Multicenter Study of Long-Term Outcomes and Quality of Life in PHACE Syndrome after Age 10.

OBJECTIVE: To characterize long-term outcomes of PHACE syndrome. STUDY DESIGN: Multicenter study with cross-sectional interviews and chart review of individuals with definite PHACE syndrome ≥10 years of age. Data from charts were collected across multiple PHACE-related topics. Data not available in charts were collected from patients directly. Likert scales were used to assess the impact of specific findings. Patient-Reported Outcomes Measurement Information System (PROMIS) scales were used to assess quality of life domains. RESULTS: A total of 104/153 (68%) individuals contacted participated in the study at a median of 14 years of age (range 10-77 years). There were infantile hemangioma (IH) residua in 94.1%. Approximately one-half had received laser treatment for residual IH, and the majority (89.5%) of participants were satisfied or very satisfied with the appearance. Neurocognitive manifestations were common including headaches/migraines (72.1%), participant-reported learning differences (45.1%), and need for individualized education plans (39.4%). Cerebrovascular arteriopathy was present in 91.3%, with progression identified in 20/68 (29.4%) of those with available follow-up imaging reports. Among these, 6/68 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite the prevalence of cerebrovascular arteriopathy, the proportion of those with ischemic stroke was low (2/104; 1.9%). PROMIS global health scores were lower than population norms by at least 1 SD. CONCLUSIONS: PHACE syndrome is associated with long-term, mild to severe morbidities including IH residua, headaches, learning differences, and progressive arteriopathy. Primary and specialty follow-up care is critical for PHACE patients into adulthood.

PHACES-like syndrome with TMEM260 compound heterozygous variants.

PHACES syndrome is a multiple congenital disorder with unknown etiology that is characterized by Posterior fossa anomalies, Hemangioma, Arterial lesions, Cardiac abnormalities/coarctation of the aorta, Eye anomalies, and Sternal cleft. Compound heterozygous or homozygous TMEM260 variants cause structural heart defects and renal anomalies syndrome (SHDRA). We describe a 10-year-old male patient with a PHACES-like syndrome and TMEM260 compound heterozygous variants who demonstrated overlapping phenotypes between the two syndromes. He presented with truncus arteriosus, supraumbilical raphe, ophthalmological abnormality, vertebral abnormality, borderline intellectual disability, and hearing loss. He had normal serum creatinine. In proband exome sequencing, compound heterozygous TMEM260 variants (NM_017799.4 c.1617delG p.(Trp539Cysfs*9)/c.1858C > T p.(Gln620*)) were identified. Twelve patients have been reported with TMEM260-related SHDRA: 10 had truncus arteriosus and 6 had renal failure. One previously reported patient had facial port wine nevus and another patient had supraumbilical raphe, which are the cardinal signs for PHACES syndrome. TMEM260-related SHDRA could share overlapping clinical features with PHACES syndrome. This report expands the phenotypic spectrum of a TMEM260-related disorder.

Clinical overlap of PHACE and LUMBAR syndromes.

Segmental infantile hemangiomas affecting the upper body are associated with PHACE(S) (Posterior fossa anomalies, Hemangioma, Arterial anomalies, Cardiac anomalies, Eye anomalies, and Sternal defects) syndrome, whereas segmental infantile hemangiomas affecting the lower body are the cutaneous hallmark of LUMBAR (Lower body hemangioma and other skin defects, Urogenital anomalies and Ulceration, Myelopathy, Bony deformities, Anorectal malformations and Arterial anomalies, and Renal anomalies) syndrome. We present two individuals with concurrent features of both PHACE and LUMBAR syndromes demonstrating an overlap phenotype. The overlapping features seen in our patients suggest that these syndromes occur on the same phenotypic spectrum and derive from a common embryonic pathophysiology.

PHACES Syndrome and Associated Anomalies: Risk Associated With Small and Large Facial Hemangiomas.

OBJECTIVE. PHACES syndrome includes posterior fossa malformations, hemangioma, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities, and sternal defect with or without supraumbilical raphe. Usually, brain imaging is performed when facial hemangiomas are larger than 5 cm. Data on associated anomalies regardless of hemangioma size are sparse. The objective of this study was to determine, first, the prevalence of PHACES-like associated anomalies in a large sample of infants with all sizes of segmental facial or periorbital focal infantile hemangioma and, second, whether the cutaneous localization of the hemangioma correlates with the type of anomalies present. MATERIALS AND METHODS. The records of all patients of a vascular anomalies practice who had a diagnosis of segmental facial or periorbital focal infantile hemangioma and who had clinical photographs and brain MRI available were reviewed. The clinical photographs were reviewed to determine the localization by segment and lateralization. MRI was reviewed by two experienced pediatric radiologists. If present, cardiovascular anomalies, sternal defects, and eye anomalies were recorded. The criteria for definite and possible PHACES were used. RESULTS. The study included 122 children (90 girls, 32 boys; mean age, 16.6 months). Forty-five (36.9%) children had a facial infantile hemangioma larger than 5 cm. Twenty-two patients (18.0%) had PHACES or possible PHACES syndrome. Cerebrovascular structural anomalies were seen in 14 of 22 and brain anomalies in 6 of 22 patients with PHACES syndrome but in none and one of the patients in the group without PHACES (p < .001). Cardiovascular anomalies were seen in six patients and ocular anomalies in eight patients. All but one of them had PHACES syndrome. CONCLUSION. Clinical concern about associated extracutaneous anomalies is warranted for all children with facial segmental or periorbital focal infantile hemangiomas, including those with small hemangiomas. Further studies are needed to correlate cerebrovascular anomalies with the clinical evolution of hemangiomas and their effects on cerebral perfusion.

