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.

Delphi Consensus on Diagnostic Criteria for LUMBAR Syndrome.

OBJECTIVE: To develop consensus on diagnostic criteria for LUMBAR syndrome, the association of segmental infantile hemangiomas that affect the Lower body with Urogenital anomalies, Ulceration, spinal cord Malformations, Bony defects, Anorectal malformations, Arterial anomalies and/or Renal anomalies. STUDY DESIGN: These diagnostic criteria were developed by an expert multidisciplinary and multi-institutional team based on analysis of peer-reviewed data, followed by electronic-Delphi consensus of a panel of 61 international pediatric specialists. RESULTS: After 2 Delphi rounds, a 92% or higher level of agreement was reached for each Delphi statement. 98% of panelists agreed with the diagnostic criteria, and 100% agreed the criteria would be useful in clinical practice. The diagnosis of LUMBAR requires the presence of a segmental, or patterned, infantile hemangioma of the lumbosacral, sacrococcygeal, or pelvic cutaneous regions plus one additional criterion of the urogenital, spinal, bony, anorectal, arterial, or renal organ systems. CONCLUSIONS: These diagnostic criteria will enhance clinical care by improving screening, detection, and overall awareness of this poorly understood neurocutaneous disorder. The criteria can be utilized by a wide variety of pediatric subspecialists. In addition, formal criteria will improve phenotypic uniformity among LUMBAR syndrome cohorts and a patient registry, allowing investigators to assess clinical features, long-term outcomes, and results of genetic sequencing in a standardized manner. Finally, these criteria will serve as a starting point for prospective studies to establish formal screening and management guidelines.

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.

A rare combination of post-ductal coarctation of the aorta and adjunct tortuous aneurysm: a neonate with Posterior fossa anomalies, Haemangiomas of the head and neck, Arterial, Cardiovascular, and Eye anomalies and ventral developmental defect syndrome.

A 4-day-old girl with Posterior fossa anomalies, Haemangiomas of the head and neck, Arterial, Cardiovascular, and Eye anomalies and ventral developmental defect syndrome comprising a facial haemangioma, aortic coarctation at the aortic arch, torturous aortic aneurysm distal to coarctation, and ductus arteriosus originating proximal to the coarctation is presented. The aortic arch was successfully reconstructed without cardiopulmonary bypass, and she is currently doing well after 4 years and 8 months.

Epidemiology, Clinical Features, and Use of Early Supportive Measures in PHACE Syndrome: A European Multinational Observational Study.

BACKGROUND: PHACE syndrome is a rare inborn condition characterized by large facial hemangiomas and variable malformations of the arterial system, heart, central nervous system, and eyes. According to Orphanet estimates, the prevalence is <1.0 per million. Data from Europe are limited to small case series, and there are no population-based data available. OBJECTIVES: We conducted the present study to provide population-based estimates of the disease prevalence of PHACE syndrome in children in Germany, Switzerland, and Austria. We compared these first systematic data on PHACE syndrome from Europe to published data from the PHACE Syndrome International Clinical Registry and Genetic Repository (USA). Clinical features in our cohort with PHACE syndrome were assessed in detail, including the need for early supportive measures. METHODS: We used a population-based approach by means of a previously well-established network of child neurologists from Germany, Switzerland, and Austria ("ESNEK") to identify potential patients. The patients' guardians and child neurologists were asked to fill in questionnaires developed in collaboration with the International PHACE Registry. RESULTS: We identified 19 patients with PHACE syndrome. Estimated prevalence rates were 6.5 per million in Switzerland, 0.59 per million in Germany, and 0.65 per million in Austria. A subset of 10 patients from Germany and Switzerland participated in our study, providing detailed clinical assessment (median age: 2.5 years; 9 females, 1 male). Cerebrovascular involvement was frequent (80%). Facial hemangioma extent correlated significantly with the number of organs involved (p = 0.011). In 9 out of 10 patients, facial hemangiomas were treated successfully with oral propranolol. Baseline demographic data as well as the rate of cerebrovascular and cardiovascular anomalies were in line with those from the US International PHACE Registry and other published PHACE cohorts. CONCLUSIONS: Our study provides population-based estimates for PHACE syndrome in 3 German-speaking countries. The data from Switzerland indicate that PHACE syndrome may be more prevalent than demonstrated by previous reports. Underreporting of PHACE syndrome in Germany and Austria likely accounts for the differences in prevalence rates. The clinical observation of a potential association between the size of facial hemangioma and extent of organ involvement warrants further investigation.

