PHACE syndrome is associated with intracranial ...

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ing pathways responsible for cellular responses to oxidative stress [18, 32, 37], including KRIT1 [9], CCM2 [22], and. PDCD10 [3]. It has been well documented ...
Childs Nerv Syst DOI 10.1007/s00381-016-3097-z

ORIGINAL PAPER

PHACE syndrome is associated with intracranial cavernous malformations Kimberly A. Foster 1 & William J. Ares 1 & Zachary J. Tempel 1 & Andrew A. McCormick 2 & Ashok Panigrahy 3 & Lorelei J. Grunwaldt 4 & Stephanie Greene 1

Received: 14 February 2016 / Accepted: 18 April 2016 # Springer-Verlag Berlin Heidelberg 2016

Abstract Introduction PHACE syndrome is a neurocutaneous disorder involving large facial hemangiomas in association with posterior fossa abnormalities, cerebral arterial anomalies, cardiac defects, and eye abnormalities. A recent consensus statement has delineated criteria necessary for the diagnosis of PHACE syndrome. Extracutaneous manifestations of PHACE syndrome predominately affect the cerebrovascular system. To date, there are no reports of cerebral cavernous malformations (CCMs) in children with PHACE syndrome. Methods We reviewed the charts of children admitted to the Children’'s Hospital of Pittsburgh who met criteria for PHACE syndrome, and evaluated neuroimaging for cerebrovascular abnormalities, including the finding of CCMs. Results Six children met criteria for PHACE syndrome at our institution over a 10-year period. All children were female. All children had cerebrovascular abnormalities sufficient to meet major criteria for diagnosis. Four children (66.7 %) were found incidentally to have CCMs; all lesions measured less than 5 mm at the time of diagnosis and were asymptomatic.

* Kimberly A. Foster [email protected]

1

Department of Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, 4401 Penn Ave, Faculty Pavilion, 4th Floor, Pittsburgh, PA 15224, USA

2

Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

3

Department of Neuroradiology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

4

Department of Plastic and Reconstructive Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Conclusion At present, CCMs are not listed among the diagnostic criteria for PHACE syndrome, and they have not previously been reported in association with PHACE syndrome. Hypoxic injury in utero may be the common denominator in the pathogenesis of many of the abnormalities already accepted in the criteria for PHACE syndrome and the formation of CCMs. In the setting of PHACE syndrome, we encourage clinicians to evaluate children for CCMs, which are readily apparent on the already-recommended screening MRIs. Keywords PHACE syndrome . Cavernous malformation . Pediatric

Introduction PHACE syndrome is a neurocutaneous disorder involving large facial hemangiomas in association with posterior fossa abnormalities, cerebral arterial anomalies, cardiac defects, and eye abnormalities [13]. An s is sometimes appended to the acronym to include sternal defects. Initially described in 1996, Frieden and colleagues reported 43 patients with facial hemangiomas and various systemic manifestations [13]. Although rare in the general population, a 2010 series of children with large facial hemangiomas showed that about one third were found to have PHACE syndrome after further systemic evaluation [14]. Criteria for the diagnosis of PHACE syndrome have most recently been updated in 2009, as outlined by the consensus statement set forth by Metry and colleagues [24]. Diagnosis requires the presence of one large segmental hemangioma (greater than 5 cm2) of the face or scalp and one major or two minor criteria (involving two different organ systems). Major criteria include an anomaly of the cerebral vasculature, a posterior fossa structural abnormality including DandyWalker complex or cerebellar hypoplasia, an aortic arch

