Extracranial Vascular Anomalies Driven by RAS/MAPK Variants: Spectrum and Genotype-Phenotype Correlations

Abstract

Background: We aimed to correlate alterations in the rat sarcoma virus (RAS)/mitogen-activated protein kinase pathway in vascular anomalies to the clinical phenotype for improved patient and treatment stratification.

Methods and results: This retrospective multicenter cohort study included 29 patients with extracranial vascular anomalies containing mosaic pathogenic variants (PVs) in genes of the RAS/mitogen-activated protein kinase pathway. Tissue samples were collected during invasive treatment or clinically indicated biopsies. PVs were detected by the targeted sequencing of panels of genes known to be associated with vascular anomalies, performed using DNA from affected tissue. Subgroup analyses were performed according to the affected genes with regard to phenotypic characteristics in a descriptive manner. Twenty-five vascular malformations, 3 vascular tumors, and 1 patient with both a vascular malformation and vascular tumor presented the following distribution of PVs in genes: Kirsten rat sarcoma viral oncogene (n=10), neuroblastoma ras viral oncogene homolog (n=1), Harvey rat sarcoma viral oncogene homolog (n=5), V-Raf murine sarcoma viral oncogene homolog B (n=8), and mitogen-activated protein kinase kinase 1 (n=5). Patients with RAS PVs had advanced disease stages according to the Schobinger classification (stage 3-4: RAS, 9/13 versus non-RAS, 3/11) and more frequent progression after treatment (RAS, 10/13 versus non-RAS, 2/11). Lesions with Kirsten rat sarcoma viral oncogene PVs infiltrated more tissue layers compared with the other PVs including other RAS PVs (multiple tissue layers: Kirsten rat sarcoma viral oncogene, 8/10 versus other PVs, 6/19).

Conclusions: This comparison of patients with various PVs in genes of the RAS/MAPK pathway provides potential associations with certain morphological and clinical phenotypes. RAS variants were associated with more aggressive phenotypes, generating preliminary data and hypothesis for future larger studies.

Keywords: RAS/MAPK pathway; clinical characteristics; mosaicism; pathogenic variants; vascular anomalies.

Figure 1. Patient 1: 20‐year‐old female patient with arteriovenous malformation (AVM) paravertebral and a HRAS pathogenic variant (PV).

A, Axial T1‐weighted turbo spin‐echo sequence image presenting an AVM (asterisk) located paravertebrally on the left side with intramuscular extension and involvement of the spinal canal and compression of the dural tube. Digital subtraction image before (B) and after (C) the first session of embolotherapy with ethylene‐vinyl‐alcohol copolymer (Squid‐18, BALT Germany GmbH). C, The image shows near complete embolization of the lesion (2020). D, Axial T1‐weighted turbo spin‐echo sequence image after 3 sessions of embolization presenting newly perfused vessels confirming clinically suspected progression, which was characterized by increasing pain and functional movement impairment (2023). Preprocedural (E) and periprocedural (F) digital subtraction images of the fourth embolotherapy session, both showing the newly embolized vascularized components of the progressive AVM (2023).

Figure 2. Patient 27: 20‐year‐old male patient with an infiltrative phenotype and a MAP2K1 pathogenic variant (PV).

A, Clinical infiltration of the lip; notice the prominent blood vessels on the left side of the lower lip. B, Time‐resolved angiography with interleaved stochastic trajectories showing contrast enhancement of the lip and around the mandible. C and D, Contrast‐enhanced vessels in computed tomography reconstruction of the digital subtraction angiography. Notice the fine vessels infiltrating the tongue and the left side of the face, most prominent at the base of the ear. E, Correlating to the prominent vessels at the base of the ear is the enlarged ear, including the ear lobe. F, Digital subtraction angiography of the ear, demonstrating 3 large feeders into the outer ear.

Figure 3. Patient 20: 10‐year‐old female patient with an infiltrative arteriovenous malformation and a BRAF pathogenic variant (PV).

A, Clinical manifestation with capillary malformation (CM) of the sole of the right foot; also note the wormlike mass and dilated veins. B and C, Sagittal T2‐weighted turbo‐inversion recovery‐magnitude and coronal T1‐weighted turbo spin‐echo sequence images; note the flow voids in deeper tissues of the foot (labeled with white arrows). D, Time‐resolved angiography with interleaved stochastic trajectories angiography showing the marked hyperperfusion of the foot including cutaneous tissue. E, Correlating to the hyperperfusion, dilated veins can be seen on the back of the affected right foot of the patient.