PHACE syndrome

INTRODUCTION — PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies) syndrome is an uncommon disorder of unknown etiology characterized by large segmental hemangiomas of the face and various developmental defects. The term "PHACE(S)" is sometimes used in the presence of ventral developmental defects, which include sternal cleft, supraumbilical raphe, or both. Since the original description in 1996 [1], significant advances have been made in refining the diagnostic criteria, imaging guidelines, and knowledge of associated morbidities and complications [2]. Previous terms for this condition have included "Pascual-Castroviejo syndrome" [3] and "sternal malformation-vascular dysplasia association" [4].

This topic will review the pathogenesis, clinical features, diagnosis, and management of PHACE syndrome. Infantile hemangiomas are discussed separately.

●(See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications".)

●(See "Infantile hemangiomas: Evaluation and diagnosis".)

●(See "Infantile hemangiomas: Management".)

EPIDEMIOLOGY — PHACE syndrome is an uncommon disorder. Its exact incidence and prevalence are unknown. There are over 300 individual case reports and case series published in the literature, and the PHACE Syndrome International Clinical Registry and Genetic Repository has over 270 individuals enrolled [5].

PHACE syndrome has been reported in many ethnic groups, with a predilection for the female sex. In a series of 33 infants with PHACE, 74 percent were White Americans, 14 percent were Hispanic Americans, 4 percent were African Americans, and 4 percent were Asian Americans, with a female-to-male ratio of 5.6:1 [6]. In an analysis of 150 patients with PHACE syndrome from the PHACE Syndrome International Clinical Registry, the female-to-male ratio was 4.2:1 [7].

PATHOGENESIS — The cause of PHACE syndrome is unknown. It is a sporadic condition, and there are no reports of familial occurrence. Some authors have suggested that the cause may be a somatic mosaic mutation in a cell of neural crest origin. The neural crest cells are important in cell migration during embryogenesis and midline structural development of the heart, trunk, and brain. The midline defects of the sternum and brain, as well as the cervical and cerebral arterial anomalies, suggest that pathogenic events or developmental field defects occur between 3 and 12 weeks of gestation, which is the period of early vasculogenesis [8,9]. It is possible that PHACE has a complex pathogenetic mechanism involving gene-environment interactions, in utero hypoxia, or multifactorial causes.

The female predominance has led some authors to hypothesize that PHACE is an X-linked condition with possible male lethality. If this were the case, it would be expected that males have a more severe phenotype. However, in a study comparing 59 males with 213 females with PHACE, male patients did not have a more severe phenotype [10]. The only significant difference between males and females was a slightly higher rate of structural brain anomalies in males.

It has also been hypothesized that some cases of PHACE syndrome are due to X-linked inheritance, but favorable skewing of chromosome X inactivation in the mothers may prevent the development of a severe phenotype. However, the analysis of the X-inactivation patterns of 31 females with PHACE syndrome and their mothers did not reveal a significant pattern of skewed X-chromosome inactivation in the mothers [11].

Likewise, a genome-wide copy number variation analysis in a cohort of 98 individuals with PHACE did not reveal a common deletion or duplication [12].

CLINICAL FEATURES

Infantile hemangiomas — The infantile hemangioma is often the first sign of PHACE. The presence of the hemangioma is the feature that prompts the imaging evaluation of the brain, head and neck arteries, and heart, which identify the features suggestive of the diagnosis (see 'Diagnostic criteria' below and 'Postdiagnosis evaluations and health care maintenance' below). If these studies are completed in a timely manner, the diagnosis can be made in the neonatal period. However, if the diagnosis is not considered and the imaging studies are not done during infancy, there can be a significant delay in diagnosis until adulthood.

At birth, the hemangioma may appear as a bruised or vasoconstricted patch. Over the first couple weeks of life, the hemangioma becomes more apparent. The hemangiomas in PHACE syndrome most commonly have a segmental distribution on the face (picture 1). A mapping study of large facial hemangiomas identified four primary segments involved (figure 1) [13]. These segments were updated in 2021 (figure 2) [14]:

●Frontotemporal, including the lateral forehead, anterior temporal and frontal scalp, and often the ipsilateral eyelid

●Maxillary, including the medial cheek and the ipsilateral upper lip but limited medially by the nasomedial sulcus

●Mandibular, including the preauricular cheek, mandible, chin, and lower lip

●Frontonasal, including medial frontal scalp and bridge, tip, ala, and philtrum of the nose

