Abstract：Infant hemangioma, the most common benign tumor in children, is characterized by rapid proliferation, followed by slower spontaneous involution. However, some patients with facial segmental hemangioma are associated with PHACE syndrome. PHACE syndrome is characterized by vascular nerve and vascular cutaneous lesions of multiple systemic systems, often resulting in structural and functional impairments. Recent studies have demonstrated that the possible pathogeneses of PHACE syndrome mainly include hypoxia, abnormality of mesodermal vascular endothelial cells, genetic abnormality, and abnormality of interstitial mesenchymal stem cells. The current medications for hemangioma with PHACE syndrome include beta blockers, glucocorticoids, and mTOR inhibitors. This review article mainly describes the pathogenesis, diagnoses and treatments of PHACE syndrome, in order to provide directions for diagnosis and treatment of this disorder.
PENG Su-Hua,YANG Kai-Ying,CHEN Si-Yuan et al. Research progresses in the pathogenesis, diagnosis and treatment of infantile hemangioma with PHACE syndrome[J]. CJCP, 2017, 19(12): 1291-1296.
Harbi S, Wang R, Gregory M, et al. Infantile hemangioma originates from a dysregulated but not fully transformed multipotent stem cell[J]. Sci Rep, 2016, 6:35811.
[3]
Ji Y, Wang Q, Chen S, et al. Oral atenolol therapy for proliferating infantile hemangioma:a prospective study[J]. Medicine (Baltimore), 2016, 95(24):e3908.
[4]
Haggstrom AN, Garzon MC, Baselga E, et al. Risk for PHACE syndrome in infants with large facial hemangiomas[J]. Pediatrics, 2010, 126(2):e418-e426.
[5]
Fernández-Ibieta M, López-Gutiérrez JC. Lymphatic malformation, retinoblastoma, or facial cleft:atypical presentations of PHACE syndrome[J]. Case Rep Dermatol Med, 2015, 2015:487562.
[6]
Winter PR, Itinteang T, Leadbitter P, et al. PHACE syndrome-clinical features, aetiology and management[J]. Acta Paediatr, 2016, 105(2):145-153.
[7]
Hoornweg MJ, Smeulders MJ, Ubbink DT, et al. The prevalence and risk factors of infantile haemangiomas:a case-control study in the Dutch population[J]. Paediatr Perinat Epidemiol, 2012, 26(2):156-162.
[8]
Metry D, Heyer G, Hess C, et al. Consensus statement on diagnostic criteria for PHACE syndrome[J]. Pediatrics, 2009, 124(5):1447-1456.
[9]
Chen TS, Eichenfield LF, Friedlander SF. Infantile hemangiomas:an update on pathogenesis and therapy[J]. Pediatrics, 2013, 131(1):99-108.
[10]
Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities[J]. Arch Dermatol, 1996, 132(3):307-311.
[11]
Garzon MC, Epstein LG, Heyer GL, et al. PHACE syndrome:consensus-derived diagnosis and care recommendations[J]. J Pediatr, 2016, 178:24-33.e2.
[12]
Hess CP, Fullerton HJ, Metry DW, et al. Cervical and intracranial arterial anomalies in 70 patients with PHACE syndrome[J]. AJNR Am J Neuroradiol, 2010, 31(10):1980-1986.
[13]
Itinteang T, Withers AH, Davis PF, et al. Biology of infantile hemangioma[J]. Front Surg, 2014, 1:38.
[14]
Darrow DH, Greene AK, Mancini AJ, et al. Diagnosis and management of infantile hemangioma[J]. Pediatrics, 2015, 136(4):e1060-e1104.
[15]
Dai Y, Hou F, Buckmiller L, et al. Decreased eNOS protein expression in involuting and propranolol-treated hemangiomas[J]. Arch Otolaryngol Head Neck Surg, 2012, 138(2):177-182.
[16]
Kleinman ME, Blei F, Gurtner GC. Circulating endothelial progenitor cells and vascular anomalies[J]. Lymphat Res Biol, 2005, 3(4):234-239.
[17]
Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children:a classification based on endothelial characteristics[J]. Plast Reconstr Surg, 1982, 69(3):412-422.
[18]
Kim ME, Cancel M, Metry D, et al. Evaluation of maternal history of miscarriage, infertility, and in vitro fertilization as associated factors in PHACE[J]. Br J Dermatol, 2017, 177(4):e90-e91.
[19]
Schilter KF, Steiner JE, Demos W, et al. RNF213 variants in a child with PHACE syndrome and moyamoya vasculopathy[J]. Am J Med Genet A, 2017, 173(9):2557-2561.
[20]
Cecchi AC, Guo D, Ren Z, et al. RNF213 rare variants in an ethnically diverse population with Moyamoya disease[J]. Stroke, 2014, 45(11):3200-3207.
[21]
Sullivan CT, Christian SL, Shieh JT, et al. X chromosome-inactivation patterns in 31 individuals with PHACE syndrome[J]. Mol Syndromol, 2013, 4(3):114-118.
[22]
Colonna V, Resta L, Napoli A, et al. Placental hypoxia and neonatal haemangioma:clinical and histological observations[J]. Br J Dermatol, 2010, 162(1):208-209.
[23]
Nabatian AS, Milgraum SS, Hess CP, et al. PHACE without face? Infantile hemangiomas of the upper body region with minimal or absent facial hemangiomas and associated structural malformations[J]. Pediatr Dermatol, 2011, 28(3):235-241.
