Dermatology

PHACES Syndrome

PHACE syndrome (ICD-9 228.01, 228.02, 759.7)

Are You Confident of the Diagnosis?

Infantile hemangiomas (IH) are the most common benign tumors of childhood. Most are localized, discrete, tumor-like lesions with a relatively low risk of associated complications. Less commonly, IH are of “segmental” morphology. Segmental IH are generally larger and involve characteristic, patterned regions or territories that are further discussed below. Many, but not all, have a more plaque-like morphology.

Segmental IH are important to recognize because they have a much higher risk of complications and more often require treatment. Segmental IH are associated with poorer outcomes and can be an important clue to associated extracutaneous findings. PHACE syndrome describes a constellation of systemic abnormalities that can occur in conjunction with a segmental IH.

The PHACE acronym refers to the association of:

Posterior fossa anomalies- Includes Dandy-Walker malformation, cerebellar hypoplasia or agenesis as well as other central nervous system (CNS) abnormalities

Hemangiomas- segmental facial

Arterial cerebrovascular anomalies- agenesis, aneurysms, occlusion or anomalies of arteries or persistence of fetal circulation

Cardiac abnormalities and Coarctation of the Aorta- structural heart defects and/or coarctation, aneurysm or aberrant anatomy of the aorta or the vessels that arise from the aorta

Eye abnormalities- persistent fetal vasculature and morning glory disc anomalies, microphthalmia, optic nerve hypoplasia and other ocular abnormalities

This is not an all-inclusive list. Recently, a review detailed findings in each of the above categories that can be associated with PHACE and defined consensus criteria to diagnose PHACE syndrome.

PHACE syndrome should be suspected clinically whenever a newborn exhibits a segmental hemangioma greater than 5 cm of the face and/or scalp. Subtle skin changes involving the skin overlying the sternum ( Figure 1) or above the umbilicus can also be a clue to PHACE syndrome. These include linear scars, clefts, pits, dimples, or papules.

Figure 1.

Sternal cleft with associated hemangioma.

Recent research has revealed that the risk for PHACE in the context of a segmental hemangioma (Figure 2) can vary based on which segment is involved. There are four defined segments on the face within which segmental hemangiomas may occur (Figure 3). The hemangioma need not cover the entire segment to be considered segmental. Often, patches or papules scattered or within a segment can be indicative of a segmental presentation and hemangiomas may also involve multiple contiguous or non-contiguous areas within the “territory” of that segment.

Figure 2.

Segmental Hemangioma

Figure 3.

The territories of segmental hemangiomas.

In a review of 108 patients with large facial hemangiomas (images from Haggstrom with permission), it was found that the highest risk for PHACE syndrome seems to be in patients who have hemangiomas involving the S1 and S3 segments. S4 segmental involvement also confers risk but PHACE rarely occurs with solely S4 presentations without S1 or S3 involvement. Isolated S2 involvement seems to have a lower risk of PHACE as well.

The site of involvement also has implications for which associated internal abnormalities may be present. S1 is probably most predictive of cerebrovascular and ocular abnormalities, while S3 seems to predict cardiovascular abnormalities and ventral developmental defects of the skin but also often has associated cerebrovascular disease. The number of segments involved also confers risk for PHACE. In Haggstrom et al.’s cohort, the probability of PHACE syndrome was significantly higher in patients with hemangioma involving more than one segment and with larger surface area involvement (Figure 4).

Figure 4.

Multiple segment involvement, bilateral involvement and large surface area of hemangioma.

Very early in infancy, it is not unusual for segmental hemangiomas to closely mimic port wine stains (Figure 5). Evidence of segmental hemangiomas is often present at birth as an area of telangiectasia, a bruise-like area, or a visible vascular stain. We are often asked to evaluate a newborn for Sturge-Weber syndrome (SWS), when the infant actually has PHACE It is likely that many cases of PHACE were misdiagnosed as SWS prior to its description in the literature in the mid 1990s.

Figure 5.

Segmental hemangioma mimicking port wine stain.

Clues to the presence of a hemangioma include reticular telangiectasia within the stain, a blanch at the periphery of the lesion and ulceration. Port wine stains do not normally ulcerate, while segmental hemangiomas certainly can. The course and natural history of the lesion is also helpful in differentiating the two entities. Port wine stains do not really proliferate or thicken early on in life, while segmental hemangiomas often follow the usual course of a hemangioma— proliferating and thickening early in the neonatal period and plateauing in growth at 5-7 months.

