Prenatal Risk Factors for PHACE Syndrome: A Study Using the PHACE Syndrome International Clinical Registry and Genetic Repository

Wan, Joy; Steiner, Jack E.; Baselga, Eulàlia; Blei, Francine; Cordisco, Maria; Garzon, María C.; Goddard, Deborah S.; Haggstrom, Anita N.; Krol, Alfons; Frieden, Ilona J.; Metry, Denise; Morel, Kimberly D.; Verhagen, Judith M.A.; Wargon, Orli; Drolet, Beth A.; Siegel, Dawn H.

doi:10.1016/j.jpeds.2017.06.055

Cited by 20 publications

(12 citation statements)

References 20 publications

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“…To date, the reasons for female predominance in PHACE syndrome remain to be elucidated. Regarding ethnicity, this cohort and previous reports indicate that PHACE syndrome is most prevalent in Cau- casians [3,9] while other races are less commonly affected.…”

Section: Demographic Featuressupporting

confidence: 54%

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

Disse¹,

Toelle

Schroeder

et al. 2020

Neuroepidemiology

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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.

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Section: Demographic Featuressupporting

confidence: 54%

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

Disse¹,

Toelle

Schroeder

et al. 2020

Neuroepidemiology

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“…2 Hemangiomas are also associated with PHACE syndrome, in which hemangiomas are associated with other abnormalities, including posterior fossa brain malformations, and cardiac abnormalities. 1,30 The fortuitous discovery of propranolol causing regression of hemangiomas has revolutionized the treatment of these lesions. 4 However, treatment of hemangiomas with propranolol is not risk free because propranolol may cause bradycardia, hypotension, and hypoglycemia as a consequence of beta blockade.…”

Section: Discussionmentioning

confidence: 99%

Propranolol exhibits activity against hemangiomas independent of beta blockade

et al. 2019

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Propranolol is a widely used beta blocker that consists of a racemic mixture of R and S stereoisomers. Only the S stereoisomer has significant activity against the beta-adrenergic receptor. A fortuitous clinical observation was made in an infant who received propranolol for cardiac disease, and regression of a hemangioma of infancy was noted. This has led to the widespread use of propranolol for the treatment of large and life-threatening hemangiomas of infancy. Infants receiving propranolol require monitoring to ensure that they do not suffer from side effects related to beta blockade. The exact mechanism of activity of propranolol in hemangioma of infancy is unknown. In this study, we treated hemangioma stem cells with both beta blockade active S- and inactive R-propranolol and looked for genes that were coordinately regulated by this treatment. Among the genes commonly downregulated, Angiopoietin-like 4 (ANGPTL4) was among the most regulated. We confirmed that propranolol isomers downregulated ANGPTL4 in endothelial cells, with greater downregulation of ANGPTL4 using the beta blockade inactive R-propranolol. ANGPTL4 is present in human hemangiomas of infancy. Finally, R-propranolol inhibited the growth of bEnd.3 hemangioma cells in vivo. The implication of this is that hemangioma growth can be blocked without the side effects of beta blockade. Given that humans have been exposed to racemic propranolol for decades and thus to R-propranolol, clinical development of R-propranolol for hemangiomas of infancy and other angiogenic diseases is warranted.

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“…This study found that the rates of preeclampsia and placenta previa during the gestation of the individuals with PHACE syndrome were significantly higher than rates of preeclampsia and placenta previa in the general population. In a survey of mothers of children with PHACE syndrome, known or suspected miscarriage was reported in 40.7%, which is statistically significantly higher than the general population rate of 10–20%, p < .001(Wan et al, ). There was no significant difference in the rates of infertility treatment between the PHACE cohort and the general population.…”

Section: Evidence For a Genetic Basis And Clues For Timing During Devmentioning

confidence: 94%

“…There have been several reports of twins with only one twin affected with PHACE syndrome (Chiappa et al, ; Patil, Moray, Kiran, & Battu, ). In a study of the PHACE syndrome registry, 5.9% individuals with PHACE syndrome were the product of a multiple gestation pregnancy, this is slightly higher than the US population prevalence (3.5%), but does not reach statistical significance (Wan et al, ). Therefore, multiple gestation does not appear to confer a higher risk of PHACE syndrome.…”

Section: Evidence For a Genetic Basis And Clues For Timing During Devmentioning

confidence: 96%

“…There is a female predominance in PHACE syndrome. Early studies reported a striking female to male ratio of 9:1, however this ratio of females to males has decreased slightly as a larger cohort has been established with a 4:1 female to male ratio (Wan et al, ). The female predominance has raised the question of whether skewed X‐inactivation may be playing a role in the pathogenesis of PHACE syndrome.…”

Section: Evidence For a Genetic Basis And Clues For Timing During Devmentioning

confidence: 99%

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

Siegel

2018

Am J Med Genet

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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.

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Prenatal Risk Factors for PHACE Syndrome: A Study Using the PHACE Syndrome International Clinical Registry and Genetic Repository

Cited by 20 publications

References 20 publications

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

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

Propranolol exhibits activity against hemangiomas independent of beta blockade

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

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