Capillary Malformation–Arteriovenous Malformation and RASA1 Mutations

Laurence M Boon, Université catholique de Louvain, Brussels, Belgium
Nicole Revencu, Université catholique de Louvain, Brussels, Belgium
Miikka Vikkula, Université catholique de Louvain, Brussels, Belgium

Published online: September 2011

DOI: 10.1002/9780470015902.a0022479

Capillary malformation–arteriovenous malformation (CM–AVM) is a subtype of CM that is inherited as an autosomal-dominant disorder. Patients typically have multiple small pinkish-reddish CMs, often with a halo. These lesions are randomly distributed on the body. About 15–20% of patients have an associated arteriovenous fistula or malformation often located on head and neck. The fast-flow lesions involve skin, subcutaneous tissue, muscle and/or bone or the brain or the spine. Parkes Weber syndrome and vein of Galen aneurysmal malformation are also part of CM–AVM. Most CM–AVM patients have a detectable RASA1 mutation causing loss-of-function of p120RASGAP, a guanosine triphosphatase-activating protein, which participates in the regulation of the Ras signalling pathway. Most mutations are private and no genotype–phenotype correlation has been identified. A somatic second hit is likely necessary to produce lesional, complete loss-of-function of p120RASGAP, as the malformations are localised, and often multifocal. Ras-pathway modulators may provide futuristic therapies for CM–AVM.

Key Concepts:

  • Multifocal, often small, capillary malformations may be hereditary.
  • Lesions with pale reddish-brownish colour, a halo and/or a good demarcation line suggest CM–AVM.
  • Numerous miliary telangiectasias (often on extremities) are also suggestive of CM–AVM.
  • Many, but not all patients, also have a fast-flow lesion.
  • Distribution of fast-flow lesions differs from that of hereditary haemorrhagic telangiectasia.
  • Until better statistics exist, clinical examination should include T1/T2 brain MRI, when molecular diagnosis is confirmed.
  • These CMs do not respond well to current lasers.
  • RASA1-dominant mutations are mostly private, that is, specific to each family.
  • Parkes Weber syndrome patients with CMs elsewhere on the body are likely to carry a RASA1 mutation.
  • Family history is not necessarily present, as de novo mutations occur.

Keywords: Parkes Weber syndrome; Klippel–Trenaunay syndrome; arteriovenous fistula; hypertrophy; telangiectasia; vein of Galen aneurysmal malformation; genetic; gene