●C-shaped segment on the posterior auricular scalp

The face and scalp segment update was based on a study of 549 infantile hemangiomas that evaluated the recurrent patterns of infantile hemangiomas on the face and scalp using heat map densitometry [14]. The borders of the frontotemporal (S1) and frontonasal (S4) segments remained unchanged compared with prior reports (figure 2). The preauricular skin was found to segregate with the mandibular (S3) segment, rather than the maxillary (S2) segment. The pattern of segmental infantile hemangioma on the posterior auricular region occurred in a C-shaped pattern. Indeterminant infantile hemangiomas were larger than focal, round infantile hemangiomas, and although they did not involve the entire segment, they were found to respect the borders of the segments in which they were located.

The risk of PHACE syndrome is higher in infants with more than one facial segment involved. In addition, it is now recognized that large segmental hemangiomas on the scalp, trunk, or upper extremity can also be associated with PHACE-related congenital anomalies, even in the absence of a facial hemangioma.

There are reports of cases of PHACE syndrome associated with small facial or orbital hemangiomas [15,16]. These patients are classified as "possible PHACE" (table 1) [2]. Although the management guidelines recommend screening for PHACE in patients with large segmental infantile hemangiomas greater than 5 cm on the face, infantile hemangiomas smaller than 5 cm in high-risk segments may warrant evaluation for associated developmental anomalies. Shared decision making with caregivers is recommended.

Although the hemangiomas are frequently proliferative, a subset of patients will have infantile hemangiomas with minimal or arrested growth, which are thin and telangiectatic [17-19]. These hemangiomas should be distinguished from nascent hemangiomas observed in the first one to two weeks of life, which appear as a pink, flat patch and are often mistaken for a port wine birthmark before the proliferative phase begins (picture 2) [20]. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'Infantile hemangiomas with minimal or arrested growth'.)

Patients with PHACE may also have subglottic airway hemangiomas. These patients are at risk for airway obstruction, a potentially life-threatening complication. The presenting sign may be biphasic stridor or barking cough [21]. Mediastinal hemangiomas may also occur.

Hemangiomas in the auditory canal may cause obstruction and conductive hearing loss. Hemangiomas in the internal auditory canal are generally asymptomatic and often spontaneously involute; they can be detected on magnetic resonance imaging (MRI) of the brain.

Segmental hemangiomas of the small intestine in the region of the superior mesenteric artery may be complicated by gastrointestinal bleeding resulting in severe anemia requiring transfusions [22].

Posterior fossa anomalies — In a study of 59 brain MRIs from individuals with PHACE, 24 (41 percent) revealed structural brain anomalies [23]. The most common structural brain anomaly is unilateral cerebellar hypoplasia, which is generally ipsilateral to the arterial anomalies and hemangioma. Cerebellar hypoplasia has been detected prenatally in some cases during routine fetal ultrasound [24]. Recognition of the association of cerebellar hypoplasia with PHACE can lead to earlier diagnosis and treatment. Other cerebellar anomalies include Dandy-Walker variants and true Dandy-Walker malformation. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Dandy-Walker malformation'.)

Disorders of cortical development are seen less commonly but may include cortical dysplasia, subependymal heterotopia, and polymicrogyria. Hypoplasia of the corpus callosum and septum pellucidum have also been reported. Pituitary abnormalities, such as empty sella turcica, partially empty sella, or ectopic pituitary, are important to note as they may indicate an increased risk for endocrine dysfunction such as growth hormone deficiency [25].

Head and neck arterial anomalies — Congenital abnormalities of the medium-sized arteries of the head and neck are the most frequent extracutaneous anomaly in PHACE, occurring in approximately 40 percent of patients [6,7]. In a study of 70 patients with PHACE, the spectrum of arterial anomalies included dysplasia, narrowing, or aberrant course [23]. Persistent fetal vessels may include the hypoglossal, otic, and/or trigeminal arteries [2]. Rare cases of arteriovenous fistula and arteriovenous malformation of the dura, requiring in some cases embolization, have also been reported [10,26-28]. Cervical arterial dissections have been reported in rare cases in children, adolescents, and adults with PHACE [29,30].

Risk of acute ischemic stroke — Children with PHACE syndrome are at risk for progressive narrowing of the cerebral arteries, which increases the risk for acute ischemic stroke. The most common presenting signs of stroke in these patients are seizures and/or hemiparesis. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Clinical presentation'.)

