Capillary Malformation–Arteriovenous Malformation and RASA1 Mutations

Abstract

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.

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Further Reading

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.

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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.

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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]