Unrelenting facial segmental hemangiomas: A case series of late growth and recurrent ulcerations.

Late growth of infantile hemangiomas is an uncommon complication. We report three patients with segmental facial hemangiomas who experienced late growth and recurrent ulceration predominantly of the lower lip. These patients shared common clinical features including involvement of the S3 facial segment, oral and airway hemangiomas, and vascular anomalies associated with PHACE syndrome. This report highlights a clinical presentation at-risk for late growth and recurrent ulceration.

Segmental infantile hemangioma and concomitant hypertension in three African American neonates.

We present three African American infants with segmental, ulcerated infantile hemangiomas and concomitant, persistent hypertension. When treated with beta-blocker therapy, the hemangiomas decreased in size and the ulcerations resolved, but there was no impact on the elevated blood pressure in one of our patients. We failed to identify any associations between infantile hemangioma and hypertension in the literature.

Hamartomas and midline anomalies in association with infantile hemangiomas, PHACE, and LUMBAR syndromes.

BACKGROUND/OBJECTIVE: The pathogenesis of infantile hemangiomas (IH), PHACE, and LUMBAR syndromes remains unknown. We aim to describe histopathologic features of midline anomalies associated with IH, including patients with PHACE and LUMBAR syndromes. METHODS: A multicenter retrospective chart review was performed to identify patients with IH, PHACE, and LUMBAR syndrome with histopathologic specimens from sternal or midline anomalies. A total of 18 midline lesions from 13 patients were included. Out of 18, 14 midline lesions underwent both histopathologic and clinical review. Three hamartoma-like chin plaques and one supraumbilical raphe underwent only clinical review. RESULTS: All 13 patients had midline lesions and IH. Histopathologic diagnoses were as follows: rhabdomyomatous mesenchymal hamartoma (3), folliculosebaceous cystic hamartoma (1), fibroepithelial polyp (1), verrucous epidermal hyperplasia with vascular proliferation and fibroplasia (1), congenital midline cervical cleft (1), pericardium with fibrosis (1), fibrous components with increased collagen (1), atrophic skin/membrane (3), angiolipomatous mass with neural components (1), and lipomatous mass (1). Due to the retrospective nature of this study, it was not possible to obtain pathology slides for all midline lesions that had previously been biopsied or resected. We show clinically and histopathologically a new association between PHACE syndrome and rhabdomyomatous mesenchymal hamartoma (RMH), in addition to demonstrating the association between PHACE syndrome and chin hamartomas. We also display histopathologic findings seen in midline lesions resected from LUMBAR patients. CONCLUSION: Rhabdomyomatous mesenchymal hamartoma is thought to be related to aberrations of mesenchymal cells during development; therefore, this may provide clues to the pathogenesis of IH and related syndromes.

Ocular Complications in PHACE Syndrome: A True Association or a Coincidence?