In a review of 22 children with PHACE syndrome and stroke, the risk was significantly higher in those with narrowing or nonvisualization of two or more major cerebral arteries, with an incomplete circle of Willis being an additional risk factor [31]. Other factors associated with stroke include concurrent infection or prior treatment with oral corticosteroids [32].

Patients with long segment, high-grade stenosis, especially if more than one artery is affected, are at higher risk for the development of pial and meningeal vascular collaterals in a moyamoya-like pattern. These patients are at high risk for stroke. Presenting symptoms include change in neurologic status, twitching, and seizures. Pial synangiosis has been successfully used as the treatment in several cases [33-35]. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis", section on 'Surgical revascularization'.)

Cardiac anomalies, including aortic arch and brachiocephalic anomalies — In a study of 150 patients from the International PHACE Registry, 62 (41 percent) were found to have a cardiac anomaly (defined as intracardiac, aortic arch, or brachiocephalic vessel anomalies) [7]. Nineteen percent had coarctation of the aorta, 21 percent an aberrant subclavian artery, 3 percent a vascular ring, and 13 percent a ventricular septal defect. Of note, 6 percent also had venous anomalies, and 6 percent had other structural heart defects. Tetralogy of Fallot and ectopia cordis have both been reported in association with PHACE syndrome [7,36].

In contrast with the most common coarctation seen in the general population, which is juxtaductal, the characteristic coarctation in PHACE syndrome consists of a long-segment transverse arch narrowing, sometimes with adjacent aneurysmal dilation. Analysis of resected coarctation tissue demonstrates zones of scarring with significant loss of arterial smooth muscle cells and elastic fibers in the intima and media [7].

Additional cardiac anomalies reported include right aortic arch, double aortic arch, and interrupted aortic arch. Aberrant subclavian arteries are frequent in PHACE syndrome. Therefore, caution must be taken when evaluating for coarctation because four-extremity blood pressure assessment for a gradient between the upper and lower extremities may not be valid. In addition, patients may have a vascular ring that can cause swallowing difficulties and often requires surgical intervention.

Ventral midline anomalies — Ventral midline fusion defects associated with PHACE syndrome may include suprasternal skin abnormalities (eg, pits, dimples, papules), sternal pits, sternal clefts, and supraumbilical raphe [17]. In some patients, midline anomalies may present as thyroid aplasia, lingual thyroid, upper lip and nares clefting ipsilateral to the facial hemangioma, and cleft soft palate [37].

Eye anomalies — In a prospective study of PHACE patients, 16 percent were found to have ocular anomalies [38]. Congenital anomalies of the eye can involve the posterior or anterior segment. Posterior segment anomalies are part of the major diagnostic criteria and include persistent fetal vasculature, "morning-glory" disc (image 1), peripapillary staphyloma, and optic nerve hypoplasia. (See "Congenital and acquired abnormalities of the optic nerve".)

Anterior segment anomalies are minor diagnostic criteria and may include coloboma, iris hypoplasia, congenital cataracts, sclerocornea, and iris hypoplasia [39,40]. Congenital third nerve palsy and Horner syndrome have also been reported [17]. Patients with hemangiomas in the frontotemporal and frontonasal segments (figure 1) have the highest risk of ocular anomalies or complications.

Neurodevelopment — In a study of neurodevelopment outcomes in children with PHACE, 25 children underwent a neurodevelopmental evaluation using standardized neurocognitive tests assessing multiple domains and a parent/caregiver-completed standardized questionnaire on emotional and behavioral function [41]. Significant neurodevelopmental deficits were not identified in the group as a whole, but there was a subset of patients with delays in multiple areas. Patients with two or more domain scores at one standard deviation below the test norms had more severe phenotypes, but the highly variable clinical features among patients could not be correlated with developmental outcomes. In this study, one half of the patients were receiving speech therapy.

Speech and language delay and dysphagia — Patients with PHACE syndrome are at risk for speech and language delay, as well as dysphagia or swallowing difficulties. In a retrospective study of a cohort of PHACE syndrome patients, 17 of 34 patients had signs or symptoms of dysphagia or speech or language abnormalities [42]. Speech and language abnormalities most commonly occurred in association with posterior fossa malformations (9 of 16) and with hemangiomas involving the lip or oropharynx (10 of 16). Swallowing difficulties occurred most commonly in patients with a history of cardiac surgery and hemangiomas of the lip or oropharynx. Posterior fossa abnormalities were present in four of nine patients with dysphagia.

