Researching therapeutic reformation of the capillary malformation: Arteriovenous Malformation Syndrome

By Warren R. Heymann, MD
June 17, 2020
Vol. 2, No. 24

Small cutaneous lesions may have profound systemic implications. Astute dermatologists will recognize these lesions and assess patients accordingly, often to the surprise of referring physicians and patients alike.

The Capillary Malformation – Arteriovenous Malformation (CM-AVM) syndrome was first recognized by Eerola et al in 2003, where RASA1 mutations were detected. In addition to CM, either AVMs, arteriovenous fistulae (AVF), or Parkes-Weber syndrome (port wine stains with underlying multiple micro-AVFs, in association with soft tissue and skeletal hypertrophy) was documented in all families with a mutation. (1)

Although most cases are recognized in childhood, occasional late presentations have been reported, such as the case of a 31-year-old pregnant woman with hydrops fetalis, referred to dermatology for multiple skin lesions. (2) The authors note that this patient’s presentation was late, however, I cannot judge how long the cutaneous CMs were actually present (and perhaps previously unnoticed).

CMs are multiple round or oval pink lesions, often with a blanched halo, mostly observed on the face and limbs. The characteristic blanched halo suggests an associated steal phenomenon.

CMs may be seen in combination with AVMs or AVFs or may be the only finding. CMs may present at birth but tend to increase in number over time. Arterial flow measured by Doppler ultrasound has been reported over the CMs and is hypothesized to be a manifestation of an underlying AVM. It is uncertain if arterial flow abnormalities associated with the CMs can increase or develop over time. (3,4) Lymphatic vessel abnormalities resulting in lymphedema, chylothorax, and chylous ascites have occasionally been reported in afflicted patients. (5)

As noted by Sibley and Ramien, approximately one-third of CM-AVM syndrome patients can be associated with fast flow vascular anomalies — AVMs and AVFs — in the skin, muscle, bone, brain, and spine; these lesions can cause life-threatening complications such as bleeding, congestive heart failure, and neurologic sequelae.(4)

CM-AVM is an autosomal dominant disorder, with an incidence that may be as high as 1/10,000. According to Revencu et al: “Two genes have been identified until now: RASA1, involved in CM-AVM type 1, and EPHB4, involved in CM-AVM type 2. These two genes explain around 50% and 25% of patients, respectively. The remaining patients could be explained by genomic RASA1 or EPHB4 [Ephrin Receptor B4] rearrangements, mutations in the promoter or regulatory regions, deep intronic mutations, epigenetic downregulation, or mosaicism. Other genes could also be involved.” (6) Clinically, CV-AVM types 1 and 2 are virtually identical, except for the additional occurrence of telangiectasia in CVM-AVM type 2. (6) Phenotypic variability has raised the possibility of a “two-hit” hypothesis, with a second somatic mutation that may cause severe disease. (2)

How RASA1 mutations affect endothelial cells (EC) resulting in CM-AVM is an enigma. By using murine models of RASA1-deficiency, Chen et al found that RASA1 was essential for the survival of ECs during developmental angiogenesis in which primitive vascular plexuses are remodeled into hierarchical vascular networks. “RASA1 was required for EC survival during developmental angiogenesis because it was necessary for export of collagen IV from EC and deposition in vascular basement membranes. In the absence of RASA1, dysregulated Ras mitogen-activated protein kinase (MAPK) signal transduction in EC resulted in impaired folding of collagen IV and its retention in the endoplasmic reticulum (ER) leading to EC death.” Remarkably, the authors found that the chemical chaperone, 4-phenylbutyric acid, and small molecule inhibitors of MAPK and 2-oxoglutarate dependent collagen IV modifying enzymes rescued ER retention of collagen IV and EC apoptosis and resulted in normal developmental angiogenesis. (5) (For a discussion of chaperones, see Dermatology World Insights and Inquiries Sept. 25, 2019). Theoretically, the mTOR inhibitor, topical sirolimus, should be effective in patients with CM-AVM. An 8-year-old boy with CM-AVM with a documented EPHB4 mutation was prescribed topical sirolimus 1% cream for a CM on the left cheek for 4 weeks with limited improvement. (7) Perhaps those infrequent cases with lymphatic involvement may be more responsive to topical sirolimus, but this awaits further study.

Managing patients with CM-AVM is a multidisciplinary affair (involving genetics, interventional radiology, neurosurgery, cardiology, dermatology), depending on the degree of involvement in the proband, and a determination of family members at risk. Affected individuals should be evaluated by imaging for AVMs and AVFs at common and crucial sites such as the brain and spinal cord. (2,3) Most importantly, however, is being cognizant of the possibility of the diagnosis of CM-AVM when seeing banal vascular lesions in children, especially in those surrounded by a halo. Should you consider the diagnosis of CM-AVM and obviate severe complications of the disease, your patients will always view you as an angel with a halo.

Point to Remember: CM-AVM may be a proverbial wolf in sheep’s clothing. When noting capillary malformations, especially those surrounded by a halo, think of the disorder and assess accordingly — you may save a life.

Our expert's viewpoint

Albert C. Yan, MD
Section Chief of Dermatology, Children’s Hospital of Philadelphia

CM-AVM syndrome is an underrecognized condition that may have significant comorbidities as described in this outstanding and timely review. In my experience and other published reports, those with mutations in EPHB4 may have somewhat milder phenotypes than those with RASA1. While the classic cutaneous manifestation of this condition is the coin-sized capillary malformation with surrounding blanched halo, the CMs can vary in size. Most patients develop more lesions over time, but if I encounter a young pediatric patient with characteristic lesions and especially if a parent appears similarly affected, I will tend toward evaluating them with genetic screening and if positive, imaging, since the central nervous system AVMs are often present during early childhood and pose a time-sensitive risk of complications.

Dr. Yan had disclosed financial relationships with the following to the AAD at the time of publication: Aclaris Therapeutics, Inc., BabyDoctor.com, Dermavant Sciences, Johnson & Johnson Consumer Products Company, Ortho Dermatologics, Pfizer Inc., Procter & Gamble Company, Regeneron Pharmaceuticals, Inc., Verrica Pharmaceuticals Inc. Full disclosure information is available.

1. Eerola I, Boon LM, Mulliken JB, Burrows PE, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 2003; 73: 1240-1249.

2. Nicholson P, Holder SE, Carton J, Wakelin S. The protean manifestations of RASA1 gene mutation. Clin Exp Dermatol 2019; 44: 818-821.

3. Bayrak-Toydemir P, Stevenson D. Capillary malformation-Arteriovenous malformation syndrome. In Adam MP, Ardinger HH, Pagon RA, Wallace SE, et al (editors). GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle, 1993-2019. 2011 Feb 22 [updated 2019 Sep 12].

4. Sibley CO, Ramien ML. Capillary malformation-Arteriovenous malformation syndrome. JAMA Dermatol 2019; 155: 733.

5. Chen D, Teng JM, North PE, Lapinski PE, King PD. RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development. J Clin Invest 2019; 129: 3545-3561.

6. Revencu N, Fastre E, Ravoet M, Helaers R, et al. RASA1 mosaic mutations in patients with capillary malformation-arteriovenous malformation. J Med Genet 2019 Jul 12 [Epub ahead of print].

7. Yu J, Streicher JL, Medne L, Krantz ID, Yan YC. EPHB4 mutation implicated in capillary malformation-arteriovenous malformation syndrome: A case report. Pediatr Dermatol 2017; e227-230.

---