Sternal cleft and segmental facial hemangiomas in children with phaces syndrome: effectiveness and safety of conservative management and surgical correction.

OBJECTIVE: The aim is to determine the risk factors of sternal cleft and segmental facial hemangiomas association in children with PHACES syndrome. PATIENTS AND METHODS: Materials and methods: 32 inpatient children with segmental facial hemangiomas and 19 children with sternal cleft were investigated concerning the Metry criteria of PHACES syndrome. RESULTS: Results: In 6 children PHACE syndrome was diagnosed. Patients with bilateral S3 hemangiomas (50%, 3/6) had airway involvement with respiratory disorders. Conservative treatment was propranolol monotherapy (66.7%, 4/6), or combination of prednisolone and propranolol (33.3%, 2/6). Duration of propranolol treatment in children with PHACES syndrome was on an average 24.25 ± 4.49 months exceeding the duration of propranolol therapy in children with isolated soft tissue lesions (p<0.05). Primary surgical treatment of sternal cleft performed in children aged 2 (n=3) and 4 (n=1) months. The later period of surgery associated with the localization of hemangioma in the surgery region. Primary repair of sternal cleft was completed successfully in all cases; partial resection of the thymus made closure easier. CONCLUSION: Conclusions: Primary surgical correction of a sternal cleft performed in young children provides good results. Partial resection of the thymus prevents respiratory and cardiovascular complications. Preoperative propranolol treatment averts the hemorrhagic complications in children with hemangiomas in surgical region.

PHACES syndrome and multi-regional odontodysplasia: a case report.

PHACES syndrome is an acronym for the syndromic presentation of Posterior fossa malformation, Hemangioma, Arterial anomalies, Coarctation of aorta/cardiac defects, Eye abnormalities and Sternal malformations. Infantile hemangiomas are the most common tumors of infancy. Regional odontodysplasia, commonly referred to as "ghost teeth", is a rare localized developmental malformation of enamel and dentin with varying levels of severity that results in unusual clinical and radiographic appearances of affected teeth. This report describes a rare case of a two-year-old Caucasian male diagnosed with PHACES syndrome also presenting with multi-regional odontodysplasia. Ten of twenty teeth were dysplastic. The patient was treated under general anesthesia in a hospital setting. All affected primary teeth were extracted due to sensitivity, abscess and extremely poor long-term prognosis. Moving forward, a long-term interdisciplinary approach will be necessary to address this child's dentition as it develops.

Numerical flow experiment for assessing predictors for cerebrovascular accidents in patients with PHACES syndrome.

There is an increased risk of cerebrovascular accidents (CVA) in individuals with PHACES, yet the precise causes are not well understood. In this analysis, we aimed to examine the role of arteriopathy in PHACES syndrome as a potential contributor to CVA. We analyzed clinical and radiological data from 282 patients with suspected PHACES syndrome. We analyzed clinical features, including the presence of infantile hemangioma and radiological features based on magnetic resonance angiography or computed tomography angiography, in individuals with PHACES syndrome according to the Garzon criteria. To analyze intravascular blood flow, we conducted a simulation based on the Fluid-Structure Interaction (FSI) method, utilizing radiological data. The collected data underwent statistical analysis. Twenty patients with PHACES syndrome were included. CVAs were noted in 6 cases. Hypoplasia (p = 0.03), severe tortuosity (p < 0.01), absence of at least one main cerebral artery (p < 0.01), and presence of persistent arteries (p = 0.01) were associated with CVAs, with severe tortuosity being the strongest predictor. The in-silico analysis showed that the combination of hypoplasia and severe tortuosity resulted in a strongly thrombogenic environment. Severe tortuosity, combined with hypoplasia, is sufficient to create a hemodynamic environment conducive to thrombus formation and should be considered high-risk for cerebrovascular accidents (CVAs) in PHACES patients.