Proliferation is not essential to the diagnosis of hemangioma, however. It is not unusual for the segmental hemangiomas in PHACE to be “infantile hemangiomas with minimal or arrested growth,” as infantile hemangiomas with a proliferative component equaling less than 25% of their total surface area.

A complete evaluation for PHACE involves the following diagnostic investigations and clinical consultations.

Magnetic resonance imaging (MRI) (ideally with and without contrast) and magnetic resonance arteriography (MRA) of the head and neck

When investigating for PHACE it is important to recognize that neurologic signs and symptoms are often not present in patients with PHACE syndrome during infancy. Therefore, screening for congenital lesions by MRI with MRA should not be based on the presence or absence of abnormal neurologic examination. Rather, imaging should be considered in any at-risk patient (ie, with a segmental hemangioma of the face over 5 cm).

Recommended minimal neuroimaging for infants at risk for PHACE to define both structural brain abnormalities and intracranial/cervical vascular abnormalities are listed in Table 4 of the consensus criteria paper by Metry et al.

If abnormalities in brain structure or circulation are found, obtain neurology consultation to establish baseline neurologic exam and up on follow the patient’s neurologic exam. Even in the absence of gross abnormalities on imaging, every patient who meets PHACE criteria should have baseline neurologic evaluation and follow up if there are abnormal findings.

Evaluate for aortic arch and cardiac abnormalities. MRA may define the anatomy of the great veins and vascular anatomy better than echocardiogram. The pediatric cardiology consultants should determine whether to do echocardiogram, MRA of the chest, or both. Also, their opinion should be solicited prior the MRI/MRA of the neck and head, so that the chest MRA can be done (if desired) concurrently to avoid multiple exposures to general anesthesia.

Ophthalmology consult to examine the eyes for PHACE-associated abnormalities (particularly retinal vessel abnormalities)

Thyroid function tests to screen for PHACE or primary hemangioma associated endocrinopathy

Full-body skin exam to evaluate for subtle midline raphe, dimples or other cutaneous stigmata of PHACE and make sure there are no other hemangiomas or cutaneous anomalies (Figure 6).

Figure 6.

Subtle sternal cleft.

It is also important to remember (as discussed below) that segmental hemangiomas presenting in other areas besides the head and neck may have associated abnormalities as well. Regional associations of segmental hemangiomas and structural anomalies are well recognized when involving the face and lumbosacral skin (so-called LUMBAR, SACRAL, or PELVIS syndrome), but similar associations may occur in other sites. This patient with a segmental hemangioma of the back manifested cardiac and aortic arch anomalies (Figure 7).

Figure 7.

Truncal Segmental hemangioma is a clue to PHACE-Related cardiac anomalies or visceral hemangiomas.

Segmental hemangiomas (both in and outside the setting of PHACE) of the face, head, neck, lumbosacral or other areas can be associated with visceral hemangiomas, which are not necessarily contiguous with the cutaneous hemangiomas. The visceral hemangiomas are often in the general anatomic area of the skin segmental hemangioma, but not always. The most common sites of visceral hemangiomas in this setting include the liver, gastrointestinal tract, intracranial (often adjacent to cranial nerves), and mediastinum. Other sites such as the pancreas, spleen, lung, and kidney are very rarely involved.

An index of suspicion for extracutaneous hemangiomas is important as the morbidity and mortality associated with visceral hemangiomas is relatively high. For example, this child with a segmental hemangioma of the upper chest, back, and arm manifested a right-sided aortic arch, subclavian artery anomalies and airway involvement. She also had liver hemangiomas and intestinal hemangiomas, which resulted in gastrointestinal bleeding (Figure 8, Figure 9).

Figure 8.

Segmental hemangioma on trunk as a marker for visceral hemangiomas in the gut.

Figure 9.

Intestinal hemangiomas associated with a segmental hemangioma of the trunk.

The association of segmental hemangiomas and visceral hemangiomatosis is distinct from PHACE and also differs from the extracutaneous hemangiomas seen in patients with multifocal cutaneous hemangiomas. These patients – who have five or more localized hemangiomas– may have visceral hemangiomas, most commonly found in the liver.

Who is at Risk for Developing this Disease?

PHACE, while uncommon, is not rare and may actually be more common than the much more widely known neurocutaneous syndrome, Sturge-Weber syndrome. A prospective study of infants with segmental hemangiomas of the face with an area greater then 22 cm squared found an incidence of 31% of PHACE in these patients.