Endocrine abnormalities — Patients with PHACE syndrome are at risk for congenital or acquired hypothyroidism. Congenital hypothyroidism, which is usually detected by screening tests at birth, may be due to an absent or poorly developed pituitary gland (central hypothyroidism), congenital absence of the thyroid gland, or lingual ectopic thyroid gland [1,43,44]. Congenital absence of the thyroid gland may be detected with MRI [45]. (See "Clinical features and detection of congenital hypothyroidism".)

Acquired hypothyroidism is generally related to the presence of large hepatic hemangiomas [46]. These tumors contain very high levels of type 3 iodothyronine deiodinase, which catalyzes deiodination of T4 to reverse triiodothyronine (rT3) and triiodothyronine (T3) to diiodothyronine (T2), resulting in low serum T4 and T3 concentrations. Hypopituitarism and growth hormone deficiency is also a concern, especially in the setting of empty or partially empty sella. (See "Causes of hypopituitarism", section on 'Empty sella'.)

Presenting signs are often poor height velocity and short stature in early childhood [25,47]. Growth hormone replacement may be required [48,49]. Hypopituitarism may present in adolescence with hypogonadotropic hypogonadism and late-onset adrenal insufficiency [50]. (See "Clinical manifestations of hypopituitarism" and "Treatment of hypopituitarism".)

Headaches — Children with PHACE syndrome may experience headaches, which have an earlier onset and are more severe and more frequent than in children without PHACE [51]. In one study, the average age of onset of the headaches was 49 months [51]. Migrainous features were frequent, including vomiting, photophobia, and phonophobia.

Any new or severe headache in a child with PHACE warrants a workup for the etiology to rule out progressive cerebral arteriopathy or acute ischemic stroke. Headaches that do not respond to analgesics or are associated with a functional disability are of particular concern. In patients with intermediate or high-risk arterial anomalies, vasoconstrictive medications such as triptans should be avoided (see "Headache in children: Approach to evaluation and general management strategies"). Adults with PHACE have reported migraines mimicking transient ischemic attacks [30].

Dental issues — Dental enamel hypoplasia can be associated with PHACE syndrome. In a study of 18 PHACE patients, 5 of 11 patients with intraoral hemangiomas had dental enamel hypoplasia. The hypoplastic enamel is soft, may be discolored (yellow or brown) or cloudy, and is prone to chipping [52]. None of the patients without intraoral hemangiomas had dental enamel hypoplasia (see "Developmental defects of the teeth", section on 'Enamel defects'). Several cases of dental root abnormalities have been reported [53]. The root abnormalities affected the molars. They were not limited to the areas with the hemangioma. Panoramic dental radiographs are recommended for children with PHACE during transitional dentition to screen for abnormalities of the dental roots.

Hearing loss — Hearing loss associated with PHACE can either be conductive or sensorineural. The hemangioma is most commonly ipsilateral to the side of the hearing loss, involving the S1 and S3 segments, and sometimes also involving S2. In addition, the hemangioma may extend onto the midoccipital scalp. In a series of six patients with PHACE syndrome and hearing loss, four had intracranial hemangiomas involving the auditory structures (Eustachian tube, internal auditory canal), and one had evidence of involvement of cranial nerve VIII within the cerebellopontine angle [22].

DIAGNOSIS

When to suspect PHACE — A clinician should suspect PHACE in any patient with segmental hemangiomas on the face, scalp, or upper chest and arm. The presence of an anomaly in the sternal area (eg, congenital scar, pit or tag, or supraumbilical raphe) should also prompt suspicion. Many adults with PHACE are diagnosed when astute radiologists recognize the classic arterial anomalies on magnetic resonance angiography (MRA) examinations performed for headache, transient ischemic attacks, or acute ischemic stroke. The association of a hemangioma with ocular anomalies or coarctation of the aorta should also raise suspicion.

Screening evaluations — The screening evaluations and additional testing recommended for patients with suspected PHACE are illustrated in the algorithm (algorithm 1).

Physical examination — A full-body skin examination should be performed in infants presenting for evaluation of PHACE. Infantile hemangiomas on the face are present in the majority of patients with PHACE. The presence of additional hemangiomas should be noted. A hemangioma in the lumbosacral area may signify LUMBAR (lower-body hemangioma and other cutaneous defects, urogenital anomalies, ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies, and renal anomalies) syndrome [54]. (See "Infantile hemangiomas: Epidemiology, pathogenesis, clinical features, and complications", section on 'Lumbosacral lesions'.)