[PHACES syndrome (Pascual Castroviejo type II): prenatal and postnatal magnetic resonance imaging]. / Síndrome PHACES (Pascual Castroviejo tipo II): resonancia magnética pre y posnatal.

The neurocutaneous syndrome known by the acronym PHACE consists of the association of a segmental facial hemangioma with, among other entities, posterior fossa anomalies, cerebrovascular anomalies, cardiac involvement/aortic coarctation, and eye abnormalities. When ventral developmental defects are also present, the syndrome is referred to as PHACES. We report the prenatal and postnatal MRI findings in a case of PHACES with involvement of the right posteroinferior cerebellar artery. This case is exceptional because, to our knowledge, it is the first to report the findings at both prenatal and postnatal MRI and because of the unique vascular anomaly that widens the spectrum of possible intracranial arterial anomalies in this syndrome.

The VASCERN-VASCA working group diagnostic and management pathways for severe and/or rare infantile hemangiomas.

The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus statements on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-face meetings and in multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with severe and rare IH in a practical manner; we present an algorithmic view of the results of our work.

Nd:YAG laser in association with pulsed dye laser for the treatment of PHACES syndrome.

The acronym PHACES stands for posterior fossa malformations, hemangiomas, arterial anomalies (cardiovascular or cerebrovascular), coarctation of the aorta/cardiac defects, eye abnormalities, and sternal defects. The characteristic dermatological clinical manifestation of PHACES syndrome is a segmental and extensive hemangioma, usually on the face. A combined therapy with 1,064 nm Nd-YAG/595-nm pulsed dye laser was performed in a young 15-year-old patient with PHACES syndrome, who presented a hemangioma on the left side of the face, located in the periorbital region. A first session with Nd-YAG laser (2,5 mm spot size, fluence 100 J/cm2, pulse duration 7 ms) for the treatment of teleangectasias and subsequently, three treatment sessions with pulsed dye laser (12 mm spot size, fluence 7 J/cm2, pulse duration 0,5 ms, repetition rate 0,6 Hz), once every 2 months, were performed. No postoperative complications were recorded, except for transient purpura after the pulsed dye laser sessions. The vascular lesion had a decrease in size bigger than 75%, and these results was maintained 6 months after the last treatment. Combined therapy Nd- YAG/pulsed dye laser is an effective and noninvasive procedure for hemangiomas in patients with PHACES syndrome.

PHACES syndrome with ectopia cordis and hemihypertrophy.

PHACES is the acronym describing the phenotypic association of posterior fossa anomalies, facial hemangioma, cardiac and eye anomalies, and sternal defects. To date, more than 300 cases of PHACE(S) have been reported. We present the case of a newborn girl who was born with a variant of the PHACES syndrome. Although the sternal cleft and the small facial hemangioma were evident clinically at birth, magnetic resonance imaging of the brain provided additional information to establish the diagnosis. In addition, the patient manifested later with hemihypertrophy, an association that has not been described previously.

Corkscrew aortic arch in PHACES syndrome: Multimodal imaging of an unusual morphology of tortuous aortic arch in a rare but well-defined syndrome.

PHACES syndrome, a diffuse aortocraniocerebral vasculopathy, is a neural tube migration disorder, characterized by aortic coarctation and aberrant arch branches. Clinical diagnosis, echocardiography, and surgical management of coarctation in this syndrome are challenging due to peculiar morphological differences. Corkscrew aortic arch, an extreme tortuosity of the aortic arch described in arterial tortuosity syndrome, is not reported in PHACES syndrome so far. Multimodal imaging of this unusual corkscrew aortic arch in two patients with PHACES syndrome is presented.

The PHACES syndrome: Multiple episodes of reproliferation of subglottic hemangioma.

Subglottic hemangioma is a potentially life-threatening manifestation of the PHACES syndrome. The disease process has been treated with corticosteroids, oral chemotherapeutic agents, endoscopic airway interventions, tracheostomy, and even laryngotracheal reconstruction. Oral propranolol has emerged as an effective therapy and in many cases has led to complete regression of hemangioma during the proliferative phase. There have been several reports of patients showing signs of reproliferation after discontinuing propranolol therapy. This article illustrates a patient who has had multiple episodes of reproliferation of subglottic hemangioma after weaning from propranolol therapy.

The cerebellar "tilted telephone receiver sign" enables prenatal diagnosis of PHACES syndrome.