There is a marked female predominance. While hemangiomas in general manifest a 2-3:1 female predominance, every cohort of PHACE patients to date has revealed over 75% of cases occurring in females. Apart from female predominance, there are no other factors which suggest X-linked dominant inheritance. The severity of disease does not seem to be significantly greater in male patients with PHACE.

Mothers of affected infants do not have stigmata of PHACE themselves nor have they been found to have an increase in prior miscarriages, preeclampsia or perinatal risk factors suggestive of an environmental influence. One prospective study did show a trend for PHACE patients to be born to slightly older mothers and to be of slightly higher gestational age. Unlike hemangiomas overall, PHACE does not seem to be increased with premature birth or twin or multiple gestation.

What is the Cause of the Disease?

The pathogenesis of PHACE is unknown. Chromosome analysis of 15 cases revealed a normal karyotype in one cohort. No clues have been found to implicate a genetic cause of PHACE. Some have postulated an X-linked dominant gene mosaicism with male lethality to explain the marked female predominance but this hypothesis has not been confirmed.

Because of the tendency for hemangiomas and vascular or structural malformations to co-localize to ipsilateral sites, it has been hypothesized that PHACE is the result of either somatic mosaicism or a so-called “developmental field defect”. The structural abnormalities found in PHACE point to a developmental error occurring between 4 and 8 weeks of gestational age – a key developmental period for the aortic arch, sternal area and facial segments.

Systemic Implications and Complications

Systemic issues associated with PHACE in descending order of incidence include:

Cerebrovascular anamolies

Arterial anomalies of the head and neck are the most common extracutaneous manifestations of PHACE. In patients with cerebrovascular disease, dysplasia is the most common abnormality and includes ectasia, looping, kinking, or fusiform dilation of vessels. Narrowing or occlusion, which includes developmental hypoplasia or agenesis and acquired stenosis or occlusion are the next most common findings, followed by anomalous course and/or origin. Primitive embryonic carotid-vertebrobasilar connections are present in approximately 20% of children with CNS arteriopathy. Cutaneous hemangiomas are almost always ipsilateral to arterial abnormalities.

Many children with cerebrovasular anomalies (Figure 10) are asymptomatic but some do have neurologic abnormalities even in the absence of structural brain abnormalities including hypotonia, delayed motor milestones, developmental delay, seizures and severe, early-onset headaches. A few cases of cerebrovascular anomalies leading to acquired, progressive vessel stenosis and acute ischemic events have been reported. Progression of vasculopathy characterized by corkscrew-like kinking, tortuosity, stenosis and/or occlusion as well as extensive collateral vessel formation (moyamoya-like phenomenon) has been reported. The greatest risk for acute ischemic stroke seems to be during infancy, generally between birth and 18 months, but the potential for later ischemic events, while not well studied, may be present in a minority of patients.

Figure 10.

Cerebrovascular anomalies are severe in this PHACE patient.

Aortic and cardiac anomalies

Coarctation of the aorta is the most common cardiac finding reported. This arch abnormality is critical to recognize because it can be life-threatening. The coarcation in PHACE usually involves the transverse aorta, often occurring with long-segment hypoplasia. In some cases there is not definitive coarctation but rather an irregular contour or unusual dilation without proximal narrowing.

There also can be abnormalities of the brachiocephalic vessels and in some cases the aortic arch is right, rather than left-sided. This is in contrast to coarcts in patients without PHACE, which usually involve the descending thoracic aorta without brachiocephalic abnormalities. In PHACE patients with coarctation and brachiocephalic disease, the classical diagnostic assessment of coarctation by blood pressure difference between the arms and legs is an unreliable indicator of the presence or absence of aortic arch coarction.

The incidence of ventricular septal defect in PHACE syndrome is significantly higher than that anticipated in the general population. While there are multiple other cardiac defects that have been reported in association with PHACE, it is difficult to determine if they are PHACE-specific or related due to their high background prevalence in the population. A full description of PHACE associated cardiac anomalies that are likely PHACE specific are outlined in the new consensus criteria offered by Metry et al.

Structural brain anamolies

Structural brain anomalies (Figure 11) are another important manifestation of PHACE. Cerebellar hypoplasia or complex dysplasias of the cerebellum such as Dandy-Walker malformations are the most common. These abnormalities, of course, have implications for neuromotor development, but delayed motor milestones can be present even without obvious cerebellar abnormalities.

Figure 11.

Structural malformations of the brain.