[24]
Brandon K, Burrows P, Hess C, et al. Arteriovenous malformation:a rare manifestation of PHACE syndrome[J]. Pediatr Dermatol, 2011, 28(2):180-184.
[25]
Haggstrom AN, Lammer EJ, Schneider RA, et al. Patterns of infantile hemangiomas:new clues to hemangioma pathogenesis and embryonic facial development[J]. Pediatrics, 2006, 117(3):698-703.
[26]
Ji Y, Chen S, Xiang B, et al. Safety and tolerance of propranolol in neonates with severe infantile hemangiomas:a prospective study[J]. Sci Rep, 2017, 7(1):1503.
[27]
Hoeger PH, Harper JI, Baselga E, et al. Treatment of infantile haemangiomas:recommendations of a European expert group[J]. Eur J Pediatr, 2015, 174(7):855-865.
[28]
Lackner H, Karastaneva A, Schwinger W, et al. Sirolimus for the treatment of children with various complicated vascular anomalies[J]. Eur J Pediatr, 2015, 174(12):1579-1584.
[29]
Winter PR, Itinteang T, Leadbitter P, et al. PHACE(S) syndrome with absent intracranial internal carotid artery and anomalous circle of willis[J]. J Craniofac Surg, 2015, 26(4):e315-e317.
[30]
Vivas-Colmenares GV, Fernandez-Pineda I, Lopez-Gutierrez JC, et al. Analysis of the therapeutic evolution in the management of airway infantile hemangioma[J]. World J Clin Pediatr, 2016, 5(1):95-101.
[31]
Durr ML, Meyer AK, Huoh KC, et al. Airway hemangiomas in PHACE syndrome[J]. Laryngoscope, 2012, 122(10):2323-2329.
[32]
Ji Y, Chen S, Xu C, et al. The use of propranolol in the treatment of infantile haemangiomas:an update on potential mechanisms of action[J]. Br J Dermatol, 2015, 172(1):24-32.
[33]
Metry D, Frieden IJ, Hess C, et al. Propranolol use in PHACE syndrome with cervical and intracranial arterial anomalies:collective experience in 32 infants[J]. Pediatr Dermatol, 2013, 30(1):71-89.
[34]
Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma:report of a consensus conference[J]. Pediatrics, 2013, 131(1):128-140.
[35]
Webb AJ, Fischer U, Rothwell PM. Effects of β-blocker selectivity on blood pressure variability and stroke:a systematic review[J]. Neurology, 2011, 77(8):731-737.
[36]
Siegel DH, Tefft KA, Kelly T, et al. Stroke in children with posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome:a systematic review of the literature[J]. Stroke, 2012, 43(6):1672-1674.
[37]
Püttgen K, Lucky A, Adams D, et al. Topical timolol maleate treatment of infantile hemangiomas[J]. Pediatrics, 2016, 138(3). pii:e20160355.
[38]
Khunger N, Pahwa M. Dramatic response to topical timolol lotion of a large hemifacial infantile haemangioma associated with PHACE syndrome[J]. Br J Dermatol, 2011, 164(4):886-888.
[39]
Fontana E, Causin F, De Corti F, et al. Phace syndrome:is timolol gel a chance for treatment?[J]. J Eur Acad Dermatol Venereol, 2017, 31(7):e345-e346.
[40]
Pope E, Chakkittakandiyil A, Lara-Corrales I, et al. Expanding the therapeutic repertoire of infantile haemangiomas:cohort-blinded study of oral nadolol compared with propranolol[J]. Br J Dermatol, 2013, 168(1):222-224.
[41]
Tan CE, Itinteang T, Leadbitter P, et al. Low-dose propranolol regimen for infantile haemangioma[J]. J Paediatr Child Health, 2015, 51(4):419-424.
[42]
Kim KH, Choi TH, Choi Y, et al. Comparison of efficacy and safety between propranolol and steroid for infantile hemangioma:a randomized clinical trial[J]. JAMA Dermatol, 2017, 153(6):529-536.
[43]
Pandey A, Gangopadhyay AN, Sharma SP, et al. Evaluation of topical steroids in the treatment of superficial hemangioma[J]. Skinmed, 2010, 8(1):9-11.
[44]
Janmohamed SR, Madern GC, Nieuwenhuis K, et al. Evaluation of intra-lesional corticosteroids in the treatment of peri-ocular haemangioma of infancy:still an alternative besides propranolol[J]. Pediatr Surg Int, 2012, 28(4):393-398.
[45]
Nadal M, Giraudeau B, Tavernier E, et al. Efficacy and safety of mammalian target of rapamycin inhibitors in vascular anomalies:a systematic review[J]. Acta Derm Venereol, 2016, 96(4):448-452.
[46]
Triana P, Dore M, Cerezo VN, et al. Sirolimus in the treatment of vascular anomalies[J]. Eur J Pediatr Surg, 2017, 27(1):86-90.
[47]
Phillips JD, Zhang H, Wei T, et al. Expression of β-adrenergic receptor subtypes in proliferative, involuted, and propranolol-responsive infantile hemangiomas[J]. JAMA Facial Plast Surg, 2017, 19(2):102-107.
[48]
Ji Y, Chen S, Xiang B, et al. Sirolimus for the treatment of progressive kaposiform hemangioendothelioma:a multicenter retrospective study[J]. Int J Cancer, 2017, 141(4):848-855.
[49]
Kaylani S, Theos AJ, Pressey JG. Treatment of infantile hemangiomas with sirolimus in a patient with PHACE syndrome[J]. Pediatr Dermatol, 2013, 30(6):e194-e197.