Examination of the chest should be performed to evaluate for sternal defects, sternal tags, or pits (algorithm 1). The skin on the abdomen should be examined for the presence of a supraumbilical raphe. Patients should be examined for functional complications related to the hemangioma, such as visual axis obstruction, which could lead to blindness; ulceration of the lip, which may cause feeding difficulties; and airway obstruction.

Patients with subglottic airway hemangiomas may present with biphasic stridor or barking cough [21]. Infants with these symptoms are at risk of airway obstruction and should be promptly referred to pediatric otolaryngology for direct laryngoscopy and bronchoscopy.

Cardiac examination — Cardiac examination should include auscultation for the presence of a murmur. Four extremity blood pressure measurements may not be valid in the setting of coarctation with aberrant subclavian artery. (See "Approach to the infant or child with a cardiac murmur", section on 'Cardiovascular examination'.)

Imaging studies — The following baseline imaging studies should be performed in children suspected to have PHACE syndrome (algorithm 1) [2]:

●Echocardiogram is recommended at baseline to delineate the congenital heart defects. If abnormalities are identified, urgent evaluation by a cardiologist and ongoing imaging based upon findings are necessary (algorithm 1).

●MRI of the head, neck, and aortic arch with and without contrast should be performed as part of the baseline diagnostic evaluation for PHACE. If renal function is normal, gadolinium contrast should be used to assess the extent of the cutaneous hemangioma and to detect subglottic, periorbital, and intracranial hemangioma [2].

●Magnetic resonance angiography (MRA) of the head, neck, and aortic arch should be performed to screen for the common cerebral vascular anomalies. Catheter angiogram should be reserved for cases with severe arterial anomalies that may require surgical intervention.

Diagnostic criteria — Expert consensus-based diagnostic criteria for PHACE syndrome were published in 2009 and updated in 2016 (table 1) [2,17]. The diagnosis can be made based upon the presence of a facial hemangioma greater than 5 cm in diameter plus one major or two minor criteria.

Only a minority of patients have the complete spectrum of features included in the acronym. However, most have more than one extracutaneous finding, and the risk of having multiple extracutaneous findings is greatest in patients with two or more facial segments involved [6].

POSTDIAGNOSIS EVALUATIONS AND HEALTH CARE MAINTENANCE — Additional evaluations and health maintenance recommendations developed based on expert opinion and the consensus guidelines published in 2016 for several age groups, ranging from infancy to adulthood, are summarized in the table (table 2) [2]. However, the primary care provider and local specialists must consider an individualized management for each patient.

Ophthalmologic examination — An eye examination should be done by an ophthalmologist. Ocular complications may be directly related to the hemangioma (visual obstruction, strabismus, astigmatism) or congenital developmental anomalies (glaucoma, cataracts, optic nerve hypoplasia, etc) [55,56]. (See "Vision screening and assessment in infants and children".)

Hearing screening — When a child is diagnosed with PHACE or suspected to have PHACE, the neonatal hearing screening should be reviewed to determine if the child passed. The screening test should be performed if it was not done at birth or repeated if the child failed the newborn screening and in case the child is determined to be at high risk for hearing loss. If abnormal, the child should be referred to an audiologist or ear-nose-throat specialist to discuss intervention. (See "Screening the newborn for hearing loss".)

Endocrine evaluations — Growth charts should be followed closely. Children with poor growth should get further workup, including thyroid studies (thyroid stimulating hormone [TSH], free T4) and evaluation of growth factors (insulin-like growth factor 1 [IGF-1] and insulin-like growth factor binding protein 3 [IGFBP-3]). (See "Diagnostic approach to children and adolescents with short stature", section on 'Features suggesting genetic or endocrine disease'.)

In addition, appropriate laboratory screening should be done for children with any endocrine signs or symptoms. Endocrinology consultation is recommended for children with PHACE who demonstrate pituitary or thyroid dysfunction. MRI should be reviewed for pituitary and thyroid structural anomalies.

Dental examination — Dental examination is recommended by age one year to evaluate for dental enamel hypoplasia, especially if there is a hemangioma inside the mouth (ie, on tongue, gingiva, buccal mucosa, floor of mouth). Patients with dental enamel hypoplasia have an increased risk of dental caries. Panoramic dental radiographs are recommended for children with PHACE during transitional dentition to screen for abnormalities of the dental roots. (See "Developmental defects of the teeth".)