Dysplasias of the cerebral cortex are a less commonly observed feature of PHACE, including focal pachygyria, polymicrogyria, thickening of the cerebral cortex, cerebral volume loss or heterotopic gray matter. These lesions always occur ipsilateral to the facial hemangioma and are evident on MRI. Abnormalities of the optic disc or nerve abnormalities together with pituitary abnormalities or absent sella turcica have been reported. Developmental anomalies of the pituitary and related structures can result in multiple endocrinopathies, including hypopituitarism, hypothyroidism, growth hormone deficiency and diabetes insipidus.

Patients with PHACE and retinal abnormalities should be watched closely for clinical signs of endocrinopathy. Rarely, temperature instability, apnea, tremor, opisthotonus and, in later years, migraine headaches have been reported to be associated with PHACE. It is unclear what exact structural or cerebrovascular defects underlie each of these neurologic manifestations.

Another frequent finding is intracranial hemangiomas; these are usually asymptomatic, and noted as an incidental findings on MRI. However, we have observed cases of these causing cranial nerve palsies. The hemangiomas are often found ipsilateral to the cutaneous segmental hemangioma, tracking with cranial nerves. Intracranial hemangiomas seem to occur with greater frequency in patients with PHACE than in at-risk infants without CNS evidence of PHACE.

Segmental cutaneous hemangioma

Morbidity due to the cutaneous hemangiomas themselves can also occur within the context of PHACE syndrome. The large, segmental hemangiomas that define this syndrome are known to be inherently more likely to result in complications (Figure 12). Even controlling for size, segmental hemangiomas are eight times more likely to require treatment and eleven times more likely to cause complications then localized hemangiomas.

Figure 12.

Segmental hemangioma.

Ulceration in the large segmental hemangiomas of PHACE can have dramatic consequences. The helix of the ear, nasal septum and upper and lower lips are all particularly susceptible to severe ulceration and even necrosis (Figure 13). Once ulceration begins it can be difficult to halt. Wound care is important to avoid infection and try to limit the extent of ulcer progression and is discussed below.

Figure 13.

Ulceration of ear.

Other complications include bleeding, airway compromise, visual obstruction, facial disfigurement and auditory canal obstruction. In very large hemangiomas, cardiac complications can rarely be present secondary to shunting of large volumes of blood through the hemangioma. The guiding principles to management of hemangioma-related morbidity in PHACE are similar to that of the management of infantile hemangiomas in general; however, clinical decisions can be quite complicated because of the systemic issues related to PHACE.

As discussed below, propranolol should probably be used sparingly or with great caution in patients with PHACE and significant neurovascular disease since, at least theoretically, lowering of systemic blood pressure could precipitate CNS ischemia in patients with CNS arteriopathy and inadequate collateral circulation. The management of cutaneous hemangiomas is discussed in greater depth in the CDS chapter dedicated specifically to infantile hemangioma. Additional PHACE specific concerns are discussed below as well.

Ocular abnormalities

Ocular abnormalities are present in up to one-third of patients. The most specific to PHACE syndrome include persistent fetal vasculature, and morning glory disc anomalies, microphthalmia, optic nerve hypoplasia, glaucoma, increased retinal vascularity, Horner’s syndrome, corneal opacity, sclerocornea, cataracts, choroidal hemangiomas, colobomas, cryptophthalmus, exophthalmus and strabismus have also been reported.

If periocular hemangiomas are present, patients can have an independent risk of stimulus-deprivation related amblyopia related to the obstructive or effects of the hemangioma on the visual axis. Nystagmus can be a clue to amblyopia in infants. Astigmatism can occur as well as a result of distorting effects of pressure from the hemangioma on the globe.

Other

Central hyperthyroidism has been rarely been reported in association with large facial hemangioma and is discussed below in “Unusual clinical scenarios patient management”. This may be similar to cases of pituitary dysfunction reported in PHACE and related to problems with midline development. This is different than the acquired “peripheral” hypothyroidism secondary to enzymatic destruction of free thyroid hormone by the type 3 iodothyronine deiodinase located in the endothelium of large or multiple hemangiomas.

