantly more severe phenotype.(8)
Although IH undoubtedly are birthmarks, and as such represent "birth defects," their lack of presence at birth has resulted in omission from study in formal birth defect registries and other birth defect research, where ascertainment generally occurs in the newborn nursery. As a result, IH research has lagged behind many other, much less common, tumors. Further understanding of PHACE will best be served by collaborative research efforts between related clinical subspecialties such as dermatology, genetics, cardiology, neurology, and developmental biology. I recently established the first PHACE Patient Registry to provide a much-needed resource in this regard.
Denise W. Metry, M.D. is associate professor of Dermatology and Pediatrics at Texas Children's Hospital and Baylor College of Medicine. She holds specialty hemangioma clinics several times monthly in the Clinical Care Center. In addition to the PHACE Registry, she is actively recruiting patients for prospective studies involving three "high-risk" hemangioma groups: 1) large, segmental facial, 2) multiple (>5) and 3) lumbosacral.
Table. Type and Approximate Incidence of Reported Anomalies in PHACE Syndrome
Category of
Anomaly |
Approximate
Incidence |
Specific Defects Reported |
Structural Brain |
45% |
Posterior fossa
Hypoplasia or agenesis of
Cerebrum Corpus callosum Septum pellucidum
Subependymal and arachnoid cysts Frontal lobe calcifications Absent foramen lacerum Polymicrogyria Microcephaly
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Cerebrovascular |
38% |
Carotid arterial anomalies
Primary anomalies:
Secondary phenomena:
Persistent embryonic arteries (e.g. trigeminal, carotid-vertebrobasilar anastomoses)
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Cardiovascular |
25% |
Aortic Coarctation Aneurysms of the ascending aorta, aortic arch, subclavian or innominate arteries Right, left, double, interrupted aortic arch Congenital valvular aortic stenosis Dextroposition of the aorta Anomalous coronary arteries Ventral & atrial septal defects Patent ductus arteriosus Pulmonary stenosis Anomalous pulmonary veins Other: patent foramen ovale, cor triatriatum, tetralogy of Fallot, tricuspid atresia/stenosis, dextrocardia, persistent left superior vena cava
|
Ocular |
12% |
Microphthalmos Retinal vascular abnormality Persistent fetal retinal vessels Optic atrophy Iris vessel hypertrophy Iris hypoplasia Optic nerve hypoplasia Congenital cataracts Sclerocornea Lens coloboma Exophthalmus Congenital 3rd nerve palsy Excavated optic disc anomalies
Lens coloboma "Morning-glory" Peripapillary staphyloma
Horner syndrome
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Ventral Developmental |
25% |
Sternal defects
Supraumbilical raphe Omphalocele
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Miscellaneous |
Few reports |
Micrognathia Auricular hypoplasia or agenesis/ "low-set" ears Orofacial clefting Endocrine: absent pituitary or partially empty sella turcica, lingual ectopic thyroid
Other: spina bifida occulta, widely-spaced nipples, polydactyly, esophageal diverticulum, cervical cyst, inguinal and umbilical herniae
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References:
Haggstrom A, Drolet B, Baselga E, et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics. Pediatrics. 2006;118(3):882-887. Haggstrom AN, Lammer EJ, Schneider RA, et al. Patterns of infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Pediatrics. 2006;117(3):698-703. Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol. 2002;138(12):1567-1576. 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(3):307-311. Metry DW, Dowd CF, Barkovich AJ, et al. The many faces of PHACE syndrome. J Pediatr. 2001;139(1):117-123. Metry DW, Haggstrom AN, Drolet BA, et al. A prospective study of PHACE syndrome in infantile hemangiomas: Demographic features, clinical findings, and complications. Am J Med Genet A. 2006;140(9):975-986. Drolet BA, Dohil M, Golomb MR, et al. Early stroke and cerebral vasculopathy in children with facial hemangiomas and PHACE association. Pediatrics. 2006;117(3):959-964. Metry DW, Siegel DH, Cordisco MR, et al. A comparison of disease severity among affected males versus females with PHACE syndrome (in press).
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