Capillary Malformation-Arteriovenous Malformation

Preferred test to detect CM-AVM; assesses for RASA1-associated CM-AVM1 and EPHB4-associated CM-AVM2

Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a disorder of the vascular system characterized by enlarged capillaries that appear as small, round dots on the skin. Some affected individuals also have fast-flow vascular anomalies, including arteriovenous malformations (AVMs) or arteriovenous fistulas (AVFs) in the skin, muscle, bone, spine, or brain. Genetic testing can confirm diagnosis of RASA1-related CM-AVM disorder (CM-AVM1) or EPHB4-related CM-AVM disorder (CM-AVM2) in individuals with clinical findings 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, 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)
  • Dermal telangiectasias (CM-AVM2)
  • Bier spots (CM-AVM2)

Genetics

Genes

EPHB4 and RASA1

Inheritance

  • Autosomal dominant
  • De novo variants
    • ~33% of cases for RASA1
    • ~20% of cases for EPHB4
  • Somatic mosaicism has been described

Penetrance

  • EPHB4: 93% 
  • RASA1: 90-99%

Test Interpretation

Genes Tested

  • EPHB4 (NM_004444) and RASA1 (NM_002890)
  • See Genes Tested table for more information

Sensitivity/Specificity

  • Clinical sensitivity is not well established but is estimated at 65%
    • EPHB4
      • An estimated 15% of CM-AVM attributed to EPHB4
        • Detected in 15% of individuals with sporadic or familial CMs with or without fast-flow lesions 
      • To date, all described pathogenic variants are detectable by sequencing
      • Clinical sensitivity of deletion/duplication analysis is unknown
    • RASA1
      • An estimated 0-70% of CM-AVM attributed to RASA1
      • 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 
      • 92% of detectable RASA1 pathogenic variants are sequence variants
      • 8% of detectable RASA1 pathogenic variants are large deletions/duplications
  • Analytical sensitivity
    • For multiplex ligation-dependent probe amplification (MLPA) of RASA1: 99%
    • For massively parallel sequencing:
Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a diagnosis of CM-AVM.
  • Interpretation of the test result may be impacted if the patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted genes
    • Regulatory region and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Large deletions/duplications in EPHB4 gene
    • Noncoding transcripts
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Some variants, due to technical limitations in the presence of pseudogenes or repetitive or homologous regions
    • Low-level somatic variants
Genes Tested
Gene MIM# Disorder Inheritance

EPHB4

600011

CM-AVM2

Lymphatic malformation 7

AD

RASA1

139150

CM-AVM1

AD

AD, autosomal dominant; CM-AVM, capillary malformation-arteriovenous malformation

References

Additional Resources