Hearing loss can also be associated with PHACE due to a variety of mechanisms, including direct occlusion by hemangiomas causing conductive hearing loss. Intracranial infantile hemangiomas may also contribute to this phenomenon due to their propensity for the internal auditory canal and cerebellopontine angle ipsilateral to the facial hemangioma. Sensorineural hearing loss has also been observed.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Treatment options for PHACES syndrome
Medical Management Surgical Interventions Physical Modalities
Propranalol, prednisolone or other systemic agents to treat the hemangioma if necessary Surgical Correction of aorta if necessary Laser treatment of airway hemangiomas or ulcerated hemangiomas if present
Topical therapy for ulcerations: metrogel, lidocaine, becaplermin gel, vaseline, etc. Tracheostomy if necessary for airway hemangioma  
 Psychologic counseling and support for family    
Developmental evaluation and treatment as necessary    
     

Optimal Therapeutic Approach for this Disease

Due to the multiple organs potentially affected, the management of PHACE requires multidisciplinary care. Close communication among specialties is key to coordinating therapies so that interventions are timed and chosen to achieve maximal benefit with minimal side effects.

For instance, if aortic coarctation is a significant issue, this often takes priority over other issues in management. Surgical interventions such as grafts, extended resections with end-to-end anastamosis and angioplasty may be needed. Thus, close coordination with pediatric cardiology is vital.

Neurovascular disease, even if present, does not necessarily imply that there will be profound neurological deficits. However its presence, at the very least, mandates thorough neurological assessment and close follow-up of developmental milestones. Infants with PHACE showing developmental lags are often referred for early intervention eg, physical, occupational or speech therapy.

The management of neurovascular disease depends on the severity of disease. As mentioned, MRA is generally the study of choice for evaluating CNS vascular anomalies. CT angiogram may be helpful but the radiation dose to the developing brain makes this a less ideal option. The need for repeat MRA and the timing for this depend on the degree of vascular abnormalities. In rare instances, if progressive ischemic disease ensues, neurosurgical revascularization procedures such as pial synangiosis can be considered.

The decision to use medical treatments to prevent stroke should be made by a neurologist rather than a dermatologist. In some cases, PHACE patients who have had an acute ischemic event are treated with antithrombotic therapy with agents such as aspirin at a dose of 3-5 mg/kg per day to prevent future events. We do not routinely anticoagulate patients with PHACE who have not had ischemic events in the past.

Skin ulcerations within the hemangiomas are a relatively common problem (Figure 14). We have found metronidazole gel 0.75% applied twice a day to be helpful, particularly in sites close to mucosal surfaces. These ulcers can be quite painful and aggressive pain management with lidocaine 5% ointment, acetaminophen, acetaminophen with codeine or acetaminophen with hydrocodone will not only make the child more comfortable but also make wound care easier to perform.

Figure 14.

Ulceration in segmental hemangioma.

Once pain control is achieved, the base of the ulcer can be thoroughly cleaned with a solution of sterile saline mixed in a 3:1 proportion with hydrogen peroxide. Once the base of the wound is free of fibrinous material, we have found that the application of a thin layer of becaplermin can be quite helpful in stimulating granulation of the ulcer to speed healing.

Parents often enquire about the black box warning on this medication. However, the data that provoked this warning reflected a slight increase in metastasis when this medication was used in treatment of ulcers in patients who already had cancer. The data does not imply increased risk of cancer in patients without cancer. We counsel patients that we are usually using becaplermin in a different setting, on much smaller areas, for less time. Secondary infection is rare but does occur. If the ulcer develops purulence or odor, or other signs of infection, then culturing the wound to use targeted oral antibiotic therapy may be appropriate.

Specific options for halting the growth of or shrinking hemangiomas that are causing functional impairment of airway, eyes or other vital structures is similar to treatment of hemangioma outside the setting of PHACE and discussed in depth in other chapters of CDS. It is important to evaluate the extent of and factor in systemic complications of PHACE when considering the treatment of infantile hemangiomas in this setting. This is particularly important when considering systemic therapy with agents such as propanolol and prednisolone.

Cerebrovascular abnormalities are the most common manifestation of PHACE syndrome. One must be careful to fully investigate issues of blood flow from the heart and aorta to the brain (in concert with cardiology, neurology, neurosurgery and neuroradiology). This will help to assess specific risks of propranolol in an individual patient. Obviously, if there are areas of the brain where there are concerns of poor perfusion and collateral blood flow then beta-blockers, such as propranolol— which lowers heart rate and blood pressure— could, at least theoretically, decrease perfusion. This should be weighed in assessing risks and benefits versus other therapies such as prednisolone or vincristine.