OBJECTIVE: To characterize the risk for ocular complications in patients with PHACE syndrome. STUDY DESIGN: This study included consecutive patients with PHACE syndrome who were seen at Lurie Children's Hospital of Chicago from January 2000 through May 2017. A complete ophthalmic examination was performed in all patients, with extra attention for findings typically associated with PHACE syndrome. RESULTS: Thirty patients (67% female, median age of onset 0.08 months) were included: 38 (93%) demonstrated a segmental infantile hemangioma distribution. Twenty-one (70%) cases had a periocular involvement, and 47% had an infantile hemangioma with a deep component. Among 21 patients with periocular distribution, 9 had ocular complications secondary to the periocular location (mainly ptosis, nasolacrimal duct obstruction, and refractive errors), and one had an ocular complication specifically associated with PHACE syndrome (Horner syndrome). None of the patients without periocular distribution had an ocular complication. CONCLUSIONS: In patients with PHACE syndrome who have a periocular infantile hemangioma, a complete eye examination is recommended. Although specific ocular anomalies related to PHACE syndrome are rare, serious ocular complications secondary to the location of the hemangioma may be present. Eye examination in patients with PHACE syndrome without a periocular infantile hemangioma distribution is likely of low yield.

Dieulafoy lesions and PHACE syndrome.

Dieulafoy's lesion (DL) is a small gastrointestinal (GI) mucosal erosion due to an abnormally large caliber and persistent submucosal arteriole. Typically occurring in adults, they are an extremely rare cause of GI bleeding in pediatrics. We report a case of multiple jejunal DLs in a 9-year-old girl with posterior fossa brain malformations, hemangiomas, arterial lesions, cardiac abnormalities, eye abnormalities (PHACE) syndrome, and the first described use of rapamycin in the treatment of pediatric DLs.

Natural history of PHACE syndrome: A survey of adults with PHACE.

BACKGROUND: Awareness of PHACE syndrome has increased; however, little information exists regarding its natural history, especially in patients over the age of 18. We aim to describe the natural history of PHACE to enhance clinical management and counseling of patients. METHODS: A cohort of patients ≥ 18 years was identified through the PHACE Syndrome Registry and a Vascular Anomalies Clinic Database. A cross-sectional survey was designed after a review of the literature by PHACE experts (IF, JP, DS). Questions were selected by consensus, and the survey was conducted using the Qualtrics platform and via in-person interviews. A 75% response rate was found. RESULTS: Eighteen adults-17 females and one transgender male-completed the survey. Respondents ranged in age from 18 to 59, with 24 being the mean age. Eighty-nine percent reported experiencing headaches, and 17% reported experiencing acute but transient symptoms mimicking acute ischemic stroke, later diagnosed as atypical migraines. Thirty-three percent reported hearing loss, and 67% endorsed dental issues. One patient experienced two arterial dissections. Three-fourths who attempted conception were successful, and none of their children had clinical features of PHACE. Because results were based on a retrospective survey, data captured were prone to recall bias and not objective. Results were limited by a small sample size. CONCLUSIONS: Health care providers should be aware of a possible increased risk of neurovascular complications, including atypical migraines mimicking transient ischemic attacks and arterial dissection, in adults with PHACE. Heritability has not been demonstrated, and future studies are needed to assess the risk of infertility.

[Infantile haemangioma: an update]. / Update infantile Hämangiome.

Infantile haemangioma (IH) are the most frequent skin tumors in childhood. The diagnosis is usually established from the clinical picture and typical course of growth. Sectional imaging procedures are indicated in segmental, especially facial haemangiomas. The vast majority of IH are uncomplicated and do not require any treatment. In complicated IH, treatment should be initiated as soon as possible in order to avoid permanent damage. Propranolol is the treatment of choice for complicated IH.

PHACE syndrome: Infantile hemangiomas associated with multiple congenital anomalies: Clues to the cause.

