Child's Nervous System

, Volume 26, Issue 10, pp 1407–1415 | Cite as

Neurocutaneous vascular syndromes

  • Katherine B. PuttgenEmail author
  • Doris D. M. Lin
Special Annual Issue


There have been significant recent advances in the past several years in the field of neurocutaneous vascular syndromes, including the development of more stringent diagnostic criteria for PHACE syndrome, the renaming of macrocephaly-cutis marmorata telangiectatica congenita to macrocephaly-capillary malformation to accurately reflect the true nature of the syndrome, and discovery of new genetic mutations such as RASA-1. There have also been advances in the understanding and management of Sturge-Weber syndrome.

PHACE syndrome is a constellation of neurologic, arterial, cardiac, ophthalmologic, and sternal abnormalities associated with infantile hemangiomas. PHACE is an acronym for Posterior fossa malformation, Hemangioma, Arterial anomalies, Coarctation of the aorta, Eye abnormalities. Some authors include an “S” for PHACE(S) to denote the association of ventral defects including Sternal clefting and Supraumbilical raphe.

The accurate diagnosis and work-up of these patients require coordination of care across multiple disciplines, including neuroradiology, radiology, dermatology, neurology, surgery, and interventional radiology, among others.

This paper is meant to update clinicians and researchers about important advances in these rare, important vascular syndromes, to improve care, and lay the foundation for future directions for research.