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anomaly, a posterior segment ocular abnormality, and ventral/ midline structure defects (sternum or supraumbilical raphe). Minor criteria include persistent embryonic cerebral arteries, intracranial hemangioma or neuronal migration disorder, ventricular septal defect or right aortic arch, anterior segment ocular abnormality, cataract, coloboma or microphthalmia, hypopituitarism, and ectopic thyroid. The possibility of PHACE syndrome should be considered when a child presents with a large hemangioma and one minor criterion, a neck or upper torso hemangioma and one major or two minor criteria, or a lack of hemangioma with two major criteria met. Studies suggest that the extracutaneous manifestations of PHACE syndrome predominately affect the cerebrovascular system; the prospectively collected PHACE Registry found that more than 80 % of patients have neurologic abnormalities [26]. In comparison, only 37 and 16 % of patients in the registry had cardiovascular and ophthalmologic findings, respectively. Intracranial vascular anomalies are most often dysplasia, aplasia, or occlusion of major cerebral arteries (with or without moyamoya collaterals); aberrant origin/courses of major arteries; persistent trigeminal artery (PTA); and saccular aneurysms. To date, there are no reports of cavernous malformations—angiographically occult vascular lesions, most often intra-axial and located within the brain parenchyma—in children with PHACE syndrome [12]. We describe our single-institution experience with PHACE syndrome and note the association with cavernous malformations. The charts and films of all patients with the diagnosis of PHACE syndrome at the Children’s Hospital of Pittsburgh (CHP) from January 2005 to present were reviewed. The diagnosis of PHACE syndrome was made in accordance with the aforementioned criteria of Metry et al. and the PHACE Syndrome Research Conference, as determined by the multidisciplinary vascular anomalies team at CHP. Dermatologic, cardiovascular, and ophthalmologic evaluations were performed by a pediatric plastic surgeon, a cardiac surgeon, and an ophthalmologist, respectively. Gadolinium-enhanced MR imaging (MRI) and MR angiography (MRA) of the brain were obtained on all patients and reviewed by a pediatric neuroradiologist and neurosurgeon. Neurologic assessment was performed by a pediatric neurosurgeon and/or pediatric neurologist. Developmental delay was defined as failure to meet appropriate milestones in accordance with accepted norms. Medical charts were reviewed to assess clinical and radiographic characteristics including age, gender, size and location of hemangioma(s), and major and/or minor criteria met in the potentially affected organ systems (cerebrovascular, structural brain, cardiovascular, ocular, and ventral/midline structures). MRI/As were reviewed for cerebrovascular abnormalities (agenesis and/or hypoplasia of major intracranial vessels, aneurysms, arteriovenous malformations (AVMs), cavernous malformations, and others), and all subsequent imaging modalities were reviewed for interval radiographic progression. Charts

were also abstracted for the need for and type of surgical intervention(s), neurologic deficit or morbidity secondary to intracranial abnormalities (hemorrhage, development of moyamoya, seizure disorder/epilepsy, cranial nerve deficit, chronic or recurring headache disorder, and others), duration of follow-up, and clinical status at most recent evaluation. Institutional review board approval was obtained prior to data collection.

Case reports Six children met criteria for PHACE syndrome at our institution over a 10-year period. All children were female. To date, all children are alive. Five children were noted to have facial hemangioma(s) within a week of birth and were diagnosed with PHACE syndrome within 2 weeks to 3 months of birth. One child, born at an outside facility, was noted to have a facial skin abnormality at birth; however, diagnosis of facial hemangioma was made at 14 months and PHACE syndrome at 3 years of age. All children have been followed to date (range 4 months to 10 years). All children had left-sided facial hemangiomas, and one child had bilateral facial lesions. Hemangioma location was classified as per the segmental patterns described by Haggstrom and colleagues, including the frontotemporal (segment 1), maxillary (segment 2), mandibular (segment 3), and frontonasal (segment 4) segments [15, 24]. All children had cerebrovascular abnormalities sufficient to meet major criteria for diagnosis. Two children also had structural brain anomalies in the posterior fossa, namely, cerebellar hemisphere hypoplasia. Two other children had cardiac manifestations, and the fifth child had supraumbilical raphe. No child met major ocular criteria. All children have undergone intracranial MRI and MRA. Four children have internal carotid artery (ICA) abnormalities, including unilateral hypoplasia in two patients, bilateral hypoplasia in one child, and progressive unilateral stenosis in another. No child has undergone formal catheter-based angiography; on MRA, no child has evidence of moyamoya collaterals. Four children (66.7 %) were found incidentally to have cavernous malformations, located exclusively in the supratentorial compartment in two, within the posterior fossa only in another child, and both above and below the tentorium in the fourth patient. All lesions measured less than 5 mm at the time of diagnosis. No child has required surgical intervention for a neurologic problem. No child has suffered an arterial ischemic stroke. Five of six children are neurologically and developmentally normal, while the child born prematurely at 32 weeks with punctate areas of white matter necrosis is developmentally delayed. Of the children with cavernous malformations, one child has radiographic evidence of hemorrhage on interval imaging. No child has presented with a clinical seizure or a significant headache.