OBJECTIVES: To describe a unique posterior fossa neuroimaging characteristic of prenatal PHACES syndrome (PS): unilateral cerebellar hypoplasia (UCH) and ipsilateral posterior fossa (PF) cyst communicating with an asymmetrically distended 4th ventricle. METHODS: The registries of seven prenatal diagnosis centers were searched for cases with PF findings and a postnatal diagnosis of PS. All records were evaluated for ultrasound and MRI findings and the postnatal outcome. PS was diagnosed after birth according to the consensus statement on diagnostic criteria for PS from 2009. The imaging findings of the PS fetuses were compared to a group of consecutive cases with fetal UCH, whose postnatal diagnosis was not PS. RESULTS: The PS group included 10 fetuses. All were referred due to UCH accompanied by an ipsilateral retrocerebellar cyst. All pregnancies resulted in livebirths, all newborns had a large segmental facial hemangioma. In all PS fetuses the affected cerebellar hemisphere was upwardly displaced by an ipsilateral PF cyst communicating with an asymmetrically distended 4th ventricle. An upwardly rotated and deviated vermis merged with the contralateral cerebellar peduncles forming an elongated oblique connection between the cerebellar hemispheres, resulting in a unique cerebellar shape, "a tilted telephone receiver sign" (TTRS), on the coronal plane through the upper vermis.The non-PS group included 11 fetuses with UCH: clastic cerebellar lesions (8) and a unilateral PF arachnoid cyst (3). The TTRS was not depicted in any of them (p < 0.0005). CONCLUSIONS: The cerebellar TTRS is a specific fetal imaging feature of PHACES syndrome enabling its prenatal diagnosis.

PHACE(S) syndrome: Report of a case with new ocular and systemic manifestations.

PURPOSE: To describe an infant with PHACE(S) syndrome [posterior fossa anomalies (P), hemangiomas (H), arterial anomalies (A), cardiac abnormalities and coarctation of aorta (C), eye abnormalities (E), and the sternal defects (S)] with unusual strabismus, congenital glaucoma, and new systemic manifestations. METHODS: A 6-month-old girl was referred with large hemangiomas on the left side of the face. RESULTS: In the ocular examination, right esotropia and hypotropia, and limitation of elevation in adduction in the right eye were seen. Morning glory disk anomaly was seen in the left fundus. Intraocular pressure (IOP) was 28 mmHg in the right eye and 15 mmHg in the left eye. Brain computed tomography (CT) scan demonstrated Dandy-Walker malformation. In the CT angiography of the thoracic arteries, coarctation of aorta in descending part, the aberrant origin of the left subclavian artery from the end of the aortic arch, and anomalous origin of the left vertebral artery from the posterior aspect of the aortic arch were found. Therefore, the presence of large facial hemangioma, posterior fossa anomaly, aortic arch anomalies, and morning glory disk confirmed the diagnosis of PHACE(S) syndrome. Propranolol (0.5 mg/kg/day) was initiated to treat hemangioma and coarctation of aorta. Due to uncontrolled glaucoma, goniotomy was performed in the right eye 3 months after the first visit. One year after the initial visit, the hypotropia and esotropia of the right eye considerably decreased. CONCLUSIONS: To our knowledge, this report was the first report of a pattern like Brown's syndrome (may be called apparent Brown's syndrome) and the second report of the congenital glaucoma in a case of PHACE(S) syndrome. In addition, the anomalous origin of the vertebral artery from the aortic arch has not been reported in the PHACE(S) syndrome. Thus, the clinicians should perform the glaucoma work-up for each patient with this syndrome.

Sternal reconstruction by extracellular matrix: a rare case of phaces syndrome.

Congenital defects of the sternum are rare and due to a failure of midline development and fusion of the sternal bones. Surgical correction of a sternal cleft should be preferred during infancy for functional reasons. Chest wall reconstruction represented a complex problem in the last decades. We report our successful outcome of sternal reconstruction in a rare case of PHACES syndrome, in which the patient was submitted to reconstruction of the sternum and complete closure of the thoracic defect by the employ of an extracellular matrix XCM Biologic tissue matrix. We promote the use of extracellular matrix in surgical reconstruction of chest defects for its maneuverability, plasticity, tolerability and the possibility of growing with the children's chest getting a good compliance and optimal cosmetic results.

Propranolol-responsive cranial nerve palsies in a patient with PHACES syndrome.

PHACES syndrome is a neurocutaneous disorder characterized by the presence of segmental hemangiomas with associated anomalies of the posterior fossa, cerebral vasculature, cardiovascular system, eyes, and ventral or midline structures. We present the first case of propranolol-responsive congenital trigeminal and facial nerve palsies secondary to an intracranial hemangioma in a patient with PHACES syndrome.

Sternal Cleft associated with Patent Ductus Arteriosus, Atrial Septal Defect, and Subglottic Hemangioma: A rarity.

We present a 2-day-old female neonate with cleft of the upper sternum, patent ductus arteriosus (PDA), atrial septal defect (ASD), and subglottic hemangioma. Dimensional and Doppler echocardiography, abdominal ultrasonography, and imaging were performed. She underwent a surgical repair of sternal cleft in neonatal life. After 8 months, she developed respiratory distress, apnea due to subglottic hemangioma. She underwent urgent tracheostomy. Subglottic hemangioma was treated with the KTP532 laser.