Speech and swallow evaluation — Questions on speech and swallow should be asked to parents/caregivers in order to determine if referral for further evaluation is needed. Higher-risk patients include those with posterior fossa anomalies, history of cardiac surgery, and hemangiomas on the lip or intraoral locations. (See "Evaluation and treatment of speech and language disorders in children".)

Neurodevelopmental screening — If any developmental delays are suspected in a child with PHACE syndrome, they should be referred for neurodevelopmental testing as early as possible so that interventions can be initiated if needed. Many patients with PHACE will require speech, occupational, or physical therapy (table 2). (See "Intellectual disability (ID) in children: Management, outcomes, and prevention".)

DIFFERENTIAL DIAGNOSIS — In the neonatal period, the nascent hemangioma can be mistaken for a port wine birthmark, and therefore, Sturge-Weber syndrome is on the differential at that time. Sturge-Weber syndrome is characterized by capillary venous malformations in the brain presenting with seizures, ocular complications (including glaucoma), and cognitive disabilities. (See "Sturge-Weber syndrome".)

MANAGEMENT — The management and surveillance of patients with of PHACE syndrome should be individualized, based upon the severity of the clinical manifestations, presence of complications, and assessment of the risk associated with arterial anomalies (table 3 and algorithm 1).

Risk stratification — A proposed risk stratification system based upon the risk of progression of arteriopathy and the risk of acute ischemic stroke (AIS), as assessed by magnetic resonance angiogram (MRA), is illustrated in the table (table 3) [2]. Potential interventions are based upon risk groups:

●Low risk – Low-risk arterial anomalies are those that might be seen in the general population and are unlikely to have an impact on clinical outcome. For these arterial anomalies, no specific intervention is needed.

●Intermediate risk – Intermediate-risk arterial anomalies include dysgenesis or narrowing in locations unlikely to have hemodynamic significance. Attention should be paid to the patency of the circle of Willis.

●High risk – High-risk lesions include those that might lead to decreased perfusion and any imaging feature suggestive of ischemia. The management of children in the high-risk group requires a multidisciplinary team, which may include neurologists, neuroradiologists, neurosurgeons, cardiologists, and dermatologists.

Coarctation of the aorta increases the risk of AIS in the setting of high-risk arterial anomalies. In some cases, catheter angiography may be needed to help assess the high-risk arterial anomalies and determine if neurosurgical intervention for revascularization may be needed. Patients with a history of AIS or those who are at high risk for AIS should be referred to a pediatric stroke expert. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis".)

Patients with any structural brain anomalies should be evaluated by a neurologist. Cerebellar anomalies can be associated with speech, swallow, or coordination issues. Disorders of cortical development can be associated with developmental delay or seizures. Neurosurgical consultation is also indicated for patients with Dandy-Walker malformation and those with hydrocephalus. Most cases of unilateral cerebellar hypoplasia do not require any neurosurgical intervention.

Treatment of hemangiomas

Propranolol — Although propranolol, a nonselective beta blocker, is now considered to be first-line therapy for most infantile hemangiomas requiring treatment, systemic beta blockers should be used with caution in PHACE syndrome [57]. Consideration of the cerebrovascular and cardiac anomalies should be taken into account when making treatment decisions. (See "Infantile hemangiomas: Management", section on 'Propranolol'.)

Propranolol guideline overview — It is recommended that infants at risk for PHACE undergo a physical examination, MRI/MRA of the head and neck, and echocardiography prior to initiation of propranolol to evaluate for high-risk, cerebral, arterial anomalies and to rule out aortic arch coarctation. A lower dose (0.5 to 1 mg/kg/day) should be used if possible, and concomitant use of topical timolol should be avoided [58].

It is recommended that MRI and/or MRA of the head and neck and cardiac imaging with echocardiogram or MRA be performed prior to initiation of oral propranolol to evaluate for the presence of cervical and cerebral arteriopathy and/or coarctation of the aorta. A conservative multidisciplinary approach with input from neurologists and cardiologists is advised. However, for patients with life-threatening or function-threatening hemangiomas, such as airway hemangiomas or periocular hemangiomas, experts suggest that treatment with propranolol may be considered and discussed with parents/caregivers before imaging data are available or patients may be admitted to the hospital for urgent imaging and propranolol initiation with monitoring [2].

Recommendations for the use of propranolol in PHACE patients include using the lowest effective dose, titrating the dose up slowly, and dividing the dose three times daily to minimize abrupt blood pressure fluctuations that may increase the risk for stroke [57]. In some high-risk cases, propranolol initiation should be done in the inpatient setting.