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Case 1 A full-term female infant was born with a left-sided hemangioma involving segments 1, 2, and 3. Within the first year of life, she underwent repair of tetralogy of Fallot, right cervical aortic arch, and coarctation, as well as laser ablation of a subglottic hemangioma. Over the next 5 years, she underwent excision of the upper lip and nasal hemangiomas. At age 2 months, brain MRI/A revealed bilateral cerebellar hemispheric hypoplasia, right ICA aplasia, and a hypoplastic right vertebral artery, confirming the diagnosis of PHACE syndrome. The most recent brain MRI shows T2 abnormalities consistent with multiple, 1–2-mm cavernous malformations, scattered throughout the supratentorial white matter. The child remains neurologically asymptomatic. Imaging is shown in Fig. 1. Case 2 A full-term female was born with a single left facial hemangioma in segment 1. The lesion became apparent a few days after birth, and she was treated in infancy with propanolol. Intracranial MRI/A performed at 3 months of age showed left ICA hypoplasia, confirming the diagnosis of PHACE syndrome. Imaging also showed a 3-mm left cerebellar and 4mm right frontal cavernous malformation. The frontal lesion showed susceptibility artifact on gradient echo, suggesting prior hemorrhage. The child is less than 2 years of age at present, making assessment of symptoms difficult. There has been no clinical evidence of head pain or seizure. MRI/A is shown in Fig. 2. Case 3 A full-term female was born with a hemangioma present in left segment 1, treated in late infancy with topical timolol. In the first year of life, she underwent repair of an atrial septal defect (ASD) and cleft AV valve. The child presented to our facility at age 14 months, at which time, the first intracranial imaging was performed. MRI/A demonstrated hypoplasia of the right anterior cerebral artery (ACA), including the A1 and A2 arterial segments, and numerous supratentorial cavernous malformations, all less than 3 mm in greatest diameter. There is no radiographic evidence of hemorrhage, and the lesions have appeared stable on interval imaging. MRI/A is shown in Fig. 3. Case 4 A full-term female was born with a hemangioma present in left segments 1 and 2, currently being treated with propanolol. MRI/A performed 6 weeks after birth showed a hypoplastic right ACA (A1 segment) and three infratentorial cavernous

malformations, all less than 5 mm. No interval imaging has been performed. MRI/A is shown in Fig. 4.

Discussion PHACE syndrome is a congenital, non-hereditary condition that may be the most common vascular neurocutaneous disorder [26]. The association between infantile hemangiomas with brain abnormalities was first described in 1978 by Pascual-Castroviejo, and subsequently, the disorder was termed cutaneous hemangioma-vascular complex syndrome [29]. In 1996, Freiden and colleagues [13] introduced PHACE syndrome into the literature; some authors include sternal/midline defects and use the terminology PHACES syndrome [5]. While infantile facial hemangiomas are generally the unifying feature of PHACE syndrome (diagnosis can be achieved without hemangiomas and two major criteria satisfied), previous reports of the syndrome are generally smaller, single-institution case series with a variety of associated abnormalities. With a heterogeneous constellation of anomalies potentially present in PHACE syndrome, an expert panel consensus statement was set forth in 2009 and was inclusive of most features previously reported in the literature [24]. Clinical features of PHACE syndrome include dermatologic, neurologic, cardiac, and ocular manifestations. In a review of 130 patients, Metry et al. demonstrated that 70 % of patients diagnosed with PHACE syndrome met only one extracutaneous manifestation [25]. Of these, cerebrovascular abnormalities were most common and, in fact, the degree of intracranial structural and/or vascular abnormalities may be underestimated, as detailed neuro-axis imaging (MRI and MRA) was not available in the earlier series and may remain limited in some clinical settings. All children in our small cohort met major diagnostic cerebrovascular criteria, with varying degrees of extra-neural involvement. PHACE syndrome likely has a female predominance, with a reported female/male ratio of 9:1 and 2.8:1 in PHACE syndrome and isolated infantile hemangioma, respectively [26]. All children in our series were girls, consistent with other series, which range from 83 to 100 % female patients [2, 6, 17, 26]. While children with PHACE syndrome are at a significantly increased risk of stroke, particularly those with more than one vessel involved or coarctation of the aorta [34], no child in our small series has had an acute ischemic infarct. Not surprisingly, neurodevelopmental delay has been observed in children with PHACE syndrome [23, 25]; only one child in our series has developmental delay, which could also be related to her premature birth. The pathogenesis of PHACE syndrome remains elusive. No familial link has been shown, and PHACE syndrome is considered non-hereditary. A single unifying defect responsible for the spectrum of abnormal findings has not been