PHACE Hemangioma Sturge-Weber Macrocephaly-capillary malformation 


  1. 1.
    Aylett SE, Neville BG, Cross JH, Boyd S, Chong WK, Kirkham FJ (1999) Sturge-Weber syndrome: cerebral haemodynamics during seizure activity. Dev Med Child Neurol 41:480–485CrossRefPubMedGoogle Scholar
  2. 2.
    Bar-Sever Z, Connolly LP, Barnes PD, Treves ST (1996) Technetium-99m-HMPAO SPECT in Sturge-Weber syndrome. J Nucl Med 37:81–83PubMedGoogle Scholar
  3. 3.
    Bourgeois M, Crimmins DW, de Oliveira RS, Arzimanoglou A, Garnett M, Roujeau T, Di Rocco F, Sainte-Rose C (2007) Surgical treatment of epilepsy in Sturge-Weber syndrome in children. J Neurosurg 106:20–28PubMedGoogle Scholar
  4. 4.
    Brouillard P, Vikkula M (2007) Genetic causes of vascular malformations. Hum Mol Genet 16 Spec No 2:R140–R149CrossRefPubMedGoogle Scholar
  5. 5.
    Burrows PE, Robertson RL, Mulliken JB, Beardsley DS, Chaloupka JC, Ezekowitz RA, Scott RM (1998) Cerebral vasculopathy and neurologic sequelae in infants with cervicofacial hemangioma: report of eight patients. Radiology 207:601–607PubMedGoogle Scholar
  6. 6.
    Clayton-Smith J, Kerr B, Brunner H, Tranebjaerg L, Magee A, Hennekam RC, Mueller RF, Brueton L, Super M, Steen-Johnsen J, Donnai D (1997) Macrocephaly with cutis marmorata, haemangioma and syndactyly–a distinctive overgrowth syndrome. Clin Dysmorphol 6:291–302CrossRefPubMedGoogle Scholar
  7. 7.
    Comi AM (2003) Topical review: pathophysiology of Sturge-Weber syndrome. J Child Neurol 18:509–516CrossRefPubMedGoogle Scholar
  8. 8.
    Comi AM (2007) Update on Sturge-Weber syndrome: diagnosis, treatment, quantitative measures, and controversies. Lymphat Res Biol 5:257–264CrossRefPubMedGoogle Scholar
  9. 9.
    Comi AM (2007) Sturge-Weber syndrome and epilepsy: an argument for aggressive seizure management in these patients. Expert Rev Neurother 7:951–956CrossRefPubMedGoogle Scholar
  10. 10.
    Conway RL, Pressman BD, Dobyns WB, Danielpour M, Lee J, Sanchez-Lara PA, Butler MG, Zackai E, Campbell L, Saitta SC, Clericuzio CL, Milunsky JM, Hoyme HE, Shieh J, Moeschler JB, Crandall B, Lauzon JL, Viskochil DH, Harding B, Graham JM Jr (2007) Neuroimaging findings in macrocephaly-capillary malformation: a longitudinal study of 17 patients. Am J Med Genet A 143A:2981–3008CrossRefPubMedGoogle Scholar
  11. 11.
    Di Rocco C, Tamburrini G (2006) Sturge-Weber syndrome. Childs Nerv Syst 22:909–921CrossRefPubMedGoogle Scholar
  12. 12.
    Di Trapani G, Di Rocco C, Abbamondi AL, Caldarelli M, Pocchiari M (1982) Light microscopy and ultrastructural studies of Sturge-Weber disease. Childs Brain 9:23–36PubMedGoogle Scholar
  13. 13.
    Drolet BA, Dohil M, Golomb MR, Wells R, Murowski L, Tamburro J, Sty J, Friedlander SF (2006) Early stroke and cerebral vasculopathy in children with facial hemangiomas and PHACE association. Pediatrics 117:959–964CrossRefPubMedGoogle Scholar
  14. 14.
    Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, Vanwijck R, Vikkula M (2003) Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 73:1240–1249CrossRefPubMedGoogle Scholar
  15. 15.
    Frieden IJ, Reese V, Cohen D (1996) PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol 132:307–311CrossRefPubMedGoogle Scholar
  16. 16.
    Grewal T, Evans R, Rentero C, Tebar F, Cubells L, de Diego I, Kirchhoff MF, Hughes WE, Heeren J, Rye KA, Rinninger F, Daly RJ, Pol A, Enrich C (2005) Annexin A6 stimulates the membrane recruitment of p120GAP to modulate Ras and Raf-1 activity. Oncogene 24:5809–5820CrossRefPubMedGoogle Scholar
  17. 17.
    Griffiths PD (1996) Sturge-Weber syndrome revisited: the role of neuroradiology. Neuropediatrics 27:284–294CrossRefPubMedGoogle Scholar
  18. 18.
    Griffiths PD, Boodram MB, Blaser S, Armstrong D, Gilday DL, Harwood-Nash D (1997) 99 mTechnetium HMPAO imaging in children with the Sturge-Weber syndrome: a study of nine cases with CT and MRI correlation. Neuroradiology 39:219–224CrossRefPubMedGoogle Scholar