These assessments are difficult and good evidence-based standards for treatment decisions are lacking at this time. Ideally, these judgments will be based on advice from a multispecialty group of providers who have clinical experience with PHACE syndrome patients. It is also important to remember that some systemic problems associated with PHACE can mimic the side effects of systemic agents used to treat hemangiomas. For instance, it would be easy to miss endocrine abnormalities secondary to PHACE as discussed above by attributing them to prednisone- or propanolol-related side effects, such as changes in blood pressure, hyper or hypo-glycemia, fussiness/hyperactivity, or weakness/lethargy, etc. This is an important concept to keep in mind when assessing acute issues in PHACE patients.

Although many of the ocular manifestations of PHACE are not treatable, astigmatism and amblyopia secondary to pressure on the globe or occlusion of the visual axis may tip you towards initiating systemic therapy to shrink hemangiomas. Propanolol is more effective in actually decreasing hemangioma bulk (Figure 15), whereas prednisolone or vincristine most often halt hemangioma growth but do not cause a significant decrease in size. Clinicians should keep in mind that time may be of the essence regarding these interventions, in order to prevent the need for later ophthalmologic sequelae.

Figure 15.

Segmental hemangioma after treatment with propanolol.

Patient Management

Once the diagnosis of PHACE is made and the particular features manifested by your patient are revealed by a thorough work-up, the management of PHACE involves close follow-up by multiple specialties. Management can often be a balancing act of addressing whatever issue is most acutely dangerous to the patient at a given moment. The key to PHACE management is to try, as much as possible, to anticipate systemic complications and identify them early in order to best balance various, sometimes competing issues, when formulating a treatment plan.

Because the segmental hemangiomas found in PHACE syndrome are often the most clinically obvious finding, the dermatologist may often play a front-line role in identifying affected patients, and the dermatologist may also take a leading role in helping to coordinate the initial evaluation and long-term clinical care of patients with this syndrome. Treatment of the hemangioma is often quite patient-specific and involves complex decision-making based on the patient’s associated systemic issues. However, the dermatologist is often in the best position to gauge hemangioma response to therapy by observing cutaneous lesions. Photography is particularly helpful in this regard. Close follow-up of these patients is essential, particularly for the first few weeks to months of life.

Often when caring for patients with large hemangiomas and PHACE syndrome, there will be an initial “crisis period” where treatment of acute PHACE and hemangioma-related is required to maintain airway, visual axis, and/or hearing or avoid permanent disfigurement. This period is often quite distressing to parents. Although we don’t have much long-term data regarding these patients, in our experience, the families can be reassured that most PHACE patients do quite well over the long term, with only minor neuromotor and developmental issues. They may require lifelong surveillance as discussed below, but they usually go on to live full and productive lives.

CNS vasculopathy and arterial anomalies are the most common noncutaneous manifestation of PHACE. Clinical monitoring of children with PHACE by neurology is important. Many authors have postulated that nonspecific neurologic and neuroimaging findings seen in PHACE patients, such as cerebral hypoplasia, cortical dysplasia and frontal lobe calcifications, could be the result of undetected ischemic events. Vigilance is key to recognizing ischemic events since it is difficult to assess for headache, motor changes or aphasia in a pre-verbal child. Baseline neurologic evaluation and regular follow-up by a pediatric neurologist for thorough examination is recommended. Repeated imaging may be indicated in very high-risk patients with significant vasculopathy on initial MRA or in patients with acute events or changes in exam.

If cardiac or aortic disease is identified, follow-up with cardiology is recommended to determine whether disease is worsening, improving or stable. Aortic disease may contribute to neurovascular blood flow issues and the risk of ischemic events. Ascending aortic arch aneurysms can rarely lead to dissection and rupture, resulting in cardiac tamponade or heart failure.

The spectrum of both ocular and periocular abnormalities is wide. The ophthalmologic manifestations detailed above can combine with hemangioma-related issues to cause multifactorial visual complications. Therefore, examination is important during initial PHACE workup and follow-up is key for management of potential eye disease.

Patients with excavated optic disc abnormalities and/or optic nerve hypoplasia are more likely to have structural pituitary anomalies and multiple endocrinopathies (as discussed further below). Clinicians should not be too quick to attribute endocrine related symptoms to the side effects of systemic therapies such as prednisolone. Thyroid function tests and a detailed history and physical should be part of initial PHACE workup. If there are endocrine-related symptoms, exam signs or laboratory abnormalities, then pediatric endocrinology should provide consultation and follow up appropriate to the specific endocrine dysfunction.

A national PHACE registry has been established at Texas Children’s Hospital. Parents should be encouraged to enroll their child in the registry, as it is an important repository of information, both present and future regarding the emerging manifestations of PHACE. Parent support groups have also formed an online forum.