Infantile hemangiomas (IH) are the most common vascular tumor of infancy with an estimated 80,000 annual diagnoses in the United States. The genetic mechanisms underlying IH and the related multi-organ birth defect syndromes, PHACE (an acronym for Posterior fossa brain malformations, segmental facial Hemangiomas, Arterial anomalies, Cardiac defects, Eye anomalies, and sternal clefting or supraumbilical raphe) and LUMBAR (an acronym for Lower body hemangiomas, Urogenital anomalies, Myelopathy, Bone deformities, Anorectal malformations/Arterial anomalies, Renal anomalies) remain unsolved. With advances in next generation sequencing (NGS), genomic alterations have been identified in a wide range of vascular anomaly syndromes. We hypothesize that PHACE is a genetic disorder, caused by somatic mutations, likely in cancer genetic pathways. Identification of the genetic etiology will lead to improved diagnosis in PHACE syndrome and development of targeted therapies for IH and related congenital anomalies.

Structural malformations of the brain, eye, and pituitary gland in PHACE syndrome.

PHACE syndrome is the association of segmental facial hemangiomas with congenital arterial, brain, cardiac, and ocular anomalies. Structural brain malformations affect 41-52% of PHACE patients and can be associated with focal neurologic deficits, developmental delays, and/or intellectual disability. To better characterize the spectrum of structural brain and other intracranial anomalies in PHACE syndrome, MRI scans of the head/neck were retrospectively reviewed in 55 patients from the PHACE Syndrome International Clinical Registry and Genetic Repository. All registry patients with a diagnosis of definite PHACE syndrome who had MRI scans of satisfactory quality were included. Of 55 patients, 34 (62%) demonstrated ≥1 non-vascular intracranial anomaly; structural brain malformations were present in 19 (35%). There was no difference in the prevalence of brain anomalies between genders. Brain anomalies were more likely in patients with S1 and/or S2 distribution of facial hemangioma. The most common structural brain defects were cerebellar hypoplasia (25%) and fourth ventricle abnormalities (13%). Dandy-Walker complex and malformations of cortical development were present in 9% and 7%, respectively. Extra-axial findings such as pituitary anomalies (18%) and intracranial hemangiomas (18%) were also observed. Six patients (11%) had anomalies of the globes or optic nerve/chiasm detectable on MRI. Brain malformations comprise a diverse group of structural developmental anomalies that are common in patients with PHACE syndrome. Along with brain malformations, numerous abnormalities of the pituitary, meninges, and globes were observed, highlighting the need for careful radiologic assessment of these structures in the neuroimaging workup for PHACE syndrome.

Hearing loss in PHACE syndrome: clinical and radiologic findings.

PURPOSE: To characterize the types of hearing loss, auditory-related imaging findings, and hemangioma characteristics in patients with Posterior fossa malformations, Hemangiomas, Arterial anomalies, Cardiac defects, and abnormalities of the Eye (PHACE) syndrome. METHODS: Retrospective medical records, audiologic data, and imaging review of all patients presenting to a tertiary care children's hospital with a proven diagnosis of PHACE syndrome from 2005 to 2016. RESULTS: Twelve patients were identified with hearing and imaging data. 5/12 had hearing loss, 1 had unilateral severe sensorineural loss with minor conductive component, 1 had unilateral moderate sensorineural loss with minor conductive component, 1 had mild bilateral conductive loss, 1 had bilateral hearing loss (left severe mixed and right severe sensorineural), and 1 had moderate bilateral conductive loss. All patients passed their newborn hearing screening. Of the 5 patients with hearing loss, 3 had IAC hemangiomas (1 bilateral), 3 had enlarged IACs with prominent posterior petrous bones (1 bilateral), 2 had dysgenesis of the cerebellar vermis and hemispheres, there was 1 patient each with a deformed pinna and middle ear and mastoid effusions, and 1 patient had no abnormal auditory-related imaging findings. Patients with hearing loss were more likely to have more areas of cutaneous hemangioma involvement (mean 6.4 vs 3.1, p = .05). Laterality of hearing impairment correlated with the side of cutaneous hemangioma in all patients with hearing loss. Treatment with systemic propranolol did not improve hearing. CONCLUSIONS: Patients with PHACE are at risk for hearing loss and may demonstrate radiologic abnormalities within the ear structures, although the type of hearing loss, imaging findings, and their respective correlation vary. While our results are limited by our small sample size, comprehensive audiology evaluations (as opposed to newborn screening testing only) should be considered for PHACE patients who have extensive cutaneous hemangioma or auditory-related imaging abnormalities, such as internal auditory canal hemangiomas.