  19. 19.
    Griffiths PD, Coley SC, Romanowski CA, Hodgson T, Wilkinson ID (2003) Contrast-enhanced fluid-attenuated inversion recovery imaging for leptomeningeal disease in children. AJNR Am J Neuroradiol 24:719–723PubMedGoogle Scholar
  20. 20.
    Gripp KW, Hopkins E, Vinkler C, Lev D, Malinger G, Lerman-Sagie T, Dobyns WB (2009) Significant overlap and possible identity of macrocephaly capillary malformation and megalencephaly polymicrogyria-polydactyly hydrocephalus syndromes. Am J Med Genet A 149A:868–876CrossRefPubMedGoogle Scholar
  21. 21.
    Haggstrom A, Lammer E, Schneider R, Marcucio R, Frieden I (2006) Patterns of infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Pediatrics 117:698–703CrossRefPubMedGoogle Scholar
  22. 22.
    Henkemeyer M, Rossi DJ, Holmyard DP, Puri MC, Mbamalu G, Harpal K, Shih TS, Jacks T, Pawson T (1995) Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature 377:695–701CrossRefPubMedGoogle Scholar
  23. 23.
    Hershkovitz D, Bercovich D, Sprecher E, Lapidot M (2008) RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations. Br J Dermatol 158:1035–1040CrossRefPubMedGoogle Scholar
  24. 24.
    Hershkovitz D, Bergman R, Sprecher E (2008) A novel mutation in RASA1 causes capillary malformation and limb enlargement. Arch Dermatol Res 300:385–388CrossRefPubMedGoogle Scholar
  25. 25.
    Heyer GL, Dowling MM, Licht DJ, Tay SK-H, Morel K, Garzon MC, Meyers P (2008) The cerebral vasculopathy of PHACES syndrome. Stroke 39:308–316CrossRefPubMedGoogle Scholar
  26. 26.
    Jacobs A, Walton R (1976) The incidence of birthmarks in the neonate. Pediatrics 58:218–222PubMedGoogle Scholar
  27. 27.
    Kulkarni SV, Gish G, van der Geer P, Henkemeyer M, Pawson T (2000) Role of p120 Ras-GAP in directed cell movement. J Cell Biol 149:457–470CrossRefPubMedGoogle Scholar
  28. 28.
    Lapunzina P, Gairi A, Delicado A, Mori MA, Torres ML, Goma A, Navia M, Pajares IL (2004) Macrocephaly-cutis marmorata telangiectatica congenita: report of six new patients and a review. Am J Med Genet A 130A:45–51CrossRefPubMedGoogle Scholar
  29. 29.
    Maria B, Hoang K, Robertson R, Barnes P, Drane W, Chugani H (1999) Imaging brain structure and function in Sturge-Weber syndrome. In: Bodensteiner J, Roach E (eds) Sturge-Weber syndrome. Sturge-Weber Foundation, Mt Freedom, pp 43–69Google Scholar
  30. 30.
    Maria BL, Neufeld JA, Rosainz LC, Drane WE, Quisling RG, Ben-David K, Hamed LM (1998) Central nervous system structure and function in Sturge-Weber syndrome: evidence of neurologic and radiologic progression. J Child Neurol 13:606–618CrossRefPubMedGoogle Scholar
  31. 31.
    Metry D, Heyer G, Hess C, Garzon M, Haggstrom A, Frommelt P, Adams D, Siegel D, Hall K, Powell J, Frieden I, Drolet B (2009) Consensus statement on diagnostic criteria for PHACE syndrome. Pediatrics 124:1447–1456CrossRefPubMedGoogle Scholar
  32. 32.
    Metry DW, Haggstrom AN, Drolet BA, Baselga E, Chamlin S, Garzon M, Horii K, Lucky A, Mancini AJ, Newell B, Nopper A, Heyer G, Frieden IJ (2006) A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications. Am J Med Genet A 140A:975–986CrossRefGoogle Scholar
  33. 33.
    Moore C, Toriello H, Abuelo D, Bull M, Curry C, Hall B, Higgins J, Stevens C, Twersky S, Weksberg R, Dobyns W (1997) Macrocephaly-cutis marmorata telangiectatica congenita: a distinct disorder with developmental delay and connective tissue abnormalities. Am J Med Genet A 70:67–73CrossRefGoogle Scholar
  34. 34.
    Mulliken J, Young A (1988) Vascular birthmarks: hemangiomas and malformations. Saunders, PhiladelphiaGoogle Scholar
  35. 35.
    Namer IJ, Battaglia F, Hirsch E, Constantinesco A, Marescaux C (2005) Subtraction ictal SPECT co-registered to MRI (SISCOM) in Sturge-Weber syndrome. Clin Nucl Med 30:39–40CrossRefPubMedGoogle Scholar
  36. 36.