Unusual Clinical Scenarios to Consider in Patient Management

Hypothyroidism can occur in the setting of PHACE secondary to multiple pathogenic mechanisms. While rare, detection is important. It has been estimated that, in the first year of life, three to five IQ points are lost for each month in which hypothyroidism is untreated. Congenital hypothyroidism can occur secondary to defective brain development in PHACE syndrome. This is a central hypothyroidism, likely due to a primary defect in the brain, that manifests with an inappropriately low thyroid stimulating hormone (TSH) with concurrently decreased free T4.

Due to several reported cases of congenital hypothyroidism in PHACE patients, we now screen all PHACE children for thyroid abnormalities. Multiple other endocrinopathies have been detected in patients with PHACE (as discussed above) so the clinician should be particularly vigilant for signals of endocrine axis dysfunction when taking histories and performing exams of these children.

In rare cases, the large segmental hemangioma itself may cause a peripheral hypothyroidism. This can occur in patients who manifest any large or multiple hemangiomas (PHACE syndrome need not be present). The phenomenon has particularly been described in the setting of liver hemangiomas. In this scenario, hypothyroidism occurs due to consumption of free thyroid hormone by an enzyme located in the endothelial cells of the hemangioma, type 3 iodothyronine deiodinase. This enzyme catalyzes the conversion of active T4 to the inactive reverse T3 and T3 to the inactive T2.

The enzyme is not specific to hemangiomas in PHACE syndrome. Instead, this mechanism is more broadly applicable to all hemangiomas; and a particular problem, not in PHACE patients, but rather in patients with multiple hemangiomas and large burdens of hemangioma tumor. In this case, patients present with very elevated reverse T3 along with decreased or normal T3, T4 and elevated TSH.

Another less common association with PHACE syndrome is hearing loss. This has been described in multiple case reports and is always ipsilateral to the the large segmental hemangioma. In almost every case, the distribution of the hemangioma was similar, with S1 and S3 involvement and extension to most of the ear and the peri-auricular and mid-occipital region in a circular pattern on the scalp. Infantile hemangiomas with this distribution and ear involvement also have a particular tendency to ulcerate in the area of the superior helical rim.

Often times the hearing loss in these patients is conductive in nature and related to intracranial hemangiomas, which have a tendency to localize in or adjacent to the internal auditory canal and cerebellopontine angle. True sensorineural hearing loss has also been observed in a few PHACE patients. The pathogenesis of these cases is less clear, but may involve anatomical and developmental abnormalities caused by the PHACE syndrome.

Patients with PHACE in the high-risk patterns described above should be closely monitored for auditory deficiencies clinically with adjunctive tympanometry and auditory brainstem response as needed, even if they pass their newborn hearing screen. We recommend re-evaluation at a year of age and 18 months. Pediatricians and families should be counseled to stay vigilant for delays in language development over the first few months of life.

It makes sense that there might be an analogous association (to PHACE) of large segmental hemangiomas in the lower half of the body with regional developmental abnormalities. This type of association has, in fact, been described, albeit quite a bit less commonly then classic PHACE syndrome. Referred to in the past with various nomenclatures, we believe the acronym LUMBAR (Lower body hemangioma, Urogenital anomalies and Ulceration, Myelopathy, Bony deformities, Arterial anomalies and Renal anomalies) is more descriptive of the wide phenotypic expression of this syndrome than previous terminology.

It is easy to see how this syndrome could represent a pathogenic expression of a developmental field defect similar to PHACE. They share an association with segmental hemangioma, general regional co-occurrence of underlying congenital abnormalities with cutaneous involvement, potential for underlying arterial anomalies and female predominance. A full description and discussion of LUMBAR is beyond the scope of this text. Although much less common than PHACE syndrome, LUMBAR syndrome is an important area for future study and it will be particularly interesting to see how these two similar entities are related in terms of pathogenic mechanisms.

What is the Evidence?

Metry, D, Heyer, G, Hess, C, Garzon, M, Haggstrom, A, Frommelt, P. "PHACE Syndrome Research Conference. Consensus Statement on Diagnostic Criteria for PHACE Syndrome". Pediatrics. vol. 124. 2009 Nov. pp. 1447-56.

(This article provides the most up-to-date and consensus criteria for the diagnosis of PHACE syndrome. It provides a detailed and thorough description of the many manifestations of PHACE in multiple organ systems.)