Childs Nerv Syst Fig. 1 a SWI demonstrates multiple punctate (at least five) lesions demonstrating low signal intensity consistent with small cavernous malformations. b Three-dimensional time-of-flight MRA demonstrates aplasia of the right ICA within the petrous canal

discovered. Given the female predominance, X-linked transmission may be responsible, with prenatal male lethality. Studies have suggested abnormal neural crest development and/or aberrant organogenesis, occurring before 10-week’ gestational age. Mutations in a few specific regulatory genes mutually involved in capillary, neural, ophthalmologic, and sternal development have been implicated [25]. As described by Krings and colleagues, current theories on a developmental link for the abnormalities in PHACE syndrome point to neural crest [21], adjacent cephalic mesoderm, and, potentially, the neural plate to explain central nervous system (CNS) structural aberrancies but do not account for all potential abnormalities in PHACE syndrome [16]. As summarized by Hess et al., the vascular abnormalities, specifically arterial, may result from the disruption of normal arterial wall histologic architecture, leading to changes in the diameter and/or anatomic course of cerebral arteries [16]. The authors suggest that this arteriopathy during embryogenesis could lead to alterations in blood flow and, potentially, hypoxia, which could explain the formation of hemangiomas and brain structural abnormalities. Specifically, hemangiomas arise from endothelial progenitor/ stem cells derived from neural crest, and at birth, hemangiomas are Bprecursor^ lesions that proliferate with time [16]. Hypoxic insult may be the inciting event in the formation of such precursor lesions. Molecular studies have shown that Fig. 2 a SWI demonstrates a left cerebellar hemispheric cavernous malformation as demonstrated by a focus of low signal intensity. b Reconstructed 3D time-of-flight MRA demonstrates a hypoplastic left ICA

hemangiomas express glucose transporter 1 (GLUT1) [28], a known marker of cellular response to hypoxia, and that hypoxia-induced mediators of endothelial cell proliferation are upregulated in pediatric hemangioma [19]. Cerebral cavernous malformations (CCMs), also called cavernous hemangiomas or cavernomas, are common vascular malformations of the CNS, affecting 0.4–0.8 % of the general population [1, 4]. Up to 25 % of cavernous malformations occur in children [20]. CCMs are one of four major types of CNS vascular malformations, along with arteriovenous malformations (AVMs), capillary telangiectasias, and developmental venous anomalies (DVAs). These lesions can present with acute or chronic symptoms, including headache, seizure, and/or neurologic deficit from hemorrhage, but the most CCMs are asymptomatic throughout the patient’s lifetime and are discovered incidentally. The majority of CCMs occur sporadically, but as many as 20 % occur in a familial pattern [18]. CCMs can range in size and number and vary in their susceptibility to hemorrhage. The only therapeutic cure for CCM is complete surgical removal, limited to lesions in a surgically accessible brain or spinal cord location. Radiographically, T1 and T2 signal of CCMs is varied internally depending on the temporal proximity of a previous hemorrhage; gradient echo is the MRI sequence of choice for detecting lesions. Hemosiderin

Childs Nerv Syst Fig. 3 a SWI demonstrates a left inferior frontal cavernous malformation, just superior to the left MI segment. b Threedimensional time-of-flight MRA demonstrates a hypoplastic right A1 segment