Figure 1. Multifocal CMs in a 6-year-old girl affected with CM–AVM. Note the halo (arrow head) around lesions in (a) and (b) but not in (c).
Figure 2. Fast-flow malformations in CM–AVM patients: (a) Haemifacial AVM in an 18-year-old boy involving the skin (arrows), subcutaneous tissue, muscles and maxilla, and causing bony and gingival hypertrophy. (b) Parkes Weber syndrome in a 6-year-old girl causing leg length discrepancy. Note capillary blush on the skin (arrows).
Figure 3. Differential diagnosis of CM–AVM: (a) Stork bite, (b) sporadic CM, (c) hereditary haemorrhagic telangiectasia and (d) Klippel–Trenaunay syndrome (capillaro–lymphatico–venous malformation with limb hypertrophy).
Figure 4. Schematic representation of the RASA1 gene and the 81 distinct CM–AVM causing mutations identified until now. Exons (boxed) and introns (lines) are drawn to scale, except for intron 1 (longer than shown); untranslated regions, small open boxes. Known domains of p120-RasGAP protein marked below exons; star, frame-shift mutation; diamond, nonsense mutation; triangle, splicing mutation; square, in-frame del/ins mutation; circle, missense mutation.
close
 References
    Boon LM, Ballieux F and Vikkula M (2011b) Pathogenesis of vascular anomalies. Clinics in Plastic Surgery 38(1): 7–19.
    book Boon LM, Enjolras O, Mulliken JB and Vikkula M (2011a) "Vascular malformations". In: Irvine A, Hoeger P and Yan A (eds) Harper, Textbook of Pediatric Dermatology, 3rd edn, pp. 112.1–112.4. Oxford, UK: Wiley-Blackwell.
    Boon LM, Mulliken JB and Vikkula M (2005) RASA1: variable phenotype with capillary and arteriovenous malformations. Current Opinion in Genetics & Development 15(3): 265–269.
    Breugem CC, Alders M, Salieb-Beugelaar GB et al. (2002) A locus for hereditary capillary malformations mapped on chromosome 5q. Human Genetics 110(4): 343–347.
    Brouillard P, Boon LM, Mulliken JB et al. (2002) Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (‘glomangiomas’). American Journal of Human Genetics 70(4): 866–874.
    book Burrows PE and Fellows KE (1995) "Techniques for management of pediatric vascular anomalies". In: Cope C (ed.) Current Techniques in Interventional Radiology. Current Medicine, pp. 12–27. Philadelphia: Thieme.
    Capraro PA, Fisher J, Hammond DC and Grossman JA (2002) Klippel–Trenaunay syndrome. Plastic and Reconstructive Surgery 109(6): 2052–2060, quiz 61-2.
    Carr CW, Zimmerman HH, Martin CL et al. (2011) 5q14.3 neurocutaneous syndrome: a novel continguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C. American Journal of Medical Genetics. Part A 155: 1640–1645. doi: 10.1002/ajmg.a.34059.
    Ceballos-Quintal JM, Pinto-Escalante D and Castillo-Zapata I (1996) A new case of Klippel–Trenaunay–Weber (KTW) syndrome: evidence of autosomal dominant inheritance. American Journal of Medical Genetics 63(3): 426–427.
    Cohen MM Jr (2000) Klippel–Trenaunay syndrome. American Journal of Medical Genetics 93(3): 171–175.
    book Cohen MM, Neri G and Weksberg R (2002) Overgrowth Syndromes (Oxford Monographs on Medical Genetics), vol. 43, pp. 75–110. Oxford: Oxford University Press.
    Dompmartin A, Vikkula M and Boon LM (2010) Venous malformation: update on aetiopathogenesis, diagnosis and management. Phlebology 25: 224–235.
    Easey AJ, Wallace GM, Hughes JM et al. (2003) Should asymptomatic patients with hereditary haemorrhagic telangiectasia (HHT) be screened for cerebral vascular malformations? Data from 22,061 years of HHT patient life. Journal of Neurology Neurosurgery & Psychiatry 74(6): 743–748.
    Eerola I, Boon LM, Mulliken JB et al. (2003) Capillary malformation–arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. American Journal of Human Genetics 73(6): 1240–1249.
    Eerola I, Boon LM, Watanabe S et al. (2002) Locus for susceptibility for familial capillary malformation (‘port-wine stain’) maps to 5q. European Journal of Human Genetics 10(6): 375–380.
    Engels H, Wohlleber E, Zink A et al. (2009) A novel microdeletion syndrome involving 5q14.3–q15: clinical and molecular cytogenetic characterization of three patients. European Journal of Human Genetics 17(12): 1592–1599.
    Enjolras O, Borsik M, Herbreteau D and Merland JJ (1994) Management of arteriovenous malformations. Annales de Dermatologie et de Venereologie 121(1): 59–64.
    Gallione CJ, Repetto GM, Legius E et al. (2004) A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363(9412): 852–859.
    van der Geer P, Henkemeyer M, Jacks T and Pawson T (1997) Aberrant Ras regulation and reduced p190 tyrosine phosphorylation in cells lacking p120-Gap. Molecular and Cellular Biology 17(4): 1840–1847.
    Henkemeyer M, Rossi DJ, Holmyard DP et al. (1995) Vascular system defects and neuronal apoptosis in mice lacking ras GTPase-activating protein. Nature 377(6551): 695–701.
    Hershkovitz D, Bercovich D, Sprecher E and Lapidot M (2008a) RASA1 mutations may cause hereditary capillary malformations without arteriovenous malformations. The British Journal of Dermatology 158(5): 1035–1040.
    Hershkovitz D, Mandel H, Ishida-Yamamoto A et al. (2008b) Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B. Archives of Dermatology 144(3): 334–340.
    van der Horst CM, Koster PH, de Borgie CA, Bossuyt PM and van Gemert MJ (1998) Effect of the timing of treatment of port-wine stains with the flash-lamp-pumped pulsed-dye laser. New England Journal of Medicine 338(15): 1028–1033.
