Capillary Malformation-Arteriovenous Malformation

Most comprehensive DNA test for CM-AVM (CM-AVM1 and CM-AVM2)

Preferred DNA test for RASA1-related disorders (CM-AVM1) only

DNA test for RASA1-related disorders (CM-AVM1) only

DNA test for EPHB4-related CM-AVM (CM-AVM2) only​

Related Tests

Most comprehensive test to determine the cause of a telangiectasia/AVM disorder

Preferred DNA test to confirm clinical diagnosis of a heritable vascular malformation disorder

Useful when a pathogenic familial variant identifiable by sequencing is known

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a disorder of the vascular system characterized by enlarged capillaries that appear as small, round dots on the skin. Genetic testing can confirm diagnosis of RASA1-related CM-AVM disorder (CM-AVM1), or an EPHB4-related CM-AVM disorder (CM-AVM2), in individuals with symptoms suggestive of CM-AVM.

Disease Overview

Incidence

  • ~1/20,000 for CM-AVM1
  • ~1/12,000 for CM-AVM2  

Symptoms/Manifestations

  • Multifocal CMs; commonly localized on skin of the trunk, limbs, or face
    • Fast flow lesions
      • AVM, arteriovenous fistula (AVF), and vein of Galen malformation located in the brain, spine, skin, or muscle may cause life-threatening complications
        • Bleeding
        • Congestive heart failure
        • Neurological consequences
      • In Parkes Weber Syndrome (PKWS), diffuse subcutaneous/intramuscular micro AVFs associated with hypertrophy of the involved extremity
  • Lymphatic abnormalities
  • Recurrent epistaxis (CM-AVM2, but uncommon)
  • Telangiectasias: dermal (CM-AVM2, but less common than CMs)

Genetics

Genes

EPHB4 and RASA1

Inheritance

Autosomal dominant

Penetrance

  • EPHB4: 93% 
  • RASA1: 90-95%

De novo Variants

~33% of cases for RASA1

Variants

  • 92% of RASA1 pathogenic variants detectable by sequencing
  • 8% of RASA1 pathogenic variants detectable by deletion/duplication analysis

Test Interpretation

Sensitivity/Specificity

  • Clinical sensitivity for CM-AVM: not well established and varies based on clinical manifestations; estimates based on available publications
    • EPHB4
      • Sequencing: at least 15%
        • Detected in 15% of individuals with sporadic or familial CMs with or without fast-flow lesions 
      • Deletion/duplication: unknown
    • RASA1
      • Sequencing: ~30-70%
        • Detected in 30% of consecutive cases with or without CMs,  with higher detection rate in individuals with multifocal CMs
        • Detected in 70% of individuals with multifocal CMs with or without fast-flow lesions 
      • Deletion/duplication: ~8% 
  • Analytical sensitivity/specificity for sequencing of EPHB4 and RASA1, and MLPA of RASA1: 99%

Limitations

  • Diagnostic errors can occur due to rare sequence variations
  • Not determined or evaluated
    • Large deletions/duplications in EPHB4
    • Regulatory region and deep intronic variants
    • Breakpoints for large deletions/duplications identified in RASA1
    • Variants in genes other than EPHB4 and RASA1
    References