Several case reports and case series have described the safe and effective use of oral propranolol in patients with PHACE syndrome:

●A retrospective study reviewed 32 PHACE infants and young children treated with oral propranolol with an average dose of 1.8 mg/kg/day [59]. Generally, the patients tolerated the medication well. Reported complications included mild right-sided hemiparesis in one patient, worsening of ulceration in two patients, and acrocyanosis and small infarcts in the digits in one patient.

●A multicenter, retrospective, cohort study was conducted to determine the incidence of adverse events among 76 patients with PHACE syndrome receiving oral propranolol [58]. The median age at propranolol initiation was 56 days (range 0 to 396 days). There were no reports of serious adverse events, such as stroke, transient ischemic attack, or cardiovascular events. In this study, 12 patients were categorized as having high-risk arterial anomalies, and 30 patients were categorized as having intermediate-risk arterial anomalies. Nonserious adverse events were reported in 29 patients (38.2 percent) and included sleep disturbances, minor gastrointestinal tract symptoms, and respiratory tract symptoms.

Topical beta blockers — Topical beta blockers (timolol 0.5% ophthalmic gel forming solution) may be a therapeutic option in the treatment of superficial hemangiomas in PHACE syndrome. Although the risk of systemic effects appears to be low, systemic absorption has been shown to occur with use of topical timolol for the treatment of infantile hemangiomas [60-62]. Therefore, caution should be used, and a risk-benefit assessment should be considered when determining whether or not to treat a patient with PHACE with a topical beta blocker. (See "Infantile hemangiomas: Management", section on 'Topical beta blockers'.)

Oral corticosteroids — Prior to the introduction of propranolol for the treatment of infantile hemangiomas in 2008, oral corticosteroids were first-line therapy. Oral corticosteroids are used on a very limited basis at this time due to minimal efficacy and higher risk of side effects when compared with propranolol, including possible increased risk of stroke [32].

Prevention of acute ischemic stroke — For children with PHACE who are in the high-risk arterial anomaly group based upon the risk stratification, daily aspirin for prophylaxis against acute ischemic stroke (AIS) can be considered. Consultation with neurology is recommended when determining whether aspirin is indicated. Recommended dosing is 4 to 5 mg/kg/day up to 81 mg daily dose. (See "Ischemic stroke in children: Management and prognosis".)

Treatment of headache — When a patient with PHACE presents with headaches, an evaluation should be performed for secondary causes. This may include vasculopathy and cerebral ischemia. A neurology consult should be obtained for patients with headaches that do not respond to first-line analgesics, those with severe headaches, and those associated with functional impairment. Vasoconstrictive medications such as triptans, dihydroergotamine, and ergotamine tartrate should be avoided in patients with PHACE with arterial anomalies.

Surveillance and treatment of associated morbidities — Patients with PHACE syndrome need ongoing clinical and imaging follow-up. Expert consensus-based recommendations for health surveillance of patients with PHACE syndrome based upon the results of initial screening examinations are illustrated in the algorithm (algorithm 1). The frequency of follow-up visits and imaging surveillance should be established in the individual patient, based upon the presence and severity of associated abnormalities and complications.

Patients should be followed by a dermatologist with experience in the treatment of complicated hemangiomas (see "Infantile hemangiomas: Management", section on 'High-risk and complicated hemangiomas'). Often, the dermatologist continues to follow the patient on an annual basis throughout childhood for health supervision and care coordination.

Other specialists that may continue to be involved include ophthalmologists, endocrinologists, cardiologists, otolaryngologists, neurologists, cardiothoracic surgeons, neurosurgeons, neuroradiologists, plastic surgeons, psychiatrists, speech therapists, occupational therapists, and physical therapists.

Patients with swallowing difficulties and dysphagia due to hemangiomas of the oropharynx or brain abnormalities are at risk for aspiration and pulmonary injury and require prompt evaluation and treatment. (See "Aspiration due to swallowing dysfunction in children".)

Patients with cardiac anomalies should be followed by a cardiologist on an annual basis or more frequently, based upon the severity of the anomalies and clinical symptoms. For nonobstructive arch anomalies, patients should follow up on an annual basis with the cardiologist for examination and repeat echocardiogram. (See "Vascular rings and slings".)

If surgical intervention is needed, further imaging with cardiac MRA may be indicated. Over one-third of patients with PHACE and aortic coarctation require surgical correction. Due to the length of involvement, non-native interposition grafts are often required. (See "Management of coarctation of the aorta".)