    van der Horst CMAM, van Eijk TGJ, de Borgie CAJM et al. (1999) Hereditary port-wine stains, do they exist? Lasers in Medical Science 14(3): 238–243.
    Hurst J and Baraitser M (1988) Hereditary neurocutaneous angiomatous malformations: autosomal dominant inheritance in two families. Clinical Genetics 33(1): 44–48.
    Johnson DW, Berg JN, Baldwin MA et al. (1996) Mjjutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nature Genetics 13(2): 189–195.
    Konez O and Burrows PE (2002) Magnetic resonance of vascular anomalies. Magnetic Resonance Imaging Clinics of North America 10(2): 363–388 vii.
    Kulkarni SV, Gish G, van der Geer P, Henkemeyer M and Pawson T (2000) Role of p120 Ras-GAP in directed cell movement. Journal of Cell Biology 149(2): 457–470.
    Le Meur N, Holder-Espinasse M, Jaillard S et al. (2010) MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. Journal of Medical Genetics 47(1): 22–29.
    Letteboer TG, Mager HJ, Snijder RJ et al. (2008) Genotype–phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia. American Journal of Medical Genetics Part A 146A(21): 2733–2739.
    Limaye N, Wouters V, Uebelhoer M et al. (2009) Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Nature Genetics 41(1): 118–124.
    Lindenauer SM (1965) The Klippel–Trenaunay syndrome: varicosity, hypertrophy and hemangioma with no arteriovenous fistula. Annals of Surgery 162: 303–314.
    Liu AS, Mulliken JB, Zurakowski D, Fishman SJ and Greene AK (2010) Extracranial arteriovenous malformations: natural progression and recurrence after treatment. Plastic and Reconstructive Surgery 125(4): 1185–1194.
    Maertens O, De Schepper S, Vandesompele J et al. (2007) Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. American Journal of Human Genetics 81(2): 243–251.
    McAllister KA, Grogg KM, Johnson DW et al. (1994) Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nature Genetics 8(4): 345–351.
    McDonald J, Damjanovich K, Millson A et al. (2011) Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clinical Genetics 79(4): 335–344.
    McDonald MT, Papenberg KA, Ghosh S et al. (1994) A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33–34. Nature Genetics 6(2): 197–204.
    Paltiel HJ, Burrows PE, Kozakewich HP, Zurakowski D and Mulliken JB (2000) Soft-tissue vascular anomalies: utility of US for diagnosis. Radiology 214(3): 747–754.
    Revencu N, Boon LM, Mulliken JB et al. (2008a) Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Human Mutatation 29(7): 959–965.
    book Revencu N, Boon LM, Mulliken JB and Vikkula M (2008b) "RASA1 and capillary malformation–arteriovenous malformation". In: Epstein C, Erickson RP and Wynshaw-Boris A (eds) Inborn Errors of Development 2e, 2nd edn, pp. 647–650. New York: Oxford University Press Inc.
    Richards-Yutz J, Grant K, Chao EC, Walther SE and Ganguly A (2010) Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Human Genetics 128(1): 61–77.
    Schubbert S, Shannon K and Bollag G (2007) Hyperactive Ras in developmental disorders and cancer. Nature Reviews Cancer 7(4): 295–308.
    Shovlin CL (2010) Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Reviews 24(6): 203–219.
    Thiex R, Mulliken JB, Revencu N et al. (2010) A novel association between RASA1 mutations and spinal arteriovenous anomalies. American Journal of Neuroradiology 31(4): 775–779.
    Trovo-Marqui AB and Tajara EH (2006) Neurofibromin: a general outlook. Clinical Genetics 70(1): 1–13.
    Wojnowski L, Zimmer AM, Beck TW et al. (1997) Endothelial apoptosis in Braf-deficient mice. Nature Genetics 16(3): 293–297.
    Wu JK, Bisdorff A, Gelbert F et al. (2005) Auricular arteriovenous malformation: evaluation, management, and outcome. Plastic and Reconstructive Surgery 115(4): 985–995.
    Yakes WF, Rossi P and Odink H (1996) How I do it. Arteriovenous malformation management. Cardiovascular and Interventional Radiology 19(2): 65–71.
    Zweier M, Gregor A, Engels H et al. (2010) Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression. Human Mutation 31(6): 722–733.
 Further Reading
    book Boon LM and Vikkula M (2008) "Vascular anomalies". In: Wolff K, Goldsmith LA, Katz SI et al. (eds) Fitzpatrick's Dermatology in General Medicine. 7th edn, pp. 1651–1666. USA: McGraw-Hill Professional Publishing.
    Brouillard P and Vikkula M (2007) Genetic causes of vascular malformations. Human Molecular Genetics 16(2): R140–R149.
    Limaye N, Boon LM and Vikkula M (2009) From germline towards somatic mutations in the pathophysiology of vascular anomalies. Human Molecular Genetics 18(R1): R65–R74.
    Pocock B, Boon LM and Vikkula M (2006) Molecular basis of vascular birthmarks. Seminars in Plastic Surgery 20: 149–156.
    book Revencu N, Boon LM and Vikkula M (2008) "Arteriovenous malformation in mice and men". In: Marmé D and Fusenig N (eds) Tumor Angiogenesis, pp. 363–374. Germany: Springer Verlag.

Related Sub-Topics:

Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Capillary Malformation–Arteriovenous Malformation and RASA1 Mutations
 
How to Cite close
Boon, Laurence M, Revencu, Nicole, and Vikkula, Miikka(Sep 2011) Capillary Malformation–Arteriovenous Malformation and RASA1 Mutations. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022479]