demonstrates significant blooming on susceptibilityweighted imaging (SWI), a modality capable of detecting hemorrhage and calcification [38]. CCMs almost never contrast-enhance on MRI [30] and are angiographically occult lesions. Histologically, CCMs contain dilated, thin-walled capillaries with areas of enlarged endothelial channels (called caverns), without intervening brain parenchyma or tight junctions, and often surrounded by hemosiderin [8, 10, 11, 33]. Sporadic cases are most often solitary, while the familial variant is associated with multiple, scattered lesions and inherited in an autosomal dominant fashion [32]. Familial CCM is known to be associated with loss of function mutations in three genes that each plays a pivotal role in controlling signaling pathways responsible for cellular responses to oxidative stress [18, 32, 37], including KRIT1 [9], CCM2 [22], and PDCD10 [3]. It has been well documented that hypoxia plays a critical role in the formation of both sporadic and familial CCMs [27, 35, 39]. At present, cavernous malformations are not listed among the diagnostic criteria for PHACE syndrome. To the best of our knowledge, they have not previously been reported in association with PHACE syndrome. PHACE syndrome is associated with a predominance of arterial Fig. 4 a SWI demonstrates small bilateral cerebellar cavernous malformations, as demonstrated by punctate foci of low signal intensity. b Reconstructed 3D time-of-flight MRA demonstrates a hypoplastic right A1 segment

anomalies, as opposed to other neurocutaneous disorders that involve venous and/or capillary aberrancies, including Sturge-Weber and cerebrofacial arteriovenous metameric syndrome [7, 21, 24]. Based on the consensus statement, the majority of inclusion criteria in the cerebrovascular category do involve the arterial system; a few venous or capillary abnormalities are included, such as pial enhancement, sinus pericranii, and dural venous sinus malformations. We propose the inclusion of other nonarterial cerebrovascular abnormalities, namely, cavernous malformations. A report from Brandon and colleagues suggested AVM to be a rare manifestation of PHACE syndrome, not previously reported [7]; we acknowledge that while AVMs are high-flow arterial-containing vascular abnormalities and CCMs are low-flow capillary abnormalities, they are both on the spectrum of intraparenchymal vascular abnormalities. As stated above, it is theorized that early in utero hypoxic insults are responsible for features of PHACE syndrome, including the formation of hemangiomas and cerebral arterial malformations. Therefore, hypoxic injury may be the common denominator in the pathogenesis of many of the abnormalities already accepted in the criteria for PHACE syndrome and the formation of CCMs.

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There are multiple reports of intracranial hemangiomas occurring in PHACE syndrome, not to be confused with cavernous malformations/hemangiomas, which have not been shown in association with PHACE syndrome. Current terminology may confuse the reader as to the distinction between the reported intracranial hemangiomas and the CCMs reported here. In the original report in 1978, Pascual-Castroviejo reported one patient with an intracranial Bangiomatous malformation^ [29]. Subsequent authors reported the concomitant occurrence of (usually ipsilateral) facial hemangiomas and intracranial hemangiomas, which are dural-based, contrast-enhancing masses, often found at the cerebellopontine angle (CPA) [13, 31, 36]. Such lesions can show radiographic involution following steroid treatment [36], a response that has not been shown in CCMs. On the other hand, as aforementioned, CCMs are intra-axial (almost never dural-based) lesions with distinct MRI characteristics, including lack of contrast enhancement. There are two important limitations to this report. First, this is a small, retrospective, single-institution series, with the biases inherent of such a study. Second, it is important to again note that CCMs are somewhat common, occurring in up to 0.8 % of the general population. Therefore, the CCMs in this series could be incidental and unrelated to PHACE syndrome, albeit with a high rate of occurrence, as four of six children who met diagnostic criteria for PHACE syndrome also had CCMs. Other cerebrovascular abnormalities that occur in the general population with relative frequency, such as saccular aneurysms, pial enhancement, and acute arterial strokes, have been reported and included in the consensus report. Formal guidelines for the evaluation and care of children with PHACE syndrome have not been established. In most series, children with large cervicofacial and scalp hemangiomas undergo imaging of the head and neck, cardiac evaluation, and ophthalmologic examination [24, 25]. The recommended minimal intracranial imaging for infants at risk for PHACE syndrome includes axial spinecho T2, gradient-echo T1 or axial spin-echo T1, axial diffusion-weighted imaging (DWI), and gadoliniumenhanced T1 (with fat suppression), as well as time-offlight (TOF) and contrast-enhanced intracranial and cervical MRA [24]. These sequences would also be adequate to detect cavernous malformations. Catheter-based angiography is not recommended unless specifically warranted in particular cases. In the setting of PHACE syndrome, we encourage clinicians to evaluate children for cavernous malformations, which can be single, small, and asymptomatic and are readily apparent on the already-recommended screening MRIs. Further reports may corroborate an association between PHACE syndrome and CCMs.

Compliance with ethical standards Conflict of interest The authors have no financial disclosures.

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