    Pascual-Castroviejo I (1978) Vascular and nonvascular intracranial malformation associated with external capillary hemangiomas. Neuroradiology 16:82–84CrossRefPubMedGoogle Scholar
  37. 37.
    Pascual-Castroviejo I, Pascual-Pascual SI, Viano J, Martinez V, Coya J (1995) Sturge-Weber syndrome without facial nevus. Neuropediatrics 26:220–222CrossRefPubMedGoogle Scholar
  38. 38.
    Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, Viano J (2008) Sturge-Weber syndrome: study of 55 patients. Can J Neurol Sci 35:301–307PubMedGoogle Scholar
  39. 39.
    Peterman AF, Hayles AB, Dockerty MB, Love JG (1958) Encephalotrigeminal angiomatosis (Sturge-Weber disease); clinical study of thirty-five cases. J Am Med Assoc 167:2169–2176PubMedGoogle Scholar
  40. 40.
    Reid DE, Maria BL, Drane WE, Quisling RG, Hoang KB (1997) Central nervous system perfusion and metabolism abnormalities in Sturge-Weber syndrome. J Child Neurol 12:218–222CrossRefPubMedGoogle Scholar
  41. 41.
    Revencu N, Boon L, Mulliken J, Enjolras O, Cordisco M, Burrows P, Clapuyt P, Hammer F, Dubois J, Baselga E, Brancati F, Carder R, Quintal J, Dallapiccola B, Fischer G, Frieden I, Garzon M, Harper J, Johnson-Patel J, Labrèze C, Martorell L, Paltiel H, Pohl A, Prendiville J, Quere I, Siegel D, Valente E, Van Hagen A, Van Hest L, Vaux K, Vicente A, Weibel L, Chitayat D, Vikkula M (2008) Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat 29:959–965CrossRefPubMedGoogle Scholar
  42. 42.
    Roach E, Bodensteiner J (1999) Neurologic manifestations of Sturge-Weber syndrome. In: Bodensteiner J, Roach E (eds) Sturge-Weber syndrome. Sturge-Weber Foundation, Mt Freedom, pp 27–38Google Scholar
  43. 43.
    Sujansky E, Conradi S (1995) Sturge-Weber syndrome: age of onset of seizures and glaucoma and the prognosis for affected children. J Child Neurol 10:49–58CrossRefPubMedGoogle Scholar
  44. 44.
    Tallman B, Tan OT, Morelli JG, Piepenbrink J, Stafford TJ, Trainor S, Weston WL (1991) Location of port-wine stains and the likelihood of ophthalmic and/or central nervous system complications. Pediatrics 87:323PubMedGoogle Scholar
  45. 45.
    Thomas-Sohl KA, Vaslow DF, Maria BL (2004) Sturge-Weber syndrome: a review. Pediatr Neurol 30:303–310CrossRefPubMedGoogle Scholar
  46. 46.
    Thong MK, Thompson E, Keenan R, Simmer K, Harbord M, Davidson G, Haan E (1999) A child with hemimegalencephaly, hemihypertrophy, macrocephaly, cutaneous vascular malformation, psychomotor retardation and intestinal lymphangiectasia–a diagnostic dilemma. Clin Dysmorphol 8:283–286CrossRefPubMedGoogle Scholar
  47. 47.
    Toriello H, Mulliken J (2007) Accurately renaming macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) as macrocephaly-capillary malformation (M-CM). Am J Med Genet A 143A:3009CrossRefPubMedGoogle Scholar
  48. 48.
    Trahey M, Wong G, Halenbeck R, Rubinfeld B, Martin GA, Ladner M, Long CM, Crosier WJ, Watt K, Koths K et al (1988) Molecular cloning of two types of GAP complementary DNA from human placenta. Science 242:1697–1700CrossRefPubMedGoogle Scholar
  49. 49.
    Wright DR, Frieden IJ, Orlow SJ, Shin HT, Chamlin S, Schaffer JV, Paller AS (2009) The misnomer “macrocephaly-cutis marmorata telangiectatica congenita syndrome”: report of 12 new cases and support for revising the name to macrocephaly-capillary malformations. Arch Dermatol 145:287–293CrossRefPubMedGoogle Scholar
  50. 50.
    Yeakley JW, Woodside M, Fenstermacher MJ (1992) Bilateral neonatal Sturge-Weber-Dimitri disease: CT and MR findings. AJNR Am J Neuroradiol 13:1179–1182PubMedGoogle Scholar
  51. 51.
    Yue Y, Lypowy J, Hedhli N, Abdellatif M (2004) Ras GTPase-activating protein binds to Akt and is required for its activation. J Biol Chem 279:12883–12889CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Department of Dermatology, Division of Pediatric DermatologyJohns Hopkins HospitalBaltimoreUSA
  2. 2.Department of NeuroradiologyJohns Hopkins HospitalBaltimoreUSA

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