Haggstrom, AN, Garzon, MC, Baselga, E, Chamlin, SL, Frieden, IJ, Holland, K. "Risk for PHACE syndrome in infants with large facial hemangiomas". Pediatrics. vol. 126. 2010Aug. pp. e418-26.

(This article provides important information regarding the risk of PHACE syndrome in patients with segmental facial hemangiomas based on anatomic location and extent of the lesion. These data are quite helpful in the initial counseling of families and decision making regarding how aggressive to be in pursuing the workup for systemic complications of PHACE syndrome.)

Drolet, BA, Dohil, M, Golomb, MR, Wells, R, Murowski, L, Tamburro, J, Sty, J. "Early stroke and cerebral vasculopathy in children with facial hemangiomas and PHACE association". Pediatrics. vol. 117. 2006 Mar. pp. 959-64.

(One of the first papers to point out the risk of stroke in PHACE patients. The authors point out the progressive nature of the cerebrovascular vasculopathy and the difficulty and importance of assessing for ischemic events in the pediatric PHACE patient population.)

Heyer, GL, Millar, WS, Ghatan, S, Garzon, MC. "The neurologic aspects of PHACE: case report and review of the literature". Pediatr Neurol. vol. 35. 2006 Dec. pp. 419-24.

(A good review of the neurologic aspects of PHACE from the pediatric neurology literature.)

Hess, CP, Fullerton, HJ, Metry, DW, Drolet, BA, Siegel, DH, Auguste, KI. "Cervical and intracranial arterial anomalies in 70 patients with PHACE syndrome". Am J Neuroradiol. vol. 31. 2010 Nov. pp. 1980-6.

(An extensive review of the cervical and intracranial anomalies in patients with PHACE. This article details the anomalies that are most common and describes their neuroradiologic presentations.)

Bronzetti, G, Giardini, A, Patrizi, A, Prandstraller, D, Donti, A, Formigari, R. "Ipsilateral hemangioma and aortic arch anomalies in posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta, and cardiac defects and eye abnormalities (PHACE) anomaly: report and review". Pediatrics. vol. 113. 2004 Feb. pp. 412-5.

(This paper focuses on the aortic arch abnormalities found in PHACE. It details how the coarcts differ from those found in non-PHACE related cases. It also details 33 cases and the aortic arch anomalies described in these cases.)

Kronenberg, A, Blei, F, Ceisler, E, Steele, M, Furlan, L, Kodsi, S. "Ocular and systemic manifestations of PHACES (Posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects and coarctation of the aorta, eye abnormalities, and sternal abnormalities or ventral developmental defects)syndrome". J AAPOS. vol. 9. 2005 Apr. pp. 169-73.

(One of the few reviews from the ophthalmologic literature detailing the ocular manifestations of PHACE.)

Poindexter, G, Metry, DW, Barkovich, AJ, Frieden, IJ. "PHACE syndrome with intracerebral hemangiomas, heterotopia, and endocrine dysfunction". Pediatr Neurol. vol. 36. 2007 Jun. pp. 402-6.

(One of the first reports to detail this association. Other reports and case series have supported the hypthesis that endocrine abnormalities may be more common than we initially realized in PHACE syndrome, particularly in patients with ocular abnormalities.)

Duffy, KJ, Runge-Samuelson, C, Bayer, ML, Friedland, D, Sulman, C, Chun, R. "Association of hearing loss with PHACE syndrome". Arch Dermatol. vol. 146. 2010 Dec. pp. 1391-6.

(This article reports six patients with PHACE or probable PHACE and describes hearing loss. It also reviews prior reports and point sout the importance of initial and ongoing audiologic monitoring; particularly in patients with hemangiomas involving the ear.)

Park, C, Bodensteiner, JB. "An infant with a segmental hemangioma: Sturge-Weber". Semin Pediatr Neurol. vol. 15. 2008 Dec. pp. 164-6.

(Points out the clinical pearl that one ought to at least think about segmental hemangioma and PHACE syndrome when considering the diagnosis of Sturge-Weber syndrome.)

Iacobas, I, Burrows, PE, Frieden, IJ, Liang, MG, Mulliken, JB, Mancini, AJ. "LUMBAR: association between cutaneous infantile hemangiomas of the lower body and regional congenital anomalies". J Pediatr. vol. 157. 2010 Nov. pp. e1-7.

(This article details the association of segmental infantile hemangiomas and regional congenital abnormalities. This certainly may be an analogous developmental abnormality to PHACE syndrome presenting in the lower body rather than head and neck areas.)
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