In a review of seven patients who underwent surgical correction for coarctation of the aorta, four patients presented with obstruction within the first month of life, and the other three presented for surgery after one year of age due to significant progression of arch obstruction or aneurysmal dilation [63]. The repairs were complex and three patients experienced recurrent arch obstruction. Of note, six of seven patients had an aberrant origin of the subclavian artery that led to the inability to detect a gradient by blood pressure measurements because arteries in all extremities arose distal to the arch obstruction.

Patients with structural brain anomalies and intermediate or severe cerebrovascular anomalies should have annual follow-ups with a neurologist.

PROGNOSIS — Little is known about the long-term sequelae in PHACE syndrome. Only a limited number of adults with PHACE syndrome have been reported in the literature. The oldest patient reported is 59 years old [30]. There are no data on lifespan in PHACE, although it is presumed to be typical unless severe cerebrovascular or cardiac complications occur. Several adult patients reported in the literature were identified after they presented for stroke or transient ischemic attacks. Upon review of the neuroimaging, classic structural brain and cerebrovascular changes of PHACE syndrome were identified [64-67].

In a limited series, three-fourths of adult patients with PHACE who attempted to have children were successful, and none of the offspring had clinical features of PHACE [30].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infantile hemangiomas and PHACE syndrome".)

SUMMARY AND RECOMMENDATIONS

●Definition – PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies) syndrome is an uncommon disorder of unknown etiology characterized by large hemangiomas of the face and various developmental defects. PHACE syndrome is four to six times more common among females than males. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical features – The hemangiomas in PHACE syndrome most commonly have a segmental distribution on the face (figure 2 and picture 1). Associated anomalies include (see 'Clinical features' above):

•Brain structural anomalies, most commonly unilateral cerebellar hypoplasia

•Abnormalities of the medium-sized arteries of the head and neck

•Coarctation or interruption of the aortic arch and aberrant origin of a subclavian artery

•Posterior eye segment anomalies

•Speech/language delay and dysphagia

•Endocrine abnormalities, including congenital or acquired hypothyroidism and hypopituitarism and growth hormone deficiency

●When to suspect PHACE – PHACE should be suspected in any patient with segmental hemangiomas on the face, scalp, or upper chest and arm. (See 'When to suspect PHACE' above.)

●Screening evaluations and diagnosis – The screening evaluations and additional testing recommended for patients with suspected PHACE are illustrated in the algorithm (algorithm 1). Expert consensus-based diagnostic criteria for PHACE syndrome were updated in 2016 (table 1). The diagnosis can be made based upon the presence of a facial hemangioma greater than 5 cm in diameter plus one major or two minor criteria. (See 'Screening evaluations' above and 'Diagnostic criteria' above.)

●Postdiagnosis evaluations – Postdiagnosis evaluations and health care maintenance at different ages may include ophthalmologic examination; hearing screening; and endocrine, speech and swallowing, and neurodevelopmental evaluation (table 2). (See 'Postdiagnosis evaluations and health care maintenance' above.)

●Management – The management of patients with PHACE syndrome should be individualized, based upon the severity of the clinical manifestations, presence of complications, and assessment of the risk associated with arterial anomalies (table 3 and algorithm 1) (see 'Management' above and 'Risk stratification' above):

•Treatment of hemangiomas – Although several reports suggest that propranolol can be safely used for the treatment of hemangiomas in patients with PHACE syndrome, experts recommend that MRI and/or magnetic resonance angiogram (MRA) of the head and neck and cardiac imaging with echocardiogram or MRA be performed prior to treatment initiation to evaluate for the presence of cervical and cerebral arteriopathy and/or coarctation of the aorta. Propranolol should be used at the lowest effective dose and given daily in three divided doses to minimize abrupt blood pressure fluctuations that may increase the risk for stroke. (See 'Treatment of hemangiomas' above.)

•Treatment of associated morbidities – Patients with PHACE syndrome need ongoing follow-up, which may involve a multidisciplinary specialist team including dermatologists, ophthalmologists, endocrinologists, cardiologists, otolaryngologists, neurologists, cardiothoracic surgeons, neurosurgeons, neuroradiologists, plastic surgeons, psychiatrists, speech therapists, occupational therapists, and physical therapists. The frequency of follow-up visits and imaging surveillance should be established in the individual patient, based upon the results of initial screening examinations and the presence and severity of associated abnormalities and complications (algorithm 1). (See 'Surveillance and treatment of associated morbidities' above.)