PHACE syndrome--clinical features, aetiology and management.

UNLABELLED: PHACE syndrome comprises a spectrum of anomalies including posterior fossa malformations, haemangioma, arterial anomalies, cardiac defects and eye anomalies. PHACE should be considered in any patient with a large facial segmental infantile haemangioma (IH), and multidisciplinary management is crucial. Low-dose propranolol is effectively for the treatment of IH associated with PHACE syndrome. Recent evidence suggests IH is comprised of mesoderm-derived haemogenic endothelium. CONCLUSION: The embryonic developmental anomaly nature of IH provides an insight into the origin of PHACE syndrome.

PHACE syndrome is associated with intracranial cavernous malformations.

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. 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.

Infantile hemangiomas and structural anomalies: PHACE and LUMBAR syndrome.

In a subset of patients, infantile hemangiomas may be associated with structural anomalies. Structural anomalies may affect the upper body (PHACE Syndrome) or the lower body (LUMBAR Syndrome). Since their initial descriptions, improved understanding of these two syndromes has lead to recognition of a broader phenotypic spectrum than initially recognized. This paper aims to provide an updated review of the presentation, associated anomalies, and management of PHACE and LUMBAR syndromes, two well-characterized syndromes associated with IH.

Prenatal unilateral cerebellar hypoplasia in a series of 26 cases: significance and implications for prenatal diagnosis.

OBJECTIVE: To define imaging patterns of unilateral cerebellar hypoplasia (UCH), discuss possible pathophysiological mechanisms and underline the etiology and prognosis associated with these lesions. METHODS: In this retrospective study we reviewed the charts of 26 fetuses diagnosed between 2003 and 2011 with UCH, defined by asymmetrical cerebellar hemispheres with or without decreased transverse cerebellar diameter. The review included analysis of the anatomy of the cerebellar hemispheres, including foliation, borders and parenchymal echogenicity, and of the severity of the hypoplasia. Data from clinical and biological work-up and follow-up were obtained. RESULTS: Our series could be divided into two groups according to whether imaging features changed progressively or remained constant during follow-up. In Group 1 (n = 8), the progression of imaging features, echogenic cerebellar changes and/or hyposignal in T2*-weighted MR images were highly suggestive of ischemic/hemorrhagic insult. In Group 2 (n = 18), imaging features remained constant during follow-up; UCH was associated with abnormal foliation in three proven cases of clastic lesions, a cystic lesion was noted in three cases of PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac abnormalities/aortic coarctation, eye abnormalities) syndrome and, in the remaining cases, UCH remained unchanged, with no imaging pattern typical of hemorrhage. In 24 cases the infant was liveborn and follow-up was continued in 23, for a mean period of 3 years. Among these, neurological complications were identified in seven (in one of seven (at a mean of 46 months) in Group 1 and in six of 16 (at a mean of 35 months) in Group 2). The surface loss of cerebellar hemisphere was > 50% in 19/24 fetuses and the vermis was clearly normal in appearance in 19/24. Predisposing factors for fetal vascular insult were identified in eight cases: these included maternal alcohol addiction, diabetes mellitus, congenital cytomegalovirus infection and pathological placenta with thrombotic vasculopathy and infarctions. CONCLUSION: UCH is defined as a focal lesion of the cerebellum that may be secondary to hemorrhage and/or ischemic insult, suggesting a clastic origin, particularly when imaging follow-up reveals changes over time. UCH may also be a clue for the prenatal diagnosis of PHACE syndrome. The amount of surface loss of cerebellar hemisphere does not correlate with poor prognosis. UCH with normal vermis is often associated with normal outcome.